Doing research for a recent post, as frequently happens, I came across an interesting abstract with some hard-to-believe news. My brilliant friend Sherlock (grazie!) kindly sent me the full study, published in the Journal of Biological Chemistry in June 2007. According to the abstract (http://tinyurl.com/3yqzc6), Administration of curcumin to tumor-bearing animals resulted in restoration of progenitor, effecter, and circulating T cells. Curcumin can reinstate our T cells at every stage of their development? No way! (Yes, way). Hmmm, the question arises: why should we care about T cells? Well, if we didn’t have any T cells, we would be like nude mice, yes, the sort used in lab experiments. We would have no way of fighting off disease. T cells, in a nutshell, are crucial players in our immune response to diseased cells.

Let’s take a look at the full study: In order to establish itself, a growing tumor must evade the immune system of the host. This contributes to tumor-induced immune suppression. A growing tumor can evade the proposed immune surveillance by several mechanisms. One of these mechanisms is to kill (induce apoptosis of!) our T cells. Reading on, we learn that Increased oxidative stress because of the growing tumor can be another cause of immune disruptions. Recently, several observations indicate that a chronic inflammatory condition develops in patients with advanced cancer, causing oxidative stress that can shut off immune functions, including those of T and NK cells. Oh, this is not good at all.

Before proceeding, let me just mention that I was confused enough about all these different types of cells that today I looked everything up, from A to Z. I am now in the midst of putting together a brief (!) explanation (?) of a very complex topic. For now, let it suffice that B, T and NK (natural killer) cells are three types of lymphocytes (white blood cells) that originate from hematopoietic stem cells (HSCs), located in the bone marrow. They have different functions, but we don’t need to get into the nitty gritty, yet. If you can’t wait for my explanation, then click on the fabulous link I provide below. Back to the study, now.

A tumour has a negative influence on the production of T cells in the thymus, which is a small organ, located behind the sternum, that produces T cells (the “T” stands for “thymus,” in fact). A tumour causes a massive depletion of both thymic and circulatory T cell populations. Massive depletion of T cells? Yikes. But there is GOOD news. The administration of curcumin brought back thymic CD4+8+, CD4+, and CD8+ cells as well as circulatory effecter CD4+ and CD8+ cells to control level. (CD4 and CD8 are the two main T cell subsets, by the way.) Curcumin brought these cells back to CONTROL level? Well, knock me down with a feather!

Ah, but it gets better. Curcumin protected T cells from being killed by the tumour. When preincubated with curcumin, these cells turned into Superduperfantastic cells, resistant to any tumour attack (sort of like Harry Potter versus Voldemort). In other words, they survived. Oh, sure, this is all happening in vitro. But the researchers experimented with mice, i.e., in vivo, too. Exact same results. They conclude that from aforementioned in vitro and in vivo results, it may be envisaged that curcumin might also protect T cells from a tumor-induced demise in humans. Hey, it’s not every day that I get excited about something called thymic CD4 plus! 😉

My next topic stumped me for hours, it seems, until I came across an absolutely brilliant website that opened up a whole new world for me: the world of relatively easy biology. Itsy bitsy thingies no longer have any secrets for me thanks to John Kimball, a retired biology professor who taught at Tufts and Harvard (I must remember to write him a glowing fan letter). The updated sixth edition of his biology textbook is online (free, too): http://tinyurl.com/57ygj So from now on, if you ever have a doubt about, say, the JAK-STAT pathway, this is the place to go. 😉 Seriously, though, thank you from the bottom of my heart, Prof. Kimball! Everything is crystal clear now. Well…more or less!

Here’s what stumped me: in the curcumin T cell study, I read that tumours downregulate the anti-apoptotic Bcl-2 protein (take my word for it, this is NOT a good thing). But that’s precisely what curcumin does: it downregulates Bcl-2 in myeloma cells. Wait, how could this be? Why is the downregulation of Bcl-2 bad for T cells, good for myeloma cells? Ah, you see, perhaps, had I written out the question, I wouldn’t have spent hours trying to figure it out!

It’s very simple, really. In the case of T cells, in fact, we WANT to have a high level of Bcl-2. In the case of myeloma cells, we don’t. Prof. Kimball’s page on Bcl-2 explains that B cells, like all activated lymphocytes, die a few days after they have had a chance to do their job. This ensures that they do not linger around after the threat has been dealt with and turn their attack against self components. Aging B cells kill themselves by apoptosis. But high levels of the Bcl-2 protein protect the cells from early death by apoptosis. After reading these four sentences, a light went on in my brain: we want T cells to LIVE, but myeloma cells to DIE. Therein lies the difference. Okay, so it took me hours, not minutes, to figure this out, but I am not a biologist, and I didn’t have this wonderful reference text at my fingertips until the latter part of the afternoon.

