Chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) are caused by a fusion protein, BCR-ABL, which induces cellular transformation by activating the signaling molecules, STAT5 and Akt. The specific BCR-ABL inhibitors including imatinib, nilotinib, and dasatinib, are clinically utilized in the treatment with CML and ALL patients. Although these BCR-ABL inhibitors are initially successful in the treatment of leukemia, many patients develop drug resistance due to the appearance of the gatekeeper mutation of BCR-ABL, T315I. Recently, we found that taxodione, a quinone methide diterpene isolated from a conifer, Taxodium distichum, significantly induced apoptosis in human myelogenous leukemia-derived K562 cells, which is positive for the bcr-abl gene. Taxodione reduced the activities of mitochondrial respiratory chain complex III, leading to the production of reactive oxygen species (ROS). An antioxidant agent, N-acetylcysteine (NAC), canceled taxodione-induced ROS production and apoptotic cell death, suggesting that taxodione induced apoptosis through ROS accumulation. Furthermore, in K562 cells treated with taxodione, BCR-ABL, STAT5 and Akt were sequestered in mitochondrial fraction, and their localization changes decrease their abilities to stimulate cell proliferation. Strikingly, NAC canceled these taxodione-caused inhibition of BCR-ABL, STAT5 and Akt. In addition, taxodione significantly induced apoptosis in transformed Ba/F3 cells by not only BCR-ABL but also T315I-mutated BCR-ABL through the generation of ROS, suggesting that taxodione has potential as anti-tumor drug with high efficacy to overcome BCR-ABL T315I mutation-mediated resistance in leukemia cells. It’s also expected that these knowledge becomes an important clue in the development of anti-cancer drugs against the broad range of tumors.

For the function and survival of neurons in the central nervous system, it is indispensable that the intracellular Ca²⁺ dynamics are properly controlled. The endoplasmic reticulum (ER), a major intracellular Ca²⁺ store, plays an important role in the control of the intracellular Ca²⁺ dynamics in neurons through the supply and uptake of Ca²⁺. It has been suggested that the disruption of ER Ca²⁺ signaling is involved in neuronal cell death in various pathological conditions. Therefore, the disruption of ER Ca²⁺ signaling has attracted attention as a novel mechanism for neurodegenerative diseases including Alzheimer’s disease. In this review, we introduce the latest findings including our research on the relationship between the disruption of ER Ca²⁺ signaling and neuronal cell death. In addition, we will introduce recent developments on the technology for visualizing intraluminal Ca²⁺ dynamics within the ER, which is indispensable for promoting research in this field.

Behavioral tests using rodents are widely used for assessing mental states of animals and the effects of pharmacological drugs on psychiatric disorders. However, the results of behavioral tests are sometimes inconsistent due to individual differences. To evaluate animal’s mental states based on internal organ activity, we recently developed a new electrophysiological method to simultaneously monitor cortical local field potentials, electrocardiograms, electromyograms, respiratory signals, and vagus nerve spikes in a freely moving rodent. Here, we introduce some results obtained from an elevated plus maze test. Both cortical activity patterns and vagus nerve spike patterns are crucially related to other peripheral organ activity rather than arm types of the maze in which animal were located, which demonstrates that combining behavioral tests with peripheral physiological makers enables a more accurate evaluation of rodent mental states. Moreover, we show that functional connection patterns across cortical regions could be predictive factors accounting for stress susceptibility defined based on the irregularity of heartbeat signals, demonstrating that cortical activity may be a mechanism that causes abnormal activity of peripheral organs in response to mental stress episodes. These observations from our recording technique are a new step for understanding of the neurophysiological correlates of mind-body associations in health and disease.

In the developing mammalian cerebral cortex, newly generated neurons migrate toward the pial surface to form a mammalian-specific six-layered cerebral cortex. Genetic studies of human neurological diseases have suggested the involvement of several molecules in cortical neuronal migration. In vivo electroporation is another powerful tool for understanding the molecular mechanisms of neuronal migration. By using these techniques, however, it is difficult to understand molecular basis of time-dependent changes of neuronal morphologies. Here, we introduce a pharmacological approach to cerebral cortical development. Major advantages of the pharmacological approach include the transient suppression of molecules of interest and analyzing time-dependent changes of neuronal morphologies. It also allows us to search molecules regulating neuronal migration with comparative ease. We propose the complementarity between the pharmacological approach and genetics or in vivo electroporation experiments.

