effects of Silymarin on Inflammation

I attended the seminar by Dr. Stephen Polyak on his work, "In vitro inhibition of cellular metabolism and inflammation by Silymarin."  Silymarin has demonstrated in vitro effects of preventing and treating liver disease, as well as some anti-cancer tendencies.  It is made of two diasteriomers of silibinin (A and B) and is derived from extract from milk thistle plant seeds.  It has many affects on the body through many different mechanisms.  It can block the entry of the Hepatitis C virus, preventing it from infecting cells. It blocks NF-kB activation, which is an anti-inflammatory agent.  It can also block T-cell proliferation and pro-inflammatory cytokine production, which can help block an HIV infection. It achieves most of this by inducing rapid depletion of cellular ATP levels, which do not allow the cells to perform normally.  This process is rapidly reversible so the cells go back to normal when treatment stops.

Although most of what Dr. Polyak said was way over my head, I was surprised at how interested I found myself in what he had to say.  It was very interesting to hear the mechanisms with which the drugs work and the research that occurs behind the knowledge. I was disappointed when I had to leave early to get to work. I wish I could have heard the rest of what he had to say.

Design of Antibiotics that Target Biotin Metabolism by Dr. Courtney Aldrich

I attended a seminar on antibiotic design, specifically about antibiotics that target Biotin metabolism which is utilized by Mycobacterium tuberculosis, the organisms responsible for the disease, tuberculosis. Dr. Courtney Aldrich gave me my first insight into the field of medicinal chemistry and drug design. I’ll admit there are aspects of his lecture that I did not understand due to the fact that I have yet to take biochemistry, but I am excited to learn more. The last antibiotic discovery that was effective in treatment of tuberculosis took place around 4 decades ago. Some of the reasons for the hold up in the synthesis of new antibiotics are the fact that antibiotics are mechanism limited. There are only a couple pathways they can disrupt in order to successfully halt bacterial growth and the most commonly targeted are the translation pathway, DNA replication, or cell wall synthesis. According to Dr. Aldrich, new antibiotics will be developed through the use of the unbiased phenotypic whole-cell screening technique in which compounds with antibiotic activity are obtained and of those, the ones that are multi-target inhibitors are identified.

                Another technique employed in antibiotic construction is the biased-target-based rationale but limitation to this method are that it lacks proper genetic validation since it is an in vitro technique and may react differently in vivo. It has also been seen that there is rapid evolution of drug resistance to these single targeting drugs that mainly target the rate-limiting step of the chemical reaction.

                Dr. Aldrich’s research was specific to biotin metabolism in order to treat tuberculosis. Biotin is a cofactor that is involved in carboxylation of enzymes and fatty acid biosynthesis which is extremely important to all bacterial cells due to their cell wall structure. Biotin is extremely vital for the mycobacterial cell envelope because it is made up of 70% lipids by weight. Dr. Aldrich’s research was target-based and focused on specific enzymes in the biotin pathway with a focus on Bio enzyme A, a PLP dependent enzyme which causes the loss of a carbonyl that is replaced by an amine, the reduction of a cofactor. Almost all antibacterials were discovered using the method of isolating natural products and deriving the antibiotic from them, the natural product optimization method. A common question would be how to distinguish between which products should be pursued and the answer is simply that they are cherry-picked. Once compounds are selected they are tested on wildtype genes and mutated genes and successful targeting is tracked.  

The goal of an antibiotic (as well as most biochemical reactions) is a stabilized product. A specific drug that Dr. Aldrich worked with was Amiclenomycin, a Bio A inactivator that inhibits the synthetic mechanism for biotin. The inhibition mechanism is powered by ketolysis which produces a very reactive species.

My eyes were opened to the world of drug synthesis which would not be possible with organic chemistry. Understanding a variety of reactions and mechanisms has broader implications than simply being prepared for an exam, for those in the field of medicinal chemistry the research and development of such products are saving lives. I have much to learn before all of the terms and processes discussed in Dr. Aldrich’s lecture make complete sense to me, but this lecture definitely gave me a taste of a clinical application of how the things I’ve been learning throughout the semester serve the world in a variety of contexts.

