Brain-machine interfaces, also known as brain-computer interfaces, represent a rapidly advancing field at the intersection of neuroscience and technology, enabling direct communication pathways between the brain and external devices. This review charts the historical evolution of brain-machine interfaces, from fundamental discoveries such as electroencephalography and volitional single-neuron control to sophisticated decoding of neural population activity for real-time control of robotics and sensory reconstruction. Clinical breakthroughs lead to unprecedented success in restoring motor function after paralysis through brain-spine interfaces, enabling high-speed communication through thought-to-text/speech systems, providing sensory feedback for prosthetics, and implementing closed-loop neuromodulation for the treatment of neurological disorders such as epilepsy and depression. Beyond therapeutic applications, brain-machine interfaces drive innovation in neurotech art (neuroart) and entertainment (neurogames), allowing neural activity to directly generate music, visual art, and interactive experiences. In addition, the potential for human augmentation is expanding, with technologies that enhance physical strength, sensory perception, and cognitive abilities. These converging advances challenge fundamental concepts of human identity and suggest that brain-machine interfaces may enable humanity to transcend inherent biological limitations, potentially ushering in an era of technologically guided evolution.

One of the most significant conceptual changes brought about by the discovery of clock genes and development of circadian-clock mutant mice is the recognition that impaired circadian rhythmicity extends its impact far beyond sleep, driving pathogenesis of a wide variety of disorders such as cancer, obesity, and hypertension. However, despite this growing clinical evidence, chronobiology still lacks a coherent answer to the converse question: can restoration of circadian rhythms ameliorate—or even reverse—such diseases? In this review, three complementary pharmacological strategies—each still in preclinical development—are explored. First, direct modulation of the transcription-translation feedback loop (TTFL)—the core gene-regulatory circuit that generates 24-h rhythms in almost all nucleated cells—is reviewed as an approach to manipulation of cellular circadian biology. Second, the suprachiasmatic nucleus (SCN)-enriched G-protein-coupled receptor Gpr176 is highlighted as a central-clock target, given its ligand-independent, G_z-mediated control of cAMP signaling and demonstrated ability to reset the master pacemaker. Third, the concept of rhythmic enhancement of output function is introduced and exemplified by describing re-activation of circadian oxidized form of nicotinamide adenine dinucleotide (NAD⁺)-dependent 3β-hydroxy-steroid dehydrogenase (3β-HSD) activity in the meibomian gland—using nicotinamide mononucleotide (NMN)—to restore peripheral clock-driven steroidogenesis in this tissue, which leads to amelioration of meibomian gland dysfunction, a leading cause of dry eye disease. This review aims to highlight the molecular logic of each strategy; both mechanistic insights and safety/efficacy considerations are discussed.

Sphingosine kinase 1/2 (SphK1/2) promote the initiation and advancement of breast cancers. We performed screening on a compound library of SphK inhibitors using computer molecular docking and selected the most representative compound, ZFP-B34, for testing its antitumor activity in triple-negative breast cancer (TNBC). In TNBC cell lines ZFP-B34 effectively inhibits SphK1/2 activity, induces ceramide accumulation, and results in Sphingosine 1 phosphate (S1P) depletion without altering SphK1/2 expression in TNBC cells, making it a promising novel dual inhibitor of SphK1/2. ZFP-B34 effectively inhibits cell proliferation, cell cycle progression, and migration, leading to cellular growth arrest. ZFP-B34 induces reactive oxygen species (ROS) production and mitochondrial depolarization, leading to mitochondrial dysfunction. Simultaneously, it damages DNA, ultimately resulting in apoptosis. ZFP-B34 can also inhibit the activation of Akt-mammalian target of rapamycin (mTOR) while inducing c-Jun N-terminal kinase (JNK) activation in TNBC cells. In vivo, daily intraperitoneal injection of a single dose of ZFP-B34 effectively inhibits the growth of 4T1 allografts in mice. In conclusion, ZFP-B34 is capable of inhibiting SphK1/2 and delaying the growth of TNBC cells both in vitro and in vivo.

