Synthetic derivative of Retinoic acid can induce cell death

Retinoic acid (RA), a natural derivative of vitamin A, is the basis of a number of treatments against cancer. Nevertheless, it has certain disadvantages, such as the possibility of the appearance of retinoic acid syndrome, present in 25 % of cases and which can lead to death. The development of 4-HPR (see structure -Fenretinide 4-hydroxy(phenyl)retinamide) a synthetic derivative of RA, has meant a considerable advance due to its greater efficacy compared to its predecessor. It is able to induce the death of tumour cells as the method for reducing their proliferation, in a precise manner and without serious damage to surrounding tissue. Moreover, it halts the referred-to retinoic acid syndrome and even functions with cells that resist RA. In vitro studies corroborate its effectiveness as a chemopreventive agent and also as a chemotherapeutic agent, both with leukaemias and with ovary, breast or brain tumour cells.

Biologist Ms Aintzane Apraiz studied the 4-HPR in depth, focusing on the causes that, according to previous research, give rise to this ability to induce cell death. To this end, she applied this synthetic derivative to acute lymphoblastic leukaemia T cells (LLA-T). Her PhD thesis, defended at the University of the Basque Country (UPV/EHU), is entitled Role of sphingolipids and oxidative stress in the antineoplasic activity of 4-HPR: study in a leucemia model.

Amongst the various processes that can induce cell death, in the case of 4-HPR, apoptosis is outstanding; a precise mechanism and without inflammatory processes or serious damage to surrounding tissue. According to Ms Apraiz, previous research on LLA-T undertaken by the team of which she is a member, showed that 4-HPR induced a massive accumulation of ceramides (lipids of the cell membrane) and of reactive oxygen species (ROS), both of which can cause cell death. 

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FDA Approves Inrebic (fedratinib) for the Treatment of Patients With Myelofibrosis

Celgene Corporation (NASDAQ: CELG)  announced the U.S. Food and Drug Administration (FDA) approval of  Inrebic (fedratinib) for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis.1

“The approval of Inrebic is another important milestone for Celgene and underscores our commitment to people living with blood cancers,” said Jay Backstrom, M.D., M.P.H., Chief Medical Officer for Celgene. “We are excited to provide Inrebic as a new treatment option that may be used in patients with myelofibrosis, including patients previously treated with ruxolitinib.”

“Myelofibrosis can cause patients to suffer in many ways, including experiencing debilitating symptoms,” said Ruben Mesa, M.D., FACP, Director of the Mays Cancer Center at UT Health San Antonio Cancer Center MD Anderson. “There has not been a new treatment approved for this disease in nearly a decade. With Inrebic, physicians and patients now have another option available for myelofibrosis.”

The Inrebic development program consisted of multiple studies (including JAKARTA and JAKARTA2) in 608 patients who received more than one dose (ranging from 30 mg to 800 mg),1 of whom 459 had myelofibrosis,1 including 97 previously treated with ruxolitinib.1 The JAKARTA study evaluated the efficacy and safety of once-daily oral doses of Inrebic compared with placebo in patients with intermediate-2 or high-risk, primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis who were previously untreated with a JAK inhibitor, had enlarged spleens (a condition known as splenomegaly), and had a platelet count of ≥50 x 109/L (median baseline platelet count was 214 x 109/L; 16% <100 x 109/L and 84% ≥100 x 109/L).1,2 In the JAKARTA study, spleen volume was reduced by 35% or greater, when assessed from baseline to the end of cycle 6 (week 24), with a 4-week follow-up scan, in 37% (35 of 96) of patients treated with INREBIC 400 mg versus 1% (1 of 96) of patients who received placebo (p<0.0001).1 INREBIC also improved the Total Symptom Score as measured by the modified Myelofibrosis Symptoms Assessment Form (MFSAF) v2.0 diary2 (night sweats, itching, abdominal discomfort, early satiety, pain under ribs on left side, bone or muscle pain) by 50% or greater when assessed from baseline to the end of cycle 6 in 40% of (36 of 89) patients treated with 400 mg, versus 9% (7 of 81) of patients who received placebo (p<0.0001).1

