What do malaria, toxoplasmosis and eimeriosis have in common? All three of these diseases are caused by tiny intracellular parasites in the phylum Apicomplexa.
At first glance, these three parasites seem to be very different in terms of their life cycles, hosts, and disease severity. However, despite their differences, the parasites all share a common structure known as the apical complex.
This unique structure contains secretory organelles (rhoptries, micronemes, and dense granules), which sequentially secrete enzymes that allow the parasite to invade other cells (Figure 2). Because Plasmodium, Toxoplasma, and Eimeria all have apical complexes, they are members of the same club-the phylum Apicomplexa.
All apicomplexans are obligate, intracellular, protozoan parasites, that is, they cannot live or reproduce without a host.
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The Apicoplast as a Drug Target
One missing piece of information in the apicoplast puzzle is why apicomplexans retained a vestigial plastid despite losing the capability for photosynthesis.
A probable answer to this question is that the plastid provides a function that is important to the parasite's survival. In algae and plants, plastids are not only involved in photosynthesis, but they are also responsible for other functions.
Scientists learned that apicoplasts, like some plant plastids, participate in lipid biosynthesis and iron metabolism.
Two different lines of evidence showed that apicoplasts are essential in the apicomplexan parasites. First, chemicals affecting apicoplast metabolism resulted in parasite death.
Second, parasites that are unable to replicate the apicoplast also die. Amazingly, in both cases, the parasites only die in the next generation. This means that the parasites can survive with no apicoplast (or with a chemically damaged apicoplast) while remaining in the infected host cell.
However, the parasite is unable to establish a successful new infection. This phenomenon is called "delayed death". How is this possible? One hypothesis is that the apicoplast synthesizes a molecule that is needed for the infection process (Ralph et al. 2004).
Since apicoplasts share evolutionary similarities with chloroplasts and prokaryotes (cyanobacteria), they stand out as an attractive target for known antibiotics and herbicides. Today, researchers have learned that apicoplasts are sensitive to several antibacterials and herbicides.
Plant scientists are already exploring non-toxic herbicides that may act upon the apicoplast, and together with parasitologists, they are using bioinformatics and experimental approaches to identify key proteins and metabolic pathways in order to develop new drugs (Ralph et al. 2004) (Figure 7
The plastid-derived organelle of protozoan human parasites as a target of established and emerging drugs. Wiesner J, Seeber F. Source Justus-Liebig-Universit�t Giessen, Biochemisches Institut, Friedrichstr. 24, D-35392 Giessen, Germany.
Abstract Human diseases like malaria, toxoplasmosis or cryptosporidiosis are caused by intracellular protozoan parasites of the phylum Apicomplexa and are still a major health problem worldwide.
In the case of Plasmodium falciparum, the causative agent of tropical malaria, resistance against previously highly effective drugs is widespread and requires the continued development of new and affordable drugs.
Most apicomplexan parasites possess a single plastid-derived organelle called apicoplast, which offers the great opportunity to tailor highly specific inhibitors against vital metabolic pathways resident in this compartment.
This is due to the fact that several of these pathways, being of bacterial or algal origin, are absent in the mammalian host. In fact, the targets of several antibiotics already in use for years against some of these diseases can now be traced to the apicoplast and by knowing the molecular entities which are affected by these substances, improved drugs or drug combinations can be envisaged to emerge from this knowledge.
Likewise, apicoplast-resident pathways like fatty acid or isoprenoid biosynthesis have already been proven to be the likely targets of the next drug generation.
In this review the current knowledge on the different targets and available inhibitors (both established and experimental) will be summarised and an overview of the clinical efficacy of drugs that inhibit functions in the apicoplast and which have been tested in humans so far will be given.
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I don't know if anyone cares about this but I wanted to investigate it further for myself...
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nefferdun
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It is interesting if I can concentrate long enough to understand it. All I know is, protomyxzoa thrives on lipids and arginine.
