Phospholipids, the major components of biological membranes, usually have two fatty acids. Less common are the lysophospholipids, which have only one fatty acid. Like prostaglandins and leukotrienes, some lysophospholipids serve as mediators to regulate various cellular functions through G protein-coupled receptors (GPCRs). This review focuses on a lysophospholipid with an inositol head, lysophosphatidylinositol (LPI), and summarizes its distribution, alterations, metabolic mechanisms, and physiological and pathological functions. In addition, we will summarize the current knowledge of GPR55, a proposed G protein-coupled receptor for LPI, with a particular focus on its functions in cancer and immune responses.

The Ministry of Health, Labour and Welfare, Japan, had set guidelines for concentrations of indoor air pollutants such as di-n-butyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP) and the insecticides fenobucarb, diazinon, and chlorpyrifos, which are semi-volatile pollutants in indoor air. The Committee on Indoor Air Pollution, Japan, is reviewing the 20-year old indoor air quality guidelines. Therefore, the current levels of semi-volatile pollutants in indoor air must be established. Insecticides and phthalates are estimated separately, necessitating more efficient analytical methods. We developed a gas chromatography-mass spectrometry for simultaneous analysis of insecticides and phthalates using a cartridge composed of a quartz filter and a styrene divinylbenzene copolymer and applied it to a field survey. The recovery and relative standard deviations (RSD) for the insecticides' were 97.4–103% and 3.58–9.65%, and those for phthalates were 87.4–102% and 1.35–8.22%, respectively. The limits of quantitation (LOQ) for chlorpyrifos, diazinon, and fenobucarb were less than 1/10 of guideline values at 0.0128, 0.0201, and 0.00667 µg/m³, respectively. The LOQs of phthalates were 0.0882 µg/m³ for DBP and 0.107 µg/m³ for DEHP, each less than 1/193 and 1/935 of guideline values, respectively. The simultaneous analysis method was used to survey residential houses. Insecticides were not detected in the indoor air of residential houses. In contrast, phthalates, diethyl phthalate (DEP), DBP, and DEHP were detected, and their concentration distributions decreased from those found in the 2000s.

The seeds of jojoba (Simmondsia chinensis (Link) Schneider) contain approximately 50% of a unique oil known as jojoba oil. It is primarily composed of liquid wax monoesters, whose structure is similar to that of the wax component of human sebum and is widely employed as a cosmetic ingredient. Two types of jojoba oil are used in cosmetics: unrefined jojoba oil called “golden” jojoba oil and refined jojoba oil. Human sebum protects the epidermis by forming an emulsion with water, preventing water loss. In this study, the water-loss prevention and water-holding capacities of golden jojoba oil were measured and compared with those of refined jojoba oil and other oils. Golden jojoba oil exhibited the highest water-loss prevention and water-holding properties among the oils examined. These results suggest that golden jojoba oil is a useful cosmetic ingredient. Conversely, refined jojoba oil exhibited high water-loss prevention, albeit with the lowest water-holding capacity. These findings suggest that the minor components lost during the refining process are responsible for the high water-holding capacity of golden jojoba oil. When the methanol extract of golden jojoba oil was added to refined jojoba oil to examine water-loss prevention and water-holding capacity, no significant difference emerged between the two. Although the water-holding capacity of the refined jojoba oil increased, it remained lower than that of golden jojoba oil. These results suggest that, in addition to the minor substances in the methanol extract, other substances may contribute to the exceptional water-holding capacity of golden jojoba oil.

