Trastuzumab, a therapeutic drug for patients with breast cancer, is one of the most effective and commonly used anticancer drugs for breast cancer. However, its adverse effects include cardiotoxicity, and there is a risk of developing conditions such as arrhythmia, cardiomyopathy, and heart failure. The adverse cardiac effects associated with trastuzumab are now widely recognized, and their mechanisms are beginning to be partially understood. One of the mechanisms has been suggested to be related to the suppressive action of trastuzumab on the erythroblastic oncogene B2 receptor, which acts protectively on the myocardium. Diagnosis can be made by assessing cardiac function with echocardiography, as well as measuring serum troponin I and N-terminal pro-B-type natriuretic peptide levels as biomarkers, and magnetic resonance imaging diagnosis may be helpful for early detection. As for therapeutic and prophylactic drugs, β-blockers and angiotensin-converting enzyme inhibitors, which are used to treat heart failure, have been shown to be effective, while recently, angiotensin receptor/neprilysin and sodium–glucose cotransporter 2 inhibitors are expected to be effective. Furthermore, the cardioprotective effects of proprotein convertase subtilisin/kexin type 9 inhibitors, which are used to treat lipid disorders, have also been attracting attention. This review will summarize the mechanisms, diagnostic methods, and treatment/preventive methods of cardiotoxicity associated with antihuman epidermal growth factor receptor 2 therapies, including trastuzumab.

In recent years, radiotheranostics, a theranostic approach utilizing radioisotopes, has been gaining significant attention, primarily in the field of oncology. The success of this technology relies on the design of probes that specifically target desired sites, making the development of effective diagnostic and therapeutic agents a crucial area of research. This review provides an overview of the fundamental concepts and recent advancements in probe design for radiotheranostics, with a particular focus on pharmacokinetics and subcellular localization. Key topics discussed include: (1) multimerization, (2) introduction of the albumin-binding moiety, (3) charge modification, (4) glycosylation, (5) conjugation of cell-penetrating peptides, (6) introduction of the covalent binding moiety, (7) targeting the nucleus, and (8) utilizing drug release properties to control pharmacokinetics and intracellular localization. Through these strategies, we review the optimization and novel design possibilities for probes in radiotheranostics.

Glioblastoma (GBM) is a highly aggressive and lethal brain tumor with very poor prognosis despite recent progress in multimodal treatments. Within glioma tissue, various niche cells such as macrophages and neutrophils form a unique glioma immune microenvironment (GIME) by interacting with heterogenous cancer cells, and this has been implicated in disease progression and responsiveness to immunomodulatory therapies. This study explores novel potential prognostic markers associated with the GIME using integrated bioinformatics analyses, including single-cell RNA-sequencing (scRNA-seq), and spatial transcriptome (ST) datasets of clinical GBM specimens. We first identified 42 genes as being associated with poor prognosis in GBM from 5 different cohorts, GBM vs. nontumor tissue, grade IV vs. grade II gliomas, isocitrate dehydrogenase (IDH)-wild-type vs. IDH-mutant variants, mesenchymal vs. proneural and classical subtypes, and hazard ratio for overall survival. Among these, 32 genes were positively correlated with ESTIMATEScore, infiltration of various immune cell types, expression of known immune-related genes, and representative immune-associated biological signals. On scRNA-seq analysis, 7 genes were relatively concentrated in tumor-associated macrophages rather than in malignant cells. ST analysis revealed that Collagen beta(1-O)galactosyltransferase 1 (COLGALT1), Integrin subunit beta 2 (ITGB2), and Myosin light chain 12A (MYL12A) were distributed in the interface between the tumor and the peritumoral area, overlapping with the expression of representative immune-related genes. These findings support the potential of COLGALT1, ITGB2 and MYL12A as biomarkers for predicting the prognosis and immune responses of GBM, which can help in the development of potential immunotherapeutic strategies for GBM.