-------------------- old joke: idiopathic means the patient is pathological and the the doctor is an idiot Posts: 4676 | From western Montana | Registered: Apr 2009
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MichaelTampa
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I appreciate that you've found these, and hope to be able to understand them at some point. Maybe just too late in the day, maybe beyond reach. Either way, thanks for sharing.
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sparkle7
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Actually uses a particular fat as a treatment to cure malaria. It's a protozoa & may be different than FL1953 (I can't spell the other name).
The title -
In Vitro and in Vivo Antimalarial Activity of Linolenic and Linoleic Acids and their Methyl Esters
excerpts-
The apicoplast is an indispensable organelle for the parasite as many vital metabolic processes such as, fatty acid biosynthesis which is necessary for the growth of the parasite take place there.
The parasite needs the fatty acid for the construction of cell membranes, as a source of energy, signal transduction, protein acylation, growth, differentiation and homeostasis.
Interestingly, the Plasmodium falciparum parasite uses type II fatty acid synthase while humans make use of type I fatty acid synthase [2].
This indicates that the parasite�s fatty acid synthase system could be selectively targeted without harming the host.
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Moreso, there is a growing realisation that fatty acids have the potential to inhibit the fatty acid biosynthetic machinery of Plasmodium falciparum parasite [2].
Fatty acids have shown antimalarial, antimycobacterial and antifungal properties [2].
Essential fatty acids (EFA)m were reported to be of benefit in the prevention and management of coronary heart disease, stroke, diabetes mellitus, hypertension, cancer, depression schizophrenia, Alzhemer�s disease, and collagen vascular disease
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Bottom line -
Linolenic acid significantly inhibited the growth of parasites compared to linoleic acid.
The suppressive effect of the free acids when combined together (at a dose of 50 mg/kg each) proved to be more potent than the individual compounds alone (100 mg/kg).
Also-
The presence of vitamin E, which is an anti-oxidant, suppresses the antiparasitic activities of this class of compounds [4]. This suggests that diets rich in antioxidants such as vitamin E could counteract the antiplasmodial effect of these fatty acids.
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CONCLUSION AND RECOMMENDATION
The activity of this class of compound is partly influenced by the degree of unsaturation. Chemical modification of this compound by the introduction of additional double bonds could enhance its activity.
The oxidized form of these fatty acids showed increased activity. Therefore chemical oxidation of this class of compounds could also enhance efficacy. However, due to early recrudescence recorded in mice after a 4-day suppressive treatment, it is recommended that treatment with this compound be given 2 to 3 times a day and for a longer duration, and possibly be administered in combination with existing antimalarials.
Slow release mechanism could be explored using nanodrug delivery systems.
The non-mevalonate isoprenoid biosynthesis pathway is also shared by several other pathogens such as Mycobacterium tuberculosis and Gram negative bacteria.
This may suggest that innovative methods aimed at targeting this pathway such as nanomedicine drug delivery systems could help to deliver broad-spectrum antibacterial, antituberculous, and antimalarial agents.
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So - this may indicate that there are other ways to treat FL1953 rather than cutting out all fats. I'm not a scientist, though. I wonder if Dr. F has seen this study or if it would apply to FL1953...?
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sparkle7
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fyi - Linolenic acid can refer to either of two octadecatrienoic acids, or a mixture of the two.
Linolenate (in the form of esters of linolenic acid) is often found in vegetable oils; traditionally, such fatty acylates are reported as the fatty acids: α-Linolenic acid, an n-3 fatty acid. γ-Linolenic acid, an n-6 fatty acid
Linolenic acid is a polyunsaturated omega-3 fatty acid with 18 carbons and three double bonds. Current recommendations for omega-3 fatty acids suggest a minimum of 0.5 percent of calories from omega-3 fatty acids with 10 calories of pure alpha-linolenic acid, according to Kathleen Mahan and Sylvia Escott-Stump in "Krause's Food, Nutrition, & Diet Therapy."
