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.