Hiroyuki Inagawa

Kagawa University

The microbiome and its components on the skin and in the environment contribute to the maintenance of skin homeostasis. Here, we examined the effect of the continuous application of lipopolysaccharide (LPS), a gram-negative bacterial component, on skin sensitivity and water retention on the facial skin of 11 human subjects. To analyze the mechanism...

Lipopolysaccharide (LPS) is the principal component of the outer membrane of gram-negative bacteria. The prior oral administration of LPS attenuates inflammatory responses, such as intestinal injury and atopic dermatitis, in mouse models; however, the underlying mechanism remains unclear. Here, we examined the effect of topical LPS application on a...

Diabetes-related cognitive dysfunction (DRCD) is a serious complication induced by diabetes. However, there are currently no specific remedies for DRCD. Here, we show that streptozotocin-induced DRCD can be prevented without causing side effects through oral administration of lipopolysaccharide (LPS) derived from Pantoea agglomerans . Oral administ...

Background/aim: Diabetes is a risk factor for dementia. However, no radical preventive method for diabetes-associated dementia has yet been developed. Our previous study revealed that oral administration of lipopolysaccharide (LPS) prevents high-fat diet-induced cognitive impairment. Therefore, we investigated here whether oral administration of L...

Background/aim: Increased expression of inflammatory cytokine genes through cell interactions in tissues may cause chronic inflammation, leading to the development of lifestyle-related diseases. Since the activation of inflammatory cytokine genes in monocytes/macrophages by co-culturing with cancer cells or adipocytes was suppressed by pre-treatme...

Background/aim: We investigated the effect of Kumaizasa leaf extract (KLE) on innate immunity using the HEK293 and RAW 264.7 cell lines. Materials and methods: KLE, lipopolysaccharides (LPS), or KLE with LPS were added to RAW 264.7 cells. The TNF-α and IL-1β mRNA expression was then quantified. The expression of MAPKs, NFĸB, TNF-α and IL-1β prot...

Diabetes‑associated neuronal dysfunction (DAND) is one of the serious complications of diabetes, but there is currently no remedy for it. Streptozotocin [2‑deoxy‑2‑(3‑methy1‑3‑nitrosoureido) D‑glucopyranose; STZ] is one of the most well‑established diabetes inducers and has been used in vivo and in vitro DAND models. The aim of the present study wa...

Background/aim: Our previous studies suggested that oral administration of lipopolysaccharide (LPS) regulates the progression of various diseases via transformation of tissue-resident macrophages (MΦ). Recently, we characterized microglia transformed by repetitive low-dose LPS treatment (REPELL-microglia) in vitro, and this response was similar to...

Background/aim: We investigated whether mastication affects microglia, whose activity is thought to be associated with cognition and brain tumor progression. Materials and methods: We kept mice by feeding either a hard or soft diet for 2, 4 or 8 months. After each period, we removed the whole brains and isolated microglia. The total RNA extracte...

Background/aim: The functions of macrophages change in response to environmental factors such as lipopolysaccharide (LPS). LPS derived from Pantoea agglomerans (LPSp) is involved in macrophage activation and tissue repair when administered dermally. LPSp-activated macrophages may be useful for restoring and maintaining homeostasis of the skin. Ma...

Background: Continuous oral administration of lipopolysaccharide (LPS) enhances the phagocytic ability of macrophages, which is useful for preventing various diseases. Here, we attempted to create an in vitro model of continuous administration of LPS. Materials and methods: RAW264.7 cells were stimulated with LPS three times every 24 h (repeated...

Background: Developmental disorders are associated with microglial dysfunction. Oral administration of lipopolysaccharide derived from Pantoea agglomerans bacteria (LPSp) leads to normalization of phagocytic activity of microglia and suppression of inflammation in mice. In this article, we report on a successful trial in which we achieved a signif...

Although lipopolysaccharide (LPS) is regarded as an inducer of inflammation, previous studies have suggested that repetitive low-dose LPS has neuroprotective effects via immunomodulation of microglia, resident macrophages of brain. However, microglia transformed by the stimulus of repetitive low-dose LPS (REPELL-microglia) are not well characterize...

Dewaxed brown rice (DBR), which is prepared by removing only the outermost wax layer of brown rice using a new rice milling technique, has improved water absorbency, digestibility, and taste compared to regular brown rice. DBR has a nutritional value close to that of brown rice, including a rich amount of lipopolysaccharides that are known to impro...

