"Mmm, tar."

…Wait a minute, people still smoke cigarettes?

Okay, okay, I’m not that naive — about 1 in 5 adults in the U.S. smokes cigarettes, despite those awesome Truth commercials and the fairly common knowledge that smoking leads to cancer, heart disease, lung disease, and tons of other health problems that no one wants.

Well, cigarette smokers everywhere have just been handed their gazillionth reason not to smoke – because it apparently makes your body want cocaine. More specifically, research published today says that the nicotine in cigarettes can make long-term changes in your genetics that will make you more likely to become a coke addict.

Gateway drug, indeed.

Sucks to be a research mouse.

So, how did scientists figure this one out? In keeping with the harsh realities of disease research, it involved doing some messed up things to mice. Researchers in China gave nicotine to mice, and a week later gave them cocaine. The result was that, compared to mice who had cocaine only, the mice who had nicotine beforehand showed 98% more physical activity and a 78% increased probability of going back to the place where they got the cocaine. (No such effect was seen if the order of drugs was reversed, i.e., cocaine given a week before nicotine.)

To explain the biology of why nicotine made the mice more susceptible to cocaine’s effects, I need to briefly talk about epigenetics, which is the process by which the expression of your genes can be changed in a long-lasting way. As it turns out, our DNA isn’t just floating around in that cool twisted-ladder shape that you see on Wikipedia. It’s actually packaged in a really neat way:

In this crude diagram made on the fly using Paint, you’ll see the classic Biology 101 chromosome. This is a very high-level packaging of DNA; if you zoom in on this chromosome, there is a spaghetti-like configuration of DNA that’s still pretty compact. Zoom in further and there are “beads on a string,” which is DNA wrapping itself around these proteins called histones, and histones actually make all this packaging possible. Finally, zoom in one more time and you’ve got the double helix we all know and love.

All of this is to help make the point that nicotine loosens up the DNA that’s wrapped around the histones. When DNA is less tightly wrapped around histones, the genes in that bit of DNA can be expressed more easily. In the case of nicotine use, one of those genes with increased expression appears to be FosB, a gene that is often associated with drug addiction and whose levels have been shown to increase with each dose of cocaine.

Short version of this post

This work definitely raises interesting questions: Since epigenetic changes to DNA are potentially heritable, are these finding relevant to the offspring of smokers (or babies exposed to nicotine in utero)? Should campaigns against nicotine be even more aggressive, given this new damning evidence for nicotine-induced susceptibility to a bigger and badder drug? Do other substances, like alcohol and marijuana, induce any sort of “gateway drug” effect similar to the one shown here for nicotine?

Time (and more research) will tell. In the mean time, Try Nerdy only needs 8 more Facebook “likes” to become an official page! How awesome would that be???

Stay nerdy.

Levine, A., Huang, Y., Drisaldi, B., Griffin, E., Pollak, D., Xu, S., Yin, D., Schaffran, C., Kandel, D., & Kandel, E. (2011). Molecular Mechanism for a Gateway Drug: Epigenetic Changes Initiated by Nicotine Prime Gene Expression by Cocaine Science Translational Medicine, 3 (107), 107-107 DOI: 10.1126/scitranslmed.3003062

If you’re in good enough shape to read this post then I’m sure you’re just fine, but…well, it’s worth a look to see what the latest research says about all that refined sugar and/or alcohol you just consumed.

1. You might not remember stuff. You would think that this is because of the alcohol, but actually, this one’s about the candy. New research in Behavioral Neuroscience shows that when people are on a high fat and refined sugar diet, they have significantly impaired hippocampal memory. This means that the people in the study had trouble forming new memories about their experiences…like what they had even eaten. Depending on how many Skittles you’ve been popping, there’s a chance you might not recall as much as you would have if you’d opted for tricks instead of treats.

