Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan最新文献

Human liver organoids are expected to be a hepatocyte source for preclinical in vitro studies of drug metabolism and disposition. Although these organoids show long-term proliferation, their hepatic functions remain low. Therefore, it is necessary to enhance the hepatic functions of primary human hepatocyte (PHH)-derived organoids. Here, we propose a novel method for two dimensional (2D)-cultured hepatic differentiation from PHH-derived organoids. PHH-derived organoids were established from cryopreserved PHHs. When cultured under a 2D condition, the single cells from PHH-derived organoids were seeded on collagen type I-coated plates. Then, optimal conditions for hepatic differentiation were screened using several compounds, cytokines and growth factors. Based on the results of the screening, we determined the 2D-cultured hepatic differentiation method from PHH-derived organoids. Hepatic gene expressions in PHH-derived organoids-derived hepatocytes (Org-HEPs) were greatly increased, compared to those in PHH-derived organoids. An RNA-seq analysis showed that gene expressions related to pharmacokinetics were upregulated in Org-HEPs compared to PHH-derived organoids. The metabolic activities of CYP1A2, CYP2C8, CYP2E1 and CYP3A4 were at levels comparable to those in PHHs. We also treated Org-HEPs and PHHs with hepatotoxic drugs, such as acetaminophen, troglitazone, amiodarone and clozapine. The cell viability of Org-HEPs was almost the same as that of PHHs. These results suggested that PHH-derived organoids could be differentiated into highly functional hepatocytes in 2D culture, and Org-HEPs could be used for hepatotoxicity tests. Thus, Org-HEPs will be useful for pharmaceutical research.

The Ser/Thr-specific kinase, polo-like kinase 1 (Plk1), is a crucial eukaryotic cell cycle regulatory protein. Overexpression of this kinase is observed in many cancer cells and where it can be related to their aggressiveness. Dysfunction of Plk1 in cancer cells causes mitotic arrest and subsequent apoptosis. Accordingly, Plk1 is considered as a target for the development of anti-cancer agents. Plk1 has two domains, a catalytic kinase domain (KD) and a polo-box domain (PBD). PBD intramolecularly interacts with its KD and regulates Plk1 activity and localization. Therefore, in addition to the KD, the PBD is considered to be a potential drug target. We have been developing peptidic low-nanomolar-affinity PBD-binding inhibitors. However, these peptides do not show significant cytotoxicity, due to their low cell membrane permeability. To obtain cell-active Plk1 inhibitors, I applied a bivalent approach designed to simultaneously engage both KD and PBD regions of Plk1 for enhancing the potency, selectivity and lipophilicity. Here, I developed bivalent Plk1 inhibitors, in which the PBD-binding peptides are conjugated with the known KD-binding inhibitors BI2536 or wortmannin using PEG linkers. These bivalent inhibitors exhibit up to 100-fold enhanced Plk1 affinity relative to the best monovalent PBD-binding ligands, higher selectivity for tested kinases compared to BI2536, and significant cytotoxicity against HeLa cells.

In cancer drug therapy involving anti-epidermal growth factor receptor (EGFR) antibody drugs, skin disorders such as acneiform rash are frequently observed and often progress to severe forms, resulting in treatment discontinuation. The severity of these skin disorders has been reported to correlate with therapeutic efficacy. Therefore, appropriate management is essential to avoid interruption of treatment due to severe dermatological toxicity. Identifying patients at risk of developing serious skin disorders at the start of anti-EGFR antibody drug therapy is necessary to enable prophylactic or early intervention. However, risk factors for skin disorders induced by anti-EGFR antibody drugs remain poorly understood, and predicting the severity of these conditions is challenging. This review highlights findings from retrospective and prospective observational studies conducted to predict the severity of skin disorders associated with anti-EGFR antibody drugs.