Well, we have yet another (!) good reason to take curcumin. I can feel my T cells getting more powerful by the second…!

My brain is fried, now, and I need to get off the computer, but will certainly take a second look at this study at some point over the weekend. I would like to end by pointing out that Mary has some good advice for us (see her most recent comment to my December 3rd post). Please go have a look!

The September 2007 issue of Molecular Cancer Research has a fascinating study, co-authored by Prof. Aggarwal, titled: “Ursolic Acid Inhibits STAT3 Activation Pathway Leading to Suppression of Proliferation and Chemosensitization of Human Multiple Myeloma Cells.” The abstract can be viewed here: http://tinyurl.com/2fkrxl As usual, thanks to my friends, I have read the full study. Ursolic acid can be found in rosemary, apples, bilberries, cranberries, pears, peppermint, lavender, oregano, holy basil, thyme and prunes. There are a ton of studies on the anti-cancer effects of this plant extract, but today I want to focus on this one in particular.

First, a word or two on STAT3. According to one of the main studies on myeloma and curcumin, published in 2003 in the Journal of Immunology (full text: http://tinyurl.com/397tow), STAT3, which stands for Signal Transducer and Activator of Transcription 3,” is a cell signalling protein and a prime anticancer target because it can protect cancer cells from apoptosis. Curcumin inhibits the activation of STAT3, quelle surprise. Another inhibitor of STAT3 is capsaicin (see my capsaicin Page on the right): Capsaicin down-regulated the expression of the STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, and vascular endothelial growth factor. I used to shun spicy hot foods, but since reading the studies on capsaicin, I have begun sprinkling spicy red pepper on my food. And now I really like it. Yesterday I made an organic vegetable and free-range chicken soup (Stefano has a cold, poor dear) with the usual ingredients (garlic, onions and vegetables of all sorts), to which I added a Southern Italian hot red pepper mamma mia!, together with a bit of every single herb we have in the garden and in the house (oh yes, turmeric, too!) and a big piece of ginger. Delicious!

Back to us. The ursolic acid study tells us that STAT family proteins have been shown to play an important role in tumor cell survival and proliferation, and in particular STAT3 is often constitutively active in many human cancer cells including multiple myeloma, leukemia, lymphoma, and solid tumors. It can be activated by IL-6 (interleukin-6), by the way. Without going into too much detail, what we want to do, clearly, is inhibit STAT3. One way is through DIET, that is, eating foods that contain ursolic acid. So much for my being told, back in 2005, that there was nothing I could do to stop the obvious (by then) progression from MGUS to MM. Drat. I wish I had known back then a fraction of what I know now. But, as the saying goes, better late than never/meglio tardi che mai! 🙂

The study tells us that Ursolic acid is a pentacyclic triterpenoid that has been shown to suppress the growth of various hematopoietic tumors, inhibit tumor promotion, and inhibit tumor angiogenesis. We have recently shown that ursolic acid is a potent inhibitor of nuclear factor-kB (NF-kB) activation pathway, which is activated by inflammatory agents, carcinogens, and tumor promoters. In this study, the researchers wanted to test their theory that ursolic acid suppresses the STAT3 pathway in myeloma cells. They were successful.

The following will be of interest in particular to those taking Velcade and Thalidomide: In our experiments, ursolic acid indeed suppressed both constitutive and inducible STAT3 activation. This inhibition decreased cell survival and down-regulated expression of proliferative and angiogenic gene products, leading to suppression of proliferation, induction of apoptosis, and enhancement ofthe response to the cytotoxic effects of thalidomide (an inhibitor of tumor necrosis factor expression) and bortezomib (a proteasome inhibitor; also called PS341) in multiple myeloma cells. Further on, we read that ursolic acid significantly enhanced the apoptotic effects of thalidomide from 20% to 70% and of bortezomib from 25% to 80%. Now, those are significant numbers, I’d say!

I cannot examine every single bit of information provided by the study, but for instance ursolic acid increased the expression of Bax and Bak proteins, which cause apoptosis in myeloma cells. Yeah! Also, similarly to capsaicin, ursolic acid suppresses the expression of several STAT3-regulated genes, including proliferative (cyclin D1) and antiapoptotic gene products (survivin, Bcl-2, Bcl-xL, and Mcl-1) and angiogenic gene product (VEGF). Super. At the end of the study we find a reference also to other cancers, including head and neck cancers, hepatocellular carcinoma, lymphomas, and leukemia. They, too, also have constitutively active STAT3. The suppression of constitutively active STAT3 in multiple myeloma cells raises the possibility that this novel STAT3 inhibitor might also inhibit constitutively activated STAT3 in other types of cancer cells.