Dr. Aldrich on the synthesis of new TB drugs

On 11/15, the chemistry department seminar speaker was Courtney Aldrich, whose talk was on “Design of Antibiotics that Target Biotin Metabolism”. Dr. Aldrich, a PhD from the University of Minnesota in the department of medicinal chemistry.  His focus is on the synthesis of new antibiotics for tuberculosis.

Dr. Aldrich opened the seminar by discussing a brief history of antibiotic development. He discussed the first antibiotics which were mainly sulfide-containing antibiotics being developed in Germany in the early 1930’s and lamented that since 1987 scientists have created no new antibiotics, a period we now call “the discovery void.”  He explained that most antibiotics are created in one of two ways:  phenotypic whole-cell screening or biased-target based rationale. He states that his lab began new work on a biased-target based procedure to affect the rate-limiting step of biotin.  He explained that bacteria, unlike humans have to synthesize their own vitamins and minerals; cofactors.  Biotin is very important in the myobacterium for lipid cell wall synthesis.

Tuberculosis has been classified as a “modern emerging infectious disease” because though we are very familiar with the standard and older forms of the disease, we are much less familiar with the newer, drug resistant and fungal forms of the disease.  TB still is the leading fatal infectious disease, with mortality rates of 1.4 million people per year.  Another complication of the treatment of TB is that the microorganisms that cause TB can be affected by other diseases: for example the treatment of TB is greatly complicated by a co-infection of HIV/AIDS.  The initial tests for trial drugs showed that the rate limiting step was slower than for clindamycin.  Dr. Aldrich and those who also worked on the study then modified the side chain of the enzymes to catalyze the reaction of the synthesis of the lipids for the cell wall from biotin. By inhibiting the t-step, the biotin is produced in a less efficient manner and the bacteria cannot multiply.  Eventually the bacteria will die. It was then found that the biotinylated proteins were very effective against M strains of TB but not fungal strains.  The drug can now be targeted for myobacterium etiologies of TB.  The drugs are now being targeted for myobacterium specifically.  Dr. Aldrich concluded by stating that the development of these new biotin-targeted drugs can be effective as a product of  biased-target based rationale but he does note that it is very important to recognize the drug’s use in vivo in the body-for the drugs he has been working to synthesize as well as all other drugs.

Brewskies

I attended the ACS's (American Chemical Society) once a month seminar a couple weeks ago. They have a different topic or presentation at every month's meeting, and this one was about beer brewing! It was a scientific behind the scenes to what really goes down. So the ACS, from Wiki, is "the world's largest chemical society and one of the leading sources of authoritative scientific information." The Central North Carolina Section was represented at the seminar. There were probably 35 people at this one which seemed maybe a little inflated due to inherent science nerd interest in beer. They served awesome refreshments and then took care of some business and then Dr. Tracy Hamilton, who sounds like he's got some pretty sweet beer brewing credentials, like in PhD form, gave us his presentation.

I have some friends that brewed some pretty good stuff and I will tell you they had no idea what was really going on. The process is simple, in fact his first slide about the process had "How to brew beer, add: water, sugar, yeast." My friends, granted it was no easy task, were brewing to spec. It really would take a fundamental understanding of the chemistry to design your own beer.

Beer brewing is a perfect explanation of the connection between chemistry and biology. It was pretty sweet being able to follow a bit of where he was going with the chemistry talk. There was a lot of it. I would have taken notes if I'd known it would get so intense! The three main variables are process, ingredients, and proportions. Beer is, after all, like tea. The steeping is just 80 times more complicated. Chemistry, inorganic and organic, is a requisite tool in the beer crafting process. The meeting was sweet! Learned alot! Scared me from brewing my own beer a little bit! Still good though!

