Folia Pharmacologica Japonica最新文献

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. Its pathological features include abnormal aggregation of amyloid-β (Aβ) and tau proteins, neuronal loss, and brain atrophy. The "amyloid hypothesis" suggests that Aβ accumulation triggers disease progression, leading to the development of anti-Aβ antibody therapies. However, their effectiveness is limited once dementia has developed, highlighting the need for early intervention in the preclinical stage. This review focuses on type 2 diabetes (T2D) and insulin resistance as acquired risk factors for AD, summarizing epidemiological and experimental evidence on their impact on AD neuropathology. While early postmortem studies produced inconsistent results regarding the association between T2D, insulin resistance, and Aβ deposition, recent amyloid PET imaging studies have clarified this relationship in the human brain. Additionally, animal studies suggest that diet-induced insulin resistance promotes Aβ accumulation. Conversely, genetic disruption of insulin signaling molecules significantly suppresses Aβ pathology. These seemingly contradictory findings suggest that while reduced brain insulin signaling may inhibit Aβ pathology, peripheral metabolic disturbances associated with worsening insulin resistance may accelerate Aβ deposition. Understanding the multifaceted roles of insulin signaling and the molecular basis of these complex interactions is crucial for identifying new preventive and disease-modifying therapeutic targets. Advancing this knowledge is essential for developing innovative AD treatments.

The global surge in antimicrobial resistance (AMR) highlights the critical need for the development of innovative therapies and the appropriate use of antimicrobial agents. Our research focused on preventing, managing, and mitigating the adverse effects of treatments for infection with methicillin-resistant Staphylococcus aureus. In this review, we present our investigations utilizing medical big data. The first study aimed to elucidate the relationship between renal outcome and survival following the onset of vancomycin-associated nephrotoxicity (VAN). An initial analysis using the US Food and Drug Administration Adverse Events Reporting System (FAERS) database revealed elevated mortality rates among patients with VAN compared with those without VAN, forming the basis for further investigation. A subsequent, more rigorous, retrospective analysis using electronic medical records confirmed that poor survival outcomes were significantly associated with non-recovery from VAN, particularly when progression to acute kidney injury of stage ≥2 occurred. Therefore, preventing progression to severe VAN is critical for enhancing survival outcomes. The second study investigated the relationship between statin use and daptomycin-related musculoskeletal adverse events. By employing a mixed-method approach combining meta-analysis with disproportionality analysis of the FAERS data, a significant association between statin therapy and daptomycin-related rhabdomyolysis was identified. This highlights the importance of cautious statin and daptomycin use, with careful consideration of potential safety risks. Each medical big-data database possesses unique characteristics that require careful consideration during analysis. The accurate interpretation of medical big data, coupled with its integration with complementary methodologies, will produce more robust and reliable research outcomes across diverse fields.

Glaucoma is an age-related neurodegenerative disease and the leading cause of blindness, but currently no fundamental treatment has been present. The main treatment is to reduce intraocular pressure, which is expected to delay the progression of the disease. However, there are many glaucoma patients for whom progression cannot be controlled by lowering intraocular pressure alone, and the development of a fundamental treatment is required. Meanwhile, the clinical application of gene therapy is increasing worldwide. Various gene therapy vectors are still being developed, and technological change is much faster in this field. Gene therapy has already been clinically applied to several neurodegenerative diseases, but gene therapy for glaucoma has not yet been established. Our group is investigating the development of a new treatment for glaucoma by gene therapy using neurotrophic factor signaling. And we aim not only to suppress disease progression by neuroprotection, but also to recover the visual function by axonal regeneration.