Aim: In 2010, the maximum dosage of metformin was increased in Japan to the maximum dosage approved in the United States. This study aimed to evaluate the impact of the revised dosage in the package insert on metformin-associated lactic acidosis (MALA) reports in Japanese patients using the Japanese Adverse Drug Event Report (JADER) database. Methods: Adjusted reporting odds ratios of MALA was evaluated using multiple logistic regression models. Trends were analyzed using the Mann–Kendall test and Pettitt's test. Receiver operating characteristic (ROC) curve analysis was used to estimate the metformin dose that influenced MALA development. Results: The JADER database contains 845,956 reports submitted between April 2004 and March 2023. The number of adverse event reports and mean dose increased after the 2010 revision of the package insert. According to the ROC curve for lactic acidosis, the cutoff value was 1000.0 mg/day. Conclusions: Increase in metformin doses owing to regulatory actions and the recommendation of the Japan Diabetes Society may have influenced the increased MALA reporting rate, suggesting a dose-dependent relationship between the drug and MALA. The cutoff for the daily dose of metformin associated with MALA was the current maintenance dose listed in the package insert. We believe that MALA development must be carefully monitored in Japan even at the dosage specified in the package insert.

Inflammation can downregulate CYP isoforms and alter the pharmacokinetics of certain drugs. The expression of CYP isoforms is induced by the activation of nuclear receptors, including the pregnane X receptor (PXR). This study aimed to clarify the changes in the inducibility of CYP and in vivo relevance to pharmacokinetics in an inflammatory state. We investigated the changes in the mRNA expression of Cyp3a11 induced by pregnenolone-16α-carbonitrile (PCN), a rodent PXR agonist, in the liver and small intestine of inflammation model mice generated by injection of lipopolysaccharide (LPS). The systemic effects of inflammation on CYP induction were also investigated by measuring changes in the plasma concentration of midazolam, a CYP3A substrate. Cyp3a11 mRNA expression levels in the liver and small intestine of mice were decreased by LPS treatment and increased by PCN administration. Hepatic Cyp3a11 mRNA expression levels were significantly lower in LPS- and PCN-administered mice than in PCN-administered mice, whereas intestinal Cyp3a11 mRNA expression levels were significantly higher in LPS- and PCN-administered mice than in PCN-administered mice. The plasma concentration-time profiles and area under the concentration-time curve of midazolam and its metabolite 1’-hydroxymidazolam in LPS- and PCN-administered mice tended to be higher than those in PCN-administered mice. LPS-induced inflammation may suppress the increased metabolism of midazolam by PCN, which is consistent with the hepatic Cyp3a11 mRNA expression results. Therefore, CYP inducibility via PXR activation may be attenuated in an inflammatory state. Pharmacokinetic drug-drug interactions caused by CYP induction may be altered in patients with inflammation.

Cadmium (Cd) is an environmental toxic heavy metal that predominantly causes renal failure. Although changes in gene expression are important factors affecting Cd toxicity, the genes that determine Cd toxicity have not been identified. In this study, we tested 36 genes that are highly expressed in the kidney for their effects on Cd toxicity. After human proximal tubular cells (HK-2 cells) were transfected with small interfering RNAs (siRNAs) targeting these genes, Cd toxicity was examined. The expression of the five genes selected from the primary screen was knocked down and the effect on Cd toxicity evaluated. The knockdown of CRYAA and DPYS significantly enhanced Cd toxicity, but not the toxicity of mercury compounds. The CRYAA protein plays a chaperone role and DPYS protein regulates nucleic acid metabolism. The regulation of CRYAA and DPYS expression may affect the Cd renal toxicity.

The contamination levels of benzotriazole ultraviolet absorbers (BUVAs) were determined in breast milk samples from 36 Japanese mothers. BUVAs were detected in all samples in the ranges of 11.0-803 ng/g lipid weight. Especially, 2-(2H-benzotriazol-2-yl)-4,6-bis(1,1-dimethylethyl) phenol (UV-320) accounted for 36% of the total. The BUVAs levels were comparable to some previous reports. The total BUVAs levels in this study were higher than those of Vietnam and Korea. A comparison of primiparas and multiparas showed that the mean total BUVAs level in multiparas was 2.1 times higher than that in primiparas. In particular, UV-320 levels were significantly higher in multiparas than in primiparas (p<0.05). Subsequently, the estimated daily intake of infants was calculated to be 76.5-4,410 ng/kg/day. Further studies are needed to help develop regulations for these chemicals in our living environment and prevent harmful exposure.

