Circadian rhythms in CYP2A5 expression underlie the time-dependent effect of tegafur on breast cancer.

The chemotherapeutic agent tegafur, a prodrug that prolongs the half-life of fluorouracil (5-FU), exerts antitumor effects against various cancers. Since tegafur is metabolized to 5-FU by CYP2A6 in the liver, the expression of CYP2A6 determines the effect of tegafur. Here, we report that the expression rhythm of Cyp2a5, a homolog of human CYP2A6, in female mice causes dosing time-dependent differences in tegafur metabolism. In the livers of female mice, CYP2A5 expression showed a circadian rhythm, peaking during the dark period. This rhythm is regulated by RORA, a core clock component, and abrogation of the CYP2A5 activity abolished the time-dependent difference in the rate of tegafur metabolism in female mice. Furthermore, administration of tegafur to mice transplanted with 4T1 breast cancer cells during the dark period suppressed increases in tumor size compared to female mice treated during the light period. Our findings reveal a novel relationship between 5-FU prodrugs and circadian clock machinery, potentially influencing antitumor effects, and contributing to the development of time-aware chemotherapy regimens for breast cancer.

Time-Dependent Differences in Vancomycin Sensitivity of Macrophages Underlie Vancomycin-Induced Acute Kidney Injury.

Although vancomycin (VCM)-frequently used to treat drug-resistant bacterial infections-often induces acute kidney injury (AKI), discontinuation of the drug is the only effective treatment; therefore, analysis of effective avoidance methods is urgently needed. Here, we report the differences in the induction of AKI by VCM in 1/2-nephrectomized mice depending on the time of administration. Despite the lack of difference in the accumulation of VCM in the kidney between the light (ZT2) and dark (ZT14) phases, the expression of AKI markers due to VCM was observed only in the ZT2 treatment. Genomic analysis of the kidney suggested that the time of administration was involved in VCM-induced changes in monocyte and macrophage activity, and VCM had time-dependent effects on renal macrophage abundance, ATP activity, and interleukin (IL)-1ß expression. Furthermore, the depletion of macrophages with clodronate abolished the induction of IL-1ß and AKI marker expression by VCM administration at ZT2. This study provides evidence of the need for time-dependent pharmacodynamic considerations in the prevention of VCM-induced AKI as well as the potential for macrophage-targeted AKI therapy. SIGNIFICANCE STATEMENT: There is a time of administration at which vancomycin (VCM)-induced renal injury is more and less likely to occur, and macrophages are involved in this difference. Therefore, there is a need for time-dependent pharmacodynamic considerations in the prevention of VCM-induced acute kidney injury as well as the potential for macrophage-targeted acute kidney injury therapy.

Oral administration of vancomycin alleviates heart failure triggered by chronic kidney disease.

Chronic kidney disease (CKD) induces an imbalance in the intestinal microbiota, affecting various physiological functions and leading to cardiovascular inflammation and fibrosis. However, the cardiotoxic impact of intestinal microbiota-derived uremic substances in advanced renal dysfunction remains unexplored. Therefore, we developed a 5/6 nephrectomy (5/6Nx) mouse model to investigate the intestinal microbiota and the effects of administering vancomycin (VCM) on the microbiota and the cardiac pathology associated with CKD. Despite VCM administration after the development of irreversible glomerulosclerosis and tubulointerstitial fibrosis, blood indoxyl sulfate and phenyl sulfate levels, which are intestinal bacteria-derived uremic substances, brain natriuretic peptide levels, and the fibrotic area in the heart were decreased. Moreover, VCM administration prevented 5/6Nx-induced weight loss and prolonged survival time. Our findings suggest that VCM-induced changes in the intestinal microbiota composition ameliorate heart failure and improve survival rates by reducing intestinal microbiota-derived cardiotoxic substances despite advanced renal dysfunction. This highlights the potential of using the intestinal microbiota as a target to prevent and treat cardiovascular conditions associated with CKD.