In a 2,000-calorie diet, this recommendation could be met with 2 tsp. flaxseed, 3 tbsp. walnuts or 1 tbsp. canola or soybean oil.
Linolenic acid benefits the heart by decreasing the risk of abnormal heartbeats, decreasing triglyceride levels and slowing the growth of plaque in the arteries.
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MichaelTampa
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My guess is you've made an excellent find here! A lot here is consistent with what my pendulum has been saying lately with regard to sources of these two fatty acids (chia and hemp/walnut) and avoidance of vitamin E, as well as the craving I've had for kiwis (another source is kiwi seeds).
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Marnie
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"Scientists learned that apicoplasts, like some plant plastids, participate in
lipid biosynthesis "
Do you understand what that means?
"in animals, when there is an oversupply of dietary carbohydrate, the excess carbohydrate is converted to triglycerides.
This involves the synthesis of fatty acids from acetyl-CoA and the esterification of fatty acids in the production of triglycerides,
Ioprene-based *lipids* also include vitamin A, D, E and K.
Dare you...
Google these words: Berberine lipids
I'm trying so hard to convince you.
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sparkle7
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posted
Yeah, this is some deep stuff. The other aspect is that these apicoplasts that are inside the protozoa are from algae... Some scientists were looking at herbacides to kill malaria... (So it's a plant "organ" inside a parasite.)
- - - -
I take the berberine... I got the sample of Glycosolve (I think that's what it's called) but the berberine from Swansons dowsed a YES for me over the Glycosolve. It's alot cheaper, too. Like $10 a bottle.
The other thing that was interesting is the situation with Vit. E & possible other anti-oxidants.
re:
The presence of vitamin E, which is an anti-oxidant, suppresses the antiparasitic activities of this class of compounds [4]. This suggests that diets rich in antioxidants such as vitamin E could counteract the antiplasmodial effect of these fatty acids.
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sparkle7
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posted
From what I read - if you deprive the apicoplasts lipids (fats, basically) it might not kill the protozoa but it will make the next generation of protozoa unable to live. I think it damages the apicoplast & makes the new protozoa unstable (?)
Artemesia works by attaching to iron & "exploding" - from what I read. Somehow these apicoplasts survive through lipids & iron. (Not sure of the correct terminology?)
- re: (from above) Scientists learned that apicoplasts, like some plant plastids, participate in lipid biosynthesis and iron metabolism. -
I'm no scientist... maybe artemesia would be a good thing to take, too? Might be good to avoid extra anti-oxidants, too - for a time? I don't know how long these things take to reproduce or how long they live...
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annxyzz
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Sparkle , you understand more about science than the average person ! Good article and thank you !
-------------------- annxyzz Posts: 1178 | From East Texas | Registered: May 2009
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Marnie
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posted
Sparkle7 -
Bb follows the classical pathway (mevalonate pathway) mentioned in the following:
In contrast to the classical mevalonate pathway
of isoprenoid biosynthesis,
plants and apicomplexan protozoa such as malaria parasites
have the ability to produce their isoprenoids
(terpenoids) using an alternative pathway,
the non-mevalonate pathway, which takes place in their plastids.
BTW...just for fun and something to think about...the #5 is in the middle of the Yin-Yang symbol (ya know...the circle that is half white and half black with a curved line dividing the two). The #5 DOES have a very POWERFUL meaning.
I'll dig for the link if you want...PM me.
What are we really trying to do? Get the body back in balance because as Rife said, "A body in balance has no disease."
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sparkle7
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excerpt- Both herbicides and antibacterials disable an ancient organelle in the parasite that resembles a chloroplast found in plants. The drugs are generally safe for people because they target specific proteins in the parasite without harming the host.
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The drug, called fosmidomycin, was originally developed as an antibiotic for urinary infections in the 1980s, and has also been used in herbicides. Researchers rediscovered the drug's use for malaria two years ago when they found it disables a specific enzyme in the malaria parasite.
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I'll take a look at your links tomorrow, Marnie. Thanks!
