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Ascorbic acid: Chemistry, biology and the treatment of cancer - 0 views

www.ncbi.nlm.nih.gov/...PMC3608474 Fenton reaction ferritin vitamin C Fe cancer
shared by Nathan Goodyear on 07 Jul 19 - No Cached
  • iron and ascorbate has long been used as an oxidizing system; the combination of these two reagents is referred to as the Udenfriend system
  • ascorbate serves as a reducing cofactor for many enzymes
  • uptake of ascorbate from the intestinal tract is very tightly controlled
  • ...11 more annotations...
  • pharmacokinetic data indicate that intravenous administration of ascorbate can bypass this tight control resulting in highly elevated plasma levels
  • ascorbate readily oxidizes to produce H2O2, pharmacological ascorbate has been proposed as a prodrug for the delivery of H2O2 to tumors
  • Ascorbate is an excellent reducing agent and readily undergoes two consecutive, one-electron oxidations to form ascorbate radical (Asc•−) and dehydroascorbic acid (DHA)
  • Ascorbate oxidizes readily. The rate of oxidation is dependent on pH and is accelerated by catalytic metals
  • In near-neutral buffers with contaminating metals, the oxidation and subsequent loss of ascorbate can be very rapid
  • Ascorbate is required for maintaining iron in the ferrous state
  • In the presence of catalytic metal ions, ascorbate can also exert pro-oxidant effects
  • Ascorbate is an excellent one-electron reducing agent that can reduce ferric (Fe3+) to ferrous (Fe2+) iron, while being oxidized to ascorbate radical
  • In a classic Fenton reaction, Fe2+ reacts with H2O2 to generate Fe3+ and the very oxidizing hydroxyl radical
  • e presence of ascorbate can allow the recycling of Fe3+ back to Fe2+, which in turn will catalyze the formation of highly reactive oxidants from H2O2
  • Depending on concentrations, the effects of ascorbate on models of lipid peroxidation can be pro- or antioxidant
  • Nathan Goodyear on 07 Jul 19
     
    ferritin released enhanced pharmacologic ascorbate induced-cytotoxicity, indicating that ferritin with high iron-saturation could be a source of catalytic iron. Consistent with this, ascorbate has also been shown to be capable of releasing iron from cellular ferritin
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Intraperitoneal cisplatin with regional hyperthermia in advanced ovarian cancer: pharma... - 0 views

www.ncbi.nlm.nih.gov/...9624250 hyperthermia cisplatin cancer
shared by Nathan Goodyear on 04 Aug 19 - No Cached
  • Nathan Goodyear on 04 Aug 19
     
    combination of hyperthermia and cisplatin enhanced cell killing compared with either treatment alone. The hyperthermia induced a favorable pharmacokinetics.
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Oncotarget | NADH autofluorescence, a new metabolic biomarker for cancer stem cells: Id... - 0 views