Inrebic has a Boxed Warning for serious and fatal encephalopathy, including Wernicke’s. Serious encephalopathy was reported in 1.3% (8 of 608) of patients treated with Inrebic in clinical trials and 0.16% (1 of 608) of the cases were fatal. Wernicke’s encephalopathy is a neurologic emergency resulting from thiamine (Vitamin B1) deficiency. Thiamine levels should be assessed in all patients prior to starting Inrebic, periodically during treatment, and as clinically indicated.1 Do not start Inrebic in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue Inrebic and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

In the JAKARTA study, serious adverse reactions occurred in 21% of patients treated with Inrebic 400 mg once daily (n=96), with the most common (≥2%) being cardiac failure (5%) and anemia (2%).1 Fatal adverse reactions of cardiogenic shock occurred in 1% of patients.1 Permanent discontinuation due to an adverse reaction occurred in 14% of patients. The most frequent reasons for permanent discontinuation in ≥2% of patients receiving Inrebic included cardiac failure (3%), thrombocytopenia, myocardial ischemia, diarrhea, and increased blood creatinine (2% each).1

Dosage interruptions due to an adverse reaction during the randomized treatment period occurred in 21% of patients who received Inrebic. Adverse reactions requiring dosage interruption in >3% of patients who received Inrebic included diarrhea and nausea. Dosage reductions due to an adverse reaction during the randomized treatment period occurred in 19% of patients who received Inrebic. Adverse reactions requiring dosage reduction in >2% of patients who received Inrebic included anemia (6%), diarrhea (3%), vomiting (3%), and thrombocytopenia (2%).

“Inrebic is a much-welcomed new treatment for the myelofibrosis community,” said Ann Brazeau, Chief Executive Officer and Founder, MPN Advocacy and Education International. “This FDA approval marks an important milestone for people living with myelofibrosis as we embark on making greater strides in the diagnosis, understanding and treatment of this disease.”

https://pubchem.ncbi.nlm.nih.gov/compound/Fedratinib

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

Metabolite of oral DMF drug for multiple sclerosis appears to slow onset of Parkinson's disease

In continuation of my update on dimethylfumarate 

The metabolite of a drug that is helping patients battle multiple sclerosis appears to significantly slow the onset of Parkinson's disease, researchers say.

The oral drug, dimethylfumarate, or DMF, and its metabolite, monomethylfumarate, or MMF, both increase activity of Nrf2, a protein that helps protect the body from oxidative stress and inflammation, hallmarks of both diseases, said Dr. Bobby Thomas, neuroscientist in the Department of Pharmacology and Toxicology at the Medical College of Georgia at Augusta University.

 dimethylfumarate  monomethylfumarate, 

But the new study provides the first evidence that the metabolite, which is essentially the active portion of the parent drug, more directly targets Nrf2, potentially reducing known side effects of the parent drug that include flushing, diarrhea, nausea, vomiting, abdominal pain and the brain infection encephalopathy, said Thomas, corresponding author of the study in The Journal of Neuroscience.

Particularly, the gastrointestinal side effects can exacerbate some problems patients with Parkinson's already experience, said Dr. John Morgan, neurologist, neuroscientist and Parkinson's disease specialist in the MCG Department of Neurology. In addition to destroying neurons in the brain that produce dopamine, a neurotransmitter that enables movement and learning, Parkinson's causes nerve cell death in the gastrointestinal tract and related problems such as severe constipation.

"Nrf2 is a natural protective mechanism we have for oxidative stress," Thomas said. The fact that multiple sclerosis and Parkinson's have in common evidence of declining activity of the Nrf2 pathway has generated interest in the drug for Parkinson's and other neurodegenerative diseases.

DMF was approved for multiple sclerosis three years ago by the Food and Drug Administration. While its metabolite MMF is not quite as potent as the parent drug in increasing Nrf2 activity, the new study indicates that its action is sufficient to dramatically slow the loss of dopamine-producing neurons as well as the parent drug, in an animal model of Parkinson's.

In their model, mice given the neurotoxin MPTP experience a dramatic loss of dopamine-producing neurons, losing about half within a handful of days, and rapidly develop Parkinson's-like symptoms. Patients, on the other hand, slowly develop symptoms over many years. By the time they seek medical care, patients may have lost 30-50 percent of their dopaminergic neurons, said Morgan, a study coauthor. "Presentation is after the disease is kind of out of the gate."

To accommodate the very compressed timeline in their model and the fact that several daily doses are needed before the drug starts to work, the researchers first gave the mice either the drug or metabolite the day before they started the toxin.

