Month: April 2008

New hedgehog inhibitor: zerumbone

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I think hedgehogs are among the most adorable creatures in the world. Under certain circumstances, though, the word “hedgehog” does not have a positive connotation, as we will see in this post. I refer specifically to the hedgehog signalling pathway, or Hh.
 
If you need to refresh your memory re. Hh, please have a look at my page on cyclopamine. Just quickly, though, as we can read in the abstract, this signaling pathway causes the formation and progression of a variety of tumors. And, in the full study: Besides its crucial roles in development, aberrant Hh/GLI signaling in adult tissues has recently been implicated in cancer formation and development, in the skin, brain, prostate, upper gastrointestinal tract, pancreas and lung.
 
Is the hedgehog pathway signalling also involved with myeloma? You betcha! Just take a quick look at this study (http://tinyurl.com/3zhw9h), which shows that the subset of MM cells that manifests Hh pathway activity is markedly concentrated within the tumor stem cell compartment. Hh and myeloma stem cells are best friends, simply put. But when the researchers used cyclopamine to block Hh, the clonal expansion of the myeloma stem cells was significantly affected. The myeloma stem cells, in other words, were not able to renew themselves. Groovy!
 
I am writing about this topic today because a Beating-Myeloma list member (thank you!) sent me a note about a recent study on zerumbone, a cytotoxic substance extracted from Zingiber zerumbet Smith, a sort of wild ginger. Sherlock sent me the full study (abstract: http://tinyurl.com/54xpp5).
 
Once again we come across our friend cyclopamine, the hedgehog antagonist that specifically inhibits Smo, an acronym that stands for Smoothened, a transmembrane protein necessary for the activation of hedgehog target genes. Smo mutations can disrupt the hedgehog pathway and lead to cancer. Obviously, not good!

At any rate, the researchers found that, like cyclopamine, zerumbone, the substance I am interested in right now, antagonizes Hh. One big difference, though. Cyclopamine, as I mentioned, targets Smo, an earlier stage of Hh, whereas zerumbone (and a few of the other compounds examined in this study) affects the final stage of Hh, which is called GLI1 (the acronym stands for “glioma-associated oncogene homolog 1,” aren’t you glad you know that? ).

The researchers tested 94 compounds from our natural product library, including terpenoids, flavonoids, phenylpropanoids, their glycosides and bisindole alkaloids […] and identified two sesquiterpenes and four bisindole alkaloids as inhibitors of GLI-mediated transcription. So they found six compounds that will inhibit GLI1, including zerumbone.

They also tested another 192 tropical plant extracts (extraordinary, no?), and those that were cytotoxic were again screened at lower concentrations. This part of the text, in fact MOST of the text, was very difficult for me to follow, so I had to skip some parts that were beyond my comprehension. A lot of it had to do with the procedures used in the screening, which we don’t really need to know (if anyone wants to read this very technical part, though, I would be happy to forward the study privately; just leave me a comment here).
 
The expression of the anti-apoptotic Bcl-2 protein is also involved with hedgehog. But the level of this protein was reduced by some of the compounds under scrutiny. This proves that hedgehog inhibitors also reduce the expression of the antiapoptotic protein Bcl2. This result also supports the reported relation between Hh antagonists and inhibition of Bcl2 expression.
 
Zerumbone is one of the compounds that suppresses the expression of the antiapoptotic protein Bcl2 and up-regulates the expression of the proapoptotic protein Bax; this results in an increase in the Bax/Bcl2 ratio. […] Our findings suggest that the suppression of Bcl2 expression might be due to the inhibition of GLI-mediated transcription. Inhibit the hedgehog signalling pathway, in other words, and Bcl-2, one of the bad guys, is also affected. Two birds with one stone. Sounds good to me!
 
The researchers examined a human pancreatic cancer cell line (PANC1), which expresses numerous Hh/GLI signaling pathway components. They found that the compounds inhibit the expression of these components at the transcriptional level. Take my word for it, this is important. And since, as I have mentioned, other natural extracts were tested in addition to zerumbone, I have a lot of work ahead of me.