As of 2024, herpes zoster (HZ) vaccination for older adults was not included in Japan’s routine vaccination program. Two types of HZ vaccines are currently available at the individual’s expense. In this study, we surveyed program details for HZ vaccination in Japanese municipalities. We further explored the subsidy amount and the percentage of newly vaccinated individuals among target populations who were vaccinated by local governments under the subsidy. In June 2023, we mailed the questionnaire to 56 municipalities about HZ vaccine subsidy programs in fiscal year 2022. Information on the details of the subsidy program and the number of subsidies provided in each municipality was summarized. Fifty responses were collected from 56 municipalities (response rate: 89.3%). Across the 49 municipalities, 2 types of vaccines were subsidized in 39. The program’s subsidy amount differed by vaccine type. The median subsidy amount, including the estimated amount for the freeze-dried live-attenuated varicella zoster vaccine, was JPY 4000 (USD 32), and for the recombinant zoster vaccine, it was JPY 20000 (USD 159). The average percentage of those who were vaccinated under the subsidy program in fiscal year 2022 was 2.97%. The diffusion of the local subsidy policy for the vaccination of older adults against HZ occurred in fiscal year 2022 in Japan. A higher subsidy amount may have driven the choice for the recombinant zoster vaccine (RZV), and in the 1st year of the program, individuals who proactively sought vaccination may have been vaccinated.

Allergy immunotherapy (AIT) plays a pivotal role in the treatment of type I allergic conditions such as allergic rhinitis and rhinoconjunctivitis. However, AIT faces persistent issues, notably the risk of anaphylaxis and the need for long-term treatment. To address these issues, various strategies have been explored, including the use of adjuvants, allergen delivery systems, and allergen modifications. This study used a prophylactic mouse model of allergic sensitization to explore the potential for improving the efficacy and safety of Japanese cedar pollen (JCP) subcutaneous immunotherapy (SCIT). In this model, JCP extract was combined with an adjuvant (K3 CpG oligodeoxynucleotide [CpG-ODN]) and/or a delivery system (dilauroyl phosphatidylcholine/deoxycholic acid [DLPC/DA] micelles) for subcutaneous immunization of naïve mice. Compared to immunization with JCP alone, the combination of JCP with K3 CpG-ODN and DLPC/DA micelles resulted in a general reduction of the JCP-induced T-helper 2 (Th2) immune response, including reduced airway inflammation and allergen-specific plasma immunoglobulin E. In addition, Th1 markers were either largely unaffected (interferon-γ) or markedly increased (allergen-specific plasma IgG2a). These immunological changes coincided with reduced sneezing frequency in response to allergen exposure. For most parameters, a synergistic effect was observed when both K3 CpG-ODN and DLPC/DA micelles were combined with JCP at the time of immunization. In conclusion, the data presented here indicate that the combination of JCP, K3 CpG-ODN, and DLPC/DA micelles is a promising candidate for the development of a more effective SCIT treatment for Japanese cedar pollinosis, which may include a shorter treatment regimen and reduced risk of anaphylactic reactions.

Caco-2 cells, derived from colorectal cancer cells, are generally used to evaluate drug absorption in the gastrointestinal tract. However, differences between Caco-2 and normal intestinal cells have been observed. Cells cultured directly from crypts are maintained in their biological state. Therefore, we developed a rapid and easy method of monolayer culture of epithelial cells isolated from the jejunum of mice. We analyzed the usefulness of the jejunal epithelial cell monolayer culture system as a research tool and evaluated changes in the transport activity and mRNA expression of transporters. We focused on P-glycoprotein (P-gp) and peptide transporter 1 (Pept1) as representative transporters expressed in the small intestine. A P-gp inhibitor significantly enhanced the accumulation of Rhodamine 123 (Rho123), a substrate of P-gp, indicating that the transport activity of P-gp could be evaluated. Uptake of glycylsarcosine, a Pept1 substrate, significantly decreased in the presence of the Pept1 inhibitor, indicating that the transport activity of Pept1 could be evaluated. Rho123 accumulation significantly decreased in the group treated with calcitriol, an inducer of P-gp and Cyp3a11, suggesting that changes in P-gp expression could be evaluated. Furthermore, we examined whether mRNA expression levels of transporters and drug-metabolizing enzyme were altered. In the calcitriol-supplemented group, P-gp and Cyp3a11 mRNA levels significantly increased. However, no significant differences were observed in Pept1 mRNA levels. Overall, the jejunal epithelial cell monolayer culture system developed from intestinal tissues is a useful research tool for assessing the transport activities and expression variabilities of transporters.