www.oncotarget.com/index.php vitamin C IV vitamin C cancer cancer stem cells milk thistle silymarin ascorbic acid bee propolis CAPE glycolytic inhibitor natural
shared by Nathan Goodyear on 08 Dec 17 - No Cached
  • Vitamin C was ~10 times more potent than 2-DG for the targeting of CSCs
  • Cancer stem-like cells (CSCs) are thought to be the root cause of chemotherapy-resistance and radio-resistance
  • ultimately leading to treatment failure in patients with advanced disease [1-3]. They have been directly implicated mechanistically in tumor recurrence and metastasis, resulting in poor patient survival
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  • mitochondrial biogenesis may be a key driver of the CSC phenotype
  • Our results indicate that increased mitochondrial oxidative stress and high NADH levels are both key characteristics of the CSC metabolic phenotype
  • high levels of NAD(P)H auto-fluorescence are known to be a surrogate marker for mitochondrial “power”, high OXPHOS capacity and increased ATP production
  • CSCs may be strictly dependent on NAD(P)H to maintain their enhanced mitochondrial function
  • an intact NAD+ salvage pathway is strictly required for mammosphere formation, supporting our results using NAD(P)H auto-fluorescence, which enriched CSC activity by more than 5-fold.
  • Since glycolysis is especially critical for maintaining the TCA cycle, OXPHOS and overall mitochondrial function, we next assessed the effects of known glycolytic inhibitors
  • we show that two other natural products that function as effective glycolysis inhibitors, also inhibited mammosphere formation. More specifically, vitamin C (ascorbic acid), which induces oxidative stress and inhibits the activity of GAPDH (a key glycolytic enzyme) [17], also inhibited mammosphere formation, with an IC-50 of 1 mM (Figure 7B). Therefore, vitamin C was ~10 times more potent than 2-DG at targeting CSC propagation
  • silibinin (the major active constituent of silymarin, an extract of milk thistle seeds) [18], which specifically functions as an inhibitor of glucose uptake, blocked mammosphere formation, with an IC-50 between 200 and 400 µM
  • caffeic acid phenyl ester (CAPE), a key component of honey-bee propolis, has potent anti-cancer properties
  • Propolis has a strong history of medicinal use, dating back more than 2,000 years
  • Because of it aromatic ring structure (Figure 8), we speculated that CAPE might function as a potent inhibitor of oxidative mitochondrial metabolism
  • CAPE quantitatively inhibits the mitochondrial oxygen consumption rate (OCR) and, in turn, induces the onset of aerobic glycolysis (ECAR)
  • CAPE shows a clear selectivity for targeting CSCs and adherent cancer cells, relative to normal fibroblasts.
  • CAPE functions as a “natural” mitochondrial OXPHOS inhibitor, that preferentially targets the CSC sub-population. This could explain CAPE’s known anti-cancer properties
  • Our data directly shows that a small fraction of the total cell population, characterized by increased PGC1α activity, high mitochondrial ROS/H2O2 and high NADH levels, has the ability to survive and grow under anchorage-independent conditions, driving mammosphere formation
  • We highlight the utility of certain natural products, such as Silibinin, Vitamin C and CAPE, that could be used to therapeutically target CSCs. Silibinin is the major active component of silymarin, which is an extract prepared from milk thistle seeds.
  • high NADH is a property that is conserved between normal and cancerous stem cells
  • Previous studies have also shown that when non-CSCs and CSCs are both fed mitochondrial fuels (such as L-lactate or ketone bodies), that CSCs quantitatively produce more NADH in response to this stimulus
  • CSCs may be strictly dependent on NADH to maintain their enhanced mitochondrial function
  • The Noble Prize winner, Linus Pauling, was among the first to describe and clinically test the efficacy of Vitamin C, as a relatively non-toxic anti-cancer agent
  • Vitamin C has two mechanisms of action. First, it is a potent pro-oxidant, that actively depletes the reduced glutathione pool, leading to cellular oxidative stress and apoptosis in cancer cells. Moreover, it also behaves as an inhibitor of glycolysis, by targeting the activity of GAPDH, a key glycolytic enzyme.
  • Here, we show that Vitamin C can also be used to target the CSC population, as it is an inhibitor of energy metabolism that feeds into the mitochondrial TCA cycle and OXPHOS
  • Vitamin C may prove to be promising agent for new clinical trials, aimed at testing its ability to reduce CSC activity in cancer patients, as an add-on to more conventional therapies, to prevent tumor recurrence, further disease progression and metastasis
  • Interestingly, a breast cancer based clinical study has already shown that the use of Vitamin C, concurrent with or within 6 months of chemotherapy, significantly reduces both tumor recurrence and patient mortality
  • CAPE quantitatively reduces mitochondrial oxygen consumption (OCR), while inducing a reactive increase in glycolysis (ECAR). As such, it potently inhibits mammosphere formation with an IC-50 of ~2.5 µM. Similarly, it also significantly inhibits cell migration
  • we also demonstrate that 7 different inhibitors of key energetic pathways can be used to effectively block CSC propagation, including three natural products (silibinin, ascorbic acid and CAPE). Future studies will be necessary to test their potential for clinical benefit in cancer patients.
  • Nathan Goodyear on 08 Dec 17
     
    The future of cancer therapy is cancer stem cells.  Study finds that Vitamin C, silymarin, and bee propolis blocks mitochondrial energy pathways in cancer stem cells.  Vitamin C is a known glycolytic inhbitor. Vitamin C was found to inhibit glycolysis via GAPDH targeting to inhibit the energy pathways of the mitochondria in CSCs.  The authors propse that Vitamin C can be used as add on therapies for conventional therapies to specifically attack the CSCs and their contribution to recrurence, treatment resistance, and metastasis potential all in addition to the ability of vitamin C to reduce the side effects of chemotherapy.
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Modulated Electro-Hyperthermia-Induced Tumor Damage Mechanisms Revealed in Cancer Models - 0 views

www.ncbi.nlm.nih.gov/...PMC7504298 acid tumor cancer cancer acidic pH hypoxia apoptosis hyperthermia
shared by Nathan Goodyear on 14 Mar 21 - No Cached
  • Nathan Goodyear on 14 Mar 21
     
