Depressed patients may exhibit glucocorticoid hypersecretion, suggesting that elevated levels of glucocorticoids may play an important role in the pathophysiology of depression. Some postmortem brain studies have shown decreased pH and increased lactate levels in psychiatric patients, implying involvement of these factors in the pathogenesis. To investigate the effects of glucocorticoids on brain pH and lactate levels, and their roles in depressive symptoms, brain pH and lactate were examined in mice treated with corticosterone (CORT), the major bioactive glucocorticoid in rodents. A single administration of CORT decreased hippocampal pH after 24 h. Three weeks of CORT treatment decreased pH in the prefrontal cortex (PFC), striatum, and hippocampus (HC), whereas intake of pH 9.0 drinking water increased pH in these brain regions. pH and lactate levels were correlated in the PFC and HC of mice treated with CORT for 3 weeks. The suppression of body weight gain and decrease in adrenal weight observed after 3 weeks of CORT treatment were not alleviated by pH 9.0 water. However, an increase in immobility time in the forced swim test and a decrease in neurogenesis in the hippocampus were alleviated. The decrease in brain pH and increase in immobility time in the forced swim test and a decrease in neurogenesis in the hippocampus induced by CORT treatment were abolished by co-treatment with the glucocorticoid receptor (GR) antagonist mifepristone. These findings indicate that decreased brain pH via GRs may be related to glucocorticoid-induced depression-like behavior and decreased hippocampal neurogenesis.

Therapeutic drug monitoring (TDM) is a routine clinical practice used to individualize drug dosing to maintain drug efficacy and minimize the consequences of overexposure. TDM is applied to many drug classes, including immunosuppressants, antineoplastic agents, and antibiotics. Considerable effort has been made to establish routine TDM practices for each drug. However, because TDM has been developed within the context of specific drugs, there is insufficient understanding of historical trends within the field of TDM research as a whole. In this study, we employed text-mining approaches to explore trends in the TDM research field. We first performed a PubMed search to determine which drugs and drug classes have been extensively studied in the context of TDM. This investigation revealed that the most commonly studied drugs are tacrolimus, followed by cyclosporine and vancomycin. With regard to drug classes, most studies focused on immunosuppressants, antibiotics, and antineoplastic agents. We also subjected PubMed records of TDM-related studies to a series of text-mining pipelines. Our analyses revealed how TDM research has evolved over the years, thereby serving as a cornerstone for forecasting future research trends.

The blood–brain barrier (BBB) is a dynamic interface controlling the compound translocation between the blood and the brain, thereby maintaining neural homeostasis. There is cumulative evidence that BBB impairment during diabetes mellitus (DM) takes part in the progression of cognitive dementia. As tight junction proteins and ATP-binding cassette (ABC) transporters regulate substance exchange between the circulating blood and brain, the expression and function of these molecules under DM should be fully clarified. To understand the alteration of ABC transporter function in the BBB under DM, in vitro multicellular rat BBB spheroids consisting of conditionally immortalized rat brain capillary endothelial cells, astrocytes, and pericytes were newly developed. Immunostaining and permeability analysis of paracellular transport markers suggested the construction of tight junctions on the surface of the BBB spheroids. Transport analyses using fluorescence substrates of P-glycoprotein (P-gp), the breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 4 (MRP4) indicate the functional expression of these transporters in the spheroids. After treatment with advanced glycation end-products (AGEs), involved in various signals during DM, the mRNA expression of tight junction molecules and ABC transporters in the BBB spheroids was upregulated. Furthermore, the functional changes in P-gp and BCRP in the BBB spheroids exposed to AGEs were canceled by the inhibitors of the receptor for AGEs (RAGE). These results suggest that AGE-RAGE interaction upregulates P-gp and BCRP function in the BBB.

