Breakthrough discovery could open up new treatments for some blood cancers

Reversing runaway inflammation in the bone marrow could lead to major breakthroughs in treatments for some blood cancers, according to a new publication by scientists at Hackensack Meridian Health's Center for Discovery and Innovation.

The CDI team's findings could ultimately improve cancer treatments for people of advanced age, like that of adult acute myeloid leukemia (AML), as they indicate in the paper in the journal Nature Communications.

The study, published Feb. 3, demonstrates how endothelial (blood vessel lining) cells orchestrate inflammatory stress within the microenvironment of the bone marrow.

The scientists demonstrated the function of two connected pathways involved in myelosuppressive injuries (like those caused by chemotherapy), in which bone marrow activity decreases, leading to less blood cell production.

The myelosuppression leads to chronic activation of the mitogen-activated protein kinase (MAPK) pathway - causing local and systemic inflammation, in turn driven by the Nuclear factor-kB (NF-kB) signaling pathway. This chronic inflammation resulted in disruption of the integrity of blood vessels and functional defects to the hematopoietic stem cell.

Utilizing a genetic model to block the NF-kB dependent endothelial inflammation, led to the discovery of a novel protein, Stem Cell Growth Factor Alpha (SCGFa).

The SCGFa was tested, and the models' data showed promise. The SCGFa preserved vascular function and promoted hematopoietic recovery and hematopoietic stem cell function when infused following myelosuppressive treatments, such as chemotherapy. The scientists were also able to tamp down the vascular and hematopoietic inflammation by the administration of SCGFa, which boosted the recovery following the inflammation.

We showed that SCGFa could be used therapeutically, to allow recovery of these crucial systems following myelosuppression."Pradeep Ramalingam, study's lead author

"The elderly population tend to do worse following cancer treatments that result in myelosuppressive injury, since their bodies can't sustain as much chemotherapy as the young can," said Jason Butler, Ph.D., an associate member of the CDI, and the senior author, whose work is also part of the Georgetown Lombardi Comprehensive Cancer Center's National Cancer Institute-designated consortium. "But if we infuse patients with SCGFa, we may be able to protect their hematopoietic system and allow for rapid regeneration and rejuvenation of their bone marrow. This would allow us to potentially give patients more chemotherapy - and ultimately lead to better outcomes and lower relapse rates."

Dr. Butler and his laboratory are currently working on exciting future directions for the work, including the direct effects of SCGFa on hematopoietic stem cells - and how SCGFa may enhance the homing, engraftment, and function of hematopoietic stem cells following bone marrow transplants.

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This Strange Thing Could Happen If You Use Mouthwash After Exercise

The blood pressure-lowering effect of exercise is significantly reduced when people rinse their mouths with antibacterial mouthwash rather than water, according to a study which shows the importance of oral bacteria in cardiovascular health. The study, suggests that health professionals should pay attention to the oral environment when recommending interventions involving physical activity for high blood pressure.

"Scientists already know that blood vessels open up during exercise, as the production of nitric oxide increases the diameter of the blood vessels (known as vasodilation), increasing blood flow circulation to active muscles," said the researcher.

 "What has remained a mystery is how blood circulation remains higher after exercise, in turn triggering a blood-pressure lowering response known as post-exercise hypotension," he said.

Previous research has suggested that nitric oxide was not involved in this post-exercise response -- and only involved during exercise -- but the new study challenges these views. "It's all to do with nitric oxide degrading into a compound called nitrate, which for years was thought to have no function in the body. But research over the last decade has shown that nitrate can be absorbed in the salivary glands and excreted with saliva in the mouth," said the researcher.

Twenty-three healthy adults were asked to run on a treadmill for a total of 30 minutes on two separate occasions, after which they were monitored for two hours.

On each occasion at one, 30, 60 and 90 minutes after exercise they were asked to rinse their mouths with a liquid -- either antibacterial mouthwash (0.2 per cent chlorhexidine) or a placebo of mint-flavoured water.

Their blood pressure was measured and saliva and blood samples were taken before exercise and at 120 minutes after exercise.  The study found that when participants rinsed with the placebo, the average reduction in systolic blood pressure was 5.2 milimetres of mercury (mmHg) at one hour after exercise.

However when participants rinsed with the antibacterial mouthwash, the average systolic blood pressure was 2.0 mmHg at the same time point.

Systolic blood pressure refers to the highest blood pressure level when the heart is squeezing and pushing the blood round the body. These results show that the blood pressure-lowering effect of exercise was diminished by more than 60 per cent over the first hour of recovery, and totally abolished two hours after exercise when participants were given the antibacterial mouthwash.

Previous views also suggested that the main source of nitrite in the circulation after exercise was nitric oxide formed during exercise in the endothelial cells (cells that line the blood vessels).

However, the new study challenges this. When antibacterial mouthwash was given to the participants, their blood nitrite levels did not increase after exercise. It was only when participants used the placebo that nitrite levels in blood raised, indicating that oral bacteria are a key source of this molecule in the circulation at least over the first period of recovery after exercise.