Ferulic acid (FA), a hydroxycinnamic acid derivative abundantly present in the cell walls of cereal brans such as rice bran, has recently been suggested to suppress detrusor overactivity when administered orally. However, to the best of our knowledge, its direct inhibitory effects on urinary bladder smooth muscle (UBSM) contractions have not been investigated to date. In this study, we investigated the effects of FA on guinea pig UBSM contractions induced by two physiologically and pathophysiologically relevant agonists—acetylcholine (ACh, 10 µM) and platelet-activating factor (PAF, 1 µM)—and explored the underlying mechanisms. FA (0.3–3 mM) inhibited both ACh- and PAF-induced contractions in a concentration-dependent manner, with near-complete inhibition observed at 3 mM. These contractions were also nearly completely inhibited by diltiazem (10 µM), a selective L-type Ca²⁺ channel (LCC) blocker. FA similarly suppressed KCl-induced contractions in a concentration-dependent manner, which were almost completely abolished by diltiazem. The extent of inhibition by FA and diltiazem was generally consistent across all three stimuli. The calculated pIC₅₀ values of FA for the three types of contractions were approximately 3 (2.91 for ACh, 3.22 for PAF, and 3.05 for KCl). These findings indicate that FA strongly and non-selectively inhibits UBSM contractions induced by both physiological and pathophysiological stimuli, likely through blockade of LCCs and/or associated intracellular signaling pathways.

Statins were initially developed as lipid-lowering agents to reduce the risk of cardiovascular and cerebrovascular diseases. Recently, their anti-tumor effects have gained attention in the context of drug repositioning. However, most in vitro studies have been conducted under normoxic conditions, and limited research has examined their effects under hypoxia. Since hypoxia plays a crucial role in the tumor microenvironment by promoting cancer cell proliferation, epithelial–mesenchymal transition, invasion, metastasis, and drug resistance, evaluating the anti-tumor effects of statins under hypoxic conditions is essential. Additionally, previous in vitro studies have used statin concentrations substantially higher than those observed in the serum during hyperlipidemia treatment, raising concerns about their clinical applicability as anti-tumor agents. Here, we demonstrate that a clinically relevant concentration of atorvastatin (0.1 μM) inhibits the migration and invasion of the statin-sensitive non-small cell lung cancer (NSCLC) cell line HOP-92 under hypoxic conditions, without inducing drug resistance. Furthermore, atorvastatin (0.1–1 μM) reduced the expression of hypoxia-inducible factor-1α (HIF-1α) in the statin-resistant NSCLC cell line NCI-H322M, even though it did not inhibit cell proliferation. Since cancer cell migration and invasion are key processes in distant metastasis, and HIF-1α is a critical transcription factor that regulates metastasis, these findings suggest that statins could be repurposed as anti-metastatic agents for NSCLC, particularly under hypoxic conditions.

Vascular endothelial cells (VECs) and lymphatic endothelial cells (LECs) regulate the homeostasis of fluids, nutrients, and immune cells in the blood and lymphatic systems, respectively. These specialized functions depend on distinct cell-surface proteins and tightly regulated endocytic pathways, but the molecular determinants underlying the cell-type-specific endocytic profiles of these cells remain unclear. We sought to quantitatively characterize and compare the endocytic cell-surface proteomes of human umbilical vein endothelial cells (HUVECs) and human dermal LECs (HDLECs) using cell-surface biotinylation and internalization assays combined with sequential window acquisition of all theoretical fragment ion spectra-MS–based quantitative proteomics. HUVECs and HDLECs had a similar number of cell-surface and internalized proteins, with substantial overlap, but also included sets unique to each cell type. We identified 32 HUVEC- and HDLEC-enriched endocytic cell-surface proteins, respectively; these proteins were present in both enriched cell-surface and internalized fractions, representing cell-type-selective endocytic proteins. Functional enrichment analysis showed that HUVEC-enriched proteins were associated with angiogenesis, nutrient uptake, and metabolism, whereas HDLEC-enriched proteins were linked to immune regulation, extracellular matrix organization, and lymphangiogenesis. In conclusion, our present study demonstrates that VECs and LECs possess distinct endocytic cell-surface protein profiles that define their specialized functions and represent promising targets for endothelial-selective drug delivery and imaging.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are clinically used to control hyperglycemia and body weight in patients with type 2 diabetes mellitus and obesity. Despite their efficacy, GLP-1 RAs frequently induce nausea and vomiting as adverse effects, which are prominent factors for non-adherence to GLP-1 RAs. Therefore, new prophylaxes and treatments for GLP-1 RA-induced nausea are urgently needed. Here, we explored the U. S. Food and Drug Administration (FDA) Adverse Event Reporting System database to determine the effective drug combinations mitigating GLP-1 RA-induced nausea and vomiting in real-world settings. We further investigated the effects of the identified drugs on GLP-1 RA-induced pica behavior, a behavioral index of nausea in mice. Analysis of the FDA Adverse Event Reporting System revealed that therapeutics, including gabapentin and acetaminophen, significantly lowered the occurrence of nausea-related events in GLP-1 RA-treated patients. In mice, we confirmed that exenatide, a GLP-1 RA, significantly increased the pica behavior in a dose-dependent manner, without affecting the food intake. Finally, we found that co-treatment with gabapentin significantly decreased the pica behavior induced by exenatide. These results demonstrate the therapeutic efficacy of gabapentin against nausea and vomiting in patients administered GLP-1 RAs.