Mucosal patterns change after Helicobacter pylori eradication: Evaluation using blue laser imaging in patients with atrophic gastritis.

BACKGROUND: Mucosal patterns (MPs) observed on blue laser imaging in patients with atrophic gastritis can be classified as spotty, cracked, and mottled. Furthermore, we hypothesized that the spotty pattern may change to the cracked pattern after Helicobacter pylori (H. pylori) eradication. AIM: To further substantiate and comprehensively investigate MP changes after H. pylori eradication in a larger number of patients. METHODS: We included 768 patients who were diagnosed with atrophic gastritis with evaluable MP using upper gastrointestinal endoscopy at the Nishikawa Gas-trointestinal Clinic, Japan. Among them, 325 patients were H. pylori-positive, and of them, 101 patients who underwent upper gastrointestinal endoscopy before and after H. pylori eradication were evaluated for post-eradication MP changes. The patients' MPs were interpreted by three experienced endoscopists who were blinded to their clinical features. RESULTS: Among 76 patients with the spotty pattern before or after H. pylori eradication, the pattern disappeared or decreased in 67 patients [88.2%, 95% confidence interval (CI): 79.0%-93.6%), appeared or increased in 8 patients (10.5%, 95%CI: 5.4%-19.4%), and showed no change in 1 patient (1.3%, 95%CI: 0.2%-7.1%). In 90 patients with the cracked pattern before or after H. pylori eradication, the pattern disappeared or decreased in 7 patients (7.8%, 95%CI: 3.8%-15.2%), appeared or increased in 79 patients (87.8%, 95%CI: 79.4%-93.0%), and showed no change in 4 patients (4.4%, 95%CI: 1.7%-10.9%). In 70 patients with the mottled pattern before or after H. pylori eradication, the pattern disappeared or decreased in 28 patients (40.0%, 95%CI: 29.3%-51.7%), appeared or increased in 35 patients (50.0%, 95%CI: 38.6%-61.4%), and showed no change in 7 patients (10.0%, 95%CI: 4.9%-19.2%). CONCLUSION: After H. pylori eradication, MPs changed from spotty to cracked in most patients, which may help endoscopists easily and precisely evaluate H. pylori-related gastritis status.

Brain micro-inflammation at specific vessels dysregulates organ-homeostasis via the activation of a new neural circuit.

Impact of stress on diseases including gastrointestinal failure is well-known, but molecular mechanism is not understood. Here we show underlying molecular mechanism using EAE mice. Under stress conditions, EAE caused severe gastrointestinal failure with high-mortality. Mechanistically, autoreactive-pathogenic CD4+ T cells accumulated at specific vessels of boundary area of third-ventricle, thalamus, and dentate-gyrus to establish brain micro-inflammation via stress-gateway reflex. Importantly, induction of brain micro-inflammation at specific vessels by cytokine injection was sufficient to establish fatal gastrointestinal failure. Resulting micro-inflammation activated new neural pathway including neurons in paraventricular-nucleus, dorsomedial-nucleus-of-hypothalamus, and also vagal neurons to cause fatal gastrointestinal failure. Suppression of the brain micro-inflammation or blockage of these neural pathways inhibited the gastrointestinal failure. These results demonstrate direct link between brain micro-inflammation and fatal gastrointestinal disease via establishment of a new neural pathway under stress. They further suggest that brain micro-inflammation around specific vessels could be switch to activate new neural pathway(s) to regulate organ homeostasis.

Strong TCR-mediated signals suppress integrated stress responses induced by KDELR1 deficiency in naive T cells.