Compared with regular brown rice, dewaxed brown rice (DBR), prepared by excluding only the wax layer in the outermost layer of brown rice using a new rice milling technique, has improved water absorbency, digestibility, and taste. Dewaxed brown rice has a nutritional value close to that of brown rice and contains a large amount of lipopolysaccharid...

Background/aim: The wound-healing effect of lipopolysaccharide (LPS) reportedly results from its ability to induce the removal of foreign bodies, anti-inflammatory function, and tissue-repair function. We reported the improvement of patients with protracted wound healing after the dermal administration of topical cream containing LPS derived from...

Background/aim: A system is being developed that can be used to easily evaluate the health condition of an individual with the help of trace amounts of a blood sample by focusing on xenobiotics. The system is called "Multimodal homeostasis evaluation system" (measurement of neutrophil activity, phagocytic activity of phagocytes and quantification...

Background/aim: Dewaxed brown rice has macrophage activation ability via TLR4 and contains a high amount of lipopolysaccharides (LPS). It is expected that dewaxed brown rice can help prevent lifestyle diseases. In this study, the anti-obesity effect of dewaxed brown rice was investigated using obese and diabetic model mice. Materials and methods:...

The pathogenesis of Alzheimer’s disease (AD) remains unclear, but an imbalance between the production and clearance of amyloid-β (Aβ) peptides is known to play a critical role in AD progression. A promising preventative approach is to enhance the normal Aβ clearance activity of brain phagocytes such as microglia. In mice, the intraperitoneal inject...

The population of neutrophils and monocytes in the peripheral blood sample. The population of (A) CD45+CD11b+Ly-6G+ neutrophils and (B) CD45+CD11b+Ly-6G-Ly-6C+ monocytes are indicated as the percentage of CD45+CD11b+ cells as described in the supporting information. Values are presented as the mean ± SEM, n = 4–7. No significant difference is obser...

The escape latency in the training session of MWM test. NC, negative control mice; HFD, high-fat diet-fed mice; LPSp, lipopolysaccharide from Pantoea agglomerans; Values are presented as the mean ± SEM (s). (DOCX)

Supplementary methods. (DOCX)

Taxonomy summary dataset of microbiota analysis. (ZIP)

Gut microbiota composition. The microbiota profiles in the stool were analyzed as described in the supporting information. (A) Variation in bacterial community compositions in each stool sample at the phylum levels. Right 4 lanes indicate the average value of each group. (B) The relative abundance (%) of phylum Bacteroidetes and Firmicutes. Values...

Pantoea agglomerans (P. agglomerans) is a Gram-negative bacterium that grows symbiotically with various edible plants, and the oral or sublingual administration of lipopolysaccharide derived from P. agglomerans (LPSp) have been suggested to contribute to prevention of immune-related diseases. Our previous study indicated that orally administered LP...

The stability of LPSp in drinking water. Values are presented as the mean ± SD, n = 3. No significance difference was observed between groups (two way ANOVA, post-hoc Tukey test). (PDF)

Weekly food intake during the experiment. Values are presented as the mean ± SEM, n = 8. No significance difference was observed between groups (two way ANOVA, post-hoc Tukey test). (PDF)

The gated strategy of neutrophils and monocytes. (A-D) The gated strategy of neutrophils (CD45+CD11b+Ly-6G+ cells) and monocytes (CD45+CD11b+Ly-6G-Ly-6C+ cells). (E) Re-analysis of monocytes (blue dots) and neutrophils (green dots) in FS-SS plot to check their distribution. FS: forward scatter, SS: side scatter. (PDF)

The standard data of the present LAL assay. (DOCX)

Pearson's correlation coefficients among the ratio of atherosclerotic plaque lesion and major metabolic parameters. (DOCX)

The standard curve of the present LAL assay. The standard curve was plotted with log concentration of each standard LPS against log reaction time (n = 3). R2 indicates the coefficient of determination. (PDF)

Background/aim: Recent studies reported that lipopolysaccharide (LPS) exhibits beneficial effects on prevention of immune-related diseases by activating macrophages. We previously demonstrated that pre-treatment with LPS derived from Pantoea agglomerans (LPSp) activated amyloid β (Aβ) phagocytosis in mouse primary microglia. In the present study,...

Background/aim: Phagocytes recognize pathogens that enter the body as well as other abnormal and foreign materials that may exist within an organism (such as dead cells, oxidized lipids, and denatured proteins), and phagocytose and eliminate them to maintain a healthy state. In a previous study a simple prototype device was used, under development...

