Creatine, α-N-methyl-guanidino-acetic acid, plays a fundamental role in the storage and regeneration of high-energy phosphate in the brain. Defects in the creatine transporter gene (CRT/SLC6A8) result in a significant reduction in brain creatine levels and severe neurological symptoms such as intellectual disability. Clarifying creatine dynamics in the brain is essential to increase our understanding of CRT deficiency syndrome (CRTD) pathology and the development of CRTD therapeutics. This review comprehensively summarizes the pathophysiological roles of transporters in dynamics of creatine and related guanidine compounds in the brain barriers and brain parenchyma. Brain creatine dynamics are regulated by the cooperative actions of various influx and efflux transporters of creatine, guanidinoacetate, creatinine, and creatine biosynthetic enzymes. These transporters include CRT/SLC6A8 as a creatine/guanidinoacetate/creatinine influx transporter, MCT12/SLC16A12, and SLC22A15 for creatine efflux transport, TauT/SLC6A6, GAT2/SLC6A13, and GAT3/SLC6A11 for guanidinoacetate influx transport, and OCT3/SLC22A3 for creatinine influx transport. Transporters and creatine biosynthetic enzymes, such as arginine–glycine amidinotransferase and guanidinoacetate N-methyltransferase, exhibit cell-type specific spatio-temporal expression at the brain barrier and in neurons, astrocytes, and oligodendrocytes. To date, no effective therapeutics have been developed for the treatment of CRTD. The link between low brain creatine level and the mechanism of neurological dysfunction remains unclear. Creatine prodrugs, molecular chaperones, and adeno-associated virus-based gene therapies are potential therapeutic options for CRTD. Advanced technologies, such as omics and genetic engineering, will open new avenues for CRTD therapeutics.

Noxious temperature changes and high levels of reactive oxygen species (ROS) have traditionally been regarded as harmful stimuli. However, there is now substantial evidence for the importance of small-to-moderate changes in temperature and ROS levels—well below the thresholds that induce cell death or physiological dysfunction—as fundamental signaling cues that regulate a wide range of physiological functions in mammals. In this review, I summarize our recent findings on the regulatory roles of slight fluctuations in temperature and intracellular ROS in biological processes. In particular, this review focuses on two key examples: (A) the effects of subtle changes in physiological circadian body temperature fluctuations on the translational efficiency of the core clock gene Period2 and (B) the role of non-toxic levels of ROS as essential intracellular signals that modulate transient receptor potential ion channel activity and cold sensitivity. Our findings challenge longstanding assumptions that circadian clocks are governed solely by transcriptional and post-translational mechanisms and that the temperature sensitivity of ion channels arises exclusively from direct thermal gating. We demonstrated the pivotal roles of the translational control of mRNA and mitochondrial responses in the temperature-mediated maintenance of circadian clock function and ion channel activity. These insights provide conceptual advances relevant to chronobiology, neuroscience, and pharmacology.

Skin aging is a complex physiological process driven by both endogenous and exogenous factors, involving various mechanisms such as oxidative stress, inflammatory responses, and cellular senescence. As natural bioactive macromolecules, plant polysaccharides possess properties including antioxidant, anti-inflammatory, and free radical scavenging abilities, and have recently shown significant potential in anti-skin aging research. This article systematically reviews the molecular mechanisms of skin aging, with a focus on elucidating how plant polysaccharides exert anti-aging effects by regulating key signaling pathways. Additionally, it summarizes strategies for the extraction, purification, and structural modification of plant polysaccharides, as well as their structure–activity relationships. The aim is to provide a theoretical foundation and research directions for both fundamental studies and product development of plant polysaccharides in the field of anti-skin aging.