2. You might have ended up in the hospital. I don’t mean from alcohol poisoning, although that’s certainly the case for some, but I’m referring to alcohol-related injuries. A recent data analysis exercise estimates that a whopping 21% of hospitalized injuries are attributable to alcohol. A heavy drinker with alcohol in his/her system is anywhere between 4 and 7 times as likely to end up in the hospital with an injury when compared to someone who hasn’t hit the bottle. “But I’m not a heavy drinker!” you say. Turns out, moderate drinkers suffer more injuries per hour with alcohol in their systems than heavy drinkers do, and the occasional binge definitely raises hospital injury risk.

3. You might have had a fight with your significant other. A study in New Zealand found that alcohol was involved in more than 25% of altercations between intimate partners. Women were more likely to report anger, fear, and severity of aggression while feeling victimized, and the perceived severity was significantly greater if the male partner had been drinking. However, men and women claimed approximately equal rates of being the victim or the perpetrator of the aggression. You see, when alcohol’s involved in lovers’ spats, nobody wins.

4. You might have kick-started your heart disease. I hate to scare you, but a science journal called Atherosclerosis probably knows what it’s talking about. Researchers in New York took mice and divided them into three groups: group 1 had two drinks per day, seven days a week (“daily-moderate” drinkers; blood alcohol content 0.07%); group 2 had seven drinks per day, two days a week (“weekend-binge” drinkers; blood alcohol content 0.23%); group 3 had no alcohol (same number of calories, though). While good and bad cholesterol levels rose in both drinking groups, bad cholesterol went up significantly more in the binge-drinking mice. And although the researchers induced atherosclerosis (clogging of the arteries of the heart) in all groups, the moderate-drinking mice actually had smaller atherosclerotic plaques than the no alcohol group; plaque volume was significantly greater in the weekend-binging mice.

Don’t kill the messenger, folks! But do be safe the next time you’re out having your candy- and alcohol-fueled party nights. Your memory/uninjured body/significant other/arteries will thank you.

Stay nerdy! And look way over to the right hand side of the site – you can like us on Facebook, follow us on Twitter, and subscribe to our RSS. Everybody wins!

Francis HM, & Stevenson RJ (2011). Higher reported saturated fat and refined sugar intake is associated with reduced hippocampal-dependent memory and sensitivity to interoceptive signals. Behavioral neuroscience PMID: 22023100

Miller TR, & Spicer RS (2011). Hospital-Admitted Injury Attributable to Alcohol. Alcoholism, clinical and experimental research PMID: 22004026

Connor JL, Kypri K, Bell ML, & Cousins K (2011). Alcohol involvement in aggression between intimate partners in New Zealand: a national cross-sectional study. BMJ open, 1 (1) PMID: 22021745

Liu W, Redmond EM, Morrow D, & Cullen JP (2011). Differential effects of daily-moderate versus weekend-binge alcohol consumption on atherosclerotic plaque development in mice. Atherosclerosis PMID: 21930274

The very recent publication of a draft of the Cannabis sativa genome has inspired me to briefly review why it’s so hard to do research on weed, and to highlight studies that have shown the benefits that can come from considering marijuana as more than just an abused substance.

Some would say our brains were made for marijuana, or vice versa, because of the abundant cannabinoid receptors that are directly activated by the primary psychoactive chemical in marijuana — a cannabinoid called delta-9-tetrahydrocannabinol (THC). The human body even produces its own endocannabinoids, which activate the same cannabinoid receptors. These receptors are known to have a role in everything from pain sensation to mood to appetite, and more, with some functions perhaps yet to be discovered.

 But about that medical research: much of what’s difficult in drug trials is establishing how toxic the test drug is and what its side effects are. Well, I think it’s generally accepted that there’s no documented human fatality from THC overdose, and as for side effects…well, just watch any one of the myriad “stoner movies” out there (e.g. 1, 2, 3, 4, 5, 6, 7, and 8). Many of the side effects are known quite well.