Dopamine-producing neurons are located in a darker-pigmented central portion of the brain called the substantia nigra. Even in the absence of disease, making dopamine is a stressful job for these neurons that makes them generally more fragile and actually results in oxidative stress even in a healthy scenario, Morgan said. To make a difficult situation worse, increased oxidative stress can make dopamine toxic to neurons, he said.

To increase Nrf2 activity, the parent drug DMF also appears to first make bad matters worse. DMF increases oxidative stress by depleting the natural antioxidant, glutathione, and reduces the power of cell powerhouses, called mitochondria, by limiting their ability to use oxygen and glucose to make energy leading to reduced viability of dopamine-producing cells, Thomas said.

The metabolite MMF appears to more directly activate Nrf2, and actually increases glutathione and improves mitochondrial function, brain cell studies showed. While the parent drug ultimately produces a higher Nrf2 activation, the researchers found the MMF effect was sufficient to stop the dramatic neuron loss in the animal model.

Both DMF and MMF slowed neuron loss to a more normal level, and the neurons that survived continued to make dopamine. Inflammation and oxidative stress levels also were significantly reduced, the researchers said.

As a next step, they are working toward a clinical trial of MMF in patients with early Parkinson's disease. Although the metabolite could be easily formulated for humans, it has not yet been done, Thomas notes.

"If we can catch them early enough, maybe we can slow the disease," Morgan said. "If it can help give five to eight more years of improved quality of life that would be great for our patients."

Clinical studies of the drug in Parkinson's are being planned in the United Kingdom and additional analogues of its metabolite, which could be used clinically and which the researchers think ultimately will be the best option for patients, are under development.

Oxidative stress is a byproduct of the body's use of oxygen. Free radicals, generated by oxygen use, are unstable molecules that can interfere with usual cell function and are believed to contribute to a wide range of conditions from normal aging to Alzheimer's disease. Simply giving antioxidants, such as vitamin E, which work more like scavengers to scarf up free radicals, has not worked in combating neurodegenerative disease, Thomas said. He's optimistic that directly targeting Nrf2 will be effective in at least slowing the disease, but there remains a need for clinically safe Nrf2 activators.

Activity of the Nrf2 pathway tends to slowly decline with age. Exercise upregulates Nrf2, and Morgan regularly encourages his patients to be as active as possible. A small group of patients with Parkinson's in Europe has a concentrated activation of Nrf2 that at least delays their disease onset. Parkinson's tends to be diagnosed in the mid-to-late 50s and early 60s and is more common in men.

One concern with chronically elevating anti-oxidant and anti-inflammatory molecules with drugs like DMF and MMF is creating some of the same problems that immunosuppressive drugs given to organ transplant patients create. Chronic suppression of the immune response makes patients more susceptible to invaders like cancers and infections.

Ref : http://www.jneurosci.org/content/36/23/6332.short?sid=e7a934c5-6996-4fff-bfa9-f2c600507e1f

Metabolite of oral DMF drug for multiple sclerosis appears to slow onset of Parkinson's disease

Researchers rethink fenretinide for prevention of oral cancer

In continuation of my update on fenretinide...

For more than two decades, researchers have studied and used fenretinide, a synthetic vitamin A derivative. Fenretinide's capacity to induce both terminal differentiation and cell death yielded highly promising results with cultured human cancer cells. Likewise, studies in lung, breast skin, prostate and bladder animal cancer models re-enforced fenretinide's cancer-preventing effects at the in vivo level. However, when it came to prevention of oral cancer,  fenretinide efficacy wasn't what scientists expected. After multiple studies with lackluster results, oral cancer researchers moved away from fentretinide to look elsewhere for an answer. 

Now researchers lead by Dr. Susan Mallery started rethinking about the failure and  wanted to find  a way to circumvent issues with poor systemic uptake by delivering the compound directly to the lesion. 

Mallery found the answer in partnering with two University of Michigan pharmaceutical chemists (Steven Schwendeman and Kashappa Goud Desai) to develop a first of its kind patch that sticks to the inside of the mouth, and delivers a continuous therapeutic dose of fenretinide directly to the precancerous lesion. The patch consists of three layers: a disk saturated with fenretinide and polymers that make the lipid soluble fenretinide better adsorbed in a water-rich environment, a secondary adhesive ring to hold the disk in place, and a final backing layer that ensures the medication stays inside the area of the patch.