Aralia cordata Thunberg (Araliaceae) is a perennial plant that grows in East Asia, including Japan. Its rhizome, called Dokukatsu in Japanese, is used as a crude drug in traditional Japanese (Kampo) medicines. Aralia rhizomes are included in several Kampo formulae, such as Dokkatsuto, which is prescribed for patients with osteoarthritis-related arthralgia, due to its analgesic and anti-inflammatory properties. However, the specific compounds responsible for these effects remain unexplored. In this study, we aimed to evaluate the anti-inflammatory properties of Aralia rhizome constituents by monitoring the production of the proinflammatory mediator nitric oxide (NO) in primary cultured rat hepatocytes. An ethyl acetate (EtOAc)-soluble fraction from an Aralia rhizome extract significantly suppressed interleukin (IL)-1β-induced NO production in rat hepatocytes. Within this fraction, we identified diterpenes, such as pimaradienoic acid (most abundant), kaurenoic acid, and pimaric acid. Among these, pimaradienoic acid markedly inhibited NO production in hepatocytes. We further investigated the effects of the EtOAc-soluble fraction on mouse chondrogenic cell line ATDC5—which produces NO in response to IL-1β and bacterial lipopolysaccharide (LPS)—and found that it inhibited NO production in ATDC5 cells treated with IL-1β and LPS. Moreover, pimaradienoic acid suppressed IL-1β-induced expression of the inducible nitric oxide synthase gene and downregulated genes involved in extracellular matrix (ECM) degradation in cartilage, specifically matrix metalloproteinase-13 (Mmp13) and a disintegrin and metalloproteinase with thrombospondin motifs-5 (Adamts5) genes. These findings suggest that pimaradienoic acid contributes to the anti-inflammatory effects of Aralia rhizomes by inhibiting NO-mediated inflammation and matrix degradation in articular cartilage during osteoarthritis.

Apiaceae plants are widely utilized as spices across the globe. Fennel, a prominent member of this family, has been previously shown to possess appetite-enhancing properties, suggesting that other Apiaceae spices may exhibit similar effects. Herein, we investigated the appetite-enhancing effects of essential oils extracted from aniseed, caraway seeds, and cumin seeds. All three essential oils significantly increased food intake in mice. Analysis revealed that the major active compounds were (i) trans-anethole and pseudoisoeugenyl 2-methylbutyrate in aniseed oil, (ii) d-limonene and d-carvone in caraway oil, and (iii) cuminaldehyde in cumin oil. Intriguingly, the effective doses of d-carvone and trans-anethole were elevated when administered in combination with d-limonene and pseudoisoeugenyl 2-methylbutyrate, respectively. This newly identified modulatory effect, driven by co-occurring compounds, suggests a complex interaction between the constituents. Furthermore, the side chain structures of terpenoids were found to influence the effects analogously to those of phenylpropanoids, thereby suggesting the existence of common or similar sites of action within the mice olfactory system.

Medication history from Japanese pharmacies is potentially rich in useful information regarding drug-related events in diverse populations; however, this information has rarely been utilized as real-world data. This study aimed to evaluate the feasibility of using medication history as real-world data to assess associations between anticholinergic medications for overactive bladder (OAB) and increased risk of dementia. A retrospective prevalent-user cohort study was performed to analyze medication history using a logistic regression model. The primary exposure was anticholinergic drug use for OAB (vs. beta-3 agonists only). The risk associated with each specific anticholinergic drug was also analyzed. Adjustments included age, sex, comorbidities (diabetes, hyperlipidemia, and hypertension), and psychotropic drug use. OAB anticholinergics and age were significant predictors. The adjusted odds ratio (OR) and 95% confidence interval (CI) for OAB anticholinergics were 1.53 (95% CI: 1.10–2.14, p = 0.0110), and those for age were 1.07 (95% CI: 1.04–1.09, p < 0.0001). Among individual OAB anticholinergics, the ORs for oxybutynin (4.53; 95% CI: 2.18–9.42, p < 0.0001) and tolterodine (5.64; 95% CI: 2.42–13.17, p < 0.0001) were significant, whereas ORs for other OAB anticholinergics were not. These findings suggest the potential to identify agents with lower dementia risk. In conclusion, analysis in this prevalent-user cohort study using medication history data showed a significant association between OAB anticholinergic use and increased dementia risk, with variation by drug. These results support the feasibility of utilizing medication history as real-world data for pharmacovigilance.

