Plant flavonols significantly reduce Alzheimer’s risk

A new study published in the journal Neurology in January 2020 concludes that increasing the intake of plant flavonols steeply reduces the risk of Alzheimer’s dementia (AD) by up to a half. In other words, AD could be prevented in many people simply by regularly eating and drinking more foods containing these compounds such as tea, oranges, and broccoli.

Alzheimer’s disease

AD is a progressive brain disorder in which the individual loses cognitive skills, including memory and thinking skills, and the ability to perform simple tasks. It is by far the leading cause of such disorders and affects over 5 million Americans.

One study was carried out on over 900 people, who were part of a community-wide ongoing larger research project called the Rush Memory and Aging (MAP) Project. These participants were assessed yearly for their neurologic health and dietary patterns, for an average of 6 years, but some for as long as 12 years. The average age was 81 years, and 3 out of 4 were female.

The findings

In the first study, 220/921 participants developed AD during the study. The risk of AD fell with a greater intake of flavonols. This finding held good even after the researchers adjusted for other health-associated factors – because those with the highest total flavonol intake were also the best educated, most active and took part in more cognitive activities. They also accounted for genetic factors like the presence of the APOE4 gene, and for cardiovascular risk factors that could influence the risk of AD, such as diabetes mellitus, history of heart attack, or stroke, or hypertension.

When classified into five groups based on decreasing flavonol intake, the participants in the first group (highest intake) consumed over 15 mg of flavonols a day. Compared to those in the lowest fifth (about 5 mg a day), these individuals showed an approximately 50% reduction in AD risk.

In concrete terms, 28 of 186 patients in the highest-intake group developed AD, vs. 54 of 182 in the lowest-intake group.

With respect to individual flavonols, kaempferol intake was linked to a reduction of almost 50%, and both myricetin and isorhamnetin by 40% each. A fourth flavonol, called quercetin, had no noticeable effect on AD risk.

Participants with the highest flavonol intake drank about one cup of black tea a day. Kale, and about a glass of red wine each day, could also supply flavonols.

Sources of flavonols

Kaempferol is richly present in green leafy vegetables, including spinach, broccoli, beans, tea and kale – and also in tea. Isorhamnetin-rich foods include olive oil, red wine, pears and tomato sauce. Myricetin is found in tea, kale, oranges, tomatoes and red wine.

Researcher Thomas Holland says, “More research is needed to confirm these results, but these are promising findings. Eating more fruits and vegetables and drinking more tea could be a fairly inexpensive and easy way for people to help stave off Alzheimer's dementia.”

Implications

Many scientists disagree with the emphasis on flavonols. Though these were thought to have antioxidant activity in the body, this theory was discredited many decades earlier. Antioxidant activity ceases when they are ingested and subjected to the activity of enzymes in the digestive tract.

They point out that flavonols are found in many plants, fruits and vegetables, which have been associated with good health for centuries. Nutritionists say that the AD-delaying effects of such foods are likely due to other plant chemicals which are relatively more abundant. On the other hand, taking flavonol pills or tea extracts is unlikely to produce the same healthful effect, and overdoses could be counterproductive.

This is not to say that eating more flavonol-rich foods or drinking a cup of black tea in the morning would hurt, since any foods containing these chemicals would also contain many more healthful compounds including vitamins, minerals and plant fiber. Holland makes a valid point with his conclusion: “'With the elderly population increasing worldwide, any decrease in the number of people with this devastating disease, or even delaying it for a few years, could have an enormous benefit on public health.”

https://n.neurology.org/content/early/2020/01/29/WNL.0000000000008981

Plant flavonols significantly reduce Alzheimer’s risk

New compound prevents amyloid formation to fight Alzheimer’s disease

It is known that Alzheimer’s disease is caused by the formation of amyloid plaques and tau tangles in the brain. A novel compound shows promise in preventing amyloid formation, fighting Alzheimer’s disease development.

       

Alzheimer’s disease (AD) is the most common form of dementia, affecting about 50 million people worldwide. In the United States, 5.5 million people are living with neurodegenerative diseases, making it the 6th leading cause of death in the country.

AD is caused by the abnormal build-up of proteins, amyloid, and tau, in and around the brain. These proteins form plaques and tangles in brain cells, leading to memory loss and other symptoms. Abnormal proteins form toxic clumps, dubbed as fibrils, inside the brain, affecting brain regions that are vital for brain processes.