The research team has just completed a pharmacokinetic study in rabbits. Subsequent plans include an initial Phase zero study in humans, followed by a clinical trial to evaluate efficacy in patients with precancerous oral lesions. A companion formulation designed to prevent emergence of pre-cancerous cells within the entire mouth may also be used in the fenretinide patch clinical trial. 

Ref : http://cancer.osu.edu/mediaroom/releases/Pages/Oral-Patch.aspx

One-third of osteoporotic women taking oral bisphosphonates have elevated risk for bone fracture

Chemical structure of pyrophosphate (A, above) and bisphosphonates (B, below). P = phosphorus, O = oxygen, H = hydrogen, C = carbon, R = side chain. In bisphosphonates, the central oxygen atom is replaced with a carbon atom. All bisphosphonates share a common phosphorus-carbon-phosphorus motif with two side chains (R1 and R2 in the figure). The R2 side chain determines the chemical properties of the drug, and distinguishes individual types of bisphosphonates. This chemical structure affords a high affinity for calcium hydroxyapatite, allowing for rapid and specific skeletal targeting.

More than 53 million Americans age 50 and older, primarily women, have osteoporosis or are at high risk for the condition due to low bone density. A recent study of oral bisphosphonates, the most commonly prescribed osteoporosis treatment, found that approximately a third of women prescribed these drugs continue to be at elevated risk for bone fracture, an outcome that may have several origins.

Oral bisphosphonates are a pillar of preventive treatment for patients with osteoporosis and have been shown to be effective in reducing the risk of disabling bone fractures. It is known from clinical trials that no medication completely eliminates the risk of fracture. Additionally, medication effectiveness may be different in clinical practice compared to well-controlled research trials.

Research from the Regenstrief Institute-Merck (Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.) collaboration suggests that many women still have indicators consistent with higher risk of fracture while taking these medications. The cross-sectional population health study was based on a retrospective database analysis of 7,435 women age 50 and older taking bisphosphonates for at least two years during the 2000-2012 time period. The analysis was published in the peer-reviewed journal Bone.

"While we found that a substantial proportion of patients who took oral bisphosphonates remain at risk for hip, spine, and other major fractures, this class of drug does improve bone density in the majority of patients and should remain a mainstay of osteoporosis management," said Erik Imel, M.D., the Indiana University School of Medicine endocrinologist and Regenstrief Institute-affiliated scientist who led the study.

"We limited our study to patients who were considered to be compliant with taking their medication, based on drug dispensing days covered, with the presumption being that those who filled prescriptions took the medication properly. We would expect even less benefit if patients fail to take their medication properly. To increase treatment effectiveness, patients and their doctors should be vigilant that the drug is taken reliably and properly. However, osteoporosis drugs are not enough. Physicians and their patients are well advised to discuss additional important modifications to decrease fall risk and fracture risk. These include exercise, smoking cessation, use of assistive devices such as canes or walkers, modifying the home to avoid obstacles that might lead to falls, and taking appropriate amounts of vitamin D and calcium."

Conducted under the auspices of a Regenstrief Institute-Merck collaboration, the retrospective cohort study utilized anonymized data from the Indiana Network for Patient Care, a health information exchange founded by the Regenstrief Institute. The study authors note that the data they used reflects real-life medical practice and patient behavior from a wide range of physicians and patient backgrounds. Adherence to bisphosphonate therapy was determined by prescription fulfillment records. Clinical data included information on bone density and fractures.

"We know that taking bisphosphonates decrease fracture risk compared to those not taking these drugs," Dr. Imel said. "But what about those women who weren't getting the anticipated benefit and are not improving bone density or even are losing bone density? What predicted that? The purpose of this study was to focus attention on those not doing well, in order to begin to decrease the odds of future fractures in this large group of vulnerable patients.

"Not everyone responds the same way to oral bisphosphonates or any drug. Various factors could convey continued risk of fracture in spite of bisphosphonate therapy, including other medical problems and risk factors for falling. Since we know that such a high percentage of women continue to have elevated fracture risk we -- doctors and patients -- need to focus on these factors," Dr. Imel said. "For example, we found that women who had other medical conditions in addition to low bone density--a frequent occurrence in this older population--had higher fracture risk. Taking some medications in combination with bisphosphonates seemed to increase fracture risk. However, having more medical conditions and taking more drugs are most likely markers of heightened risk rather than causative factors."

