Could green tea have anti-inflammatory properties that can help with both rheumatoid arthritis and cardiovascular complications due to inflammation?

Cardiovascular disease and rheumatoid arthritis are two very common diseases in our society that that are not commonly thought of as being as being associated with one another but it turns out that there is some research that provides a link between the two. Atherosclerosis is the hardening of the arteries caused by plaque build up and is most commonly thought of as a lipid based disorder caused by cholesterol and fats. It turns out that cells and cytokines involved in certain inflammatory pathways can lead to the pathogenesis of cardiovascular disease. Rheumatoid arthritis is a chronic inflammatory disease that causes elevated levels of pro-inflammatory cytokines like interleukin (IL)-1β, tumor necrosis factor-α (TNF-α) and IL-6. The cytokines involved in rheumatoid arthritis can cause vascular damage and atherosclerosis leading to CVD.

Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX)-2 selective inhibitors are commonly used to treat inflammation but on their own they may lead to an increased risk of CV disease in patients with rheumatoid arthritis. Another method used to treat inflammation that is gaining more and more popularity is the use of complementary and alternative approaches such as over-the-counter drugs, vitamins and minerals, supplements, ointments, yoga and natural components found in plants. One plant component that has shown some promising results has been (−)-epigallocatechin-3-gallate (EGCG) which is found in green tea. Studies show that many of the beneficial effects from drinking green tea come from EGCG and has demonstrated its anti-inflammatory effects in numerous studies.

EGCG has been shown to have different effects on cartilage, bone and synovial fibroblast activity through modulating the expression of cytokines. EGCG inhibits the effects of IL-1β which causes many downstream effects such as inhibition of protein phosphorylation and down regulation of IL-6, IL-8 and TNF-α as well. These findings show that green tea may be beneficial in ameliorating inflammation and reducing cartilage destruction associated with different forms of arthritis.

EGCG is able to help patients with CVD as well through similar pathways. Following myocardial ischemia and subsequent reperfusion, EGCG administration has been shown to minimize ROS-mediated endothelial damage by reducing the recruitment of neutrophils and decreasing the release of IL-6 and TNF-α. A different study showed that EGCG would help dilate coronary arteries in disease states. Studies done in mice have shown that a significant reduction of plaque coverage on the aorta as well as cholesterol and triglyceride levels in mice that were given EGCG.

In conclusion, there is strong evidence that ECGC shows positive effects in both rheumatoid arthritis and CVD. We have seen a lot of articles in class that talk about natural cures for many different kinds of diseases that are out there. Natural remedies are a popular thing and I believe that they will continue to be popular and it is important that we understand how these work so that we can properly recommend them to people who want to try them. The potential drug-drug interactions and actual effectiveness are concerns that should be taken into consideration when talking to your doctor about some alternative approaches. 

Citations:

Riegsecker, Sharayah. National Center for Biotechnology Information. U.S. National Library of Medicine, 19 July 2013. Web. 29 Oct. 2014.

Could Curcumin, Reservatrol, and Simvastatin be used to treat acute Ileitis?

A team in Germany developed mouse model for acute ileitis such as that experienced by patients suffering from a flare up of Crohns disease. This model was used to test the potential to use reservatrol, simvastatin and curcumin as treatments.

 The team established a model by infecting 3 month old mice with Toxoplasma gondii, a virulent intestinal pathogen, and treating with either placebo or one of 3 experimental substances. Subsequent tests were performed to examine either what cell types predominated in situ, macroscopic signs of inflammation, types of cytokines, effect on enteric bacterial populations, and bacterial translocation

You probably have heard of, and likely ingested at least some of the three chemicals of interest. Reservatrol has already garnered attention as a polyphenol found in grapeskins that acts as an antioxidant and anti-inflammatory. Curcumin is another polyphenol also thought to have anti-inflammatory effects; this one is responsible for the spice and smell in turmeric. Simvastatin is from the statin family of drugs is used to control elevated cholesterol.

All of the experimental groups came back with some promising results. The small intestine shortened from inflammation in all groups compared to naive, non infected mice. Those experimental groups shortened intestinal length significantly less than the placebo group. Significantly less weight loss in experimental groups and better immunohistology showed the GI more intact at the end of the experiment in experimental groups.

The type and number of immune cells found at the cite of damage was very different between placebo and experimental groups. The groups that recieved treatment exhibited less T cells and Neutrophils but more T regulatory cells and proliferating cells. This is an exciting finding in diseases that have damage mediated by T cells.

The enterobacterial populations changed from a more proinflamatory Enterococcus and Escherichia coli to the anti-imflammatory Lactobacillus and Bifidobacteria  in treatment groups. Influencin the bacterial populations may in turn influence the immune system.