In the study published in the journal Chemical Communications by the Royal Society of Chemistry, reveals that the new compound, known as “C1”, can prevent the enzyme gamma-secretase from producing amyloids.

What is the role of C1?

Amyloid fibrils are made of peptide amyloid-beta, produced when certain enzymes make cuts to the amyloid precursor protein, which is found in the brain cell membrane. A type of covalent gamma-secretase inhibitor, the compound works by blocking the active site of the enzyme, hence, preventing the formation of amyloid.

The team of researchers at the Center for Biotechnology and Interdisciplinary Studies (CBIS) at Rensselaer Polytechnic Institute noted that there were samples of gamma-secretase inhibitors in the past, but these failed since they have severe side effects. What happened is, the inhibitors used stopped all the functions of gamma-secretase.

“Our compound binds to the cleavage site of the precursor protein instead of the enzyme itself, which may avoid many problems associated with traditional enzyme inhibitors,” Chunyu Wang, a professor of biological sciences and author of the study, said.

The team started to screen drugs to determine a potential compound that can target the amyloid precursor protein substrate, blocking the gamma-secretase activity that is tied to amyloid production. Using a computer model, they tested millions of compounds in the hopes of finding the one that can show promise in battling Alzheimer’s disease.

Though there were several candidates found, C1 showed high accuracy and effectiveness in cell cultures and test tubes. The patent for the compound is still pending but the researchers hope that the new drug can be studied more to determine its efficacy in people at a high risk of developing Alzheimer’s disease.

Implications of the compound

The discovery of the novel compound can pave the way for the development of new drugs that can prevent and treat Alzheimer’s disease. The new approach targets the disease, based on tis principal pathology.

Currently, there is no cure for Alzheimer’s disease and the treatment revolves around providing a safe environment for patients. Therapy is also effective in providing support, but scientists are racing to finally find a medicine for the condition.

What is Alzheimer’s disease?

Alzheimer’s disease is a type of dementia, which is a neurodegenerative disease. The disease is irreversible and progressive, which means that it worsens over time. The condition affects brain sections responsible for memory, thinking skills, and cognitive ability. In time, the symptoms worsen, often causing the inability to carry out the simplest tasks or activities of daily living.

The disease first appears in people who are in their mid-60s but can emerge earlier in some cases. Scientists don’t fully understand the exact cause of Alzheimer’s disease, but it may be a combination of various factors. These include age, since older adults are mostly affected, and hereditary because it can run in families. There is also evidences that changes in the brain starting even years before the start of the symptoms may have occurred.

https://pubs.rsc.org/en/Content/ArticleLanding/2020/CC/C9CC09170J#!divAbstract

New compound prevents amyloid formation to fight Alzheimer’s disease

Experimental Antiviral Drug to Be Tested Against New Coronavirus

In continuation of my update on Remdesivir

A clinical trial to test an experimental antiviral drug's effectiveness against the new coronavirus will be conducted in China as it battles a coronavirus outbreak there.

The drug Remdesivir -- created to fight infectious diseases such as Ebola and SARS -- will be tested by a medical team from Beijing-based China-Japan Friendship Hospital, a hospital spokeswoman told Bloomberg News. The trial will be conducted in the central Chinese city of Wuhan, the epicenter of the outbreak that has sickened more than 17,000 people and killed more than 360 in China. Researchers will recruit up to 270 patients with mild and moderate pneumonia caused by the virus, according to Chinese news outlet The Paper, Bloomberg News reported.

Remdesivir is not approved for use by any drug regulator in the world, but it is being given to patients infected with the new coronavirus because there are no approved treatments, drug maker Gilead said in a statement. The company said it is working with Chinese health officials to organize the clinical trial to determine its effectiveness and safety of the drug in patients infected with the new coronavirus. The HIV medication Kaletra has also been recommended by China's health regulator as an antiviral treatment for the new coronavirus, and clinical trials of that drug are also being arranged, according to The Paper.

