Folia Pharmacologica Japonica最新文献

Belumosudil mesylate (REZUROCK_® Tablets hereafter belumosudil) is a novel selective rho-associated, coiled-coil containing protein kinase 2 (ROCK2) inhibitor. ROCK2 is a kinase involved in immune cell differentiation and tissue fibrosis. Belumosudil exerts its effect by decreasing the inflammation and fibrosis in various organs which are the two key features of cGVHD. In the phase III clinical study in Japan, the primary endpoint was met, best overall response rate (best ORR), defined as the percentage of patients who achieved complete response (CR) or partial response (PR), was 85.7%. Belumosudil received manufacturing and marketing approval for the treatment of chronic graft-versus-host disease (cGVHD) in patients who have insufficient response to steroid therapy in March 2024 and launched in May 2024. The Japanese MHLW has also granted orphan drug designation in May 2023 for the treatment of cGVHD.

Brain microvascular endothelial cells (BMECs) are the central cellular components of the blood-brain barrier (BBB) that protect the central nervous system. The characteristic functions of the BBB, such as its strong barrier properties and selective regulation of molecular transport into the brain, are largely mediated by BMECs. Human induced pluripotent stem cell-derived BMECs (iBMECs) have garnered attention because of their robust tight junction integrity and transporter activity, distinguishing them from cells used in conventional BBB models. In recent years, iBMECs have shown great promise for drug discovery and disease modeling, particularly through integration with organ-on-a-chip technologies and the use of disease-specific iPS cells to construct disease-mimicking BBB models. This article provides an overview of the current state and future prospects of iBMECs, highlighting advances in differentiation techniques, cellular characteristics, and their emerging applications.

Allergic diseases have been considered multifactorial diseases. However, comprehensive genome sequencing, such as whole exome analysis, is revealing a group of diseases in which single genes are deeply involved in their pathogenesis. We identified a de novo missense variant of STAT6 [NM_003153:c.1255G>A,p.(Asp419Asn)] in a severely allergic patient with atopic dermatitis, hyper IgE, eosinophilic gastroenteritis, and food allergy by whole exome sequencing analysis. STAT6 is known as a transcription factor induced by IL-4 stimulation. Stimulation with IL-4 induces STAT6 phosphorylation via the JAK-STAT pathway and dimer formation. The STAT6 dimer quickly translocates into the nucleus and ultimately activates the expression of genes specific for TH2-type immune responses. Our experiments in vitro showed that nuclear translocation of mutant STAT6 (p.Asp419Asn) is enhanced compared to wild-type STAT6. In addition, even in the absence of IL-4 stimulation, we observed the translocation of mutant STAT6 in its unphosphorylated state, which activated gene expression. Mutant STAT6 knock-in mice elicited an abnormal TH2-dominant immune response in vivo, with findings similar to those observed in patients. Our findings suggest that mutant STAT6 is a gain-of-function variant. Currently, anti-IL-4Rα monoclonal antibodies, JAK inhibitors that block the JAK-STAT pathway, and non-specific anti-inflammatory drugs such as steroids are shown to be effective in treating this disease. The pathogenesis of immune dysregulation caused by gain-of-function variants of the STAT6 gene is being elucidated. Further efforts are required to elucidate the detailed mechanisms of this disease and it will hopefully lead to the development of more essential agents that specifically regulate STAT6 activity.