Todd Derek

"The Art of Brewing" Seminar

On Thursday, November 7, I attended an entertaining and intriguing Chemistry seminar presented by Tracy P. Hamilton. The speaker came from Arkansas to share his knowledge of home brewing beer; he has been brewing since 1997. During this presentation, he explained the history and story of beer, the differences between lagers, malts, etc., why beer has certain flavors, and the actual process of brewing beer.

There is no precise date known for when beer was first brewed, but it is believed that the domestic crops used for beer first appeared around 11,000 B.C. They were found in the middle east and used as a food source at first. Hops weren't first used until around 850 AD. Beer was actually discovered on accident by trial and error once the feeling of intoxication was experienced. Brewing even helped contribute to the literacy of people by providing opportunities for citizens to record and keep track of the amount of grain held in warehouses.

The basic process of brewing involves making sugar water and adding yeast; the sugar converts to alcohol and carbon dioxide. On a more specific level, first you need malted barley. Malting is the process of germinating seeds that produce enzymes which break down protein and starch. Then you dry the seeds again. The malted barley must then be gelatinized followed by mixing the grain and hot water to form "the mash". While making the mash, the enzymes within must be held at specific pH and temperature ranges depending on the type of beverage being made. Lautering comes after mashing, this involves rinsing the sugars from the mash (we want maltose, not sucrose). The sugar solution then becomes "wort" and is boiled to remove proteins. Once this is complete, yeast is added after the wort has cooled and aerated. The last step is fermentation; temperature is very important in this step, lagers are held at 50F and ale at 70F. And voila, beer!

Another interesting topic Dr. Hamilton went over was how beers have certain flavors:

H2S - rotten eggs
CO2 - gives a bite
acetaldehyde - green apple
diacetyl - butterscotch, buttery
lactic acid - sour
dimethyl sulfide - cooked corn (means infection is present)

Overall, it was really neat and definitely not your average chemistry seminar!

Department Seminar

Last Friday at the chemistry seminar a scientist named Brian J. Drouin came to speak about THZ spectroscopy at JPL (terahertz spectroscopy at Jet Propulsion Laboratory California Institute of Technology). He develops new technologies to enhance the measurements of various molecules in the atmosphere and in interstellar space. In space for example carbon dioxide and methane absorb light so the human eye doesn’t see all of the signals. That is, we only see bright lights but much more is going on in the far infrared spectrum; after stars form planets form, and Dr. Drouin ascertains that far infrared spectrums can enable such observations and collection of data. 

There are about 150 identified chemicals in interstellar space, and these technological tools could provide scientists with easier to read data by enhancing the signals on the emission spectra, ultimately aiding in the discovery of more chemicals in space. In earth science the spectrometers being developed can help to analyze with increasing accuracy and in more detail the human effects on stratospheric ozone and the chemical cycles of ozone. Planet Earth is a warm black body that needs to be able to emit heat. Current techniques do not facilitate the viewing of water from up in space, but image FIT (far infrared) can show how much heat is emitted out of Earth, so for example polar regions would be expected to show high levels of heat. This may be a way to measure global warming because less heat emitted from the Earth could be an indicator of an increase in global warming. The instruments can also sense small changes of CO2 globally. 

At present one challenge is to make the spectrometer smaller so it can be more travel friendly. Dr. Drouin talked briefly about his spectrometer, called the frequency multiplication sub millimeter spectrometer that goes from two to 90 wavenumbers, approximately two orders less frequency than IR spectroscopy. He also discussed some things of which I had a hard time following, but overall the presentation was informative.

D-Fructose

D-Fructose

D-Fructose, or fruit sugar, is a simple monosaccharide found in many plants. It is the sweetest of all sugars. It is found in honey, corn syrup, and in the fruit and other parts of plants. It is much sweeter than sucrose (cane sugar). It is a ketohexose and is often bonded to glucose to form the disaccharide sucrose. It is one of the three dietary monosaccharides, along with glucose and galactose which are absorbed directly into the bloodstream during digestion.

 It is a Ketohexose and has only 3 chiral centers, so 2³ diastereoisomers