The Gary Null Show - 05.04.21

1. Avocado discovery may point to leukemia treatment

   University of Guelph (Canada), May 1, 2021

   A compound in avocados may ultimately offer a route to better leukemia treatment, says a new University of Guelph study.

   The compound targets an enzyme that scientists have identified for the first time as being critical to cancer cell growth, said Dr. Paul Spagnuolo, Department of Food Science.

   Published recently in the journal Blood, the study focused on acute myeloid leukemia (AML), which is the most devastating form of leukemia. Most cases occur in people over age 65, and fewer than 10 per cent of patients survive five years after diagnosis.

   Leukemia cells have higher amounts of an enzyme called VLCAD involved in their metabolism, said Spagnuolo.

   “The cell relies on that pathway to survive,” he said, explaining that the compound is a likely candidate for drug therapy. “This is the first time VLCAD has been identified as a target in any cancer.”

   His team screened nutraceutical compounds among numerous compounds, looking for any substance that might inhibit the enzyme. “Lo and behold, the best one was derived from avocado,” said Spagnuolo.

   Earlier, his lab looked at avocatin B, a fat molecule found only in avocados, for potential use in preventing diabetes and managing obesity. Now he’s eager to see it used in leukemia patients.

   “VLCAD can be a good marker to identify patients suitable for this type of therapy. It can also be a marker to measure the activity of the drug,” said Spagnuolo. “That sets the stage for eventual use of this molecule in human clinical trials.”

   Currently, about half of patients over 65 diagnosed with AML enter palliative care. Others undergo chemotherapy, but drug treatments are toxic and can end up killing patients.

   “There’s been a drive to find less toxic drugs that can be used.”

   Referring to earlier work using avocatin B for diabetes, Spagnuolo said, “We completed a human study with this as an oral supplement and have been able to show that appreciable amounts are fairly well tolerated.”

   Supplement betaine treats schizophrenia in mice, restores healthy “dance” and structure of neurons

   University of Tokyo Graduate School of Medicine, April 19, 2021

   A simple dietary supplement reduces behavioral symptoms in mice with a genetic mutation that causes schizophrenia. After additional experiments, including visualizing the fluorescently stained dancing edge of immature brain cells, researchers concluded that the supplement likely protects proteins that build neurons’ cellular skeletons.

   The supplement betaine was first isolated from sugar beets and is often associated with sweetness or umami flavor. Healthy levels of betaine come from both external food sources and internal synthesis in the body. Betaine supplements are already used clinically to treat the metabolic disease homocystinuria. 

   “I don’t encourage anyone to take betaine for no reason, if a doctor has not recommended it. But, we know this drug is already used clinically, so repurposing it to treat schizophrenia should be safe,” said Project Professor Nobutaka Hirokawa, M.D., Ph.D., from the University of Tokyo Graduate School of Medicine who led the recent research project. Hirokawa has been a member of the Japan Academy, a national honorary organization recognizing scientific achievement, since 2004 and received a Person of Cultural Merit award from the Japanese government in 2013.

   Schizophrenia is estimated to affect about 1 in 100 people globally and is one of the top 15 leading causes of disability worldwide. 

   “There are treatments for schizophrenia, but they have side effects and unfortunately there is still no effective drug for patients to take that we can explain biochemically why it works,” explained Hirokawa.

   Genetic studies of people diagnosed with schizophrenia have found possible links between the disease and variations in the kinesin family 3b (kif3b) gene as well as another gene involved in the body’s internal synthesis of betaine.

   Hirokawa and his lab members have categorized all 45 members of the kinesin superfamily of genes in mammals, most of which encode motor proteins that move materials throughout the cell. Normally, the KIF3B protein links together with another kinesin superfamily protein and transports cargo throughout a neuron by traveling up and down the cell’s skeleton. 

   Mice used in the recent research had only one functional copy of the kif3b gene and are often used as an animal model of schizophrenia. These mice avoid social interactions and show the same weak response as human patients with schizophrenia in a test called prepulse inhibition, which measures how startled they are by a sudden, loud sound preceded by a quieter sound.

   Kif3b mutant mice raised on a diet supplemented with three times the normal amount of betaine had normal behavior, indicating that betaine supplements could treat schizophrenia symptoms. 