Danicopan (brand name: Voydeya^® tablets) is a new oral small molecule complement factor D inhibitor that was approved in Japan in January 2024 for paroxysmal nocturnal hemoglobinuria (PNH). PNH is a rare, chronic hematologic disorder caused by acquired mutations of hematopoietic stem cells in the PIGA gene. These mutations cause deficiencies in complement regulatory proteins CD55 and CD59 that may lead to uncontrolled terminal complement activation, intravascular hemolysis, thrombosis, and premature mortality. Complement C5 inhibitors (C5i; eculizumab and ravulizumab) are the current standard of care of PNH treatment, and control intravascular hemolysis (IVH) by inhibiting terminal complement pathway activation. However, extravascular hemolysis (EVH) with persistent symptoms, such as anemia, occurs in some C5i-treated patients with PNH. EVH is caused by the accumulation of proximal complement C3 fragment on the membrane of surviving PNH-type red blood cells. These cells subsequently undergo phagocytosis in the spleen or liver. Danicopan was developed to control EVH by targeting complement factor D involved in alternative pathway activation. Preclinical studies showed that danicopan selectively inhibits alternative complement pathway activation by reversibly binding to factor D and inhibiting its serine protease activity. A global phase III study (ALPHA study: ALXN2040-PNH-301 [NCT04469465]) investigated danicopan as add-on therapy to ravulizumab or eculizumab in patients with PNH and clinically significant EVH. Danicopan achieved statistically significant, clinically meaningful increases in hemoglobin levels, reduced transfusion, and reduced fatigue, while maintaining control of IVH. No new safety concerns were observed. Danicopan makes it possible to control EVH while controlling IVH with C5i.

Allergen-specific immunotherapy (AIT) has been a longstanding treatment for allergic diseases. Historically, subcutaneous immunotherapy was the main approach, but with the development of sublingual preparations, which are associated with fewer systemic side effects, sublingual immunotherapy is gaining global popularity. In Japan, the approval of standardized sublingual immunotherapy preparations in 2014 has significantly accelerated its adoption. The mechanism of allergic inflammation is divided into sensitization and elicitation phases. The sensitization phase involves the production of antigen-specific IgE antibodies against a particular antigen. These IgE antibodies bind to FcεRI on mast cells and basophils, preparing the body for an allergic response. The elicitation phase occurs when the body, already primed with these antibodies, is re-exposed to the same antigen, triggering inflammation and symptoms. This phase includes mechanisms where IgE-mediated mast cell activation leads to degranulation and where local Th2 cell activation induces inflammation. While the mechanisms of AIT are not fully understood, they are categorized into desensitization and immune tolerance. Desensitization is induced by reducing the responsiveness of mast cells and basophils to the antigen. Immune tolerance involves the production of antigen-specific IgG4 antibodies that compete with IgE for antigen binding, and the induction of regulatory T cells and other anti-inflammatory immune cells producing cytokines such as IL-10. AIT still faces challenges, such as the lack of predictive biomarkers for efficacy. Recent studies indicate that HLA genotypes influence AIT responsiveness. Advances in genetic and single-cell analysis are expected to address these challenges, paving the way for improved treatment outcomes.

Itch is an unpleasant sense to evoke desire to scratch skin. Itch not only disturbs daily lives, but also exacerbates inflammation in case of atopic dermatitis (AD). It had been thought that both itch and pain are transduced by the same neurons; however, it is now known that neutrons transducing either itch or pain are distinct. Moreover, TRP channels, a family of calcium channels, play an important role for transducing itch as well as pain, temperature, and pressure. Development of neuroscience and molecular biology has dramatically advanced our understanding of how itch is transduced in recent years. On the other hand, development of immunology has revealed that there exist several immune types in our host defense mechanism and that type 2 immune reaction is dominant in the pathogenesis of allergic diseases including AD. Although it had been already known that type 2 cytokines contribute to the pathogenesis of AD by binding to their receptors on both immune cells and tissue resident cells, it has been recently found that several type 2 cytokines directly transduce the itch signals by binding to peripheral nerves. Due to this discovery, we can understand more deeply the itch mechanism of AD and can develop molecularly targeted drugs for AD targeting type 2 cytokines, which has dramatically changed the treatment of AD. In this review article, we describe the progress of our recent understanding of the itch mechanism and the strategy of treatment against it.

The ocular tissue is one of the most densely populated tissues in the body with extremely small blood vessels, and vascular lesions have been reported to be a factor in vision loss and visual field defects in many ocular diseases. Currently, vascular endothelial growth factor (VEGF)-targeted agents are the first line of treatment for intraocular vascular lesions, however, there are some cases in which they are not fully effective. Therefore, we explored pathogenic molecules other than VEGF, aiming to develop new molecular-targeted therapy. Using an experimental pathological model mimicking intraocular vascular lesions, we found that B-cell CLL/lymphoma 6 member B protein (BCL6B), which has been identified as a Bric-a-brac, Tramtrack, and Broad Complex protein, may play an important role in intraocular angiogenesis and vascular hyperpermeability. In this article, we introduce the usefulness of suppressing BCL6B expression and discuss the possibility of drug discovery by targeting Notch signaling in chorioretinal vascular lesions.