Did you know?? Omega-3 Kills Cancer Cells

Docosahexanoic acid (DHA), an omega-3 fatty acid found in fish oils, has been shown to reduce the size of tumours and enhance the positive effects of the chemotherapy drug cisplatin, while limiting its harmful side effects. The rat experiments provide some support for the plethora of health benefits often ascribed to omega-3 acids.

DHA is an omega-3 fatty acid that is commonly found in cold-water fish oil, and some vegetable oils. It is a major component of brain gray matter and of the retina in most mammalian species and is considered essential for normal neurological and cellular developments. According to the authors, "While DHA has been tentatively linked with protection against cardiovascular, neurological and neoplastic diseases, there exists a paucity of research information, in particular regarding its interactions with existing chemotherapy drugs". The researchers found that, at the molecular level, DHA acts by reducing leukocytosis (white blood cell accumulation), systemic inflammation, and oxidative stress – all processes that have been linked with tumour growth.

El-Mowafy and his colleagues have called for greater deployment of omega-3 in the fight against cancer. They write, "Our results suggest a new, fruitful drug regimen in the management of solid tumors based on combining cisplatin, and possibly other chemotherapeutics, with DHA".

Human Genes Required For Hepatitis C Viral Replication Identified

Massachusetts General Hospital (MGH) researchers are investigating a new way to block reproduction of the hepatitis C virus (HCV) – targeting not the virus itself but the human genes the virus exploits in its life cycle. In the March 19 Cell Host & Microbe, they report finding nearly 100 genes that support the replication of HCV and show that blocking several of them can suppress viral replication in cultured cells.

"We identified a large number of genes that have not been previously known to be involved in hepatitis C replication," says Raymond Chung, MD, director of Hepatology in the MGH Gastrointestinal Unit, the study's senior author.

Lead author Andrew Tai, MD, PhD, also of the MGH Gastrointestinal Unit, adds, "We may be a few years away from developing therapies based on these findings, but this study is a proof of principle that targeting host factors is a viable therapeutic strategy."

Usually spread by blood-to-blood contact, HCV infection becomes chronic in 70 to 80 percent of patients, and long-term infection can lead to liver failure or liver cancer. Today HCV-related liver disease is the most common diagnosis underlying the need for liver transplantation. HCV infection is usually treated with a six- to eleven-month regimen combining peginterferon and the antiviral drug ribavirin, but treatment is not successful in many patients and has serious side effects some cannot tolerate. Other therapies targeting viral enzymes are being developed, but there is concern that HCV's ability to mutate rapidly would lead to the emergence of resistant strains, so strategies directed against factors in the infected host rather than the virus may offer a complementary approach.

These strategies are being explored in a number of diseases – including influenza, West Nile virus and HIV – and previous studies have scanned a limited number of human genes for host cofactors of HCV infection. For the current study the researchers examined whether blocking each of the approximately 21,000 predicted messenger RNA transcripts in the human genome with small interfering RNAs (siRNAs) had any effect on HCV replication. Chung notes that this approach does not rely on any prior assumptions about gene function and can thereby identify genes not previously suspected of involvement.

The siRNA scan found 96 genes that appear to have a role in viral replication, and the research team studied several of them in greater detail. One gene codes for an enzyme called PI4KA, which is believed to be involved in the formation of membrane structures within the cell that may be the site of HCV replication. Another group of genes contribute to formation of the COPI coat that covers several types of cellular vesicles and is known to have a role in the replication of poliovirus. The researchers also focused on the gene for hepcidin, a liver protein that regulates iron absorption, since iron levels in the blood and liver rise in chronic HCV infection. They found that blocking each of these genes also blocked HCV replication, as did drugs that inhibit PI4KA and COPI, although the tested agents might not be suitable for therapeutic use.

"Now we need to work to uncover the molecular mechanisms by which these genes support HCV replication to get a better idea of which would be advantageous therapeutic targets," explains Chung, an associate professor of Medicine at Harvard Medical School.

