DNALC Blogs » ygyh

Bad Cholesterol

Jermel Watkins — Thu, 12 Apr 2012 15:27:17 +0000

When someone mentions cholesterol many will say, how is your HDL? Cholesterol travels through the blood attached to lipoproteins. From a health prospective we try to maintain the good cholesterol (High density lipoproteins or HDL) and decrease the bad cholesterol (Low density lipoproteins or LDL). The HDL aids the body in removal of bad cholesterol in the blood whereas LDL causes build up of plaque within arteries restricting blood flow and hardening of the arteries that may result in heart disease. Control of cholesterol levels is through a number of ways such as low cholesterol diets, weight loss and drugs.

Cholesterol is a crucial fat-like substance produced by the liver that is required for bodily functions. It is the main sterol synthesized and transported in the blood plasma of all animals. Cholesterol is responsible for a number of functions such as:

1. Building and maintenance of the cell membranes
2. Production of sex hormones (androgens and estrogens)
3. Production of bile
4. Metabolism of fat-soluble vitamins, including vitamins A, D, E, and K
5. Insulation of nerve fibers
6. Conversion of sunshine into vitamin D

Cholesterol being a crucial part of our development can have a dark side. The gene DHCR7 (7-dehydrocholesterol reductase) found on chromosome 11 is responsible for the production of cholesterol and mutations in the gene may lead to a metabolic disorder known as SLOS (Smith-Lemli-Opitz Syndrome). This disorder currently occurs once out of every 20,000 births. Individuals with SLOS are unable to produce enough cholesterol to support normal growth and development. This leads to developmental delays, physical malformations, mental retardation and issues with major organs such as the heart. Currently the only treatment for the disorder is cholesterol supplementation to improve growth and developmental progress.

SLOS is inherited in an autosomal recessive pattern, basically both copies of the gene within a cell are mutated. This identifies that the parents of a person with SLOS each carry a mutated copy of the gene, however they do not have any symptoms or signs of SLOS. It may be that genetic counseling may be one form of a preventative method for the disorder. This brings up a great question, should genetic counseling be mandatory for potential parents to decrease transmission of severe genetic disorders?

Trying to unlock a new door…..

Jermel Watkins — Mon, 28 Nov 2011 21:59:10 +0000

How is drug development moving along? Well, this is a very good question for we are still plagued by some elusive diseases, cancer for example. There have been many drugs developed targeting proteins involved in disease states some of which have proven to be quite effective. However today the steam engine for identifying drug targets to proteins involved in disease is becoming ever more difficult.
Apparently over the past decade or so, the number of new drugs targeted toward disease has declined. This is primarily due to the fact that developing new medicine has become more difficult to do. It turns out that this is partly because we have sifted through all the ideal proteins that can be targeted by a drug. The remaining proteins are not ideal for developing a targeted drug. These proteins dawn small cavities or binding pockets and are relatively flat allowing for little to no interaction with a drug target. Its been said that 15% of proteins can be targeted by drugs. The percent of proteins that modify disease is 10 to 15 %. In order to alleviate this problem scientist have acquired the help of computer modeling to more thoroughly identify and test favorable small molecules that can block the activity of these undruggable protein populations related to disease. Dr. Stockwell an Associate professor at Columbia University, has attempted computer modeling and has come across compounds to target a class of E3 ligases, which are characteristically undruggable, and involved in just about every disease. Of these compounds one in particularly was a potent inhibitor. Dr. Stockwell will be publishing his findings in the next few months on the efficacy of the inhibitor. If it proves worthy this new drug will have an impact on cancer and neurodegenerative disease.

The Medical Sleuth

Jermel Watkins — Mon, 31 Oct 2011 12:52:49 +0000

When we think of a detective the first thing that comes to mind is an investigator, either a member of a police agency or a private entity. However there are unique detectives within the multifaceted arena of medicine. All though we might already think of most doctors as detectives there are special doctors, units, working at the National Institute of Health’s (NIH) undiagnosed disease program. Doctors such as William A. Gahl at the NIH are disease detectives that try to elucidate the causes and genetic basis involved in the hundreds of unsolved and mysterious diseases that arise each year. Dr. Gahl who was interviewed for an article in scientific American explained that his group has accepted 400 out of 1700 special cases of unsolved disease. The selection process of these cases is tough, determining which cases are new diseases and if there is a possibility of determining the genetic and biochemical basis of the disease. As each case is worked mutations are identified that are associated with each disease. But Dr. Gahl States that this is only the beginning of the puzzle. The challenge becomes to identify the genetics with the pathology.