Neurologic problems, often linked to heightened risk of falls, as well as inflammatory and other chronic joint conditions including arthritis were found to be associated with higher odds of having a fracture among those taking bisphosphonates.

"I always tell my osteoporosis patients, 'Don't fall,'" said Dr. Imel. "They usually chuckle, and then we talk about things they can do to decrease the risk of falling, including proper footwear and assistive devices. Many patients are reluctant to use a cane or a walker. I try to get them to understand the importance of using any tool that decreases the chance of falling."

Compound prevents neurological damage, shows cognitive benefits in mouse model of Alzheimer’s disease

The supplement nicotinamide riboside (NR) – a form of vitamin B3 – prevented neurological damage and improved cognitive and physical function in a new mouse model of Alzheimer’s disease. The results of the study, conducted by researchers at the National Institute on Aging (NIA) part of the National Institutes of Health, suggest a potential new target for treating Alzheimer’s disease. The findings appear in the Feb. 5, 2018, issue of Proceedings of the National Academy of Sciences.

NR acts on the brain by normalizing levels of nicotinamide adenine dinucleotide (NAD+), a metabolite vital to cellular energy, stem cell self-renewal, resistance to neuronal stress and DNA repair. In Alzheimer’s disease, the brain’s usual DNA repair activity is impaired, leading to mitochondrial dysfunction, lower neuron production, and increased neuronal dysfunction and inflammation.

“The pursuit of interventions to prevent or delay Alzheimer’s and related dementias is an important national priority,” said Richard J. Hodes, M.D., director of the NIA. “We are encouraging the testing of a variety of new approaches, and this study’s positive results suggest one avenue to pursue further.”

The international team of scientists was led by Vilhelm A. Bohr, M.D., Ph.D., senior investigator and chief of the Laboratory of Molecular Gerontology of the NIA’s Intramural Research Program, with Dr. Yujun Hou, a postdoctoral investigator in the laboratory.

Based on their studies in human postmortem brain, they developed a new strain of mice mimicking major features of human Alzheimer’s such as tau pathology, failing synapses, neuronal death and cognitive impairment. Using this animal model, the researchers tested the effects of an NR supplement by adding it to the drinking water of the mice. Over a three-month period, researchers found that mice who received NR showed reduced tau in their brains, but no change in amyloid-beta.

The NR-treated mice also had less DNA damage, higher neuroplasticity (activity and reorganization of brain cells associated with learning or memory), increased production of new neurons from neuronal stem cells, and lower levels of neuronal damage and death. In the hippocampus area of the brain – in which damage and loss of volume is found in people with dementia – NR seemed to either clear existing DNA damage or prevent it from spreading further.

The NR-treated mice also performed better than control mice on multiple behavioral and memory tests, such as water mazes and object recognition. NR mice also showed better muscular and grip strength, higher endurance, and improved gait compared to their control counterparts. The research team believes that these physical and cognitive benefits are due to a rejuvenating effect NR had on stem cells in both muscle and brain tissue.

“We are encouraged by these findings that see an effect in this Alzheimer’s disease model,” said Dr. Bohr. “We are looking forward to further testing of how NR or similar compounds might be pursued for their possible therapeutic benefit for people with dementia.”

Next steps for the research team include further studies on the underlying mechanisms and preparations towards intervention in humans.

The team’s work also included contributions from researchers at the Danish Aging Research Center at the University of Aarhus, and the Center for Healthy Aging at the University of Copenhagen. The Bohr lab has a Cooperative Research and Development Agreement -- which allows NIH investigators to join colleagues from industry and academia to pursue common research goals -- with ChromaDex Corp.

Compound prevents neurological damage, shows cognitive benefits in mouse model of Alzheimer’s disease

Research finding offers hope for more powerful aspirin-like drugs

Researchers have found that salicylic acid targets the activities of HMGB1, an inflammatory protein associated with a wide variety of diseases, offering hope that more powerful aspirin-like drugs may be developed.

Aspirin is one of the oldest and most commonly used medicines, but many of its beneficial health effects have been hard for scientists and physicians to explain. A recent study conducted by researchers at the Boyce Thompson Institute (BTI), in collaboration with colleagues at Rutgers University and San Raffaele University and Research Institute, shows that aspirin's main breakdown product, salicylic acid, blocks HMGB1, which may explain many of the drug's therapeutic properties. The findings appear Sept. 23, 2015 in the journal Molecular Medicine.