On Sunday, officials reported three more cases of the new coronavirus in California, bringing the total in the United States to 11. Worldwide, there are now 146 coronavirus cases in at least 23 countries outside China, according to the World Health Organization. One death outside China has been reported in the Philippines.

https://www.bloomberg.com/news/articles/2020-02-03/gilead-drug-to-undergo-human-trials-in-china-to-cure-coronavirus

https://en.wikipedia.org/wiki/Remdesivir

Bumetanide Promising for Reducing Autism Symptoms

Bumetanide seems effective for improving symptoms of autism spectrum disorder (ASD) in young children, according to a study published online Jan. 27 in Translational Psychiatry.

Lingli Zhang, from the Shanghai Jiao Tong University School of Medicine, and colleagues examined the efficacy of bumetanide in a trial involving 83 children with ASD, aged 3 to 6 years, who were randomly assigned to receive bumetanide or no bumetanide (control).

The researchers found that the bumetanide group had a significant reduction in symptom severity compared with the control group, as indicated by the total Children Autism Rating Scale score and number of items assigned a score of ≥3. The Clinical Global Impressions confirmed the improvement in clinical symptoms. In both the insular cortex (IC) and visual cortex, the γ-aminobutyric acid (GABA)/glutamate ratio decreased more rapidly during the three-month period in the bumetanide versus the control group. In the bumetanide group, this decrease in the IC correlated with symptom improvement.

"This study is important and exciting because it means that there is a drug that can improve social learning and reduce ASD symptoms during the time when the brains of these children are still developing," one coauthor said in a statement. "We know that GABA and glutamate are key chemicals in the brain for plasticity and learning, and so these children should have an opportunity for better quality of life and well-being."

https://www.nature.com/articles/s41398-020-0692-2

https://en.wikipedia.org/wiki/Bumetanide

A high-fiber diet may counteract the harmful health effects of pollutants

In continuation of my update on a diet high in fiber

Research from the University of Kentucky's Superfund Research Center (UK-SRC) shows that a diet high in fiber could possibly reverse the adverse effects that environmental toxins have on cardiovascular health.

The findings are part of UK-SRC's "Project #1," which examines how nutrients affect toxicity caused by polychlorinated biphenyls (PCBs) in vascular tissues.

PCBs are man-made chemicals that were used in industrial and commercial applications and have been linked to a number of adverse health effects in humans and animals. Although they were banned more than 40 years ago, PCBs can still be released into the environment from poorly maintained hazardous waste sites.

Prior UK-SRC research in the lab of Bernhard Hennig, a professor in UK's Department of Animal & Food Sciences, found a connection between PCBs and cardiovascular disease. Pan Deng, a postdoctoral researcher working in Hennig's lab, is continuing this research with a study that found that nutrients including fiber reduced PCB toxicity in multiple organ systems, including gut microbiota, liver and vasculature.

https://www.youtube.com/watch?v=o1NZnho5zOU#action=share

Deng's field of research is called metabolomics, and it examines how metabolites within a cell, tissue or biofluid of an organism respond to external stressors—in this case the toxic exposure from PCBs. Deng checks levels of nutrients and pollutants in the cells through liquid and gas chromatography testing. The process is called metabolic profiling.

"Metabolic profiling gave us the power to discover how environmental pollutants contribute to human disease. The very important thing is that this technology can be applied to biological samples obtained from humans," said Deng.
"Using animal models, we found that eating a high-fiber diet can prevent pollutant-induced cardiovascular disease," said Deng. "This finding may lead to nutritional and therapeutic interventions in people who are exposed to PCBs."

The findings may be beneficial to those impacted by or residing near toxic Superfund chemicals, which include PCBs.

The Environmental Protection Agency (EPA) has designated thousands of contaminated sites in the U.S. as "Superfund" sites. They include manufacturing facilities, processing plants, landfills and mining sites where hazardous waste has been improperly managed.

Kentucky is home to 20 (13 active) EPA National Priorities List Superfund hazardous waste sites. The UK-SRC is an interdisciplinary program including researchers from several UK colleges that strives to reduce the negative health and environmental impacts of chlorinated organic compounds found at these sites across Kentucky and the U.S.

The UK-SRC is funded by the National Institutes of Health/National Institute of Environmental Health Science (NIEHS) and is one of NIEHS's nationwide family of Superfund Research Programs. Specifically, UK-SRC biomedical research examines potential roles for nutritional components and lifestyle choices to minimize negative human health impacts related to chemical exposures.

https://phys.org/news/2016-11-interaction-environmental-toxin-exposure-nutrition.html

Vegetarian diet linked with lower risk of urinary tract infections

In continuation of my update on a vegetarian diet



A vegetarian diet may be associated with a lower risk of urinary tract infections (UTIs), a study in Scientific Reports suggests.

