Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan最新文献

Microplastics (MPs), defined as plastic particles less than 5 mm in size, are ubiquitous in the environment. The accumulation of MPs in various environmental compartments, such as the ocean, soil, and air, has raised considerable concerns regarding their impact on ecological systems, including marine life and human health. Notably, MPs have been detected in marine organisms such as shellfish and fish, and have even been found in the human body, including in the blood and placenta. Moreover, considering that MPs have been detected in drinking water, human exposure to these particles in daily life is inevitable. To assess the risk posed by MPs to human health, it is essential to consider their physiological and chemical properties, including size, shape, surface modification, and material composition. However, current risk analyses focus primarily on spherical MPs with smooth surfaces, which differ substantially from most of the MPs detected in the environment. Environmental factors, such as ocean waves and ultraviolet radiation, alter the properties of MPs, including size, shape, and surface characteristics. In this review, we summarize current research on MPs, with a particular emphasis on the effects of MP degradation on human health. Furthermore, we generated MPs with surface degradation and evaluated their impact on cell toxicity, along with the underlying biological mechanisms.

Normal differentiation and proliferation of cells are essential for maintaining homeostasis. Following the successful completion of whole genome sequencing, protein modification has been attracted increasing attention in order to understand the roles of protein diversification in protein function and to elucidate molecular targets in mechanisms of signal transduction. Vitamin A is an essential nutrient for health maintenance. It is present as β-carotene in green and yellow vegetables and retinyl ester in animal products and absorbed into the body from the intestines. After ingestion, it is converted to retinol and oxidized in target cells to retinal, which plays critical roles in vision. It is then further oxidized to retinoic acid (RA), which exhibits a number of effects prior to being metabolized by cytochrome P450 and excreted from the body. Since RA exhibits cell differentiation-inducing actions, it is used as a therapeutic agent for patients with acute promyelocytic leukemia. The current paper describes: (1) HL60 cell differentiation and cell differentiation induction therapy by RA; (2) roles played by RA and retinal and their mechanisms of action; (3) retinoylation, post-translational protein-modified by RA, a novel non-genomic RA mechanism of action without RA receptor; (4) new actions of β-carotene and retinol in vivo and (5) potent anticancer effects of p-dodecylaminophenol (p-DDAP), a novel vitamin A derivative created from the RA derivative fenretinide. We propose that nutritional management of vitamin A can be effective at preventing and treating diseases, and that p-DDAP is a promising anticancer drug.

Allergic diseases (e.g., food allergies) are a growing problem, with increasing numbers of individuals experiencing them worldwide. Congruently, the adverse reactions (e.g., anaphylaxis) associated with the administration of vaccines against emerging infectious diseases such as coronavirus disease 2019 (COVID-19) have become a familiar problem. Allergic diseases, which have a wide variety of symptoms, are difficult to prevent or cure; treatment is currently limited to therapeutic drugs or allergen immunotherapy. Therefore, elucidating new allergic regulatory factors that control the allergic (i.e., mast cell) responses is important. While investigating the regulatory mechanisms of the wide range of allergic responses of mast cells, we found that the affinity of allergens to immunoglobin E (IgE) regulates allergic inflammation through the differences in the secretory responses of mast cells and the types and interactions of the cells infiltrating the tissues. Here, we present our recent findings regarding the affinity of allergens to IgE in regulating allergic inflammation, heterogeneous secretory granules inducing diverse secretory responses, and mast cells interacting with neutrophils, thereby regulating the various allergic responses.

A series of antitumor bicyclic hexapeptide RA-VII analogues modified at residue 2, 3, or 6 were prepared by the chemical transformation of the hydroxy, methoxy, or carboxy groups or the aromatic rings of natural peptides RA-II, III, V, VII, and X. Analogues with modified side chains or peptide backbones, which cannot be prepared by the chemical transformation of their natural peptides, and newly isolated peptides from Rubia cordifolia roots were synthesized by using protected cycloisodityrosines prepared by the degradation of bis(thioamide) obtained from RA-VII or the diphenyl ether formation of boronodipeptide under the modified Chan-Lam coupling reaction conditions. Studies of the conformational features of the analogues and the newly isolated peptides and their relationships with cytotoxic activities against the HCT-116, HL-60, KATO-III, KB, L1210, MCF-7, and P-388 cell lines revealed the following: the methoxy group at residue 3 is essential for the potent cytotoxic activity; the methyl group at Ala-2 and Ala-4 but not at D-Ala-1 is required to establish the bioactive conformation; the N-methyl group at Tyr-5 is necessary for the peptides to adopt the active conformation preferentially; and the orientation of Tyr-5 and/or Tyr-6 phenyl rings has a significant effect on the cytotoxic activity.

The membrane permeability, and its evaluation, is crucial factor in the process of uptake of compounds from outside to inside the cell and in the inhibition of the activity of disease-causing target proteins. Although molecular dynamics (MD) simulations have been shown to be able to reproduce the conformational changes of compounds occurring during membrane permeation, it is still challenging to extract the membrane permeability at an affordable computational workload solely by conventional MD. Indeed, the time scale accessible by MD is far below the one characterizing the actual permeation process. Phenomena occurring in living organisms escaping the reach of standard MD are generally referred to as biological rare events, and the membrane permeation process is one of them. To overcome this time-scale problem, several enhanced sampling methods have been proposed over the years to improve conformational sampling. In this review, a hybrid sampling method that combines the parallel cascade selection MD (PaCS-MD) and the outlier flooding method (OFLOOD), introduced and developed by our group, is proposed as a tool to study the membrane permeation from structural sampling (rare-event sampling). The obtained trajectories are used to estimate the free energy profiles for the membrane permeation and to compute the membrane permeation coefficients. Moreover, we present an example of application of the free energy reaction network method as a versatile way for incorporating explicitly into reaction coordinates the degrees of freedom related to internal motion.

