perjantai 22. elokuuta 2014

Memorial Sloan Kettering Cancer Center - Graviola Clinical Summary


INTEGRATIVE MEDICINE  Graviola



Clinical Summary
Graviola, a tree prevalent in the rain forests of Africa, South America, and Southeast Asia, has been used in traditional medicine in many countries.

Extracts of graviola show antiviral (1), antiparasitic, antirheumatic, astringent, emetic (2), antileishmanial and cytotoxic (3) (4), antinociceptive, anti-inflammatory (9), antihyperglycemic (10) and anticancer effects (5)(12) (13) in vitro and in vivo.

Purported Uses
  • Cancer treatment
  • Herpes
  • Infections
  • Parasitic infections
  • Sedation
Constituents
  • Acetogenins
  • Quinolines and isoquinolines
  • Annopentocins
  • Annomuricins
  • Coreximine and reticuline
    (6) (7)  

Mechanism of Action

Annonaceous acetogenins, phytochemicals isolated from the leaves, bark and twigs of graviola, are thought to be the active ingredients. 

The ethanolic extract of Annona muricata was found to inhibit the Herpes simplex virus (1) and effective against Leishmania braziliensisL. panamensis promastigotes, and the cancer cell line U 937 (3) and hepatoma cell lines (8) in vitro.

Graviola extracts were shown to be lethal to the fresh-water mollusk Biomphalaria glabrata, which acts as a host for the parasitic worm, Schistosoma mansoni (2).
Alkaloids from graviola are detrimental to the survival of dopaminergic nerve cells in vitro. This may result in neuronal dysfunction and degeneration. 
Graviola-induced cell death was inhibited by glucose supplementation suggesting that cell death may have been caused by energy depletion (6) 
Graviola has also been shown to stimulate serotonine receptors (7).

Graviola extracts were effective against the growth of Adriamycin-resistant human mammary adenocarcinoma (MCF-7/Adr) by blocking access of cancer cells to ATP and by inhibiting the actions of plasma membrane glycoprotein (5).
They also inhibited expression of HIF-1α, NF-κB, glucose transporters, and glycolytic enzymes resulting in decreased glucose uptake and ATP production in pancreatic cancer cells (12); and downregulated EGFR expression in another study (13).
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Graviola's purported anti-cancer potency comes largely from its ability to reduce the supply of adenosine triphosphate (ATP) to cancer cells
ATP often provides metabolic energy to healthy cells as well, and some nutritional supplements, notably Coenzyme Q10, are known for increasing ATP. For this reason, CoQ10 may neutralize the effect of graviola and they should not be taken together [source: Taylor].
Some side effects follow from graviola's areas of bioactivity.
Studies on animal subjects have demonstrated that the plant can dilate blood vessels and lower blood pressure, so those whose blood pressure is already low, or are already on medication to reduce hypertension, should consult their physician before taking graviola [source: Wright]. Also, a large dose taken at one time can cause nausea and vomiting [source: Taylor].



Elektroninsiirtoketju



I entsyymi on NADH-dehydrogenaasi, II on sukkinaattidehydrogenaasi, III on sytokromi b-ckompleksi ja IV entsyymi on sytokromi-c-oksidaasi

Elektroninsiirtoketju on mitokondrion sisäkalvolla (eukaryootit) tai solukalvon kalvoproteiineissa (bakteerit) tapahtuva energiaa tuottava reaktiosarja,jossa sitruunahappokierrossa ja sitä edeltäneissä reaktioissa koentsyymeille NADH ja FADHsiirtyneitä elektroneja siirrellään elektroninsiirtoketjun entsyymiltä toiselle, jolloin elektronit menettävät potentiaalienergiaansa vähitellen, vapauttaen samalla energiaa.Vapautuvan energian avulla mitokondrion matriksista pumpataan protoneja mitokondrion kalvojen välitilaan, mikä aiheuttaa elektrokemiallisen gradientin eli potentiaali- ja protonikonsentraatioeron matriksin ja välitilan välille. Muodostunut gradientti purkautuu ATP-syntaasientsyymin kautta, jolloin muodostuu suurenergiaista fosfaattiyhdistettä, ATP:tä.
https://fi.wikipedia.org/wiki/Elektroninsiirtoketju

Electron transfer chain in the inner-membrane of mitochondrion. The electron transfer chain contains five complexes designated as complex I, II, III, IV, and V (F 1 F 0 -ATP synthase). The electrochemical H + gradient provided by these membrane-bound complexes serve as energy source for ATP synthesis from ADP and inorganic phosphate by an F 1 F 0 -ATP synthase


https://www.researchgate.net/figure/Electron-transfer-chain-in-the-inner-membrane-of-mitochondrion-The-electron-transfer_fig1_232699942


