News 30 march 2009
Scientists identify new role for
lung epithelial cells in sensing allergens in the air
Researchers at the National Institute of
Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and at
Ghent University in Ghent, Belgium, have identified a new role for certain lung cells in
the immune response to airborne allergens. Many foreign substances, called antigens, are
inhaled daily, but the lungs have mechanisms that usually prevent people from making
unwanted immune responses to these materials. Sometimes, however, immune responses are
generated to these substances, resulting in allergic responses and asthma. Scientists have
been working to understand what triggers these undesirable airway responses. In this new
study, conducted in mice, scientists discovered that special sensors called Toll-like
receptors (TLRs), which dot the surface of epithelial cells that line the lungs, detect
the presence of antigens and produce signals that activate immune cells. The researchers
observed that a particular TLR, TLR4, promoted allergic airway responses to antigen
mixtures containing bacterial material or a very common allergen from house dust mites.
Previously, it was unclear whether TLRs on non-immune epithelial cells at mucosal surfaces
such as those in the lungs were involved in antigen sensing, or if it was TLRs found on
immune cells in these areas that were critical to these allergic responses. The research
team observed that TLR4 on airway epithelial cells, not on immune cells, helped induce the
initial immune response to antigens in the lungs. Eliminating TLR4 or blocking TLR4
function on the airway epithelial cells reduced the recruitment of immune cells to the
lungs and the development of allergic disease. This study demonstrates that TLR4 found on
non-immune cells in the lungs contributes to the immune response to airborne antigens. The
new results suggest that targeting TLRs may be a research avenue for developing novel
treatments for allergic diseases such as asthma.
Melatonin may be served as a
potential anti-fibrotic drug
In China, the incidence of liver cirrhosis
is still high. Liver cirrhosis results from fibrosis. If treated properly at fibrosis
stage, cirrhosis can be prevented. However, no effective antifibrosis drugs are available
at present. Several lines of evidences suggest that oxidative stress plays an important
role in the etiopathogenesis of hepatic fibrosis. Melatonin can protect cells, tissues,
and organs against oxidative damage induced by a variety of free-radical-generating agents
and processes. A research team led by Professor Jian-Ming Xu from the First Affiliated
Hospital of Anhui Medical University, China evaluated the possible fibrosuppressant effect
of melatonin in rat. Their study will be published on March 28, 2009 in the World Journal
of Gastroenterology. In this study, hepatic fibrosis in rats was successfully induced by
subcutaneous injection of sterile CCl4 twice weekly for a total of 12 wk. At the beginning
of injection of CCl4, melatonin (2.5, 5, 10 mg/kg body weight) was intraperitoneally
administered to the rats daily for 12 wk. Hepatic fibrotic changes were evaluated
biochemically by measuring tissue hydroxyproline levels and histopathogical examination.
The serum activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST)
were used to evaluate the hepatic injury. Hepatic oxidative stress markers were evaluated
by changes in the amount of lipid peroxides, measured as malondialdehyde (MDA) and
glutathione peroxidase (GPx) in liver homogenates. Serum hyaluronic acid (HA), laminin
(LN), and procollagen 3 N-terminal peptide (P3NP) were determined as serum markers of
hepatic fibrogenesis.Their results suggested that treatment with melatonin (10 mg/kg)
could decrease the scores of hepatic fibrosis grading, reduced the contents of HA, LN in
serum and Hydroxyproline (HYP) in liver, treatment with melatonin (5,10 mg/kg ) could
decrease serum levels of ALT, AST and blocked the increase in MDA in rats with hepatic
injury caused by CCl4. Their result indicated melatonin could ameliorate CCl4-induced
hepatic fibrosis in rats. The protective effect of melatonin on hepatic fibrosis may be
related to its antioxidant activities. This may provide a basis for further studies on the
potentially protective effect of melatonin on liver function in cirrhotic patients
Gene linked to lupus might explain
gender difference in disease risk
In an international human genetic study,
researchers at UT Southwestern Medical Center have identified a gene linked to the
autoimmune disease lupus, and its location on the X chromosome might help explain why
females are 10 times more susceptible to the disease than males. Identifying this gene,
IRAK1, as a disease gene may also have therapeutic implications, said Dr. Chandra Mohan,
professor of internal medicine and senior author of the study. “Our work also shows
that blocking IRAK1 action shuts down lupus in an animal model. Though many genes may be
involved in lupus, we only have very limited information on them,” he said.The study
appears online this week in the Proceedings of the National Academy of Sciences. Locating
IRAK1 on the X chromosome also represents a breakthrough in explaining why lupus seems to
be sex-linked, Dr. Mohan said. For decades, researchers have focused on hormonal
differences between males and females as a cause of the gender difference, he pointed out.