Schisandrin A (SA), a major lignan isolated from the fruits of Schisandra chinensis, has been reported to modulate smooth muscle (SM) function in several tissues; however, its direct effects on intestinal SM have not been fully characterized. In the present study, we investigated the effects of SA on contractile responses in guinea pig (GP) ileal longitudinal smooth muscle (ILSM) and examined the involvement of L-type voltage-dependent Ca²⁺ channels (VDCCs). SA (1–100 µM) concentration-dependently inhibited contractions induced by acetylcholine (1 µM), histamine (1 µM), and prostaglandin F_2α (10 µM). These agonist-induced contractions were completely suppressed by the L-type VDCC inhibitor diltiazem (10 µM). SA also attenuated depolarization-induced contractions evoked by high-KCl (80 mM), which were similarly sensitive to diltiazem. In A7r5 vascular SM cells, high-KCl (100 mM) elicited marked increases in intracellular Ca²⁺ concentration ([Ca²⁺]_i), and these responses were substantially inhibited by SA (30 µM) as well as by diltiazem (30 µM). Furthermore, molecular docking simulations using the Ca_V1.2 channel structure (PDB ID: 8HMA) suggested that SA may interact with the tetrandrine-binding pocket, potentially forming a hydrogen bond with Tyr1508. Taken together, these findings indicate that SA suppresses intestinal SM contraction primarily by inhibiting Ca²⁺ influx through L-type VDCCs, likely via direct interaction with Ca_V1.2. This mechanism may partly underlie the traditional use of S. chinensis fruits in the treatment of gastrointestinal disorders such as diarrhea.

The 23-valent pneumococcal polysaccharide (PPSV23) and 13-valent pneumococcal conjugate (PCV13) vaccines are available for the prevention of infections caused by Streptococcus pneumoniae. This systematic review and meta-analysis evaluated the immunogenicity and safety of PPSV23 and PCV13 co-vaccination (PCV13/PPSV23) compared with PPSV23 monotherapy in adult populations. PubMed, Cochrane Library, Web of Science, and ClinicalTrials.gov were systematically searched for randomized controlled trials (RCTs) comparing PCV13/PPSV23 co-vaccination with PPSV23 monotherapy published until September 15, 2023. Immunogenicity was assessed using the geometric mean titer ratio (GMTR) of opsonophagocytic activity (OPA), which reflects bactericidal activity against each serotype. The safety outcomes included local and systemic adverse events. The risk ratios and 95% confidence intervals were calculated using the inverse variance-weighted method. The meta-analysis included 4 RCTs involving 2739 participants. The OPA GMTRs for 11 of the 13 evaluated serotypes were significantly higher in the PCV13/PPSV23 group than those in the PPSV23 group. The safety analysis showed no statistically significant differences in the incidence of adverse events between the 2 groups across all assessed outcomes. PCV13/PPSV23 showed significantly higher immunogenicity against the pneumococcal serotypes and maintained a safety profile comparable to that of PPSV23. These results support the potential utility of PCV13/PPSV23 as an effective strategy for preventing pneumococcal diseases in older adults.

Teicoplanin is an important antibiotic for methicillin-resistant Staphylococcus aureus infections. To enhance its clinical effectiveness while preventing adverse effects, therapeutic drug monitoring (TDM) of teicoplanin trough concentration is recommended. Given the importance of the early attainment of therapeutic concentrations for treatment success, initial dosing regimens, including loading and maintenance doses, are deliberately designed based on patient information. However, initial dose planning for teicoplanin strongly relies on clinician expertise. This study aimed to use a machine learning (ML) approach to integrate clinicians’ knowledge into a predictive model for initial teicoplanin dose planning. First, we confirmed that dose planning by pharmacists specialized in TDM (TDM pharmacists) significantly improved early therapeutic target attainment for patients who were not admitted to intensive or high care units. Subsequently, we used a dataset of initial teicoplanin dose plans created by TDM pharmacists to train the model that emulates their dosing decision-making process. Although the prediction accuracies of the ML model were modest (45.8 and 66.7% for the loading and maintenance doses, respectively), the model successfully learned the basic policy of dose planning, suggesting that ML approaches have potential utility in supporting appropriate initial teicoplanin treatment.