One last bit of intriguing news, though: zerumbone also inhibits the Epstein-Barr virus…see: http://tinyurl.com/4lbh92 Well, it’s getting late, and I must get off this computer.

I can tell that this is going to be a long hedgehog weekend! 

Healthy writing

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I keep getting distracted by items that I read here and there and that take me away from my regularly scheduled research (I have about a zillion studies to read…). But this bit of news was too appealing to be ignored.
 
According to a new study reported by Reuters (http://tinyurl.com/4y2j5y), Writing about the experience of dealing with cancer may help boost some patients’ well-being. Hah! I knew there was an excellent reason for spending most of my day doing research, writing and blogging! I just knew it was healthful!

And read this: Expressive writing refers to writing about one’s deepest thoughts and feelings about life experiences. Studies have shown that the practice can benefit people with health conditions such as asthma, arthritis, pelvic pain and cancer. The benefits, in some studies, have included physical ones, like reduced pain and improved immune function, the researchers explain in the journal The Oncologist.

Improved immune function…!

The writing experiment was conducted in a cancer clinic waiting room: In a survey taken immediately afterward, half of the patients said that the writing experience had changed the way they thought about their disease. Three weeks later, slightly more — 54 percent — felt that way. Moreover, patients who reported such changes tended to score higher on a standard measure of quality of life than they did before the writing exercise.

And how long was this writing session? Twenty minutes. Ehhhh? That’s it??? That means that my quality of life should be even better than that of a groundhog living in a field of daisies! 

Hold on to your socks!

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In spite of the title, this is actually going to be a serious post. Remember my recent one on nanotechnology? Well, this is sort of a follow-up. I just finished reading a rather alarming April 7 Science Daily article (see: http://tinyurl.com/4s5zoh) on “toxic socks.” These are special socks permeated with nanoparticle silver, which has antibacterial and odour-fighting properties.
 
Problem is, if you buy these socks (or anything else containing nanosilver), you won’t be able to wash them. Ever! If you forget and throw them into the washing machine, tiny silver particles will probably be released into the waterwaste system and end up flowing into natural watercourses where they could have unwanted and deleterious effects on the organisms living in the water, and possibly, eventually, on us, too.
 
Two Arizona State University researchers brought the issue of nanosilver to our attention after conducting a recent experiment. They bought six pairs of no-smell socks, one from the UK (!), soaked them in a jar of room temperature distilled water, shook the contents for an hour and tested the water for two types of silver — the harmful "ionic" form and the less-studied nanoparticle variety. "From what we saw, different socks released silver at different rates, suggesting that there may be a manufacturing process that will keep the silver in the socks better," said Benn. "Some of the sock materials released all of the silver in the first few washings, others gradually released it. Some didn’t release any silver."
 
So if you wash these socks, possibly even large amounts of nanosilver will eventually end up in lakes and rivers. Ionic silver, the dissolved form of the element, does not just attack odor-causing bacteria. It can also hijack chemical processes essential for life in other microbes and aquatic animals. It can, for instance, kill fish by seeping into their gills, thereby disrupting their blood and tissue chemistries. And what happens to our gills and blood/tissue chemistries if we eat teenysilver-ridden fish? 
 
Oh boy, let me tell ya, I wouldn’t go near these socks, let alone touch them with my bare hands or put them on my feet! I will also never ever (never!) buy infection-fighting bandaids (oh yes, nanosilver is in those, too!). And, if you happen to be in the market for a new washing machine, avoid the ones that advertise “silvercare.”
 
After reading this piece, my advice is: let your socks smell a bit. It seems like a tiny price to pay compared to the potentially very negative environmental impact of the no-smell silver socks. Talk about nanoCRUD!