Nurr1 (NR4A2) is a member of nuclear receptor superfamily that regulates gene transcription in midbrain dopaminergic neurons and also inhibits nuclear factor-κB-mediated inflammatory responses in brain microglial cells. To date, various compounds have been reported to stimulate transcriptional activity of Nurr1 on neuronal genes, but their anti-inflammatory actions are poorly characterized. The present study examined the effects of three kinds of Nurr1 ligands, amodiaquine, 1,1-bis(3′-indolyl)-1-(p-chlorophenyl)-methane (C-DIM12) and 5-chloronaphthalen-1-amine (5-CNA), on inflammatory responses of microglial BV-2 cells. Lipopolysaccharide (LPS)-induced upregulation of interleukin-1β mRNA and tumor necrosis factor α mRNA was inhibited by all three compounds, whereas upregulation of interleukin-6 mRNA and inducible nitric oxide synthase (iNOS) mRNA was significantly inhibited only by 5-CNA. On the other hand, LPS-induced nuclear translocation of p65 subunit of nuclear factor-κB was prevented only by amodiaquine. C-DIM12 increased nuclear localization of Nurr1 and transiently upregulated Nurr1 protein expression, whereas amodiaquine and 5-CNA had no effect on these parameters. Notably, inhibitory effect of 5-CNA on iNOS mRNA upregulation was reversed by co-application of amodiaquine. Conversely, inhibitory effect of amodiaquine on p65 nuclear translocation was cancelled by 5-CNA. These results reveal distinct characteristics of anti-inflammatory actions of Nurr1 ligands.

Cellular aging causes declining cell functionality, gradually disrupting cellular homeostasis. Mitochondria are crucial in numerous metabolic processes, including the electron transport chain and fatty acid β-oxidation. Mitochondrial dysfunction is closely linked to aging-related liver dysfunction because it impairs fatty acid metabolism, potentially leading to nonalcoholic fatty liver disease. We demonstrated that neferine-induced autophagy suppressed the aging phenotype in proliferative and replicative aging-induced cells and aging liver tissue by reactivating mitochondrial function. Pharmacological analyses revealed that neferine-induced autophagy via the death-associated protein kinase 1 (DAPK1) and c-Jun N-terminal kinase (JNK) signaling pathways despite the lack of AMP activated protein kinase (AMPK) signaling activation. Furthermore, neferine stimulated ATP production and β-oxidation activity in aging cells. Our in vivo experiments demonstrated that oral administration of neferine rejuvenated aging liver tissue, suppressed fatty acid accumulation in the liver, and reduced senescence-associated β-galactosidase activity. Thus, neferine rejuvenated aging cells and liver tissue by inducing autophagy to reactivate mitochondrial function.

The systemic RNA interference defective 1 (SID-1) family proteins are putative double-stranded RNA (dsRNA) transporters. Two mammalian homologs, SIDT1 and SIDT2 have been linked to many functions such as innate immune responses, microRNA uptake and lysosomal degradation of RNA/DNA whereas Caenorhabditis elegans SID-1 is essential for systemic RNA interference. However, dsRNA uptake mechanism is largely unknown. In this review, we discuss our current understanding of the molecular functions of SID-1 family proteins at a structure level, which highlights recent structural studies.

Itch is a prominent symptom of atopic dermatitis (AD). However, the underlying mechanism remains complex and has not yet been fully elucidated. Mas-related G protein-coupled receptor A3 (MrgprA3) has emerged attention as a marker of primary sensory neurons that specifically transmit itch signals; however, its involvement in AD-related itch has not been extensively explored. In this study, we developed an AD itch mouse model by repeatedly applying house dust mite (HDM) extract to barrier-impaired skin via a special diet. To clarify the role of MrgprA3⁺ neurons in itch behavior in our AD model, we adopted a toxin receptor-mediated cell knockout strategy using transgenic mice in which the diphtheria toxin receptor (DTR) gene was placed under the control of the Mrgpra3 promoter. When the HDM extract was repeatedly applied to the face and back skin of special diet-fed mice, the mice exhibited AD-like dry and eczematous skin lesions accompanied by three types of itch-related behaviors:1) spontaneous scratching, 2) acute scratching after antigen challenge, and 3) light touch-evoked scratching. Upon diphtheria toxin administration, substantial depletion of DTR⁺/MrgprA3⁺ neurons was observed in the dorsal root ganglion. Ablation of MrgprA3⁺ neurons suppressed acute itch responses after HDM application, whereas spontaneous and touch-evoked itch behaviors remained unaffected. Our findings unequivocally demonstrate that in our AD model, MrgprA3⁺ primary sensory neurons mediate acute allergic itch responses, whereas these neurons are not involved in spontaneous itch or alloknesis.