Apelin is an endogenous peptide ligand for APJ receptor, which is widely expressed in human body, and exerts various physiological effects such as vasodilation, inotropic effect, water balance, heart development, angiogenesis and energy metabolism. The beneficial effects of Apelin in cardiovascular diseases have been elucidated, and the roles of Apelin in aging-associated diseases are recently implicated. The mechanisms for therapeutic effects of Aplein include an antagonistic action to renin-angiotensin system (RAS) in addition to inotropic and vasodilatory actions. We have revealed that endogenous Apelin negatively regulates RAS via upregulation of Angiotensin converting enzyme 2 (ACE2). In addition, a second ligand for APJ receptor, Elabela/Toddler, was identified as an essential hormone for heart development, and it has been reported to have physiological effects similar to Apelin. We and others have shown that Elabela exerts inotropic and protective effects in the heart. Although the number of heart failure patients is rapidly increasing, the pathophysiology of heart failure remains elusive and further development of new therapeutic option is awaited. Apelin is a unique bifunctional molecule, which has both inotropic and cardioprotective effects in heart failure, and thus further elucidation of the mechanisms for Apelin/Elabela-APJ signaling would contribute to development of a novel therapeutics for heart failure patients.

Rapid expansion of aged population is predicted worldwide. To cope with problems expected from this situation and extend the period of active and healthy life of people as much as possible, it is important to elucidate not only the biological mechanisms of “aging”, but also the etiology of various “age-related diseases”. To attain this goal, extensive studies using excellent animal models are indispensable. Senescence-accelerated mouse (SAM) is a series of inbred mouse strains that includes SAMP1, SAMP6, SAMP8, SAMP10, and SAMR1. SAMP strains exhibit accelerated senescence and short lifespan. In addition, each strain shows specific age-related disease phenotypes which are similar to symptoms observed in humans, such as senile amyloidosis (SAMP1), senile osteoporosis (SAMP6), and age-dependent deficits in learning and memory (SAMP8), making SAM mice useful for an aging research. In this review, we introduce the characteristics and application of SAM in geriatrics and aging biology.

Drug metabolism in the liver is a major factor affecting pharmacokinetics of drugs, and cytochrome P450s (P450s) are major enzymes responsible for it. Since drug-drug interactions (DDIs) can affect the pharmacokinetics of concomitantly administrated drugs, it may limit the drug therapy such as dose adjustment and contraindications for co-administration and lead to dose adjustment and contraindications for co-administration. DDI is thus one of the risk factors to be reduced in the lead-optimization stage. Therefore, it is important to estimate DDI risk in the early drug discovery stage and develop candidates with low DDI risk. P450 induction is one of the important mechanisms causing DDIs and the activation of nuclear receptors is involved in this phenomenon. In this manuscript, the mechanism and evaluation methods of P450 induction are briefly reviewed, and then the new in silico methods for the prediction of P450 induction, which have been recently established by us, and its application to drug development are introduced.

Letermovir is an anti-human cytomegalovirus (HCMV) drug with a novel mechanism of action. Virological characterization and sequence analysis of resistant viruses indicate that the viral DNA terminase complex is the target of this compound. Unlike currently marketed anti-HCMV drugs, which act via inhibition of the viral DNA polymerase, the terminase inhibitor interferes with viral DNA cleavage and packaging of monomeric genome units into capsids. Letermovir has potent anti-HCMV activity, with 50% effective concentration of single-digit nanomolar against most clinical HCMV isolates in cell-culture models of infection. Besides its excellent in vitro inhibitory activity against laboratory and clinical HCMV isolates, letermovir exhibits activity against virus strains resistant to the currently approved anti-HCMV drugs. Letermovir is specific for human cytomegalovirus but lacks inhibitory activity against major pathogenic viruses including other Herpesviridae. In a xenograft mouse infection model, the 50% and 90% effective doses of the letermovir were 3 and 8 mg/kg/day, respectively. HCMV infection and disease in recipients of allogeneic hematopoietic stem cell transplant (HSCT) is a serious disease leading to significant morbidity and mortality. In the Phase 3 trial, the preventive effect of clinically significant HCMV infection by oral or intravenous administration of letermovir in allogeneic HSCT patients was confirmed, and letermovir was well tolerated with no suggestions of myelotoxicity or nephrotoxicity.