Background/aim: A decrease in gastrointestinal motility causing weakened lipopolysaccharide (LPS) - toll-like receptor (TLR)4 signaling along with a decline in the number of enteric bacteria is known to be a cause of constipation due to the administration of antibiotics. A new type of brown rice with its wax layer removed, resulting in quick-cooki...

A polysaccharide fraction was isolated from the Pantoea agglomerans IG1 lipopolysaccharide (IP-PA1), and its O-antigenic polysaccharide was characterized by chemical analyses and 1D and 2D ¹H and ¹³C NMR spectroscopy. The polysaccharide is composed of linear tetrasaccharide repeating units, consisting of glucose and rhamnose, where 40% of one of th...

Background/aim: Oral ingestion of lipopolysaccharide (LPS) has been shown to be effective in diseases' prevention. Brown rice contains large amounts of LPS not actively consumed because of bad taste. Recently, a new type of brown rice with its wax layer removed has been produced. In this report, we measured the LPS content of this dewaxed rice and...

Background/aim: It has been reported that oral administration of lipopolysaccharide (LPS) recovers an individual's immune condition and induces the exclusion of foreign matter, inflammation and tissue repair. We orally administered LPS from the wheat symbiotic bacteria Pantoea agglomerans, which has been ingested and proven to be safe, to cancer p...

Background/aim: Phagocytic activity is affected by a number of different stress and age-dependent factors. An easy measurement of phagocytic activity is thought to allow an indicator of an individual's health. In this study, we investigated conditions of measurement to easily evaluate the activity of phagocytosis of phagocytic cells (macrophages a...

Background/aim: Monophosphoryl lipid A, lipopolysaccharide (LPS)-derived Toll-like receptor (TLR) 4 agonist, has been shown to be effective in the prevention of Alzheimer's disease (AD) by enhancing phagocytosis of amyloid β (Aβ) by brain microglia. Our recent study demonstrated that oral administration of LPS derived from Pantoea agglomerans (LPS...

Background/aim: Monocytes migrate into the tissue where they differentiate into various types of macrophages with tissue-specific characteristics. When human monocytes are co-cultured with colon cancer cells they exhibit increased mRNA expression of angiogenesis- and signaling pathway-related genes; however, this increase is suppressed by pretreat...

One or more distinct forms of the nuclear estrogen receptor (ER) have been isolated from many vertebrates to date. To better understand the molecular evolution of ERs, we cloned and characterized er cDNAs from the inshore hagfish, Eptatretus burgeri, a modern representative of the most primitive vertebrates, the agnathans. Two er cDNAs, er1 and er2...

Background/aim: Bacterial lipopolysaccharide (LPS) is involved in the activation of the innate immune responses on monocytes/macrophages in vitro, and by intravenous injection. Although small quantities of LPS are usually found in traditional Chinese medicines, vegetables and fruits, the mode of action of orally administered LPS is still unclear....

Intestinal microbes are known to influence host homeostasis by producing various substances. Recently, the presence of a diverse range of intestinal microbiota has been shown to play a key role in the maintenance of health, along with influencing the host's innate immunity towards various diseases. For example, fecal microbiota transplantation (FMT...

Oral intake of lipopolysaccharide (LPS) has been demonstrated to be effective in the prevention of various diseases. We have found that the subaleurone layer of rice contains a large amount of LPS. The aim of this study was to evaluate the role of this layer in innate immunity. Using the Saika-style rice polishing process, a sbaleurone layer and th...

The increased mRNA expression of chemotaxis- and angiogenesis-related factors in human monocytes following interaction with colon cancer cells has been shown to be suppressed by pre-treatment with low-dose lipopolysaccharide (LPS) (100 pg/ml). It has been demonstrated that low-dose LPS reduced the expression of RelB, a member of the nuclear factor...

Pantoea agglomerans LPS (immunopotentiator from Pantoea agglomerans 1: IP-PA1) has been reported to have anti-inflammatory effects in in vitro and in vivo models. The aim of the present study was to investigate the effects of orally-administered IP-PA1 on atopic dermatitis (AD) symptoms induced by Dermatophagoides farinae body extract (DFE) in NC/N...

Oral administration of lipopolysaccharide (LPS), a major outer-membrane component of Gram-negative bacteria, has been found to prevent infection in mammals and fish. Oral administration of LPS is believed to increase phagocytic activity and promote cytokine production, thus associating it with priming. The present study aimed to elucidate the effec...