So what’s the big deal? Well, it all comes down to the fact that the Drug Enforcement Agency (DEA) classifies marijuana as a Schedule 1 drug, where it joins such baddies as heroin, LSD, and ecstasy. Schedule 1 drugs are defined as those that “have no currently accepted medical use in treatment in the United States.” The fact that marijuana is listed among these drugs can be perplexing, what with medical marijuana being legal in at least 16 states and our nation’s capitol.

"No medical use"? Let science decide.

So let’s say you’re a medical researcher, and you want to study the efficacy of marijuana in treating disease X; here are the three hurdles you have to jump: 1) applying for and receiving a license from the DEA, who fears Schedule 1 drugs getting into the wrong hands; 2) getting express approval from your research institution, who just might not want the stigma that comes with your research; and 3) securing funding, which, for Schedule 1 drugs, mostly comes from the National Institute on Drug Abuse (NIDA). NIDA has a government-sanctioned monopoly as the only legal source of marijuana for research in the U.S., and word on the street is that they don’t like to fund research that could conflict with their interest in, well, drug abuse.

To make a long story short, the debate over legalizing marijuana for medical research has a lot to it. Even if this legalization did occur, there would need to be firm oversight to make sure everyone and their mom didn’t run to sign up for studies just to get some reefer. But, in hopes of tilting the balance of this plant’s reputation, I am featuring a list of research studies in which THC, marijuana’s main active compound, appears to have done some good:

1. Cannabinoid Neuroimmune Modulation of SIV Disease. Monkeys with simian immunodeficiency virus (SIV, the monkey version of HIV) were given THC and experienced slowed disease progression, decreased amounts of virus, and milder tissue inflammation.

2. Chronic administration of THC prevents the behavioral effects of intermittent adolescent MDMA administration and attenuates MDMA-induced hyperthermia and neurotoxicity in rats. THC protected rats from ecstasy-induced hyperthermia and neurotoxicity, as well as prevented ecstasy’s behavioral effects.

3. Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability. In inflammatory bowl diseases (IBD) like Crohn’s disease and ulcerative colitis, the intestines are inflamed; in this study, THC accelerated recovery from induced inflammation in human colorectal cells.

4. Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington’s disease. A THC-based treatment delayed the progression of Huntington’s Disease in rats.

5. Targeting cannabinoid receptors as a novel approach in the treatment of graft-versus-host disease: evidence from an experimental murine model. Mice with graft-versus-host disease were given THC and had increased numbers of immune cells, less tissue injury, less weight loss, and better overall survival.

6. Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy. THC reduced the viability of human hepatocellular carcinoma (liver cancer) cells and of tumors grown from human cancer cells implanted in mice.

7. The cannabinoid receptor agonist THC attenuates weight loss in a rodent model of activity-based anorexia. THC caused anorexic rats to gain weight.

8. Pre- and post-conditioning treatment with an ultra-low dose of Δ9-tetrahydrocannabinol (THC) protects against pentylenetetrazole (PTZ)-induced cognitive damage. Mice given THC before or after induced epilepsy (a model of brain injury) were protected from long-lasting deficits in learning and memory.

9. A combined preclinical therapy of cannabinoids and temozolomide against glioma. THC had anti-tumor effects against gliomas (brain tumors) that were resistant to temozolomide, the standard treatment for gliomas; the gliomas in the studies were grown by implanting human glioma cells in mice.

10. Acute and chronic cannabinoid extracts administration affects motor function in a CREAE model of multiple sclerosis. In a mouse model of multiple sclerosis, injection with a THC-rich Cannabis sativa extract reduced neurological deficits.

…And that’s all just from this year.

van Bakel H, Stout JM, Cote AG, Tallon CM, Sharpe AG, Hughes TR, & Page JE (2011). The draft genome and transcriptome of Cannabis sativa. Genome biology, 12 (10) PMID: 22014239

Yeah, you should check this out:

The authors started off by looking at the genes expressed in muscle biopsies from muscles undergoing atrophy, and they made note of which genes had high or low expression. Then, they screened 1300+ compounds for any that could (basically) decrease the high genes and increase the low genes, the idea being that any compound that could reverse the gene expression in muscle atrophy might be a good treatment. And they were right.