The primary aim of this study is to examine whether the appearance of pharmacists in Japan is an issue worthy of discussion. A web-based survey was conducted in June 2023 among 500 men and women aged 25-74 (male/female ratio=1 : 1, equally assigned to five age categories). The respondents were asked about their trust in eight pictures of male pharmacists with different appearance factors (trust scale: seven questions, 6-point response). The pictures were combined using an orthogonal table for five factors (hair color (black and brown), hair length (normal and long), accessories, white coat condition (clean and dirty), and clothing under white coat (Y shirt+tie, Y shirt+T-shirt)). The data were analyzed through conjoint analysis. The median age of the 500 respondents was 50.5 (38-62) years. The highest mean confidence score for each of the eight images was 28.8(SD6.4) and the lowest was 16.1 (SD7.1). Conjoint analysis indicated that the relative importance of clothing and hair to trustworthiness was 50.9% and 33.8%, respectively. The condition of the white coat was high at 29.1%. The level utilities scores were 0.341 for "Y-shirt" and -0.008 for "Y-shirt+tie" for clothing under the white coat. Notably, cleanliness of the white coat had a greater impact than hair color or length. The results indicate that the appearance of male pharmacists significantly affects initial trust. Thus, appearance standards for pharmacists, including females, should be actively discussed.

The work of pharmacists has shifted from object-centered based on dispensing to interpersonal work with a high degree of patient and local-resident interactions, while society has come to require advanced clinical practice skills. To cultivate clinical practice skills, improving themselves as a medical professional and enhancing their problem-solving skills is important, so graduation research is thought to play a major role. This paper introduces the daily laboratory activities of the Laboratory of Promotion of Pharmaceutical Education, with which I am affiliated. At one point, I realized that I was intervening too much in my graduation research guidance to students, which led me to drastically change my guidance methods. I engage with the students in dialog as we conduct the graduation research together, and I believe that trusting the students, entrusting them with the core of the research activities, and increasing their independence in the graduation research helps foster their scientific inquisitiveness.

In recent years, the number of people suffering from lifestyle diseases such as hyperlipidemia and fatty liver disease has increased rapidly due to westernization of dietary patterns. Among fatty liver diseases, those that are not caused by alcohol are referred to as nonalcoholic fatty liver disease (NAFLD). Some NAFLD can progress to nonalcoholic steatohepatitis (NASH), and further progression of NAFLD can lead to cirrhosis and liver cancer. Although numerous studies have demonstrated the efficacy of dietary polyunsaturated fatty acids (PUFAs), particularly omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), against NAFLD, the detailed mechanisms by which these PUFAs exert their protective effects on the pathogenesis and progression of NAFLD are not well understood. Recent studies using knockout mouse models and genome-wide association studies have suggested a potential role for the enzymes responsible for the biosynthesis of PUFAs (FADS1, FADS2, ELOVL2, and ELOVL5) and their incorporation into phospholipids (LPCAT3/MBOAT5/LPLAT12 and LPIAT1/MBOAT7/LPLAT11) in the development of NAFLD. In this review, we summarize recent findings on the association of NAFLD and PUFAs with a focus on PUFA biosynthetic and metabolic enzymes to discuss the potential role of PUFAs in the prevention of NAFLD.

The incidence of type 2 diabetes mellitus (T2DM), a major lifestyle-related disease, is increasing worldwide. T2DM, which accounts for approximately 90-95% of all diabetes mellitus cases, is caused by deficient insulin secretion, tissue insulin resistance, or both. Many therapeutic drugs for T2DM have been developed that target the pancreas, which secretes insulin. The liver is the central organ for glucose and lipid metabolism, and failure of hepatic regulatory mechanisms leads to hyperglycemia, insulin resistance, and lipid accumulation. Here, we focused on the liver as a novel therapeutic target for T2DM. The fatty acid composition of phospholipids, a major component of biological membranes, has received considerable research attention owing to their involvement in T2DM onset and progression. Fatty acids in phospholipids are cleaved by phospholipase A to form lysophospholipids, which are subsequently remodeled back into phospholipids by lysophospholipid acyltransferases (LPLATs). LPLATs play an important role in lipid metabolism and homeostasis by regulating the abundance of various phospholipid species in multiple cell and tissue types. We investigated whether overexpression of LPLAT10, also called LPCAT4 and LPEAT2, in the liver could improve abnormalities in glucose metabolism and help treat T2DM. For overexpression, we generated an LPLAT10-expressing adenovirus (Ad) vector using an improved Ad vector named Ad-E4-122aT, which exhibited higher and longer-term transgene expression and lower hepatotoxicity than conventional Ad vectors. In this article, we review the current findings that changes in hepatic phospholipid species due to liver-specific LPLAT10 overexpression affect the pancreas and suppress postprandial hyperglycemia by increasing postprandial insulin secretion.