Dr. Gahls’ group has been working on a case in which a patient has endured pain for approximately twenty years and muscles of their legs have turned as hard as bricks limiting mobility. It was determined that the patient had a rare condition in which their blood vessels bore a thick coat of calcium that restricted blood flow. One of the first steps taken in the study was to examine the parents of the patient. The parents after examination were healthy, which lead the group to believe that the patients’ disposition might be due to a recessive mutation. Meaning that each parent had only one copy of a unique mutation but upon having children probability lead to the patient receiving two copies of the mutation. After an in depth study Dr. Gahls’ group identified the location of the mutation and the error prone gene associated. The gene that was identified is NT5E. NT5E is involved in the production of the nucleoside adenosine (which is involved in a number of biochemical processes). To examine this gene closely doctors cultured the patients skin cells and inserted the normal gene of NT5E and even introduced adenosine alone into the cells and miraculously they observed a reduction in calcification. Through this analysis a better understanding of adenosine in the regulation of calcium has been brought to light. However Dr. Gahl explains that there are a number of reasons why patients cannot just receive adenosine, but there is a class of osteoporosis drugs that pose as good candidates for treatment and they are waiting to see how these drugs perform.

Will insulin come to the rescue of AD patients?

Jermel Watkins — Tue, 27 Sep 2011 13:20:34 +0000

Alzheimer disease (AD) is a neurodegenerative disease of the brain that is divided into early- and late-onset groups. AD is characterized by the build up of amyloid plaques, neurofibrillary tangles and the loss of connections between neurons. It is the most common type of dementia especially in the elderly. The exact causes of AD are elusive at the moment but are most likely the result of genetics and other factors. Scientist have been working hard to identify individual and or groups of genes responsible for the disease. Although the scientific community has identified may genes involved in early and late onset groups, a new discovery has shed some light on the subject. In the intimate interplay of activities within the cells of the brain scientists have identified a key player, insulin. It is thought that dysfunction of insulin plays a crucial part in the exacerbation of symptoms.

The regions of the brain such as the hippocampus and the frontal cortex are densely populated with insulin receptors. As well they are found in synapses in which insulin signaling participates in synaptic remodeling and synaptogenesis (1,2). In parallel insulin regulatesthe utilization of glucose in the hippocampus and other regions of the brain to promote optimal memory in normal metabolism (3). In AD, it has been shown that reduced levels of insulin and insulin activity exist (4,5). Interestingly insulin has a tight relationship to amyloid beta, a toxic peptide responsible for the onset of the disease. Insulin can regulate the levels of amyloid beta to deliver protection from the degenerative nature of the peptide on neurons (6-8).

A pilot clinical trial published in the archives of neurology titled, Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment, has shown insulin’ ability to be a protective new therapy in the fight against AD. The trial hosted 104 participants, of which 30 participated in the use of a placebo, while insulin at 20IU and 40IU were delivered to 36 and 38 participants respectively. The insulin was administered through a nasal drug delivery device for a total of 4 months. Surprisingly the 20IU and 40IU group experienced improved memory recall and preserved general cognition.

It was very important to identify a method of administration of insulin properly and direct to the brain without disrupting blood sugar levels. When taken as a nasal spray it reaches the brain in just a few minutes with no apparent adverse affects on the body. Although a very promising study, it is still a preliminary study, more research will have to be carried out to ensure the safety and effectiveness of insulin as a therapy for longterm use against AD.