This is excellent news. Stefano and I grow quite a variety of herbs in our garden, including at least four or five different types of thyme and two of rosemary. We even have an oregano plant. Herbs add taste to any dish, as we know…but using herbs in our cooking goes way beyond taste enhancement, now that we have discovered that ursolic acid inhibits a crucial myeloma survival pathway, inhibits the proliferation of myeloma cells AND induces apoptosis in the same…why, I believe it’s time for a little dance of joy…! And before it gets dark, I really must go outside to gather some rosemary for dinner tonight. 🙂 Ciao!

Hah, and you thought that perhaps I was DONE with baicalein, eh? Nope. Not by a long shot. I still have a few baicalein studies to read…Besides, at lunchtime TODAY I will start taking Scutellaria baicalensis, which contains a high percentage of baicalein and also a bit of wogonin. I will also start taking Zyflamend, which is a blend of various herbal extracts (see my page on Polyherbal Zyflamend). Of course, I will keep taking my curcumin-quercetin-cocoa mass-honey mixture at night, since I didn’t give it enough time to work before having blood tests done a couple of weeks ago (I should have my results by next week, by the way). We shall see what happens. Of course, my next set of tests may be influenced by the flu vaccine (which apparently can increase IgG levels for up to six months after administration!), so they may need a bit of interpretation.

Thanks to a friend (thanks you! 😉 ), I got my hands on a very interesting study that I looked at more carefully this morning, even though I really SHOULD BE preparing my English classes for tomorrow, sigh. Published in the November 2007 issue of Clinical and Molecular Allergy, the study is titled: Baicalein inhibits IL-1b- and TNF-a-induced inflammatory cytokine production from human mast cells via regulation of the NF-kB pathway. Let’s quickly examine the title. IL-1beta is an inflammatory cytokine that is a potent inducer of the important myeloma growth factor, IL-6. (see these two Mayo Clinic study abstracts from 2006 and 2007, respectively: http://tinyurl.com/2hu4am and http://tinyurl.com/27ffa4). Anything that induces IL-6 is no friend of mine! I am almost certain that I have already written about TNF-alpha, or tumour necrosis factor-alpha, but just in case I haven’t, here goes: it is a growth and SURVIVAL factor for myeloma cells, albeit not as powerful as IL-6. So, also not good news for us.

A few remarks on human mast cells. As the abstract (see: http://tinyurl.com/24f2ge) informs us, these are multifunctional cells capable of a wide variety of inflammatory responses. According to the full study, these cells accumulate wherever there is an inflammatory process going on and even mediate the production of inflammatory cytokines. Now, that’s really no good, no good at all, especially since Inflammatory cytokines are important factors in chronic inflammation, allergy, asthma, atherogenesis, and autoimmune diseases. Reading on, we are told that mast cells have been implicated in acute and chronic inflammatory responses and in many diseases characterized by inflammation. Oh, and read this: activated mast cells secrete IL-6! Tsk, tsk. Bad BAD mast cells!

Another interesting bit: The activation of NF-kB requires phosphorylation and proteolytic degradation of the inhibitory protein IkBa. This sentence takes us back to the discussion section of the 2005 Blood study on baicalein and myeloma (full text: http://tinyurl.com/2jnlej). I quote: NF-kB regulates the expression of many genes (IkB-a, Bcl-xL, IL-6, and cyclin D1) important for the proliferation and survival of myeloma cells.

Well, on page 16, the November 2007 study states: The results suggest BAI inhibits the NF-kB activation via inhibition of IkBa phosphorylation and degradation. BAI, by the way, stands for baicalein.

Hmmm, how about THAT? So, is it lunchtime yet? 😉

I am doing the groundwork for my Scutellaria baicalensis experiment, which has brought me to view a few new studies, such as one published in the November 2007 issue of “Molecular Cancer Therapeutics,” see abstract: http://tinyurl.com/266g6y (many thanks to a new friend for sending me the full study AND also to my friend Sherlock for trying to locate it).

Here’s a quick review taken from this study (you can also see my Page on Scutellaria baicalensis). Baicalein, extracted from the root of Scutellaria baicalensis, is an active flavonoid that has been found to have anticancer properties, leading “to cell cycle arrest and suppression of proliferation in cancer cells. And yes, in case you were wondering, that includes myeloma cells in vitro only, thus far. Hence, my upcoming experiment…on myself.