KDEL receptor 1 (KDELR1) regulates integrated stress responses (ISR) to promote naive T-cell survival in vivo. In a mouse line having nonfunctional KDELR1, T-Red (naive T-cell reduced) mice, polyclonal naive T cells show excessive ISR and eventually undergo apoptosis. However, breeding T-Red mice with TCR-transgenic mice bearing relatively high TCR affinity rescued the T-Red phenotype, implying a link between ISR-induced apoptosis and TCR-mediated signaling. Here, we showed that strong TCR stimulation reduces ISR in naive T cells. In mice lacking functional KDELR1, surviving naive T cells expressed significantly higher levels of CD5, a surrogate marker of TCR self-reactivity. In addition, higher TCR affinity/avidity was confirmed using a tetramer dissociation assay on the surviving naive T cells, suggesting that among the naive T-cell repertoire, those that receive relatively stronger TCR-mediated signals via self-antigens survive enhanced ISR. Consistent with this observation, weak TCR stimulation with altered peptide ligands decreased the survival and proliferation of naive T cells, whereas stimulation with ligands having higher affinity had no such effect. These results suggest a novel role of TCR-mediated signals in the attenuation of ISR in vivo.

A pain-mediated neural signal induces relapse in murine autoimmune encephalomyelitis, a multiple sclerosis model.

Although pain is a common symptom of various diseases and disorders, its contribution to disease pathogenesis is not well understood. Here we show using murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), that pain induces EAE relapse. Mechanistic analysis showed that pain induction activates a sensory-sympathetic signal followed by a chemokine-mediated accumulation of MHC class II+CD11b+ cells that showed antigen-presentation activity at specific ventral vessels in the fifth lumbar cord of EAE-recovered mice. Following this accumulation, various immune cells including pathogenic CD4+ T cells recruited in the spinal cord in a manner dependent on a local chemokine inducer in endothelial cells, resulting in EAE relapse. Our results demonstrate that a pain-mediated neural signal can be transformed into an inflammation reaction at specific vessels to induce disease relapse, thus making this signal a potential therapeutic target.

KDEL receptor 1 regulates T-cell homeostasis via PP1 that is a key phosphatase for ISR.

KDEL receptors are responsible for retrotransporting endoplasmic reticulum (ER) chaperones from the Golgi complex to the ER. Here we describe a role for KDEL receptor 1 (KDELR1) that involves the regulation of integrated stress responses (ISR) in T cells. Designing and using an N-ethyl-N-nitrosourea (ENU)-mutant mouse line, T-Red (naïve T-cell reduced), we show that a point mutation in KDELR1 is responsible for the reduction in the number of naïve T cells in this model owing to an increase in ISR. Mechanistic analysis shows that KDELR1 directly regulates protein phosphatase 1 (PP1), a key phosphatase for ISR in naïve T cells. T-Red KDELR1 does not associate with PP1, resulting in reduced phosphatase activity against eIF2α and subsequent expression of stress responsive genes including the proapoptotic factor Bim. These results demonstrate that KDELR1 regulates naïve T-cell homeostasis by controlling ISR.

Theoretical Explanation of the Lotus Effect: Superhydrophobic Property Changes by Removal of Nanostructures from the Surface of a Lotus Leaf.

Theoretical study is presented on the wetting behaviors of water droplets over a lotus leaf. Experimental results are interpreted to clarify the trade-offs among the potential energy change, the local pinning energy, and the adhesion energy. The theoretical parameters, calculated from the experimental results, are used to qualitatively explain the relations among surface fractal dimension, surface morphology, and dynamic wetting behaviors. The surface of a lotus leaf, which shows the superhydrophobic lotus effect, was dipped in ethanol to remove the plant waxes. As a result, the lotus effect is lost. The contact angle of a water drop decreased dramatically from 161° of the original surface to 122°. The water droplet was pinned on the surface. From the fractal analysis, the fractal region of the original surface was divided into two regions: a smaller-sized roughness region of 0.3-1.7 µm with D of 1.48 and a region of 1.7-19 µm with D of 1.36. By dipping the leaf in ethanol, the former fractal region, characterized by wax tubes, was lost, and only the latter large fractal region remained. The lotus effect is attributed to a surface structure that is covered with needle-shaped wax tubes, and the remaining surface allows invasion of the water droplet and enlarges the interaction with water.