UTIs are usually caused by gut bacteria, such as E. coli, which enter the urinary tract through the urethra and affect the kidneys and bladder. Previous research has shown that meat is a major reservoir for E. coli strains known to cause UTIs, but it is unknown whether avoiding meat reduces the risk of UTIs.

Chin-Lon Lin and colleagues assessed the incidence of UTIs in 9,724 Buddhists in Taiwan, who participated in the Tzu Chi Vegetarian Study, a study investigating the role of a vegetarian diet on health outcomes in Taiwanese Buddhists. The authors found that the overall risk of UTIs was 16% lower in vegetarians than in non-vegetarians. Of the 3,040 vegetarians in the study, 217 developed a UTI compared to 444 UTI cases in 6,684 non-vegetarians studied. The reduced UTI risk associated with a vegetarian diet was greater in men than women, although overall UTI risk for men was 79% lower than for women, regardless of diet.

The authors suggest that by not eating common sources of E. coli, such as poultry and pork, vegetarians may avoid ingesting E. coli that may cause UTIs. They also propose that the higher fibre diet of many vegetarians may prevent the growth of E. coli in the gut and decrease UTI risk by making the intestine more acidic.

 https://en.wikipedia.org/wiki/Vegetarianism

Vegetarian diet linked with lower risk of urinary tract infections

New treatment kills off infection that can be deadly to cystic fibrosis patients

A new treatment developed by researchers at Aston University and Birmingham Children's Hospital has been found to completely kill a bacterial infection that can be deadly to cystic fibrosis patients and other chronic lung conditions such as bronchiectasis.

The findings, which are published in the journal Scientific Reports, show that scientists from Aston University, Mycobacterial Research Group, combined doses of three antibiotics—amoxicillin and imipenem-relebactam and found it was 100% effective in killing off the infection which is usually extremely difficult to treat in patients with cystic fibrosis. The infection results in severe decline in lung function and sometimes death.

                                

amoxicillin                                                                   Imipenem  \

 Relebactam

Cystic fibrosis (CF) is a genetic condition affecting more than 10,000 people in the UK (Cystic Fibrosis Trust) and there are more than 70,000 people with the condition worldwide (Cystic Fibrosis Foundation). While bronchiectasis affects 210,000 people in the UK (British Lung Foundation).

Mycobacterium abscessus is a bacterial pathogen from the same family that causes tuberculosis, which causes serious lung infections in people (particularly children) with lung disorders, most notably cystic fibrosis. It is highly drug resistant. Currently patients are given a cocktail of antibiotics that cause serious side effects including severe hearing loss and often doesn't result in cure.

The researchers used samples of the pathogen taken from 16 infected cystic fibrosis patients and tested the new drug combination to discover how much was required to kill the bacteria. They found the amounts of amoxicillin-imipenem-relebactam required were low enough to be given safely to patients.

Until now Mycobacterium abscessus has been virtually impossible to eradicate in people with cystic fibrosis. It can also be deadly if the patient requires a lung transplant because they are not eligible for surgery if the infection is present.

In the UK, of the 10,000 people living with cystic fibrosis, Mycobacterium abscessus infects 13% of all patients with the condition. This new treatment is advantageous not only because it kills off the infection, but it does not have any side-effects on patients, thus ensuring their quality of life and greatly improving survival chances for infected CF patients.

Dr. Jonathan Cox, Lecturer in Microbiology, Aston University and leader of the team that discovered this new treatment said: "This new drug combination is a significant step forward for patients with cystic fibrosis that get infected with the deadly Mycobacterium abscessus bacteria. Our new drug combination is significantly less toxic than those currently used, and so far we have managed to kill every patient's bacterial isolate that we have received.

"This shows our drugs, when used in combination, are widely effective and could therefore make a huge difference to people whose treatment options are currently limited.

"Because amoxicillin is already widely available and imipenem-relebactam has just been approved for use by the Food and Drug Administration (FDA) in the US, these drugs are already available to clinicians. We therefore hope to start treating patients as soon as possible. "

The findings of this research will impact children being treated for the infection at Birmingham Children's Hospital—who part funded the research—but it can also be used nationally and further afield.