Metallo-β-lactamases (MBLs)—Zn²⁺-dependent β-lactamases that compromise the efficacy of most β-lactam antibiotics, including carbapenems—are difficult to monitor rapidly with broadly applicable small-molecule probes due to the structural diversity among the MBLs. Fluorescent thiol-based probes that bind to the dinuclear Zn²⁺ active site would offer a mechanistically different approach for the selective detection and inhibition of MBLs compared to serine β-lactamases (SBLs); however, their performance across genetically divergent MBLs remains poorly defined. To clarify the structural determinants governing probe recognition across different MBLs, we examined the structure–activity relationships using a homologous series of dansyl-based thiol probes, DansylC_nSH (n = 2 and 4–6) toward BlaB, a class B MBL of Elizabethkingia meningoseptica, and compared their behavior with those of the clinically relevant MBLs imipenemase-1 (IMP-1) and Verona integron-encoded metallo-β-lactamase 2 (VIM-2). Consistent with the minimal differences in fluorescence enhancement among the series, BlaB inhibition exhibited only modest spacer-length dependence (IC₅₀ = 29–51 μM; apparent inhibition constants (K_i^app) = 3600–5910 nM). In contrast, IMP-1 and VIM-2 showed markedly stronger fluorescence emission and inhibitory potencies (IMP-1: IC₅₀ = 0.7–5.2 μM; K_i^app = 140–1100 nM; VIM-2: IC₅₀ = 1.5–2.1 μM; K_i^app = 286–370 nM), reflecting their distinct active-site architectures. Docking analyses further revealed distinct binding orientations that explain their photophysical behaviors. No fluorescence enhancement or inhibition was observed with the class A SBL Guiana extended-spectrum β-lactamase-3 (GES-3), confirming the high selectivity and specificity of the DansylC_nSH series. These findings allow identifying key structural determinants governing selective activation and inhibition of fluorescence from each MBL.

Reishi (Ganoderma lucidum) is known to enhance intestinal immunity, with ganoderic acid A (GA-A) identified as one of its active constituents. However, the specific role of GA-A in regulating immune components such as immunoglobulin A (IgA) from Peyer’s patches (PPs) and α-defensin 5 from Paneth cells remains unclear. Additionally, the ability of Reishi to counteract oxidative stress-induced intestinal immune suppression has not been fully elucidated. Therefore, in this study, we aimed to examine the effects of Reishi and GA-A on intestinal immunity in a rat model of ischemia–reperfusion (I/R) injury. Oral administration of GA-A increased IgA secretion from PP cells isolated from rat small intestine and upregulated the mRNA expression of rat α-defensin 5 (RD-5) and toll-like receptor 4 (TLR4) in the ileum, similar to Reishi. In contrast, GA-A did not exhibit immunostimulatory effects in TLR4-deficient mice. In the I/R rat model, both Reishi and GA-A significantly restored IgA secretion and RD-5 mRNA expression, mitigating immune suppression. They were also associated with changes in superoxide dismutase 1 (SOD1) and SOD3 mRNA expression under I/R conditions and prevented villus shedding and Paneth cell loss, indicating protection against I/R-induced intestinal immune decline. These results were comparable to those observed with caffeic acid, the positive control. Overall, these findings suggest that Reishi mitigates intestinal immune suppression caused by I/R injury, with GA-A serving as a key active component mediating these protective effects.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease marked by inflammation of the colon. Although various dextran sulfate sodium (DSS)-induced UC models are available, the traditional free-drinking model involves oral administration, which complicates the assessment of extracolonic organs because of widespread intestinal exposure. This study aimed to create a localized UC model through rectal administration of DSS and evaluate whether this approach minimized direct DSS exposure to the small intestine and liver. Rats received 40% DSS rectally for 13 d. Changes in body weight, Disease Activity Index, and histological scores were monitored. The effects of 5-aminosalicylic acid treatment were examined, and small intestinal morphology, inflammatory markers, bile flow, and mRNA levels of hepatic bile salt export pump were analyzed. Rectal DSS induced localized inflammation in the distal colon and rectum, mimicking key features of UC such as weight loss, mucosal injury, and elevated disease activity. Some of these effects were partially alleviated by 5-aminosalicylic acid treatment. The small intestine shortened without infiltration of inflammatory cells or cytokine increase, indicating a non-inflammatory structural change. Bile flow and hepatic bile salt export pump expression significantly decreased in DSS-treated rats, suggesting hepatobiliary excretory dysfunction. Overall, the rectal DSS model offers a controlled and reproducible way to induce colon-specific inflammation, overcoming the limitations of the free-drinking model, which hinders extracolonic evaluation due to oral DSS exposure. This model may provide a research basis for further study of inter-organ interactions, particularly gut–liver axis dysfunction and intestinal barrier-related drug absorption in UC.