Adropin is a 43-amino acid peptide that is highly conserved among mammals. First identified in the mouse liver in 2008, adropin is broadly expressed throughout the body and has been implicated in various pathological conditions, including obesity, altered food intake, insulin resistance, glucose intolerance, and other disorders related to energy metabolism. However, its precise physiological role remains unclear. In this study, we developed a specific competitive enzyme-linked immunosorbent assay (ELISA) for adropin using an in-house generated anti-adropin polyclonal antibody. We then examined plasma adropin levels in mice under different energy metabolic conditions: fed a normal diet, subjected to short-term fasting, and fed a long-term high-fat diet. In addition, we assessed hepatic and hypothalamic expression of Enho mRNA, which encodes adropin. We observed a wide range of plasma adropin levels, spanning from those in normal healthy mice on a high-fat diet to preclinical and obese diabetic mice. Both plasma adropin concentrations and hepatic Enho mRNA expression increased in response to feeding and high-fat diet intake. Multiple regression analysis revealed a significant negative correlation between plasma adropin and plasma glucagon concentrations. These findings suggest that adropin secretion is modulated by the peripheral hormone glucagon and may contribute to the maintenance of energy metabolic homeostasis. In conclusion, the ELISA developed in this study provides a useful and reliable tool for investigating the mechanisms underlying energy metabolism.

Diuretics have long been central to the treatment of heart failure (HF) and hypertension, and are widely used in clinical settings. Herein, we performed a retrospective analysis of seasonal variations in diuretic-induced dehydration (DID) using the Japanese Adverse Drug Event Report (JADER) database, a platform that presents data on real-world clinical practice. A total of 11 diuretics prescribed in Japan, categorized into six groups, were included. The monthly reporting ratio (RR) of DID in the JADER database was determined from January 2003 to December 2023. DID was most common in January, followed by August. Furthermore, it was frequently reported during the winter months of December, January, and February. It is important for healthcare providers to understand that DID is common in both winter and summer, and thus recommend adequate water intake even in the former for patients taking diuretics. These findings can contribute to the management of dehydration in patients taking diuretics and are beneficial to healthcare professionals involved in the treatment of HF and hypertension.

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.

Parthanatos is a noncanonical form of regulated cell death mediated by the overactivation of poly(ADP-ribose) polymerase-1, yet its regulatory mechanisms are not fully understood. To fully elucidate its regulatory mechanisms, it is necessary to establish useful research tools to investigate parthanatos. We have previously identified the human fibrosarcoma HT1080 cells as highly sensitive cells to parthanatos, and cefotaxime, a 3rd-generation cephem antibiotic, as the parthanatos inducer. In this study, we comprehensively characterized the ability of various cephem antibiotics, including cephalothin (also called cefalotin) (CET), cefoxitin, ceftriaxone, cefoperazone, ceftezole, and cefalexin, to induce parthanatos. Among them, CET exhibited the lowest LD₅₀. Therefore, our results show that CET works as the more potent and useful parthanatos inducer.

Neuroimaging in rodents holds promise for advancing our understanding of the central nervous system (CNS) mechanisms that underlie chronic pain. Employing two established, but pathophysiologically distinct rodent models of chronic pain, the aim of the present study was to characterize chronic pain-related functional changes with resting-state functional magnetic resonance imaging (fMRI). In Experiment 1, we report findings from Lewis rats 3 weeks after Complete Freund’s adjuvant (CFA) injection into the knee joint (n = 16) compared with the controls (n = 14). In Experiment 2, Sprague–Dawley rats were scanned 2 weeks after partial sciatic nerve ligation (PSNL) (n = 25) or sham surgery (n = 19). CFA and PSNL induced typical behavioral patterns consistent with inflammatory and neuropathic pain, respectively. Functional magnetic resonance imaging analyses comprised (1) independent component analysis (ICA) decompositions, (2) assessment of graph measures, (3) seed-based functional connectivities, and (4) predictions of chronic pain based on supervised machine learning. In both models, we detected changes in default mode network (DMN) activity. Local and global graph measures were generally similar across groups. However, regardless of the pain model, we observed a significant reduction in the betweenness centrality hub disruption index (HDI) in chronic pain compared with the controls. Finally, employing supervised machine learning in combination with a deep learning approach, chronic pain became predictable based on the functional connectivity patterns. The results indicate changes in DMN activity and betweenness centrality HDI in chronic pain. The predictability of chronic pain using machine learning points to an information content in the connectivity patterns that has not yet been captured in conventional network analyses.