The elderly Japanese population is growing rapidly due to increasing longevity and declining birth rates. These findings have implications for drug development and safety in elderly patients; however, the Japanese stakeholders have been slow to adapt. This study aimed at examining methods for providing sufficient information on safe use of pharmaceuticals in elderly patients in Japan. For new drugs recently approved in Japan for diseases with a high prevalence among the elderly, we investigated the state of safety information provision for elderly patients through the package insert and also safety data evaluation in elderly patients in clinical studies. Of the 64 targeted drugs, only 14 provided geriatric use information based on clinical study data or indication, 38 had general cautionary descriptions, and 12 did not have geriatric use information. Most drugs met the recommendation of enrolling >100 elderly patients in the clinical development program. However, a discrepancy was observed in the proportion of elderly patients in clinical trials compared to that in real-world clinical setting. Twenty-nine drugs compared the incidence of key adverse events (AEs) in elderly and younger patients, whereas 25 only reported the overall incidence of AEs. To improve healthcare outcomes, healthcare professionals need access to sufficient safety information through package inserts containing data from clinical trials. Marketing authorization holders and regulatory authorities must work together to ensure that such safety information based on sufficient data is included in package inserts.

Timosaponin AIII (TAIII), a steroidal saponin isolated from the root of Anemarrhena asphodeloides Bunge, exhibits various pharmacological activities, including anti-cancer properties. TAIII inhibits the migration and invasion of various cancer cell types. However, the mechanism underlying how TAIII regulates the motility of cancer cells remains incompletely understood. In this study, we demonstrate that TAIII disrupted cell–extracellular matrix (ECM) interactions by inhibiting internalization of cell surface proteins, such as integrins. We found that TAIII inhibited cell adhesion on various ECMs. Structure–activity relationship analysis demonstrated that TAIII exhibited unique activity among the saponins from Anemarrhena asphodeloides Bunge and that the number and position of saccharide moieties were important for TAIII to exert its activity. Time lapse imaging revealed that TAIII also suppressed cell spreading on the ECM, membrane ruffling, and lamellipodia formation. Furthermore, we examined integrin β1 behaviors in response to TAIII treatment and found that TAIII blocked its internalization. These findings contribute to delineating the potential molecular mechanisms by which TAIII exerts anti-metastatic activity.

Rho kinase inhibitor fasudil exerts therapeutic effects against vasospasms. In this study, we aimed to compare its suppressive effects on serotonin (5-HT)- and noradrenaline (NAd)-induced contractions of human endothelium-denuded internal thoracic arteries (ITAs) and saphenous veins (SVs). NAd and 5-HT induced concentration-dependent contractions in both ITAs and SVs. However, fasudil (3 µmol/L) pretreatment decreased these constrictor-induced contractions in both ITAs and SVs. Fasudil exerted similar inhibitory effects on 5-HT and NAd in ITAs. However, in SVs, fasudil exerted stronger inhibitory effects on NAd-induced contractions than on 5-HT-induced contractions. Therefore, inhibitory effects of fasudil on 5-HT-induced contractions were stronger in ITAs than in SVs. Overall, these results suggest that Rho kinases exert different effects on the two vasoconstrictors in SVs, but not in ITAs, thus explaining their different graft patencies.

Since its first discovery as a bioactive phospholipid inducing potent platelet aggregation, platelet-activating factor (PAF) has been shown to be involved in a wide variety of inflammatory and allergic disease states. Many pharmacological studies in the 1980s and 1990s also showed that PAF induces endothelium-dependent vascular relaxation and contraction of various smooth muscles (SMs), including those in the airway, gastrointestinal organs, and uterus. However, since the late 1990s, there have been few reports on the SM contractions induced by PAF. The lower urinary tract (LUT), particularly the urinary bladder (UB) has attracted recent attention in SM pharmacology research because patients with LUT dysfunctions including overactive bladder are increasing as the population ages. In addition, recent clinical studies have implicated the substantial role of PAF in the inflammatory state in LUT because its production increases with smoking and with cancer. However, the effects of PAF on mechanical activities of LUT SMs including UBSM have not been investigated to date. Recently, we found that PAF very strongly increased mechanical activities of UBSM in guinea pigs and mice, and partly elucidated the possible mechanisms underlying these actions of PAF. In this review, we describe the effects of PAF on LUT SMs by introducing our recent findings obtained in isolated UBSMs and discuss the physiological and pathophysiological significance. We also introduce our data showing the effects of PAF on the SM mechanical activities of genital tissues (prostate and vas deferens).

