Endoplasmic reticulum (ER) stress is linked to insulin resistance and several muscle diseases, including myopathies. ER defects are also implicated in skeletal muscle dysfunction associated with aging. Physical contact between the ER and mitochondria is essential for the local transport of materials and effective signal transduction between these organelles. Nicotinamide phosphoribosyltransferase (NAMPT) regulates mitochondrial biogenesis and maintains skeletal muscle function and integrity. Our study aims to investigate the effect of the NAMPT activator P7C3-A20 on tunicamycin-induced ER stress using an in-vitro myoblast cell model. We found that tunicamycin treatment decreased the expression of several mitochondrial proteins, such as NAMPT and the mitophagy regulator PINK1 in C2C12 murine myoblast cells. It also reduced the phosphorylation of Drp1, a master regulator of mitochondrial fission, in C2C12 cells treated with tunicamycin. JC-1 imaging revealed that treatment with P7C3-A20 for 6 h at concentrations of 1, 5, and 10 μM increased mitochondrial potential in C2C12 cells. Moreover, P7C3-A20 ameliorated tunicamycin-induced cell death in a concentration-dependent manner. In conclusion, the NAMPT activator P7C3-A20 can mitigate tunicamycin-induced cell damage in C2C12 murine myoblasts. Activation of NAMPT is a potential novel therapeutic approach for muscle diseases associated with ER stress, such as sarcopenia.

Capivasertib is an oral molecular targeted drug for treating hormone receptor-positive, human epidermal growth factor receptor 2-negative inoperable or recurrent breast cancer with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, AKT serine/threonine kinase 1, and phosphatase and tensin homolog mutations. Moderate intra- and inter-individual variabilities have been reported in the pharmacokinetic study of capivasertib. Furthermore, because capivasertib is a substrate and weak inhibitor of CYP3A4, drug–drug interactions are expected in elderly patients with breast cancer due to the concomitant use of multiple drugs for co-morbidities. These factors suggest that the therapeutic drug monitoring (TDM) of patients receiving capivasertib may improve therapeutic efficacy while decreasing the onset of adverse events. However, to the best of our knowledge, there are no reports on methods to measure the capivasertib concentration in human plasma. Therefore, this study proposes a method for determining the capivasertib concentration in human plasma using HPLC-UV. Following protein precipitation with methanol, capivasertib and pirfenidone (internal standard) were separated using isocratic elution on a C18 column using a mobile phase of 0.5% KH₂PO₄ (pH 4.5)/acetonitrile in a 73:27 (vol/vol) ratio, pumped at a constant flow rate of 1.0 mL/min. Quantification was performed at 219 nm. The calibration curves were linear over the range of 50–1000 ng/mL. Intra- and inter-day coefficients of variation were less than 10.2%. The assay accuracy ranged from -7.2–2.9%, and the recovery was >93.8%. This simple and cost-effective method may contribute to the TDM of capivasertib in clinical practice.

Background: In Japan, measures are being taken to strengthen the cooperation between local hospitals and pharmacies to improve the quality of cancer treatment. Objective: To evaluate the progress of the medical care provision system in terms of the collaboration between hospital pharmacists and community pharmacists in outpatient chemotherapy. Methods: We focused on the Additional Fee for Outpatient Chemotherapy 1 (when anticancer drugs are injected) (A1OC) as an indicator of high-quality medical care, Additional Fee for Enhanced Collaboration (AEC) as an indicator of hospital pharmacist involvement, and Additional Fee for Specific Drug Management Guidance 2 (ASD2) as an indicator of community pharmacist involvement. Using prefecture-specific receipt claims data from NDB Open Data Japan (NODJ) and from e-Stat, we investigated the number of insurance claims made by hospitals and pharmacies for outpatient chemotherapy involving pharmacists and the factors associated with them. Results: The coefficients of determination (R²) for A1OC, AEC, and ASD2 claims with respect to the number of anticancer drugs injected were 0.9960, 0.8298, and 0.7244, respectively. A higher number of claims for ASD2 was observed in prefectures in which the average age of community pharmacists was lower. Conclusion: The number of A1OC claims, which represents the number of times high-quality medical care was provided, suggests that the quality of the facilities for outpatient chemotherapy delivery systems varies little between prefectures. The involvement of hospital pharmacists varied by region more than A1OC did, and the involvement of community pharmacists varied even more. Reducing these regional differences is necessary to standardize the quality of outpatient cancer chemotherapy in Japan. Our study findings indicate the need for promoting the further involvement of community pharmacists with patients and their collaboration with hospital pharmacists to prevent adverse effects and enhance the quality of life of patients undergoing outpatient chemotherapy. Through such activities, the local collaborative efforts and reimbursement requirements may be improved.

