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.

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.

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.

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.

Effect of the Administration of Cordyceps militaris Mycelium Extract on Blood Markers for Anemia in Long-Distance Runners.

In the present study, we conducted a placebo-controlled, double-blind, parallel-group comparison trial in which an extract of Cordyceps militaris (CM) mycelium was administered to long-distance runners for 16 weeks during the pre-season training period and blood test markers for anemia were investigated. The results indicated that the change rates of serum ferritin levels were moderately increased in the CM group (n = 11) but decreased in the placebo group (n = 11) during the study period, and the levels were significantly increased in the CM group compared with those in the placebo group at 4 weeks and 8 weeks after the test food intake (p < 0.05). Moreover, the change rates of hemoglobin and hematocrit were significantly increased in the CM group compared with those in the placebo group at 8 weeks after the test food intake (p < 0.05). These observations suggest that the intake of test food containing Cordyceps militaris mycelium extract is expected to effectively maintain the hemoglobin and hematocrit levels in long-distance runners, possibly via the suppression of the decrease in iron storage, which is reflected by serum ferritin, during pre-season training. Furthermore, the levels of creatine kinase were increased above the normal range in both the placebo and CM groups at registration. Interestingly, the creatine kinase levels were significantly decreased in the CM group compared with those in the placebo group at 16 weeks after the test food intake (p < 0.05). These results suggest that Cordyceps militaris mycelium extract exhibits a protective action on the muscle damage observed in long-distance runners and may suppress muscle injury. Together, these observations suggest that Cordyceps militaris mycelium extract exhibits an improving effect on the markers for not only anemia, but also muscle injury in long-distance runners during pre-season training.

Pulmonary TCR γδ T cells induce the early inflammation of granuloma formation by a glycolipid trehalose 6,6'-dimycolate (TDM) isolated from Mycobacterium tuberculosis.

We previously showed that formation of pulmonary granulomas in mice in response to a mycobacterial glycolipid, trehalose 6,6'-dimycolate (TDM) is due to the action of TNF-α and not of IFN-γ. However, the mechanisms of formation and maintenance of pulmonary granulomas are not yet clear. The purpose of the present study is to evaluate the mechanisms of granuloma formation by TDM at the early phase. Histological analysis showed that inflammatory cells infiltrated the murine pulmonary interstitium on day 2 after an intravenous injection with TDM as a w/o/w emulsion. Clear granuloma formation was observed on day 7 after the injection. The mRNA expression of IL-17, IFN-γ and macrophage inflammatory protein 2 was found in lung mononuclear cells at the day after TDM injection. The major IL-17-producing cells were T-cell receptor (TCR) γδ T cells expressing Vγ6. In mice depleted of γδ T cells by treatment with anti-TCR γδ monoclonal antibody, the number of TDM-induced granuloma was decreased, but the size of granuloma was not affected. Our results suggest that the mycobacterial glycolipid TDM causes activation of IL-17-producing TCR γδ T cells and stimulates chemotaxis of inflammatory cells including neutrophils in to lung.

Suppression of inflammatory responses after onset of collagen-induced arthritis in mice by oral administration of the Citrus flavanone naringin.

Rheumatoid arthritis (RA) is closely related to the pathogenesis of tumor necrosis factor α in lesions. We investigated the suppressive effects of a Citrus flavanone naringin on inflammatory responses in mice with collagen-induced arthritis (CIA), a mouse model for RA. To investigate potential preventive and therapeutic effects of naringin, mice were given naringin orally three times a week from the second immunization with collagen (day 21) and from day 31, when symptoms of CIA had reached a plateau, respectively. In both cases, inflammation-related clinical scores for knee joints were significantly reduced by administration of naringin. Histological analyses demonstrated that representative phenomena, such as damage to interchondral joints, infiltration of inflammatory cells and pannus formation, were significantly depressed by treatment with naringin. In addition, increases in the expression of high-mobility group box-1 protein in the joints of mice with CIA were suppressed by naringin. These results suggest that oral administration of naringin might be effective for treating human patients with RA.