Baicalein (just like curcumin, let me add: see my link to the article on curcumin and survivin, right-hand side of my homepage) reduces the expression of survivin, a protein that inhibits apoptosis in cancer cells, including myeloma cells. If you need convincing that survivin (not to be confused with the adjective “SURVIVING,” by the way!) has relevance for myeloma, take a look at this February 2007 Leukemia abstract: http://tinyurl.com/2s9xon My comment: survivin may be fascinating, but, according to the above-mentioned Molecular Cancer Therapeutics study, it is associated with decreased survival, unfavorable prognosis, and accelerated rates of recurrences in cancer therapy. Nothing “fascinating” about that, methinks…

Anyway, the Molecular Cancer Therapeutics study suggests that the inhibition of CDC2/cyclin B1 by baicalein contributes to the reduction of survivin and the proliferation inhibition in cancer cells. CDC2 is a kinase also present in myeloma…hmmm. Six flavonoids, baicalin, catechin, genistein, quercetin and rutin, in addition to baicalein, were examined by these researchers. The most toxic to bladder cancer cells was found to be baicalein, which was, and, this is significant!, NOT toxic to healthy cells. Does that sound familiar?

I have read the same thing over and over again: Toxic to cancer cells, Not Toxic to healthy cells! Okay, so where ARE the clinical trials!?! Well, quelle coincidence (!), since I wrote my May 31st post on Scutellaria baicalensis, two more clinical trials testing Scutellaria-derived substances have been added to the one I mentioned. One is testing an aqueous extract from herba Scutellaria Barbata D. Don on metastatic breast cancer patients; the other is testing a botanic formulation called PHY906, consisting of: Scutellariae baicalensis Georgi, white peony root, licorice, and the fruit of Fructus ziziphi (date). According to the patent application (see: http://tinyurl.com/28sfez), This specific formulation was established more than 1500 years ago for the treatment of diarrhea, abdominal spasms, fever, headache, vomiting, nausea, extreme thirst, and subcardial distention,” and “each herb possesses a distinct pharmacological profile that includes anticancer and antiviral activity, hematological and immunological stimulation, analgesic activity, vasodilation, liver protection, antioxidation, and appetite improvement. PHY906 is being tested together with a chemo drug on advanced pancreatic cancer patients. Well, three trials are better than just one, I suppose. If you want to read more about these trials, just go to http://tinyurl.com/28gasl

Speaking of clinical trials, according to the Molecular Cancer Therapeutics study, Although this study provides the potential cancer therapy of baicalein by human cancerous cells in vitro, the human cancer therapeutics by baicalein or combination of the survivin gene knockdown need to be determined by in vivo model before clinical trials. Moreover, the possible pharmacokinetic and toxicologic barriers need further characterization. Very true, but let me point out that Scutellaria baicalensis has been used as an anti-inflammatory remedy in traditional Chinese medicine for more than 2000 years to treat fevers, hypertension, coughing, and other ailments, according to Drugs dot com (see: http://tinyurl.com/2d5fvj). This brings me to my warnings section.

Warnings: according to the Memorial Sloan-Kettering website, Scutellaria baicalensis MAY cause stupor, confusion, and seizures. Am I worried about that? Naaaah, not in the slightest. In the past, I have taken HUGE doses of antibiotics, even recently (now that I think about it), and if you paid any attention to the list of possible side effects associated with half the stuff you take for common ailments, you wouldn’t let it come within a few meters of you, let alone swallow it (or, worse, have your mother-in-law inject it into your hip, as happened to me earlier this fall when I was forced to take elephant-doses of antibiotics for a case of acute bronchitis…). The only other big warning about Scutellaria is that it may interact with cyclosporine, a drug that suppresses the immune system. And then there are the usual pregnancy or breastfeeding warnings, which don’t apply to my case anyway.

Final note: I would like to take this opportunity to thank the two people who have been sending me the full studies that give more “flesh” to my blog posts. One is my beloved Italian friend Sherlock, the other lives and works in the U.S. Thanks to them, I now have the FULL studies of the abstracts that I quoted in my first baicalein post. And much much more! Thank you so very very very much, both of you. Now, I just have to find the time to read all this stuff…eh!!!

One of my blog readers (thank you!) sent me this story, which gave me quite a few chuckles. Before telling the story, though, I just wanted to reassure all of Peekaboo’s many fans that she is doing just fine, scampering about, terrorizing the other cats…in sum, she’s as mischievous as ever! Ok, here goes:

The following concerns a question in a physics degree exam at the University of Copenhagen: “Describe how to determine the height of a skyscraper with a barometer.”

One student replied: “You tie a long piece of string to the neck of the barometer, then lower the barometer from the roof of the skyscraper to the ground. The length of the string plus the length of the barometer will equal the height of the building.”