Additional co-authors of the Cell Host & Microbe paper are Yair Benita, PhD, Sun-Suk Kim, MD, and Ramnik Xavier, MB,ChB, MGH Gastrointestinal Unit; and Naoya Sakamoto, MD, PhD,Tokyo Medical and Dental University. The study was supported by grants from the National Institutes of Health, the Massachusetts Biomedical Research Corporation, the American Gastrointestinal Association and the American Liver Foundation.

Newly Identified Protein May Inhibit Hepatitis Virus

A newly identified family of proteins may inhibit replication of the
Hepatitis B (HBV) and C (HCV) viruses say researchers from California.
Their findings appear in the March 2005 issue of the Journal of
Virology.Hepatitis B (HBV) and C (HCV) are viruses that infect the liver, and in some cases can cause liver failure requiring a transplant for survival. The protein interferon, produced by animal cells when they are invaded by viruses, is released into the bloodstream or intercellular fluid to induce healthy cells to manufacture an enzyme that counters the infection. One class of interferons (alpha) is used to treat chronic infection with HBV and HCV. There is a vaccine available to prevent the spread of HBV but not HCV.

In the study, a new class of interferons, interferon lambda, was tested for its ability to inhibit HBV and HCV replication. Results showed 90% inhibition of HBV after twenty-four hours and 90-99% inhibition in HCV five days posttreatment.

“We have demonstrated here that replication of HBV and HCV is sensitive to the antiviral activities of interferon lambda,” say the researchers. “These results suggest the possibility that interferon lambda may be therapeutically useful in the treatment of chronic HBV or HCV infection.”

(M.D. Robek, B.S. Boyd, F.V. Chisari. 2005. Lambda interferon inhibits hepatitis B and C virus replication. Journal of Virology, 79. 6: 3851-3854.)

Mutated Gene In Zebrafish Sheds Light On Blindness In Humans

Described in a paper published in the Proceedings of the National Academy of Sciences (PNAS), the landmark study of retinal development in zebrafish larvae and the genetic switch it has identified should shed new light on the molecular mechanisms underlying that development and, consequently, provide needed insight on inherited retinal diseases in humans.

From FSU's Department of Biological Science and Program in Neuroscience, doctoral candidate Karen Alvarez-Delfin (first author of the PNAS paper), postdoctoral fellow Ann Morris (second author), and Associate Professor James M. Fadool are the first scientists to identify the crucial function of a previously known gene called "tbx2b." The researchers have named the newfound allele (a different form of a gene) "lor" -- for "lots-of-rods" -- because the mutation results in too many rods and fewer ultraviolet cones than in the normal eye.

"Our goal is to generate animal models of inherited diseases of the eye and retina to understand the progression of disease and find more effective treatments for blindness," said Fadool, faculty advisor to Alvarez-Delfin and principal investigator for Morris's ongoing research. "We are excited about the mutation that Karen has identified because it is one of the few mutations in this clinically critical pathway that is responsible for cells developing into one photoreceptor subtype rather than another."

"What is striking in this case is that the photoreceptor cell changes we observed in the retinas of zebrafish are opposite to the changes identified in Enhanced S-cone syndrome (ESCS), an inherited human retinal dystrophy in which the rods express genes usually only found in cones, eventually leading to blindness," Alvarez-Delfin said. "Equally surprising is that this study and others from our lab show that while alterations in photoreceptor development in the human and mouse eyes lead to retinal degeneration and blindness, they don't in zebrafish. Therefore, the work from our Florida State lab and with our collaborators at the University of Pennsylvania, Vanderbilt University and the University of Louisville should provide a model for better understanding the differences in outcomes between mammals and fish, and why the human mutation leads to degenerative disease."

Morris calls the zebrafish an ideal genetic model for studies of development and disease. The common aquarium species are vertebrates, like humans. Their retinal organization and cell types are similar to those in humans. Zebrafish mature rapidly, and lay many eggs. The embryos are transparent, and they develop externally, unlike mammals, which develop in utero.

"This lets us study developmental processes such as the formation of tissues and organs in living animals," she said.