Skin pigmentation induced by irinotecan—an anticancer drug—is clinically recognized; however, strain-dependent and skin site-specific differences in its manifestation have not been sufficiently investigated in mice. In this study, we compared melanocyte activation in plantar and genital skin following repeated irinotecan administration in three mouse strains: ICR (Slc:ICR), C57BL/6 (C57BL/6JmsSlc), and C3H (C3H/HeSlc). Melanocyte activation was assessed by 3,4-dihydroxyphenylalanine (DOPA) staining and immunofluorescence staining for microphthalmia-associated transcription factor (MITF). Although no obvious macroscopic pigmentation was observed in any strain or skin site, DOPA staining revealed an increased number of DOPA-positive cells in the plantar skin of all three mouse strains. By contrast, marked strain-dependent differences were observed in the genital skin: DOPA-positive cells were detected in ICR (Slc:ICR) and C57BL/6 (C57BL/6JmsSlc) mice but not in C3H (C3H/HeSlc) mice. MITF immunofluorescence staining results were consistent with the DOPA staining findings, demonstrating enhanced MITF signals in skin sites exhibiting melanocyte activation. Notably, the induction of DOPA-positive cells in the genital skin of albino ICR mice was an unexpected finding, suggesting that drug-induced melanocyte activation may occur independently of intrinsic melanin-producing capacity and instead involve upstream regulatory pathways. Collectively, these findings demonstrate clear strain-dependent and skin site-specific differences in irinotecan-induced melanocyte responses and provide important insights into the heterogeneity of drug-induced skin pigmentation.

Although numerous biological properties of curcumin, a bioactive polyphenol from the rhizome of turmeric (Curcuma longa), have been documented, its poor bioavailability limits clinical application. Therefore, identifying new analogs with improved pharmacokinetics and pharmacological properties is essential. Given that curcumin and its related compounds are known to inhibit cancer cell progression and metastasis through nuclear factor-kappaB (NF-κB) signaling inhibition, we investigated 58 newly synthesized, structurally diverse monocarbonyl curcumin analogs. Their inhibitory effects on intrinsic NF-κB activity were assessed in breast cancer cells using the 4T1 cell line expressing a luciferase NF-κB reporter. Among the 58 monocarbonyl curcumin analogs, 3,5-bis(2-ethoxybenzylidene)piperidin-4-one (E145) exhibited potent inhibition of NF-κB activity in 4T1 breast cancer cells. Based on the structure–activity relationship analysis, the central heterocyclic monocarbonyl linker structure of E145 contributed to its increased potency in NF-κB inhibition.

Sotorasib is a molecularly targeted drug that exerts antitumor effects by selectively binding to KRAS G12C through a Michael addition reaction, irreversibly inhibiting KRAS. However, the frequent occurrence of adverse events, such as gastrointestinal and hepatic disorders, has raised major concerns. These toxicities are thought to arise from interactions between sotorasib and proteins other than KRAS in normal cells. In this study, we generated a specific antibody against sotorasib and established an immunohistochemical method capable of detecting sotorasib–protein conjugates. Using this technique, we clarified the localization of sotorasib–protein conjugates in the digestive tract of rats, including the duodenum, jejunum, ileum, and colon. Sotorasib–protein conjugates were strongly localized to the villous epithelial cells of the small intestine but were scarcely detected in the colon, highlighting regional differences. This study elucidates the localization of sotorasib–protein conjugates in the gastrointestinal tract of rats and provides important insights into the mechanisms underlying sotorasib-induced gastrointestinal disorders.