This highly original answer so incensed the examiner that the student was failed immediately. He appealed on the grounds that his answer was indisputably correct, and the university appointed an independent arbiter to decide the case. The arbiter judged that the answer was indeed correct, but did not display any noticeable knowledge of physics. To resolve the problem, it was decided to call the student in and allow him six minutes in which to provide a verbal answer which showed at least a minimal familiarity with the basic principles of physics. For five minutes the student sat in silence, forehead creased in thought. The arbiter reminded him that time was running out, to which the student replied that he had several extremely relevant answers, but couldn’t make up his mind which to use. On being advised to hurry up the student replied as follows:

“Firstly, you could take the barometer up to the roof of the skyscraper, drop it over the edge, and measure the time it takes to reach the ground. The height of the building can then be worked out from the formula H =0.5g x t squared. But bad luck on the barometer.”

“Or if the sun is shining you could measure the height of the barometer, then set it on end and measure the length of its shadow. Then you measure the length of the skyscraper’s shadow, and thereafter it is a simple matter of proportional arithmetic to work out the height of the skyscraper.”

“But if you wanted to be highly scientific about it, you could tie a short piece of string to the barometer and swing it like a pendulum, first at ground level and then on the roof of the skyscraper. The height is worked out by the difference in the gravitational restoring force T = 2 pi square root (l / g).”

“Or if the skyscraper has an outside emergency staircase, it would be easier to walk up it and mark off the height of the skyscraper in barometer lengths, then add them up.”

“If you merely wanted to be boring and orthodox about it, of course, you could use the barometer to measure the air pressure on the roof of the skyscraper and on the ground, and convert the difference in millibars into feet to give the height of the building.”

“But since we are constantly being exhorted to exercise independence of mind and apply scientific methods, undoubtedly the best way would be to knock on the janitor’s door and say to him ‘If you would like a nice new barometer, I will give you this one if you tell me the height of this skyscraper’.”

The student was Nils Bohr, the only Dane to win the Nobel prize for Physics. 🙂

Siede la terra dove nata fui
su la marina dove ‘l Po discende
per aver pace co’ seguaci sui.
Amor, ch’al cor gentil ratto s’apprende
prese costui de la bella persona
che mi fu tolta; e ‘l modo ancor m’offende.
Amor, ch’a nullo amato amar perdona,
mi prese del costui piacer sì forte,
che, come vedi, ancor non m’abbandona.
Amor condusse noi ad una morte:
Caina attende chi a vita ci spense.

Totally off-topic today. Sometimes we need that. Or I do, at least! 😉

A while ago I read online that Roberto Benigni, an Italian actor and film director, is the equivalent of a double shot of espresso coffee. I agree. Some of you may remember him excitedly jumping onto the backs of seats during the 1999 Academy Award ceremony after his La vita è bella, or Life is beautiful won three Oscars. Deservedly so, in my opinion.

Anyway, I am writing about Benigni because yesterday evening he put on an extraordinary one-man show on TV (Rai Uno, one of the Italian state channels). Absolutely brilliant. After a bit of contemporary political satire, Benigni, using his unique expressive communication style, launched into a passionate and eloquent explanation of the Divine Comedy’s 5th Canto. For two and a half hours, he barely stopped to take a breath. Fantastico. I was glued to the screen. Verse by verse, at times word by word, Benigni described every detail of this famous Canto, which centers on the tragic story of two lovers, Paolo Malatesta and Francesca da Rimini. He put into plain language the most intricate and difficult passages and concepts, at times drawing on current Italian social and political events to make his point more clearly. Keep in mind that Dante Alighieri wrote the Divine Comedy in vernacular Italian at the beginning of the 14th century, so this wasn’t as easy as it sounds.

I would like to note that I went through the Italian public school system (yep, I am one of those odd bilingual creatures), where I studied Dante’s Divine Comedy. I also examined each and every verse while doing research for my Ph.D. thesis (don’t ask! 😉 ). My interest, however, has always been superficial…related to schoolwork. But yesterday evening Benigni infected me with his fervour. I want to reread the Divine Comedy.

Benigni ended his performance by reciting the entire 5th Canto from memory. Now, I am no lover of poetry, but this final part brought tears to my eyes. Benigni’s declamation came from the gut, it had feeling, it had passion. Last year, for his interpretation of Dante, Benigni was nominated for the Nobel prize in literature. He didn’t win, but in my opinion, he should have. Grazie, Roberto!