 Translocation to Mesenteric lymph nodes and the spleen was lowest in reservatrol treated mice, followed by curcumin treated groups with no significant decrease from placebo to simvistatin. The reservatrol group exhibited higher rates of long term survival, too.

This set of tests may prove helpful to understand the acute episodes of ileitis in humans. For now, at least it seems that these chemicals are proving very interesting avenues of treatment down the line.

1. Bereswill S, Muñoz M, Fischer A, et al. Anti-inflammatory effects of resveratrol, curcumin and simvastatin in acute small intestinal inflammation. PloS one. 2010;5:e15099.

Treatment with helminths for IBD

Could our immune systems benefit from the presence of some parasites? A review article from 2008 suggests that at least in certain disease states, including Irritable Bowel Disease (IBD), the immune system may benefit from the presence of helminths or some of the molecules they secrete. A correlation has been shown between places with higher hygienic standards and those locations that see a rise in allergies, Type 1 Diabetes, and IBD. "the hygiene hypothesis" as it has come to be known, provides a promising but not completely understood link between our low parasite loads, and relatively higher levels of autoimmunity and inflammatory diseases.


An overview of gastrointestinal immune system function shows how IBD pathologies including Crohns disease and Ulcerative colitis are probably Th1 mediated. That is, T helper cells are responsible for the pattern of damage to the intestines. When mammalian immune systems respond to parasitic infections, Th2 or Tfh cells are called into duty. The different kind of T cells down regulate the activity of each other. Th1 suppresses and is suppressed by Tfh. in this way, researchers interested in helminth based therapies may be getting closer to figuring out a sound mechanism for the action of the therapies.
And the therapies are promising. Some of those studies cited showed that a treatment of Schistosoma mansoni was sufficient to reduce induced colitis in murine model. Similar findings have been found in murine models for the tapeworm Hymenolepis diminuta and the nematode Trichinella spiralis.

Worm based therapies already are gaining some traction in human patients, too. Pediatric Crohns disease patient was successfully treated with Trichuris suis ova. Many groups seem intent on isolating active compounds from the helminth treatments to eliminate the need to infect patients with living parasites. The culmination of these efforts may be validating to the findings that are already accruing in helminth based treatments.

Do these treatments seem plausible for future medical use? Could assumptions inherent to the culture and established medical field prove too much for their acceptance? The researchers responsible also have some of these concerns. Share your thoughts in the comments below.

1. Ruyssers NE, De Winter BY, De Man JG, et al. Worms and the treatment of inflammatory bowel disease: are molecules the answer? Clinical & developmental immunology. 2008;2008:567314-7.

IBD and Surgery

As stated in our previous classes, we know that the 2 common forms of Inflammatory Bowel Syndrome are Ulcerative Colitis and Crohn's Disease. But while these two are the most commonly diagnosed amongst IBD patients, they have many differences. Two differences will be discussed in this topic: the location of inflammation and how inflammation works.

For people diagnosed with Crohn's Disease, they are typically seen to have general inflammation. This means that the inflammation can basically occur anywhere along the digestive tract/GI. Ulcerative Colitis based patients, however, are only seen to have inflammation along the large intestine (colon). Another major difference is that with Crohn's Disease, inflammation can occur randomly and in patches while UC causes an inflammation that is continuous along affected areas.

Knowing these differences between Crohns' Disease and Ulcerative Colitis is important for surgical purposes since this determines whether or not surgery can be used as a cure or a method to calm down the disease.

Since UC is more localized, surgery can be used to remove the affected areas. One method used is to remove the entire colon/rectum and attach the lowest part of the small intestine to a hole made in the internal abdominal wall. This will act as a substitute for the rectum in that it will allow waste products to leave the body and empty into an external bag. The most common procedure, however, is the Ileal Pouch Anal Anastomosis (IPAA). The colon and rectum are still removed with this method but a new rectum called the J-Pouch is surgically created out of the Small Intestine. This procedure will allow patients to have regular bowel movements without the usage of an external bag. And while this may be undesirable, many people still choose this route when the UC begins to affect their daily life and work.

Crohn's Disease, however, cannot be cured with surgery; only treated. This is due to the wide range of places in the digestive tract that can be affected and inflamed. So even if surgery is used to remove the inflamed area, the only thing that surgery will do is cause CD to go into remission. It can last for weeks, months, or years but there is no way to completely rid a patient of CD through surgery.

To be clear, picture this. A patient with CD on the colon undergoes surgery to remove said colon but four months later, the same patient comes back to the hospital in regards to CD inflammation showing up on the small intestine and/or esophagus this time. This is why surgery cannot cure Crohn's Disease.