    "Cells are more responsive and sensitive to heat under oxygen-deprived and highly acidic conditions, which are common in cancer tissue due to aggressive growth and enhanced glycolysis"
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Hypoxia Regulates Insulin Receptor Substrate-2 Expression to Promote Breast Carcinoma C... - 0 views

cancerres.aacrjournals.org/...8894 HIF-1alpha insulin receptor substrate 2 IRS-2 Akt hypoxia breast cancer cancer
shared by Nathan Goodyear on 14 Jan 21 - No Cached
  • Nathan Goodyear on 14 Jan 21
     
    IRS-2 expression, but not IRS-1 expression, is increased by hypoxia (HIF-1alpha), which selects for tumor cells with increased metastatic potential. IRS-2 is active to mediate insulin-like growth factor I-dependent signals in hypoxia, and enhanced activation of Akt in hypoxia is dependent on IRS-2 expression. It is Akt that increases insulin receptor expression. This ties hypoxia to increase in insulin signaling and insulin receptor expression. Boom!
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Melatonin enhances hyperthermia-induced apoptotic cell death in human leukemia cells - ... - 0 views

scholars.uthscsa.edu/...uced-apoptotic-cell-death-in-h hyperthermia melatonin apoptosis cancer leukemia
shared by Nathan Goodyear on 13 Oct 20 - No Cached
  • Nathan Goodyear on 13 Oct 20
     
    Melatonin and hyperthermia synergistic in stimulation of apoptosis.
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Cheap Flights, Airline Tickets & Airfares - Find Deals on Flights at WayAway.io - 0 views

wayaway.tp.st/H2IZEX39 hotel
shared by forestgood on 15 Aug 23 - No Cached
  • forestgood on 15 Aug 23
     
    Here's some additional information about the specific hotels and brand offers available through our platform: Hotels: Our handpicked selection of hotels caters to a variety of tastes and preferences. Whether you're seeking a tranquil beachfront retreat, a vibrant city center stay, or a cozy countryside escape, we have partnered with top-notch establishments to ensure a memorable experience. Each hotel offers unique amenities, luxurious accommodations, and exceptional service, ensuring your stay is nothing short of extraordinary. Tickets: Our ticket offerings encompass a wide range of events and attractions. From sports games and concerts to theater performances and cultural exhibitions, we provide access to sought-after experiences. With our ticket deals, you can secure coveted seats, enjoy VIP access, and immerse yourself in the excitement of live entertainment. Enhance your travel itinerary with unforgettable memories. Brand Offers: We have collaborated with renowned brands to bring you exclusive offers and promotions across various industries. From fashion and beauty to technology and lifestyle, our brand partners have crafted special deals tailored to our community. Enjoy discounts, unique packages, and access to limited-edition products, elevating your everyday life with exceptional quality and value. By going straight to the product page, our platform ensures a streamlined and user-friendly experience. This allows you to explore the details, features, and pricing of each hotel, ticket, or brand offer directly, increasing the convenience and efficiency of your purchase process. Discover extraordinary accommodations, secure tickets to unforgettable events, and indulge in exclusive brand offers through our platform. Begin your journey and unlock remarkable experiences today! VISIT THIS BY CLICKING HERE: https://sharecta.com/l/40x4cx4xarc44
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Computer Science: Computer hardware - 0 views

computersciencetopper.blogspot.com/...computer-hardware.html Best computer computer computer Science it blog
shared by umar111 on 26 Apr 23 - No Cached
  • umar111 on 26 Apr 23
     
    Computer Science Tuesday, April 25, 2023 Computer hardware Computer hardware is the physical components that make up a computer system. It includes everything from the central processing unit (CPU) to the monitor, keyboard, and mouse. Understanding the different types of hardware and how they work together is essential for anyone who works with computers. In this article, we will explore the various components of computer hardware, including internal and external components, and the peripherals that connect to them. We will also discuss the importance of hardware maintenance, the latest advancements in computer technology, and factors to consider when choosing the right hardware for your needs. Whether you are a computer technician, a gamer, or simply someone who uses a computer for everyday tasks, this article will help you better understand the world of computer hardware. Introduction to Computer Hardware Computer hardware refers to the physical components that make up a computer system. It includes everything from the processor and memory to input/output devices such as the keyboard and monitor. In this article, we will explore the different types of computer hardware and their functions. What is Computer Hardware Computer hardware refers to the physical components of a computer system. It includes all the components that can be touched, seen, and used to interact with a computer, such as the monitor, keyboard, and mouse. Hardware is different from computer software, which refers to the programs and applications that run on a computer system. History of Computer Hardware The history of computer hardware dates back to the 1820s when Charles Babbage, an English mathematician, and inventor, designed the first analytical engine, which was considered to be the first mechanical computer. With time, more complex electronic computers were developed, including the first Intel microprocessor in 1971. Since then, computer hardware has continued to evolve, becoming
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https://www.sightcare-co.com/ - 0 views