Inhibitory effects of fermented grape marc from Vitis vinifera Negroamaro on antigen-induced degranulation.

To investigate the antiallergic effects of fermented grape marc from Negroamaro (N-FGM), we examined antigen (Ag)-induced degranulation of rat basophilic leukemia (RBL-2H3) cells. Among supernatants of N-FGM suspensions in water, ethanol, and dimethyl sulfoxide (DMSO), supernatants of DMSO-suspended N-FGM but not of nonfermented Negroamaro grape marc (N-GM) markedly suppressed the Ag-induced degranulation and phosphorylation of Syk in RBL-2H3 cells. Supernatants of DMSO-suspended N-FGM did not reduce the expression of FcepsilonRI on RBL-2H3 cells. Analyses of supernatants of N-FGM suspensions in water, ethanol, and DMSO by high-performance liquid chromatography revealed higher amounts of quercetin in supernatants of DMSO-suspended N-FGM than those in the other supernatants. Quercetin also suppressed the Ag-induced degranulation and phosphorylation of Syk but did not reduce the expression of FcepsilonRI on RBL-2H3 cells. These results suggest that inhibition of the Ag-induced degranulation and Syk phosphorylation by N-FGM might be due to the action of quercetin, as an active component in N-FGM.

Suppression of type-I allergic responses by oral administration of grape marc fermented with Lactobacillus plantarum.

We investigated the inhibitory effects of fermented grape marc (FGM), lyophilized fine powder of skin, and seeds of Vitis vinifera Koshu grape prepared by fermentation with Lactobacillus plantarum, on type-I allergic responses in mice. Repeated oral administration of FGM, but not non-fermented grape marc (GM), to BALB/c mice primed with ovalbumin (OVA) resulted in a significant reduction of serum IgE levels, compared with those of immunized controls. After OVA challenge, increased numbers of eosinophils in bronchial alveolar lavage fluids (BALF) significantly decreased by treatment with FGM but not with GM. For passive cutaneous anaphylaxis (PCA) reaction, BALB/c mice received intradermal sensitization with anti-OVA IgE serum and were challenged intravenously with OVA containing Evans blue at 24 h after IgE sensitization. Oral administration of FGM at 30 min before OVA challenge significantly suppressed the PCA reaction. On the other hand, Lactobacillus alone and non-fermented GM did not show any suppressive effects. Interestingly, FGM samples prepared from grapes for red wine, such as Negroamaro (rich in resveratrol) or Tannat (rich in oligomeric procyanidin), did not suppress the reaction. These results indicate that oral administration of FGM, prepared from Koshu grape for white wine but not from grapes for red wine, could suppress both phases of type-I allergic responses. A fraction extractable with acetone was responsible for the suppressive effects of FGM.

Potentiation of murine innate immunity by alpha-galacturonosyl-type glycosphingolipids isolated from Sphingomonas yanoikuyae and S. terrae.

Glycosphingolipids (GSLs) are components of the outer membrane of Sphingomonas species, commonly classified into two types, alpha-glucuronosyl ceramide (alpha-GlcACer) and alpha-galacturonosyl ceramide (alpha-GalACer), respectively. GSL-7 from S. yanoikuyae and GSL-13 from S. terrae, with alpha-GalACer-type structure, possess dihydrosphingosine but with a different ratio of C21cyclopropane to C20:1, while other parts remain similar. We therefore examined if this difference in the ratio of C21cyclopropane to C20:1 in the two ceramides may influence activation of, not only invariant natural killer T (iNKT) cells, but also other cells involved in innate immunity. GSL-7 with a large proportion of C21cyclopropane induced stronger activation of iNKT cells, natural killer cells, dendritic cells, and macrophages than GSL-13 with a large proportion of C20:1. The results show that a higher ratio of C21cyclopropane to C20:1 in the dihydrosphingosine molecule allows a more optimal activation of iNKT cells and other cell types.

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.

Potent Inhibitory Effects of Quercetin on Inflammatory Responses of Collagen-Induced Arthritis in Mice.