With more funding, the next stage of the research will be to test the treatment on more people with CF infected by this bacterium, comparing it to the antibiotics that are currently used.

Dr. Maya Desai, Consultant in Respiratory Paediatrics, Birmingham Children's Hospital added: "This exciting development will significantly impact on the care of CF patients globally. It has been possible only with close collaboration between Aston University and Birmingham Children's Hospital both from a clinical research and financial point of view."

Dr. Paula Sommer, Head of Research at the Cystic Fibrosis Trust said: "It's exciting that these lab-based studies investigating new antibiotic treatments for M. abscessus infection are showing such promise and adding to our expanding knowledge of this devastating bug.

"Mycobacterium abscessus also known as NTM, is the most feared infection a person with cystic fibrosis can develop. Taking drugs to treat NTM can add to an already significant regime of daily treatments and take up to a year to clear infections. We look forward to a time when effective, short courses of treatment are available to treat NTM."

https://en.wikipedia.org/wiki/Amoxicillin

https://en.wikipedia.org/wiki/Imipenem                                                                                                      https://en.wikipedia.org/wiki/Relebactam

https://medicalxpress.com/news/2019-10-fda-drug-common-cystic-fibrosis.html

Study: Antioxidant flavonol linked to lower risk of Alzheimer's dementia

In continuation of my update on kaempferol, myricetin and  quercetin

 

                                                                 kaempferol

                                                                       

                                                                      myricetin

                                                 

                                                                          Quercetin

        

People who eat or drink more foods with the antioxidant flavonol, which is found in nearly all fruits and vegetables as well as tea, may be less likely to develop Alzheimer's dementia years later, according to a study published in the January 29, 2020, online issue of Neurology, the medical journal of the American Academy of Neurology.

"More research is needed to confirm these results, but these are promising findings," said study author Thomas M. Holland, MD, of Rush University in Chicago. "Eating more fruits and vegetables and drinking more tea could be a fairly inexpensive and easy way for people to help stave off Alzheimer's dementia. With the elderly population increasing worldwide, any decrease in the number of people with this devastating disease, or even delaying it for a few years, could have an enormous benefit on public health."

Flavonols are a type of flavonoid, a group of phytochemicals found in plant pigments known for its beneficial effects on health.

The study involved 921 people with an average age of 81 who did not have Alzheimer's dementia. The people filled out a questionnaire each year on how often they ate certain foods. They were also asked about other factors, such as their level of education, how much time they spent doing physical activities and how much time they spent doing mentally engaging activities such as reading and playing games.

The people were tested yearly to see if they had developed Alzheimer's dementia. They were followed for an average of six years. The researchers used various tests to determine that 220 people developed Alzheimer's dementia during the study.

The people were divided into five groups based on how much flavonol they had in their diet. The average amount of flavonol intake in US adults is about 16 to 20 milligrams per day. In the study, the lowest group had intake of about 5.3 mg per day and the highest group consumed an average of 15.3 mg per day.

The study found that people in the highest group were 48 percent less likely to later develop Alzheimer's dementia than the people in the lowest group after adjusting for genetic predisposition and demographic and lifestyle factors. Of the 186 people in the highest group, 28 people, or 15 percent, developed Alzheimer's dementia, compared to 54 people, or 30 percent, of the 182 people in the lowest group.

The results were the same after researchers adjusted for other factors that could affect the risk of Alzheimer's dementia, such as, diabetes, previous heart attack, stroke and high blood pressure.

The study also broke the flavonols down into four types: isorhamnetin, kaempferol, myricetin and quercetin. The top food contributors for each category were: pears, olive oil, wine and tomato sauce for isorhamnetin; kale, beans, tea, spinach and broccoli for kaempferol; tea, wine, kale, oranges and tomatoes for myricetin; and tomatoes, kale, apples and tea for quercetin.

People who had high intake of isorhamnetin were 38 percent less likely to develop Alzheimer's. Those with high intake of kaempferol were 51 percent less likely to develop dementia. And those with high intake of myricetin were also 38 percent less likely to develop dementia. Quercetin was not tied to a lower risk of Alzheimer's dementia.

Holland noted that the study shows an association between dietary flavonols and Alzheimer's risk but does not prove that flavonols directly cause a reduction in disease risk.

