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An omega-3 that’s poison for tumors
Catholic University of Louvain (Belgium), June 11, 2021
So-called “good fatty acids” are essential for human health and much sought after by those who try to eat healthily. Among the Omega-3 fatty acids, DHA or docosahexaenoic acid is crucial to brain function, vision and the regulation of inflammatory phenomena.
In addition to these virtues, DHA is also associated with a reduction in the incidence of cancer. How it works is the subject of a major discovery by a multidisciplinary team of University of Louvain (UCLouvain) researchers, who have just elucidated the biochemical mechanism that allows DHA and other related fatty acids to slow the development of tumours. This is a major advance that has recently been published in the prestigious journal Cell Metabolism.
Key to the discovery: interdisciplinarity
In 2016, Olivier Feron’s UCLouvain team, which specialises in oncology, discovered that cells in an acidic microenvironment (acidosis) within tumours replace glucose with lipids as an energy source in order to multiply. In collaboration with UCLouvain’s Cyril Corbet, Prof. Feron demonstrated in 2020 that these same cells are the most aggressive and acquire the ability to leave the original tumour to generate metastases. Meanwhile, Yvan Larondelle, a professor in the UCLouvain Faculty of Bioengineering, whose team is developing improved dietary lipid sources, proposed to Prof. Feron that they combine their skills in a research project, led by PhD candidate Emeline Dierge, to evaluate the behaviour of tumour cells in the presence of different fatty acids.
Thanks to the support of the Fondation Louvain, the Belgian Cancer Foundation and the Télévie telethon, the team quickly identified that these acidotic tumour cells responded in diametrically opposite ways depending on the fatty acid they were absorbing. Within a few weeks, the results were both impressive and surprising. “We soon found that certain fatty acids stimulated the tumour cells while others killed them,” the researchers explained. DHA literally poisons them.
A fatal overload
The poison acts on tumour cells via a phenomenon called ferroptosis, a type of cell death linked to the peroxidation of certain fatty acids. The greater the amount of unsaturated fatty acids in the cell, the greater the risk of their oxidation. Normally, in the acidic compartment within tumours, cells store these fatty acids in lipid droplets, a kind of bundle in which fatty acids are protected from oxidation. But in the presence of a large amount of DHA, the tumour cell is overwhelmed and cannot store the DHA, which oxidises and leads to cell death. By using a lipid metabolism inhibitor that prevents the formation of lipid droplets, researchers were able to observe that this phenomenon is further amplified, which confirms the identified mechanism and opens the door to combined treatment possibilities.
For their study, UCLouvain researchers used a 3D tumour cell culture system, called spheroids. In the presence of DHA, spheroids first grow and then implode. The team also administered a DHA-enriched diet to mice with tumours. The result: tumour development was significantly slowed compared to that in mice on a conventional diet.
This UCLouvain study shows the value of DHA in fighting cancer. “For an adult,” the UCLouvain researchers stated, “it’s recommended to consume at least 250 mg of DHA per day. But studies show that our diet provides on average only 50 to 100 mg per day. This is well below the minimum recommended intake.”
The effect of barberry consumption on flow-mediated dilation and inflammatory biomarkers in patients with hypertension: A randomized controlled trial
Shahid Beheshti University of Medical Sciences (Iran), May 28, 2021
Hypertension is considered as an important cardiovascular risk factor and evidence suggests that hypertension and endothelial dysfunction reinforce each other. Polyphenol-rich foods, such as barberry can reduce the risk of cardiovascular disease. Our aim was to investigate the effects of barberry consumption on vascular function and inflammatory markers in hypertensive subject. In this randomized controlled parallel trial, 84 hypertensive subjects of both genders (aged 54.06 ± 10.19 years; body mass index 28.02 ± 2.18 kg/m2) were randomly allocated to consume barberry (10 g/day dried barberry) or placebo for 8 weeks. Before and after the intervention, changes in brachial flow-mediated dilation (FMD) and plasma macrophage/monocyte chemo-attractant protein-1 (MCP-1), vascular cellular adhesion molecule-1, and intracellular adhesion molecule-1 (ICAM-1) were measured. An intention-to-treat analysis was performed. Compared to placebo (n = 42), barberry consumption (n = 42) improved FMD (B [95% CI] was 6.54% [4.39, 8.70]; p < .001) and decreased plasma ICAM-1 (B [95% CI] was −1.61 ng/ml [−2.74, −0.48]; p = .006). MCP-1 was significantly lower in the barberry group compared with the placebo group (B [95% CI] was −37.62 pg/ml [−72.07, −3.17]; p = .033). Our results indicate that barberry consumption improves FMD and has a beneficial effect on plasma ICAM-1 and MCP-1 in hypertensive patients.
