Owing to their ability to induce excitation of specific molecular orbitals or initiate chemical reactions, photochemical reactions have the potential to be more effective at selectively activating target molecules than thermal reactions. The thermal reactions transfer thermal energy to activate molecules, which often leads to the activation of multiple molecular species, including undesired ones, resulting in non-selectivity. This nonselectivity may result in undesirable side reactions or decrease reaction efficiency. Additionally, photochemical reactions can induce selective activation by absorbing specific wavelengths of light. However, visible light-driven photocatalytic reactions typically require expensive transition metal catalysts or organic dyes, leaving plenty of room for improvement. To address the aforementioned issues, the photochemical properties of the main group elements, such as halogens, were optimized and methodologies for visible light-induced reactions were developed. Activation of molecular halogen, halogen–carbon bonds, and halogen bonding interactions were independently investigated and various methodologies were reported. These developed reactions are excellent methodologies that use inexpensive raw materials and are thus predicted to contribute significantly toward sustainability.
The nuclear receptor superfamily comprises 48 members in humans. In various organs, nuclear receptors regulate a variety of physiological functions through transcription of target genes. They are associated with the development and progression of endocrine and metabolic disorders, as well as with cancer development. Therefore, agonists and antagonists targeting nuclear receptors are currently being developed as therapeutic drugs for these diseases. Nuclear receptors can be activated through ligand binding or phosphorylation, which is mediated by various cellular signaling pathways. Activation of a nuclear receptor necessitates significant structural modifications in each of its domains. My research has been focused on unraveling the intricate mechanisms underlying the activation of nuclear receptors using constitutive androstane receptor (CAR) and pregnane X receptor (PXR) as model nuclear receptor proteins. CAR and PXR are highly expressed in the liver and are activated by a wide range of xenobiotics. Given their crucial roles in the metabolism and disposition of xenobiotics, as well as their potential in mediating drug–drug interactions, it is imperative to extensively study the mechanisms of xenobiotic-induced activation of these receptors. Such studies are essential for advancements in drug development, as well as for ensuring food and chemical safety. In this review, I elucidate the molecular basis underlying the activation of xenobiotic-responsive nuclear receptors.
Complement (C) activation occurs via three pathways, namely the classical, lectin, and alternative pathways. Intercommunication occurs between the complement and coagulation systems, which can trigger tissue injury and inflammation. Disseminated intravascular coagulation (DIC) is a life-threatening disease characterized by disordered coagulation and systemic inflammation; here, the intercommunication between the complement and coagulation systems contributes to the development of DIC. Extracellular histones, which are contributors to the damage-associated molecular pattern, induce severe thrombosis. C5 is a key molecule in the intercommunication between the complement and coagulation systems and is associated with the development of lethal histone-induced thrombosis. Heparin and chondroitin sulfate (CS) are negatively charged, allowing them to bind to extracellular histones. As the coagulation system is less affected by CS than heparin, CS shows potential as an effective drug for the treatment of patients with DIC who have a high risk of bleeding. Complement receptor type-1-related gene Y (Crry) inhibits the complement pathway via binding to C3b and C4b. Hence, Crry is a potent inhibitor of the classical and alternative C pathways. The expression of Crry is decreased by the endothelial damage induced by extracellular histones. Crry dysfunction promotes the activation of C on the surface of endothelial cells. The prevention of C3 cleavage on endothelial cells might be a useful therapy targeting acute lung injury.
Ketamine, an N-methyl-D-aspartate receptor antagonist, elicits swift antidepressant effects even in subjects with treatment-resistant depression. Nonetheless, owing to the serious adverse effects associated with ketamine, including psychotomimetic effects, the development of safer rapid-acting antidepressants is imperative. The elucidation of the mechanisms underlying the antidepressant effects of ketamine will facilitate the advancement of these alternative treatments. Previous preclinical studies have indicated that the antidepressant properties of ketamine are mediated by the activity-dependent release of brain-derived neurotrophic factor (BDNF) and the subsequent activation of mechanistic target of rapamycin complex 1 (mTORC1) in the medial prefrontal cortex (mPFC). Our research has demonstrated that ketamine exerts antidepressant-like effects by inducing the release of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) in the mPFC. Furthermore, our recent findings have revealed that resolvins (RvD1, RvD2, RvE1, RvE2, and RvE3), which are bioactive lipid mediators derived from docosahexaenoic and eicosapentaenoic acids, exhibit antidepressant-like effects in rodent models. Notably, the antidepressant-like effects of RvD1, RvD2, and RvE1 require mTORC1 activation. Moreover, the intranasal administration of RvE1 elicits rapid antidepressant-like effects through the release of BDNF and VEGF in the mPFC and hippocampal dentate gyrus (DG), as well as mTORC1 activation in the mPFC, albeit not in the DG. These findings strongly suggest that resolvins, particularly RvD1, RvD2, and RvE1, hold promise as prospective candidates for novel, safer, and rapid-acting antidepressants.
Lipid-based formulations (LBFs) are isotropic mixtures typically comprising lipids, surfactants, and/or co-solvents, in which drugs are pre-solubilized. After oral administration, LBFs are piggybacked into endogenous lipid digestion pathways. This triggers drug super-saturation and improves absorption. However, super-saturation poses a risk of drug precipitation, which generally leads to poor drug absorption. Furthermore, a series of aqueous colloidal species including digestion products (typically fatty acids and monoglycerides) and endogenous molecules (bile acids and phospholipids) increase the drug solubilization capacity of the intestinal fluid (compared with that of the normal intestinal fluid). However, the solubilization/precipitation behavior may change according to the LBF composition (e.g., the drug loading amount and type of formulation excipients), which may ultimately lead to differences in oral absorption. This review summarizes the results of the evaluation and prediction of the effect of LBFs composition on oral absorption and provides an in-depth understanding of the drug absorption mechanisms when using LBFs.