Lipopolysaccharide (LPS), a major component of the cell wall of Gram-negative bacteria, is known to possess strong immune-regulatory activity. We have found and reported the existence of biologically-active LPS in acetic acid bacteria. The LPS shows Limulus-positive activity and activation of macrophages to produce nitric oxide and tumor necrosis f...

Lipopolysaccharide from Pantoea agglomerans (LPSp) facilitates Ca and P turnover in chicken calvaria and femurs. This study investigated osteoporosis prevention by the oral administration of LPSp in mice and in double-blind clinical tests. Using ovariectomized (OVX) osteoporosis mice model, we investigated the effects of LPSp on the bone density an...

Many publications show that macrophages are closely involved in etiology of diseases, such as cancer, diabetes, arteriosclerosis, and Alzheimer's disease. Recent studies show that waste products (e.g. dead cells, denatured proteins, oxidized lipids, and advanced glycation end-products) are the real causative agents of lifestyle-associated diseases....

Background: We have previously reported that mRNA expression of chemotaxis- and angiogenesis-related factors in human monocytes increased following interaction with colon cancer cells. Recently, it was also reported that mRNA expression of the chemotaxis-related factor, monocyte chemotactic protein (MCP)-1, in mouse macrophages following treatment...

Vitellogenesis has been extensively studied in oviparous vertebrates, including teleost fishes, while not much is known with regard to jawless hagfishes, modern representatives of the most primitive vertebrate class. This study aimed to characterize vitellogenin (Vtg) and yolk protein (YP) in the inshore hagfish (Eptatretus burgeri) as an initial s...

Macrophages reside in every tissue of the body and play an important role in maintaining homeostasis. The intestinal mucosa is the largest immune organ and harbors macrophages in abundance. Dysfunction of intestinal macrophages is characteristic of patients with certain inflammatory bowel diseases. Although intestinal macrophages exhibit hyporespon...

Lipopolysaccharide derived from Pantoea agglomerans (LPSp) mainly consists of two aggregates, the high-molecular aggregate (HMM-LPSp) and the low-molecular aggregate (LMM-LPSp). The structural differences between HMM-LPSp and LMM-LPSp seem to depend on the length of the O-antigen polysaccharide because the lipid A regions of the two fractions are q...

In tumors, monocytes differentiate into tumor-associated macrophages following interaction with cancer cells. We have previously reported that angiogenesis- and chemotaxis-related factors are associated with human monocyte differentiation following interaction with colon cancer cells. However, the exact nature of factors remains unknown. We investi...

It has been found that a limulus-positive glycolipid is present in xanthan gum derived from Xanthomonas, which has been commercially available and eaten for many years, and this was purified, and it has been found that this limulus-positive glycolipid has an immunopotentiation effect. A method for safely and inexpensively producing the limulus-posi...

Immunostimulants represent a promising aquaculture tool for enhancing disease and stress resistance in cultured fish. Moreover, the term and dose for acting immunostimulants is an important thing for fish farmer. This study investigated the immune parameters of common carp after oral administration of LPS (5, 10, 20 μg/kg/days) for 30 and 60 days,...

It is well known that the activation of innate immune cells, especially antigen-presenting cells such as macrophages and dendritic cells, can ameliorate or exacerbate various diseases, including cancer. Currently, the macrophages and dendritic cells are categorized into several groups by their cell surface and intracellular molecules. However, the...

Bacterial lipopolysaccharide (LPS), which is generally considered to be an endotoxin, is the major constituent of the outer membrane of Gram-negative bacteria. The structure of LPS consists of three regions; lipid A, core oligosaccharide and O-antigen polysaccharide (O-PS). The structures of lipid A and core oligosaccharide are highly conserved amo...

Pantoea agglomerans is a Gram-negative bacterium that grows symbiotically with various plants. Here we report the 4.8-Mb genome sequence of P. agglomerans strain IG1. The lipopolysaccharides derived from P. agglomerans IG1 have been shown to be effective in the prevention of various diseases, such as bacterial or viral infection, lifestyle-related...

Galectin-9 (Gal-9) expanded plasmacytoid dendritic cell-like macrophages (pDC-Mϕs) in lung cancer-bearing mice and prolonged the survival. Gal-9 increased the frequency of CD11c(high) cells in M-CSF- but not GM-CSF-induced Mϕs in vitro in a Tim-3 independent manner. CD11c(high) cells differentiated with M-CSF+Gal-9 expressed pDC-Mϕ markers, such as...