The placenta, which acts as an interface between fetal and maternal circulations, is an indispensable organ for fetal growth in mammalian pregnancy. It mediates the transportation of nutrients, the exchange of gases such as oxygen and carbon dioxide, and the excretion of waste products between the fetus and mother. The surface of placental villi is covered by two layers of mononuclear undifferentiated cytotrophoblasts (CT) and multinucleated syncytiotrophoblasts (ST). The formation of the multinucleated ST layer via fusion of CT is referred to as syncytialization, which is a well-characterized morphological sign of terminal differentiation. STs function not only as the placental barrier to separate maternal blood from fetal tissue but also as the main source of human chorionic gonadotropin (hCG) and progesterone (P4) during pregnancy. The significance of appropriate differentiation and fusion of CTs to form STs is demonstrated by the finding that disturbance of these processes is linked to the pathogenesis of pregnancy-associated complications such as hypertensive disorders of pregnancy (HDP) and fetal growth restriction (FGR). In this review, we focused on trophoblast differentiation, cell fusion and microvilli formation, and showed the role of short-chain fatty acid butyrate and progesterone receptor membrane component 1 (PGRMC1) in these processes. Furthermore, we described the evaluation of placental function and its prospects utilizing a quantitative trophoblast cell fusion system and microfluidic device.

In addition to direct activation by pathogens and antigens, immune cell functions are further modulated by G protein-coupled receptor (GPCR) signals that are evoked by environmental factors produced in response to immune responses. Recent studies have revealed that membrane-derived lysophospholipids are such environmental factors. When immune cells are activated, phospholipid metabolism becomes active, and under such conditions lysophospholipids are produced by the action of various phospholipases. As a result, the immune responses are regulated positively or negatively via GPCR-type receptors. These lysophospholipids include lysophosphatidic acid (LPA), lysophosphatidylserine (LysoPS), and lysophosphatidylinositol (LPI). Here, we summarize our current knowledge of the synthetic pathways, receptors signaling for these LPLs, and discuss updated findings on the immunomodulatory functions of lysophospholipids, with a particular focus on the recently identified bioactive lysophospholipid, LysoPS.

Despite that the Japanese package insert for vonoprazan (VPZ) includes a precaution that the potassium ion-competitive acid blocker may potentiate the effects of midazolam (MDZ), reports on the actual effects in clinical practice are lacking. Therefore, in this study, we evaluated whether VPZ-taking patients experience clinical effects under MDZ sedation during endoscopy. The participants were outpatients who underwent upper gastrointestinal endoscopy under MDZ anesthesia between April 2021 and April 2022. Comparisons were made between the VPZ(+) and VPZ(-) groups, and the patient background was adjusted using propensity score matching. The post-examination observation time was prolonged in 16.4% of patients in the VPZ(+) group and 13.7% in the VPZ(-) group, but the difference was not statistically significant (p=0.818). The two patients groups also showed no statistically significant differences in the percentage of individuals who received oxygen administration during the examination or in post-examination oxygen saturation and blood pressure values. These results suggest that the use of MDZ for sedation during upper gastrointestinal endoscopy may have minimal clinical effects arising from drug interaction with VPZ.