   To figure out why betaine had this effect on mice, researchers grew nerve cells with the kif3b mutation in the laboratory and added fluorescent labels so they could watch the cellular skeleton take shape.

   The shape of a healthy neuron is reminiscent of a tree: a cell body surrounded by branches, the dendrites, attached to a long trunk, the axon. Kif3b mutant neurons grown in the lab have an unusual, hyperbranched structure with too many dendrites. Similar hyperbranched neurons are also seen in brain samples donated by people with schizophrenia, regardless of what treatments or medications they took while they were alive. 

   During healthy neuron development, the main body of the cell fills with a skeleton component called tubulin. Meanwhile, the front growth cone of the cell builds outwards in a spiky, erratic dance due to the movements of another skeleton component called filamentous actin. In kif3b mutants, this dancing movement, which experts refer to as lamellipodial dynamics, is noticeably reduced and the division between tubulin and actin is blurred. 

   The actin in a neuron’s cellular skeleton is assembled in part by another protein called CRMP2. Chemical analyses of the brains of kif3b mutant mice and human schizophrenia patients reveal significant chemical damage to CRMP2, which causes the proteins to clump together.

   Betaine is known to prevent the type of chemical damage, carbonyl stress, that causes this CRMP2 dysfunction. 

   “In postmortem brains of schizophrenia patients, CRMP2 is the protein in the brain with the most carbonyl stress. Betaine likely eliminates the carbonyl stress portion of the schizophrenia equation,” said Hirokawa. 

   By protecting CRMP2 from damage, betaine treatment allows kif3b mutant neurons to build proper structures. With a structurally sound skeleton to navigate, the remaining functional KIF3B protein can shuttle cargo around the cell. Other test tube experiments revealed that KIF3B and CRMP2 can bind together, but their exact relationship remains unclear. 

   “We know that the amount of betaine decreases in schizophrenia patients’ brains, so this study strongly suggests betaine could be therapeutic for at least some kinds of schizophrenia,” said Hirokawa. 

   The UTokyo research team is planning future collaborations with pharmaceutical companies and clinical studies of betaine supplements as a treatment for schizophrenia.

   Study reveals your neighbourhood may affect your brain health

   University of Wisconsin School of Medicine, April 20, 2021

   Middle-aged and older people living in more disadvantaged neighbourhoods — areas with higher poverty levels and fewer educational and employment opportunities–had more brain shrinkage on brain scans and showed a faster decline on cognitive tests than people living in neighbourhoods with fewer disadvantages, according to a new study.

   The study published in the online issue of Neurology, the medical journal of the American Academy of Neurology. Researchers say such brain ageing may be a sign of the earliest stages of dementia.

   “Worldwide, dementia is a major cause of illness and a devastating diagnosis,” said study author Amy J. H. Kind M.D., PhD, of the University of Wisconsin School of Medicine and Public Health in Madison.

   “There are currently no treatments to cure the disease, so identifying possible modifiable risk factors is important. Compelling evidence exists that the social, economic, cultural and physical conditions in which humans live may affect health. We wanted to determine if these neighbourhood conditions increase the risk for the neurodegeneration and cognitive decline associated with the earliest stages of Alzheimer’s disease and dementia.”

   For the study, researchers identified 601 people from two larger studies of Wisconsin residents. Participants had an average age of 59 and no thinking or memory problems at the start of the study, although 69% had a family history of dementia. They were followed for 10 years.

   Participants had an initial MRI brain scan and then additional scans every three to five years. With each scan, researchers measured brain volume in areas of the brain linked to the development of Alzheimer’s dementia. Participants also took thinking and memory tests every two years, including tests that measured processing speed, mental flexibility and executive function.

   Researchers used the residential address of each participant and a measure called the Area Deprivation Index to determine if each participant lived in an advantaged or disadvantaged neighbourhood. Neighbourhoods in the index are determined by census areas of 1,500 residents. The index incorporates information on the socio-economic conditions of each neighbourhood and its residents, ranking neighbourhoods based on 17 indicators including income, employment, education and housing quality.

   Of all participants, 19 people lived in the 20% of most disadvantaged neighbourhoods in their state and 582 people lived in 80% of all other neighbourhoods in their state. People in the first group were then matched one to four to people in the second group for race, sex, age and education and compared.