But while surgery can only push CD into remission, it may be necessary and required for a patient due to certain complications like toxic megacolon (the stretching of the colon which allows toxins to spread through the blood) and the formation of a fistula (connections between two body parts that are not supposed to connect). So when it comes to surgery for UC and CD, it's not a one-fits-all kind of treatment but more for a case-by-case study.

"Differences between Crohn's Disease and Ulcerative Disease." Columbia St. Mary's. N.p., n.d. Web. 24 Oct. 2014.
"Slideshow: Ulcerative Colitis Surgery – What to Expect." WebMD. WebMD, n.d. Web. 24 Oct. 2014.
"Surgery for Crohn's Disease: Types of Surgery, Complications, Recovery, and More." WebMD. WebMD, n.d. Web. 24 Oct. 2014.

Mechanisms of the Therapeutic Effects of Cigarette Smoking in Ulcerative Colitis

           In both of our discussions the past few weeks cigarette smoking was shown to be therapeutic in patients with ulcerative colitis, one of the two main categories of inflammatory bowel disease. The mechanism by which cigarettes treat ulcerative colitis is widely unknown; which prompted me to look for some more recent studies done on the topic. I found a study that mimicked cigarette smoking in mouse models for ulcerative colitis. The study set out to measure the levels of certain immune cells in order to pin down which cells are most effected by cigarette smoke. They found that while the levels of T, NK, and NKT cells did not change, iNKT cells increased. Invariant NKT cells (iNKT) are a subset of natural killer t cells that recognize lipids that contain the CD1d marker. Studies done on these cells have shown that they have both protective and harmful effects, depending on the situation.

            Because of this duality of iNKT, the researchers followed up and tried to determine if the raised levels proved to be therapeutic for the mice. They artificially raised the levels of iNKT in the mouse models and found that there was reduction of both Th1 and Th17 cytokines, which are both pro-inflammatory. These findings showed that the increase of iNKT in ulcerative colitis is in fact protective.
         
            I found this study to be very interesting. Since as we all probably know, cigarette smoking is a dangerous habit, I felt that it was important to find out the mechanism of the therapeutic effect of cigarette smoking in ulcerative colitis. Once the mechanism is found out it would be possible to develop treatments that cause the downstream effects of cigarette smoking, without the many negative effects of actually smoking. I see this study as a base for a whole new method in treatment of ulcerative colitis. If a medication or procedure is able to increase the levels of iNKT the patients could enjoy the therapeutic effects that were shown in this study. I think that the findings of this study need to be researched more, but still show a lot of promise in the continued development of new methods to treat ulcerative colitis.

Citations:

Montbarbon, Muriel, et al. "Colonic Inflammation in Mice Is Improved by Cigarette Smoke through iNKT Cells Recruitment." PloS one 8.4 (2013): e62208.

Stress and IBD

Over these past two weeks, we have discussed how smoking is positively correlated with Chron’s Disease and inversely correlated with Ulcerative Colitis. Although, the mechanism is still unknown, many of us brought up the environmental factor stress. I know when I was reading the articles; I thought that a possible explanation as to why smoking can help people’s symptoms was just the fact that smoking may alleviate stress in an individual.

When looking at the effects of stress and the immune system in general, we know that stress causes the release of cortisol, which is an immunodepressor. Additionally, immunodepressed individuals are also more prone to inflammation. Furthermore, acute stress in individuals causes a release of catecholamine’s, thus cortisol, and inflammatory cytokines. All of these factors seem to link stress with IBD.

However, previous studies have a hard time proving this. One reason is because of “recall bias”. There is potential skew of data due to the fact that people falsely report, or don't simply remember when the stress occurred and if it was associated with their flare up. Another factor that was mentioned, that I didn’t think of, was that stress is relative. One individual might think that an event in life is extremely stressful while another individual might not interpret it the same way. Taking these issues into consideration, past studies (also small) show a slight correlation with stress and IBD.

Another interesting fact is the role of neural influence and IBD. There was a case in which a man, diagnosed with Ulcerative Colitis, had became paralyzed at the C5 level, and had consequently went into complete remission. This further supports the idea that the factors released from stress may be associated with IBD. With this fact in mind, trials have been conducted using Lidocaine, a neuromodulator drug, in treatment of Ulcerative Colitis, and have had some success.

As of now, there is no concrete evidence to support this theory, so further studies must be performed. However, most people recommend trying to keep stress levels down when diagnosed with IBD to help prevent further flare-ups.

Feature, Charlotte. "The Link Between Stress and Ulcerative Colitis." WebMD. WebMD, 28 Sept. 2011. Web. 22 Oct. 2014.

