White blood cell enzyme contributes to inflammation and obesity

Many recent studies have suggested that obesity is associated with chronic inflammation in fat tissues. Researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) have discovered that an imbalance between an enzyme called neutrophil elastase and its inhibitor causes inflammation, obesity, insulin resistance, and fatty liver disease. This enzyme is produced by white blood cells called neutrophils, which play an important role in the body's immune defense against bacteria. The researchers found that obese humans and mice have increased neutrophil elastase activity and decreased levels of α1-antitrypsin, a protein that inhibits the elastase. When the team reversed this imbalance in a mouse model and fed them a high-fat diet, the mice were resistant to body weight gain, insulin resistance (a precursor to type 2 diabetes), and fatty liver disease

Left: In fat tissue from a lean mouse, neutrophil elastase and a1-antitrypsin levels are balanced. Right: In fat tissue from an obese mouse, they are imbalanced -- neutrophil elastase levels are high (dark staining) and a1-antitrypsin levels are low. Credit: Sanford-Burnham Medical Research Institute

Their study appears April 2 in Cell Metabolism.

"The imbalance between neutrophil elastase and its inhibitor, α1-antitrypsin, is likely an important contributing factor in the development of obesity, inflammation, and other health problems. Shifting this balance—by either reducing one or increasing the other—could provide a new therapeutic approach to preventing and treating obesity and several obesity-related conditions," said Zhen Jiang, Ph.D., assistant professor in Sanford-Burnham's Diabetes and Obesity Research Center at Lake Nona, Orlando and senior author of the study.

What happens when you reduce neutrophil elastase levels

This study began when Jiang and his team noticed that neutrophil elastase levels are particularly high and α1-antitrypsin levels are low in a mouse model of obesity. Then they saw the same thing in blood samples from human male volunteers. To further probe this curious neutrophil elastase-obesity relationship, the researcher turned once again to mouse models. They found that mice completely lacking the neutrophil elastase enzyme don't get as fat as normal mice, even when fed a high-fat diet. Those mice were also protected against inflammation, insulin resistance, and fatty liver. The same was true in a mouse model genetically modified to produce human α1-antitrypsin, which inhibits neutrophil elastase. Normal mice on a high-fat diet were also protected against inflammation, insulin resistance, and fatty liver when they were given a chemical compound that inhibits neutrophil elastase. This finding helps validate the team's conclusions about neutrophil elastase's role in inflammation and metabolism and also suggests that a medicinal drug could someday be developed to target this enzyme.

Mechanism: how neutrophil elastase influences inflammation and metabolism

How do high neutrophil elastase levels increase inflammation and cause weight gain and other metabolic problems?

Jiang and his team began connecting the mechanistic dots. They discovered that neutrophil elastase-deficient mice have increased levels of several factors, including adiponectin, AMPK, and fatty acid oxidation. These are known for their roles in increasing energy expenditure, thus helping the body burn excess fat. 

Journal reference: Cell Metabolism 

Provided by Sanford-Burnham Medical Research Institute.

Read More

Teens, obesity and links to sleep, TV time and Vitamin D: Healthy Living

Scientists seem to spend a lot of time pondering teens and their weight. Check out a few of the studies making news:

SNOOZE TIME: Parents might want to let junior sleep in.

A new study by researchers from the Perelman School of Medicine at the University of Pennsylvania and published in the journal Pediatrics, showed that fewer hours of sleep is associated with greater increases in adolescent body mass index among study participants aged 14 to 18. Increasing sleep duration to 10 hours per day, especially for those in the upper half of the BMI distribution, the study suggests, could help to reduce the prevalence of adolescent obesity.

TV TIME: Researchers at Boston Children's Hospital have shown that paying attention to TV is strongly associated with higher body mass index, medicalxpress.com reports. The study, published in next month's issue of Pediatrics but already online, found no association between BMI and attention to video games or computers, despite the duration of use.