BACKGROUND: Production of tumor necrosis factor (TNF)-α by inflammatory cells in lesions is the hallmark of the pathogenesis of rheumatoid arthritis (RA). Regulation of inflammatory responses in knee joints of patients with RA is critical for improving severe symptoms. Flavonoids have inhibitory effects on the acute and chronic inflammatory responses caused by TNF-α. The flavonoid quercetin (QUER) is one of the most prominent dietary antioxidants. OBJECTIVE: The present study investigated the preventive and therapeutic effects of QUER on inflammatory responses in collagen-induced arthritis (CIA) in mice. METHODS: Mice with CIA, a mouse model for RA, were treated with QUER orally three times a week either from the second immunization with collagen (day 21) or day 28 when symptoms of CIA had developed midway. RESULTS: In both cases, inflammation-related clinical scores of knee joints were significantly reduced by treatment with QUER. Histological analyses showed that the representative characteristics of RA, such as damage to interchondral joints, infiltration of inflammatory cells, and pannus formation, were significantly reduced by QUER treatment. Oral administration of QUER significantly decreases lipopolysaccharide (LPS)-induced TNF-α production in a dose-dependent manner. Expression of TNF- α mRNA in knee joints was decreased in QUER-treated mice, compared with those of CIA controls. CONCLUSION: These results suggest that oral administration of QUER might effectively improve symptoms of RA.

Quercetin but not luteolin suppresses the induction of lethal shock upon infection of mice with Salmonella typhimurium.

Tumor necrosis factor-alpha (TNF-alpha) is important for the induction of systemic inflammatory responses that lead to lethal shock. Quercetin and luteolin, which differ by one hydroxyl group, are known to suppress the lipopolysaccharide-induced production of TNF-alpha in vitro. We show differing inhibitory effects of quercetin and luteolin on the induction of lethal shock in Salmonella typhimurium aroA-infected mice. In a time- and dose-dependent manner, quercetin reduced the plasma levels of TNF-alpha, lowered bacterial titers in livers, prevented liver damage and prolonged survival, while luteolin had little or no effect. Compared with luteolin, quercetin increased the infiltration of Gr-1(+)CD69(+) neutrophils into the peritoneal cavity and lowered heat shock protein 70 expression. Obviously, the additional hydroxyl group in quercetin is important for suppressing infection-induced lethal shock in mice.

Amelioration of skewed Th1/Th2 balance in tumor-bearing and asthma-induced mice by oral administration of Agaricus blazei extracts.

We showed in a previous study that hot-water extracts of Agaricus blazei (Agaricus extracts) had anti-tumor activity to Meth A fibrosarcoma, but it remains unclear whether the Agaricus extracts ameliorate the skewed balance of type-1 T helper (Th1) and type-2 T helper (Th2) cells. We examined whether Agaricus extracts effect the skewed Th1/Th2 balance in tumor-bearing and asthma-induced mice. When Meth A-bearing mice were given orally either Agaricus extracts or water once a day starting 5 days after tumor implantation, spleen T cells, prepared from tumor-bearing mice treated with Agaricus extracts, in response to anti-CD3 monoclonal antibody produced significantly higher levels of interferon gamma (IFN-gamma) than that of controls. The mRNA expression of IFN-gamma-inducing protein 10 and the frequency of CD69(+) or CD49d(+) cells, among activated T cells infiltrated into tumors, significantly increased in Agaricus-treated mice, compared with those of tumor-controls. In asthma-induced mice, treatment with the Agaricus extracts caused significant downregulation of OVA-specific antibody responses of IgG1 and IgE but not of IgG2a, and significantly decreased total cell numbers, levels of interleukin 5, and eosinophil numbers in bronchial alveolar lavage fluids. IFN-gamma production by anti-CD3-stimulated spleen cells, obtained from Agaricus-treated mice, significantly increased. Our results strongly suggest that oral administration of Agaricus extracts ameliorates the Th1/Th2 balance from the Th2-skewed conditions.

