The Potential Use of Vitamin D3 and Phytochemicals for Their Anti-Ageing Effects.

Unlike other vitamins, vitamin D3 is synthesised in skin cells in the body. Vitamin D3 has been known as a bone-related hormone. Recently, however, it has been considered as an immune vitamin. Vitamin D3 deficiency influences the onset of a variety of diseases. Vitamin D3 regulates the production of proinflammatory cytokines such as tumour necrosis factor-α (TNF-α) through binding to vitamin D receptors (VDRs) in immune cells. Since blood levels of vitamin D3 (25-OH-D3) were low in coronavirus disease 2019 (COVID-19) patients, there has been growing interest in the importance of vitamin D3 to maintaining a healthy condition. On the other hand, phytochemicals are compounds derived from plants with over 7000 varieties and have various biological activities. They mainly have health-promoting effects and are classified as terpenoids, carotenoids, flavonoids, etc. Flavonoids are known as the anti-inflammatory compounds that control TNF-α production. Chronic inflammation is induced by the continuous production of TNF-α and is the fundamental cause of diseases like obesity, dyslipidaemia, diabetes, heart and brain diseases, autoimmune diseases, Alzheimer's disease, and cancer. In addition, the ageing process is induced by chronic inflammation. This review explains the cooperative effects of vitamin D3 and phytochemicals in the suppression of inflammatory responses, how it balances the natural immune response, and its link to anti-ageing effects. In addition, vitamin D3 and phytochemicals synergistically contribute to anti-ageing by working with ageing-related genes. Furthermore, prevention of ageing processes induced by the chronic inflammation requires the maintenance of healthy gut microbiota, which is related to daily dietary habits. In this regard, supplementation of vitamin D3 and phytochemicals plays an important role. Recently, the association of the prevention of the non-disease condition called "ME-BYO" with the maintenance of a healthy condition has been an attractive regimen, and the anti-ageing effect discussed here is important for a healthy and long life.

The Recommendation of the Mediterranean-styled Japanese Diet for Healthy Longevity.

BACKGROUND: The Mediterranean diet, listed as the intangible cultural heritage of humanity by UNESCO, is known as healthy and consumed worldwide. The Japanese diet is also listed and considered healthy. This narrative review compares the Mediterranean diet with its Japanese counterpart. DISCUSSION: Research has reported that people in Mediterranean regions, such as Italy and Greece, have one-third of the mortality ratio from cardiovascular diseases compared to people in the United States and Northern Europe because of the difference in eating habits. Therefore, Mediterranean diets are considered as healthy. A typical Western diet containing high amounts of fat, sugar, and calories is responsible for several diseases like metabolic syndrome and obesity, which are induced by chronic inflammation. In contrast, Mediterranean and Japanese diets contain them only less. The similarity between Mediterranean and Japanese diets is the substantial intake of vegetables, beans, and fish. On the other hand, the Mediterranean diet consumes large amounts of olive oil, especially polyphenol-rich extra virgin olive oil and dairy products, but meat consumption is relatively small. In contrast, the Japanese diet does not use oil and fat, contains abundant fermented foods, and consumes seaweed. Japan is known for its longevity, and people think that a well-balanced diet daily is good for preventing and curing illness. In this regard, finding non-disease conditions, so-called "ME-BYO," and curing them before the manifestation of diseases is becoming more common. In this review, we discuss the healthy eating habit, "The Mediterranean-styled Japanese diet," which prevents ME-BYO condition and reduces the risk of various diseases. CONCLUSION: The Mediterranean-styled Japanese diet, a hybrid of Mediterranean and Japanese diets, reduces the risk of various diseases by suppressing chronic inflammation. This nutritional intervention prevents ME-BYO and is beneficial for healthy longevity. Hence, a Mediterraneanstyled Japanese diet might be helpful for healthy longevity in Japan and around the world.

Phytochemicals and Vitamin D for a Healthy Life and Prevention of Diseases.