www.sightcare-co.com sight care sightcare group training nearsightedness food for eyesight carey codd vitasight vision how to cure bad eye tips fix improve your red light eyes diet improvement skincare malaysia costos de medicare indonesia singapore eyecare
shared by fitspresso on 27 Sep 23 - No Cached
  • fitspresso on 27 Sep 23
     
    Sight Care | Official Site sightcare-co.com · by Sight Care Sight Care Only $49/Bottle Limited Time Offer! Sight Care Special Deal + Special 67% Discount Save $600 + 180 Days Money Back Guarantee #1.The Sight Care vision supplement is a dietary supplement for helping you improve your vision and brain health. Sight Care eye supplements are formulated to provide a synergistic blend of vitamins, minerals, antioxidants, and other bioactive compounds that are essential for maintaining healthy vision Regular Price: 147/per bottle Only for: $49/per bottle What Is Sight Care? This powerful vision support supplement is made with a unique blend of natural ingredients and plant extracts that work together synergistically to deliver numerous benefits for your brain and eye health. With Sight Care, you can expect to experience increased energy levels, improved eyesight, and an overall revitalized sense of well-being. Taking care of your vision health is not just about seeing clearly; it's also about maintaining your overall brain health. As we age, our vision deteriorates, and our eyes and brain can experience a decline in function, but there are steps you can take to support your visual and cognitive health. Regular eye exams are crucial for detecting and treating vision problems early on, and making healthy choices such as eating a nutritious diet and exercising regularly can also help. However, with busy schedules, it can be difficult to find the time to devote to a healthy lifestyle. This is where the Sight Care supplement comes in. It's designed to support both vision and brain health with its blend of natural ingredients that have been shown to promote healthy vision and cognitive function You must not compromise your eye health for momentary exhilaration. If you are glued to digital screens day and night, you must take measures to prevent eye diseases like age-related macular degeneration. The SightCare vision supplement has been made using 100% natura
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LeanBiome™ (Official) | Get Save UpTo $540 Today Only! - 0 views

usleanbiome.com leanbiome us lean biome usa uk buy get does work discount 2022 australia legit weight loss bioma customer reviews review canada website ireland product
shared by fitspresso on 27 Sep 23 - No Cached
  • fitspresso on 27 Sep 23
     
    LeanBiome™ (Official) | Get Save UpTo $540 Today Only! usleanbiome.com LeanBiome™ Hurry Up! Offer Expires in: 00 HOUR 29 MINUTE 59 SECOND LeanBiome Attention! Get Special 84% Discount Today Faster fat burning and weight loss Healthy cholesterol and sugar levels Higher energy levels Regular price: $129 Only for: 39$ What Is LeanBiome? LeanBiome Lean for Good is a weight loss dietary supplement derived from scientifically researched ingredients and comprehensively developed to help people achieve sustainable weight control. The formula comes in a capsule format that is easy to take and is made with natural ingredients from plants and other sources to achieve its goals. The main ingredient in LeanBiome is piperine, which has been found to affect the body's ability to absorb micronutrients and other compounds more effectively. LeanBiome is a dietary supplement that claims to help weight management. It contains 100% natural ingredients that support healthy weight loss. It does not interfere with any natural process making it safe for use. It ranks among the top weight loss supplements that claim to provide a permanent solution. LeanBiome is made by a company named Lean for Good. It is made with natural and research-backed ingredients that help you lose excess fat without hassles. It is sold in capsule form. The company assures the composition is GMO, gluten, and soy-free. As for manufacturing standards, you need not fret. The company makes the supplement in a facility certified by the FDA. How Does LeanBiome Work? The starting period of the LeanBiome program includes a detoxification process that effectively removes any accumulated ree radicals, toxins, fand oxidative stress. This cleansing enables improved blood circulation, setting the stage for the body to initiate its own fat-burning mechanisms. To enhance metabolic activity, introducing the lean bacteria contained in LeanBiome to your gut microbiome is a beneficial approach. This activation triggers r
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https://www.fitspresso-co.com/ - 0 views

www.fitspresso-co.com fitspresso fit spresso us uk buy usa 2023 pros 2022 2024 pills order price weight loss espresso fitespresso review amazon tablet reviews customer supplement does it work
shared by fitspresso on 27 Sep 23 - No Cached
  • fitspresso on 27 Sep 23
     