Adult T-cell leukemia/lymphoma (ATL) is a malignant tumor of mature T lymphocytes induced by human T-cell leukemia virus 1, and it has a poor prognosis. Brentuximab vedotin (BV) is included in the treatment of CD30-positive ATL, but there are no predictive biomarkers for the treatment effects of BV. Serum soluble CD30 (sCD30) concentrations are increased in aggressive ATL at the time of diagnosis, but the effect of extracellular CD30 on BV-induced cell death in ATL is unknown. Similarly, a disintegrin and metalloproteinase 10 (ADAM10) and ADAM17 possess CD30 sheddase activity in anaplastic large cell lymphoma, but this activity is unclear in ATL. In this study, we showed that sCD30 concentrations were associated with BV activity in ATL-associated cell lines. Extracellular vesicles, such as exosomes containing CD30, also inhibited BV activity. Furthermore, knockdown of ADAM10/17 significantly reduced sCD30 concentrations and increased BV-induced cell death. These results suggest that ADAM10 and ADAM17 are involved in sCD30 production in ATL. Furthermore, endogenous extracellular CD30, such as sCD30 and CD30-positive extracellular vesicles shed by ADAM10/17, may be involved in BV-induced cell death. Taken together, our findings suggest that extracellular CD30 concentrations, including CD30 on extracellular vesicles, are a useful biomarker for BV therapy in ATL.

Allergic contact dermatitis (ACD) is a common skin disorder caused by contact with allergens. ACD treatment is based on patient education to avoid contact with allergens. However, sometimes patients may not be able to avoid the allergen because of its close proximity to their living environment. Thus, a novel therapeutic strategy that does not involve the avoidance of allergens is required. We previously reported that methionine, an essential amino acid, significantly suppressed ACD development caused by the repeated application of 1-fluoro-2,4-dinitrobenzene (DNFB). However, the magnitude of this suppressive effect of methionine depended on the mouse strain used to establish ACD, and the mechanism of this difference was still unclear in past studies. In this study, we investigated the mechanism underlying these strain differences and found that a lack of selenium-binding protein 1 (SBP1) enhanced the ACD-suppressive effect of methionine. The lack of SBP1 does not affect ACD progression; however, it reduces the hepatic beta-homocysteine methyltransferase (Bhmt) expression suppression by ACD. In support of this hypothesis, the lack of SBP1 reduced the suppression of hepatic dimethylglycine (DMG) production by ACD. These results suggest that the lack of SBP1 enhances the suppressive effects of methionine on ACD by suppressing DMG production.

Hepatic organoids (iHOs) generated from human-induced pluripotent stem cell-derived hepatocyte-like cells (HLCs) have attracted attention as a new source of hepatocytes to replace primary human hepatocytes (PHHs) in drug discovery research. Recently, we established iHOs from HLCs, which proliferated for more than 10 passages, and developed a two-dimensional (2D) culture protocol for iHOs, by which the cells showed much higher hepatic functions. In this study, we examined the cryopreservation of iHOs for the purpose of improving their versatility. Cryopreserved iHOs had comparable cell proliferative capacity to fresh iHOs. Hepatocyte marker gene expression levels in the cryopreserved iHOs were comparable to those without cryopreservation. When cryopreserved iHOs were directly matured by our 2D culture protocol, they showed higher hepatocyte marker gene expression levels and higher CYP3A4 activity than HLCs. Some of the hepatic functions in 2D-cultured cryopreserved iHOs were at levels comparable to those in PHHs. These results suggest that cryopreserved iHOs also differentiated into mature hepatocytes by 2D culture. We expect cryopreserved iHOs to be used as a user-friendly cell source for drug discovery research in many laboratories.