Unexpected discovery with zinc opens a new way to regulate blood pressure
International research team uncovers underappreciated metal’s role in lowering blood pressure
University of Vermont, June 9, 2021
High blood pressure, or hypertension, is the leading modifiable risk factor for cardiovascular diseases and premature death worldwide. And key to treating patients with conditions ranging from chest pain to stroke is understanding the intricacies of how the cells around arteries and other blood vessels work to control blood pressure. While the importance of metals like potassium and calcium in this process are known, a new discovery about a critical and underappreciated role of another metal – zinc – offers a potential new pathway for therapies to treat hypertension.
The study results were published recently in Nature Communications.
All the body’s functions depend on arteries channeling oxygen-rich blood – energy – to where it’s needed, and smooth muscle cells within these vessels direct how fast or slow the blood gets to each destination. As smooth muscles contract, they narrow the artery and increase the blood pressure, and as the muscle relaxes, the artery expands and blood pressure falls. If the blood pressure is too low the blood flow will not be enough to sustain a person’s body with oxygen and nutrients. If the blood pressure is too high, the blood vessels risk being damaged or even ruptured.
“Fundamental discoveries going back more than 60 years have established that the levels of the calcium and potassium in the muscle surrounding blood vessels control how they expand and contract,” say lead author Ashenafi Betrie, Ph.D., and senior authors Scott Ayton, Ph.D., and Christine Wright, Ph.D., of the Florey Institute of Neuroscience and Mental Health and The University of Melbourne in Australia.
Specifically, the researchers explain, potassium regulates calcium in the muscle, and calcium is known to be responsible for causing the narrowing of the arteries and veins that elevate blood pressure and restrict blood flow. Other cells that surround the blood vessel, including endothelial cells and sensory nerves, also regulate the calcium and potassium within the muscle of the artery, and are themselves regulated by the levels of these metals contained within them.
“Our discovery that zinc is also important was serendipitous because we’d been researching the brain, not blood pressure,” says Betrie. “We were investigating the impact of zinc-based drugs on brain function in Alzheimer’s disease when we noticed a pronounced and unexpected decrease in blood pressure in mouse models treated with the drugs.”
In collaboration with researchers at the University of Vermont’s Larner College of Medicine in the United States and TEDA International Cardiovascular Hospital in China, the investigators learned that coordinated action by zinc within sensory nerves, endothelial cells and the muscle of arteries triggers lower calcium levels in the muscle of the blood vessel. This makes the vessel relax, decreasing blood pressure and increasing blood flow. The scientists found that blood vessels in the brain and the heart were more sensitive to zinc than blood vessels in other areas of the body – an observation that warrants further research.
“Essentially, zinc has the opposite effect to calcium on blood flow and pressure,” says Ayton. “Zinc is an important metal ion in biology and, given that calcium and potassium are famous for controlling blood flow and pressure, it’s surprising that the role of zinc hasn’t previously been appreciated.”
Another surprising fact is that genes that control zinc levels within cells are known to be associated with cardiovascular diseases including hypertension, and hypertension is also a known side effect of zinc deficiency. This new research provides explanations for these previously known associations.
“While there are a range of existing drugs that are available to lower blood pressure, many people develop resistance to them,” says Wright, who added that a number of cardiovascular diseases, including pulmonary hypertension, are poorly treated by currently available therapies. “New zinc-based blood pressure drugs would be a huge outcome for an accidental discovery, reminding us that in research, it isn’t just about looking for something specific, but also about just looking.”