Ursolic acid

The screen identified ursolic acid, a compound found in large quantities in apple peels, as the only potential inhibitor of muscle atrophy. So the researchers injected ursolic acid into mice with atrophic muscles, which stopped muscle loss and increased muscle weight by 7%. Seven percent might not sound like a lot, but it is, considering that, again, this is the first compound shown to stop muscle loss at all. A 7% increase in muscle weight in a 180 lb man with typical muscle mass would mean a gain of over 5 pounds of muscle.

Ursolic acid diet shrinks fat cells

Things got even more interesting when normal mice were put on a diet with 0.27% ursolic acid: muscles got bigger and significantly stronger, blood levels of fat and cholesterol decreased, and fat cells shrank considerably, thus reducing fat weight significantly (see for yourself in a figure from the article, left). This is all in addition to the lowered blood sugar in fasting mice who received ursolic acid injections. To make things even better, the authors were able to identify genes that were increased or decreased by treatment, and that were probably responsible for these effects.

In my opinion, these scientists stumbled across something even greater than what they hoped to find. Their data on ursolic acid suggests its usefulness in treating everything from muscle atrophy to obesity to metabolic syndrome to type 2 diabetes. Not even mentioned in this paper is the work that has previously shown the ability of ursolic acid to inhibit cancer cells and Alzheimer’s proteins.

Okay, I’m impressed. What doesn’t ursolic acid do? Seems like it could be a future wonder drug! I’m very interested to see what scientists will try with this compound next…

Have a nerdy weekend!

Kunkel SD, Suneja M, Ebert SM, Bongers KS, Fox DK, Malmberg SE, Alipour F, Shields RK, & Adams CM (2011). mRNA expression signatures of human skeletal muscle atrophy identify a natural compound that increases muscle mass. Cell metabolism, 13 (6), 627-38 PMID: 21641545

Shishodia S, Majumdar S, Banerjee S, & Aggarwal BB (2003). Ursolic acid inhibits nuclear factor-kappaB activation induced by carcinogenic agents through suppression of IkappaBalpha kinase and p65 phosphorylation: correlation with down-regulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1. Cancer research, 63 (15), 4375-83 PMID: 12907607

Pathak AK, Bhutani M, Nair AS, Ahn KS, Chakraborty A, Kadara H, Guha S, Sethi G, & Aggarwal BB (2007). Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells. Molecular cancer research : MCR, 5 (9), 943-55 PMID: 17855663

Wilkinson K, Boyd JD, Glicksman M, Moore KJ, & El Khoury J (2011). A high-content drug screen identifies ursolic acid as an inhibitor of amyloid-{beta} interactions with its receptor CD36. The Journal of biological chemistry PMID: 21835916

These researchers exploit this tryptophan-neurodegeneration link to make headway in finding better treatments for neurodegenerative diseases.

Title: Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration

Authors: Daniel Zwilling, Shao-Yi Huang, Korrapati V. Sathyasaikumar, Francesca M. Notarangelo, Paolo Guidetti, Hui-Qiu Wu, Jason Lee, Jennifer Truong, Yaisa Andrews-Zwilling, Eric W. Hsieh, Jamie Y. Louie, Tiffany Wu, Kimberly Scearce-Levie, Christina Patrick, Anthony Adame, Flaviano Giorgini, Saliha Moussaoui, Grit Laue, Arash Rassoulpour, Gunnar Flik, Yadong Huang, Joseph M. Muchowski, Eliezer Masliah, Robert Schwarcz and Paul J. Muchowski

Date of publication: June 6, 2011

Direct link: http://www.sciencedirect.com/science/article/pii/S0092867411005812

PMID: 21640374

Abstract: When the amino acid tryptophan is broken down by the body, a metabolite called kynurenine is produced, and this metabolite also goes on to be broken down into other products. One of the products of kynurenine breakdown is kynurenic acid, which is thought to have a protective effect on the brain and is decreased in those with neurodegenerative disease. The authors of this paper synthesized a drug called JM6 that inhibits the enzyme responsible for breaking down kynurenic acid – theoretically this drug would allow kynurenic acid levels to remain high and provide continued neuroprotection. In mouse models of Alzheimer’s and Huntington’s, administration of JM6 led to fewer memory deficits and longer lifespans, among other improvements in brain function.