Naïve T Cell Homeostasis Regulated by Stress Responses and TCR Signaling.

The survival of naïve T cells is believed to require signals from TCR-pMHC interactions and cytokines such as IL-7. In contrast, signals that negatively impact naïve T cell survival are less understood. We conducted a forward genetic screening of mice and found a mutant mouse line with reduced number of naïve T cells (T-Red mice). T-Red mice have a point mutation in the Kdelr1 gene, and their naïve T cells show enhanced integrated stress response (ISR), which eventually induces their apoptosis. Therefore, naïve T cells require a KDEL receptor-mediated mechanism that efficiently relieves cellular stress for their survival in vivo. Interestingly, naïve T cells expressing TCR with higher affinity/avidity to self-antigens survive in T-Red mice, suggesting the possible link between TCR-mediated survival and ISR-induced apoptosis. In this article, we discuss the regulation of naïve T cell homeostasis, keeping special attention on the ISR and TCR signal.

Theoretical explanation of the photoswitchable superhydrophobicity of diarylethene microcrystalline surfaces.

Two types of superhydrophobic surfaces which show lotus and petal effects were induced on photochromic diarylethene microcrystalline surfaces by UV and visible light irradiation and temperature control. On the surfaces showing the lotus effect, a low-adhesion superhydrophobic property is attributed to the surface structure being covered with densely standing needle-shaped crystals of the closed-ring isomer. On surfaces showing the petal effect, a high-adhesion superhydrophobic surface consists of fine needle-shaped crystals with high density together with a few rod-shaped crystals, where an invasion phenomenon occurs between these rod-shaped crystals. Furthermore, the different superhydrophobic properties of the surfaces are theoretically explained using multipillar surface models.

[Case of papillary fibroelastoma which caused cardiopulmonary arrest leading to emergent extirpation surgery].

A 73-year-old woman with cardiac tumor arising from aortic valve was scheduled for extirpation surgery. She has a symptom of chest discomfort during her walk. Contrasted CT scan around the aortic valve demonstrated a 1 cm-size tumor close to the left coronary inlet. Coronary blood flow was preserved. On the day of admission she became unconscious during preoperative interview with the surgeon. Cardiopulmonary resuscitation was immediately initiated and she regained her consciousness. Emergency operation was scheduled and started about two hours after the event of syncope. Cardiac tumor attached to the left cusp of the aortic valve was found and later identified as papillary fibroelastoma by pathological diagnosis. She was discharged on the 13th day from admission without neurological deficit. Occlusion of the left coronary artery inlet was strongly suspected from preoperative event of her syncope. Cardiac tumor around aortic value may cause significant derangement of circulation, and we should closely monitor the patient's status and prompt operation was indicated especially when tumor is impeding coronary artery inlet.

Photoinduced self-epitaxial crystal growth of a diarylethene derivative with antireflection moth-eye and superhydrophobic lotus effects.

We identified the mechanism of the formation of needle-shaped microcrystals on which the contact angle of a water droplet exceeds 170° [Nishikawa, N. et al. Langmuir, 2012, 28, 17817-17824]. The standing needle-shaped crystal of the closed-ring isomer of a diarylethene 3c grew at a much lower temperature than the eutectic temperature by irradiation of UV light on the thin films of the open-ring isomer 3o, due to the epitaxial growth of the 013 plane of 3c over the 110 plane of the crystal lattice of 3o in the subphase. Therefore, the new crystal-growth mechanism triggered by the photoisomerization does not require special inorganic single-crystal substrates and may be called self-epitaxial crystal growth. The needle-shaped crystals appeared well-ordered and stood inclined at an angle of about 60° to the surface. Consequently, the photo-induced rough surface shows not only the superhydrophobic lotus effect, but also the antireflection moth-eye effect, and these effects were switchable by alternate irradiation with UV and visible light.