Peekaboo came home yesterday and is doing well. I went to pick her up at the vet’s at 5 PM. I had to keep her separated from the other cats until this morning so I put her in my parents’ room. She was not very steady on her feet and kept bumping into things (the litter box, the furniture ). I stayed with her until Stefano got home, then we took turns eating dinner so that one of us could be with her (we tried to leave her alone, but she howled). I know, only big-time cat lovers will understand this! 🙂 I spent the night in my parents’ room with Peekaboo, and Stefano slept with the other cats in our room. We have so rarely slept apart in all the years we have been together so, yes, last night was very odd. Anyway, Peekaboo was very happy to be home, nestled in my lap all evening, purring like mad and batting her blue eyes at me. She even did something she has never done before: she kneaded my legs. Cutie pie. This morning she isn’t jumping around like she normally does, but she seems just fine. A bit subdued, that’s all. To be expected.

I have a ton of things to post about, lots of news, but new things keep popping up in my e-mail box just as I think I have finished doing all my research and writing. Aaargh! So I have more reading to do today. In the meantime, I will post about a new clinical trial: http://tinyurl.com/2ap4k8 Yesterday the Geron Corporation announced that it has enrolled the first myeloma patient in its GRN163L clinical trial. GRN163L is a novel inhibitor of telomerase, an enzyme that is expressed in all major types of cancer cells. This enzyme is essential for malignant cell growth and is absent or expressed transiently at low levels in most normal adult tissues. The most interesting aspect of this trial, however, as a MMA list member pointed out yesterday, is that GRN163L has been shown to target cancer STEM cells. Just like DMAPT (from parthenolide or feverfew). Now, if we can get rid of cancer stem cells, the ones that are resistant to conventional treatments and that cause cancer (myeloma, too, of course) to recur well, let’s just digest the implications of THAT statement…! 🙂

Today another MMA list member posted about a study in this month’s issue of “Blood” discussing how the Notch signaling pathway, a new one to me!, protects myeloma cells from apoptosis (death). You can read the abstract here: http://tinyurl.com/ysv9gg Well, I immediately, as usual!, googled Notch signaling and curcumin, and to my surprise (I wonder WHY I am still surprised…!), I found that, yes, apparently curcumin inhibits this signaling pathway (important, by the way, for cell to cell communication), see this 2006 abstract on pancreatic cancer cells in vitro: http://tinyurl.com/2cjgpr See also this December 2007 abstract on leukaemic cells: http://tinyurl.com/2hp5z2 I don’t have time to do more research on Notch and curcumin today (busy in other fields…), but it’s always good to come across another good reason to be taking the orange powder! Yeah!

Tomorrow I am taking Peekaboo to the vet to be spayed. I hate to put her through the trauma, but there is no help for it. So I am a bit distracted, well, even a bit distraught, right now. I know that this is for her own good, and the others are spayed/neutered, too, but I just want it to be all over, and have her back safe and sound with me. I took a few photos of her sweet trusting little face earlier this afternoon, as though she will look at me differently from now on, with mistrust or even hatred! I know, I know, I am being silly. But it was an excuse to take lots of photos. This one is my favourite.

Change of subject. Today, as I was driving home from work, I thought about how much I have come to love my students. They are sooo entertaining. In fact, I am beginning to suspect that at least a couple of them must have attended drama school at some point in the past. Their funny nonverbal communication skills include comical faces, animated gesticulation, rapid speech (usually in Italian, as much as I try to forbid it!)…in short, everything you would expect from the stereotypical image of an excited Italian. And more! When one of my students makes a mistake, she rolls her eyes and flails her arms about, finally throwing her head down on the table (with an audible bonk!). Another screws up her face in pretend agony, then bursts into peals of infectious laughter. I should really start taking notes (or making videos!) for my upcoming bestselling book titled “Laughing English.” 😉

I thought that my intermediate English students would be happy today at the news that I wanted to tell them a joke (mostly in the past tense, which is what we are studying at the moment) instead of doing grammar. A joke versus grammar? Where’s the competition? But, oh no, they began protesting loudly that they couldn’t understand jokes even in Italian (yeah, likely story!). Silly beans! I mean, I had to CONVINCE them to listen to the joke! In the end, they did understand it (one of my blog jokes, actually), including the irregular forms of the past tense, AND they liked it. 🙂 Yes, it was a fun lesson. We all enjoyed it.

