Drug discovery study identifies promising new compound to open constricted airways

Despite the progress made in managing asthma and chronic obstructive pulmonary disease (COPD), poorly controlled symptoms for both respiratory diseases can lead to severe shortness of breath, hospitalizations or even death.

"Only about 50 percent of asthmatics, and an even lower percentage of people with COPD, achieve adequate control of lung inflammation and airway constriction with currently available medications," said Stephen Liggett, MD, vice dean for research at the University of South Florida Morsani College of Medicine and a USF Health professor of medicine, molecular pharmacology and physiology, and biomedical engineering. "So, we're clearly missing something from our drug armamentarium to help all these patients."

Dr. Liggett's laboratory has discovered several subtypes of bitter taste receptors (TAS2Rs)—G protein-coupled receptors expressed on human smooth airway muscle cells deep inside the lungs. In asthma and COPD, tightening of smooth muscles surrounding bronchial tubes narrows the airway and reduces air flow, and Dr. Liggett's lab found that these taste receptors open the airway when activated. They are now looking for new drugs to treat asthma and other obstructive lung diseases by targeting smooth muscle TAS2Rs to open constricted airways.

A promising bronchodilator agonist rises to the top

In a preclinical study published Nov. 5 in ACS Pharmacology and Translational Science, Dr. Liggett and colleagues identified and characterized 18 new compounds (agonists) that activate bitter taste receptor subtype TAS2R5 to promote relaxation (dilation) of human airway smooth muscle cells. The cross-disciplinary team found 1,10 phenanthroline-5,6-dione (T5-8 for short) to be the most promising of several lead compounds (drug candidates). T5-8 was 1,000 times more potent than some of the other compounds tested, and it demonstrated marked effectiveness in human airway smooth muscle cells grown in the laboratory.

For this drug discovery project, Dr. Liggett's laboratory collaborated with Jim Leahy, Ph.D., professor and chair of chemistry at the USF College of Arts and Sciences, and Steven An, Ph.D., professor of pharmacology at the Rutgers Robert Wood Johnson Medical School.

In an extensive screening conducted previously, another research group identified only one compound that would bind to and specifically activate the TASR5 bitter taste receptor—although apparently with limited effectiveness. Using this particular agonist (called T5-1 in the paper) as a starting point, the team relied on their collective disciplines to devise new activators, aiming for a much better drug profile for administration to humans.

"The two key questions we asked were: 'Is it possible to find a more potent agonist that activates this receptor?' and 'Is it feasible to deliver by inhalation given the potencies that we find?'" said Dr. Liggett, the paper's senior author. "T5-8 was the bronchodilator agonist that worked best. There were a few others that were very good as well, so we now have multiple potential new drugs to carry out the next steps."

The researchers developed screening techniques to determine just how potent and effective the 18 compounds were. A biochemical test assessed how well these new agonists activated TAS2R5 in airway smooth muscle cells isolated from non-asthmatic human donor lungs. Then, the researchers validated the effect on airway smooth muscle relaxation using a technique known as magnetic twisting cytometry, pioneered by Dr. An.

'Team science' solves a structural problem

"The biggest challenge we faced was not having a 3-D crystal structure of TAS2R5, so we had no idea exactly how agonist T5-1 fit into this mysterious bitter taste receptor," Dr. Liggett said. "By merging our strength in receptors, pharmacology, physiology, and drug development, our team was able to make the breakthrough."

T5-8 was superior to all the other bronchodilator agonists screened, exhibiting a maximum relaxation response (50%) substantially greater than that of albuterol (27%). Albuterol belongs to the only class of direct bronchodilators (beta-2 agonists) available to treat wheezing and shortness of breath caused by asthma and COPD. However, this drug or its derivatives, often prescribed as a rescue inhaler, does not work for all patients and overuse has been linked to increased hospitalizations, Dr. Liggett said. "Having two distinct classes of drugs that work in different ways to open the airways would be an important step to help patients optimally control their symptoms."

The ACS Pharmacology paper highlights the importance of translational research in bridging the gap between laboratory discoveries and new therapies to improve human health, he added. "This study yielded a drug discovery that successfully meets most of the criteria needed to advance the compound toward its first trial as a potential first-in-class bronchodilator targeting airway receptor TAS2R5."

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Compound in Cabbage Helps Fight Fatty Liver Disease

A natural compound found in cruciferous vegetables such as cabbage, kale, cauliflower and Brussels sprouts can help control non-alcoholic fatty liver disease (NAFLD), new research has found.