Photoinduced formation of superhydrophobic surface on which contact angle of a water droplet exceeds 170° by reversible topographical changes on a diarylethene microcrystalline surface.

A superhydrophobic surface on which the contact angle of a water droplet exceeds 170° was reversibly produced by alternate irradiation with UV and visible light. Superhydrophobicity is due to the formation of densely generated submicrometer sized needle-shaped crystals (less than 0.2-0.3 µm diameter and 2.2-2.5 µm long) at 30 °C, which is much lower than the eutectic temperature of either isomers of the diarylethene. Below the eutectic temperature, the generated crystals were much smaller than those generated above the eutectic temperature. These smaller crystals more effectively enhanced the superhydrophobicity.

Photoinduced reversible topographical changes on diarylethene microcrystalline surfaces with biomimetic wetting properties.

Reversible topographical changes were observed on a photochromic diarylethene microcrystalline film surface by alternate irradiation with UV and visible light. Two types of surfaces were prepared from this film: 1) Storage of the film at 30 °C for 24 hours in the dark after UV irradiation afforded a surface that was covered with needle-shaped crystals, whose diameter and length were approximately 1 µm and 10 µm, respectively, and showed a superhydrophobic lotus effect. 2) Storage of the film at 70 °C for 3 hours in the dark caused the needle-shaped crystals to be converted into larger rod-like crystals (5~8 µm wide and 20~30 µm long) by Ostwald ripening and a disappearance of the lotus effect. The obtained activation energy of the formation of the needle- and rod-shaped crystals was 143 and 162 kJ mol(-1), respectively. Subsequent UV irradiation to the surface, which was followed by storage at 50 °C for 1 hour in the dark, gave a doubly rough structure; small needle-shaped crystals were formed between the larger rod-shaped crystals. The surface showed both superhydrophobic properties and the pinned effect of the water droplet: the petal effect. Fractal analysis of both surfaces were carried out using a box-counting method, and the lotus effect was observed in the presence of smaller-sized crystals, whilst the petal effect was observed with larger sized crystals (ca. 100 µm). We demonstrated that the hydrophobic property was controlled by the distribution in crystal size of the closed-ring isomer of the diarylethene. Visible-light irradiation of both rough surfaces afforded surfaces with cubic-shaped micro-crystals of the open-ring isomer.

[Survey on the attitudes of pregnant and lactating women about the use of drugs].

The purposes of this survey were to determine the attitudes and the extent of anxiety of pregnant and lactating women about drug use, and to research priority issues for pharmacists' intervention. Postpartum lactating women and mothers with children in a Growing Care Unit (GCU) in hospitals certified as Baby Friendly Hospital (BFH) were surveyed. The questions included the images the respondents had of drugs before pregnancy, the extent of anxiety about drug use, and ways to relieve it. The highest number of respondents (49.1%) did not want to use drugs often before pregnancy, but said "physician-prescribed drugs are fine". 24.5% had no negative images, and they "take drugs when necessary without worrying". An additional 14.2% did not like drugs, and "avoid them whenever possible", followed by 9.4% who did not want to use drugs, but were willing to take health food and other over-the-counter items. The respondents reported that the extent of anxiety about drug use was 79.3% during pregnancy, which was higher than 71.7% during lactation. It was not influenced by birth experience and age. "The images of drugs before pregnancy" and "the extent to which the anxiety was relieved during pregnancy" were extracted as factors related to the extent of anxiety, verifying that negative images of drugs and low degrees of relief from anxiety raise the anxiety of pregnant women. The above shows that pharmacists need to understand the anxiety of pregnant and lactating women about drug use, and the images they had of drugs before pregnancy, thereby they are expected to work actively to determine and relieve the anxiety.

[Assessment of chemotherapy-induced nausea and vomiting(CINV)using MASCC antiemesis tool].