The signal transducer and activator of transcription 3 (STAT3) protein is a key regulator of cell differentiation, proliferation, and survival in hematopoiesis, immune responses, and other biological systems. STAT3 transcriptional activity is strictly regulated through various mechanisms, such as phosphorylation and dephosphorylation. In this study, we attempted to identify novel phosphatases which regulate STAT3 activity in response to cytokine stimulations. To this end, leukemia inhibitory factor (LIF)/STAT3 dependent phosphatase induction was evaluated in the mouse hepatoma cell line Hepa1–6. After LIF stimulation, the expression of several atypical dual specific phosphatases (aDUSPs) was upregulated in Hepa1–6 cells. Among the LIF-induced aDUSPs, we focused on DUSP15 and clarified its functions in LIF/STAT3 signaling using RNA interference. DUSP15 knockdown decreased LIF-induced Socs3 mRNA expression and STAT3 translocation. Furthermore, loss of DUSP15 reduced the phosphorylation of STAT3 at Tyr705 and Janus family tyrosine kinase 1 (Jak1) at Tyr1034/1035 in response to LIF. The interaction between Jak1 and DUSP15 was observed in LIF-stimulated Hepa1–6 cells. We also demonstrated the suppression of granulocyte colony-stimulating factor (G-CSF)-mediated gp130/STAT3-dependent cell growth of Ba/F-G133 cells via DUSP15 knockdown. Therefore, DUSP15 functions as a positive feedback regulator in the Jak1/STAT3 signaling cascade.

Signal transducer and activator of transcription 3 (STAT3) is a pleiotropic factor involved in multiple vital biological processes and a key mediator of gene transcription in response to cytokines, growth factors and aberrant activation of oncogenic signaling. STAT3 has two splicing isoforms, STAT3α and STAT3β, derived from alternative splicing of exon 23 within pre-mRNA. STAT3β differs from STAT3α by replacement of 55 amino-acid residues in the C-terminal transactivation domain with 7 specific amino acids. Thus, a shorter STAT3β was originally regarded as a dominant negative isoform of STAT3α. Recently accumulating evidence from independent studies have shown STAT3 splicing isoforms confer distinct and overlapping functions in many fundamental cellular regulatory steps such as cell differentiation, inflammatory responses, and cancer progression. However, relatively little is known about the mechanisms of STAT3 pre-mRNA splicing, and it remains undiscovered which chemical compounds or bioactive substances can induce the STAT3β expression. In this study, we generated a potent reporter for detection of alternative splicing of STAT3 pre-mRNA optimized for the screening of function-known chemical library, and successfully identified entinostat, a histone deacetylase inhibitor, as a novel inducer of STAT3β through modulating mRNA splicing. Our findings demonstrate that alternative splicing of STAT3 can be regulated by a compound, providing an important clue for understanding the regulation mechanisms of the expression balance of STAT3 isoforms in a chemical biology approach. Entinostat is likely to be a promising seed compound for elucidating how the higher ratio of STAT3β expression impacts on biological responses associated with Janus kinase (JAK)/STAT3 signaling pathway.

Siweixizangmaoru decoction (SXD) is widely used as an anti-rheumatoid arthritis (RA) in Tibet, however, the specific anti-inflammatory mechanism of SXD is still unclear. This research attempts to examine the efficacy and possible mechanisms of SXD in treating RA. The primary chemical components of SXD were identified using UHPLC-Q-Exactive Orbitrap MS. We established a lipopolysaccharide (LPS)-induced RAW264.7 macrophage inflammatory injury model to explore the anti-inflammatory mechanism of SXD and validated it through in vivo experiments. According to our research in vitro as well as in vivo, SXD exhibits anti-inflammatory qualities. SXD can suppress nitric oxide (NO) and pro-inflammatory factor production in RAW264.7 cells activated by LPS. The mechanism underlying this effect might be connected to the janus tyrosine kinase 2–signal transducer and activator of transcription 3 (JAK2/STAT3) and nuclear factor-κB (NF-κB) signaling pathways. In vivo, SXD alleviates joint swelling, decreases the generation of inflammatory factors in the serum, lowers oxidative stress, and improves joint damage. In short, SXD improves joint degeneration and lowers symptoms associated with RA by regulating inflammation via the suppression of NF-κB and JAK2/STAT3 signaling pathway activation.