Last but certainly NOT least, Stefano got some excellent news today regarding his job. YIPPEEEEEE!!! I can’t wait for him to get home and tell me all the details. Fidget fidget…fidget! We have some celebrating to do later this evening. Oh, if only I weren’t taking my baby to the vet tomorrow morning…!!! 🙁

As promised, here is the chapter on glucuronidation. 😉 First, what IS it? According to Wikipedia, Glucuronidation, the conversion of chemical compounds to glucuronides, is a method that organisms use to assist in the excretion of substances that cannot be used as an energy source. Glucuronic acid is attached via a glycosidic bond with the substance, and the resulting glucuronide, which has a much higher water solubility than the original substance, is eventually excreted by the kidneys. So glucuronidation is used by the body usually to get rid of toxic substances.

What happens once we have swallowed curcumin? A blog reader has already explained this process to us, but let’s have a look at what the MD Anderson researchers write: Once absorbed, curcumin is subjected to conjugations like sulfation and glucuronidation at various tissue sites. They discuss a study published in Life Sciences in 2000 (abstract: http://tinyurl.com/3ybfhm): in rats, it would appear that orally administered curcumin is absorbed from the alimentary tract and present in the general blood circulation after largely being metabolized to the form of glucuronide/sulfate conjugates. Curcumin sulfate and curcumin glucuronide were identified in the colorectal tissue of colorectal cancer patients who ingested curcumin capsules. Metabolites, by the way, are substances produced during digestion. Okay, so once ingested, curcumin is transformed into these metabolites. But are these substances completely useless as far as cancer patients are concerned?

On page 7 we read the following: Whether curcumin metabolites are as active as curcumin itself is, unfortunately, not clear. While most studies indicate that curcumin glucuronides and THC are less active than curcumin itself, there are other studies which suggest that they may actually be more active than curcumin. THC is tetrahydrocurcumin, one of the major metabolites of curcumin. The section on curcumin metabolites concludes: “The lack of availability of curcumin glucuronides and related compounds contributes to a continued lack of clear understanding of the relative pharmacologic activities of observed curucmin metabolites.” So we don’t have a clear answer. Yet.

Are there ways of addressing all of the problems dealing with poor absorption, rapid metabolism and elimination? Sure there are! The MD Anderson team suggests that Nanoparticles, liposomes, micelles, and phospholipid complexes are other promising novel formulations, which appear to provide longer circulation, better permeability, and resistance to metabolic processes. So, no doldrums! (I like that word…)

The researchers examine studies on piperine, a known inhibitor of hepatic and intestinal glucuronidation. According to a 1998 study published in Planta Medica (abstract: http://tinyurl.com/2eb84u), in humans receiving a dose of 2 g curcumin alone, serum levels were either undetectable or very low. Concomitant administration of piperine, however, produced 2000% increase in bioavailability. Conclusion: The glucuronidation inhibiting effect of piperine and the established lesser activity of curcumin glucorinides will indicate that inhibition of glucuronidation by piperine may be the major mechanism by which it increases the bioavailability of curcumin.

Quercetin is also mentioned. Yippeeeee! (I am already taking it, you see 😉 ). In a clinical study published in 2006, five familial adenomatous polyposis (FAP) patients with prior colectomy received curcumin (480 mg) and quercetin (20 mg) orally three times a day. The polyps decreased in number and size (60.4% and 50.9%, respectively) after approximately six months. See full study: http://tinyurl.com/3b46wd

Okay, all of this may sound discouraging, but it really isn’t, in my view. Of course, it’s also true that I don’t get discouraged easily! 😉 Seriously, though, in my opinion there are ways we can make curcumin more bioavailable. Some methods may work better for some of us, but the important thing is that those methods EXIST. On this topic…have a look at what this 2005 Clinical Cancer Research study (full study: http://tinyurl.com/2cugub) on head and neck squamous cell carcinoma (HNSCC) has to report: In the nude mice studies, we compared two different methods of delivery of curcumin: intratumoral injection and topical application of the curcumin paste onto the tumor. To our knowledge, we are the first to attempt in vivo studies using curcumin paste in nude mice. Use of this method of delivery could overcome the problem of low bioavailability encountered in studies of oral curcumin in colorectal and other cancers in mice and in humans. Now, ok, this method wouldn’t work with myeloma (but couldn’t curcumin be injected right into plasmacytomas?), but it sounds promising for solid tumour cancers and of course skin cancer. As you know, I have tested a few bioavailability methods on myself: some worked, some didn’t, and I am awaiting the results from my most recent tests so the jury is still out on my most recent experiment. A few days ago, though, Stefano suggested that I quit experimenting and start focusing instead on the methods that have already worked for me. He’s right. Besides, if my IgG level goes up anymore, I will have to adopt Don’s kitchen sink approach!

There is more food for thought in the MD Anderson study, but I need a change, so I will work on something different now. Speaking of working, drat, I still have to prepare my classes for tomorrow! YIKES! Ciao!

