Folia Pharmacologica Japonica最新文献

With every heartbeat, cardiomyocytes are exposed to mechanical stress, and yet they effectively retain a highly ordered internal structure, while flexibly adapting to their environment, a capacity referred to as resilience. Under physiological conditions, the cardiomyocytes in adult mammals are characterized by a limited proliferative capacity, thereby necessitating the maintenance of cellular homeostasis via structural and functional plasticity. In this review, we focus on the transverse-tubule (T-tubule) membrane as a key structural element underlying this cellular resilience. Traditionally recognized as a pivotal site associated with calcium signaling during excitation-contraction coupling, it has now been established that T-tubule membranes are more than merely static anatomical features. The findings of recent studies have revealed that during contraction, these membranes undergo passive deformation and are actively remodeled in response to mechanical load, demonstrating a capacity for structural resilience. Furthermore, T-tubules contribute to a unique membranous microenvironment deep within the cell, facilitating the spatiotemporal regulation of calcium signaling and enabling rapid responses to external stimuli. Importantly, structural disorganization of the T-tubule network is frequently observed prior to the onset of heart failure, thus highlighting its essential role in maintaining cardiomyocyte function. By examining the dynamic interplay between T-tubule structure and function, in this review, we provide new insights into the mechanisms underlying cardiomyocyte resilience and identify potential therapeutic targets for preserving structural homeostasis in cardiac disease.

Upacicalcet sodium hydrate (upacicalcet) is a novel small-molecule calcium-sensing receptor (CaSR) modulator with an amino acid structure, developed in Japan as a derivative from research into taste enhancement. Upacicalcet specifically targets CaSR and is thought to inhibit parathyroid hormone (PTH) secretion by activating the receptor in the presence of extracellular calcium (Ca). In nonclinical studies, upacicalcet was evaluated for its pharmacological properties, binding characteristics, and effects on ectopic calcification, parathyroid hyperplasia, and bone disorders associated with secondary hyperparathyroidism (SHPT). The results supported its mechanisms of action, binding mode, and efficacy in suppressing disease progression. In clinical trials, upacicalcet demonstrated efficacy and safety in patients with SHPT undergoing hemodialysis, as assessed in domestic Phase I/II trial (AJ1001 trial), Phase II trial (AJ1002 trial), Phase III placebo-controlled trial (AJ1004 trial), and Phase III long-term administration trial (AJ1003 trial). Upacicalcet was approved in June 2021 for the treatment of secondary hyperparathyroidism (SHPT) in patients undergoing hemodialysis and was launched in August of the same year.

Synovial sarcoma is a type of soft tissue sarcoma that predominantly occurs near the joints of the extremities in young adults. Its hallmark is a recurrent and pathogenic chromosomal translocation, t(X;18)(p11.2;q11.2), which results in the fusion of the SSX1 or SSX2 gene with SS18. The expressed SS18-SSX fusion protein induces abnormalities in the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, a chromatin remodeling complex. In this paper, we refer specifically to the human SWI/SNF complex as mSWI/SNF. Since 2020, significant progress has been made in elucidating the molecular mechanisms underlying the initial event in synovial sarcomagenesis, particularly in structural biology, thereby opening new possibilities for structure-based drug design (SBDD). SS18-SSX1 replaces the wild-type SS18, an essential subunit of mSWI/SNF, and in turn ejects SMARCB1, another core subunit of the complex. This aberrant mSWI/SNF complex (ssSWI/SNF) is then relocated to nucleosomes containing H2A K119Ub. H2A is one of the core histone proteins, and its 119th lysine residue is ubiquitinated to form H2A K119Ub. Chromatin domains harboring nucleosomes with this modification typically exhibit suppressed gene expression patterns. Furthermore, this region is occupied by polycomb complexes, but ssSWI/SNF competes with them, leading to gene activation, which constitutes the initial event in synovial sarcomagenesis. Given that SSX1 is normally expressed primarily in the testes, it is plausible that its ectopic expression leads to aberrant function within the chromatin remodeling complex. Ultimately, the C-terminal region of SSX1 was found to bind to the acidic patch within the nucleosome, and its structural details have been elucidated through cryo-electron microscopy.

Pregnancy can affect the absorption, distribution, metabolism, and excretion of several drugs due to pregnancy-induced physiological changes. Risperidone, a second-generation antipsychotic, is prescribed to pregnant women when the benefits outweigh the risks to the fetus. Serum concentrations of risperidone and its active metabolite paliperidone in a pregnant woman as well as her newborn were measured, and physiologically-based pharmacokinetic (PBPK) models of both drugs were developed. The effects of pregnancy on pharmacokinetic parameters of both drugs were quantitively assessed by the developed PBPK model. As a result, serum concentrations of risperidone and paliperidone decrease in the pregnant status and abruptly recover to the non-pregnant level after delivery mainly due to cytochrome P450 (CYP) 2D6 activity changes, and therefore, close and careful monitoring of clinical symptoms should be considered during pregnancy and after delivery. In the 10 different models for estimating the renal function of children, the Flanders metadata equation showed the lowest absolute bias and the greatest precision in predicting paliperidone serum concentration in the neonate. PBPK model-informed approach could help with the precision dosing in special populations, such as pregnant women and neonates.

The prevalence of allergic diseases has been increasing, and sensitization to allergens such as cedar pollen and house dust mites has become a social issue. Allergic inflammation is primarily driven by type 2 inflammation, which is mediated by interleukin (IL)-4, IL-5, and IL-13 produced by Th2 cells and group 2 innate lymphoid cells (ILC2s). Recent studies have suggested that extracellular vesicle (EV) also plays critical roles in the pathogenesis of allergic diseases. EVs are lipid bilayer-enclosed particles containing proteins, mRNA, and microRNA (miRNA), which function as carriers of cytokines, antigens, and miRNAs, thereby activating Th2 cells and ILC2s and contributing to the progression of various inflammatory diseases. In contrast, we demonstrated that EVs contributed to the regression of allergic disease: EVs derived from the serum of allergen immunotherapy-treated mice exhibited suppression of ILC2 activation. Given their dual roles in both promoting and suppressing immune responses, EVs are emerging as promising targets and tools for novel treatment strategies. Understanding the immunomodulatory mechanisms mediated by EVs will be a crucial step toward developing safer and more effective therapies for allergic diseases. This review provides an overview of the role of EVs in allergic inflammation and highlights our recent findings on how allergen immunotherapy influences the properties and functions of EVs, thereby contributing to the regulation of immune responses and alleviation of allergic symptoms.