Biological & pharmaceutical bulletin最新文献

Ferroptosis is involved in the progression of sepsis-induced acute lung injury (ALI). Kaempferol is a flavonoid compound that can protect against ALI. 5-Methylcytosine (m5C) is involved in the pathogenesis of sepsis. This study aimed to investigate the impact of kaempferol on ferroptosis and the underlying mechanism, focusing on m5C methylation. MLE-12 cells were exposed to lipopolysaccharide (LPS) to induce cell injury, and treated with kaempferol to assess ferroptosis by detecting ferrous, glutathione, malonaldehyde, and lipid-reactive oxygen species levels using commercial kits. m5C methylation was assessed using dot blot, RNA immunoprecipitation, dual-luciferase reporter analysis, and RNA stability assay. The results showed that kaempferol inhibited ferroptosis in LPS-induced cells and NOP2/Sun RNA methyltransferase family member 7 (NSUN7)-mediated m5C modification levels. Overexpression of NSUN7 reversed the inhibition of ferroptosis caused by kaempferol. Moreover, NSUN7 knockdown reduced transferrin receptor (TFRC) stability by suppressing its m5C methylation, and TFRC overexpression promoted ferroptosis in cells with NSUN7 downregulation. In conclusion, kaempferol inhibits ferroptosis in lung epithelial cells by suppressing NSUN7-mediated m5C methylation of TFRC. These findings suggest that kaempferol and targeting m5C methylation may be used for the treatment of sepsis-induced ALI.

Histone deacetylases (HDACs) regulate chromatin structure and gene expression, and their inhibition has been proposed as a radioprotective strategy. However, few studies have compared multiple HDAC inhibitors (HDACis) under identical conditions. This study evaluated the efficacy of seven HDACis in a mouse total body irradiation (TBI) model. Male ICR mice received 7.5 Gy TBI followed by a single administration of valproic acid (VPA; 300 or 600 mg/kg), sodium butyrate (NaB; 500 or 1000 mg/kg), trichostatin A (TSA; 0.5 or 1.0 mg/kg), vorinostat (10 or 50 mg/kg), panobinostat (25 or 50 mg/kg), givinostat (5 or 10 mg/kg), or entinostat (25 or 50 mg/kg). Survival was monitored for 20 d. Only VPA at 600 mg/kg significantly improved survival compared with vehicle (overall p = 0.00241; p = 0.0039 vs. vehicle), while all other HDACis showed no significant benefit. VPA's efficacy may reflect a combination of effects on DNA repair, inflammation, and redox regulation rather than HDAC inhibition alone. These findings suggest VPA to be a promising candidate for radioprotection and emphasize the need for further studies to optimize dosing and explore underlying mechanisms.

Area under the concentration-time curve (AUC)-guided vancomycin dosing is recommended to measure peak and trough concentrations. While recent studies have shown that AUC on Day 1 and Day 2 are associated with early clinical response and nephrotoxicity, data confirming the accuracy of AUC estimation using trough-only data on Day 1 and Day 2 are scarce. The aim of this study was to evaluate the agreement of AUC calculated using trough-only data compared with 2-point sampling on Day 1 and Day 2 using the Bayesian-based, free web application PAT (Practical AUC-guided TDM for vancomycin). We conducted a single-center, cohort study to evaluate the agreement of AUC calculated using trough-only data compared to peak-trough sampling on Day 1 and Day 2. The ratios of trough/peak-trough AUC for AUC_0-24 and AUC_24-48 were within the acceptable range of 0.8-1.2. Furthermore, AUCs estimated using trough-only data and those estimated using peak-trough concentrations showed high agreement. In addition, multivariate ordinal logistic regression analysis showed that estimated glomerular filtration rate and serum albumin were significant factors affecting the deviation of trough/peak-trough AUC_24-48 (p = 0.001 and p = 0.040, respectively). In conclusion, trough-only data may be sufficient for AUC estimation in AUC-guided dosing in patients identified as suitable candidates, even when obtained on Day 2. Further, renal function and serum albumin were found to be factors affecting the agreement rate of AUC on Day 2 when using trough-only data.

Tumor necrosis factor-α inhibitors (TNFis) are associated with a risk of paradoxical psoriasis, but quantitative data remain limited. One proposed mechanism is the induction of interferon (IFN) production following TNFi administration. Etanercept and certolizumab pegol, which contain immunoglobulin fragments in their structures, reportedly induce IFN production in T cells more than monoclonal antibody (mAb) TNFi agents. Based on this, we hypothesized that non-mAb TNFi agents might carry a higher risk of paradoxical psoriasis than mAb agents. This study compared the risk of paradoxical psoriasis between mAb and non-mAb TNFi agents in rheumatoid arthritis (RA) patients. Using a claims database, we identified 1577 subjects in the mAb group and 1517 in the non-mAb group. Patient characteristics, including sex, age, and prior RA treatment, were extracted, and the onset of psoriasis was identified. Multivariable Cox regression analysis showed the hazard ratio (HR) for psoriasis onset in the mAb group versus the non-mAb group was 1.66 (95% confidence interval [CI]: 0.79-3.48). Subgroup analyses revealed that compared to etanercept, the HR for adalimumab was 1.43 (95% CI: 0.49-4.19), and compared to certolizumab pegol, it was 0.67 (95% CI: 0.19-2.39). These findings suggest that our hypothesis was not supported and that the risk of paradoxical psoriasis may vary even among non-mAb agents, as indicated by differences observed between etanercept and certolizumab pegol.