    FitSpresso™ | Official Site fitspresso-co.com FitSpresso Only $39/Bottle Limited Time Offer! FitSpresso Special Deal + Special 51% Discount Save $660 + 180 Days Money Back Guarantee FitSpresso Herpesyl Five Star A dietary product formulated to assist users in reducing weight can increase other advantages that can support overall health. This product can assist users in getting closer to the desirable body weight. Regular Price: 149/per bottle Only for: $39/per bottle Buy Now What IsFitSpresso? FitSpresso is promoted as a natural supplement that comes in the form of diet pills, and it can aid in rapid and efficient weight loss, similar to many other supplements. The term "natural supplements refers to a nutritional supplement that is made entirely of natural, chemical-free materials. You can utilize these organic ingredients to aid in natural weight loss. It can speed up your body's metabolism and assist with other crucial processes. All parts of our bodies are impacted by weight increase, and not only do we need to deal with the increased weight, but we also need to deal with the numerous problems and illnesses that come along with it. This refers to the risk of developing chronic cardiac conditions, low blood pressure, and, in some circumstances, problems with blood sugar. However, FitSpresso even with its bright and bold claims, can help you efficiently manage your weight and completely avoid these extra uncomfortable problems. FitSpresso is a supplement that comes in the form of a pill, which makes it tasty, simple to swallow, and handy. According to the manufacturer, these diet tablets are GMO-free and toxic-free, making them edible. This is why we have things such as weight loss supplements. Thanks to modern advancements, we can just take a dietary supplement pill to bring about significant weight loss in a completely healthy and natural manner. Not only this, but dietary supplements can also support healthy blood sugar levels and help with
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New PROTI 360° Family of Implants to Enhance Spinal Fusion Surgery India - 10... - 0 views

www.101pressrelease.com/ce-spinal-fusion-surgery-india Affordable spinal fusion surgery hospital India spinal fusion surgery India Low cost Hospital
shared by spineneuro on 03 Feb 22 - No Cached
  • spineneuro on 03 Feb 22
     
    About 400,000 sufferers undergo spinal fusion surgery India annually to help lessen pain and nerve root infection in India alone. During this method, a disc is eliminated and an interbody spacer is implanted to doubtlessly restore natural height between two vertebrae and create solid bone. International Helpline Number : +91-9325887033 Email Id: enquiry@spineandneurosurgeryhospitalindia.com
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Cirq Robotic Arm By Dr Mihir Bapat Nanavati Enhances Spine Surgeries and Increases Prec... - 0 views

www.briefingwire.com/...geries-and-increases-precision Dr. Mihir Bapat Nanavati minimally invasive spine surgery Nanavati Hospital Mumbai
shared by spineneuro on 05 Feb 22 - No Cached
  • spineneuro on 05 Feb 22
     
    Dr. Mihir Bapat Nanavati was the first healthcare professional in India to perform minimally invasive spine surgery using the Cirq® arm. Cirq is a medical professional-controlled robotic arm, designed to increase the precision in navigating complex spinal surgeries. Phone No.: +91 9325887033 Email: dr.mihirbapat@neurospinehospital.com
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Quality VBT Surgery at a Fraction of the Cost in India - 0 views

spineandneuro.livepositively.com/-fraction-of-the-cost-in-india cost of VBT surgery in India VBT surgery in India VBT surgery in India hospital Scoliosis Treatment in India
shared by spineneuro on 20 Apr 24 - No Cached
  • spineneuro on 20 Apr 24
     