Quantitative NMR (qNMR) has been adopted by documentary standards, including the Japanese Pharmacopoeia (JP), United States Pharmacopoeia (USP), and International Organization for Standardization (ISO), owing to its reliability and efficiency. Note that qNMR can be used for quantifying target components using the signal integration ratio of an analyte to a reference. In qNMR, a modern NMR instrument with high resolution and sensitivity is used to record reliable spectra. This instrument can detect small signals from impurities in a solvent, which may result in inaccurate signal integration in the spectrum. In this study, we investigated the influence of solvent quality on qNMR accuracy focusing on organic impurities, water content, and deuteration ratio. If signals from organic impurities and signals from the analyte overlap, the duplication of signal integration will directly affect the qNMR analytical result. To examine overlapping, we performed blank solvent tests. Additionally, a high water content and low deuteration ratio affect the detection sensitivity, thus reducing the signal-to-noise (S/N) ratio of the target. Thus, these factors must be considered to obtain accurate qNMR results.

Cancer therapies have evolved considerably thereby substantially improving the survival of patients with cancer. However, cardiotoxicity, such as myocarditis and heart failure, induced by anticancer drugs, including immune checkpoint inhibitor(ICI)s and doxorubicin, present serious challenges. Numerous observations have indicated increased risks of cardiotoxicity- and cancer-related mortality in patients with drug-induced cardiotoxicity. Therefore, the prevention and management of drug-induced cardiotoxicity should be prioritized to enable sustainable long-term treatment while preserving patients' quality of life. Recently, medical research has been primarily focused on elucidation of therapeutic benefits and adverse events using medical big data, including worldwide databases of adverse events. The aim of the present study was to establish prevention strategies for drug-induced cardiotoxicity and advance data analytics. A data-driven approach was adopted to comprehensively analyze patient data and drug-induced cardiotoxicity. These data analytics revealed numerous risk factors, leading to the development of drugs that mitigate these factors. Furthermore, many unknown adverse events with molecularly targeted drugs were brought to light. Consequently, the importance of managing adverse events, guided by insights from data science, is predicted to increase. In this symposium review, we introduce our research exemplifying pharmaceutical studies utilizing medical big data. In particular, we discuss in detail the risk factors associated with myocarditis induced by immune checkpoint inhibitors along with prophylactic agents to mitigate doxorubicin-induced cardiotoxicity.

This study focuses on the modulation of protein aggregation and immunogenicity. As a starting point for investigating long-range interactions within a non-native protein, the effects of perturbing denatured protein states on their aggregation, including the formation of amyloid fibrils, were evaluated. The effects of adducts, sugar modifications, and stabilization on protein aggregation were then examined. We also investigated how protein immunogenicity was affected by enhancing protein conformational stability and other factors.

Sleep is fundamental for living animals. Although they are not conscious during sleep, their brains are continuously working. This neural activity during sleep can be reflected by neural oscillations closely related to cognitive function. While the relationship between neural activity in sleep and cognition has been extensively investigated, it is not fully understood how neural activity in sleep and relevant memory are modulated by specific receptors. In particular, I focused on melatonin receptors and their agonist, ramelteon. While the effects of ramelteon on sleep have been widely documented, it is still poorly understood how ramelteon affects learning and memory as well as neural activity in sleep. To address this question, I first recorded neural oscillations in the neocortex of rats treated with ramelteon and found that ramelteon promoted non-rapid eye movement (NREM) sleep and increased fast gamma power in the primary motor cortex during NREM sleep. I then evaluated the behavioral performance of ramelteon-treated mice using the novel object recognition task and the spontaneous alternation task, demonstrating that ramelteon enhanced object recognition memory and spatial working memory. These results shed light on new aspects of the functions of melatonin receptors.

Venetoclax (VEN) is used in patients with acute myeloid leukemia (AML) and is primarily metabolized by CYP3A4, a major drug-metabolizing enzyme. Patients with AML simultaneously administered VEN and CYP3A4 inhibitors require a more appropriate management of drug-drug interactions (DDIs). Here, we report two cases of patients with AML (54-year-old man and 22-year-old woman) administrated VEN and CYP3A4 inhibitors, such as posaconazole, cyclosporine, or danazol. In the first case, we evaluated the appropriateness of timing for adjusting VEN dosage subsequent to the cessation of posaconazole. Consequently, modifying the VEN dosage in conjunction with the cessation of Posaconazole simultaneously may result in elevated plasma VEN levels. In the second case, plasma VEN concentrations were markedly elevated when co-administered with several CYP3A4 inhibitors. Additionally, in vitro assays were conducted for reverse translational studies to analyze CYP3A4 inhibition. CYP3A4 inhibition by combinatorial administration of cyclosporine A and danazol was demonstrated in vitro, which potentially explains the increasing plasma VEN concentrations observed in clinical settings. Although the acquisition of therapeutic effects is a major priority for patients, frequent therapeutic drug monitoring and dosage adjustments considering DDIs would be important factors in chemotherapy.