In my November 22nd post, I mentioned a newly published MD Anderson study, co-authored by Prof. Aggarwal (abstract: http://tinyurl.com/35w4mn). Thanks to Sherlock (grazie mille!), I was able to read the full study, which I have read but must read again, as it is filled with so many significant details etc. My original post turned out to be too long, so I will divide it into chapters, at least two.

Titled Bioavailability of Curcumin: Problems and Promises, the study was published in the November 14th issue of Molecular Pharmaceutics. It begins with an overview of curcumin, which, as we know by now, has been shown to exhibit antioxidant, anti-inflammatory, antimicrobial, and anticarcinogenic activities. Additionally, the hepato- and nephro-protective, thrombosis supressing, myocardial infarction protective, hypoglycemic, and antirheumatic effects of curcumin are also well established. Even at high doses, up to 12 grams a day, curcumin is well tolerated. I know I have written all this before, but I think it’s good to go over known information sometimes.

Curcumin’s main problem, as we (again!) know, is bioavailability: studies over the past three decades related to absorption, distribution, metabolism and excretion of curcumin have revealed poor absorption and rapid metabolism of curcumin that severely curtails its bioavailability. The serum levels of curcumin are extremely low. Let us keep in mind, though, that the UK Phase I Clinical Trial of Oral Curcumin (full study: http://tinyurl.com/32kwok), which tested regular curcumin (C3 Complex without bioperine) on patients with advanced colorectal cancer, ends with the following statement: The findings of the study presented here lead us to conclude that the systemic pharmacological properties of a daily dose of 3.6 g of curcumin are suitable for its evaluation in the prevention of malignancies at sites other than the gastrointestinal tract. 3.6 grams. Very little, compared to the 8 grams that I am taking. This Phase I clinical trial in fact showed that consumption of 3.6 g of curcumin daily generates detectable levels of parent compound and conjugates in plasma and urine, where the parent compound was curcumin, of course. The study contains headache-causing (for a non-scientific brain!) amounts of details, but, unless I am much mistaken, a few are lacking, which I would be curious to know, for instance: 1. what time of day was curcumin taken by the patients and 2. did they take it on a full or empty stomach?

Speaking of time of day, as I was reading through the description of all the studies cited by the MD Anderson team, a BIG question popped into my head. Relevant or not, here it is. Remember my November 11th post on circadian rhythms, in particular the part about human versus rat testing? Well, here’s a memory refresher: Despite this evidence of variation, drug research is almost always done during daylight hours, when the humans leading the studies are awake and alert. And in the animal testing stage, it’s almost always done with mice and rats, which are nocturnal €”the middle of our day is the middle of their night. This can lead to gross misestimations of the effectiveness and toxicity of a drug intended for humans. My question: could circadian rhythms possibly affect the curcumin testing being conducted on mice and rats? And what about the curcumin testing on humans? What if these tests were conducted at different times of the day and night? Would there be differences in the results? My feeling is that there would be. Take a look at this sentence in the MD Anderson study: the serum levels of curcumin in rats and in human are not directly comparable. Hmmm. Well, okay, that makes sense on all sorts of levels, of course, even though I enjoy a bite of cheese probably as much as a mouse does 😉 , BUT could this divergence also be due, at least in part, to daylight testing on nocturnal animals? Another point. We don’t know what time of day or under what circumstances the human subjects in these trials took their dose of curcumin. And, for instance, we are informed that some folks developed diarrhea but others didn’t. Did both groups take curcumin at the same time? All this information would indeed be interesting to have. Okay, I realize that I’m in over my head here, and that my suspicions may turn out to be irrelevant rubbish. I must read the MD Anderson study again, and look up all the studies, one by one (yeah, that’s likely to happen… 😉 ). Ok, enough about circadian rhythms.

The MD Anderson researchers point out that the issue of curcumin levels found in body tissues has been relatively ignored. Interesting, I thought. One of the few studies dealing with body tissues dates to 1980 (abstract: http://tinyurl.com/3a93ko). I quote from the MD Anderson study: after oral administration of 400 mg of curcumin to rats only traces of unchanged drug were found in the liver and kidney. At 30 min, 90% of curcumin was found in the stomach and small intestine, but only 1% was present at 24 h. The team points out also that Although many curcumin analogues are found to show improved biological activity over curcumin, specific evaluations of structural analogues and/or derivatives of curcumin to show improved tissue and plasma distribution are lacking. More studies are needed!

There is lots more, including mentions of substances we can take to enhance the bioavailability of curcumin and novel bioavailability methods, some of which I have mentioned in previous posts. But this post is getting to be too long, so I will stop here for now. In chapter two, I will discuss glucuronidation! 😉