Bone resorption inhibitors, such as bisphosphonates, infrequently cause refractory medication-related osteonecrosis of the jaw (MRONJ). Oral care, including maintaining oral hygiene and preventing oral infections, is important for preventing MRONJ. However, the extent of oral care in patients taking bisphosphonates is unclear. We recommended dental visits to 790 outpatients taking bisphosphonates who visited the pharmacy at Ehime University Hospital. The effect of this recommendation was determined by evaluating changes in the rate of dental visits within 6 months among patients with and without a family dentist. Following recommendations by pharmacists, the dental visit rate increased from 46.2 to 67.6%, and the proportion of patients with a family dentist increased from 55.9 to 76.5%. Furthermore, patients with a family dentist had a significantly higher rate of dental visits than those without a family dentist (79.9 vs. 6.8%). The findings in this study suggest that pharmacists' recommendations for oral health care may lead to early detection and avoidance of MRONJ.

The Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2) system plays an important role in defense against oxidative stress, and its involvement has been implicated in body weight reduction under obese conditions. While the effect on white adipose tissue (WAT) has been intensely studied, focusing on the anti-inflammatory and anti-oxidative stress effects exerted by Nrf2 activation, the involvement of skeletal muscle has not been investigated. We assessed the body weight changes induced by Nrf2 activation by comparing its effect on WAT with those on skeletal muscle. We evaluated TBE-31, a potent Nrf2 activator, in a high-fat diet (HFD)-induced obesity model. Notably, TBE-31 significantly suppressed HFD-induced body weight gain compared with vehicle treatment. While treatment with TBE-31 induced a significant WAT weight decrease compared with vehicle, skeletal muscle weight was not affected. In addition, body weight changes were significantly correlated with WAT but not with skeletal muscle. Lipid deposition was remarkably improved in the adipose tissue, but muscle histology was not affected. A gene expression analysis revealed that Ucp-1 was upregulated and Il-6 downregulated by TBE-31 treatment in an Nrf2-dependent manner. Taken together, these findings suggest that pharmacological activation of Nrf2 suppressed HFD-induced body weight gain by affecting WAT.

Adriamycin (ADR)-induced cardiotoxicity was previously shown to be attenuated by the preadministration of docetaxel (DOC-ADR), with DOC given 12 h before ADR, and may involve the inhibition of ADR-induced increases in free radical production in myocardial tissue. However, the mechanisms by which DOC suppresses the production of free radicals remain unclear. Therefore, we herein investigated the mechanisms responsible in more detail. The direct effects of DOC on free radical scavenging were examined using a primary cardiomyocyte culture system and the organic radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). To assess the indirect effects of DOC, in vivo components with radical-scavenging activities were measured after the administration of DOC. Cell viability did not improve in the DOC-ADR group, and was lower than that in the ADR group. Furthermore, DOC did not scavenge DPPH. The radical-scavenging activities of antioxidant enzymes did not significantly differ between the DOC-ADR and ADR groups. On the other hand, ceruloplasmin (CP) oxidase activity, which acts on iron ions and suppresses reactive oxygen species (ROS) production, showed a marked transient change that peaked at 12 h after DOC was given (just before the administration of ADR). Therefore, ADR-induced ROS production may have been suppressed by CP activity, which was increased by the preadministration of DOC.