Soy isoflavonoids were applied to commercially available baker's yeast in vitro to find metabolites. Tyrosol, an ingredient in olive oil and wine, and tryptophol were found in the culture media. To test whether tyrosol is a metabolite of soy isoflavonoids, we prepared 2,4-dideuterated equol and applied it to yeast. According to LC-MS analysis of the culture media, deuterated tyrosol was not produced. Therefore, tyrosol is assumed to be a tyrosine metabolite of yeast known as the Ehrlich pathway. We then evaluated the in vitro activities of the 2 amino acid-derived alcohols. Both tyrosol and tryptophol similarly showed anti-inflammatory activity, as evaluated by monocyte chemoattractant protein-1 in 3T3-L1 murine adipocytes in vitro. Our results suggested that the amino acid-derived alcohols may contribute to the anti-inflammatory activity of fermented foods.

Epstein-Barr virus (EBV) is one of the most pervasive viruses worldwide, and EBV infection is inextricably linked to a multitude of lymphoid and epithelial neoplasms. EBV is responsible for the advancement of malignant disease by modifying the tumor microenvironment (TME), which is a sophisticated and evolving system that facilitates tumor growth, invasion, and metastasis. EBV infection has a profound impact on the cellular and noncellular components that constitute the TME. Our review presents a summary of the composition of the EBV-remodeled TME, with a particular focus on EBV-induced functional phenotypes in non-tumor cells. Furthermore, we discuss the potential for reversing EBV-driven TME remodeling as a therapeutic strategy for treating the malignancies associated with EBV infection.

Drug lag is a serious issue for patients with life-threatening diseases such as cancer. Japan and Korea have been facing a large drug lag, despite having a large market and a good clinical trial environment. We analyzed drug lags for anticancer drugs between these countries, using the information on 82 anticancer drugs approved in the United States between 2017 and 2022. The national health insurance coverage status was also investigated. The approval lag, defined as the number of days from the date of approval in the United States to the date of approval in the country of interest, was used as the indicator of drug lag and was calculated for each drug. The median for all drugs was estimated using the Kaplan-Meier method, with the lag for locally unapproved drugs treated as censored data. The median approval lag in Japan and Korea for all drugs, including locally unapproved drugs, were 1547 d (4.2 years) and 1000 d (2.7 years), respectively. The approval lags for the approved drugs were 216 and 655 d in Japan and Korea, respectively. All drugs approved in Japan were covered by national health insurance whereas many drugs recently approved in Korea were not yet covered. The overall drug lag in Japan was greater than that in Korea due to the high number of unapproved drugs in Japan. In Korea, more drugs have been approved; however, it generally takes longer for them to become widely available to the public.

Vitamin D plays a crucial role in immune system function. Several studies have indicated that genetic variations in the vitamin D receptor (VDR) and vitamin D binding protein (VDBP, encoded by GC gene) increase the risk of developing asthma. However, the effect of these variations on the prognosis and clinical outcomes of asthma remains unclear. This study, involving 152 adult patients with asthma, aimed to assess the influence of VDR and GC polymorphisms on asthma severity and its exacerbation. Gene polymorphisms previously associated with asthma risk were analyzed, and VDR mRNA expression levels were evaluated in peripheral blood mononuclear cells. The AA genotype of the VDR rs2228570 polymorphism was associated with an elevated risk of severe asthma compared to the AG/GG genotype (odds ratio, 3.20; 95% confidence interval [CI], 1.24-8.28). Furthermore, patients with the rs2228570 AA genotype showed an elevated risk of exacerbation during the 1-year follow-up period (hazard ratio, 4.01; 95% CI, 1.75-9.15). VDR mRNA expression was significantly reduced in patients with the AA genotype. Furthermore, the mRNA expression levels of GLCCI1, HDAC2, NR3C1, and NFE2L2, which are associated with steroid response, were reduced in patients with the AA genotype. Our findings indicate that patients with the AA genotype of VDR rs2228570 are more likely to experience severe asthma and exacerbations. This polymorphism has the potential to reduce vitamin D efficacy by altering VDR function and expression, potentially resulting in increased inflammation and reduced steroid responsiveness in patients with asthma.

As unexpected adverse events and successful drug repositioning have shown, drug effects are complex and include aspects not recognized by developers. How can we understand these unrecognized drug effects? Drug effects can be numerized by encompassing biological responses to drugs. For instance, the transcriptome data of cultured cells and toxicopathological images of mice treated with a compound represent the effects of the compound in vitro and in vivo, respectively. As a next step, we focused on pattern recognition, a data science framework to extract essentially important low-dimensional latent variables from high-dimensional observed data such as latent variable models. Latent variables are low-dimensional, allowing us to visualize drug effects in an easily recognizable form, such as a radar chart. This bird's-eye view of drug effects enables us to compare them with existing knowledge, potentially articulating the effects of drugs as the known knowns and known unknowns. We believe that the three-step strategy of numerization, visualization, and articulation will allow us to understand drug effects comprehensively, and we are currently verifying this approach. In this review, we will introduce these candidate studies and hope to share our interest in "pattern recognition of biological responses," the pillar of our group.

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.