Methods: These researchers first developed “slow release” versions of a drug already known to increase kynurenic acid levels by inhibiting the enzyme responsible for kynurenic acid breakdown. Slow-release drugs remain in blood circulation for an extended time and are thought to be more effective for that reason; the slow-release drug tested in this paper is called JM6. In mice known to have Alzheimer’s or Huntington’s like conditions, JM6 was given daily before the onset of disease symptoms. At 6-7 months of age, mice were behaviorally assessed (e.g. by time spent completing a maze) and some mice were sacrificed in order to study changes in brain tissue.

Results: In short, the drug JM6 works quite well in mouse models of both Alzheimer’s and Huntington’s Diseases, as evidenced by better spatial memory and longer lives in mice treated with the drug compared to mice that did not receive treatment. Alzheimer’s mice that were receiving JM6 were about 10% better at performing maze tasks than mice who did not receive the drug, which was a statistically significant difference. These mice also showed a more appropriate response to anxiety-inducing situations, which is important because in human Alzheimer’s cases, patients often display social and/or sexual “disinhibition” stemming from a loss of anxiety responses. Lastly, the mice modeling Huntington’s Disease lived significantly longer (on the order of a few weeks) with JM6 treatment than without. Both the Alzheimer’s and the Huntington’s mice treated with JM6 showed healthier brain tissue, e.g. an undiminished number of synapses, which are responsible for sending messages between cells in the brain.

Bottom line: In mice (not humans!) fated to develop Alzheimer’s and Huntington’s-like symptoms, the drug JM6 worked convincingly well to improve mental condition. Whether or not this drug could work in humans remains to be seen, but this research is powerful because the authors know that the drug JM6 works by increasing the amount of kynurenine in the blood (recall: kynurenine is a product of breaking down the amino acid tryptophan). This means that a potentially new approach to finding treatments for Alzheimer’s and/or Huntington’s could be to develop more drugs that act by increasing the body’s levels of kynurenine; and knowing what to target with a drug is often the first step to creating an effective treatment.

Zwilling D, Huang SY, Sathyasaikumar KV, Notarangelo FM, Guidetti P, Wu HQ, Lee J, Truong J, Andrews-Zwilling Y, Hsieh EW, Louie JY, Wu T, Scearce-Levie K, Patrick C, Adame A, Giorgini F, Moussaoui S, Laue G, Rassoulpour A, Flik G, Huang Y, Muchowski JM, Masliah E, Schwarcz R, & Muchowski PJ (2011). Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell, 145 (6), 863-74 PMID: 21640374

Because many complications can occur with any type of transplant, one example being immune rejection, stimulating the body’s own stem cells to make new heart cells would be ideal. This idea serves as the motivation for this entry’s article.

Title: De novo cardiomyocytes from within the activated adult heart after injury

Authors: Nicola Smart, Sveva Bollini, Karina N. Dubé, Joaquim M. Vieira, Bin Zhou, Sean Davidson, Derek Yellon, Johannes Riegler, Anthony N. Price, Mark F. Lythgoe, William T. Pu & Paul R. Riley

Date of publication: June 8, 2011

Direct link: ttp://www.nature.com/nature/journal/v474/n7353/full/nature10188.html