The research, published in the journal Hepatology, suggests that this natural compound called indole may lead to new treatments or preventive measures for fatty liver disease.

"Based on this research, we believe healthy foods with high capacity for indole production are essential for preventing NAFLD and are beneficial for improving the health of those with it," said principal investigator for the study Chaodong Wu, Faculty Fellow at Texas A&M AgriLife Research in the US.

"This is another example where altering the diet can help prevent or treat disease and improve the well-being of the individual," Wu said.

NAFLD occurs when the liver becomes "marbled" with fat, sometimes due to unhealthy nutrition, such as excessive intake of saturated fats.

If not properly addressed, this condition can lead to life-threatening liver disease, including cirrhosis or liver cancer.

Many diverse factors contribute to NAFLD.

The present study examined the effect of indole concentrations on people, animal models and individual cells to help determine indole's effect on liver inflammation and its potential benefits to people with NAFLD.

For the study, the researchers investigated the effects of indole on 137 Chinese individuals with fatty livers.

The research team discovered people with a higher body mass index tended to have lower levels of indole in their blood.

This result will likely extend to other ethnicities, said research collaborator Qifu Li, a physician at Chongqing Medical University in China.

To further determine the impact of indole, the research team used animal models fed a low-fat diet as a control and high-fat diet to simulate the effects of NAFLD.

The research team also studied how indole affected individual cells.

In addition to reducing the amount of fat in liver cells, indole also acts on cells in the intestine, which send out molecular signals that dampen inflammation, said Shannon Glaser, Professor of Texas A&M Health Science Center.

"Foods with a high capacity of indole production or medicines that mimic its effects may be new therapies for treatment of NAFLD," Wu said, adding prevention is another important aspect to consider. 

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Avocado Fruit Might Help You Prevent Diabetes Type 2

Avocado fruit is life. Literally. Diabetes type 2 is a very common disease that doctors encounter worldwide. Indeed, today is World Diabetes Day. The statistics show more people die worldwide as a result of suffering from diabetes type 2, than those with AIDS and cancer combined. So what is the connection with avocado?  There’s a compound found in avocado fruit that suggests you should make eating avocado a daily habit. Apparently, this compound is a fat molecule that’s only found in an avocado. Researchers state that it shows signs of strengthening insulin sensitivity when tested in mice. This is big news for those who battle diabetes type 2.

No matter what you do, if you’re living an unhealthy lifestyle and eating a poor diet. The chances of developing type 2 diabetes will increase significantly. But with the addition of a clean eating plan and some creamy avocado, you could do wonders to protect yourself. Avocado fruit is great to include in your diet because it’s highly versatile and tastes incredible. Adding an avocado to your meal can make your meal much more satisfying because this fruit is full of healthy fats, antioxidants, it has a deliciously creamy texture and lots of fiber. Therefore, avocado fruit is more than a tasty addition to your diet. And according to recent studies, they contain a rare fat molecule that may safely reduce insulin resistance.

Researchers from the University of Guelph, in Canada, explain that this compound may delay or prevent the development of type 2 diabetes in mice. Remember that this compound is supposedly only found in avocado fruit. We’re not complaining. The more avo’s, the better. Right?
The research team also tested the safety of this compound in human participants.

Avocado Fruit Is a Life-Saver

Diabetes type 2 is a big health problem

Firstly, we need to explain why this should be an area of concern for you in your life. Just because you think you’re invincible, it doesn’t mean you are. As humans, we are not perfect and will all encounter rough patches at certain stages of our lives. For this very reason, we need to try to remain as healthy as we can with our diet and daily habits.

Not sure what type 2 diabetes is? Basically, it’s a disease that prevents the body from successfully processing glucose, or sugar, in the blood. If you are somebody who does not have diabetes, your pancreas which produces insulin is what assists this process. However, if you do have diabetes, your body either does not produce enough of the hormone insulin, or it cannot use it effectively.

Either way, whether you have diabetes type 1 or 2, it can cause too much glucose to remain in the blood. This is a very unhealthy state for the body to be in.  If you do not manage it, you can cause a range of serious issues, including heart disease, stroke, kidney or nerve damage.

A Balanced Lifestyle

“We advocate healthy eating and exercise as solutions to the problem, but that’s difficult for some people. We’ve known this for decades, and obesity and diabetes are still a significant health problem.” – Nawaz Ahmed, lead author of the paper

The researchers looked particularly at insulin resistance.