“This first demonstration of an X chromosome gene as a disease susceptibility factor
in human lupus raises the possibility that the gender difference in rates may in part be
attributed to sex chromosome genes,” Dr. Mohan said. Systemic lupus erythematosus, or
lupus for short, causes a wide range of symptoms such as rashes, fever or fatigue that
make it difficult to diagnose. The multicenter study involved 759 people who developed
lupus as children, 5,337 patients who developed it as adults, and 5,317 healthy controls.
Each group comprised four ethnicities: European-Americans, African-Americans,
Asian-Americans and Hispanic-Americans.
Cancer mutations in the heart of
gene regulation?
Researchers have identified a new cancer
gene - one that is common to many cancers and affects the most basic regulation of our
genes. The new example - a gene on the X chromosome called UTX - is found in 10% of cases
of multiple myeloma and 8% of oesophageal cancers. UTX plays a role in overall regulation
of the activity of many genes and it is possible that other genes with similar roles will
also be found to be involved in different tumour types. This is the first example of
mutations in a gene of this functional class. The finding arose from a study of mutations
in 4000 genes in kidney cancer. "UTX is an important component of the transcriptional
control machinery - it influences some of the most fundamental mechanisms controlling gene
activity in our cells," explains Dr Andy Futreal, co-leader of the Cancer Genome
Project at the Wellcome Trust Sanger Institute. "Unlike many cancer genes, UTX does
not appear to be directly involved in cell division or cell death but in basic gene
regulation and shows the depths to which cancers will plumb in order to get themselves
ready to go." The normal UTX protein modifies part of the structure holding DNA
together in our cells. The composite DNA-protein structure, called chromatin, is not
simply a scaffold, but plays an active role in controlling gene activity. The UTX protein
alters a key organising subunit component of chromatin, called a histone. The protein is
likely to be involved in both turning genes on and off, making it a key regulator of the
yin-yang of gene control. In the massive DNA sequencing study, the team found rare
mutations of the UTX gene in clear cell renal cancer - a type of kidney cancer. When they
expanded the search they found mutations in many cancer types - including one in ten
multiple myeloma and one in twelve oesophageal cancer cases. "This work shows that
mutations in genes with different functions can be found in human cancer through
systematic approaches. These results indicate that cancer genes are not restricted to
'classical' roles of survival and cell proliferation, but can affect a variety of other
cellular mechanisms," explains Professor Victor Velculescu, Associate Professor of
Oncology and Director of Cancer Genetics from the Ludwig Center at Johns Hopkins and
co-Director of Cancer Biology, at Johns Hopkins Kimmel Cancer Center. "UTX wouldn't
have been found without this high-throughput type of study and indicates the type of novel
findings we might expect from the International Cancer Genome Consortium."
Tea tree oil and silver together
make more effective antiseptics
In the fight against infected skin wounds,
mixing tea tree oil and silver or putting them in liposomes, (small spheres made from
natural lipids), greatly increases their antimicrobial activity and may minimise any side
effects. Wan Li Low and colleagues from the University of Wolverhampton presented research
at the Society for General Microbiology meeting in Harrogate today (30 March) which showed
that although both tea tree oil and silver (in the form of silver nitrate) were effective
against a range of micro-organisms, when low concentrations of the two agents were
combined, their antimicrobial activity increased. They carried out laboratory tests on
pathogens that are involved in skin infections. Bacteria such as Staphylococcus aureus
(which is a common cause of skin infections and abscesses), and the yeast Candida
albicans, which causes thrush, were killed. These positive findings led the researchers to
use microscopic spherical bodies called liposomes, made of phospholipids, the naturally
occurring lipids or fats in the cell wallsmembranes, to deliver the silver and tea tree
oil mix to infected wounds the pathogens. This technique allows controlled release and
therefore has the potential to use lower, less toxic, concentrations of the antimicrobial
agents to treat infected wounds. This may also be of value to treat antibiotic resistant
strains such as MRSA. Used alone, both silver and tea tree oil can cause side effects in
patients. Over exposure to silver can cause a bluish-grey discolouration of the skin and
applying unregulated amounts of tea tree oil externally can cause skin irritation. With
increasing life expectancy, age related conditions such as chronic leg ulcers or bedsores
are likely to become more common. Current treatments using traditional silver-based creams
and dressings use relatively high metal concentrations. Creams containing lower amounts of
the agents could provide safer and readily available over-the-counter antiseptic compounds
for effective treatment without damaging the surrounding skin.