---
More-
Babesia bovis: A comprehensive phylogenetic analysis of plastid-encoded genes supports green algal origin of apicoplasts
Since the first genome report in Plasmodium (Gardner et al., 2002), apicoplast genomes have been detected in Theileria, Eimeria, Toxoplasma, and Babesia through complete genome sequencing ef- forts (Abrahamsen et al., 2004; Brayton et al., 2007; Dunn et al., 1998; Gardner et al., 2002, 2005; Toso and Omoto, 2007a,b; Xu et al., 2004).
Notably, genome sequencing has failed to detect the presence of an apicoplast genome for Cryptosporidium spp. (Abra- hamsen et al., 2004; Xu et al., 2004), and ultrastructural studies indicate that the more distantly related Gregarines (Toso and Omot- o, 2007a,b) and Archigregarines (Simdyanov and Kuvardina, 2007) do not appear to contain an apicoplast.
While the specific role of the apicoplast in the Apicomplexan life cycle is for the most part un- clear, in Plasmodium falciparum, the causative agent of malaria, the apicoplast has been demonstrated to be involved in de novo fatty acid synthesis (Waller et al., 2003). This biosynthetic pathway, which is considered a novel chemotherapeutic target (Gornicki, 2003), is identical to those utilized in plant chloroplasts and bacteria.
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The close phylogenetic position of this green alga to the Apicomplexans further strengthens the argument that the apicoplast is of green algal origin. Interestingly, the association of the apicoplast with a non-photosynthetic green alga raises the question of when the plastid became non- photosynthetic.
----
I believe that this apicoplast is related to chlorella... Don't know what that might mean in regards to treatment...?
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posted
Fry Labs has a twitter acct that you can follow. It will explain what they are finding with low fat in breaking down the Biofilm. Then you can get to the protozoan to kill it better.
Post your info on their page and see what they state back to you if you feel this is an important discovery.
I'm sure the scientists would love help in figuring this out.
-------------------- Lyme, Babs, Fry Bug..... Whatever it is, may a treatment be discovered to make us all whole again! Posts: 941 | From AZ-MT | Registered: Oct 2004
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Marnie
Frequent Contributor (5K+ posts)
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posted
Sparkle7...
Google this:
ricin cancer
RICIN! Yikes!
Not DNP (in a class with cyanide!).
Holy....
Count me out...either one.
AKT8 is bad enough!
[ 08-13-2012, 06:31 PM: Message edited by: Marnie ]
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sparkle7
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posted
Thanks Hadlyme. I'm going to look into the biofilm aspect. I got kind of fascinated with this apicoplast & how it's actually related to plant life. I kind of forgot about the biofilm as being the reason for the low fat diet.
Marnie - I looked at the ricin cancer articles. I'm not sure what it has to do with Fosmidomycin. Is that what you are drawing a comparison to?
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Wikipedia -
Fosmidomycin is an antibiotic that was originally isolated from culture broths of bacteria of the genus Streptomyces.[1] It specifically inhibits DXP reductoisomerase, a key enzyme in the non-mevalonate pathway of isoprenoid biosynthesis.
It is a structural analogue of 2-C-methyl-D-erythrose 4-phosphate. It inhibits the E. coli enzyme with a KI value of 38 nM (4), MTB at 80 nM, and the Francisella enzyme at 99 nM.[2]
The discovery of the non-mevalonate pathway in malaria parasites has indicated the use of fosmidomycin and other such inhibitors as antimalarial drugs.[3] Indeed, fosmidomycin has been tested in combination treatment with clindamycin for treatment of malaria with favorable results.[4][5][6]
It has been shown that an increase in copy number of the target enzyme (DXP reductoisomerase) correlates with in vitro fosmidomycin resistance in the lethal malaria parasite, Plasmodium falciparum.[7]
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I think artemesia as a treatment may be something to look into next. I was thinking about Dr. Ks Lyme cocktail & how the artemesia is made into a liposome.
I'm going to have to research it later. I'm a little tied up at the moment.
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