As the number of consumers suffering from rough hands and dermatitis caused by the frequent daily use of synthetic surfactants increases, biocompatible materials are required. Biosurfactants (BSs), compounds excreted or produced by microbial cells, attract attention as cosmetic substrates suitable for human skin and the environment. This study evaluated the utility of the glycolipid-type sophorolipid (SL) produced by the non-pathogenic yeast Starmerella bombicola, as a BS. The cytotoxicity of open-chain acid type SL (SL acid) among SLs, is approximately 100–250 times less than that of commercially available surfactants in all cells. Therefore, SL acid is a promising surfactant with a high safety profile. In contrast, the critical micelle concentration (CMC) of SL acid, surfactin, and rhamnolipid were 1,000 mg/L, 16 mg/L, and 38 mg/L, respectively, indicating that SL acid has lower functionality than the other BSs. Finally, the safety range was analyzed for each BS to indicate practicality. The safety range, the concentration range where each BS can exhibit its function without cytotoxicity, was defined based on the lethal concentration 50 (LC₅₀)/CMC value. As a result, the safety range of SL acid is 3.9–4.4 times wilder than that of surfactin and rhamnolipids. Consequently, SL acid could be a promising BS with a wider safety range than other BSs, such as surfuctin and rhamnolipids.

Plasminogen activator inhibitor 1 (PAI-1) stabilizes the thrombus by suppressing the activation of plasminogen to plasmin at the site where the thrombus is formed, thereby inhibiting fibrinolytic reaction. Because inhibition of PAI-1 production or activity facilitates fibrin degradation and eliminates unnecessary thrombus, it is believed that suppression of PAI-1 production or activity prevent thrombosis. Some natural substances that inhibit PAI-1 production and activity were found from medicinal plants, health foods, and purified natural substances and they have potential for realistic use in clinical field or as functional foods. Here, we reviewed these natural products that inhibit PAI-1 production and activity. In addition, we described the potential applications of these substances in clinical field or as functional foods.

Alzheimer’s disease (AD) is one of the most common types of progressive dementia. Recently, endoplasmic reticulum (ER) stress was suggested as a potential event involved in AD development. Thus, targeting ER stress may be an effective AD treatment. The involvement of ER stress in the brains of amyloid precursor protein knock-in AD model mice (App^{NL-G-F/NL-G-F}) with Swedish/Iberian/Arctic mutations found in human familial AD remains unclear. This study aimed to clarify whether the expression of ER stress marker C/EBP homologous protein (CHOP) was enhanced in the brains of App^{NL-G-F/NL-G-F} AD model mice. Our immunofluorescence staining results showed that similar to the expression pattern of amyloid-β (Aβ), CHOP demonstrated an age-dependent increase in the numbers and sizes of spotted signals in the cerebral cortex and hippocampus of these 4- to 10-month-old AD model mice but not in their age-matched controls. These findings suggested that CHOP expression was upregulated in close association with Aβ expression, and that CHOP was involved in neuropathy caused by Aβ accumulation. Future investigations of the localization and variations in expression levels of other ER stress-related proteins in this mouse model using immunofluorescence staining will lead to a more detailed estimation of the relationship between ER stress and AD pathogenesis.

The Ministry of Health, Labour and Welfare of Japan has set the guideline values for indoor air concentrations of 13 volatile organic compounds (VOCs) and semi-volatile organic compounds from 1997 to 2002. However, in 2019, the guideline values for three of these substances, including xylene, were revised and regulated more strictly. Additionally, the manual for analysis of VOCs in indoor air, established in 2001 by the Committee on Sick House Syndrome: Indoor Air Pollution, has not been updated for over 20 years. In this study, we confirmed that the current analytical method for VOCs in indoor air using solvent extraction which was established in 2001, is applicable to VOCs that have been revised or added since then. We proposed it as a standard test method and performed an inter-laboratory validation study in five laboratories to prove this. This validation study included nine substances: six VOCs with current guideline values and three VOCs as candidates for newly setting guideline values. Additional amount in this study was set as 1 µg, less than one-tenth of the guideline value for xylene. The results showed that the average recovery, repeatability, and reproducibility for the nine substances in the five laboratories were 75.4%–115%, 0.78%–9.6%, and 3.6%–21%, respectively. These values satisfied the determined criteria ranges, suggesting that our proposed analytical method can be used as a standard test method.