"We've identified what we believe is a key target of aspirin's active form in the body, salicylic acid, which is responsible for some of the many therapeutic effects that aspirin has. This protein, HMGB1, is associated with many prevalent, devastating diseases in humans, including rheumatoid arthritis, heart disease, sepsis and inflammation-associated cancers, such as colorectal cancer and mesothelioma," said senior author Daniel Klessig, a professor at BTI and Cornell University.

Aspirin's pain relieving effects have long been attributed to its ability to block the enzymes cyclooxygenase 1 and 2, which produce prostaglandins--hormone-like compounds that cause inflammation and pain--a discovery that netted its discoverer, John Vane, a Nobel prize. However, the body rapidly converts aspirin to salicylic acid, which is a much less effective inhibitor of cyclooxygenase 1 and 2 than aspirin. Nonetheless, it has similar pharmacological effects as aspirin, suggesting that salicylic acid may interact with additional proteins.

"Some scientists have suggested that salicylic acid should be called 'vitamin S', due to its tremendous beneficial effects on human health, and I concur," said lead author Hyong Woo Choi, a research associate at BTI.

In the current study, researchers discovered the interaction between salicylic acid and HMGB1 by screening extracts prepared from human tissue culture cells to find proteins that could bind to salicylic acid. They identified one of these proteins as HMGB1. These screens have also identified a key suspect in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, plus approximately two dozen additional candidates that have yet to be characterized.

To further investigate the interactions between salicylic acid and HMGB1's role in the body, Klessig worked with Marco Bianchi of San Raffaele University and Research Institute, who initially discovered that HMGB1 is a trigger of inflammation. Using assays that measured the effects of salicylic acid on the recruitment and activation of immune cells, they showed that salicylic acid could block both of these functions at concentrations similar to those found in people on low-dose aspirin.

"We've found that HMGB1 is involved in countless situations where the body confronts damage to its own cells, which occur in many disease conditions. In retrospect, it's almost obvious that a very general anti-inflammatory compound blocks a very general inflammation trigger," said Bianchi.

Klessig also teamed up with biophysicist Gaetano Montelione at Rutgers, The State University of New Jersey, to not only confirm that salicylic acid can bind to HMGB1, but also to identify the salicylic acid binding sites.

More at research paper

Research finding offers hope for more powerful aspirin-like drugs

Walnuts may improve your colon health: Eating walnuts changes the gut microbiome and reduces cancer growth, study shows

In continuation of my update on walnuts  

A team of researchers from UConn Health and The Jackson Laboratory for Genomic Medicine found that mice that ate 7-10.5 percent of their total calories as walnuts developed fewer colon cancers. The effect was most pronounced in male mice, which had 2.3 times fewer tumors when fed walnuts as part of a diet similar to the typical American's. That's equivalent to a human eating about an ounce of walnuts a day.

"Our results show for the first time that walnut consumption may reduce colon tumor development," said Principal Investigator Dr. Daniel W. Rosenberg of UConn Health. "There is accumulating evidence that eating walnuts may offer a variety of benefits related to health issues like cancer. This study shows that walnuts may also act as a probiotic to make the colon healthy, which in turn offers protection against colon tumors."

Walnuts are packed with compounds known to be important nutritionally. They have the most polyunsaturated fatty acids of all the commonly eaten tree nuts, as well as the highest ratio of omega-3 to omega-6 fatty acids, and high levels of a form of Vitamin E with anti-cancer properties.

But walnuts are not merely the sum of their chemical parts, and it may be as a whole food that they pack the most significant anti-cancer punch against colon cancer, the third most common cancer in the world. Other studies have shown walnuts have promise warding off diseases connected to diet and lifestyle, including heart disease, diabetes and neurological disorders.

Rosenberg, a cancer researcher and professor of medicine at UConn Health and Dr. Masako Nakanishi, a research associate in the Center for Molecular Medicine at UConn Health tested the cancer prevention qualities of walnuts on mice fed two different diets. One group of mice ate a standard lab mouse chow, while the other group ate a chow that captured the nutritional profile of the typical American diet. Subsets of both groups were supplemented with walnuts.

Interestingly, male mice fed the Western diet fortified with 10.5 percent walnuts showed the greatest decrease in colon tumors compared with mice fed no walnuts.