VITAMIN D: Vitamin D supplements can help obese children and teens control their blood-sugar levels, which may help them stave off Type 2 diabetes, researchers found in a study involving pre-diabetic obese children and adolescents in the University of Missouri's Adolescent Diabetic Obesity Program.

Read more: Vitamins are very nutrients in the living things

"For clinicians, the main message from this research is to check the vitamin D status of their obese patients, because they're likely to have insufficient amounts," said Catherine Peterson, associate professor of nutrition and exercise physiology. "Adding vitamin D supplements to their diets may be an effective addition to treating obesity and its associated insulin resistance."

Read More: Vitamin D may help protect smokers’ lungs

The study was published in the American Journal of Clinical Nutrition.

Source: Visit The Oregonian (Portland, Ore.)

Read More

Gene linked to higher Alzheimer's risk

A new gene mutation has been identified that nearly doubles African Americans' risk for Alzheimer's disease, a large, government-funded report said Tuesday (9th April 2013).

The mutation in the gene ABCA7 is not the first linked to Alzheimer's disease, but its discovery is a major breakthrough in research, suggesting there could be multiple causes of Alzheimer's and therefore multiple ways to treat the most common form of dementia, says the report, published Tuesday in the Journal of the American Medical Association.

There is no effective way to prevent, cure or delay Alzheimer's, a neurodegenerative illness that robs people of memory and other cognitive and emotional functions.

The predominant late-onset form of Alzheimer's occurs after age 65 and is more common in blacks than whites. The study involved almost 6,000 black volunteers who received genetic testing; about 2,000 were diagnosed with probable Alzheimer's, and 4,000 were cognitively normal.

"The first thing this tells us is there are probably many different ways to get Alzheimer's," says the study's senior author, Richard Mayeux, chairman of the department of neurology at Columbia University Medical Center in New York.

"It might be like some forms of cancer where the type of cancer you have dictates the type of treatment you receive."

The ABCA7 gene is involved in producing cholesterol and lipids, suggesting they may be a more important pathway in Alzheimer's disease in blacks than in whites, the authors say. High cholesterol and lipid levels can lead to vascular disease, heart attacks and strokes and are more common in blacks. Treatments that lower cholesterol and lipids might be an effective way to reduce or delay Alzheimer's in patients with the gene variant, Mayeux says.

A variant, or mutation, is an abnormal change in the sequence of the chemicals inside a gene. Whites with the ABCA7 mutation are also at increased risk, but not as significantly as blacks, he adds.

Several gene mutations have been linked with Alzheimer's risk; the most significant in whites and blacks alike has been APOE-e4, Mayeux says. But the study's authors say that both ABCA7 and APOE-e4 are "major genetic risk factors" in blacks.

"This is a major finding because it shows that blacks have an additional risk factor compared to whites," says Neil Buckholtz, director of neuroscience at the National Institute on Aging, a branch of the National Institutes of Health. NIH financed the study.

"It's a highly significant risk that doesn't exist in other populations. In order to find interventions, we need to explore all the various risks."

APOE-e4 is associated with an increased number of amyloid plaques in the brain, which form into toxic clumps that destroy brain cells. Other processes, such as inflammation and insulin receptivity, are also being explored as possible contributors. ABCA7 also transports a precursor of amyloid plaques.

"We're definitely finding that there are layers to the disease," says Heather Snyder, a researcher for the Alzheimer's Association. She was not involved in the study.

"We need to do more research to find out what these targets are doing in the brain so we can find treatments and ways of delaying the disease from starting," she says.

About 5 million adults in the USA have Alzheimer's, and numbers are expected to almost triple by 2050 and cost $1.1 trillion a year.

About one-third of the people who have late-onset Alzheimer's are 80 and older. It is the only disease among the top 10 killers that has no effective treatments.

Snyder says the Alzheimer's Association does not recommend that people get genetic testing because the links aren't clearly established and some people who have the gene variants do not develop the disease.