To clarify the relationship between smartphone addiction and headaches, we conducted a questionnaire survey of women who were aware of having headaches. A questionnaire survey was conducted on the Internet of 600 women between the ages of 20 and 40 who had suffered from headaches in the past three months. The subjects were divided into a smartphone addiction group (n = 120) and a smartphone non-addiction group (n = 480). The addiction group had more complaints of photophobia and phonophobia, which are accompanying symptoms of headaches, and the impact of headache attacks on daily life was greater than the non-addiction group. There was no significant difference in sleep time between the groups, but the addiction group used their smartphones longer on average and felt more sleepy during the day. More respondents in the addiction group complained of decreased visual acuity, dry eyes, and blurred vision than the non-addiction group, suggesting that blue light from computers and smartphones affected their eyes. Moreover, the frequency of headaches, stiff shoulders, fatigue, sleeping disorders, hormonal imbalance, and dark circles and wrinkles around the eyes were higher in the addiction group compared to the non-addiction group. Although smartphone addiction has not been established as a disease, our findings suggest that it reduces sleep quality and worsens headaches.

In humans, influenza A virus (IAV) causes mild to severe respiratory disease, posing a major threat to public health worldwide. Increasing evidence suggests that myeloid-derived suppressor cells (MDSCs) are involved in viral infection outcomes in genetically modified mice; however, the mechanisms by which MDSCs contribute to lung pathology under normal genetic conditions remain controversial. In the present study, we intranasally infected mice with mouse-adapted IAV (A/Puerto Rico/8/1934 [PR8]) and adoptively transferred MDSCs differentiated in vitro intravenously to assess their functional relevance in vivo. After PR8 infection, the adoptive transfer of MDSCs significantly improved the survival of mice. Furthermore, MDSC transfer increased CD4⁺ T cell and eosinophil infiltration into the lungs and decreased interleukin-6 and tumor necrosis factor-α levels in the bronchoalveolar lavage fluid. However, the viral load did not significantly decrease; this suggests that MDSCs affect virus clearance. Inducible nitric oxide synthase (iNOS) is a key factor responsible for the immunosuppressive activity of MDSCs. However, the transfer of Nos2-deficient MDSCs can decrease PR8 infection-induced mortality; nevertheless, the absence of iNOS in MDSCs did not affect the infiltration of inflammatory cells into the lung, suggesting that MDSCs function independently of their iNOS expression and downstream pathways. Taken together, our findings suggest that transferred MDSCs decrease IAV disease-induced mortality in vivo in an iNOS-independent manner. The adoptive cellular transfer of MDSCs may be an attractive therapeutic strategy for IAV infections.

PD-L1 molecules on a tumor have attracted attention because PD-L1 on a tumor plays an important role in escape for host immune responses. It has been shown that genistein attenuates immune checkpoint therapy for B16F1 melanoma in mice. We examined the effect of genistein on expression of PD-L1 in B16F1 melanoma cells and found that genistein increases the expression of IFN-γ-induced PD-L1 molecules at both protein and mRNA levels. Genistein increased the mRNA expression of STAT1 and STAT3 in IFN-γ-treated B16F1 cells. We compared the effects of ten types of flavonoids on PD-L1 expression and found that genistein is a strong inducer of PD-L1 expression among the flavonoids.