Omega-3 and angiogenesis

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The April 1 issue of “Blood” has an interesting study that examines the role played by n-3 polyunsaturated fatty acids (PUFAs, gotta love that acronym! Oh, "n" stands for omega, by the way) in angiogenesis, which, in just a few words, is a process whereby tumours develop a blood supply and are able to grow and live as happily as clams at high tide. So clearly one of our goals should be to block the blood ( = food) supply to tumours. As we have seen, a couple of simple ways we can do that is to take curcumin and drink coffee (probably not at the same time, though I haven’t tried doing that, I admit…).
 
The full study (abstract: http://tinyurl.com/2nvqnm), which I was able to read thanks to Sherlock tells us that n-3 PUFAs inhibit the formation of new blood vessels (angiogenesis), a critical process that affects tumor growth and dissemination. So we can now add n-3 to our list of angiogenesis inhibitors. Excellent.

But what about n-6 fatty acids? The abstract tells us that n-6 PUFAs stimulate angiogenesis.  Does that make n-6 one of the bad guys? That’s what I thought, at first. But no, we need both these fatty acids in order to be healthy, so eliminating n-6s from our diet would be a very VERY bad move.

What we lack is BALANCE between the two omegas. Read this: In terms of the consequences for human health, it has been shown that Japanese who migrated to the United States and acquired the local dietary habits leading to an increase in the dietary n-6/n-3 PUFA ratio of 16:1 resulted in health problems in the migrants similar to those that already existed in the local population. Sixteen to one! That’s astounding. Even more astounding: the ideal balance should be 1:1, at the most 4:1. But the average North American diet, and probably European by now, ranges from 11:1 to 30:1. Yikes!

According to Andrew Weil, M.D., This dietary imbalance may explain the rise of such diseases as asthma, coronary heart disease, many forms of cancer, autoimmunity and neurodegenerative diseases, all of which are believed to stem from inflammation in the body. The imbalance between omega-3 and omega-6 fatty acids may also contribute to obesity, depression, dyslexia, hyperactivity and even a tendency toward violence.(see: http://tinyurl.com/4s32fc; see also: http://tinyurl.com/565h8n).

Now, what happens when we ingest n-3s and n-6s? They get converted by so-called PUFA bioconversion enzymes. Otherwise, these fatty acids would not be of any use to us at all. The researchers state that their findings suggest that n-6 and n-3 PUFAs compete for enzymes involved in PUFA biotransformation. It is widely believed that PUFA bioconversion enzymes have a greater affinity for n-3 PUFAs so that their biotransformation is favored when the dietary n-3 PUFA intake is high. This simply means that the two omegas compete for the attention of these bioconversion enzymes, and n-3s happen to be the winners.

Hmmm, interesting little fact that I didn’t know: n-3 PUFAs inhibit NF-kappaB AND Bcl-2. Well, well. Another good reason to include them in our diet.

At any rate, our bodies are not able to produce these fatty acids from scratch, and in fact that is why they are called "essential" (essential for health, but cannot be made inside the body), so we need to get them from our food.

Dietary sources of n-3s: mainly cold water fish such as salmon, herring, anchovies, but be careful about the potential presence of heavy metals, PCBs and dioxin (!); also, but to a lesser degree, flax, pumpkin seeds, walnuts, pecans, butternuts, nut oils, as well as the seeds of: chia sage, kiwi, lingonberry, black raspberry. For more info: http://en.wikipedia.org/wiki/Omega_3. By the way, today I learned that mercury does not get stored in fish oil (only in the tissue). How about that? I also learned that some manufacturers are able to purify fish oil via molecular distillation, which increases the cost, but who wants to be swallowing dioxin or pesticides, after all? I would rather pay more for a high quality product. So, do your research, watch what you buy, and don’t go for el cheapo.

Fanatic Cook tells us that walnuts, soy and canola oil contain more n-6 than n-3. She has some excellent pages on n-3, including this one (http://tinyurl.com/22xd95), where she informs us that only a TINY part of n-3s from nuts and non-animal sources has anti-inflammatory effects. She explains why. N-3 has to be converted, and, as she notes, if you want to make sure you’re getting enough of the active forms of n-3, it’s best to eat an animal that has done the conversion for you. Interesting. Okay, I am beginning to see more fish in my future. We are lucky to get our fish from a small Tuscan fishing cooperative, so we can be sure that the fish is fresh and that no mass fish slaughters take place in the Tyrrhenian Sea. That’s always a consideration for my tender heart.