Chiu SL, Chen CM, Cline HT. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron. 2008;58(5):708-719. PUBMED
Zhao WQ, Townsend M. Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer’s disease. Biochim Biophys Acta. 2009;1792(5):482-496. PUBMED
McNay EC, Ong CT, McCrimmon RJ, Cresswell J, Bogan JS, Sherwin RS. Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem. 2010;93(4):546-553. PUBMED
Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte D Jr. Cerebrospinal fluid and plasma insulin levels in Alzheimer’s disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology. 1998;50(1):164-168. FREE FULL TEXT
Steen E, Terry BM, Rivera EJ; et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—is this type 3 diabetes? J Alzheimers Dis. 2005;7(1):63-80. PUBMED
De Felice FG, Vieira MN, Bomfim TR; et al. Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A. 2009;106(6):1971-1976. FREE FULL TEXT
Gasparini L, Gouras GK, Wang R; et al. Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci. 2001;21(8):2561-2570. FREE FULL TEXT
Lee CC, Kuo YM, Huang CC, Hsu KS. Insulin rescues amyloid beta-induced impairment of hippocampal long-term potentiation. Neurobiol Aging. 2009;30(3):377-387. PUBMED

Genetic Disorders Go B/Hollywood

Uwe Hilgert — Tue, 01 Dec 2009 17:15:42 +0000

Remember Brad Pitt as Benjamin Button? Benjamin’s disorder, that had him being born looking like an 80-year-old man and “reverse aging” to pass away as a baby? Well, while I still am not aware of a real disorder that causes this kind of a phenomenon, there is a disorder that indeed makes people age much faster than normal: Hutchinson-Gilford Progeria Syndrome (Progeria for short), which is about to be depicted in a movie of its own.

Progeria is a very rare, genetic disorder that afflicts roughly one in 5 million people. It is caused by a mutation in the LaminA gene on chromosome 1. The most striking symptom of Progeria-afflicted children is that they age rapidly. They frequently succumb to coronary artery disease before they reach 20 years of age.

Directed by R Balakrishnan the Indian movie company AB Corp Ltd. has released the movie “Paa”. The picture’s protagonist is a 13-year old boy afflicted with progeria – and is being played by an actor who is actually in his 60s. AB Corp Ltd. proclaims that Paa is not a movie about the disease Progeria, but about “how special children can fill your life with special brightness.”

Read more: about Progeria at the Progeria Research Foundation; about living with serious genetic disorders at the DNALC’s Your Genes, Your Health site.

How can I prolong health? Hmmm…..

Jermel Watkins — Sat, 07 Nov 2009 00:33:03 +0000

Having an edge on the stock market can allow one to make hundreds, thousands or even millions of dollars. But rarely do we think of having an edge on life. Since the sequencing of the human genome our understanding of human genes and their interaction has grown. Geneticists now have the capability to analyze genetic make-ups, and elucidate what genetic patterns will evolve into certain conditions or disease states.

Any individual has a unique genetic profile different from that of another person. Contained within these differences are unique genetic variations that may make a person more susceptible to diseases such as cancer and diabetes. There are genetic profiling centers that can assist you in identifying your genetic variations. With this information you and your physician can watch your health where it is at risk to becoming a problem and mold a life style toward prolonged health. In order to decrease the impact of a possible problem, it is important that you’re analysis be broad-spectrum and precise. It will be of great interest to identify the premier centers for analysis of genetic variants. Be curious and talk with your physician about the resources that will give you the edge in enhancing your quality of life.

Medicine or Poison? It’s in Your Genes, duh…

Uwe Hilgert — Thu, 24 Sep 2009 20:48:05 +0000

As the ongoing deciphering of the human genome provides us with more and more insights about our predisposition for diseases and genetic disorders, (see Your Genes Your Health for examples) I am equally, if not more astounded by what it tells us about our ability to utilize medicines to counteract diseases.

Just recently, a group of researchers at the University of Maryland School of Medicine have identified a variant of a gene that is believed to play a major role in determining why people do not respond to a popular anti-clotting medication. This gene variant, carried by as many as a third of the general population can put patients at increased risk for subsequent heart attacks, strokes and other serious cardiovascular problems. The interesting thing is, that this increased risk is not due to patients genetic predisposition for these disorders, but because it renders their medication ineffective.

Medicines that we introduce into our bodies often require one or several important mechanisms to unfold their intended effects: they may have to be actively transported into our cells, biochemically altered and thereby activated, or they may require deactivation and/or removal in order to not do more harm then good. Any of these processes may involve proteins on one level or another and, therefore, depend on genes. Thus, as we have maps that indicate the loci associated with genetic disorders (visit Tour > genome spots in DNA Interactive), we will soon have maps that tell us where to look if we wish to know our predisposition to the medications we use to cure ailments: whether they will do us any good, are totally useless or, in a worst case scenario, can even harm us.