In recent years, multinational clinical trials (MCTs) have become a cornerstone of drug development. MCTs involve the participation of multiple regions in a single trial, with regulatory submissions based on the same trial results across all participating regions. While it is generally assumed that approved doses will align across regions, few studies have specifically analyzed the differences in approved doses between Japan and the U.S. in recent years. MCTs have been shown to reduce drug approval timing differences (drug lag) between Japan and the U.S. in certain therapeutic areas. However, data on drug lag for recently developed drugs remain limited. This study investigates differences in approved doses and drug lag between Japan and the U.S. for drugs approved in Japan between 2012 and 2021. The study analyzed 579 drugs with comparable dose information in Japan and the U.S., and confirmed that MCTs play a role in minimizing dose differences between Japan and the U.S. Additionally, the study confirmed that drug development through MCTs significantly shortens drug lag in these drugs, similar to previous studies with different target drugs. Overall, the findings highlight that drug development through international clinical trials not only reduces drug lag but also minimizes differences in approved doses between Japan and the U.S.

In this study, we investigated guanidinylated chitosan (GCS), a chemically modified derivative of unmodified low-molecular-weight chitosan (CS), as a multifunctional excipient to enhance the solubility and absorption of poorly water-soluble drugs. Flurbiprofen (FP) was selected as a model drug to compare the performance of kneaded dispersions GCS-based (FP-GCS) and CS-based (FP-CS). Both GCS and CS increased the solubility of FP in a concentration-dependent manner, with no significant differences between them. However, dissolution testing showed that FP-GCS kneaded dispersion significantly enhanced the dissolution rate of FP alone in water and simulated gastric fluid (pH 1.2), but not under simulated intestinal conditions (pH 6.8). In vivo pharmacokinetic studies in rats demonstrated that FP-GCS kneaded dispersion achieved the highest plasma concentration of FP, suggesting enhanced gastrointestinal permeability. Moreover, FP-GCS kneaded dispersion markedly reduced gastric ulceration in a rat ulcer model. These results indicate that GCS is an effective oral drug delivery excipient capable of improving both the bioavailability and gastrointestinal safety of FP.

Cancer is an age-related disease that affects one in two Japanese individuals, placing a significant burden on both patients and caregivers due to its clinical characteristics, high treatment costs, and associated adverse events (AEs). Consequently, cancer treatment remains a major public concern. In recent years, patient-centered medical care has gained increasing attention and is strongly desired in cancer treatment. Companion diagnostics (CDx) are expected to facilitate personalized treatment; however, their current status remains unclear. In this study, we evaluated the role of CDx in anticancer drug treatment based on data available at the time of drug approval. Our analysis revealed that the benefit–risk ratio, defined as the objective response rate of an anticancer drug divided by the incidence of severe AEs, was significantly higher for anticancer drugs requiring CDx (wCDx) in Japanese patients (1.54-fold, p < 0.0135) than for anticancer drugs not requiring CDx. Although the objective response rate did not differ between the 2 groups, the incidence of severe AEs was lower in the wCDx group. These findings suggest that CDx helps identify patients who are better suited for specific anticancer treatments and/or that active pharmaceutical ingredients in wCDx therapies carry a lower risk of severe AEs. To further promote patient-centered medical care, the active development of CDx alongside new anticancer drugs should be encouraged, despite the higher development hurdles, through regulatory support, particularly since drug pricing does not differ between the 2 groups.

Pigmentation is one of the most prominent side effects caused by anticancer drugs, especially in female patients, as these changes in appearance can decrease QOL. A typical drug causing such pigmentation is 5-fluorouracil (5-FU); we have previously shown that 5-FU-induced pigmentation is associated with increased adrenocorticotropic hormone (ACTH) and reactive oxygen species (ROS) levels. In male Hos:HRM-2 mice, 5-FU administration resulted in pigmentation appearing in the genital area, accompanied by elevations in neutrophils, ACTH, and ROS. By contrast, female mice showed increases in neutrophils and noradrenaline, but not in ACTH or ROS levels; furthermore, they did not develop pigmentation. In addition, estradiol levels were markedly decreased in female mice, which may have enhanced neutrophil apoptosis and suppressed ROS production. In addition, noradrenaline reflects the stress response and may contribute to the decrease in estradiol, suggesting the hypothalamus–pituitary–adrenal axis and sex hormones may interact in the formation of sex differences. These results suggest that sex differences exist in the development of 5-FU-induced hyperpigmentation and that fluctuations in estradiol and associated changes in neutrophils, ROS, and ACTH may underlie this phenomenon.