A variety of phytocompounds contained in medical plants have been used as medication, including Kampo (traditional Japanese) medicine. Phytochemicals are one category of the chemical compounds mainly known as antioxidants, and recently, their anti-inflammatory effects in preventing chronic inflammation have received much attention. Here, we present a narrative review of the health-promotion and disease-prevention effects of phytochemicals, including polyphenols, the latter of which are abundant in onions, oranges, tea, soybeans, turmeric, cacao, and grapes, along with the synergetic effects of vitamin D. A phenomenon currently gaining popularity in Japan is finding non-disease conditions, so-called ME-BYO (mibyou) and treating them before they develop into illnesses. In addition to lifestyle-related diseases such as metabolic syndrome and obesity, dementia and frailty, commonly found in the elderly, are included as underlying conditions. These conditions are typically induced by chronic inflammation and might result in multiple organ failure or cancer if left untreated. Maintaining gut microbiota is important for suppressing (recently increasing) intestinal disorders and for upregulating immunity. During the COVID-19 pandemic, the interest in phytochemicals and vitamin D for disease prevention increased, as viral and bacterial infection to the lung causes fatal inflammation, and chronic inflammation induces pulmonary fibrosis. Furthermore, sepsis is a disorder inducing severe organ failure by the infection of microbes, with a high mortality ratio in non-coronary ICUs. However, antimicrobial peptides (AMPs) working using natural immunity suppress sepsis at the early stage. The intake of phytochemicals and vitamin D enhances anti-inflammatory effects, upregulates immunity, and reduces the risk of chronic disorders by means of keeping healthy gut microbiota. Evidence acquired during the COVID-19 pandemic revealed that daily improvement and prevention of underlying conditions, in terms of lifestyle-related diseases, is very important because they increase the risk of infectious diseases. This narrative review discusses the importance of the intake of phytochemicals and vitamin D for a healthy lifestyle and the prevention of ME-BYO, non-disease conditions.

Prevention of Metabolic Syndrome by Phytochemicals and Vitamin D.

In recent years, attention has focused on the roles of phytochemicals in fruits and vegetables in maintaining and improving the intestinal environment and preventing metabolic syndrome. A high-fat and high-sugar diet, lack of exercise, and excess energy accumulation in the body can cause metabolic syndrome and induce obesity, diabetes, and disorders of the circulatory system and liver. Therefore, the prevention of metabolic syndrome is important. The current review shows that the simultaneous intake of phytochemicals contained in citruses and grapes together with vitamin D improves the state of gut microbiota and immunity, preventing metabolic syndrome and related diseases. Phytochemicals contained in citruses include polyphenols such as hesperidin, rutin, and naringin; those in grapes include quercetin, procyanidin, and oleanolic acid. The intake of these phytochemicals and vitamin D, along with prebiotics and probiotics, nurture good gut microbiota. In general, Firmicutes are obese-prone gut microbiota and Bacteroidetes are lean-prone gut microbiota; good gut microbiota nurture regulatory T cells, which suppress inflammatory responses and upregulate immunity. Maintaining good gut microbiota suppresses TNF-α, an inflammatory cytokine that is also considered to be a pathogenic contributor adipokine, and prevents chronic inflammation, thereby helping to prevent metabolic syndrome. Maintaining good gut microbiota also enhances adiponectin, a protector adipokine that prevents metabolic syndrome. For the prevention of metabolic syndrome and the reduction of various disease risks, the intake of phytochemicals and vitamin D will be important for human health in the future.

Healthy Diet, Grape Phytochemicals, and Vitamin D: Preventing Chronic Inflammation and Keeping Good Microbiota.