In many medical institutions, standardized eGFR, which is based on generalized body surface area, is used for drug dosing evaluations. This can lead to overdosing. This study aimed to investigate the discrepancy between personalized eGFR and standardized eGFR and to identify indicators necessary for pharmacists to perform appropriate pharmacotherapy. From October 2022 to February 2023, the study targeted patients aged 18 years and older who continuously visited the Saera Pharmacy Kurashiki. Among the 347 participants, a significant discrepancy of 6.3 mL/min was observed between personalized eGFR and standardized eGFR (p < 0.001). Factors predicting an eGFR discrepancy of 10 mL/min or more were identified as follows: for males, a serum Na level below 140 mEq/L (area under the ROC curve: AUC = 0.656), and for females, a BUN level below 13 mg/dL (AUC = 0.647). Recognizing that patients with these factors are at risk of inaccurate renal function assessment, it is considered beneficial for pharmacists to prioritize obtaining height and weight measurements to ensure appropriate dosing of renally excreted drugs.

Over the past few decades, the number of older adults in desperate demand of social support is inevitably increasing with an aging population. Thus, there is a need for a social framework that can improve the quality of life of older adults. In Japan, where the population faces a super-aging society, the aim is to establish a community-based integrated care system that supports the elderly throughout the community. In August 2021, the Japanese government partially amended the Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices to expand the flexible healthcare provision, which forms the basis of that system. This amendment encourages patients to choose pharmacies that better meet their needs by establishing a framework for publicly certifying pharmacies that play essential roles in community healthcare, including home healthcare, and pharmacies that can provide specialized medical care. However, the actual effects of the intervention remain unclear. Thus, we explored changes in efforts related to regional medical collaboration and functions in community pharmacies before and after the enforcement of the amended Act. Our survey revealed that the amendment increased the stockpiles of generic medicines at each pharmacy without a clear increase in the number of employees. Additionally, there was an across-the-board improvement in the provision of information to other medical providers and patients. These results indicated that the amendment to the Act directly or indirectly promoted a shift from conventional pharmacy to a more patient-oriented approach.

To investigate the characteristics of fine particulate matter (PM_2.5) pollution in Taichung, Taiwan, atmospheric concentrations of PM_2.5 and polycyclic aromatic hydrocarbons (PAHs) were measured weekly from 2016 to 2017 in Taichung and Saitama in the Tokyo metropolitan area of Japan. The following conclusions were drawn: (1) the annual mean concentration of PM_2.5 in Taichung was 27.7 µg/m³ (2016) and 31.1 µg/m³ (2017), which was twice that of Saitama and exceeded the long-term environmental standard of 15 µg/m³ in both years. (2) Two-year mean concentration of the 10 PAHs was 1.42 ng/m³, which was twice that in Saitama. (3) PM_2.5 and PAH concentrations were higher with the winter monsoon from China being most likely cause. (4) The correlation between PM_2.5 and the other pollutant concentrations revealed that the primary sources of PM_2.5, automobiles, thermal power plants, and factories were also significant. Based on the findings, reducing PM_2.5 concentration in Taichung requires not only reducing emissions from automobiles, but also implementing measures against power plants and factories. Additionally, it is effective in reducing PM_2.5 in China. We hope that the reduction in air pollutants in Taiwan and China will clean air in Taichung.