Other limitations of the study are that the food frequency questionnaire, although valid, was self-reported, so people may not accurately remember what they eat, and the majority of participants were white people, so the results may not reflect the general population.

https://en.wikipedia.org/wiki/Myricetin

https://en.wikipedia.org/wiki/Quercetin

https://medicalxpress.com/news/2019-07-high-hemoglobin-linked-dementia.html

Elagolix Cuts Heavy Menstrual Bleeding in Women With Fibroids

In continuation of my update on elagolix

For women with uterine fibroids, elagolix with add-back hormonal therapy is associated with a reduction in heavy menstrual bleeding compared with placebo, according to a study published in the Jan. 23 issue of the New England Journal of Medicine.

William D. Schlaff, M.D., from Thomas Jefferson University in Philadelphia, and colleagues conducted two randomized, placebo-controlled phase 3 trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2]) to assess the efficacy and safety of elagolix twice daily with hormonal add-back therapy to replace reduced levels of endogenous hormones. Overall, 412 women in UF-1 and 378 in UF-2 were randomly assigned in a 2:1:1 ratio to receive elagolix with add-back therapy, elagolix alone, or placebo. The primary end point was menstrual blood loss <80 mL in the final month of treatment and ≥50 percent reduction in menstrual blood loss from baseline to the final month.

The researchers found that in UF-1 and UF-2, the criteria for the primary end point were met by 68.5 percent of 206 and 76.5 percent of 189 women, respectively, who received elagolix plus add-back therapy, compared with 8.7 percent of 102 and 10 percent of 94 women, respectively, who received placebo. The primary end point was met by 84.1 percent of 104 women and 77 percent of 95 women in UF-1 and UF-2, respectively, who received elagolix alone. With add-back therapy, hypoestrogenic effects of elagolix were attenuated.

"In both trials reported here, the risk of heavy menstrual bleeding among premenopausal women with uterine fibroids was significantly lower among women who received elagolix," the authors write.

Several authors disclosed financial ties to biopharmaceutical companies, including AbbVie, which manufactures elagolix and funded the study.

https://www.nejm.org/doi/full/10.1056/NEJMoa1904351

https://en.wikipedia.org/wiki/Elagolix

Naloxone Prescribing Increasing but Still Very Low

In continuation of my update on Naloxone

Naloxone prescribing has increased but is still very low among patients at risk for opioid overdose, according to a study recently published in the Journal of General Internal Medicine.

Lewei (Allison) Lin, M.D., from the University of Michigan in Ann Arbor, and colleagues compared adults who received opioids and naloxone from January 2014 to June 2017 to those who received opioids without naloxone using a U.S.-wide health insurance claims dataset. A total of 3,963 opioid+naloxone and 19,815 opioid-only patients were matched based on gender, age, month/year of opioid fill, and number of opioid claims.

The researchers found that high opioid daily dosage (50 to <90 morphine milligram equivalents [MME] and ≥90 MME versus <50 MME: adjusted odds ratios, 2.43 and 3.94, respectively), receiving concurrent benzodiazepines (adjusted odds ratio, 1.27), and having a diagnosis of opioid use disorder (adjusted odds ratio, 1.56) were key factors associated with naloxone fills. There was an increase in the percentage of patients receiving naloxone, but by the last six months of the study period, less than 2 percent of patients in any of the key overdose risk factor groups received naloxone.

"Increasing naloxone availability is one of the most promising interventions to reduce opioid overdose," the authors write. "These findings suggest there is substantial further work needed to increase naloxone for patients at risk for opioid overdose."

One author disclosed financial ties to the pharmaceutical industry.

https://link.springer.com/article/10.1007%2Fs11606-019-05423-7

https://en.wikipedia.org/wiki/Naloxone

Suvorexant May Improve Insomnia With Alzheimer Disease

In continuation of my update on Suvorexant

Suvorexant improves total sleep time (TST) in patients with probable Alzheimer disease (AD) dementia and insomnia, according to a study published online Jan. 15 in Alzheimer's & Dementia.

W. Joseph Herring, M.D., Ph.D., from Merck & Co., in Kenilworth, New Jersey, and colleagues randomly assigned patients with both probable AD dementia and insomnia to four weeks of suvorexant 10 mg (136 patients; could be increased to 20 mg based on clinical response) or placebo (141 patients). Overnight polysomnography in a sleep laboratory was used to assess TST.