 

The study shows how a compound found only in avocados can inhibit cellular processes that normally lead to diabetes. The team also found that the substance was absorbed into the blood with no harmful effects in the kidney, liver or muscle.

 

Why does insulin resistance happen?
Researchers state that this happens when mitochondria in cells cannot effectively burn fatty acids through oxidation. This is because when you have diabetes type 2, the oxidation is incomplete.

Understanding The Science Of Avocado Fruit And Diabetes

You’re probably wondering what this magical fat molecule compound found in avocado fruit is. According to scientists, it’s called avocatin B, or AvoB. This is what might potentially help reduce diabetes type 2 among the general population. If you’re not an avocado fan, then you need to reconsider.

According to researchers, the study looked at the potential anti-obesity benefits of AVbob which is focused on Fatty Acid Oxidation (FAO) by the mitochondria. These are energy powerhouses in the body’s cells which help regulate and prevent diabetes type 2.  The researchers fed mice a high-fat diet for 8 weeks to promote obesity and insulin resistance. Then, the team added AvoB to the diet of half the mice for the next 5 weeks.

Normally, the fatty acid oxidation process allows your body to burn fat. However, diabetes type 2 prevents this process from happening. This is where AvoB comes in, as these researchers discovered how it can counter incomplete oxidation in skeletal muscles and the pancreas to reduce insulin resistance.

Interestingly, at the end of the 13 weeks, the mice that had ingested AvoB had gained weight at a slower rate than their counterparts. In addition, their insulin sensitivity had increased. This meant that their bodies were able to absorb and burn blood glucose which improved their response to insulin.

What About Avocado Fruit And Humans?

Once the researchers received positive results from testing the mice. They then performed a phase one clinical trial using humans. All of which ate a regular Western diet. Guess what? When you consume AvoB through dietary supplements it can be absorbed safely into the blood without affecting the liver, kidneys or skeletal muscles.

The participants also lost some weight, but the results were not mind-blowing. Therefore, by improving your pancreatic performance, beta-cell functioning, and insulin sensitivity the body as a whole will burn fat and digest optimally. Having demonstrated its safety in humans. Doctors plan to conduct clinical trials to test AvoB’s efficacy in treating metabolic ailments in people.

Know-How To Source Your Avocado Fruit

Researchers state that this was a very important safety trial. Mainly because it helped the team determine just how much AvoB to include in the supplement formulation. Dosages were either 50 milligrams (mg) or 200 mg. It’s possible to prevent diabetes type 2. This is because Health Canada has approved AvoB as a dietary supplement. Doctors will start selling AvoB in powder and pill forms in 2020. This will be done through SP Nutraceuticals Inc. This is a Burlington, Ontario-based natural health products company.

There is a downside to all of this new research though. You can’t just eat avocado fruit and think that it will be enough. Unfortunately, the amount of natural avocatin B varies from avocado fruit to fruit. Researchers also don’t fully understand exactly how we digest and absorb AvoB when we consume a whole avocado. The trick is to try to buy top quality avocado fruit to reap the most health benefits. Sometimes the fruit might not even contain enough AvoB for you to properly absorb the avocado’s true benefits.

That’s why further research will reveal whether AvoB will turn out to be a missing piece of a difficult diabetes management puzzle. All the more reason to eat lots of avocado fruit!

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Soybeans’ compound may prevent marijuana-induced blood vessel damage

While many believe marijuana is helpful in treating a variety of health problems, its exposure actually damages cells of the heart and vascular system. But a recent study found a compound in soybeans, that blocked the damage and may have the potential of preventing cardiovascular  side effects of marijuana use.

Marijuana is the most widely used illicit drug worldwide and is increasingly being made legal for recreational and medicinal purposes. However, there have been studies that link marijuana smoking to an increased risk of heart attack and stroke.

There can also be cardiovascular side effects, including changes in heart rate and blood pressure, when people take FDA-approved medications containing a synthetic version of delta-9-tetrahydrocannabinol (THC), the main compound in marijuana that gives the sensation of being high.

 

“These medications are prescribed to reduce nausea and vomiting induced by chemotherapy and to increase appetite in certain people with acquired immune deficiency syndrome. The goal of our studies is to investigate the mechanisms of marijuana-induced damage and discover new drugs to prevent those side effects,” said  the lead author of the study.