Transcription of mRNA consists of three critical steps - initiation, elongation, and termination - and is driven by RNA polymerase II (Pol II), whose activity is regulated by a unique C-terminal domain (CTD). The transcription-related kinases CDK7, CDK9, and CDK12 regulate transcription by differentially phosphorylating serine 2, serine 5, and serine 7 of the Pol II CTD, although their functional interactions are not yet fully understood. Since these CDKs are involved in cancer cell proliferation and survival, elucidating these interactions is useful for cancer treatment. We focused on CDK12, which plays an important role in the late phase of transcription and identified several novel autophosphorylation sites of CDK12. Among these, serine 423 on CDK12 was found to be a critical residue affecting the half-life of the CDK12 protein and its phosphorylation is mediated by both CDK12 and CDK7. Additionally, comprehensive phosphoproteomic analysis revealed that CDK7 and CDK9 affect the phosphorylation of CDK12 and the CDK12 interactome, suggesting crosstalk between these kinases. Inhibition of CDK7 disrupted the interaction between CDK12 and proteins phosphorylated by CDK12, including RNA processing factors, while inhibition of CDK7 and CDK9 enhanced the interaction between CDK12 and splicing factors. In conclusion, our results indicate that CDK7 and CDK9 functionally regulate CDK12 upstream, suggesting that transcriptional CDKs cooperatively regulate RNA transcription and subsequent transcriptional processes.

Diabetes mellitus includes type 1 and type 2 diabetes. Type 1 diabetes is an autoimmune disease affecting young people. Although several factors that worsen type 1 diabetes are known, information on the effects of blue light remains obscure. In this study, we investigated the effects of blue light irradiation on diabetes using mice with streptozotocin (STZ)-induced type 1 diabetes. Furthermore, we investigated the potential of selected compounds in rescuing the blue light-induced aggravation of diabetes. Blue light irradiation exacerbated type 1 diabetes. It activated insulin-like growth factor-1 and reactive oxygen species/caspase 3/apoptosis/endothelial-monocyte activating polypeptide II/neutrophil/neutrophil extracellular trap-associated cell death (NETosis) system signaling and increased the expression of angiopoietin-like protein 2 (Agptl2). These results indicate that blue light worsens type 1 diabetes by increasing NETosis production and the expression of Agptl2. Administration of pantethine or tranexamic acid prevented the blue light-induced worsening of type 1 diabetes by suppressing neutrophil production and Agptl2 expression. Our results provide insights into the effects of blue light on type 1 diabetes and highlight the potential of compounds that can be used in ameliorating such effects.

We chose colistin as a new potentiator, which exhibited the relatively good potentiation activity of OMT against Escherichia coli and Klebsiella pneumoniae. This study uncovered new insight into an OMT based combination therapy.

Fatty liver can progress into serious conditions, and the number of patients with fatty liver disease has risen globally in recent years. Various lipid metabolism disorders can cause fatty liver, and in vitro models, such as hepatoma cell lines, have been utilized in research related to lipid metabolism disorders, including the development of treatment strategies. We previously demonstrated that fresh hepatocytes (PXB-cells^®) from chimeric mice with humanized livers display lipid metabolism similar to that of normal human hepatocytes. Additionally, we developed PXB-cells Lipid Analysis (PXB-cells LA) as a model of non-alcoholic fatty liver disease (NAFLD). PXB-cells LA exhibited increased levels of intracellular lipid droplets and lipids, especially triglycerides, compared to PXB-cells. Additionally, albumin secretion, drug metabolism, bile excretion transporters, mitochondria-derived oxidative phosphorylation, and intracellular adenosine triphosphate levels were attenuated in PXB-cells LA, while inflammatory marker levels were elevated. Collectively, these findings indicate hepatic dysfunction. Additionally, PXB-cells LA showed a fractional profile with a peak in very low-density lipoproteins, similar to PXB-cells. PXB-cells LA also secreted lipoproteins with a higher triglyceride content, associated with NAFLD. Taken together, these results suggest that PXB-cells LA is a useful cellular model of human NAFLD.

Mesothelin (MSLN) is a glycosyl phosphatidyl inositol-anchored glycoprotein involved in the carcinogenesis and metastasis of some cancers such as ovarian cancer, pancreatic cancer, and mesothelioma. The interaction between cancer antigen 125 (CA125) and MSLN enhances tumor metastasis. MSLNs are highly expressed in cancer and are therefore promising targets for cancer therapy. Variable domains of heavy chain of heavy chain (VHH; also known as nanobodies) monoclonal antibodies (mAbs) from alpacas exhibit unique properties such as high affinity, low immunogenicity, and thermal stability. Herein, we aimed to investigate the effects of anti-MSLN VHH mAbs on MSLN binding affinity. Two anti-MSLN VHH mAb clones (MT1A1 and MT3C2), targeting the extracellular domain of human MSLN, were used. MT1A1 and MT3C2 are specific to human and mouse MSLN. MT1A1 and MT3C2 bound to MSLN are expressed on ovarian, pancreatic, and mesothelioma cancer cells. These antibodies recognize the region (296–390) at the N-terminal of MSLN on the cell surface and relying on their conformation-dependent recognition. MT1A1 and MT3C2 significantly inhibited the MSLN-CA125 interaction. Overall, our results suggest that MT1A1 and MT3C2 are promising anticancer agents.

