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o-Toluidine has been used for multiple industrial purposes, but causes bladder carcinogenesis in exposed workers. However, its underlying mechanism is still unclear. In this study, we examined oxidative and nitrative DNA damage caused by o-toluidine and its metabolites, 2-amino-m-cresol, 4-amino-m-cresol (4AC) and N-(4-hydroxy-2-methylphenyl) acetamide, using T24 human bladder epithelial cells. MTT assay showed that 4AC induced the most potent cytotoxicity among o-toluidine and its metabolites. In flow cytometry, 4AC showed the strongest ability of generating reactive oxygen species (ROS) and nitric oxide (NO) in exposed cells. Fluorescence immunocytochemistry revealed that 4AC significantly increased the staining intensities of an oxidative DNA lesion, 8-oxo-2’-deoxyguanosine, and a nitrative DNA lesion, 8-nitroguanine, at 5 nM. Their staining intensities were stronger than the other compounds. The comet assay showed that o-toluidine and its metabolites significantly increased the olive tail moment after the treatment with formamidopyrimidine DNA glycosylase. DNA damage was significantly reduced by transfection with small interfering RNA and antibodies against high-mobility group box-1 (HMGB1), receptor for advanced glycation end-products (RAGE) and Toll-like receptor (TLR) 9. These findings indicate that o-toluidine and its metabolites induce the release of HMGB1, which forms a complex with CpG DNA to bind to RAGE on neighboring cells and then is recognized by TLR9 in lysosomes, leading to ROS and NO production and DNA damage. In o-toluidine-induced carcinogenesis, TLR9-mediated inflammatory response and DNA damage induced by its metabolites, especially 4AC, may play a substantial role.
Older individuals generally have decreased food intake owing to physical, social, psychological, and behavioral limitations. However, the characteristics of food and nutrient intake resulting from these limitations are poorly organized. Organizing knowledge for practical application in older adults is necessary when considering nutrition care strategies. This review aimed to characterize food and nutrient intake according to these exposure factors in older individuals. This systematic review followed the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines (PROSPERO, CRD42024582151). MEDLINE and Web of Science were searched in September 2024 using the following inclusion criteria: community-dwelling older adults aged ≥65 years (participants); factors contributing to physical, social, psychological, or behavioral limitations affecting food and nutrient intake (exposure); food and/or nutrient intake, dietary patterns, and overall diet quality (outcomes); and cross-sectional and cohort studies (study design). Among the 2,354 studies screened, 29 studies were analyzed. These included studies addressed the following exposure factors: oral function and physical activity (physical); economic status, marital status, household size, and educational attainment (social); depressive symptoms (psychological); and food security, nutritional knowledge, and cooking skills (behavioral). Reduced oral function was associated with lower intakes of meat, fish, legumes, vegetables, and fruits. Low economic status and educational level were associated with poor diet quality. However, there was limited research characterizing the dietary intakes of individuals with other factors, such as poor cooking skills or decreased sense of taste and smell. Further research is needed.
Numerous studies have applied machine learning to diagnosis and screening in the medical and welfare fields. However, it is rare for the resulting machine learning models to be widely adopted in clinical practice. This study proposes a method for deriving diagnostic rules from machine learning models that can be applied manually without the use of computers. The proposed method involves inputting all possible patterns into a trained model, generating a truth table with the corresponding prediction results, and then using the Quine–McCluskey method to derive logical expressions that serve as manual diagnostic rules. In the experiments, the proposed method was compared with conventional methods for deriving manual diagnostic rules from datasets: the point score system, a method based on likelihood ratios, and a logic derivation method based on rough set theory. Only the proposed method achieved a positive clinical utility index of 0.81 or higher—classified as “excellent”—even when the number of rules was limited to just two or three.
Abstract Platinum-based drugs (Pt-drugs), such as cisplatin, are essential chemotherapeutic agents that exhibit strong tumor-reducing effects against a wide range of cancers. Their success has greatly stimulated cancer research in the field of inorganic biochemistry. However, the current consensus is that cisplatin derivatives with closely related structures do not offer sufficient clinical advantages to replace existing Pt-drugs. In particular, the next-generation of Pt-drugs are expected to be effective against cancers that are resistant or insensitive to standard treatments. Therefore, there is a need to design platinum complexes with fundamentally different structures. Based on this goal, our group has designed and investigated a series of azolato-bridged dinuclear platinum(II) complexes, [{cis-Pt(NH3)2}µ-OH)(µ-azolato)]An (where azolato = pyrazolato, 1,2,3-triazolato, or tetrazolato; A = NO3 or ClO4; and n = 1 or 2), that have unique mechanisms of action and in vivo antitumor efficacy. Promising compounds in this series are represented by the general formula [{cis-Pt(NH3)2}2(µ-OH)(µ-5-R-tetrazolato-N2,N3)]An and were derived using tetrazoles with various substituents (R) at the tetrazole C5 position. Notably, both antitumor efficacy and toxicity varies markedly depending on the substituent. This review summarizes the unique mechanisms of action and structure–activity relationships of these complexes based on in vitro and in vivo studies.