Atrophic age-related macular degeneration (AMD) is a progressive form with macular atrophy. Unfortunately, the mechanism of atrophic AMD progression is not fully revealed, and the effective remedy to improve patient’s visual acuity is none today. This study aims to explore a new therapeutic target for atrophic AMD. Microarray analysis of the retinal pigment epithelium (RPE)-choroid-sclera complex from sodium iodate (NaIO₃)-administered retinal degeneration model mice revealed that the expression of G protein-coupled receptor 35 (Gpr35) mRNA was markedly increased. This result was similar to that of an analysis using the NCBI Gene Expression Omnibus database, which showed a trend toward increased expression of Gpr35 in the macular RPE-choroid of atrophic AMD patients. NaIO₃-induced retinal degeneration model mice showed different severities depending on the dose of NaIO₃. Gpr35 mRNA level was markedly upregulated in RPE-choroid-sclera complexes treated with 40 mg/kg NaIO₃, whereas those treated with 20 mg/kg NaIO₃ showed an increasing but non-significant trend. Immunostaining images showed that GPR35 expression was observed around the RPE layer after treatment with 40 mg/kg NaIO₃ and was merged with macrophage/microglia marker F4/80. Interestingly, the GPR35 agonist cromolyn suppressed NaIO₃-induced RPE cell death. These findings suggest that GPR35 might be a novel potential therapeutic target for the pathological progression of atrophic AMD.

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants, and their harmful effects on humans and animals are a major concern. Although the mechanisms of PCB toxicity have been studied, and they are known to largely accumulate in adipose tissue and liver, no therapy for PCB exposure has been established. To develop excretion-enhancing methods or antidotes for PCBs, animal models reflecting actual PCB bioaccumulation should be used. To establish such a model, we administered four levels of [³H]-labeled PCB-126 (710.4 × 10⁴, 142.1 × 10⁴, 28.4 × 10⁴, and 5.7 × 10⁴ dpm) to mice and investigated their excretion and tissue distribution. Lindane was used as a readily excreted comparator. 28.4 × 10⁴ or 5.7 × 10⁴ dpm [³H]PCB-126 resulted in excretion and tissue-distribution levels that were close to the detection limit. Administration of the maximum dose of [³H]PCB-126 resulted in continual excretion in feces and urine over the 8-day experimental period. In the mouse administered 142.1 × 10⁴ dpm [³H]PCB-126, the fecal and urinary excretion were reduced to a constant low level by day 8 after exposure, suggesting that the distribution of [³H]PCB-126 into the tissues had almost been completed. Our results suggest that mice administered 142.1 × 10⁴ dpm [³H]PCB-126 could be suitable as a PCB-126 bioaccumulation model for research to facilitate methods to enhance PCBs excretion and to develop therapies for PCBs toxicity.

Objective: Platinum- and anthracycline-based chemotherapy regimens cause nausea and vomiting in clinical practice, resulting in the deterioration of patients’ QoL, discontinuation of chemotherapy, and reduced therapeutic outcomes. Using pica behavior as an indicator, we aimed to clarify whether anamorelin, an orally active ghrelin receptor agonist, exerts antiemetic effects against cisplatin-induced nausea and vomiting in rats. Materials and Methods: Sprague–Dawley rats were treated with cisplatin (5 mg/kg, i.p.), three-drug or four-drug antiemetics (granisetron [0.3 mg/kg, p.o.], dexamethasone [1.5 mg/kg, p.o.], fosaprepitant [12.5 mg/kg, i.p.], with or without anamorelin [30 mg/kg, p.o.]). Data on kaolin intake, normal food intake, and spontaneous motor activity (SMA) were recorded 1 d before and 5 d after cisplatin administration. Body weight (BW) was measured daily, and the percentage change in BW from baseline was calculated. Results: At the primary endpoint, kaolin intake was significantly higher in the cisplatin-only group than in the pretreatment and vehicle groups (p < 0.05). Additionally, kaolin food intake was not significantly low in cisplatin-treated mice treated with three-drug antiemetics with or without anamorelin. At the secondary endpoints, normal food intake, SMA, and percentage change in BW were significantly lower in the cisplatin-only group than in the vehicle group. Conclusion: Our findings suggest that the prophylactic administration of standard three-drug antiemetics, besides anamorelin, may not improve cisplatin-induced nausea and vomiting. Further studies using methods suitable for evaluating anamorelin levels are required.