To figure out why walnuts were beneficial, the UConn Health team collaborated with Dr. George Weinstock and colleagues at The Jackson Laboratory. Weinstock's lab took fecal samples from the mice and analyzed the communities of bacteria living in their digestive tracts. They found that walnut consumption tended to push the gut microbiome toward an ecology that was potentially protective against cancer. It's not clear exactly how this works, but there are clues. For example, previous research has shown that some gut bacteria digest fiber into compounds with anti-inflammatory properties that may reduce tumor initiation. The microbiome analyses also reflected interesting differences between male and female. Males on walnut-free diets tended to have less-diverse gut flora than females. Adding walnuts to the diets of male mice brought their microbiomes closer to those of female mice on either of the diets. Whether this change contributes to the protection seen in male mice remains to be determined.

Because the studies were done only in mice, more testing needs to be done in humans before walnuts can be unequivocally recommended as a cancer-prevention agent. Rosenberg's group is working with a nutritionist and surveying human colonoscopy patients about their diets as part of a longer term study in humans.

However, Rosenberg isn't waiting for the final word. Even right now, he says, "I try to eat walnuts every day."

Tocotrienol could help reduce stroke damage

In continuation of my update on the benefits of  Vitamin  E

Tocotrienol could help reduce stroke damage

Daily Multivitamin May Protect Against Cognitive Decline in Older Adults

In continuation of my update on Vitamin and their importance 

A daily multivitamin may provide cognitive benefits for older adults, according to a study published online Sept. 14 in Alzheimer’s & Dementia.

Laura D. Baker, Ph.D., from the Wake Forest University School of Medicine in Winston-Salem, North Carolina, and colleagues assessed whether daily use of cocoa extract (containing 500 mg/day flavanols) versus placebo and a commercial multivitamin-mineral (MVM) versus placebo improved cognition in 2,262 older women and men (mean age, 73 years).

The researchers found that cocoa extract had no effect on global cognition. However, compared with placebo, daily MVM supplementation resulted in a statistically significant benefit on global cognition, with a more pronounced effect seen in participants with a history of cardiovascular disease. Benefits of MVM were also seen for memory and executive function. There were no significant interactions observed between cocoa extract and MVM for any of the cognitive composites.

"Our study showed that although cocoa extract did not affect cognition, daily multivitamin-mineral supplementation resulted in statistically significant cognitive improvement. This is the first evidence of cognitive benefit in a large longer-term study of multivitamin supplementation in older adults," Baker said in a statement. "It's too early to recommend daily multivitamin supplementation to prevent cognitive decline. While these preliminary findings are promising, additional research is needed in a larger and more diverse group of people."

Ref : Daily Multivitamin May Protect Against Cognitive Decline in Older Adults 

Immunotherapy and Chemotherapy Regimen May Prolong Survival in Advanced Cancers

In continuation of my update on interleukin and retinoic acid

Cancer patients who receive a combination of low-dose interleukin-2 and retinoic acid after conventional therapy seem to live longer than those who don't get the combination. 

Retinoic acid is derived from vitamin A. Interleukin-2, a compound that fortifies the immune system, is approved at high doses to treat "metastatic" melanoma and kidney cancer. Metastatic means that a cancer has spread.

The study showed that "these biological compounds may work at low doses. Bigger doses are not always better," said lead author Dr. Francesco Recchia, director of the oncology department at Civilian Hospital in Avezzano, Italy.

Recchia stumbled upon the possibility of using low-dose interleukin-2 (IL-2) when he switched a patient with metastatic melanoma who didn't tolerate high doses to a lower dose, and the patient had an extended response to the therapy.

This study involved 500 patients who had already responded well to chemotherapy. They had a variety of cancers, including ovarian, lung, colon, stomach, kidney, melanoma, breast and pancreatic.

Immunotherapy and Chemotherapy Regimen May Prolong Survival in Advanced Cancers

Health Benefits of Ragi | Medindia

Finger millet (Eleusine coracana L.) also known as Ragi in India is one of the important cereals which occupies the highest area under cultivation among the small millets. The state of Karnataka is the largest producer of ragi in India. Ragi is a crop which can withstand severe drought conditions and can be easily grown throughout the year. Nutritionally, when ragi is used as a whole grain, it is higher in protein and minerals in comparison to all other cereals and millets. It is a remarkable source of protein, making it perfect for vegetarian diets.....