    The affordability of cost of VBT surgery in India, coupled with high success rates, further enhances its appeal to patients seeking effective spinal treatment options. At the same time, the cost of VBT surgery in India is significantly lower compared to other countries, making it a wise decision for patients to travel to India for surgical treatment.
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We're Not "DON" Yet: Optimal Dosing and Prodrug Delivery of 6-Diazo-5-oxo-L-norleucine ... - 0 views

www.ncbi.nlm.nih.gov/...PMC6130910 glutamine DON dosing cancer
shared by Nathan Goodyear on 17 Mar 24 - No Cached
  • Glutamine is the most abundant amino acid in blood
  • Rapidly proliferating healthy cells (GI epithelium, lymphocytes) or cells under physiologic stress have increased demand for glutamine
  • Glutamine is transported into cells by one of multiple amino acid transporters (e.g. ASCT2, BOAT2), several of which are thought to be upregulated in cancer cells
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  • it is hydrolyzed to glutamate and ammonia by glutaminase (‘glutaminolysis’)
  • Glutamate, produced from glutamine by glutaminase and glutamine amidotransferase activities, may be further metabolized to alpha ketoglutarate and provide a carbon skeleton source for the mitochondrial tricarboxylic acid cycle (TCA cycle)
  • Glutamine-derived glutamate is also involved in the synthesis of the reducing equivalent glutathione, vital to maintaining cellular redox status
  • Many tumors become largely dependent on glutamine to provide carbon and nitrogen building blocks needed for proliferation
  • In cancer model systems, Eagle and colleagues first demonstrated tumor cells in culture require supplementation with exogenous glutamine for efficient proliferation
  • It was subsequently shown that when deprived of glutamine tumor cells undergo apoptosis
  • The most well-characterized oncogene to regulate glutamine metabolism is MYC (9), which enhances glutaminase expression, upregulates glutamine transporters, and enhances glutamine utilization in energy production and biosynthesis
  • Other pro-tumorigenic regulators such as KRAS and mTOR, as well as tumor suppressors (p53, VHL) have also been associated with alterations in glutamine metabolism
  • Tumor cells are highly adaptable and alter nutrient uptake and metabolic networks to resist single agent glutaminase inhibition
  • cells in the microenvironment of several tumor types upregulate glutamine production, thereby enabling tumor cells to escape glutaminase inhibition
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American College of Cardiology Foundation | Journal of the American College of Cardiolo... - 0 views

content.onlinejacc.org/article.aspx mitochondria oxidative stress heart failure heart
shared by Nathan Goodyear on 19 Mar 13 - No Cached
  • Although currently no drugs that specifically target mitochondrial biogenesis in HF are available, acceleration of this process through adenosine monophosphate–activated kinase (AMPK), endothelial nitric oxide synthase (eNOS), and other pathways may represent a promising therapeutic approach
  • Mitochondrial biogenesis can be enhanced therapeutically with the use of adenosine monophosphate kinase (AMPK) agonists, stimulants of nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway (including phosphodiesteraes type 5 inhibitors), or resveratrol
  • metformin, a commonly used antidiabetic drug that activates AMPK signaling
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  • Recent evidence suggests that the eNOS/NO/cGMP pathway is an important activator of mitochondrial biogenesis
  • BH4 (tetrahydrobiopterin) supplementation can prevent eNOS uncoupling and was found to reduce left ventricular hypertrophy
  • folic acid is known to replenish reduced BH4 and has been shown to protect the heart through increased eNOS activity
  • Both folate deficiency and inhibition of BH4 synthesis were associated with reduced mitochondrial number and function
  • Resveratrol, a polyphenol compound responsible for the cardioprotective properties of red wine, was recently identified as a potent stimulator of mitochondrial biogenesis
  • epidemiological studies reveal a reduced risk of cardiovascular disease in premenopausal, but not post-menopausal, women compared with men
  • post-menopausal women
    • Nathan Goodyear
      Nathan Goodyear on 19 Mar 13
       
      I would hypothesis that a change in the predominance of ER expression is one of ER beta to ER alpha: creating a more pro-inflammatory signal.
  • The majority of ROS in the heart appear to come from uncoupling of mitochondrial electron transport chain at the level of complexes I and III
  • Because the majority of ROS in HF comes from mitochondria, these organelles are the primary target of oxidative damage.
  • cardioprotective therapies such as angiotensin-converting enzyme inhibitors and ATII receptor blockers were shown to possess antioxidant properties, although it is not known whether they target mitochondrial ROS directly or indirectly
  • Nathan Goodyear on 19 Mar 13
     
    great review of mitochondrial biogenesis, oxidative stress and heart failure.  
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Testosterone: a vascular hormone in health and disease - 0 views