Spreading antibiotics in the soil
affects microbial ecosystems
Antibiotics used extensively in intensive
livestock production may be having an adverse effect on agricultural soil ecosystems. In a
presentation to the Society for General Microbiology meeting at Harrogate International
Centre, today (Monday 30 March), Dr Heike Schmitt from the University of Utrecht, the
Netherlands described how antibiotics passed from the animals in manure that was then
spread on farmland. Although higher organisms, such as earthworms, would only be affected
at unrealistic concentrations of antibiotics, changes in soil bacterial communities have
been found repeatedly using molecular microbiological techniques. Bacteria involved in the
nitrogen cycle, which replenishes nutrients in the soil, seem to be particularly affected.
The effects persisted over several weeks and were still seen even when the antibiotics had
broken down significantly. In addition the microbial population of the soil changed as
fungi replaced the bacteria suppressed by the antibiotics. "The antibiotic
concentrations that to date have been found in agricultural soils are smaller than the
concentrations at which the adverse effects start occurring", said Dr Schmitt,
"However, this might not be the case for 'hot spots", for example, when manure
is not mixed thoroughly in the soil."
Skin cancer study uncovers new
tumor suppressor gene
National Institutes of Health (NIH)
researchers have identified a gene that suppresses tumor growth in melanoma, the deadliest
form of skin cancer. The finding is reported today in the journal Nature Genetics as part
of a systematic genetic analysis of a group of enzymes implicated in skin cancer and many
other types of cancer. The NIH analysis found that one-quarter of human melanoma tumors
had changes, or mutations, in genes that code for matrix metalloproteinase (MMP) enzymes.
The findings lay the foundation for more individualized cancer treatment strategies where
MMP and other key enzymes play a functional role in tumor growth and spread of the
disease. Tumor suppressor genes encode proteins that normally serve as a brake on cell
growth. When such genes are mutated, the brake may be lifted, resulting in the runaway
cell growth known as cancer. In contrast, oncogenes are genes that encode proteins
involved in normal cell growth. When such genes are mutated, they also may cause cancer,
but they do so by activating growth-promoting signals. Cancer therapies that target
oncogenes usually seek to block or reduce their action, while those aimed at tumor
suppressor genes seek to restore or increase their action. The new study may help to
explain the disappointing performance of drugs designed to treat cancer by blocking MMP
enzymes. Because members of the MMP gene family were thought to be oncogenes and many
tumors express high levels of MMP enzymes, researchers have spent decades pursuing MMPs as
promising targets for cancer therapies. However, when MMP inhibitors were tested in people
with a wide range of cancers, the drugs failed to slow -- and in some cases even sped up
-- tumor growth. Now, it turns out that one of the most often mutated MMP genes in
melanoma is not an oncogene at all. In its study, the team led by researchers from the
National Human Genome Research Institute (NHGRI) found that MMP-8 actually serves as a
tumor suppressor gene in melanoma. Consequently, in the estimated 6 percent of melanoma
patients whose tumors harbor a mutated MMP-8 gene or related tumor suppressor(s), it may
not be wise to block all MMPs. The study suggests that a better approach may be to look
for drugs that restore or increase MMP-8 function or for drugs that block only those MMPs
that are truly oncogenes.
Autism skews developing brain with
synchronous motion and sound
Individuals with autism spectrum disorders
(ASD) tend to stare at people's mouths rather than their eyes. Now, an NIH-funded study in
2-year-olds with the social deficit disorder suggests why they might find mouths so
attractive: lip-sync—the exact match of lip motion and speech sound. Such audiovisual
synchrony preoccupied toddlers who have autism, while their unaffected peers focused on
socially meaningful movements of the human body, such as gestures and facial expressions.