PMID: 21654746

Abstract: Knowing that there are several limitations to cell transplantation as a means of replacing damaged heart tissue following a heart attack, these researchers set out to try to identify a pool of stem cells in the adult heart that could potentially be utilized to restore damaged heart tissue from within. The authors ultimately found that these adult stem/progenitor cells could be identified by the expression of a gene called Wt1, which was turned on after treating with a peptide (essentially a small version of protein) called thymosin b4. These progenitor cells are suggested to have derived from the epicardium, which is the outer layer of the heart. Stimulating these adult stem cells with thymosin b4 caused them to integrate with damaged heart tissue and become mature cardiomyoctyes (heart muscle cells). Developing a way to utilize these inherent progenitor cells to help mend a damaged heart would be a powerful way to minimize the use of drugs or the need for transplanted tissue.

Methods: The authors made use of mice whose cells would turn green if the Wt1 gene was turned on – recall, the hypothesis is that if Wt1 is turned on in a cell, then that cell may be a heart stem cell. The fact that the cells would turn green when the gene turned on allowed for easier studying of those particular cells later. Mice were injected for 7 days with thymosin b4, because it had previously been shown to improve the function of heart stem cells, before being induced to have a myocardial infarction (heart attack). The researchers induced heart attacks by anesthetizing the mice and then sealing off a major artery of the heart (the left anterior descending artery).  At 2, 4, 7, or 14 days after sealing the artery, the heart was removed and those green progenitor cells could be studied within the heart tissue or isolated from the tissue. Additionally, the authors used some of these isolated stem cells to transplant them into other mice that had had heart attacks, to see if the stem cells could improve the condition of the mice.

Results: Mice pretreated with thymosin b4 before myocardial infarction had significantly more progenitor-like cells in their hearts after myocardial infarction, compared to mice that did not receive these injections. Although mice injected with a negative control did show an increase in progenitor cells following a heart attack, thymosin b4 significantly increased this response. The authors could see that these cells had traveled to the scar on the heart caused by the heart attack, and had started to express some of the genes specific to heart cells – meaning that the stem cells were turning into heart tissue and helping to heal. The progenitor cells isolated from one mouse and transplanted into the heart region of another mouse that had had a heart attack started to turn into heart cells and help to heal the injury in the heart of the recipient mouse as well.

Bottom line: In mice, which are clearly not humans but are the most closely related common lab animal, these researchers identify a pool of cells in the heart with the ability to generate additional heart cells following a heart injury, and this ability is significantly enhanced by the peptide thymosin b4. Although thymosin b4 treatment was not as efficient as an ideal human cell-based therapy would be, the work in this article justifies the search for other molecules that can similarly increase the response of progenitor cells in our hearts to heal and replace the damaged heart tissue that results from heart attacks.

Interesting fact: Working with mice is expensive. Maintaining a mouse cage costs $1-2 per day. Just 30 mouse cages, which this work seemed like it would have needed, at least, would cost $10,950-$21,900 for one year of research. And it is typical for the research in a major publication to represent at least a year’s worth of work, if not four or more.

Stem cells: To make a human, or most any other animal, the first step is sperm meeting egg. The two cells fuse and since each one contains half the genetic information for a whole animal, the fused sperm and egg are considered one cell, called a “zygote.” Obviously an animal is ultimately made up of more than one cell, so the zygote needs to divide to become two cells, then four, then eight, then sixteen, and so on. From that one zygote, there needs to be created a heart, skin, lungs, bone – many kinds of tissues. To get from one cell to many different kinds of cells, many of the early embryonic cells are stem cells or have varying potencies to divide and produce other types of cells (“other types of cells” can include heart cells, fat cells, kidney cells, and even other stem cells). Even as an adult, some of our tissues retain a small population of stem cells so that in the event of injury, for example, damaged tissue can be remade.

 
Smart N, Bollini S, Dubé KN, Vieira JM, Zhou B, Davidson S, Yellon D, Riegler J, Price AN, Lythgoe MF, Pu WT, & Riley PR (2011). De novo cardiomyocytes from within the activated adult heart after injury. Nature, 474 (7353), 640-4 PMID: 21654746