joe.endocrinology-journals.org/...R47.full testosterone hormone health disease hormones men male cardiovascular disease CVD
shared by Nathan Goodyear on 13 May 13 - No Cached
  • Testosterone has beneficial effects on several cardiovascular risk factors, which include cholesterol, endothelial dysfunction and inflammation
  • In clinical studies, acute and chronic testosterone administration increases coronary artery diameter and flow, improves cardiac ischaemia and symptoms in men with chronic stable angina and reduces peripheral vascular resistance in chronic heart failure.
  • testosterone is an L-calcium channel blocker and induces potassium channel activation in vascular smooth muscle cells
  • ...54 more annotations...
  • Animal studies have consistently demonstrated that testosterone is atheroprotective, whereas testosterone deficiency promotes the early stages of atherogenesis
  • there is no compelling evidence that testosterone replacement to levels within the normal healthy range contributes adversely to the pathogenesis of CVD (Carson & Rosano 2011) or prostate cancer (Morgentaler & Schulman 2009)
  • bidirectional effect between decreased testosterone concentrations and disease pathology exists as concomitant cardiovascular risk factors (including inflammation, obesity and insulin resistance) are known to reduce testosterone levels and that testosterone confers beneficial effects on these cardiovascular risk factors
  • Achieving a normal physiological testosterone concentration through the administration of testosterone replacement therapy (TRT) has been shown to improve risk factors for atherosclerosis including reducing central adiposity and insulin resistance and improving lipid profiles (in particular, lowering cholesterol), clotting and inflammatory profiles and vascular function
  • It is well known that impaired erectile function and CVD are closely related in that ED can be the first clinical manifestation of atherosclerosis often preceding a cardiovascular event by 3–5 years
  • no decrease in the response (i.e. no tachyphylaxis) of testosterone and that patient benefit persists in the long term.
  • free testosterone levels within the physiological range, has been shown to result in a marked increase in both flow- and nitroglycerin-mediated brachial artery vasodilation in men with CAD
  • Clinical studies, however, have revealed either small reductions of 2–3 mm in diastolic pressure or no significant effects when testosterone is replaced within normal physiological limits in humans
  • Endothelium-independent mechanisms of testosterone are considered to occur primarily via the inhibition of voltage-operated Ca2+ channels (VOCCs) and/or activation of K+ channels (KCs) on smooth muscle cells (SMCs)
  • Testosterone shares the same molecular binding site as nifedipine
  • Testosterone increases the expression of endothelial nitric oxide synthase (eNOS) and enhances nitric oxide (NO) production
  • Testosterone also inhibited the Ca2+ influx response to PGF2α
  • one of the major actions of testosterone is on NO and its signalling pathways
  • In addition to direct effects on NOS expression, testosterone may also affect phosphodiesterase type 5 (PDE5 (PDE5A)) gene expression, an enzyme controlling the degradation of cGMP, which acts as a vasodilatory second messenger
  • the significance of the action of testosterone on VSMC apoptosis and proliferation in atherosclerosis is difficult to delineate and may be dependent upon the stage of plaque development
  • Several human studies have shown that carotid IMT (CIMT) and aortic calcification negatively correlate with serum testosterone
  • t long-term testosterone treatment reduced CIMT in men with low testosterone levels and angina
  • neither intracellular nor membrane-associated ARs are required for the rapid vasodilator effect
  • acute responses appear to be AR independent, long-term AR-mediated effects on the vasculature have also been described, primarily in the context of vascular tone regulation via the modulation of gene transcription
  • Testosterone and DHT increased the expression of eNOS in HUVECs
  • oestrogens have been shown to activate eNOS and stimulate NO production in an ERα-dependent manner
  • Several studies, however, have demonstrated that the vasodilatory actions of testosterone are not reduced by aromatase inhibition
  • non-aromatisable DHT elicited similar vasodilation to testosterone treatment in arterial smooth muscle
  • increased endothelial NOS (eNOS) expression and phosphorylation were observed in testosterone- and DHT-treated human umbilical vein endothelial cells
  • Androgen deprivation leads to a reduction in neuronal NOS expression associated with a decrease of intracavernosal pressure in penile arteries during erection, an effect that is promptly reversed by androgen replacement therapy
  • Observational evidence suggests that several pro-inflammatory cytokines (including interleukin 1β (IL1β), IL6, tumour necrosis factor α (TNFα), and highly sensitive CRP) and serum testosterone levels are inversely associated in patients with CAD, T2DM and/or hypogonadism