Suppressive effects of the flavonoids quercetin and luteolin on the accumulation of lipid rafts after signal transduction via receptors.

Quercetin (QUER) and luteolin (LUTE) are dietary flavonoids capable of regulating the production of cytokines, such as tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6). However, their mechanisms of action are not fully understood. In lipopolysaccharide-triggered (LPS)-triggered signaling via Toll-like receptor 4 (TLR4), QUER and LUTE suppresses not only the degradation of the inhibitor of kappaB (IkappaB), with resultant activation of nuclear factor-kappaB (NF-kappaB), but also the phosphorylation of p38 and Akt in bone marrow-derived macrophages that have been stimulated with LPS. We report here that, in TNF-alpha-induced signaling, QUER and LUTE significantly suppressed the production of IL-6 and activation of NF-kappaB. Accumulation of lipid rafts, the initial step in the signaling pathway, was significantly inhibited when macrophages were treated with QUER or with LUTE prior to exposure to LPS. Similarly, the accumulation of lipid rafts was inhibited by the flavonoids when B cells were activated via the membrane IgM and when T cells were activated via CD3. In contrast, QUER and LUTE did not inhibit the activation of phorbol myristate acetate-induced NF-kappaB in macrophages. Our observations suggest that QUER and LUTE interact with receptors on the cell surface and suppress the accumulation of lipid rafts that occurs downstream of the activation of the receptors.

Effects of alpha-glucosylhesperidin, a bioactive food material, on collagen-induced arthritis in mice and rheumatoid arthritis in humans.

Hesperidin (Hsp) is an abundant flavonoid in citrus fruits, and the oral administration of Hsp has been recently reported to suppress collagen-induced arthritis in mice. Therefore, we sought to determine whether alpha-glucosylhesperidin (Hsp-G), which is an Hsp derivative with enhanced water-solubility, is effective on treating arthritis in both mice and humans. Hsp-G was orally administered to mice with collagen-induced arthritis, and its effects were evaluated clinically and histologically. Oral administration of Hsp-G improved collagen-induced arthritis when administered before the onset of arthritis as well as when administered after its onset. A decrease in tumor necrosis factor-alpha production was found to cause this improvement. In the human study, 19 patients with rheumatoid arthritis (RA) were enrolled in a 12-week double-blind, placebo-controlled trial. Patients were administered beverages containing 3 g Hsp-G (n = 9) or placebo (n = 10) every morning for the duration of the 3-month trial. Additionally, patients received standard therapy from a physician every 4 weeks. As a result, 3 of 9 patients in the Hsp-G group improved, while only 1 of 10 patients in the placebo group improved; this was in accordance with the American College of Rheumatology criteria. The present study revealed that the food material Hsp-G was effective when administered with standard anti-rheumatoid therapy in ameliorating RA in mice and humans without any adverse effects and may improve the quality of life for patients with RA as a complementary/alternative medicine.

Morphometrical and Morphological Alterations of Human Leukocytes Exposed to 1.8 GHz Electromagnetic Radiations: In Vitro Protective Effects Induced by Polyphenols.

BACKGROUND: Our recent findings have demonstrated that electromagnetic radiations (EMR) (1.8 GHz radiofrequency) are able to in vitro induce morphometrical and morphological modifications of human leukocytes from normal donors. METHODS: In view of the evidence that polyphenols exert many beneficial effects on plants, animals and humans, leukocytes from human peripheral blood were pre-treated for 1 h with two polyphenol preparations from red grape before EMR exposure (1.8 GHz). RESULTS: Our data will show that polyphenol pre-treatment reverts to normality the morphology of irradiated leukocytes in comparison to irradiated cells only. Conversely, leukocyte morphometry seems to be not affected by this treatment. CONCLUSION: Here, we demonstrate that polyphenols are also able to normalize leukocyte morphology per se altered before as well as after irradiation. Finally, a working hypothesis aimed at clarifying the protective mechanisms exerted by polyphenols on irradiated leukocytes will be illustrated.