Chemotherapy-induced nausea and vomiting (CINV) is one of the side effects causing significant psychological and physical suffering in patients receiving chemotherapy. Because CINV often impairs patients' quality of life and leads to cessation of treatments, antiemetic therapy has been thought important. Recently, the development of new antiemetic agents and the antiemetic guidelines provided by ASCO, NCCN, and MASCC etc. allow us to palliate CINV with appropriate antiemetic therapy. For appropriate antiemetic therapy, the patient must obtain accurate CINV information, particularly regarding whether it will be acute or delayed. MASCC first developed and posted the MASCC Antiemesis Tool (MAT) in 2004. The MAT is an eight-term scale for the assessment of acute and delayed nausea and vomiting, and is completed once per chemotherapy course. Although it is now validated in the US and UK and used worldwide, few reports have been available in Japan to use assessment tools including the MAT for acute and delayed CINV. We prospectively investigated the utility of the MAT. Fifteen ambulatory patients with breast cancer were subjected to evaluation, aged 29 to 73(median 58)years. In the results, the MAT allowed us to easily find patients treated with inappropriate antiemetic therapy. At the same time, it was easy to determine acute or delayed CINV, resulting in more appropriate treatment. The scale questions were unfamiliar to patients, but they clearly understood by means of a detailed explanation. Thus, it was suggested that the MAT is useful to assess antiemetic therapy. Consequently, it could contribute to completion of the chemotherapy.

Structure and performance of cationic assembly dispersed in amphoteric surfactants solution as a shampoo for hair damaged by coloring.

In recent years, hair coloring gains popularity as a trend of consumer's hair care. This coloring frequently damages hair. In response to this, a new shampoo-base was developed for repairing hair damaged by coloring. The new shampoo-base was prepared by dispersing cationic assembly in a solution of amphoteric surfactants. The mixture of behenyl trimethyl ammonium chloride (C22TAC) and behenyl alcohol (C22OH) was applied as the cationic assembly, which are dispersed in amido propyl betaine laurate (LPB) solution. LPB, which behaves as an amphoteric surfactant, was used as the wash-base. It was verified from the results on the measurements of DSC, calorimeter polarization, cryo-SEM and X-ray diffraction that the cationic assembly has a crystalline structure in the LPB solution. The new shampoo-base was highly efficient to change the color-damaged hair from hydrophilic to hydrophobic. The friction level of the hair washed with the new shampoo-base recovered to the same state as that of healthy hair. The exfoliation of cuticle was reduced after washing with the new shampoo-base.

Studies of human hair by friction force microscopy with the hair-model-probe.

We employed a cantilever modified with a self-assembled monolayer (SAM) as a "hair-model-probe" for friction force microscopy (FFM) to measure friction acting between hair and hair-like surfaces. The "hair-model-probe" was prepared by forming a SAM of octadecanethiol on a gold-coated cantilever. We investigated frictional properties of human hair at both root and tip, and the dependency on applied load, influence of scanning direction, and local frictional distribution. The friction coefficient of the hair tip was greater than that of the hair root. Load dependency of friction at the hair tip was clearly observed, while friction at the hair root was less dependent on applied load. At the hair root, an anisotropic frictional property was observed: friction force along the long axis of the hair fiber was about 1.5-2 times larger than that along the short axis. Atomic force microscopy (AFM) images showed striations on the cuticle cells that have about 6 nm depth and their long axis oriented in the direction of the hair fiber. The frictional distribution images revealed that the local areas showing strong shear corresponded to striations. Since such distribution of friction was not observed at the hair tip, it is suggested that the anisotropic frictional property at the hair root was caused mainly by the striations. The frictional distribution in regions that excluded the striations also showed the anisotropic frictional property that friction parallel to the long axis of the hair fiber is greater than that along the short axis. This result suggests that the orientation of fatty acid molecules comprising the fat layer (F-layer) may also contribute to the anisotropic frictional property. We have concluded that loss of the F-layer is a dominant cause of strong friction detected at the hair tip, and at the striations of the hair root.