 

Finger millet contains important amino acids viz., isoleucine, leucine, methionine and phenyl alanine which are not present in other starchy meals. It has the highest amount of calcium (344 mg %) and potassium (408 mg %). Ragi is a great source of iron making it beneficial for individuals with low hemoglobin levels.        

Millets also contains B vitamins, especially niacin, B6 and folic acid. Some of the health benefits of ragi are attributed to its polyphenol and dietary fiber contents. Due to its high content of polyphenols and dietary fiber ragi exhibits anti-diabetic and antioxidant and antimicrobial properties; it protects against tumors and atherosclerosis (narrowing and hardening of blood vessels). Being low in fat and gluten free, ragi is easy to digest. It is therefore, given as first foods to babies in the form of ragi porridge.

Malted ragi grains are ground and consumed, mixed with milk, boiled water or yogurt. In southern parts of India, it is a recommended food, by doctors, for infants of six months and above because of its high nutritional content. Homemade ragi malt is one of the most popular infant foods till date.  Malting characteristics of finger millet are superior to other millets. On malting the vitamin-C is elaborated, phosphorus availability is increased, digestion is easier and amino acids are synthesized. In south India, the malted ragi flour is extensively used in preparation of weaning foods, instant mixes and beverages.

Despite finger millet's rich nutrient profile, low cost and easy availability recent studies indicate its lower consumption in general by urban Indians. Obesity has become a matter of health concern in India. Unhealthy foods have increasingly become a part of the food choices made by youth. Large populations of children in the country are malnourished and are deficient in calcium and protein. The millet ragi then could be the answer to all the above problems relating to nutrient deficiencies. Ragi is truly a wonder cereal grain and should be consciously incorporated in the diets in one way or the other.

 

Health Benefits of Ragi | Medindia

Walnuts could be key to happier state-of-mind in young healthy men

In continuation of my update on walnuts

College can be a stressful time for young adults as they figure out how to manage intense daily routines that include work, study and play. Eat well, exercise and get plenty of sleep is a familiar mantra to alleviate this stress, but now with the results of his latest study, UNM Nutrition Professor Peter Pribis is able to tell college students that walnuts could be a key to a happier state-of-mind. 

In this first intervention study in humans, Pribis measured the effect of walnut consumption on mood.

"In the past, studies on walnuts have shown beneficial effects on many health outcomes like heart disease, diabetes and obesity," said Pribis. "Our study was different because we focused on cognition, and in this controlled randomized trial (CRT) we measured mood outcomes in males and females."

The participants of the study were 64 students between the ages of 18-25. They represented most ethnic groups: Caucasian, African American, Hispanic and Asian.

The participants were asked to eat three slices of banana bread every day for sixteen weeks--eight weeks of banana bread with walnuts and eight weeks of banana bread without walnuts. The nuts were finely ground into the dough so the two banana breads were similar in taste and appearance. While eating banana bread with walnuts the participants consumed half a cup of walnuts daily.

The mood of the students was measured at the end of each eight-week period.

"We used a validated questionnaire called Profiles of Mood States (POMS)," says Pribis. "It is one of the most widely used and accepted mood scales in studies on cognition. The test has six mood domains: tension, depression, anger, fatigue, vigor, confusion and also provides a Total Mood Disturbance score (TMD). The lower the TMD score the better the mood."

In this double-blind, randomized, placebo controlled, cross-over feeding trial with walnuts for eight weeks, Pribis observed a significant improvement in mood in young, healthy males.

"There was a meaningful, 28 percent improvement of mood in young men," said Pribis. "However we did not observe any improvement of mood in females. Why this is we do not know."

There are several nutrients in walnuts that could be responsible for the improved mood like alpha-Linolenic acid, vitamin E, folate, polyphenols or melatonin. However, this was a whole food study, so in the end it was the synergy and interaction of all the nutrients in the walnuts combined.

For Pribis, the lesson learned from this food study is clear, "Eat more walnuts. This is an easy intervention. They're not only good for your mood, but overall health as well. The recommended amount is one handful per day."

With this knowledge in hand--and hopefully walnuts in the other--young men can happily tackle life's daily stress.

Ref: http://news.unm.edu/news/the-key-to-a-better-mood-for-young-men-is-a-nut




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