At present, lifestyle-related diseases are one of the most critical health issues worldwide. It has been reported that lipopolysaccharide derived from a Gram-negative bacteria (IP-PA1) symbiotic with wheat exhibited several advantageous biological effects, such as the reduction of plasma glucose levels in NOD mice and low-density lipoprotein (LDL)...

Anti-lipopolysaccharide factor (ALF) is an antimicrobial peptide (AMP) and a key effector molecule of the innate immune system in crustaceans. However, little is known about the role of its indirect killing against bacteria. The possible regulatory role of this peptide (M-ALF) in kuruma prawns, Marsupenaeus japonicus, was investigated. The activiti...

It is well known that intravenous administration of lipopolysaccharide (LPS) induces severe toxicity in mammals. The maximum tolerated dose of intravenous administration of LPS in humans is reported to be only 1 to 4 ng/kg body weight. However, oral administration of a high dose of LPS caused no toxicity or systemic inflammation in other mammals, b...

Chronic psychological stress impairs health and induces various diseases by causing an imbalance in the immune, neuropsychiatric and endocrine systems. The primary reason for the development of stress-induced disease is suppression of macrophage function, which plays a pivotal role in innate immunity. In fact, surgical stress has been shown to exac...

Lipopolysaccharide derived from a symbiotic bacterium in wheat (Pantoea agglomerans, LPSp) has shown multiple positive effects, such as prophylactic, antiallergic and antitumour effects, without serious side-effects. LPSp has differential biological activities in comparison to other LPS, such as those from Escherichia coli (LPSe). The only differen...

Unlabelled: Monocytes are known to differentiate into tissue-specific macrophages in response to the tissue environment, and it has been suggested that tumor-associated macrophages might promote angiogenesis. Therefore, the factors associated with monocyte differentiation into tumor-associated macrophages may become new targets for cancer therapy....

Macrophage cells differentiate into killer macrophages, named M1 macrophages, that effectively eliminate cancer cells by generating cytokines. We examined the feasibility of a lung cancer therapy using lipopolysaccharide (LPS), which triggers this differentiation. It is expected that the delivery via inhalation of LPS directly into the lungs, where...

It is possible that macrophages may be effective for cancer treatment because once activated, lung macrophages have enhanced contact with lung tumor cells and have a cytotoxic effect. In this paper, we report that nitric oxide (NO) produced by lung macrophages activated with lipopolysaccharide (LPS) suppressed cell growth of human lung adenocarcino...

Intradermal and/or oral administration of lipopolysaccharides derived from Pantoea agglomerans (IP-PA1) have shown multiple positive effects such as phylactic, anti-allergic and anti-tumor effects. It has been reported that the effects of IP-PA1 were derived from the induction of activated macrophages. However, it has not been actually clarified wh...

In lung tumor biotherapy, local macrophages such as alveolar macrophages and tumor-associated macrophages (TAMs) which normally exist in contact with tumor cells are thought to be hopeful target. It is advantageous to clarify the potential for and mechanism by which lung tumor cells are killed by the neighboring macrophages in order to establish ne...

The response to fluoropyrimidine chemotherapeutic drugs is different in individual tumors. Predictive biomarkers of antitumor effects by these drugs are unknown. 5'-Deoxy-5-fluorouridine (5'-DFUR), a fluoro-pyrimidine chemotherapeutic drug, is converted to 5-fluorouracil (5-FU) by pyrimidine nucleoside phosphorylase (PyNPase). It is suggested that...

Nitric oxide (NO), synthesized from l-arginine by NO synthases, is a small, lipophilic, diffusible, highly reactive molecule with dichotomous regulatory roles in many biological events under physiological and pathological conditions. NO promotes apoptosis in some tumor cells, but provokes anti-apoptotic activity in other tumor cells. For this reaso...

Tumor necrosis factor-alpha (TNF-alpha) is a key inflammatory mediator and has also the potential as a prominent biomarker of innate immunity. In this study, we identified and characterized TNF-alpha from bluefin tuna, which is an important cultured species. Two types of TNF-alpha were also cloned incidentally (TNF1 and TNF2). The open reading fram...

Inhalation delivery of poly(lactic-co-glycolic) acid (PLGA) microspheres (MS) loaded with the anti-tuberculosis agent rifampicin (RFP-PLGA MS) to alveolar macrophage (M phi) cells could be an effective drug delivery system for the treatment of tuberculosis. To examine this possibility, we studied (1) the bactericidal effect of RFP-PLGA MS on Mycoba...