Folia Pharmacologica Japonica最新文献

We are living in an era in which AI technology has become widely available and accessible to many people. The field of drug discovery is no exception, and many pharmaceutical companies have actually begun to utilize AI technology in drug discovery research. In the field of image analysis, which is our main business, AI technology is also advancing and being applied to drug discovery research. In this era of "democratization of AI", what is the role of AI vendors including our company? What is needed for drug discovery researchers to use the technology correctly and appropriately in their research, and for more researchers to benefit from the technology than ever before? We would like to share with you what we have been doing so far and what we will do in the future for "true democratization of AI", including examples of applications of image analysis AI technology to drug discovery research.

Chemokines are a group of cytokines which are involved in the migration of immune cells as well as other cell types such as endothelial cells. These molecules normally regulate the homeostasis in our body's immune system. Furthermore, it has been reported that chemokines mediate the onset and progression of various diseases including allergic diseases, autoimmune diseases, and cancers through the recruitment of immune cells to inflammatory sites. Glioblastoma is one of the primary brain tumors with a significantly poor prognosis. Similarly to other tumors, it has been observed that various immune cells infiltrate into the brain tumor tissues. However, the details of the mechanisms remain unclear. At present, cancer immunotherapy is vigorously researched, and is proved to be effective for many cancers. Unfortunately, the effectiveness of cancer immunotherapy has not yet been shown in glioblastoma. Chemokine is thought to be one of the important factors for cancer immunotherapy. Therefore, understanding the role of chemokines in glioblastoma is considered to be beneficial for the development of cancer immunotherapy. In this review, we overview the role of chemokines and these receptors in glioblastoma.

Aging is a physiological process caused by various genetic and environmental factors. Recently, it has been proposed that the disturbance of the nutritional-metabolic sensing pathway is one of the aging characteristics. In particular, nicotinamide adenine dinucleotide (NAD⁺) plays an important role in this pathway and is considered the regulator of aging. NAD⁺ regulates an energy metabolism as a co-factor and is also involved in various biological processes including transcription, stress responses, DNA repair, inflammatory responses as well as post-transcriptional modifications, as a substrate for sirtuins, poly ADP-ribose polymerase (PARP), and CD38. With age, DNA damage and chronic inflammation increase in organs, resulting in overconsumption of NAD⁺ via PARP and CD38. The reduced NAD⁺ levels decrease the activity of sirtuins and PARPs and impair energy metabolism, ultimately leading to aging and aging-related diseases. However, the precise metabolism of NAD⁺ in vivo and the mechanism of how NAD⁺ regulates aging remain elusive. Moreover, the clinical application of NAD⁺ supplementation therapy is still under development. In this review, we overview the NAD⁺ metabolism and its relation to aging. In addition, we describe the current issue and perspective of NAD⁺ supplementation therapy to promote a healthy lifespan.

Hypoxic condition is formed in our body when the oxygen demand exceeds the supply. Hypoxic response is triggered under such condition to maintain homeostasis. However, it had been unclear for a long time how cells sense changes of surrounding oxygen environment and activate hypoxic response. Studies of molecular machinery responding to hypoxia largely progressed in the mid 90's after the identification of Hypoxia-Inducible Factor, HIF. Then, the prolyl hydroxylase domain-containing protein (PHD)-HIF pathway was characterized as a central pathway for cells to monitor the decrease in oxygen concentration and maintain cellular function in hypoxia. PHD is recognized as one of the cellular oxygen sensors because it requires oxygen molecule for its enzymatic activity. Importantly, there is a large enzyme family named 2-oxoglutarate-dependent dioxygenase (2OGDD), which require O₂, Fe²⁺, 2-oxoglutarate as co-factors like PHD. In this review, we will overview how 2OGDDs operate, and what are their roles in pathological situation. We also discuss possible direction of how we can establish drugs to target 2OGDDs.

In recent years, the "translational gap" has become problematic in drug development, wherein promising results from animal experiments and in vitro tests fail to demonstrate the expected efficacy and safety in clinical trials. This translational gap has also impacted on the development of therapeutic agents for brain diseases, including Alzheimer's disease (AD). While microglia, which are immune cells in the brain, have gained attention as therapeutic targets of AD, the inter-species difference in microglia between humans and experimental model animals may cause this gap. To reveal the pathogenic mechanisms of AD and develop a therapeutic strategy, experimental models that appropriately reproduce pathological conditions using human-derived materials are required. Pluripotent stem cells can differentiate into various cells such as neurons and microglia. Therefore, it is expected that the creation of neural organoids from human pluripotent stem cells will enable the construction of a human-based analysis system that can reproduce three-dimensional brain structures and intercellular interactions, thereby overcoming the translational gap. Furthermore, combining patient-derived induced pluripotent stem cells and gene editing technology with neural organoid technology is leading to cutting-edge research. In this review, we introduce global research trends aimed at developing neural organoids containing microglia derived from human pluripotent stem cells and applying them to elucidate the pathogenesis and to develop therapeutic drugs for AD.