The effects of THC occur after it binds to one of two cannabinoid receptors (CB1 and CB2) that are found throughout the brain and body and are also acted on by naturally occurring cannabinoids.
In the current study, the researchers used endothelial cells (like those that line blood vessels) derived from the stem cells of five healthy people. Exposing the cells to THC, they found that THC exposure-induced inflammation and oxidative stress, which are known to affect the inner linings of blood vessels and are associated with the development of heart disease.

Lab techniques that block access to the CB1 receptor by THC eliminated the effects of THC exposure on endothelial cells. Treatment with JW-1, an antioxidant compound found in soybeans, eliminated the effects of THC exposure.

In addition, the researchers used a laboratory technique called wire myography to examine the response of mouse arteries to THC, finding that JW-1 blocked THC’s negative effects on the function of the inner lining.

An earlier attempt to gain health benefits from blocking the CB1 receptor proved problematic.

“Previously, a drug that blocked CB1 was approved in Europe for the treatment of obesity, but it had to be withdrawn because of severe psychiatric side effects. In contrast, as an antioxidant, JW-1 may have neuroprotective effects. Discovering a new way to protect blood vessels without psychiatric side effects would be clinically important with the rapid growth of cannabis use worldwide,” the author said.

The researchers are currently extending their research by testing cells derived from regular marijuana users and those who smoke both cigarettes and marijuana. In addition, they are looking at the impact of THC along with the other main component of marijuana, cannabidiol.

“Meanwhile, if you have heart disease, talk to your doctor before you use marijuana or one of the synthetic THC-containing medications. Marijuana may cause more severe effects on the cardiovascular system in those with pre-existing heart disease,” the author concluded.

 

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Compound found in broccoli, cabbage and avocado could slow down aging

Humans, though they well know that we all age, but they don't want to look their age? I, on the other hand feels there are lots of advantages of being a senior citizen. 
1) People give you place to sit down if you're standing in a crowd.
2) People do show respect for the silver hair. They're polite and ask if they can do some help.
3) For travel, you do get concession in some airlines, train.

Of course, cosmetic companies come out with n number of products, saying it will keep you young, fair, slim and so on. I always feel, it is better to use natural products, as you won't have any side-effects, much safer in every way.

A recent study has shown that a compound exists in broccoli, cabbage, cucumber, edamame and avocado that may lead to a decrease in the signs of physical aging. The compound, nicotinamide mononucleotide (NMN), was tested on laboratory mice and found that not only did it reduce skeletal muscle issues, poor liver function, lower bone density and declining eye function, but it was shown to also help boost metabolism.

As the body gets older, it slowly begins to lose its ability to produce nicotinamide adenine dinucleotide  ( NAD), a coenzyme form of the vitamin niacin. As NAD alone is not effective in slowing or reversing the aging process when it is administered directly, it must be administered indirectly. Thus, scientists looked to nicotinamide mononucleotide instead. Once the NMN was mixed with water and given to the mice, it quickly reached the blood stream.

As the NMN reaches the blood stream, it is rapidly converted into NAD. In the clinical trials, the scientists observed that the mice were experiencing positive effects with regard to immune function, insulin levels, body weight, eyesight, liver function, bones and skeletal muscles. They also noted a marked increased in physical activity status. It should be mentioned that these trials only appeared to have an effect on older lab mice, while younger mice did not see any change. This means that the older test mice were experiencing the same energy levels and metabolic functions as seen in the younger mice.

Since humans also rely on the same process to derive energy, scientists are hopeful that future use of nicotinamide adenine dinucleotide will become a method by which people can essentially live healthier,longer. The next step in the testing procedure will move from laboratory animals to humans in clinical trials in Japan. Should those trials prove successful, it would appear that quest for the Fountain of Youth could have simply required planting a garden containing cabbage, cucumbers and broccoli.

THIS IS ONLY FOR INFORMATION, ALWAYS CONSULT YOU PHYSICIAN BEFORE HAVING ANY PARTICULAR FOOD/ MEDICATION/EXERCISE/OTHER REMEDIES.                                    PS- THOSE INTERESTED IN RECIPES ARE FREE TO  VIEW MY BLOG-                                                                                           https://gseasyrecipes.blogspot.com/                                                                                                                                                         FOR INFO ABOUT KNEE REPLACEMENT, YOU CAN VIEW MY BLOG-                                                  https:// kneereplacement-stickclub.blogspot.com/           

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