Cell transplantation therapy is a promising new treatment for myocardial infarction and heart failure. Developing methods to promote the engraftment of cardiac stem cells into cardiac tissue and their differentiation into cardiac cells is a strategy for improving the efficacy of cell transplantation therapy. Tanshinone VI (TanVI), a component extracted from the roots of Salvia miltiorrhiza Bunge (Labiatae), is a possible pharmacological agent for ischemic heart disease. However, since the effects of TanVI on the differentiation of cardiac stem cells remain unclear, we examined the effects of TanVI on the cardiac differentiation potential of cardiac stem cells. Cardiosphere-derived cells (CDCs), the cardiac stem/progenitor cells, were prepared from adult rat hearts. After CDCs were cultured in the presence of TanVI, cell numbers, expression of cardiomyocyte markers, and intracellular signaling protein levels involved in the differentiation into cardiomyocytes were measured. Treatment of CDCs with TanVI inhibited the increase in cell numbers and induced their expression of cardiomyocyte marker proteins. TanVI treatment also inhibited the Akt/glycogen synthase kinase 3β (GSK3β)/β-catenin and c-Raf/MEK1/2/extracellular signal-regulated kinase 1/2 (ERK1/2) pathways. We found that TanVI promotes cardiac differentiation of CDCs. Our findings also suggest that inhibition of the Akt/GSK3β/β-catenin pathway and the c-Raf/MEK1/2/ERK1/2 pathway may contribute to the differentiation from CDCs to cardiomyocytes. TanVI may play an adjunctive role in cardiac stem cell transplantation therapy.

The broad-spectrum antifungal agent voriconazole elicits different responses. Polymorphisms in cytochrome P450 (P450) 2C19 may partially explain this variability. This study generated virtual plasma/hepatic exposures to voriconazole in Japanese P450 2C19 poor metabolizers using both simplified and population-based full physiologically based pharmacokinetic (PBPK) modeling systems. The input parameters for the simplified PBPK model were based on the reported plasma concentrations for a 200-mg dose of voriconazole; the predicted concentrations in extensive metabolizers were in good accordance with the reported data. For poor metabolizers, the in vivo hepatic intrinsic clearance was reduced to 14.5 from 39.1 L/h; the plasma concentrations for poor metabolizers generated by the simplified PBPK model were consistent with reported values. The virtual maximum plasma/hepatic concentrations of voriconazole and the areas under the concentration–time curves in extensive and poor metabolizers were generated using the simplified and full PBPK models; the results of the two models were in good agreement. High hepatic exposure to voriconazole was predicted in poor metabolizers. This finding could be related to liver disorders, e.g., to adverse events seen in the Japanese Adverse Drug Event Report database. These results suggest that virtual plasma/hepatic exposures to voriconazole in P450 2C19 poor metabolizers can be evaluated using either simplified or full PBPK modeling systems. A half-dose of voriconazole is recommended in many countries worldwide for P450 2C19 poor metabolizer patients; despite the limited references to P450 2C19 polymorphisms in current Japanese drug labeling, the in silico information provided here could be clinically informative.

Stress granules (SGs) are non-membranous biomolecular condensates formed through liquid–liquid phase separation (LLPS) of RNA-binding proteins (RBPs) and RNA under stress conditions. T-cell intracellular antigen-1 (TIA-1), a major RBP of SGs, can undergo LLPS via its low-complexity domain, contributing to SG nucleation. Integrated stress response inhibitor (ISRIB), a small molecule that enhances eIF2B activity and inhibits the integrated stress response, has been widely studied for its therapeutic potential in neurodegenerative diseases. However, little is known about how ISRIB directly affects the behavior of SG proteins. Here, we show that ISRIB enhances TIA-1 phase separation and promotes its aggregation in vitro. Interestingly, this effect was mitigated in the presence of RNA or cell lysates, suggesting that RNA-binding plays a protective role against ISRIB-induced aggregation. These findings imply that ISRIB alters the physical properties of SGs in an RNA-dependent manner, raising important considerations for their therapeutic application.