Study links consumption of high-fructose corn syrup to intestinal tumor growth
Weill Cornell Medicine, June 8, 2021
A recent study has found that high-fructose corn syrup (HFCS), a common sweetener used in soft drinks, promotes the growth of intestinal tumors. Excessive consumption of products sweetened with HFCS is also linked to obesity and metabolic syndrome.
According to the researchers behind the study, the epidemic of obesity seen around the world today is primarily caused by the increased consumption of sugar-laden beverages. Coincidentally, this rise in obesity rates is also paralleled by an increase in colorectal cancer incidence, especially among young and middle-aged adults.
As early as 2013, studies have emerged suggesting that obesity increases the risk of colorectal cancer. Some of the plausible mechanisms believed to be behind this association include insulin resistance, chronic inflammation and alterations in the levels of growth factors, adipocytokines (hormones secreted by fat cells) and steroid hormones. However, the influence of these proposed mechanisms still remains to be fully explored.
Another thing that is unclear about all this is if heavily sweetened products — the main culprits behind obesity — directly promote colorectal cancer development. To remove obesity and the metabolic syndrome as confounding factors, the researchers mimicked the consumption of sugar-laden drinks in mice that have been genetically engineered to develop intestinal tumors. This allowed them to determine whether HFCS, in particular, enhances tumor growth.
Fructose transport and tumor growth
In their report, which appeared in the journal Science, the researchers explained the difference between how fructose and glucose are processed in the intestine and the liver, and how these differences lead to enhanced tumor growth.
Using mice that lack the adenomatous polyposis coli (APC) gene, a key tumor suppressor, they first looked at the effects of adding HCFS to a regular diet. They reported that over an eight-week period, the genetically engineered mice became obese while normal mice showed signs of metabolic dysfunction. (Related: Food companies hiding harmful high fructose corn syrup under new name.)
To distinguish between the metabolic effects of HFCS consumption and HFCS-induced obesity, the researchers fed another set of genetically engineered mice a modest amount of the sweetener daily. In terms of human consumption, the amount was calorically equivalent to 12 ounces of a sugar-laden drink. The researchers found that despite the restriction, HFCS significantly increased the number of large adenomas (benign tumor) and high-grade tumors in the mice. This suggests that even in the absence of obesity and metabolic syndrome, regular consumption of even small amounts of HFCS promotes tumor growth.
To understand how HFCS achieves this, the researchers looked at how fructose and glucose are transported by tumors in the small intestine and colon. According to the researchers, fructose and glucose are transported by intestinal epithelial cells (IECs) in the small intestine differently. While there are designated active transporters for glucose, fructose transport occurs via a passive transporter called GLUT5. Previous studies show that consuming as little as five grams of fructose is enough to saturate GLUT5 and cause fructose malabsorption. This means that regular intake of HFCS can lead to fructose accumulation in the colon.
The researchers hypothesized that intestinal tumors may have the means to efficiently transport and metabolize fructose, and this is how HFCS enhances tumor growth. To test this hypothesis, they gave normal and genetically engineered mice a bolus of radiolabeled glucose and fructose. The researchers found that the tumors in the genetically engineered mice efficiently transported both sugars. But compared to the normal mice, the amount of fructose that reached the genetically engineered mice’s blood and livers was smaller, suggesting that intestinal tumors can trap fructose and use it as a source of energy.
The researchers also found that, compared to normal IECs, intestinal tumors have higher levels of GLUT5 and fructose-metabolizing enzymes. These findings suggest that intestinal tumors can transport fructose directly from the intestinal lumen, where the sugar accumulates once GLUT5 transporters in IECs are saturated.
Fructose metabolism and tumor growth
The metabolism of glucose and fructose in the liver and IECs also vary extensively. Whereas the activity of the enzyme that initiates glucose breakdown (glycolysis) is tightly regulated by the product of its first step, the activity of the enzyme that processes fructose is not subject to this kind of inhibition. As a result, the first product of fructose breakdown (F1P) rapidly accumulates in the liver, accompanied by a depletion in ATP, the principal molecule used by cells to store and transfer energy.