Copyright USA TODAY 2013

Read More

What is RNase? What is the importance in living things?

RNase means Ribonuclease. It is RNA digesting enzyme. It is another noteworthy example of a protein with tertiary structure.  Let us see the basic details now.

• The molecular weight of RNase is 13,700.
• Christian Anfinsen (1950) and William stein (1958) have elucidated the complete structure of this pancreatic protein.
• RNase consists of 124 amino acids in one polypeptide chain with 4 disulphide linkages.
• The RNAse is hydrolyzed by Pepsin and Trypsin.

Classification of RNase enzymes:

Ribonucleases can be divided into Endoribonucleases and Exoribonucleases, and comprise several sub-classes within the EC 2.7 (for the phosphorolytic enzymes) and 3.1 (for the hydrolytic enzymes) classes of enzymes.

Major types of Endoribonucleases:

• RNase A is an RNase that is commonly used in research. RNase A (e.g., bovine pancreatic ribonuclease A) is one of the hardiest enzymes in common laboratory usage; one method of isolating it is to boil a crude cellular extract until all enzymes other than RNase A are denatured. It is specific for single-stranded RNAs. It cleaves the 3'-end of unpaired C and U residues, ultimately forming a 3'-phosphorylated product via a 2',3'-cyclic monophosphate intermediate.

• RNase H is a ribonuclease that cleaves the RNA in a DNA/RNA duplex to produce ssDNA. RNase H is a non-specific endonuclease and catalyzes the cleavage of RNA via a hydrolytic mechanism, aided by an enzyme-bound divalent metal ion. RNase H leaves a 5'-phosphorylated product.

• RNase I cleaves 3'-end of ssRNA at all dinucleotide bonds leaving a 5'-hydroxyl, and 3'-phosphate, via a 2',3'-cyclic monophosphate intermediate.

• RNase III is a type of ribonuclease that cleaves rRNA (16s rRNA and 23s rRNA) from transcribed polycistronic RNA operon in prokaryotes. It also digests double strands RNA (dsRNS)-Dicer family of RNAse, cutting pre-miRNA (60–70bp long) at a specific site and transforming it in miRNA (22–30bp), that is actively involved in the regulation of transcription and mRNA life-time.

• RNase L is an interferon-induced nuclease that, upon activation, destroys all RNA within the cell

• RNase P is a type of ribonuclease that is unique in that it is a ribozyme – a ribonucleic acid that acts as a catalyst in the same way as an enzyme. Its function is to cleave off an extra, or precursor, sequence on tRNA molecules. RNase P is one of two known multiple turnover ribozymes in nature. A form of RNase P that is a protein and does not contain RNA has recently been discovered.

• RNase PhyM is sequence specific for single-stranded RNAs. It cleaves 3'-end of unpaired A and U residues.

• RNase T1 is sequence specific for single-stranded RNAs. It cleaves 3'-end of unpaired G residues.

• RNase T2 is sequence specific for single-stranded RNAs. It cleaves 3'-end of all 4 residues, but preferentially 3'-end of As.

• RNase U2 is sequence specific for single-stranded RNAs. It cleaves 3'-end of unpaired A residues.

• RNase V1 is non-sequence specific for double-stranded RNAs. It cleaves base-paired nucleotide residues.

• RNase V

Major categories of Exoribonucleases:

• Polynucleotide Phosphorylase (PNPase) functions as an exonuclease as well as a nucleotidyltransferase.

• RNase PH functions as an exonuclease as well as a nucleotidyltransferase.

• RNase II is responsible for the processive 3'-to-5' degradation of single-stranded RNA.

• RNase R is a close homolog of RNase II, but it can, unlike RNase II, degrade RNA with secondary structures without help of accessory factors.

• RNase D is involved in the 3'-to-5' processing of pre-tRNAs.

• RNase T is the major contributor for the 3'-to-5' maturation of many stable RNAs.

• Oligoribonuclease degrades short oligonucleotides to mononucleotides.