Claims data can be a resource for epidemiological evaluations in long-term care patients at increased risk of urinary tract infections (UTI) from antimicrobial-resistant bacteria. However, as claims data are primarily collected for administrative purposes, validating diagnostic accuracy is required. This study evaluated the validity of claims-based UTI identification in this patient population. This retrospective study included patients in long-term care wards between January 2023 and December 2024. Using diagnoses from electronic medical records as the gold standard, we evaluated the positive predictive value (PPV) of claims-based identification of UTI and catheter-associated UTI (CAUTI). Diagnoses were identified using International Classification of Diseases, 10th Revision (ICD-10) codes or urinalysis with microscopy, urine culture, antibiotic prescriptions, or indwelling bladder catheter procedures. Sensitivity analysis excluding suspected diagnoses was performed. Among 523 patients, 200 with at least one ICD-10 code for UTI were randomly selected. The PPV for identifying UTI using ICD-10 codes improved from 66.0 to 77.8% when additional codes were combined, and that for CAUTI improved from 45.5 to 86.8% with indwelling bladder catheter procedures. Excluding suspected diagnoses further improved the accuracy. Integrating ICD-10 codes, urinalysis with microscopy, urine culture, antibiotic prescriptions, and, when relevant, indwelling bladder catheter procedures while excluding suspected diagnoses enhances the validity of claims-based UTI identification and may be applicable to database studies using claims data.

Chronic kidney disease (CKD) progresses to renal fibrosis and anemia, ultimately leading to chronic renal failure (CRF). Renal anemia, primarily caused by impaired erythropoietin (EPO) production and dysregulated iron metabolism, reduces QOL and increases cardiovascular risk. To establish an experimental model of CRF-associated anemia, male Wistar rats underwent 5/6 nephrectomy (Nx). In a subset of Nx rats, tacrolimus (TAC, 1 mg/kg, subcutaneously every other day for two weeks starting at week 4) was administered to exacerbate renal injury. Renal function, hematological parameters, iron-related indices, and fibrotic changes were evaluated at defined postoperative time points. The Nx rats developed progressive renal dysfunction and interstitial fibrosis, accompanied by declining hematocrit and reduced plasma EPO levels and attenuation of renal hypoxia-inducible factor-2α expression. TAC administration further aggravated renal injury and anemia and resulted in a lower hematocrit despite detectable circulating EPO levels. This pattern may suggest a relative inadequacy of erythropoietic response under aggravated renal injury conditions rather than absolute EPO deficiency. These findings indicate that the Nx model reproducibly recapitulates key features of CKD-associated anemia. The addition of TAC accelerates pathological progression within this established model and facilitates the induction of advanced renal injury. This experimental system provides a practical preclinical platform for investigating the molecular mechanisms underlying CKD/CRF-related anemia and for evaluating therapeutic strategies targeting fibrosis, iron metabolism, or impaired erythropoietic response.

Abortion remains a significant public health concern and often results from unintended pregnancies. Although abortion rates have declined, approximately 40% are still due to unplanned pregnancies. We conducted a subanalysis of the FIKA study, a survey on sexuality among Japanese women aged 18–45 years, to examine factors correlated with abortion. We analyzed responses obtained from 3228 sexually experienced women, who were categorized based on abortion history. Sources of knowledge about intercourse and contraceptives were assessed using a standardized questionnaire. A decision tree analysis was performed to identify associated risk factors. Among the participants, 410 women (12.7%) had undergone an abortion. Women who had undergone an abortion were significantly more likely to rely on friends as a source of contraceptive information than women who had not had an abortion (p = 0.0024). Participants with abortion experience showed greater variation in knowledge about contraceptive scores, with most of them being in the lowest knowledge group. Decision tree analysis revealed two key factors: sexual debut before the age of 17 years and only compulsory education. The abortion rate was 39.5% among women with both factors, compared to 7.9% among those with none. Early sexual initiation and limited education were strongly associated with abortion experience. Reliance on informal sources may also contribute to a poor understanding of reproductive health. These findings underscore the need for early, comprehensive, and formal sex education to improve sexual literacy and reduce unintended pregnancies.