Cellular aging is one of the most extraordinary phenomena that mammalian cells undergo in vivo and in vitro. We have been observing their behavior for approximately 4 decades and here would like to summarize some of our salient findings. Normal cells such as human diploid cells exhibit finite growth potential in vitro as well as a set of senescent cell phenotypes. Those changes appear probabilistic and irreversible. In the search of the factor(s) to evoke the features we have observed that cellular glycosaminoglycan molecules plays significant roles in the cell physiology. Besides, CCAAT-box binding transcription factor NF-Y relates to the aging-coupled changes in gene expression, and aging of gastric mucosal cells may relate to a decrease in cytoprotection. As to the intracellular signaling, we have confirmed that the breakdown of phosphatidylinositol bisphosphate is critical for mitogenesis by using micro-injection of its antibody. Subsequently, we have discovered a novel, pivotal adaptor protein Grb2/Ash, a missing link between the receptor tyrosine kinases and their downstream target Ras. The limiting factors for the cellular life span have been considered as telomere shortening and accumulation of cellular and genomic damages. We have observed that telomerase-expressing cells exhibit expanded division potential; yet oxidative stress similarly induces senescent cell phenotypes. Herein we have demonstrated that the treatment of senescent cells with nicotinamide or related reagents elicits unique cellular responses, which might indicate the capability of the cells to recover from the aging.
This review describes aging studies employing in vitro animal cell cultures, on which the author has been working for more than 40 years after pharmacist education and then cell biology researches. The author started observation and comparison as the cell undergoes aging, proceeded to analysis of cell surface components, and discovered novel adaptor proteins and intracellular signaling for the control of senescence. The presentation here would be appropriate introduction to the cellular aging for researchers with pharmaceutical or biological interest.
Most drug candidates developed in recent years are poorly water-soluble, which is a key challenge in pharmaceutical science. Various solubilization methods have been investigated thus far, most of which require solubilizers that provide a local hydrophobic environment wherein a drug can dissolve or induce interactions with drug molecules. We have focused on amphiphilic 2-methacryloyloxyethyl phosphoryl choline (MPC) polymers. In addition to the ease of molecular design of amphiphilic MPC polymers owing to their chemical structures, they have been reported to possess high biocompatibility in various biomaterial applications. Additionally, amphiphilic MPC polymers have been applied in the pharmaceutical field, especially in solubilization. We have qualitatively and quantitatively evaluated the effects of the chemical structure and physical properties of the solubilizer on the MPC polymers. In particular, MPC polymers with different chemical structures were designed and synthesized. The inner polarity and molecular mobility in the polymer aggregates were evaluated, indicating that the intrinsic properties reflect the chemical structure of the polymer. Additionally, amphiphilic MPC polymers were used to improve the solubility of poorly water-soluble drugs and as solid dispersion carriers, and they exhibited superior solubilizing abilities compared to a commonly used polymer. Furthermore, the solubility of biopharmaceuticals, such as peptides, was improved. It is possible to design and synthesize optimal structures based on the polarity of the hydrophobic environment and the intermolecular interaction with a drug. This research provides a unified interpretation of drugs and efficiently summarizes knowledge about drug development, which will facilitate the efficient and rapid development of drug formulations.
Cooperative care between hospitals and community pharmacies is important to safe and effective pharmacotherapy for outpatients. We developed a protocol comprising three agreements about alternative drugs and dosing schedules with the aim of minimizing inquiries about prescriptions to doctors. The protocol was implemented under an agreement between core hospitals in Gifu City and community pharmacy members of the Gifu City Pharmaceutical Association from October 2019. Here, we examined the impact of this protocol on patient waiting time in pharmacies. Before introduction of the protocol, median patient waiting time for questionable prescriptions requiring an inquiry to a doctor was significantly longer than that for prescriptions not requiring an inquiry (23.0 min vs. 10.0 min, p<0.001). After introduction of the protocol, median time for prescriptions which were questionable but nevertheless under the protocol did not require an inquiry to a doctor was significantly reduced compared with those which were questionable and still did require an inquiry (15.0 min vs. 24.0 min, p=0.038). In conclusion, introduction of a protocol aimed at minimizing inquiries about prescriptions to doctors from a community pharmacy was useful in reducing the waiting time of patients, and also likely in decreasing the working times of medical doctors and pharmacists.
The pharmacy pharmacist’s function as a family pharmacist is expected to improve adherence to medication in patients suffering from chronic diseases, including dyslipidemia. This is true even in infectious disease epidemics. In this study, using anonymously processed receipt data from 700 insurance pharmacies in our group, we evaluated medication adherence in patients taking statin drugs before, during the first and second years of coronavirus disease 2019 (COVID-19) epidemic in terms of medication persistence and medication possession, and compared the results between the family pharmacist group (FP group) and non-family pharmacist group (NoFP group). The odds ratios of good medication adherence (medication persistence and medication possession) rates for the FP group relative to the NoFP group were 1.446 [95% confidence interval (CI): 1.210–1.727] in the pre-epidemic period, 1.428 (1.192–1.710) in the first year of the epidemic, and 1.270 (1.113–1.450) in the second year of the epidemic. The FP group was significantly higher in all time periods. Therefore, it is suggested that the family pharmacist function improves adherence to statins not only before but also during the COVID-19 epidemic.