20.5.15

Is this thing on?

Hi folks. Not sure if there's anyone still out there, but I thought I should let you know that I made a new blog! Here's a fancy link to it!

I might update this one at some point? We'll see.

22.8.08

Listeriolysin O - Basically why listeriosis sucks so bad

Every so often, the narcissistic tendencies of Listeria monocytogenes get to be too much for this annoying Gram-positive bacterium to bear, and it decides to make the news by causing a listeriosis outbreak. Typically this involves a major food manufacturer having to recall a product that has become contaminated with the bug. The media loves bacterial narcissism.

Based on what I've read (Wikipedia, obviously), listeriosis is fairly uncommon and largely associated with infants, old people, and those with compromised immune systems. It's actually more common in animals, particularly cows and stuff. Wikipedia also points out that although L. monocytogenes was first described in 1926, it wasn't identified as a cause of foodborne disease until 1981 (in Halifax, Nova Scotia, of all places). Listeriosis often presents as a flu-like illness (fever, puking, feeling like you're gonna puke, and getting the runs) that eventually subsides or else worsens into such fun things as septicemia (blood poisoning), encephalitis/meningitis (brain/brain membrane inflammation), corneal (eye) ulcer (Google Image or bust!), or pneumonia.

Listeriolysin O (LLO) is a protein toxin secreted by L. monocytogenes that helps the bacterium get inside cells, where it can reproduce like crazy while remaining hidden from the the immune system. The entire process starts with the bacterium tricking white blood cells into engulfing it into a container called a phagosome. At this point, LLO creates a hole in the phagosome, permitting the bacteria to escape its container into the cytoplasm of the cell, where it can start dividing like a mofo.

Here's the really cool part. LLO is activated only under the more acidic conditions it encounters within a phagosome, so once it forms a pore and spills out along with the bacterium into the more basic cytoplasm, it's activity is reduced. This means that LLO won't form pores in the plasma (outer) membrane of the cell, which would likely kill it, thus ensuring the maintenance of a nice little cell incubator for Listeria to multiply in.

References
- Schnupf P, Portnoy DA. 2007. Listeriolysin O: a phagosome-specific lysin. Microbes and Infection 9(10):1176-1187.

15.8.08

Diisopropyl fluorophosphate (DFP) - Sarin's little brother

Organophosphates are a class of chemical compounds that possess a phosphate atom bound to a couple of oxygen atoms. They include among their ranks such essential-for-life biochemicals as nucleic acids and ATP, as well as life-ending insecticides, herbicides, and nerve agents.

Nerve agents kill you by inhibiting an enzyme called acetylcholinesterase, which hangs out wherever nerves from your brain/spinal cord connect with your muscles in order to tell them what to do. When the nervous system wishes a muscle to bend to its will (lol), a neurotransmitter (chemical facilitator of communication between nerve and muscle) called acetylcholine is released from nerves and binds to sites on muscle to cause them to contract. Normally, acetylcholinesterase then breaks down the acetylcholine so that the muscle can relax. Organophosphates bind to a special site on acetylcholinesterase and prevent it from breaking down acetylcholine, resulting in prolonged muscle contraction (i.e. being paralyzed). Since you need muscles to breathe, organophosphates are somewhat problematic, causing asphyxiation and death death death.

Diisopropyl fluorophosphate (DFP) is an organosphate nerve gas; an insecticide gone wrong, if you will. It was originally developed by a British dude named Bernard Charles Saunders, who was trying to break into the exciting world of chemical warfare products (aren't we all). In a major setback for Mr. Saunders, DFP was found to be less toxic than similar compounds like tabun or sarin. However, he stuck with his little toxic friend, and eventually figured out that it could be mixed with mustard gas to produce a mixture with a sufficiently low enough melting point to be used in cold weather, which was apparently a big deal at the time. Mustard gas: Now able to blister you to hell all year round.

Since DFP resembles much more toxic chemical agents (taurin, sarin, soman, cyclosarin, etc.), it has been used by military forces as a substitute for such agents in training drills and top-secret experiments and stuff. DFP is actually a structural analog of sarin, meaning that it contains the same atoms but they are arranged differently.

DFP has been used by eye doctors and vets to produce miosis (constriction of the pupil of the eye), which is beneficial to the treatment of chronic glaucoma and some other stuff. Neuroscience researchers have been known to play around with it since it inhibits acetylcholinesterase and so can be used to induce delayed peripheral neuropathy, permitting this condition to be studied.

24.7.08

Persin - Exploring the secret pharmacological life of the humble avocado

An important message for the under-the-table pet feeders of the world: If you feed your animal friend a bunch of avocado, it may get very sick [1]. This is thanks to a toxin called persin, which is found in both the fruit and leaves of the avocado tree (Persea americana). Persin is an polyketide that is made via the same biochemical pathways that the avocado plant uses to make its delicious, delicious fatty acids. In fact, it closely resembles linoleic acid, an essential omega-6 fatty acid.

For some reason, persin is usually harmless to humans (though it may be responsible for some avocado allergies) but can seriously mess with all sorts of other animals including birds, mammals (other than us), and fish. Lactating rodents and livestock that eat avocado leaves often develop udder-related problems such as inflammation and wonky milk secretion [2]. Avocado consumption has also been linked to heart damage (necrosis of myocardial fibres) in several mammals. This sort of selective toxicity is actually fairly common among drugs. For example, penicillin is pretty darn safe for humans (provided you aren't allergic), but it kills off guinea pigs like a gator in a...well, guinea pig factory. Keep this in mind the next time your little furry bundle of joy and frequent excretion gets an infection and requires black market antibiotics.

Persin is also capable of harming fungi and insects, particularly those species that infect/eat the avocado plant (e.g. Colletotrichum gloeosporioides, which also attacks citrus fruits and papayas). This may explain why the compound exists in the first place!

In keeping with its toxic nature, persin is capable of killing breast cancer cells (hooray!). Not only that, it can boost the effects of tamoxifen, a popular breast cancer drug [3]. This synergistic effect is thought to be in part due to persin messing with steroid hormone receptor signaling so as to make breast cancer cells more susceptible to the estrogen receptor modulatory effects of tamoxifen.

References
[1] Buoro IB, Nyamwange SB, Chai D, Munyua SM. (1994). Putative avocado toxicity in two dogs. Onderstepoort J Vet Res. 61(1):107-109.
[2] Oelrichs PB, Ng JC, Seawright AA, Ward A, Schäffeler L, MacLeod JK. (1995). Isolation and identification of a compound from avocado (Persea americana) leaves which causes necrosis of the acinar epithelium of the lactating mammary gland and the myocardium. Nat Toxins. 3(5):344-349.
[3] Roberts CG, Gurisik E, Biden TJ, Sutherland RL, Butt AJ. (2007). Synergistic cytotoxicity between tamoxifen and the plant toxin persin in human breast cancer cells is dependent on Bim expression and mediated by modulation of ceramide metabolism. Mol Cancer Ther. 6(10):2777-2785.