BACKGROUND: Since the discovery of penicillin, natural antibiotics have protected humans from malicious microbes. A breakthrough, however, is needed to tackle problems like antimicrobial resistance (AMR). This review introduces one of the new approaches for the prevention of several diseases through a healthy diet, grape phytochemicals, and vitamin D, which nurture the growth of beneficial bacteria, including gut microbiota, suppressing chronic inflammation and up-regulating immunity. Antibiotics provide protection against infectious diseases by preventing the growth of pathogenic microbes. However, inappropriate use of antibiotics increases antimicrobial resistance to bacteria and limits the benefits of antibiotics. In addition, it is well known that antibiotics kill not only pathogenic microbes but also beneficial ones that reside in healthy individuals. As a result, the excess use of antibiotics increases the threat of diseases caused by antibiotic-resistant bacteria. We can reduce the risk of several diseases, including infectious diseases, in the future by nurturing the good microbes that live in the human body, thereby preventing chronic inflammation induced by the proinflammatory cytokine TNF-α, improving predisposition, and up-regulating immunity. Along with human evolution, residing bacteria in the skin, digestive system, and other areas have changed. They defend their hosts from malicious microbes in the surrounding environment. With the progress of medicine, science, and technology, the quality of life and environmental public health have improved over the years. Under these circumstances, it is necessary to reduce the risk of illness and keep ourselves healthy by nurturing the good resident microbiota in our bodies and preventing chronic inflammation through the diet and the intake of phytochemicals and vitamin D. This new approach is important, along with the traditional method for preventing emerging infectious diseases in the future.

Grape Phytochemicals and Vitamin D in the Alleviation of Lung Disorders.

BACKGROUND: Typical lung diseases are pneumonia, asthma, sleep apnea syndrome (SA), interstitial pneumonia (IP), lung cancer, and chronic obstructive pulmonary disease (COPD). Coronavirus disease 2019 (COVID-19) is a type of viral pneumonia. Many researchers have reported that phytochemicals (chemical compounds produced by plants) and vitamin D are useful in stimulating our immunity. This review discusses the alleviation of lung diseases by grape phytochemicals and vitamin D. DISCUSSION: Pneumonia is an acute inflammation caused by the infection of pathogens; the worst case is a fatal cytokine storm in the lung. In asthma, allergens, tobacco smoke, or air pollution may cause seizures. Lung diseases caused by lung fibrosis may manifest chronic inflammation, progress into alveolar fibrosis, and cause respiratory malfunction. SA is a lifestyle disease related to obesity and metabolic syndrome. To alleviate these symptoms, changing the eating habit is one of the strategies. Improvement in the daily lifestyle reduces the risk of lung cancer. Self-management, including nutritional management and exercise, is very important for COPD patients in addition to pharmacotherapy. CONCLUSION: The intake of grape phytochemicals and vitamin D prevents the progress of lung diseases. Both phytochemicals and vitamin D prevent the production of proinflammatory cytokine, TNF-α, that is responsible for inflammation and lung diseases. Daily intake of grape phytochemicals is important. The optimum vitamin D level in serum is > 30 ng/mL. For the prevention of lung diseases, upregulating immunity and maintaining good gut microbiota are important because gut microbiota change depending on what we eat.

The Potential Use of Grape Phytochemicals for Preventing the Development of Intestine-Related and Subsequent Inflammatory Diseases.

BACKGROUND: Grape phytochemicals prevent intestine-related and subsequent other inflammatory diseases. Phytochemicals and vitamin D are useful for the regulation of inflammatory responses. Phytochemicals is the generic name for terpenoids, carotenoids, and flavonoids that consist of a variety of chemicals contained in vegetables and fruits. There are a variety of grape cultivars that contain many kinds of phytochemicals in their skin and seeds. Grape phytochemicals including Grape Seed Extracts (GSE) have already been used to maintain healthy condition through manipulating inflammatory responses by decreasing the expression of inflammation-related factors. DISCUSSION: Grape phytochemicals mainly consist of a variety of chemicals that include terpenoid (oleanolic acid), carotenoids (ß-carotene, lutein), and flavonoids: flavon-3-ols (quercetin), flavan-3-ols (catechins), anthocyanins, oligomers and polymers (tannins and proanthocyanidins), and resveratrol. Phytochemicals improve the dysbiosis (gut microbiota complication) induced by metabolic syndrome and regulate inflammatory diseases induced by TNF-α production. Once absorbed, flavonoids change into glucuronide-form, move into the bloodstream and reach the inflammatory sites including liver, lung, and sites of arteriosclerosis, where they become active. Furthermore, oleanolic acid acts on TGR5 - the cholic acid receptor, as an agonist of cholic acid. These anti-inflammatory effects of phytochemicals have been proven by the experimental animal studies and the clinical trials. CONCLUSION: It is expected the new health food products will be created from grape skins and seeds since grape phytochemicals participate in the prevention of inflammatory diseases like intestine-related inflammatory diseases.