Currently, a variety of anticancer agents are used in the treatment of cancer. Since anticancer agents are used continuously over a long time, they carry the risk of side effects. One of the major side effects is cardiac dysfunction. For example, doxorubicin, an anthracycline-type anticancer agent, is clinically restricted because of its dose-dependent cardiotoxicity. Cardiotoxicity includes decreased ejection fraction, arrhythmias, and congestive heart failure, all of which are associated with high mortality rates. Therefore, it is important to assess the risk of cardiotoxicity of anticancer agents in advance. Cardiomyocytes require energy to beat and retain an abundance of mitochondria. We established quantitative measurements of mitochondrial length and respiratory activities using cardiomyocytes. We found that exposure of human iPS cell-derived cardiomyocytes (hiPSC-CMs) to anticancer agents with reported cardiotoxicity enhanced mitochondrial hyperfission and the oxygen consumption rate was significantly reduced. Knockdown of dynamin-related protein 1 (Drp1), mitochondrial fission-accelerating GTP-binding protein, suppressed mitochondrial hyperfission in hiPSC-CMs. This indicates that visualizing mitochondrial functions in hiPSC-CMs will be helpful in assessing the risk of cardiotoxicity caused by anticancer agents and that maintaining mitochondrial quality will become a new strategy to reduce anticancer agents-induced cardiotoxicity. In this review, we present the evaluation of cardiotoxicity targeting mitochondrial quality in anticancer agents, using osimertinib, a non-small cell lung cancer drug, as an example.

Approximately 80% of all the information we receive about the world comes through the visual pathways and visual function deterioration causes severe decline in QOL. Glaucoma is the leading cause of blindness in the world, in which visual field deficit deteriorates as the optic nerve degeneration progresses. Hence, the development of fundamental cure is needed. Our research focuses on the signaling of brain-derived neurotrophic factor (BDNF), one neurotrophic factor reduced with aging and glaucoma patients. We generated modified tropomyosin receptor kinase B (TrkB) which can be constitutively activated in the absence of its ligand BDNF. The active site of TrkB is localized to the plasma membrane, allowing for constitutive activation of intracellular signaling. Gene therapy with the modified TrkB in a mouse model of glaucoma was proven to be protective. In addition, our group reported that apoptosis signal-regulating kinase 1 (ASK1), one of the stress response factors, is related to the severity of optic neuritis and myelitis in model mice of multiple sclerosis. We generated four lines of cell type specific ASK1 conditional knockout mice and found that ASK1 in glial cells increased the severity of neuroinflammation while ASK1 deficiency in immune cells had no significant effects. Further, we found that ASK1 is required in microglia and astrocytes to cause and maintain neuroinflammation by a feedback loop between these two cell types. Our results suggest that ASK1 might be a promising therapeutic target for reducing neuroinflammation including optic neuritis.

Molecularly targeted drugs currently used in breast cancer target the epidermal growth factor receptors, and are less effective when used against breast cancer subtypes with low levels of these receptors. There is therefore an urgent need to identify a new target molecule for such breast cancer subtypes. Vasoactive intestinal peptide (VIP) receptor 2 (VIPR2) is a G-protein-coupled receptor that binds to Gαs, Gαi, and Gαq proteins to regulate their downstream signaling. VIPR2 is known to be highly expressed in the suprachiasmatic nucleus of the brain, but is also expressed in many peripheral organs. VIPR2 expression has also been reported in thyroid cancer, gastric cancer, lung cancer, pancreatic adenocarcinoma, sarcoma, and neuroendocrine tumors, and VIPR2 mRNA expression and VIPR2 gene copy number are particularly elevated in breast cancer. We therefore investigated the involvement of VIPR2 in the proliferation and migration of breast cancer cells. We showed that VIP-VIPR2 is a novel molecular mechanism that controls cell migration by activating phosphatidylinositol-3 kinaseγ (PI3Kγ), promoting the production of phosphatidylinositol 3,4,5-triphosphate, and then regulating the formation and extension of pseudopodia. VIP-VIPR2 also regulated cyclin D1 levels through the cAMP/PKA/extracellular signal-regulated kinase and PI3K/AKT/Akt-glycogen synthase kinase-3β signaling pathways, thereby controlling cell proliferation by regulating the G1/S transition in the cell cycle. Treatment with a selective VIPR2 antagonist peptide KS-133 suppressed VIP-induced cell proliferation and migration. These results suggest that VIPR2 is a novel target molecule associated with breast cancer and that KS-133 is a potential molecular targeted drug for breast cancer.