The researchers found that at week 4, the mean improvement from baseline in TST was 73 minutes for the suvorexant group and 45 minutes for the placebo group. Patients taking suvorexant were twice as likely to show an improvement of ≥60 minutes in TST compared with those taking placebo. In suvorexant-treated patients, somnolence was reported by 4.2 percent of participants versus 1.4 percent of placebo-treated patients.

"Suvorexant did not appear to impair next-day cognitive or psychomotor performance as assessed by objective tests, although these assessments do not constitute a comprehensive assessment of cognition," the authors write.

Several authors disclosed financial ties to pharmaceutical companies, including Merck, which manufactures suvorexant and funded the study.

https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.12035

https://en.wikipedia.org/wiki/Suvorexant

Fermented soy products linked to lower risk of death

In continuation of my update on the benefits of soy

Natto with Miso and Mayonnaise

A higher intake of fermented soy products, such as miso and natto, is associated with a lower risk of death, finds a study from Japan published by The BMJ today.

However, the researchers stress that the findings should be interpreted with caution as they may have been affected by unmeasured (confounding) factors.

In Asian countries, especially Japan, several types of soy products are widely consumed, such as natto (soybeans fermented with Bacillus subtilis), miso (soybeans fermented with Aspergillus oryzae), and tofu (soybean curd).

It is, however, still unclear whether different soy products, especially fermented soy products, are associated with specific health effects.

So a team of researchers in Japan set out to investigate the association between several types of soy products and death from any cause ("all cause mortality") and from cancer, total cardiovascular disease (heart disease and cerebrovascular disease), respiratory disease, and injury.

They base their findings on 42,750 men and 50,165 women aged 45-74 years who were taking part in a study based in 11 of Japan's public health centre areas.

Participants filled in detailed questionnaires about their dietary habits, lifestyle, and health status. Deaths were identified from residential registries and death certificates over a follow-up period of nearly 15 years.

The researchers found that a higher intake of fermented soy (natto and miso) was associated with a significantly lower (10%) risk of all cause mortality, but total soy product intake was not associated with all cause mortality.

Men and women who ate natto also had a lower risk of cardiovascular mortality than those who did not eat natto, but there was no association between soy intake and cancer related mortality.

These results persisted even after further adjusting for intake of vegetables, which was higher among those consuming larger portions of natto.

The authors point out that fermented soy products are richer in fibre, potassium and bioactive components than their non-fermented counterparts, which may help to explain their associations.

However, this is an observational study, so can't establish cause, and the researchers cannot rule out the possibility that some of the observed risk may be due to other unmeasured factors.

They conclude: "In this large prospective study conducted in Japan with a high rate of soy consumption, no significant association was found between intake of total soy products and all cause mortality. In contrast, a higher intake of fermented soy products (natto and miso) was associated with a lower risk of mortality."

Increasing evidence has suggested that fermented soy products are associated with health benefits, write researchers in a linked editorial. Whether people eat those products depends on their food culture, they say, but some countries already include soy and fermented soy products in their dietary guidelines.

Further studies are still required, however, "to refine our understanding of the health effects of fermented soy, and perhaps to inform the development of healthier and more palatable products," they conclude. "These efforts should be collaborative, including not only researchers but also policy makers and the food industry."

https://phys.org/news/2018-09-video-natto-stinky-slimy-soybean.html

Researchers uncover two-drug combo that halts the growth of cancer cells

                       Everolimus

Neratinib

In continuation of my update on Neratinib  and Everolimus

UT Southwestern Simmons Cancer Center researchers have discovered a two-drug combo that halts the growth of cancer cells that carry HER2 mutations.

The findings, published today in the journal Cancer Cell, were prompted by the observation that, after an initial response, patients with cancers harboring HER2 mutations eventually develop resistance to a promising new cancer drug currently in clinical trials.

The scientists found that another drug, already on the market, counters that resistance and blocks the cancer, thereby providing the basis for a novel drug combination against cancers with mutations in the HER2 gene.