• Exoribonuclease I degrades single-stranded RNA from 5'-to-3', exists only in eukaryotes.

•  Exoribonuclease II is a close homolog of Exoribonuclease I.

Function:

• All organisms studied contain many RNases of many different classes, showing that RNA degradation is a very ancient and important process.
• As well as cleaning of cellular RNA that is no longer required, RNases play key roles in the maturation of all RNA molecules, both messenger RNAs that carry genetic material for making proteins, and non-coding RNAs that function in varied cellular processes.
• In addition, active RNA degradation systems are a first defense against RNA viruses, and provide the underlying machinery for more advanced cellular immune strategies such as RNAi.

Read More:

1. What is Proteins? How the proteins are classified?
2. Protein fundamental molecules are Amino acids
3. What is Peptide Bond?
4. What is the primary structure of Proteins?
5. How the Proteins are classified in Secondary structure?
6. What type of stabilization forces are involved in protein organization?
7. How the proteins are organized in tertiary structure?
8. How the Proteins are organized in quaternary structure?    

Read More

What is Myoglobin? What is the function of Myoglobin?

One of the most important proteins in the human body is MYOGLOBIN. Today we are discussing about Myoglobin in this post. Generally Myoglobin is found in muscle tissue, where it binds oxygen, helping to provide extra oxygen to release energy to power muscular contractions.

Let us come to the history of Myoglobin, Myoglobin was the first protein whose structure was determined. In 1958, Max Perutz and John Kendrew determined the 3D structure of myoglobin by X-ray crystallography. In 1962 a share of the Nobel Prize for Chemistry was awarded to John C. Kendrew for work, utilizing the technique of X-ray diffraction, that permitted construction of a three-dimensional model of crystalline sperm-whale myoglobin.

Ok Now let us know the basic points of Myoglobin:

• Myoglobin (myo^G-Muscle; globin^G=a type of protein) is a relatively small, oxygen-binding heme protein, found in muscle cells.
• Myoglobin is a monomeric protein that has 153 amino acids residues.
• It consists of eight α-helix connected through the turns with a Oxygen binding site.
• Out of 153 amino acids, 121 (79%) are present on the helical regions and the remaining 32 amino acids are distributed over the non-helical areas.
• It has a globular structure.
• The molecular weight of Myolobin is 16,700, is an extremely compact macromolecule with oblate, spheroid shaped macromolecule.
• The overall molecular dimensions are 45 X 35 X 25 A^o_.
• Myoglobin contains a heme (prosthetic) group which is responsible for its main function (carrying of oxygen molecules to muscle tissues) and Globin protein.
• Myoglobin is a protein found in muscles that binds oxygen with its heme group like hemoglobin.
• Heme group consists of protoporphyrin organic component and an iron atom located in its center.
• The heme group gives muscle and blood their distinctive red color.
• Oxidation of the iron atom (Fe²⁺ -> Fe³⁺) is mainly responsible for the color of muscle and blood.
• The prosthetic heme group binds to proximal histidine group while a distal histidine group interact on the other side of the plane in the structure.
• Myoglobin without its heme prosthetic group is designated apomyoglobin. The main function of apomyoglobin is to provide a hydrophobic environment for the heme group.

Disease: When muscle tissue is damaged, very large concentrations of myoglobin enters the kidneys. When this happens, myoglobin is then considered highly toxic and may contribute to acute renal failure. Muscle injury is commonly associated with the release of myoglobin, and is known to be the cause of heart attacks and many other myoalgia. Studies have shown that acute mycocardial infarction can be detected with the help of the monitoring of creatine kinase and troponin by electrocardiogram

Read More:

1. What is Proteins? How the proteins are classified?
2. Protein fundamental molecules are Amino acids
3. What is Peptide Bond?
4. What is the primary structure of Proteins?
5. How the Proteins are classified in Secondary structure?
6. What type of stabilization forces are involved in protein organization?
7. How the proteins are organized in tertiary structure?

Read More