"Typically developing children pay special attention to human movement from very
early in life, within days of being born. But in children with autism, even as old as two
years, we saw no evidence of this," explained Ami Klin, Ph.D., of the Yale Child
Study Center, who led the research. "Toddlers with autism are missing rich social
information imparted by these cues, and this is likely to adversely affect the course of
their development." Klin, Warren Jones, Ph.D., and colleagues at Yale, report the
findings of their study, funded in part by the National Institute of Health's National
Institute of Mental Health, online March 29, 2009 in the journal Nature. For the first
time, this study has pinpointed what grabs the attention of toddlers with ASDs," said
NIMH Director Thomas R. Insel, M.D. "In addition to potential uses in screening for
early diagnosis, this line of research holds promise for development of new therapies
based on redirecting visual attention in children with these disorders."
A eureka moment in the research came when researchers followed up on a clue from
children's responses to audiovisual synchrony embedded in a nursery rhyme cartoon. While
it was known that people with autism do not spontaneously orient to social signals, it was
unclear what early-emerging mechanism may contribute to that. Nor was it clear exactly
what they were attending to instead. To find out, Klin, Jones and colleagues tracked the
eye movements of two-year-olds with and without the disorder while they looked at cartoon
animations on split-screen displays.The researchers borrowed a technique from the video
game industry, called motion capture. They then reduced the movements to only points of
light at each joint in the body, like animated constellations. These cartoons played
normally – upright and forward – on one half of the screen, but upside-down and
in reverse on the other half. The inverted presentation engages different brain circuits
and is known to disrupt perception of biological motion in young children. The normal
soundtrack of the actor's voice, recorded when the animations were made, accompanied the
presentations.
Mayo Clinic researchers discover
and manipulate molecular interplay that moves cancer cells
Based on research that reveals new insight
into mechanisms that allow invasive tumor cells to move, researchers at the Mayo Clinic
campus in Florida have a new understanding about how to stop cancer from spreading. A
cancer that spreads elsewhere in the body, known as metastasis, is the process that most
often leads to death from the disease. In the March 29 online issue of Nature Cell
Biology, researchers say that a molecule known as protein kinase D1 (PKD1) is key to the
ability of a tumor cell to "remodel" its structure, enabling it to migrate and
invade. The researchers found that if PKD1 is active, tumor cells cannot move, a finding
they say explains why PKD1 is silenced in some invasive cancers. During metastasis,
invasive cancer cells respond to biological signals to move away from a primary tumor.
Multiple research groups at Mayo Clinic in Florida are especially interested in this
process. One team, led by cancer biologist Peter Storz, Ph.D., has been investigating a
process known as actin remodeling at the leading edge - the most forward point - of these
migrating tumor cells. "The events that reorganize the actin cytoskeleton at the
leading edge are complex — a multitude of molecules act in concert," Dr. Storz
says. "But it appears that PKD1 must be turned off if cancer cells are to
migrate." Actin filaments help make up the cytoskeleton of cells. For cancer cells to
move, the actin-based cell structure has to be continually reorganized, Dr. Storz says,
and to do this, new actin filaments need to be generated to shift the cell forward. Dr.
Storz' group discovered that PKD1 was critical to this process. The researchers found that
PKD1 inhibits another protein known as slingshot, which regulates the severing of existing
actin structures so that new actin filaments can be synthesized, an event that is
essential for cell movement.
After heart attack, bone marrow
stem cells increase blood flow within heart
Patients treated with their own bone marrow
stem cells after a heart attack experienced increased circulation within the heart, a
study by Emory University School of Medicine physicians has found. Principal investigator
Arshed Quyyumi, MD, professor of medicine at Emory University School of Medicine, presents
the results Monday at the American College of Cardiology conference in Orlando.
"These results show that treatment with a patient's own bone marrow stem cells has
the potential to reduce long-term complications after a heart attack," Quyyumi says.
"We are encouraged by these results and are planning to conduct a more extensive
study." A severe enough heart attack can lead to remodeling of the heart muscle and
increased risk of heart failure and other complications. Several groups of researchers
around the world have reported clinical trials in which cells from the bone marrow are
used to try to restore the heart's pumping power, with mixed results. This study was one
of the first to use a preparation of bone marrow cells enriched for endothelial progenitor
cells, which are thought to replenish the linings of blood vessels. Emory University,
Vanderbilt University, The Lindner Research Center, Cincinnati, and Texas Heart Center in
Houston participated. In the clinical trial, which began in June 2006, 31 patients were
treated by angioplasty and stent placement after a heart attack. Within a week after their
heart attacks, 16 of the patients had bone marrow cells infused into the coronary artery
where a blockage caused the heart attack.