The researchers hypothesized that this depletion may lead to the activation of phosphofructokinase (PFK), the most critical regulatory enzyme in glycolysis that is normally inhibited by ATP. PFK activation would then facilitate glucose metabolism via glycolysis in intestinal tumors without APC. Again, using radiolabeled glucose and fructose, the researchers confirmed their hypothesis and found that lactate production is enhanced in tumors in the presence of fructose.
Cancer cells are known to derive most of their energy from glycolysis, specifically, by converting glucose into lactate for energy. These findings clearly show that fructose promotes cancer growth by enhancing glucose metabolism in intestinal tumors.
Another underlying mechanism the researchers discovered is that cancer cells also use glycolysis as a carbon source for fatty acid synthesis. Many studies have shown that cancer cells rely on fatty acid synthesis — also known as de novo lipogenesis — for many things, such as forming cellular membranes, producing and storing energy and communicating with other cells. A look at the expression levels of enzymes involved in lipogenesis confirmed that the intestinal tumors of mice given a bolus of HFCS have higher levels of these enzymes as well as long-chain fatty acids than IECs.
Altogether these findings show that fructose allows cancer cells to thrive by causing them to rewire their metabolic pathways in favor of glycolysis and fatty acid synthesis. (Related: Fructose can cause far more damage than glucose.)
“In this study, we have found that HFCS, the primary sweetener used in [sugar-sweetened beverages], contributes to intestinal tumorigenesis in mice by accelerating glycolysis and de novo lipogenesis. These effects are independent of obesity and metabolic syndrome. HFCS in liquid form rapidly increases the levels of fructose and glucose in the intestinal lumen and serum, respectively, which allows intestinal tumors to take up these sugars for their growth,” the researchers wrote in their report.
“Our study also provides important preclinical evidence that the combination of dietary glucose and fructose, even at moderate dose, can enhance intestinal tumor growth.”
Memory biomarkers confirm aerobic exercise helps cognitive function in older adults
Florida State University, June 10, 2021
Increasing evidence shows that physical activity and exercise training may delay or prevent the onset of Alzheimer’s disease (AD). In aging humans, aerobic exercise training increases gray and white matter volume, enhances blood flow, and improves memory function. The ability to measure the effects of exercise on systemic biomarkers associated with risk for AD and relating them to key metabolomic alterations may further prevention, monitoring, and treatment efforts. However, systemic biomarkers that can measure exercise effects on brain function and that link to relevant metabolic responses are lacking.
To address this issue, Henriette van Praag, Ph.D., from Florida Atlantic University’s Schmidt College of Medicine and Brain Institute and Ozioma Okonkwo, Ph.D., Wisconsin Alzheimer’s Disease Research Center and Department of Medicine at the University of Wisconsin-Madison and their collaborators, tested the hypotheses that three specific biomarkers, which are implicated in learning and memory, would increase in older adults following exercise training and correlate with cognition and metabolomics markers of brain health. They examined myokine Cathepsin B (CTSB), brain derived neurotrophic factor (BDNF), and klotho, as well as metabolomics, which have become increasingly utilized to understand biochemical pathways that may be affected by AD.
Researchers performed a metabolomics analysis in blood samples of 23 asymptomatic late middle-aged adults, with familial and genetic risk for AD (mean age 65 years old, 50 percent female) who participated in the “aeRobic Exercise And Cognitive Health (REACH) Pilot Study” (NCT02384993) at the University of Wisconsin. The participants were divided into two groups: usual physical activity (UPA) and enhanced physical activity (EPA). The EPA group underwent 26 weeks of supervised treadmill training. Blood samples for both groups were taken at baseline and after 26 weeks.
Results of the study, published in the journal Frontiers in Endocrinology, showed that plasma CTSB levels were increased following this 26-week structured aerobic exercise training in older adults at risk for AD. Verbal learning and memory correlated positively with change in CTSB but was not related to BDNF or klotho. The present correlation between CTSB and verbal learning and memory suggests that CTSB may be useful as a marker for cognitive changes relevant to hippocampal function after exercise in a population at risk for dementia.