   At the start of the study, there was no difference in brain volume between people living in the most disadvantaged neighbourhoods and those in other neighbourhoods. But in the end, researchers found brain shrinkage in areas of the brain associated with dementia in people in the most disadvantaged neighbourhoods, while there was no shrinkage in the other group. Researchers also found a higher rate of decline on tests that measure the risk of Alzheimer’s disease.

   “Our findings suggest that increased vigilance by healthcare providers for early signs of dementia may be particularly important in this vulnerable population,” said Kind. “Some possible causes of these brain changes may include air pollution, lack of access to healthy food and healthcare and stressful life events. Further research into possible social and biological pathways may help physicians, researchers and policymakers identify effective avenues for prevention and intervention in Alzheimer’s disease and related dementia.”

   Limitations of the study included a small number of participants from highly disadvantaged neighbourhoods and a limited geographic setting. Future studies should involve larger and more diverse groups of people over longer periods of time.

   Alpha-lipoic acid increases collagen synthesis and deposition in nondiabetic and diabetic kidneys

   University of Belgrade (Serbia), April 21, 2021

   According to news originating from Belgrade, Serbia, research stated, “Alpha-Lipoic acid (ALA) is widely used as a nutritional supplement and therapeutic agent in diabetes management. Well-established antioxidant and hypoglycemic effects of ALA were considered to be particularly important in combating diabetic complications including renal injury.”

   Our news journalists obtained a quote from the research from the University of Belgrade, “The present study evaluated the potential of ALA to affect profibrotic events in kidney that could alter its structure and functioning. ALA was administered intraperitoneally (10 mg/kg) to nondiabetic and streptozotocin-induced diabetic male Wistar rats for 4 and 8 weeks. The effects of ALA were assessed starting from structural/morphological alterations through changes that characterize profibrotic processes, to regulation of collagen gene expression in kidney. Here, we demonstrated that ALA improved systemic glucose and urea level, reduced formation of renal advanced glycation end products (AGEs), and maintained renal structural integrity in diabetic rats. However, profibrotic events provoked in diabetes were not alleviated by ALA since collagen synthesis/deposition and expression of transforming growth factor-beta 1 (TGF-beta 1) and alpha-smooth muscle actin (alpha-SMA) remained elevated in ALA-treated diabetic rats, especially after 8 weeks of diabetes onset. Moreover, 8 weeks treatment of nondiabetic rats with ALA led to the development of profibrotic features reflected in increased collagen synthesis/deposition. Besides the TGF-beta 1 downstream signaling, the additional mechanism underlying the upregulation of collagen IV in nondiabetic rats treated with ALA involves decreased DNA methylation of its promoter that could arise from increased Tet1 expression.”

   According to the news editors, the research concluded: “These findings emphasize the therapeutic caution in the use of ALA, especially in patients with renal diabetic complication.”

   Obesity, high-salt diet pose different cardiovascular risks in females, males

   Medical College of Georgia at Augusta University, April 30, 2021

   Obesity and a high-salt diet are both bad for our hearts but they are bigger, seemingly synergistic risks for females, scientists report.

   “We see younger and younger women having cardiovascular disease and the question is: What is the cause?” says Dr. Eric Belin de Chantemele, physiologist in the Vascular Biology Center and Department of Medicine at the Medical College of Georgia at Augusta University. “We think the fact that females are more salt sensitive and more sensitive to obesity are among the reasons they have lost the natural protection youth and estrogen are thought to provide.” 

   His message to women based on the sex differences they are finding: “First reduce your consumption of salt, a message the American Heart Association has been pushing for years, which should also result in a reduction in your intake of highly processed, high-calorie food and drink.”

   Belin de Chantemele, whose research team has been exploring why so many young women are now getting cardiovascular disease, is presenting their findings during the Henry Pickering Bowditch Award Lectureship at the American Physiological Society Annual Meeting at Experimental Biology 2021 this week. The award, which honors the scientist who created the first physiology lab in the country and was the American Physiological Society’s first president, recognizes original and outstanding accomplishments in the field of physiology by a young investigator. 

   The sex hormone estrogen, which has some protective powers like keeping blood vessels more flexible, is considered a natural protection for premenopausal women yet, along with soaring rates of severe obesity in young women, heart disease is now the third leading cause of death in females between the ages 20-44 — fourth for males in that age group — then moves up to second place for the next 20 years in both sexes, and is the number one killer for both men and women looking at all ages, according to the National Vital Statistics Reports. 