The safety profiles of iguratimod in large cohorts are lacking. The clinical characteristics and time-to-onset of adverse events remain completely unclear. Our real-world study aims to provide more comprehensive data for the risk management of iguratimod in the actual application environment. All data of iguratimod were obtained from the Japanese Adverse Drug Event Report (JADER) database. Four disproportionality analysis methods were used to detect significant pharmacovigilance signals. The Weibull shape parameter test was used to analyze the time-to-onset of adverse events. In our study, a total of 1472 adverse events associated with iguratimod treatment were collected, which refers to 22 System Organ Class. Within the standardized MedDRA queries, 23 positive signals were detected; 55 preferred terms (PTs) were detected by all 4 disproportionality analysis methods; and 30 PTs associated with infection were gained. Fourteen PTs were not listed in the directions, including 5 potential tumor signals. The most-mentioned PT is interstitial lung disease. Close to half of the adverse events (48.74%) occurred in the first 3 months of iguratimod treatment. The Weibull shape parameter test results showed that all of the disproportionality signals had an early failure-type profile, but infective signals present a random failure profile. This pharmacovigilance study provides valuable information for risk monitor and management of iguratimod, which helps enhance the safety of the clinical application.

Although regulated-upon-activation normal T-cell expressed and secreted (RANTES), a chemokine originally identified as a T-cell-specific gene product, has been shown to influence various cellular processes, its effects on vascular reactivity remain unclear. Therefore, we investigated the direct effects of prolonged RANTES exposure on responses to various vasoactive agents in isolated rat carotid arteries. Contractile responses to serotonin, isotonic high K⁺, noradrenaline, the thromboxane A₂ analog U46619, and endothelin-1 were similar between the control and RANTES-treated groups (100 ng/mL for approximately 24 h). However, RANTES treatment impaired acetylcholine-induced relaxation, whereas relaxations induced by the nitric oxide donor sodium nitroprusside, the ATP-sensitive potassium channel activator cromakalim, and the large-conductance calcium–activated potassium channel activator NS19504 were unaffected. Acute incubation with the nitric oxide synthase inhibitor N^G-nitro-l-arginine abolished acetylcholine-induced relaxation and eliminated the differences between the control and RANTES-treated groups. Furthermore, the cyclooxygenase inhibitor indomethacin also abolished the differences in acetylcholine-induced relaxation between the 2 groups. Co-treatment with the antioxidant N-acetyl-l-cysteine enhanced acetylcholine-induced relaxation in the presence of RANTES, while co-treatment with the C–C motif chemokine receptor 5 antagonist maraviroc slightly improved the relaxation response. These findings suggest that RANTES impairs acetylcholine-induced relaxation, likely due to the reduction of nitric oxide bioavailability and the unmasking of vasoconstrictor prostanoids through increased reactive oxygen species.

The high plasma glucose induced in glucose metabolism disorders leads to secondary pathologies, including bone disease. Fish scales, similar to mammalian bone, are composed of osteoblasts, osteoclasts, and calcified bone matrix and have been used as a system to analyze hyperglycemia-induced bone abnormalities. Here, we developed a hyperglycemia model in fish to study abnormalities in bone metabolism linked to increased plasma glucose and to analyze the function of calcitonin, the suppressor of osteoclastic activity, while maintaining high glucose levels. Following a 1-d fast and exposure to 5% glucose, plasma glucose concentrations increased significantly. We then examined plasma calcium and osteoclast activity of scales related to bone metabolism in goldfish treated with glucose for 5 d after a 1-d fast. The results showed that glucose treatment significantly increased plasma calcium levels at 3 and 5 d with a decrease in calcium content in the scales of goldfish. Hyperglycemia in glucose-exposed goldfish induced osteoclastic activation in scales, as indicated by the ratio of the osteoclastic activating factor (rankl) to the osteoclast inhibiting factor (osteoprotegerin, opg). Plasma calcitonin was found to be increased in glucose-exposed goldfish, which appears to suppress bone resorption by regulating the rankl/opg ratio. This hyperglycemia model, capable of examining both glucose and bone metabolism, would be valuable for analyzing the mechanism underlying abnormal bone metabolism caused by hyperglycemia.