"These findings show that nitrite synthesis by oral bacteria is hugely important in kick-starting how our bodies react to exercise over the first period of recovery, promoting lower blood pressure and greater muscle oxygenation," said  the researcher.

"In effect, it's like oral bacteria are the 'key' to opening up the blood vessels. If they are removed, nitrite can't be produced and the vessels remain in their current state," he said.

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Flavoured E-Cigarettes Trigger Heart Disease

The flavours used in electronic cigarettes (e-cigarette), especially cinnamon and menthol, can increase the risk of cardiovascular diseases (CVD) when inhaled, says a study.

The research team investigated the effect of the e-liquids on endothelial cells that line the interior of blood vessels.

The study, found that endothelial cells exposed to the e-liquids or to blood collected from e-cigarette users shortly after vaping, exhibit significantly increased levels of molecules implicated in DNA damage and cell death.

The severity of the damage, aspects of which occur even in the absence of nicotine, varies among popular flavours, said the researchers, adding that cinnamon and menthol were found to be particularly harmful.

“This study clearly shows that e-cigarettes are not a safe alternative to traditional cigarettes,” said a Prof.

For the study, the researchers investigated the effect of six different popular e-liquid flavours – fruit, tobacco, sweet tobacco with caramel and vanilla, sweet butterscotch, cinnamon and menthol – with varied nicotine levels on endothelial cells derived from human induced pluripotent stem cells or iPS cells.

“When we exposed the cells to six different flavours of e-liquid with varying levels of nicotine, we saw significant damage. The cells were less viable in culture, and they began to exhibit multiple symptoms of dysfunction,” the Prof. said.

The researchers found that while several of the liquids were moderately toxic to the endothelial cells, the cinnamon- and menthol-flavoured e-liquids significantly decreased the viability of the cells in culture even in the absence of nicotine.

“It’s important for e-cigarette users to realise that these chemicals are circulating within their bodies and affecting their vascular health,” the Prof. said. 

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Obesity can impair learning, memory

Obesity can break down our protective blood brain barrier resulting in problems with learning and memory, a study has found.

Chronic activation of the receptor, Adora2a on the endothelial cells that line this important barrier in our brain can let factors from the blood enter the brain and affect the function of our neurons, scientists said. The team has shown that when they block Adora2a in a model of diet-induced obesity, this important barrier function is maintained.

We know that obesity and insulin resistance break down the blood brain barrier in humans and animal models, but exactly how has remained a mystery, said a neuroscientist. In the brain, adenosine is a neurotransmitter that helps us sleep and helps regulate our blood pressure, in the body it's also a component of the cell fuel adenosine triphosphate, or ATP. Adenosine also activates receptors Adora1a and Adora2a on endothelial cells, which normally supports healthy relationships between brain activity and blood flow.

Problems arise with chronic activation, particularly in the brain, which is what happens with obesity, the author said. People who have obesity and diabetes have higher rates of cognitive impairment as they age and most of the related structural changes are in the hippocampus, a centre of learning and memory. Fat is a source of inflammation and there is evidence that reducing chronic inflammation in the brain helps prevent obesity-related memory loss.

For the study, young mice fed a high-fat diet got fat within 2 weeks, and by 16 weeks they had increases in fasting glucose and insulin concentrations, all signs that diabetes is in their future. In the minute vasculature of the hippocampus, the researchers saw the obesity first increased permeability of the blood brain barrier to tiny molecules like flurophore sodium fluorescein or NaFl. Diet-induced insulin resistance heightened that permeability so that a larger molecule, Evans Blue, which has a high affinity for serum albumin, the most abundant protein in blood, also could get through.

When they looked with electron microscopy, they saw a changed landscape. Resulting diabetes promoted shrinkage of the usually tight junctions between endothelial cells and actual holes in those cells. When they gave a drug to temporarily block Adora2a, it also blocked problems with barrier permeability. Whether that could work in humans and long term as a way to avoid cognitive decline in obese humans, remains to be seen, he said.

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Obesity can break down our protective blood brain barrier resulting in problems with learning and memory, a study has found. Chronic activation of the receptor Adora2a on the endothelial cells that line this important barrier in our brain can let factors from the blood enter the brain and affect the function of our neurons, scientists said. The team from Augusta University in the US have shown that when they block Adora2a in a model of diet-induced obesity, this important barrier function is maintained.

https://www.thehansindia.com/life-style/health/obesity-can-impair-learning-memory-study-523166

Obesity can break down our protective blood brain barrier resulting in problems with learning and memory, a study has found. Chronic activation of the receptor Adora2a on the endothelial cells that line this important barrier in our brain can let factors from the blood enter the brain and affect the function of our neurons, scientists said. The team from Augusta University in the US have shown that when they block Adora2a in a model of diet-induced obesity, this important barrier function is maintained.

https://www.thehansindia.com/life-style/health/obesity-can-impair-learning-memory-study-523166

Serum from lupus patients affects enzyme responsible for producing nitric oxide

A new research has shown that the enzyme responsible for nitric oxide production stops working properly when exposed to serum from lupus patients.