Dietary sources of n-6s: poultry, eggs, cereals, whole-grain breads, baked goods, most plant-based cooking oils (sunflower, corn etc.), nuts, borage oil. See also: http://en.wikipedia.org/wiki/Omega_6

In sum, have I reached any conclusions? Well, more research is needed, but I think I will switch from flaxseed oil to fish oil or, perhaps even better, krill oil. The diet of cold water fish consists mainly of krill (a step down the food chain, see image on the left), and the main advantage of swallowing krill oil is that it contains fewer pollutants; a disadvantage is that it has less n-3 compared to its predators. Oh well, we can’t have everything! 

Disappearing photos

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Hi everyone! My blog photos have disappeared. All of them. Swallowed up by cyberspace or by the vengeful Google Ads.  Gulp! I have gotten in touch with the Healthblogs manager, and am sure that order will be restored as soon as she reads the message (it’s still the middle of the night in the U.S., so she’s still asleep for sure). Anyway, no worries.

Yesterday I received more information concerning the DMAPT clinical trial. The UK trial is open only to UK citizens. Well, that takes care of that!

I now do know where the trial is going to be held, though: at the University of Cardiff, under Dr. Alan Burnett, Head of the Haematology Department. As of today, though, there is no information on the trial on the U. of Cardiff website. The waiting game continues.

I am working on a post, so off I go!

Cheeky!

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I didn’t mean to sound disrespectful in yesterday’s post, but this morning I reread it and felt I should post a sort of apology. My nanocrud comment was meant to be a bit tongue-in-cheek, that’s all. I do believe that nanotechnology is a promising approach. It just won’t be useful to us in the near future. Problems such as those pointed out by the UO chemist, as well as others that I have read about here and there, need to be resolved. It will probably take years…
 
As for the DMAPT trial, I admit to being a bit disappointed, but I understand why I must wait. Too bad, though, since I was rather looking forward to travelling to the UK and perhaps meeting a few of my close blog readers/friends, you know who you are!  Well, if Berlusconi wins the upcoming Italian elections, , Stefano, the cats and I may well move to Northumberland to live with the puffins. Or to the North Pole.
 
One more thing. Yesterday I noticed that a few Google ads had mysteriously materialized at the bottom of my blog. Have they always been there? I’d never noticed them before. Anyway, I would like to state that I have nothing to do with any of it. I have asked the Healthblogs manager to remove them, if possible, so I hope they will soon get blasted back into cyberspace, never to return.   
 
It’s a gorgeous sunny day in Florence, and I have errands to run, so I must be off. Ciao a tutti!

Nanocrud

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I confess to being a bit amused, I admit (apart from the rabbit business…see below). This morning I read a couple of Science Daily updates where I found two conflicting items. The first (http://tinyurl.com/5p4lzn), dated April 3, was about the potential risks involved in nanotechnology. It just so happens that yesterday I added a link to a study on nanocurcumin sent to me by a blog reader (thanks!). See under "useful links."

At any rate, the Science Daily article discusses a University of Oregon chemist’s concern about the potential hazards and lack of information concerning nanotechnology.

An excerpt ("he" is the UO chemist, by the way): Nanomaterials are complex, as are their interactions with biological organisms and the environment. While microscopically sized, they come in all sizes, shapes and compositions. "To confound the situation further," he writes, "the methods of production are still immature for most materials, often resulting in batch-to-batch variability in composition and purity." Impurities, he says, are hard to detect, difficult to extract and may obscure the real effects of nanomaterials. Nanoimpurities? Yikes!

Interestingly, this scientist is pushing for a green chemistry approach, which simplifies purification processes. Well, I am certainly all in favour of solving problems before they occur, and using an environmentally friendly approach makes a lot of sense to me.