The Annonaceous acetogenins are promising new antitumor and pesticidal agents that are found only in the plant family Annonaceae. 
Chemically, they are derivatives of long-chain fatty acids. Biologically, they exhibit their potent bioactivities through depletion of ATP levels via inhibiting complex I of mitochondria and inhibiting the NADH oxidase of plasma membranes of tumor cells. Thus, they thwart ATP-driven resistance mechanisms. This review presents the progress made in the chemistry, biology, and development of these compounds since December 1995

https://pubs.acs.org/doi/abs/10.1021/np980406d



Understanding mitochondrial complex I assembly in health and disease


Complex I (NADH:ubiquinone oxidoreductase) is the largest multimeric enzyme complex of the mitochondrial respiratory chain, which is responsible for electron transport and the generation of a proton gradient across the mitochondrial inner membrane to drive ATP production. Eukaryotic complex I consists of 14 conserved subunits, which are homologous to the bacterial subunits, and more than 26 accessory subunits. In mammals, complex I consists of 45 subunits, which must be assembled correctly to form the properly functioning mature complex. Complex I dysfunction is the most common oxidative phosphorylation (OXPHOS) disorder in humans and defects in the complex I assembly process are often observed.


Researchers exploring the mechanisms that graviola uses claim that the acetogenins in the plant can distinguish cancerous cells from healthy cells because cancer cells have a consistently higher level of cellular activity. 
The acetogenins recognize and selectively inhibit the cancer cells. 
Pregnant women are advised to avoid graviola because the high energy in the cells of the developing fetus may trigger the botanical's toxic activity [source: Wright]. The plant was also found to stimulate the uterus in an animal study [source: Taylor].
The most detrimental effect attributed to graviola is that it "may cause neural dysfunction and degeneration leading to symptoms reminiscent of Parkinson's Disease" [source: Memorial Sloan-Kettering]. The first study to make this assertion was conducted by French researchers in Guadeloupe, who found an abnormally high presence of atypical Parkinson's amongst a poor population that used graviola for both food and medicine. However, the outbreak of neurological disorders was relatively confined, whereas the popularity of graviola is widespread in the region [source: Wright]. In her book "The Healing Power of Rainforest Herbs," botanist Leslie Taylor acknowledges that graviola seeds and roots contain alkaloids that have shown neurotoxic effects in tests. For this reason, she recommends using the leaves instead [source: Taylor].

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Graviola -hedelmän ja -lehtien aineosat, annonaceus acetogenins, etsivät
nopeasti kasvavat, paljon energiaa tuhlaavat syöpäsolut ja estävät niiden ravinnon
ja hapen saannin.
- Graviolan aineosat pysäyttävät syöpäsolujen kasvun jo niiden energian-
tuotannossa, mitokondrioissa, Complex 1: n elektronisiirto -ketjussa.
Electron transport chain COMPLEX 1 (NADH ubiquinone oxidoreductase)

The Warburg hypothesis, sometimes known as the Warburg theory of cancer,
postulates that the driver of tumorigenesis is an insufficient cellular respiration caused by insult to mitochondria.[1] The term Warburg effect describes the observation that

cancer cells, and many cells grown in-vitro, exhibit glucose fermentation even when
enough oxygen is present to properly respire. In other words, instead of fully respiring
in the presence of adequate oxygen, cancer cells ferment.

He hypothesized that cancer, malignant growth, and tumor growth are caused by the
fact that tumor cells mainly generate energy (as e.g., adenosine triphosphate / ATP)
by non-oxidative breakdown of glucose (a process called glycolysis).
This is in contrast to "healthy" cells which mainly generate energy from oxidative
breakdown of pyruvate.
Pyruvate is an end-product of glycolysis, and is oxidized within the mitochondria



4.2. Annonaceous Acetogenins
AGEs are a unique class of C-35/C37 secondary metabolites derived from long chain
(C-32/C34) fatty acids in the polyketide pathway. They are usually characterized by a combination of fatty acids with a 2-propanol unit at C-2 that forms a methyl-substituted α,β-unsaturated γ-lactone [72]. Since the discovery of uvaricin from Uvaria accuminata
in 1982, more than 500 AGEs have been identified from different parts of the plants in the Annonaceae family [73,74]. Due to the special structures and extensive biological activities, AGEs have attracted significant scientific interest in recent years.
Various biological activities have been reported for AGEs, including antimalarial, antiparasitic and pesticidal activities [72,75].

However, the biological activities of AGEs are primarily characterized with toxicity against cancer cells and inhibitory effects against the mitochondrial complex I (mitochondrial NADH: ubiquinone oxidoreductase) [76,77].

Phytochemical investigations and biological studies on different parts of the A. muricata plant resulted in the identification of a wide array of AGE compounds, as summarized in Table 1.
The chemical structures of the major acetogenins are shown inFigure 2.
To the best of our knowledge, at the time of preparation (January 2015) of the present review over 100 AGEs have been identified in A. muricata.



