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Calorie restriction could protect against a number of diseases
February 15 2019. Research presented on February 11, 2019 at FAPESP (São Paulo Research Foundation) Week London supports the potential for calorie restriction to protect against several diseases. The studies were conducted under the auspices of the Center for Research on Redox Processes in Biomedicine, which is funded by FAPESP. "We are looking at how changes to the diet affect metabolism and how that ends up changing the odds of having diseases associated with aging," commented researcher Alicia Kowaltowski, of the University of São Paulo.
In one experiment, a group of mice was allowed to consume as much food as they desired, and the number of calories consumed daily was calculated. Another group was given a diet that contained 40% fewer calories than the number consumed by the unrestricted mice. After two weeks, the animals received injections of a compound that causes seizures and the death of neurons. Mice that received low calorie diets were protected against seizures, which suggests an ability of calorie restriction to prevent the death of neurons that characterizes neurodegenerative diseases.
In other research, blood serum from mice given varying amounts of calories was administered to cultured beta cells (which produce insulin). Cells treated with serum from animals who consumed fewer calories exhibited normal insulin secretion, while beta cells from animals who consumed a high number of calories and became obese did not release insulin normally. "Obese individuals are much more likely to have age-related diseases,” Dr Kowaltowski noted. “This includes neurodegenerative diseases like Alzheimer's, proliferative diseases like cancer, and metabolic diseases themselves, such as type 2 diabetes, hyperlipidemia, heart attack and cerebrovascular accident."
"That's why if we try to understand the mechanisms through which obesity increases those diseases, we will have more tools to fight and prevent them," she concluded.
Lower risk of prostate cancer mortality among regular aspirin users
Elizabeth A. Platz of Johns Hopkins Bloomberg School of Public Health and colleagues analyzed data from 5,060 Caucasian and 1,534 African-American participants in the Atherosclerosis Risk in Communities study who did not have a history of cancer upon enrollment between 1987 and 1989. Information concerning the use of nonsteroidal anti-inflammatory drugs (NSAIDs) was obtained during four study visits conducted from 1987 to 1998. Cancer diagnoses were confirmed through 2012.
There was no association observed between the use of aspirin and the incidence of prostate cancer. Nevertheless, subjects who reporting being aspirin users at the last study visit had a 41% lower risk of dying from the disease in comparison with nonusers. The association was valid for both Caucasian and African American men and was significant for those who used aspirin daily and/or for the prevention of cardiovascular disease. Low dose and regular strength aspirin were both associated with a lower risk of dying from prostate cancer. Among the group of men who used aspirin prior to their prostate cancer diagnosis, there was a 57% adjusted reduction in mortality from the disease in comparison with prostate cancer patients who did not use aspirin, which suggests that the compound may modify the risk of early metastasis. The use of non-aspirin NSAIDs was not associated with prostate cancer mortality.
“This prospective, community-based study of white and black men provides evidence that aspirin may protect against prostate cancer mortality,” the authors conclude. “Additional studies are needed to confirm these findings, build support for a causal relationship, and assess the influence of dose, frequency, and timing of aspirin use.”
Metformin boosts breast cancer treatment in mice
February 11 2019. A report published on February 6, 2019 in Nature Communications reveals a role for the diabetes drug metformin in combination with the BCL-2 protein inhibitor venetoclax in the treatment of breast cancer.
The combination was designed to take advantage of an increased sensitivity of breast cancer cells to undergo apoptosis (a type of programmed cell death) associated with the presence of a cancer-initiating gene known as MYC, which is overexpressed in more than 40% of breast cancers. Metformin increases ventoclax’s ability to induce apoptosis in cancer cells.
"This drug combo exploits specific metabolic vulnerabilities that high levels of MYC create in tumor cells,” explained lead researcher Juha Klefström of the University of Helsinki. “Metformin and venetoclax, when given together, killed breast tumor cells in culture and blocked tumor growth in breast cancer animal models. Furthermore, the drugs efficiently killed authentic breast cancer tissue donated by breast cancer patients."