Para-Nonylphenol Induces Apoptosis of U937 Human Monocyte Leukemia Cells in vitro.

BACKGROUND: Human autoimmune diseases are caused by a variety of factors, such as environmental chemicals, including para-nonylphenol. Macrophages play many critical roles in the regulation of immunity and the progression of autoimmune diseases. However, little information is available regarding the effects of para-nonylphenol on cellular signaling pathways and the death of these cells in vitro. Here, we show that very high concentrations of para-nonylphenol (50-100 µM) induce apoptosis in U937 human monocyte leukemia cells in a dose-dependent manner. METHODS: Cell viability was judged using the trypan blue exclusion method. FACS analysis for DNA fragmentation was conducted, cellular signaling pathways were evaluated using western blot analysis, and caspase activity was measured by using substrates. U937 cells were differentiated by PMA. RESULTS: Treatment with > 50 µM para-nonylphenol induced apoptosis in U937 monocyte cells and MCF- 7 and MDA-MB231 human breast cancer cells. We found cytochrome c release from the mitochondria to the cytoplasm, DNA fragmentation, and decreased expression of anti-apoptotic protein Bcl-XL. Caspase 3 and 9 were induced, but caspase 1 and 3-inhibitor treatment suppressed apoptosis. Para-nonylphenol decreased the levels of activated AKT and increased the levels of activated JNK/SAPK at 15 min after treatment. Furthermore, with PMA treatment, U937 cells were differentiated into a macrophage-like phenotype and showed attenuated cell death against para-nonylphenol. CONCLUSION: As this assay system is simple and rapid, it may represent a useful artificial tool to clarify the signaling pathways of apoptotic cell death in human monocytes in vitro.

Enhanced expression of B7.2 (CD86) by percutaneous sensitization with house dust mite antigen.

House dust mite antigen is a well-known allergen in the pathogenesis of atopic dermatitis (AD), a chronic relapsing inflammatory skin disease. We evaluated the AD model mice sensitized with house dust mite antigen and observed a Th2-dominant immune response. In this experiment, BALB/c mice were sensitized percutaneously with house dust mite antigen three times with 7 days interval after skin barrier disruption. A remarkable infiltration of polymorphonuclear granulocytes and monocytes in the cutis was observed in mice treated with this antigen, high serum IgE levels and IL-4 mRNA expression in local lymph node cells was also observed. CD19(+) B cell numbers overturned to CD4(+) helper T cells. In these mice, there was significant increase of B7.2 (CD86) expression on CD19(+) B cells. These results indicate that house dust mite antigen sensitizes BALB/c mice and skews their Th1/Th2 balance toward Th2.

Effect of orally administered Hochu-ekki-to, a Japanese herbal medicine, on contact hypersensitivity caused by repeated application of antigen.

The effects of oral administration of Hochu-ekki-to (HET; bu-zhong-yi-qi-tang in Chinese), a traditional Japanese and Chinese herbal medicine, on chronic contact hypersensitivity were investigated. HET suppressed ear swelling due to chronic contact hypersensitivity caused by repeated application of 2,4,6-trinitro-1-chlorobenzene (TNCB). HET significantly suppressed not only increases in hapten-specific immunoglobulin E (IgE) and IgG1 titer due to repeated application of TNCB, but also total IgE and IgG1 concentration in the serum. Interleukin 4 (IL-4) level in inflamed ear tissue was significantly increased by repeated application of TNCB, and this increase in IL-4 level in the ear was significantly suppressed by oral administration of HET. Interferon gamma (IFN-gamma), IL-2, IL-5, IL-10 and IL-12 levels are not changed as much as IL4 by TNCB and HET did not alter these cytokines as much as IL-4. These results suggest that oral administration of HET suppresses chronic contact hypersensitivity, and it can be assumed that the suppression of serum Ig E and Ig G1 and IL-4 in inflamed ear.