  • patients with the highest IL1β concentrations had lower endogenous testosterone levels
  • TRT has been reported to significantly reduce TNFα and elevate the circulating anti-inflammatory IL10 in hypogonadal men with CVD
  • testosterone treatment to normalise levels in hypogonadal men with the MetS resulted in a significant reduction in the circulating CRP, IL1β and TNFα, with a trend towards lower IL6 compared with placebo
  • parenteral testosterone undecanoate, CRP decreased significantly in hypogonadal elderly men
  • Higher levels of serum adiponectin have been shown to lower cardiovascular risk
  • Research suggests that the expression of VCAM-1, as induced by pro-inflammatory cytokines such as TNFα or interferon γ (IFNγ (IFNG)) in endothelial cells, can be attenuated by treatment with testosterone
  • Testosterone also inhibits the production of pro-inflammatory cytokines such as IL6, IL1β and TNFα in a range of cell types including human endothelial cells
  • decreased inflammatory response to TNFα and lipopolysaccharide (LPS) in human endothelial cells when treated with DHT
  • The key to unravelling the link between testosterone and its role in atherosclerosis may lay in the understanding of testosterone signalling and the cross-talk between receptors and intracellular events that result in pro- and/or anti-inflammatory actions in athero-sensitive cells.
  • testosterone functions through the AR to modulate adhesion molecule expression
  • pre-treatment with DHT reduced the cytokine-stimulated inflammatory response
  • DHT inhibited NFκB activation
  • DHT could inhibit an LPS-induced upregulation of MCP1
  • Both NFκB and AR act at the transcriptional level and have been experimentally found to be antagonistic to each other
  • As the AR and NFκB are mutual antagonists, their interaction and influence on functions can be bidirectional, with inflammatory agents that activate NFκB interfering with normal androgen signalling as well as the AR interrupting NFκB inflammatory transcription
  • prolonged exposure of vascular cells to the inflammatory activation of NFκB associated with atherosclerosis may reduce or alter any potentially protective effects of testosterone
  • DHT and IFNγ also modulate each other's signalling through interaction at the transcriptional level, suggesting that androgens down-regulate IFN-induced genes
  • (Simoncini et al. 2000a,b). Norata et al. (2010) suggest that part of the testosterone-mediated atheroprotective effects could depend on ER activation mediated by the testosterone/DHT 3β-derivative, 3β-Adiol
  • TNFα-induced induction of ICAM-1, VCAM-1 and E-selectin as well as MCP1 and IL6 was significantly reduced by a pre-incubation with 3β-Adiol in HUVECs
  • 3β-Adiol also reduced LPS-induced gene expression of IL6, TNFα, cyclooxygenase 2 (COX2 (PTGS2)), CD40, CX3CR1, plasminogen activator inhibitor-1, MMP9, resistin, pentraxin-3 and MCP1 in the monocytic cell line U937 (Norata et al. 2010)
  • This study suggests that testosterone metabolites, other than those generated through aromatisation, could exert anti-inflammatory effects that are mediated by ER activation.
  • The authors suggest that DHT differentially effects COX2 levels under physiological and pathophysiological conditions in human coronary artery smooth muscle cells and via AR-dependent and -independent mechanisms influenced by the physiological state of the cell
  • There are, however, a number of systematic meta-analyses of clinical trials of TRT that have not demonstrated an increased risk of adverse cardiovascular events or mortality
  • The TOM trial, which was designed to investigate the effect of TRT on frailty in elderly men, was terminated prematurely as a result of an increased incidence of cardiovascular-related events after 6 months in the treatment arm
  • trials of TRT in men with either chronic stable angina or chronic cardiac failure have also found no increase in either cardiovascular events or mortality in studies up to 12 months
  • Evidence may therefore suggest that low testosterone levels and testosterone levels above the normal range have an adverse effect on CVD, whereas testosterone levels titrated to within the mid- to upper-normal range have at least a neutral effect or, taking into account the knowledge of the beneficial effects of testosterone on a series of cardiovascular risk factors, there may possibly be a cardioprotective action
  • The effect of testosterone on human vascular function is a complex issue and may be dependent upon the underlying androgen and/or disease status.
  • the majority of studies suggest that testosterone may display both acute and chronic vasodilatory effects upon various vascular beds at both physiological and supraphysiological concentrations and via endothelium-dependent and -independent mechanisms
  • Nathan Goodyear on 13 May 13
     
    Good deep look into the testosterone and CVD link.
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