Although the metformin plus venetoclax combination was effective in mice with implanted breast tumors, withdrawal of the drugs led to tumor regrowth. The addition of a PD-1-targeted immunotherapy to the two-drug regimen after the removal of the primary tumor prolonged the activity of killer lymphocytes, even after drug withdrawal. "With this combination the survival of mice carrying implanted tumors was extended dramatically in comparison to mice that were treated with only single or double combinations,” Dr Klefström stated.
"We finally have a drug combination that efficiently exploits MYC's apoptotic function and most importantly, these drugs can be tested in the clinic in real patients," he concluded.
"This is a great example of how scientists in academia, leveraging highly specialized tumor models and applying their unique insights, can contribute to the discovery of potential new treatments for people with cancer,” added co-senior author Joel Leverson, PhD.
CoQ10 shows promise in experimental model of Alzheimer’s disease
February 08 2019. A study reported on February 2, 2019 in Brain Research Bulletin found a protective effect for supplementation with coenzyme Q10 (CoQ10) against a decline in synaptic plasticity in a rat model of Alzheimer’s disease. The ability of the synapses (which connect nerve cells) to adapt to changes is essential to memory and learning. This synaptic plasticity decreases in the hippocampus (an organ involved in memory and learning) of the brains of people with Alzheimer’s disease.
Hamidreza Komaki and colleagues divided male rats into five groups that received an injection of amyloid beta into the brain to model Alzheimer’s disease, injection of saline into the brain, CoQ10 administered by gavage once daily for six weeks, amyloid beta injected into the brain plus CoQ10 daily for three weeks before and after the injection, or daily saline administered by oral gavage. Following treatment, blood samples were analyzed for malondialdehyde (a marker of oxidative stress), total oxidant status and total antioxidant capacity, and the animals underwent electrophysiological monitoring of the brain.
Rats that were injected with amyloid beta showed a decrease in hippocampal long-term potentiation (defined as a strengthening of synapses based on recent patterns of activity), which is a form of synaptic plasticity. However, amyloid beta-treated animals that received CoQ10 experienced less of a decline.
While amyloid beta injection was associated with an increase in malondialdehyde and total oxidant status, CoQ10 supplementation was associated with a protective effect against this increase, while boosting the animals’ total antioxidant capacity.
“Overall, the present study demonstrated that Q10 significantly improved long term potentiation by impeding amyloid beta toxicity,” the authors write. “This protective role may be because of the antioxidant, anti-inflammatory, and antiapoptotic activities of Q10. Therefore, Q10 is a potential neuroprotective agent against neurodegenerative disease, such as Alzheimer’s disease.”
Fibrinogen implicated in dementia
February 06 2019. Research reported on February 5, 2019 in Neuron reveals a role for fibrinogen, a protein in the blood that is a precursor to fibrin (which is involved in blood clotting), in the development of cognitive decline that characterizes dementia.
Using three-dimensional volume imaging, Katerina Akassoglou, PhD and colleagues observed leakage of the blood-brain barrier in Alzheimer’s disease patients. They also determined that fibrinogen, when leaked into the brain from the bloodstream, activates immune cells that can destroy the synapses that facilitate the transmission of impulses between brain cells known as neurons. This contributes to the memory loss that occurs with Alzheimer’s disease and other types of dementia.
"We found that blood leaks in the brain can cause elimination of neuronal connections that are important for memory functions," explained Dr. Akassoglou. "This could change the way we think about the cause and possible cure of cognitive decline in Alzheimer's disease and other neurological diseases."
"Traditionally, the build-up of amyloid plaques in the brain has been seen as the root of memory loss and cognitive decline in Alzheimer's disease," noted first author Mario Merlini. "Our work identifies an alternative culprit that could be responsible for the destruction of synapses."