Electron Transport Chain | 8.12.2016
The Electron Transport Chain & complexes I-IV that pump protons out of the Mitochondria by the transfer of the electrons carried on NADH & FADH2 to maintain the concentration gradient of the protons "high in the intermembrane space & low in the matrix of the Mitochondria"




Characterization of the Annonaceous acetogenin, annonacinone, a natural product inhibitor of plasminogen activator inhibitor-1
(Scientific Reports volume 6, Article number: 36462 (2016) doi:10.1038/srep36462)

In this study, we evaluated a novel PAI-1 inhibitor, annonacinone, a natural product from the Annonaceous acetogenins group
- High plasma levels of PAI-1 are related to the development of thrombosis as well as several other pathologies such as cardiovascular diseases and metabolic disturbances1,2,3
- Moreover PAI-1 is able to promote tumor angiogenesis and high PAI-1 level in solid tumors are associated with a poor prognosis 4,5. 

http://graviolateam.blogspot.com/2018/05/graviola-aka-soursop-what-you-need-to.html
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Graviolan hedelmiä, siemeniä, kuorta, lehtiä ja juurta on Keski- ja Etelä-Amerikan sekä Karibian kansojen keskuudessa jo vuosisatojen ajan käytetty myös perinteisinä luonnonrohtoina saatujen kokemusten ja monipuolisiksi havaittujen vaikutustensa vuoksi. 

Paitsi hedelmiä, myös sen siemeniä, varsia ja lehtiä on perinteisesti käytetty kansanlääkinnässä mitä erilaisemmissa terveysongelmissa ja erilaisempiin tarkoituksiin. Parhaiten Graviolan käyttö tunnetaankin Etelä-Amerikassa, jossa sen kuoresta, juurista ja lehdistä on valmistettu teetä erilaisten vaivojen hoitoon. 

Perun Andien alkuperäiskansojen tiedetään käyttävän graviolan lehtiteetä lisäämään limakalvojen liman eritystä ja rauhoittamaan niitä. Joissakin Perun osissa diabeetikot käyttävät sekä kuorta että lehtiä tasaamaan veren sokeria. Guyanassa lehtiteetä käytetään lähinnä elinvoimaa parantavana ja virkistävänä juomana, Braziliassa maksan toimintaa edistämään sekä Länsi-Intian saarilla puolestaan helpottamaan yskää ja avaamaan hengitystä.
Nykyisin myös tutkijat ovat kiinnostuneet graviolan perinteisestä käytössä ja sen mahdollisista vaikutuksista jopa joidenkin vakavien sairauksen hoidossa.
Mm. New Yorkissa sijaitsevassa maailmankuulussa syöpätutkimuskeskuksessa Memorial Sloan-Kettering Centerissä tehdyissä tutkimuksissa on havainnut graviolalla olevan vaikutusta viruksiin, parasiitteihin sekä reumaan.
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http://graviola.fi/kauppa-uutuudet/graviola-tee-pulver/


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Graviola -mehut

GRAVIOLA MEHU - Todella voimallinen juoma! - Info puh. 041-492 6015 -
Totuttele varovasti maistelemalla ja laimentamalla.
- Graviola -mehun vaikutus on välitön ja tehokas!
100% puhdasta mehua tuoreista ja kypsistä Graviola-hedelmistä Graviola –mehu on puhdasta, erittäin laadukasta Graviolan hedelmälihaa, johon ei ole lisätty vettä ja mehu onkin melko sakeaa.

Kypsät Graviola-hedelmät poimitaan käsin, kuoritaan ja niiden hedelmälihasta poistetaan siemenet. Tämän jälkeen hedelmäliha mehustetaan tynnyreissä ja jäädytetään välittömästi tuottajamme toimesta, jotta mehun laatu ja aineksien säilyvyys saadaan taattua. Pian tämän jälkeen mehu pastöroidaan ja pullotetaan laadun ja hyllyiän maksimoimiseksi.

Mehu on täysin säilöntä- ja torjunta-aineetonta. Jokainen hedelmätoimitus tarkistetaan torjunta-aineiden varalta ulkoistetussa, erikoistuneessa laboratoriossa.

Sisältö: Graviola (Annona muricata)
Suositeltu käyttö: n. 50-100ml päivittäin.
Herkullisen makunsa ansiosta Graviolalla on lukuisia käyttötapoja: virkistävän smoothien pohjana tai osana pirtelöä, siitä voi tehdä herkullista sorbettia tai jäätelöä tai vaikka käyttää osana aivan uutta cocktailia.

Aluksi on suositeltavaa sekoittaa mehu veteen tai toiseen tuoremehuun Graviolan vomakkuuden vuoksi.

Säilytä avattuna jääkaapissa ja nauti 5 päivän sisään kuten muutkin aidot tuoremehut.
Ravintoarvot 100g Energia 60 kcal Proteiini 1 g Hiilihydraatteja 15 g Rasvaa 0 g Kuituja 1 g C-vitamiinia 26 mg. 
Toimitus: Toimitusaika 8 vrk

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