   While he refers to bad nutrition as the “world’s biggest killer” and obesity as a major risk factor for hypertension in both sexes, his lab has mounting evidence that obesity and high salt intake are even bigger risks for females, who have naturally higher levels of two additional hormones, leptin and aldosterone, setting the stage for the potentially deadly cardiovascular disparities. 

   Many of us likely think of leptin as the “satiety hormone” that sends our brain cues to stop eating when our stomach is full, but in obesity, the brain typically stops listening to the full message but the cardiovascular system of women starts getting unhealthy cues. 

   Belin de Chantemele has shown that in females leptin prompts the adrenal glands, which make aldosterone, to make even more of this powerful blood vessel constrictor. Like leptin, females, regardless of their weight, already have naturally higher levels of aldosterone and actually bigger adrenal glands as well. 

   A result: Obesity actually produces larger blood pressure increases in females, and studies indicate that females also are more prone to obesity associated vascular dysfunction — things like more rigid blood vessels that are not as adept as dilating. On the other hand, leptin actually increases production of the vasodilator nitric oxide — which reduces blood pressure — in the male mice, one of many cardiovascular differences they are finding between males and females. 

   Here’s another. “The major role of aldosterone is to regulate your blood volume,” Belin de Chantemele says. Increased salt intake should suppress aldosterone, and it does work that way in males, Belin de Chantemele says. But in females it appears to set them up for more trouble. 

   Aldosterone is the main mineralocorticoid, a class of hormones that helps maintain salt balance, and Belin de Chantemele and his team reported in 2019 in the journal Hypertension that the hormone progesterone, which enables pregnancy, also enables high levels of these mineralocorticoid receptors for aldosterone in the endothelial cells that line blood vessels in both female lab animals and human blood vessels. 

   When they removed the ovaries, which make estrogen and progesterone, from the female lab animals it equalized the mineralocorticoid receptor number, helping confirm that progesterone regulates the expression of the receptor in the females’ blood vessels. When they deleted either the mineralocorticoid or progesterone receptor in the females, it prevented the blood vessel dysfunction that typically follows, and just knocking out the progesterone receptor also suppressed the aldosterone receptor.

   The bottom line is that progesterone is key to the sex difference in aldosterone receptor expression on endothelial cells, which predisposes females to obesity associated, high-leptin driven endothelial dysfunction and likely high blood pressure, Belin de Chantemele says. 

   They reported a few years before in the same journal that higher leptin levels produced by more fat prompts the adrenal glands to make more aldosterone in females. “If you have higher aldosterone levels you will retain sodium and your blood volume will be higher,” he says. 

   They’ve also reported, as have others, that females are more salt sensitive than males. High sodium intake is known to raise blood pressure, by increasing fluid retention, and both pre- and postmenopausal females are more salt sensitive than males, Black females even more so, he says. 

   They’ve shown, for example, that in just seven days on a high-salt diet, the ability of female mice to relax blood vessels decreased as blood pressure increased. Treatment with the aldosterone agonist eplerenone helped correct both. 

   Because females already make more aldosterone, and the normal response of the body when you eat a lot of salt is to make even more aldosterone to help eliminate some of it, his team now proposes that females appear to have an impaired ability to reduce both the levels of the enzyme that makes aldosterone and the hormone itself, which makes them more salt sensitive. 

   One thing that means is that salt raises females’ blood pressure without them actually retaining more salt than the males. It also means that they think that blood vessels are more important in blood pressure regulation in females than males, which means they may need different treatment than males. To further compound the scenario, high salt increases the adrenal leptin receptor in the females, providing more points of action for leptin, which probably helps explain why aldosterone levels don’t decrease in females like they do in males. 

   A new $2.6 million grant (1R01HL155265-01) from the National Heart, Lung and Blood Institute is enabling them to further investigate, in both lab animals and human tissue, the female’s unique responses to a high-salt diet, include the specific contributions of the failure of aldosterone levels to drop, along with the increased expression of aldosterone and leptin receptors. 

   While trends in being overweight in about the last 50 years have held pretty steady for men and women, with decreases for men in the last handful of years, rates of severe obesity have been climbing, with women far outpacing men. 