The discovery contributes to the understanding of studies in which individuals with vascular pathology showed similar rates of cognitive decline as age-matched subjects with amyloid pathology characteristic of Alzheimer’s disease, while those with both pathologies experienced much worse decline.
"These exciting findings greatly advance our understanding of the contributions that vascular pathology and brain inflammation make to the progression of Alzheimer's disease," added coauthor Lennart Mucke, MD. "The mechanisms our study identified may also be at work in a range of other diseases that combine leaks in the blood-brain barrier with neurological decline, including multiple sclerosis, traumatic brain injury, and chronic traumatic encephalopathy. It has far-reaching therapeutic implications."
Meta-analysis finds association between omega-3 supplementation and dry eye improvement
February 04 2019. Results from a meta-analysis reported on January 29, 2019 in the journal Cornea conclude a benefit for supplementation with omega-3 fatty acids in patients with dry eye disease, a source of eye discomfort and visual disturbance that can significantly impact quality of life and work productivity.
For the meta-analysis, researchers at the University of Bologna in Italy selected 17 randomized, placebo-controlled trials that evaluated the effects of omega-3 fatty acid supplementation in 3,363 participants with dry eye. Subjects included men and women with dry eye disease caused by meibomian gland dysfunction, visual display terminal use, Sjögren syndrome, contact lens wear, rosacea and unspecified causes. Average follow-up periods ranged from one to twelve months. Twelve of the 17 trials evaluated the effects of the omega-3 fatty acids EPA plus DHA, while the remainder tested EPA plus DHA combined with other fatty acids, or flaxseed oil alone (which contains the omega-3 precursor ALA). Dry eye symptoms were assessed at the beginning and end of the trials.
In a pooled analysis of all participants, omega-3 fatty acid supplementation was associated with a reduction in dry eye symptoms and corneal fluorescein staining (an indicator of corneal abrasion) in comparison with a placebo. Tear breakup time and Schirmer test values (a measure of tear production) increased in association with omega-3.
“To our knowledge, this is the largest meta-analysis to investigate the efficacy of omega-3 fatty acid supplementation for dry eye disease,” authors Giuseppe Giannaccare, MD, PhD, and colleagues announced. “This systematic review and meta-analysis indicate that omega-3 fatty acid supplementation improves dry eye symptoms, tear film stability, and tear production in patients with dry eye disease. Based on current evidence available, omega-3 fatty acid supplementation may be recommended in clinical practice for treatment of this condition.”
Calorie restriction prevents asthma symptoms in mice
"Previous studies suggested that the high fat or high sugar content in diets that led to obesity promoted inflammation and caused asthma," explained senior author Vsevolod Polotsky, MD, PhD. "However, our study shows that obesity leads to inflammation-associated asthma symptoms regardless of the makeup of the diet, and that restricting calories by any means may prevent or treat asthma by reducing inflammation."
The research involved mice allowed to consume as much as they desired of high calorie diets that included high fat, high fat plus fructose, or high trans-fat plus fructose regimens, or the same diets that were restricted to provide the number of calories of low-calorie laboratory chow received by a control group. Compared to mice that became obese by the consumption of unlimited diets, animals that consumed lower calorie diets experienced protection against the development of increased airway hyperresponsiveness that characterizes asthma, regardless of the diets’ fat or sugar content. Obese mice were found to have significant increases in lung interleukin-1 beta (IL-1β, a mediator of inflammation) messenger RNA expression compared to the restricted and control mice. In another experiment, animals that received a high fat diet for 8 weeks were protected against airway hyperresponsiveness by a drug that reduces inflammation by blocking the IL-1β receptor.
“The relationship between obesity and asthma is well established,” the authors write. “The main finding of our study was that, in mice on a high fat hypercaloric diet, caloric restriction prevented the development of airway hyperresponsiveness and upregulation of IL-1β gene expression in lung parenchyma, regardless of the diet. Taken together our data suggest that caloric restriction should be used for prevention of obese asthma and that IL-1β blockade may be considered as an adjunct therapy.”