The pathogenesis of stress-related disorders involves aberrant glucocorticoid secretion, and decreased pH and increased lactate in the brain are common phenotypes in several psychiatric disorders. Mice treated with glucocorticoids develop these phenotypes, but it is unclear how glucocorticoids affect brain pH. Therefore, we investigated the effect of corticosterone (CORT), the main glucocorticoid in rodents, on extracellular pH and lactate release in cultured astrocytes, which are the main glial cells that produce lactate in the brain. CORT treatment for one week decreased the extracellular pH and increased the extracellular lactate level via glucocorticoid receptors. CORT also increased the intracellular pyruvate level and upregulated pyruvate dehydrogenase kinase 4 (PDK4), while PDK4 overexpression increased extracellular lactate and decreased the extracellular pH. Furthermore, PDK4 inhibition suppressed the increase in extracellular lactate and the decrease in extracellular pH induced by CORT. These results suggest that increased lactate release via accumulation of intracellular pyruvate in astrocytes by chronic glucocorticoid exposure contributes to decreased brain pH.

Helicobacter pylori eradication is crucial in the treatment of peptic ulcers caused by H. pylori infection, a disease highly prevalent in Asia. We present a pooled analysis of two randomized, double-blind, double-dummy, phase 3 studies evaluating the efficacy and safety of vonoprazan-based bismuth-containing quadruple therapy for H. pylori eradication. Patients aged ≥18 years with endoscopically confirmed duodenal or gastric ulcers were randomized 1 : 1 to receive vonoprazan 20 mg or lansoprazole 30 mg once daily for up to 6 (duodenal ulcers) or 8 weeks (gastric ulcers). H. pylori–positive patients received vonoprazan- or lansoprazole-based bismuth-containing quadruple therapy for the first 2 weeks. H. pylori eradication was determined using the carbon-13 urea breath test at a follow-up visit 4 weeks post-treatment. The H. pylori eradication rate was 90.6% with vonoprazan vs. 85.2% with lansoprazole (difference: 5.4%; 95% confidence interval (CI): −0.1, 10.8). H. pylori eradication rates were 7.1% (95% CI: 1.4, 12.8) and 12.6% (95% CI: 3.9, 22.0) higher in patients aged <65 years and current smokers, respectively, with vonoprazan vs. lansoprazole. In the Chinese subpopulation, the H. pylori eradication rate was 92.0% with vonoprazan vs. 86.0% with lansoprazole (difference: 6.1%; 95% CI: 0.5, 11.7). Treatment-emergent adverse events occurred in 72.7 vs. 62.6% of H. pylori–positive patients at baseline in the vonoprazan vs. lansoprazole arm. H. pylori eradication with vonoprazan-based quadruple therapy was noninferior to lansoprazole-based quadruple therapy and exceeded 90%, a clinically relevant threshold for determining the efficacy of H. pylori eradication regimens (ClinicalTrials.gov identifier: NCT03050359; NCT03050307).

The efficacy of mesenchymal stem cell (MSC) transplantation has been reported for various diseases. We previously developed a drug delivery system targeting mitochondria (MITO-Porter) by using a microfluidic device to encapsulate Coenzyme Q₁₀ (CoQ₁₀) on a large scale. The current study aimed to confirm if treatment with CoQ₁₀ encapsulated by MITO-Porter enhanced mitochondrial functions in MSCs, with the potential to improve MSC transplantation therapy. We used highly purified human bone marrow-derived MSCs, described as rapidly expanding clones (RECs), and attempted to control and increase the amount of CoQ₁₀ encapsulated in the MITO-Porter using microfluidic device system. We treated these RECs with CoQ₁₀ encapsulated MITO-Porter, and evaluated its cellular uptake, co-localization with mitochondria, changes in mitochondrial respiratory capacity, and cellular toxicity. There was no significant change in mitochondrial respiratory capacity following treatment with the previous CoQ₁₀ encapsulated MITO-Porter; however, mitochondrial respiratory capacity in RECs was significantly increased by treatment with CoQ₁₀-rich MITO-Porter. Utilization of a microfluidic device enabled the amount of CoQ₁₀ encapsulated in MITO-Porter to be controlled, and treatment with CoQ₁₀-rich MITO-Porter successfully activated mitochondrial functions in MSCs. The MITO-Porter system thus provides a promising tool to improve MSC cell transplantation therapy.