Patients with lupus, an inflammatory disease in which the body's immune system attacks its own tissues, are on average seven to nine times more likely to develop heart disease than the general population. Younger women with lupus are 50 times as likely to develop the disease as young women without the disease.

The endothelium, the single layer of cells lining blood vessel walls, is thought to protect against heart disease. It does so in part by producing nitric oxide.

The article provides proof of the concept that the enzyme could be a therapeutic target for heart disease in lupus. Restoring the enzyme's function could also help protect lupus patients against kidney disease.

The findings suggest that restoring the protective function of endothelial cells could be a strategy for treating heart disease more broadly.

"Our study demonstrates that therapies directed towards restoring the function of the enzyme that makes nitric oxide might be effective in restoring the function of the endothelium," explained the senior author on the article.

"So it's a proof of concept that allows us to move forward in studying the enzyme, nitric oxide synthase, or restoring its function as a target for vascular disease in lupus," he added.

"This is the first step in a long process of trying to identify therapeutics that might be useful for preventing this accelerated phenotype of  cardiovascular disease in lupus patients," said another researcher.

For the study, the team collected serum samples from a cohort of African American patients, specifically Gullah patients, with lupus who have been followed since 2003.

The team showed that exposing endothelial cells to serum from patients with lupus caused the enzyme that produced nitric oxide to quit working properly. That enzyme is known as endothelial nitric oxide synthase.

Instead of producing the protective nitric oxide, it began producing super-oxide, which promoted damaging inflammation.

In essence, the enzyme lost its power to protect against heart disease and instead promoted conditions that could lead to it. A co-factor needed for the proper function of the enzyme had been rendered unusable by exposure of the endothelial cells to the serum of lupus patients.

Administering L-sepiapterin to the cells restored the enzyme's ability to produce nitric oxide by providing a new and more reliable source of that co-factor.

"If you try to give the co-factor itself, it's rapidly oxidised by the same process that leads to the  dysfunction of the enzyme," he explained. "So giving L-sepiapterin, a precursor to the co-factor, makes it less susceptible to that rapid breakdown."

L-sepiapterin is not currently approved for administration in humans. However, it is under investigation for the treatment of a number of diseases, including diabetic gastroparesis.

Before it can be administered to patients, both in animal models and in clinical trials, it will be necessary to confirm its efficacy and safety profile.

"Many people focus on controlling cholesterol to protect against the heart diseases," explained Buie. "Our study focuses the attention on making endothelial cells happy and functional. It identifies therapeutic targets on endothelial cells as being important."

That's not to say that controlling cholesterol and other lifestyle changes aren't important. They too can affect how well the endothelium protects against heart disease.

"Lifestyle modifications can affect the endothelium. The Western diet, characterised by highly processed foods that are high in saturated and trans-fat and low in good oils like omega-3 fatty acids, contributes to heart disease in everybody, not just lupus patients," he explains. "So changing to a healthy diet and becoming more active goes a long way."

But these findings suggest that pharmaceutically restoring endothelial function deserves further study as an additional therapeutic approach for patients with lupus and others at high risk of heart disease.

 

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Vitamin D3 May Heal And Prevent Cardiovascular Damage

According to a study, a little more sunlight might help restore damage to your cardiovascular system. The study has revealed that vitamin D3 could help restore cardiovascular damage caused by diseases like diabetes and hypertension or high blood pressure. Researchers claim that vitaminD3 is associated with the bones. However, in recent years, in clinical settings people recognize that many patients who have a heart attack will have a deficiency of D3. It didn't mean that the deficiency caused the heart attack, but definitely increased the chances of it.

The team of researchers developed unique methods and systems of measurements using nanosensors that are about 1,000 times smaller in diameter than a human hair, to track the impacts of vitaminD3 on single endothelial cells, which is a vital regulatory component of the cardiovascular system. The results revealed that vitamin D3 is a powerful stimulator of nitric oxide that is a major signaling molecule in the regulation of blood flow and the prevention of the formation of clots in the cardio-vasculature. It also reduced the level of oxidative stress in the cardiovascular system.

Vitamin D3 is an important source to keep your bones and cardiovascular system healthy. Other than sunlight, load up on these foods that somewhat have vitamin D3 to avoid any problem in the long run.

Eat more and more cheese, egg yolks and fatty fish that contain small amount of vitaminD3 and are known to be the best dietary sources of D3. Cod liver oil is a time-tested potent source of D3. Moreover, add fortified milk and orange juices that contain sufficient amount of vitamin D.

Do not take supplements until recommended by a doctor and take doses under supervision in order to extract benefits out of them. Best source apart from these foods is sunlight. Ensure you are exposed to enough sunlight in the morning to get the best out it.

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