Grape-derived compounds may promote resilience against depression

Scientists from the Icahn School of Medicine at Mount Sinai describe an extensive analysis of novel grape-derived compounds, dihydrocaffeic acid (DHCA) and malvidin-3'-O-glucoside (Mal-gluc), which might be developed as therapeutic agents for the treatment of depression. The study results indicate that these natural compounds may attenuate depression by targeting newly discovered underlying mechanisms of the disease.

Conventional pharmacological treatments are estimated to produce temporary remission in less than 50 percent of patients, and they are often associated with severe adverse effects. Thus, there is an urgent need for a wider spectrum of novel therapeutics.

Depression is associated with a multitude of pathological processes, including inflammation of the peripheral immune system, a set of biological structures and processes in the lymph nodes and other tissues that protect against disease and abnormalities involving synapses, the structures that permit neurons to pass an electrical or chemical signal to other neurons.

However, currently available antidepressants are largely restricted to targeting the systems that regulate serotonin, dopamine, and other related neurotransmitters, and these treatments do not specifically address inflammation and synaptic maladaptations that are now known to be associated with MDD.

Previous research has found that grape-derived polyphenols have some efficacy in modulating aspects of depression, yet the mechanisms of action had largely remained unknown until now. The new study, led by Giulio Maria Pasinetti, PhD, Saunders Professor of Neurology, and a team of investigators from the Center for Integrative Molecular Neuroresilience at the Icahn School of Medicine at Mount Sinai, found that a bioactive dietary polyphenol preparation-a combination of three grape-derived polyphenol products, including a select Concord grape juice, a select grape seed extract, and trans-resveratrol was effective in promoting resilience against stress-induced depression in mice.

Specifically, researchers found that DHCA and Mal-gluc can promote resilience in mouse models of depression by modulating inflammation and synaptic plasticity, respectively. DHCA reduces interleukin 6 (IL-6), a pro-inflammatory substance secreted by T cells and macrophages to stimulate immune response, by epigenetically modulating the non-coding sequence of the IL-6 gene. Mal-gluc modulates histone acetylation of the Rac1 gene and allows transcription activators to access the DNA for increased transcription in the brain, which influences the expression of genes responsible for synaptic plasticity.

Researchers also demonstrated that DHCA/Mal-gluc treatment was effective in attenuating depression-like phenotypes in a mouse model of increased systemic inflammation induced by transplantation of cells from the bone marrow of stress-susceptible mice. The research shows that combination treatment with the two compounds can promote resilience against stress-mediated depression-like phenotypes by modulating systemic inflammatory responses and brain synaptic plasticity in a mouse model of depression.

The Mount Sinai study provides novel preclinical evidence supporting the targeting of multiple key disease mechanisms through DNA epigenetic modification for the treatment of depression. This study strongly supports the need to test and identify novel compounds that target alternative pathologic mechanisms, such as inflammation and synaptic maladaptation, for individuals who are resistant to currently available treatment.

Using combination treatment of DHCA and Mal-gluc to simultaneously inhibit peripheral inflammation and modulate synaptic plasticity in the brain works synergistically to optimize resilience against chronic stress-induced depression-like phenotypes. The discovery of these new, natural grape-derived polyphenol compounds targeting cellular and molecular pathways associated with inflammation may provide an effective way to treat a subset of people with depression and anxiety, a condition that affects so many people.
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Vitamin D boosts fertility

Women undergoing fertility treatment were 33 per cent more likely to have a baby if their vitamin D levels were healthy. NHS recommends taking of vitamin D supplement for women who are pregnant or trying to conceive for the sake of the development of their baby.

The researchers believe vitamin D may help dampen the immune system’s inflammatory response, improving the chances that an embryo successfully implants in the lining of the womb at the very start of pregnancy. Sun exposure and greater sunlight luminosity increases the body’s store of vitamin D, thereby yielding higher conception rates in summer and autumn.

Oily fish such as sardines or mackerel, red meat, liver or eggs are all rich in vitamin D.The vitamin is important during pregnancy because it affect the way a baby’s bones grow in the womb.
women should beware taking very high doses of vitamin D in a bid to conceive - as it is possible to overdose.

The NHS recommended dose of 10 micrograms a day is considered to be safe. Women should beware that taking more than this without medical advice can lead to too much calcium building up in the body, which can weaken bones and damage the heart and kidneys.
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Targeted cell metabolism can improve immune system

Immune system can become so over-activated when fighting infections that the resulting inflammatory response can lead to death. Excessive response by the immune system can be modulated by targeted manipulation of the sugar metabolism to produce an immune response that eliminates the pathogens without causing any harmful to the immune system.

Using 2-Deoxy-D-glucose 2-DG during the infection make this possible, adding 2-DG, that prevents glycolysis, causes increased production of interleukin-12 IL-12, a pro-inflammatory cytokine, while suppressing the production of interleukin-10, an anti-inflammatory cytokine.

IL-12 triggers a specific T-cell immune response, which is part of the cellular immune response, to specifically boost the defence mechanisms that serve to eliminate intracellular pathogens like listeria. Addition of 2-DG changes the nature of the immune response and the intensity of the inflammatory process, inflammation is controlled so that the immune system is able to manage the situation without allowing the infection to leads to a deadly outcome.

This prevents excessive inflammatory responses, following addition of of 2-DG, only p40 is upregulated, while no p35 is produced. This modified cytokine profile, there is also a simultaneous increase in IL-23 expression which could subsequently bring about modified recruitment of immune cells and hence have a decisive influence on the intensity of the immune response.

The metabolic increased production of activating mediators with simultaneous inhibition of immunosuppressive mediators. Manipulation of the sugar metabolism and associated modulation of the immune system could open up new options for treating specific infectious and autoimmune diseases
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Low calories diet prevents aging

Low-calorie diet and eating less keeps the body younger. Body's biological clock change as a result of physiological aging, the clock controlled circuit that directly connects to the process of aging is based on efficient metabolism of energy within cells.

Energy is metabolized within cells under precise circadian controls.
The researchers found that the 24-hour cycle in the circadian-controlled metabolic system of older mice remained the same, but there were notable changes in the circadian mechanism that turns genes on and off based upon the cells' energy usage.

Older cells processed energy inefficiently. Caloric restriction works by sprucing up the biological clock. According to scientists, low-calorie diet conserved most of the rhythmic functions in young people.

The low-calorie diet greatly contributes to preventing the effects of physiological aging. Keeping the rhythm of stem cells young is important because these cells renew and preserve day-night cycles in tissue.

Eating less prevent tissue aging, therefore, it prevents stem cells from reprogramming their circadian activities. Calorie restriction influences the body's circadian rhythms involvement with the aging process in cells. Circadian rhythm-metabolism link circadian enzyme protein called SIRT1 works.

 SIRT1 senses energy levels in cells; its activity is modulated by how many nutrients a cell is consuming. It helps cells resist oxidative and radiation-induced stress. SIRT1 has also been linked to the inflammatory response, diabetes and aging.
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