Plasma BDNF levels decreased in conjunction with metabolomic changes, including reductions in ceramides, sphingo- and phospholipids, as well as changes in gut microbiome metabolites and redox homeostasis. Indeed, multiple lipid metabolites relevant to AD were modified by exercise in a manner that may be neuroprotective. Serum klotho was unchanged but was associated with cardiorespiratory fitness.
“Our findings position CTSB, BDNF, and klotho as exercise biomarkers for evaluating the effect of lifestyle interventions on brain function,” said van Praag, corresponding author, an associate professor of biomedical science, FAU’s Schmidt College of Medicine, and a member of the FAU Brain Institute and the FAU Institute for Human Health & Disease Intervention (I-HEALTH). “Human studies often utilize expensive and low throughput brain imaging analyses that are not practical for large population-wide studies. Systemic biomarkers that can measure the effect of exercise interventions on Alzheimer’s-related outcomes quickly and at low-cost could be used to inform disease progression and to develop novel therapeutic targets.”
CTSB, a lysosomal enzyme, is secreted from muscle into circulation after exercise and is associated with memory function and adult hippocampal neurogenesis. Older adults with cognitive impairment have lower serum and brain CTSB levels. BDNF is a protein that is upregulated in the rodent hippocampus and cortex by running and is important for adult neurogenesis, synaptic plasticity, and memory function. Klotho is a circulating protein that can enhance cognition and synaptic function and is associated with resilience to neurodegenerative disease, possibly by supporting brain structures responsible for memory and learning.
“The positive association between CTSB and cognition, and the substantial modulation of lipid metabolites implicated in dementia, support the beneficial effects of exercise training on brain function and brain health in asymptomatic individuals at risk for Alzheimer’s disease,” said van Praag.
Ginsenoside alleviates antibiotic-induced intestinal inflammation by regulating the TLR4-MyD88-MAPK pathway and gut microbiota composition.
Northwest University (China), June 4, 2021
Mediterranean diet linked to rheumatoid arthritis benefits: Japan study
Osaka City University (Japan), June 13, 2021
Adopting a Mediterranean diet, rich in monounsaturated fatty acids (MUFA), could help suppress disease activity in rheumatoid arthritis patients, researchers in Japan report.
They said a study of more than 400 people revealed a significantly lower intake of monounsaturated fatty acids (MUFA) and meat in the rheumatoid arthritis (RA) patients than in a control group.
“The present results indicate that MUFA intake affects RA disease activity and that increasing daily MUFA intake might suppress disease activity in patients with RA,” said researchers.
Writing in the journal Clinical Nutrition, they said a previous study had shown that the abundant MUFAs in olive oil had affected RA disease activity.
“However, some methodological aspects of that study are limited. Thus, the present study aimed to identify components of the Mediterranean diet that suppress RA disease activity in patients and provide the basis for an effective and minimally burdensome dietary intervention to achieve the same goal.”
The study included 208 patients with RA and 205 age and sex matched healthy volunteers. Food and nutrient intake was assessed using a self-administered diet history questionnaire, while Mediterranean diet scores were calculated based on intake and disease activity.
Positive correlation
The study found that Intake of MUFA, SFA, alcohol, pulses, other vegetables, total vegetables, meat, milk and other dairy products, key components of the Mediterranean diet, were significantly lower in the RA than the control group.
By assessing the disease activity score in 28 joints (DAS28-ESR) and the intake of components of the Mediterranean diet, they found a positive correlation.
“DAS28-ESR significantly correlated with MUFA/SFA intake after age adjustment. Logistic regression analysis selected high MUFA intake as an independent predictor of remission in the RA group with borderline boundary significance,” they wrote.
Furthermore, meat intake significantly and negatively correlated with a swollen joint count.
However, academics warned against increasing meat consumption to boost MUFA levels.
“Increased meat intake is associated with increased intake of SFA and specific antigens such as proteins that are thought to trigger RA symptoms. Therefore, olive and avocado oils are considered to be ideal sources of MUFA,” said the researchers, from Osaka City University.
They study concluded that increasing daily MUFA intake might suppress disease activity in patients with RA, but cautioned: “The results might not be generalizable because the study population included only Japanese participants, most of whom were women, especially elderly women, because of the epidemiology of RA.”