Now for the second article. published on the following day (http://tinyurl.com/6qzpmv). It discusses the effect of nanotechnology on tumours. Unlike the University of Oregon piece, this article talks exclusively about the benefits of nanotechnology. As follows.

A group of researchers at the Washington University School of Medicine (St. Louis) tested a powerful drug directly on tumors  in rabbits (aaagh! ) using drug-coated nanoparticles. They found that a drug dose 1,000 times lower than used previously for this purpose markedly slowed tumor growth. "Many chemotherapeutic drugs have unwanted side effects, and we’ve shown that our nanoparticle technology has the potential to increase drug effectiveness and decrease drug dose to alleviate harmful side effects," says lead author Patrick M. Winter, Ph.D., research assistant professor of medicine and biomedical engineering.

By the way, these nanoparticles contained a fungal toxin called fumagillin, which has been shown to be an effective cancer treatment, so the article states, in human clinical trials in combination with other drugs. The process whereby the tumours’ growth was slowed down is interesting: the nanoparticles latched on to sites of blood vessel proliferation and released their fumagillin load into blood vessel cells. Fumagillin blocks multiplication of blood vessel cells, so it inhibited tumors from expanding their blood supply and slowed their growth.

Aha, so fumagillin inhibits angiogenesis…very interesting. I will have to have a closer look at this toxin at some point.

Well, nanotechnology is interesting on many levels, but I have to admit that the issue of nanocrud (I just coined this term, you may use it with my permission…) does make me wary. I guess I won’t be testing nanocurcumin any time soon…

DMAPT response

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Well, no DMAPT trial for yours truly. I received an answer just now and, in a nutshell, I was advised, given my current (good) clinical status, to wait and see how the initial trials work out. This could take a couple of years, I was told.

I would like to note that the reply I received was very straightforward. And very kind. Much appreciated.

I will certainly be following the trials carefully…and at least I tried.

DMAPT update

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This morning I received a Google Alert about DMAPT, which, as you may recall, is the parthenolide analogue (from feverfew, see image on the left) that targets leukemic stem cells and will be tested soon (I hope!) in clinical trials. For more info on this topic, see my parthenolide/DMAPT page on the right-hand of your screen.

The first clinical trial will begin in England. If successful, it will be followed by others in the States. Apparently, there have been some bureaucratic hurdles (such as regulatory approval), but patient selection in the UK may begin this month.

I want to see if I might qualify for this trial, so this morning I decided to write to the chief investigators to obtain more information, if possible.

I have already sent off one e-mail and will write another, more detailed one, later on today. I hope to be a frequent flyer to the UK soon! Fingers crossed!

Late morning update: I just sent a query to the senior author of the DMAPT "Blood" study. Now I just have to sit back and wait.

Stretch out with your peelings!

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It’s Friday, and I don’t feel like posting about anything too serious. But I did want to say something about BCM-95. A few blog readers have sent me messages about this supposedly more bioavailable form of curcumin. I would like to point out that BCM-95 is Biocurcumax, which is made by the Arjuna company located in India (you can check out its website). Sherlock and I tested Biocurcumax a couple of months ago, and our numbers, I am sorry to say, worsened. So it didn’t work for us. It may work for others, of course, and also for different ailments (arthritis and whatnot). But I am not going to risk taking it ever again.

My cousin (thanks!) sent me a very amusing link yesterday (well done!). It gives food for thought, not that we need any convincing in this particular field, I’m sure…! At any rate, even if you have never seen any of the Star Wars movies, please check it out: http://tinyurl.com/2gq3vh Besides, it is the only way today’s post title will make any sense . My favourites: “Chewbroccoli” ( = Chewbacca) and “Dark Tater" (guess who?).

May the Farm be with you!

P.S. If you haven’t yet seen the April Fools 2008 "amazing flying penguins" BBC video, here it is: http://tinyurl.com/29csjp (and yes, it’s a joke, but so well done! I have added it to my FUNNY/cute video links, which I will keep updating as I come across funny stuff; today I added a few more links, by the way).