"Inflammatory Bowel Disease (IBD)." Lifestyle and Home Remedies. Mayo Clinic. Web. 22 Oct. 2014.

Mawdsley, J., and D. Rampton. "Physiological Stress in IBD." National Center for Biotechnology Information. U.S. National Library of Medicine, 26 Mar. 2005. Web. 22 Oct. 2014.

Inflammatory Bowel Disease and Weight Gain

It's pretty well known that a good number of people in our class are fitness junkies. Some swim, some run, and some bike. But regardless as to what form of exercise we commit ourselves to, we all know that working out does our body and physical health a lot of good. It helps relieve stress, make us feel good, keep the pounds off, and ward off undesirable diseases and disorders. But keeping up with your physical health can become incredibly difficult when you're diagnosed with Inflammatory Bowel Disease. "Abdominal pain, diarrhea, weight loss, lack of energy, and sudden bathroom urges" come hand in hand with IBD after all and these symptoms are often exacerbated due to the force and impact given off from certain exercises.

And what's worse is that the medications that are meant to control Ulcerative Colitis and Crohn's Disease also cause problems themselves; some cause IBD diagnosed individuals to gain weight, feel lethargic and out of energy. So always feeling the need to go to the bathroom coupled with the medications' side effects makes working out and staying in shape all the more challenging.

It's not impossible though. In the article that I've been going through, it lists off many different exercising tips and the first one that it mentions is To Minimize Impact which makes sense. The less impact you're putting your body under, the less likely you'll find yourself needing to rush to the bathroom. So running is probably a no-go while yoga and swimming would be very beneficial!

But overall, I think that it's all about how motivated we are in wanting to stay healthy no matter what form of fitness we decide to undertake. Neal Patel, a man in this article, was diagnosed with Ulcerative Colitis and gained 30 pounds due to the medicine he was taking. But with time and consistent exercise, he was able to lose 15 pounds! So as I've said before, it's all about how much you're willing to invest into your health regardless of the circumstances and disadvantages.

Feature, Bill Hendrick WebMD. "Exercising When You Have IBD, Ulcerative Colitis, Crohn's Disease." WebMD. WebMD, n.d. Web. 17 Oct. 2014.

Vedolizumab: A Novel Approach to IBD Treatment

As was mentioned in class, most of the treatments for inflammatory bowel disease that were available around the time the review articles were published focused on treating the downstream effects of inflammation, rather than preventing it in the first place. That sparked me to want to find if there was any more recent research done to try to find a drug that focused on preventing activation of the inflammatory cascade in the first place.

After some research, I came across a drug called Vedolizumab. In general, inflammatory bowel disease is characterized by chronic inflammation in the gut. Therefore, a very simple cure for inflammatory bowel disease would be to just “turn off” the immune system. Obviously this is not a viable treatment, as it would cause widespread problems throughout the rest of the body. Vedolizumab takes advantage of the fact that the body is able to selectively send T cells to the part of the body they are needed. It has been discovered that one of the main ways the body directs T cells to the gut is using the glycoprotein α4β7. α4β7 is an integral membrane protein in T cells and when it binds to a molecule called MAdCAM-1, which is located in the mucosa, the T cell is able to move through the submucosa into the gut. From there the T cell can contribute to the immune response needed in the GI tract. Vedolizumab is a monoclonal antibody that is specific for the α4β7 protein. Vedolizumab is able to bind to α4β7, preventing it from being able to bind to MADCAM-1, and therefore inhibiting the movement of T cells into the gut. In this way, Vedolizumab is able to “shut off” the immune response in the gut, while still allowing the immune system to function in the rest of the body.

I found this to be a fascinating way to go about treating inflammatory bowel disease. I feel that too often in medicine the focus is on medicating the effect rather than the cause. As mentioned above, this was also the case in inflammatory bowel disease; there were medications to mitigate the effects of the chronic inflammation, but nothing to inhibit the inflammation from occurring in the first place. Since it goes to the route of the cause of inflammation, I believe that Vedolizumab shows great promise as a treatment for inflammatory bowel disease. It will be interesting to follow up on this drug after it has been more extensively tested.

Sources:

Fedyk, E. R., Wyant, T., Yang, L.-L., Csizmadia, V., Burke, K., Yang, H. and Kadambi, V. J. (2012), Exclusive antagonism of the α4β7 integrin by vedolizumab confirms the gut-selectivity of this pathway in primates. Inflamm Bowel Dis, 18: 2107–2119. doi: 10.1002/ibd.22940

Feagan BG, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. The New England Journal of Medicine. 2013;369:699.

Sandborn WJ, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. The New England Journal of Medicine. 2013;369:711.