CYP2D6 variants contain various single nucleotide polymorphisms as well as differing levels of metabolic activity. Among these, one of the less active variants CYP2D6*10 (100C > T) is the most prevalent mutation in East Asians, including Japanese. This mutation leads to an amino acid substitution from proline to serine, which reduces the stability of CYP2D6 and consequently decreases its metabolic activity. In this study, we used a genome editing technology called the Precise Integration into Target Chromosome (PITCh) system to stably express six drug-metabolizing enzymes (CYP3A4, POR, uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), CYP1A2, CYP2C19, CYP2C9, and CYP2D6*10) in HepG2 (CYP2D6*10 KI-HepG2) cells to examine the effect of CYP2D6*10 on drug metabolism prediction. The protein expression levels of CYP2D6 in CYP2D6*10 KI-HepG2 cells were reduced relative to those in the CYP3A4-POR-UGT1A1-CYP1A2-CYP2C19-CYP2C9-CYP2D6 knock-in-HepG2 (CYPs-UGT1A1 KI-HepG2) cells. Consistent with the CYP2D6 protein expression results, CYP2D6 metabolic activity in CYP2D6*10 KI-HepG2 cells was reduced relative to CYPs-UGT1A1 KI-HepG2 cells. We successfully generated CYP2D6*10 KI-HepG2 cells with highly expressed, functional CYP2D6*10, as well as CYP1A2, 2C9, 2C19 and 3A4. CYP2D6*10 KI-HepG2 cells could be an invaluable model for hepatic metabolism and hepatotoxicity studies in East Asians, including Japanese.

Bisdemethoxycurcumin (BDMC) is one of major forms of curcuminoids found in the rhizomes of turmeric. Docetaxel (DTX) is the standard of care for men diagnosed with androgen-independent prostate cancers. Here we report for the first time that BDMC could reinforce the effect of DTX against prostate cancer in vitro and in vivo. In vitro study, PC3 and LNCaP cells were cultured and treated with BDMC and DTX alone or in combination. The effects on cell viability were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was assessed by annexin V/propidium iodide (PI) staining, while cell cycle was assessed by PI staining. Bax, Bcl-2, caspase, poly(ADP-ribose)polymerase (PARP), cyclin B1 and CDK1 expression were assayed by Western blot. We found that a combination treatment of BDMC (10 µM) with DTX (10 nM) was more effective in the inhibition of PC3 and LNCaP cell growth and induction of apoptosis as well as G2/M arrest, which is accompanied with the significant inhibition of Bcl-2, cyclin B1, CDK1 expression and significant increase of Bax, cleaved caspase-9, cleaved caspase-3 and cleaved PARP, than those by treatment of BDMC or DTX alone. Moreover, in vivo evaluation further demonstrated the superior anticancer efficacy of BDMC and DTX compared to DTX alone in a murine prostate cancer model. These results suggest that BDMC can be an attractive therapeutic candidate in enhancing the efficacy of DTX in prostate cancer treatment.

Research on sex differences has increased across various fields, including cancer and its treatment domains. Reports have indicated sex differences in cancer incidence, survival rates, and the efficacy of anticancer drugs. However, such reports are limited, and in-depth assessments of the underlying mechanisms are still in progress. Although various chemotherapeutic regimens are applicable for breast cancer treatment, reports have surfaced regarding weight gain in female patients undergoing fluorouracil, epirubicin, cyclophosphamide (FEC) or cyclophosphamide, methotrexate, fluorouracil (CMF) therapy. We hypothesized the potential of 5-fluorouracil (5-FU) in weight gain and sex-related differences. To address this, we conducted experiments in mice to confirm weight gain and sex differences following 5-FU administration, and elucidate the underlying mechanisms. Our findings revealed weight gain and increased food intake in female mice following 5-FU administration. Additionally, female mice receiving 5-FU exhibited increased norepinephrine and α1- and α2-adrenergic receptor expression, reduced estradiol levels, and increased ghrelin levels. These results indicate 5-FU administration-induced sex differences in weight gain and implicate increased food intake because of increased norepinephrine and α1- and α2-adrenergic receptor expression, reduced estradiol levels, and a subsequent increase in ghrelin levels, which contribute to weight gain in female patients undergoing CMF therapy.