We investigated the effects of docosahexaenoic acid (DHA) on noradrenaline (NA)-induced contractile responses in rat vas deferens smooth muscle (VDSM). DHA (3 × 10⁻⁶–3 × 10⁻⁵ M) significantly inhibited phasic contractions induced by NA (3 × 10⁻⁵ M) in a concentration-dependent manner. In contrast, under Ca²⁺-free conditions, DHA (3 × 10⁻⁵ M) slightly enhanced NA-induced contractile responses. DHA did not inhibit NA-induced contractile responses in the prostate, which are mediated by α_1A-adrenoceptor stimulation, similar to those in VDSM. Although verapamil (10⁻⁵ M), an L-type Ca²⁺ channel inhibitor, partially suppressed NA-induced contractile responses in VDSM, a substantial phasic component persisted. The residual phasic component was unaffected by LOE-908 (a receptor-operated Ca²⁺ channel inhibitor, 3 × 10⁻⁵ M), but was markedly inhibited by SKF-96365 (an inhibitor of both receptor-operated and store-operated Ca²⁺ channels, 3 × 10⁻⁵ M). Among inhibitors targeting store-operated Ca²⁺ channel candidates with high mRNA expression in VDSM, GSK417651A (10⁻⁵ M) and Pyr10 (3 × 10⁻⁵ M)—both putative inhibitors of transient receptor potential canonical 3/6 (TRPC3/6) channels—effectively inhibited the contractile response, whereas inhibitors targeting Orai1, transient receptor potential vanilloid 4 (TRPV4), or TRPC1/4/5 did not exert inhibitory effects. Similarly, under combined treatment with verapamil and LOE-908, contractile responses induced by cyclopiazonic acid (3 × 10⁻⁵ M, a sarco/endoplasmic reticulum Ca²⁺-ATPase inhibitor) were reduced by DHA, SKF-96365, and putative TRPC3/6 inhibitors, but not by inhibitors of Orai1, TRPV4, or TRPC1/4/5. These findings indicate that DHA suppresses NA-induced contractile responses in VDSM, primarily through inhibition of TRPC3/6 channels.

Cyclodextrins (CDs) are cyclic oligosaccharides that encapsulate hydrophobic molecules such as cholesterol. Hydroxypropyl-β-cyclodextrin (HP-β-CD), a cyclic heptasaccharide, has gained attention as a protective agent for chronic kidney diseases, particularly the genetic kidney disease Alport syndrome, due to its anti-inflammatory property and the ability to reduce cholesterol content in Alport kidneys. However, HP-β-CD has side effects of hearing loss and kidney injury. These concerns are important issues for Alport syndrome patients who have pre-existing hearing abnormalities and kidney dysfunction. We previously revealed that 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD), a cyclic octasaccharide, is less toxic than HP-β-CD. Here, we examined the dose-dependent effects of HP-γ-CD (0.71, 1.42, 2.85 mmol/kg, once a week) on the progressive disease phenotype in the Alport mouse model (Col4a5-G5X). HP-γ-CD at 0.71 mmol/kg suppressed the renal inflammation, glomerulosclerosis, and tubular injury in Alport mice, but did not prevent the decline in kidney function. Moreover, HP-γ-CD at 2.85 mmol/kg increased proteinuria and decreased the body weight of Alport mice. Interestingly, HP-γ-CD did not reduce the unesterified cholesterol (UC) content in Alport mouse kidneys, especially in the glomeruli. These results suggested that HP-γ-CD exerted its anti-inflammatory effect, but did not improve the progressive phenotype in the Col4a5 G5X Alport mouse model. Our findings add more information on the use and dosage effects of HP-γ-CD for experimental Alport syndrome.