Structural analysis of sphingophospholipids derived from Sphingobacterium spiritivorum, the type species of genus Sphingobacterium.

The unique feature of the genus Sphingobacterium is the presence of sphingophospholipids and ceramides, besides diacylglycerophospholipids. As major cellular lipid components, five kinds of sphingophospholipids were purified from Sphingobacterium spiritivorum ATCC 33861(T), the type species of genus Sphingobacterium. They were identified as ceramide phosphorylethanolamines (CerPE-1 and CerPE-2), ceramide phosphoryl-myo-inositols (CerPI-1 and CerPI-2), and ceramide phosphorylmannose (CerPM-1). The ceramide of CerPE-1, CerPI-1, and CerPM-1 was composed of 15-methylhexadecasphinganine (isoheptadeca sphinganine, iso-C17:0) and 13-methyltetradecanoic acid (isopentadecanoic acid, iso-C15:0), whereas that of CerPE-2 and CerPI-2 was composed of isoheptadeca sphinganine and 2-hydroxy-13-methyltetradecanoic acid (2-hydroxy isopentadecanoic acid, 2-OH iso-C15:0). These sphingophospholipids were also found in cellular lipids of Sphingobacterium multivorum ATCC 33613(T), Sphingobacterium mizutaii ATCC 33299(T), Sphingobacterium faecium IFO 15299(T), Sphingobacterium thalpophilum ATCC 43320(T), and Sphingobacterium antarcticum ATCC 51969(T). To our knowledge, the existence of CerPM-1 is a novel sphingophospholipid through eukaryotic and prokaryotic cells.

Does high mobility group 1 protein function as a late mediator for LPS- or TNF-induced shock in galactosamine-sensitized mice?

The role of high mobility group-1 protein (HMG-1) in LPS- and TNF-alpha-induced lethal shock in galactosamine (GalN)-sensitized mice was investigated. No detectable HMG-1 levels were observed by immunoblotting analysis in plasma from untreated or GalN-sensitized BALB/c mice 5 h after LPS injection, although significant levels of HMG-1 were detected in plasma 6 h after the challenge. All GalN-sensitized BALB/c but not BALB/lps(d) mice succumbed by 6 h after LPS injection. When GalN-sensitized mice were injected with TNF-alpha, the presence of HMG-1 was seen at 5.5 h in plasma of BALB/c mice and at 6 h in BALB/lps(d) mice, although almost all GalN-sensitized BALB/c mice died by 6 h after challenge. The time-dependent phenomenon correlated with elevated serum aspartate aminotransferase (AST) levels and the appearance of apoptotic cells in livers. Administration of pooled plasma, equivalent to approximately 200 microg recombinant murine HMG-1, taken from mice on the verge of near death, did not result in induction of lethal shock in GalN-sensitized mice. Taken together with the late appearance of HMG-1 in moribund mice, these data suggest that HMG-1 does not decisively contribute to lethality in the GalN sensitization model.

Inhibitory effect of quercetin on carrageenan-induced inflammation in rats.

We examined the effect of quercetin on the inflammatory response induced by carrageenan in the rat. Air pouches were induced subcutaneously on the backs of rats and injected with carrageenan. The rats were treated with either vehicle or quercetin at a dose of 10 mg/kg one hour before carrageenan challenge. Fourty-eight hour after carrageenan challenge, the air pouches were removed and analyzed. The volume, protein amounts and cell counts in the exudation obtained from the quercetin-treated animals were significantly reduced compared to those from vehicle-treated animals. The contents of PGE(2), TNF-alpha, RANTES, MIP-2 and the mRNA for cyclooxygenase-2 were also suppressed in these rats. The histological examination displayed the suppression of the inflammatory response in the pouch tissues from quercetin-treated rats. As the anti-inflammatory effect of the flavonols was more or less at the similar level among the quercetin-, isoquercitrin- or rutin-treated rats, it appeared that the sugar parts did not influence on the anti-inflammatory effect. Our study indicated that the flavonols modulated the inflammatory response, at least in part, by modulating the prostanoid synthesis as well as cytokine production.