Background: Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor treatment for non-small-cell lung cancer. Area under the blood concentration-time curve (AUC) of osimertinib can be related to the development of adverse events (AEs). Furthermore, the dose-per-body constitutional parameters (BCPs), such as body weight, body surface area (BSA), or lean body mass (LBM), are closely related to the AUC. However, BCPs other than weight have not been considered in clinical trials. Therefore, in this retrospective study, we investigated the association between doses per BCP (Dose/BCPs) and AEs of osimertinib. Method: Forty-two patients who received osimertinib between January 2010 and December 2020 were investigated. Differences in Dose/BCPs were compared between patients with and without AEs. Results: Among the patients, 54.8%, 38.1%, and 28.6% developed thrombocytopenia, neutropenia, and leukopenia, respectively. The Dose/BSA and Dose/LBM were significantly higher in patients who developed leukopenia than in those who did not (p < 0.05). The cutoff values of Dose/BSA and Dose/LBM associated with leukopenia were 50.0 mg/m² and 1.86 mg/kg, respectively. Conclusion: This study suggests that Dose/BCPs are associated with the development of leukopenia. Now, fixed dose regardless of BCPs is approved on almost of oral molecular targeting agents. However, the patients with low BCPs can be also received these medications in clinical practices. Therefore, although the sample size is small, the results of this study suggests the potential risk on the fixed dose. Moreover, Dose/BSA or Dose/LBM may be a useful parameter for assessing the risk of leukopenia with osimertinib.

Tapinarof is a non-steroidal, small molecule aryl hydrocarbon receptor (AhR) agonist that is being developed for the treatment of atopic dermatitis (AD). AD is a chronic inflammatory skin disease mediated by type 2 helper T (Th2) cells, characterized by impaired epidermal differentiation and skin barrier function. Tapinarof has been reported to regulate target gene expression through activation of AhR, improve skin barrier function, and exhibit an antioxidant effect. In this study, we investigated the pharmacological properties of tapinarof and its efficacy in mice with AD-like skin inflammation induced by 2, 4-dinitrofluorobenzene (DNFB). Tapinarof induced the mRNA expression of CYP1A1, an indicator of AhR activation, induced the mRNA expression of NAD(P)H: quinone oxidoreductase (NQO1), an antioxidant enzyme in human peripheral blood mononuclear cells (PBMCs) stimulated with T-cell activators. It also suppressed the production of interleukin (IL)-4, a Th2 cytokine. In mice with AD-like dermatitis, topical administration of tapinarof promoted the expression of Cyp1a1 and Nqo1 in the skin. It suppressed IL-4 production, the ear swelling, and histopathological changes. Tapinarof also suppressed an increase in transepidermal water loss (TEWL), an indicator of skin barrier function. These results indicate that tapinarof suppresses AD-like skin dermatitis and suggest that a variety of pharmacological actions, including an antioxidant effect, inhibition of Th2 cytokine, and improvement in barrier function, are involved.

Tapinarof is a non-steroidal, small molecule aryl hydrocarbon receptor (AhR) agonist that has demonstrated clinical efficacy and safety in patients with plaque psoriasis. In this study, we investigated the effects of tapinarof on interleukin (IL)-23-induced psoriasis-like dermatitis, which is a direct reflection of IL-23/type 17 helper T (Th17) axis activation considered pivotal in the pathogenesis of psoriasis, or normal skin in mice to elucidate its pharmacological properties. In mice with dermatitis, topical administration of tapinarof induced AhR activation, promoted the expression of an antioxidant molecule, and suppressed Th17 cytokine production in the skin, resulting in the reduction of skin swelling and histopathological changes. In normal mice, tapinarof did not induce the skin thinning observed with dexamethasone. These findings suggest that tapinarof represents a new topical treatment option for psoriasis carrying a lower risk of skin atrophy.