   “We want to continue to put the puzzle together with the goal of helping restore protection from cardiovascular disease to young women, when a healthy diet and increased physical activity do not,” Belin de Chantemele says. 

   His research team includes Galina Antonova, research assistant; Dr. Reem Atawia, postdoctoral fellow; Simone Kennard, research associate; Taylor Kress and Candee Barris, graduate students; Vinay Mehta, undergraduate student at AU, Laszlo Kovacs, assistant research scientist; and Dr. Jessica Faulkner, postdoctoral fellow.

   Just 10 minutes of meditation helps anxious people have better focus

   University of Waterloo (Canada) May 1, 2021 

   Just 10 minutes of daily mindful meditation can help prevent your mind from wandering and is particularly effective if you tend to have repetitive, anxious thoughts, according to a study from the University of Waterloo.

   The study, which assessed the impact of meditation with 82 participants who experience anxiety, found that developing an awareness of the present moment reduced incidents of repetitive, off-task thinking, a hallmark of anxiety.

   “Our results indicate that mindfulness training may have protective effects on mind wandering for anxious individuals,” said Mengran Xu, a researcher and PhD candidate at Waterloo. “We also found that meditation practice appears to help anxious people to shift their attention from their own internal worries to the present-moment external world, which enables better focus on a task at hand.”

   The term mindfulness is commonly defined as paying attention on purpose, in the present moment, and without judgement.

   As part of the study, participants were asked to perform a task on a computer while experiencing interruptions to gauge their ability to stay focused on the task. Researchers then put the participants into two groups at random, with the control group given an audio story to listen to and the other group asked to engage in a short meditation exercise prior to being reassessed.

   “Mind wandering accounts for nearly half of any person’s daily stream of consciousness,” said Xu. “For people with anxiety, repetitive off-task thoughts can negatively affect their ability to learn, to complete tasks, or even function safely.

   “It would be interesting to see what the impacts would be if mindful meditation was practiced by anxious populations more widely.”

   The study, co-authored by Waterloo psychology professors Christine Purdon and Daniel Smilek and Harvard University’s Paul Seli, was published in Consciousness and Cognition.

   Researchers find breastfeeding linked to higher neurocognitive testing scores

   University of Rochester Medical Center, April 27, 2021

   New research finds that children who were breastfed scored higher on neurocognitive tests. Researchers in the Del Monte Institute for Neuroscience at the University of Rochester Medical Center (URMC) analyzed thousands of cognitive tests taken by nine and ten-year-olds whose mothers reported they were breastfed, and compared those results to scores of children who were not.

   “Our findings suggest that any amount of breastfeeding has a positive cognitive impact, even after just a few months.” Daniel Adan Lopez, Ph.D. candidate in the Epidemiology program who is first author on the study recently published in the journal Frontiers in Public Health. “That’s what’s exciting about these results. Hopefully from a policy standpoint, this can help improve the motivation to breastfeed.”

   Hayley Martin, Ph.D., a fourth year medical student in the Medical Scientist Training Program and co-author of the study, focuses her research on breastfeeding. “There’s already established research showing the numerous benefits breastfeeding has for both mother and child. This study’s findings are important for families particularly before and soon after birth when breastfeeding decisions are made. It may encourage breastfeeding goals of one year or more. It also highlights the critical importance of continued work to provide equity focused access to breastfeeding support, prenatal education, and practices to eliminate structural barriers to breastfeeding.”

   Researchers reviewed the test results of more than 9,000 nine and ten-year-old participants in the Adolescent Brain Cognitive Development (ABCD) study. Variations were found in the cumulative cognitive test scores of breastfed and non-breastfed children. There was also evidence that the longer a child was breastfed, the higher they scored. 

   “The strongest association was in children who were breastfed more than 12 months,” said Lopez. “The scores of children breastfed until they were seven to 12 months were slightly less, and then the one to six month-old scores dips a little more. But all scores were higher when compared to children who didn’t breastfeed at all.” Previous studies found breastfeeding does not impact executive function or memory, findings in this study made similar findings.

   “This supports the foundation of work already being done around lactation and breastfeeding and its impact on a child’s health,” said Ed Freedman, Ph.D., the principal investigator of the ABCD study in Rochester and lead author of the study. “These are findings that would have not been possible without the ABCD Study and the expansive data set it provides.”