Dhivya Sudhan, Ph.D., a postdoctoral research fellow in the Harold C. Simmons Comprehensive Cancer Center, and collaborators evaluated data from a molecularly guided trial where patients with tumors with HER2 mutations were treated with the HER2 inhibitor neratinib. In this study, patients' cancers were sequenced as the disease progressed during treatment. Based on this analysis, Sudhan discovered in the laboratory that an effective way to offset eventual resistance to neratinib is with everolimus, a TORC1 inhibitor commonly used to treat other types of breast cancer.

"This finding may give clinicians an effective response to neratinib resistance. That could make a real difference for patients with breast, ovarian, lung, and other cancers harboring HER2 mutations," says Carlos L. Arteaga, M.D., Director of the Simmons Cancer Center at UT Southwestern and corresponding author of the study.

HER2 mutations have long been identified as a key driver in breast and other cancers. The authors of this study zeroed in on a signaling network driven by TORC1, which they showed is the pathway through which HER2-mutant cancers become neratinib-resistant.

"We consistently noted activation of TORC1 signaling as a mechanism of resistance to neratinib across different types of HER2-mutant cancers. Different cancer types used different strategies to escape neratinib, but they all converged on TORC1 signaling," Sudhan says.

In addition to studying tumor sequencing data from HER2-mutant cancer patients across the country who are in clinical trials for neratinib, Sudhan also studied neratinib-resistant cells and tumors that continue to live and grow in the laboratory.

The sequencing of the patients' cancer before and during the clinical trial showed that some patients already had a mutation that could activate the TORC1 pathway. Others would develop it eventually, but they could benefit from everolimus which is currently used as a TORC1 inhibitor to address the other roles TORC1 plays in cancer. Everolimus would allow the patient to continue benefiting from neratinib's inhibition of HER2.

Sudhan says the combination of neratinib and everolimus worked in cell lines, organoids established from patient-derived tumors, and in mice harboring HER2 mutant tumors. The next step will be testing this two-drug combo in humans.

https://en.wikipedia.org/wiki/Neratinib

https://en.wikipedia.org/wiki/Everolimus

https://www.sciencedirect.com/science/article/abs/pii/S1535610819305835?via%3Dihub

Taking aim at gastric cancer: New approach to selective chemotherapy

A novel drug, named "FerriIridium," can simultaneously help diagnose and treat gastric cancer. The initially weakly active precursor (prodrug), based on an iridium-containing compound, is selectively activated only after reaching the interior of a tumor cell. This is possible because of the higher amount of iron present there, report scientists in the journal Angewandte Chemie. Selective activation reduces undesired side effects.

Cells transport substances from their exterior to their interior by folding in small regions of their membrane and then binding them off (endocytosis). This is how FerriIridium enters target cells. The resulting vesicles then fuse with lysosomes. These cell organelles have an acidic environment that contains trivalent iron ions, Fe(III), and enzymes, with which they dismantle cell components that are no longer needed. In gastric cancer cells, the Fe(III) concentration within the lysosomes is significantly elevated.

Scientists working with Yu Chen and Hui Chao at Sun Yat-Sen University, Guangzhou, and Hunan University of Science and Technology, Xiangtan (China) made use of this feature. They equipped FerriIridium with a special functional group (the m-iminocatechol group) that selectively binds to Fe(III). When bound, the functional group is oxidized while the iron ions are reduced to Fe(II). Under the acidic conditions within the lysosomes, the FerriIridium is then split into two components: an iridium complex and a benzoquinone derivative.

This reaction mechanism has a threefold effect. First, Fe(II) ions can catalyze a reaction that produces highly reactive hydroxyl radicals. Second, benzoquinones are highly oxidizing. With certain cellular substances, such as NADPH, they form hydroxyquinones, which react with oxygen to produce radical oxygen species, as well as hydrogen peroxide, which in turn can react with Fe(II) to produce hydroxyl radicals. Benzoquinone compounds can also disrupt cellular respiration. The radicals destroy the lysosomes, releasing their contents. Third, the splitting of FerriIridium drastically increases both the phosphorescence and the toxicity of the iridium complex. The phosphorescence can be used to diagnose the tumor. Most importantly, however, the toxic iridium complex is absorbed by mitochondria, the "cellular power plants." It destroys them from the inside out by collapsing their membrane potential. Together, these effects lead to the death of the gastric cancer cells and shrinking of the tumors, as demonstrated by experiments on cell lines and mice.

https://www.chemistryviews.org/details/ezine/11214563/Taking_Aim_at_Gastric_Cancer.html