Basophils are recognized as effectors of type 2 immune responses, producing IL-4 in response to various stimuli such as IL-3 and papain in addition to IgE. In this study, we have established a novel cell-based reporter system that can monitor the activation of the transcription factor NFAT using retroviral vectors. Using this system, we examined whether papain, which is known to induce IL-4 in an FcRγ-dependent manner, could be used to identify its receptor. We created a chimeric receptor in which the extracellular and transmembrane portions are CD8 and the cytoplasmic domain is FcRγ. This chimeric receptor was able to induce GFP in RBL by cross-linking with anti-CD8 antibody. Furthermore, we found that this chimeric receptor can function as a papain receptor, as GFP was upregulated by papain stimulation. On the other hand, statins were able to suppress the expression of GFP by IgE crosslinking. This reporter system can be used to transduce candidate receptors and examine their papain receptor activity using GFP expression as an indicator, and is therefore a useful system that can be used for expression-cloning of unknown papain receptors and for the study of various inhibitors.

Sodium chlorite (NaClO₂) is applied as a disinfectant for the sanitization of food and environmental surfaces. HClO₂ (pKa = 1.86) is believed to be the main species responsible for the antimicrobial effects, whereas NaClO₂ solution ([HClO₂] / [ClO₂^-] = 10^-5.64 at pH 7.5) shows only weak antimicrobial activity at neutral pH conditions. However, NaClO₂ solution at a neutral pH has the advantages of having very low reactivity to organic materials and high stability for long-term storage at around room temperature. In our previous screening of food additives, phytochemicals, and related compounds, we found that caffeine could strongly promote the antimicrobial effects of NaClO₂ solution at a neutral pH. Caffeine is a purine alkaloid found in nearly 100 plant species that has very weak antibacterial properties against many bacteria. In the present study, we evaluated the antimicrobial activity of NaClO₂ in combination with caffeine against Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans strains. We found that caffeine strongly potentiated the antimicrobial action of NaClO₂ in all four strains, indicating that this combination has potential as a disinfectant.

Non-small cell lung cancer (NSCLC) accounts for 80%–90% of all lung cancers. The metastasis of NSCLC has a considerable impact on prognosis and systemic status. Cycloalliin, an organosulfur compound found in garlic, is known for its health benefits on cardiovascular disease and obesity. However, the role of cycloalliin in cancer cell invasion and metastasis remains unknown. In this study, we investigated the effect of cycloalliin on the epithelial-to-mesenchymal transition (EMT) and invasiveness of the NSCLC cell line A549. Cycloalliin inhibited transforming growth factor (TGF)-β-induced EMT and invasive potential of A549 cells. Furthermore, we found that cycloalliin suppressed Smad3 phosphorylation and expression of Snail, a transcription factor that promotes EMT, during the early stages of TGF-β-mediated EMT. This study provides valuable insights into the inhibitory potential of cycloalliin on EMT, suggesting that this compound may have a therapeutic role against EMT in NSCLC cells.

The type-III sodium-dependent phosphate transporters, SLC20A1 and SLC20A2, are distributed throughout the body, including the central nervous system. Various neurodegenerative diseases, including primary basal ganglia calcification (PBGC), involve the disruption of phosphate homeostasis. Patients with PBGC harbor a mutated SLC20A2. Previously, we demonstrated that the phosphate transport activity of SLC20A2 was involved in PBGC pathology. Thus, we hypothesized the activation of phosphate transport as one of the therapeutic targets for PBGC. It was previously reported that SLC20A1 and SLC20A2 were increased at vascular smooth muscle cell of ATF4-overexpression mice. This study investigated the effect of TIC10/ONC201, a potential activator of ATF4, on phosphate transport in SH-SY5Y, a neuronal cell model. Treatment with 3 µM TIC10, which did not cause cell death, increased phosphate uptake along with the ATF4 and SLC20A1 but not SLC20A2. Treatment with 3 µM TIC10 also enhanced phosphate uptake in SLC20A2-knockdowned cells but not SLC20A1-knockdowned cells. In conclusion, TIC10 enhanced phosphate uptake in SH-SY5Y cells via SLC20A1 but not SLC20A2.

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.