"From a developmental biology perspective, our research will help us unravel the competing signals necessary for generating the different photoreceptor cell types in their appropriate numbers and arrangement," Morris said. "The highly specialized nature of rods and cones may make them particularly vulnerable to inherited diseases and environmental damage in humans. Understanding the genetic processes of photoreceptor development could lead to clinical treatments for the millions of people affected by photoreceptor cell dystrophies such as retinitis pigmentosa and macular degeneration."

The mosaic arrangement of photoreceptors in fish was first described more than 100 years ago, but the J. Fadool laboratory at Florida State was the first to successfully take advantage of the pattern to identify mutations affecting photoreceptor development and degeneration.

"Imagine a tile mosaic," Fadool said. "That is the kind of geometric pattern formed by the rod and cone photoreceptors in the zebrafish retina. This mosaic is similar to the pattern of a checkerboard but with four colors rather than two alternating in a square pattern. The red-, green-, blue-, and ultraviolet-sensitive cones are always arranged in a precise repeating pattern. Human retinas have a photoreceptor mosaic, too, but here the term is used loosely, because while the arrangement of the different photoreceptors is nonrandom, they don't form the geometric pattern observed in zebrafish.

"So how do we ask a fish if it has photoreceptor defects?" he asked.

Fadool explained that because the mosaic pattern of zebrafish photoreceptors is so precise, mutations causing subtle alterations are easier to uncover than in retinas with a "messier" arrangement.

"Just as we can easily recognize a checkerboard mistakenly manufactured with some of the squares changed from black to red or with all-black squares, by using fluorescent labeling and fluorescence microscopes we can see similar changes in the pattern of the zebrafish photoreceptor mosaic," he said. "Karen showed that within the mosaic of the lots-of-rod fish, the position on the checkerboard normally occupied by a UV cone is replaced with a rod. The identity of the mutated gene is then discovered using a combination of classical genetics and genomic resources."

Funding for the Fadool laboratory's zebrafish research comes in large part from a five-year grant totaling more than $1.7 million from the National Institutes of Health.

Rejoice Fatboys!! Fitness More Than Fatness Determines Your Health and Longevity

Did you know that fitness level is a strong predictor of longevity, especially for adults over age 60? While obesity receives much airtime as a public health problem, it seems that being thin is not the be-all and end-all of a healthy body.

Results of a 12-year study have indicated that fitness levels can be more important than your weight levels and can definitely influence whether or not you suffer from health problems and die earlier than those who are physically fit but not necessarily thin.

The 12-year study was conducted by Professor Steven Blair from the University of South Carolina in Columbia. Researchers looked at the relationship between body fat, fitness and longevity in 2,603 people over the age of 60.

At the start of the study, fitness levels were assessed using a treadmill stress test and body fat was calculated by various measures, including BMI, waist circumference and fat percentages. The volunteers had follow-up medical checks over the 12-year study period.

The overall results showed that fit adults who engage in cardiovascular exercise on a regular basis outlived the unfit, regardless of their level of obesity or waist size. There were 450 deaths during the study. Researchers found that those who died were older, had lower fitness levels and had more cardiovascular risk factors than survivors.

Death rates for those with higher fitness levels were less than half of the rates for those who were unfit and not surprisingly they were less likely to have risk factors for cardiovascular disease, such as hypertension, diabetes, or high cholesterol levels. The exception however was with those who were severely obese or with large amounts of abdominal fat.

The message from these study results is that there is great benefit to being physically active on a regular basis even if you are overweight. Exercise has a systematic effect on many levels - it strengthens the heart, the lungs and builds up the skeletal muscles. It also provides great benefit to the brain and the overall well-being of the person. It is important though to maintain a healthy body weight at the same time.

"Our data provides further evidence regarding the complex long-term relationship among fitness, body size and survival. It may be possible to reduce all-cause death rates among older adults, including those who are obese, by promoting regular physical activity, such as brisk walking for 30 minutes or more on most days of the week," said Dr. Xuemei Sui of the University of South Carolina.