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mRNA expression of molecules related to the activity of nitric oxide or prostaglandin E2, the critical regulators maintaining the ductus arteriosus patency, was examined in rat ductus arteriosus at preterm (days 18.5 and 19.5 of pregnancy) and near term (days 20.5 and 21.5). The endothelial nitric oxide synthase mRNA level increased transiently at preterm and then decreased at near term. The cyclooxygenase 2 mRNA increased gradually from near-term to the term complementary to the reduced endothelial nitric oxide synthase mRNA. These results suggest that the role shift between nitric oxide and prostaglandin E2 in maintaining ductus arteriosus patency at preterm and near term may be due to complementary expression changes of endothelial nitric oxide synthase and cyclooxygenase 2 at the transcriptional level. This article is protected by copyright. All rights reserved.

Neuronal differentiation of adipose tissue-derived stem cells (ASCs) is potently promoted by valproic acid (VPA) through a gaseous signaling molecule, nitric oxide (NO). Here, we investigated the involvement of hydrogen sulfide (H

The involvement of nitric oxide (NO) signaling in apoptosis was examined in the placental bed of mid-to-late pregnant rats. Pregnant rats were treated with l-NAME, a nitric oxide synthase inhibitor, by subcutaneous infusion for 48 hours before the examination at day 13.5, 17.5, or 21.5. l-NAME induced apoptosis in the placental bed to a limited extent at days 13.5 and 17.5, but not at day 21.5. When the placental bed was examined at day 17.5, the protein expression of both executioner (C-Cas3) and inhibitor (XIAP) of apoptosis was increased by l-NAME, but they did not co-localized with apoptosis. It was presumed that placental bed apoptosis induced by l-NAME is regulated through the expression of both executioner and inhibitor, possibly involving protein S-nitrosylation.

Hemodialysis patients often develop constipation. We analyzed the advantage of synbiotics over prebiotics based on the stool form due to the intestinal environment in hemodialysis patients. Patients received either synbiotics or prebiotics for four weeks. The synbiotics group was treated with partially hydrolyzed guar gum containing Bifidobacterium longum BB536, while the prebiotics group was treated with the same fiber alone. The defecation status was assessed using the Bristol Stool Form Scale and abdominal bloating was evaluated using a visual analog scale. The fecal microbiota, measured by a terminal restriction fragment length polymorphism analysis, and the fecal short-chain fatty acid concentrations, measured by gas chromatography, were compared between the two groups. Synbiotics ingestion improved the individual stool form and abdominal bloating, and increased Bifidobacterium, which produces short-chain fatty acid, 13.9-fold after ingestion. In particular, acetic acid increased 2.5-fold in the synbiotics group. On the other hand, butyric acid increased 3.0-fold in the prebiotics group. Synbiotics improved the stool form in hemodialysis patients due to the composition of the intestinal microbiota and short-chain fatty acid concentrations.

Expression of desmin, an intermediate filament, in the myometrium and cervix were investigated in peripartum rats (full term day 22 of pregnancy (DP22)). Des mRNA was expressed in lesser amounts in the cervix at peripartum (DP17 and 21, and day of birth 1 (DB1)), compared to those in the cervixes of ovariectomized rats. Immunohistochemical analysis revealed that desmin protein was diffusely present in the myometrium, and locally in the epithelium of the cervix. Western blot analysis showed that desmin protein levels in the myometrium increased 4- to 6-fold at DP17, 21 and DB1, and decreased rapidly at DB2 to the basal level observed in ovariectomized or non-pregnant rats. In contrast, cervical desmin protein levels increased approximately 10-fold at DP21 compared to those in ovariectomized rats, but decreased rapidly at DB1, indicating its decrease at parturition and an inconsistency between mRNA and protein expression. The administration of 17β-estradiol to ovariectomized rats increased desmin protein levels in the myometrium and cervix after 24 h. S-nitrosylated desmin protein was detected in the myometrium and cervix at DP21. The mRNA expression of inducible nitric oxide synthase was consistent with the expression of desmin protein. Thus, desmin, which is regulated by estradiol, is differentially expressed in the myometrium and cervix at peripartum possibly for successful pregnancy and parturition. In the cervix, desmin protein expression seems to be regulated by estradiol at the translational level. S-nitrosylation of desmin may have a potential role in the peripartum uterus.

Highlights • 4-MeMBI, 5-MeMBI and MBI inhibit CYP3A2 activity in cultured rat hepatocytes. • 4-MeMBI and 5-MeMBI, not MBI, induce CYP1A1/2 activity in cultured rat hepatocytes. • Effects of the chemicals on CYP3A2 suggest metabolic drug-drug interaction potential. • 4-MeMBI and 5-MeMBI induce CYPs 3A4 and 1A1/2 activity in cultured human hepatocytes. • Primary cultured hepatocytes are useful in CYP experiments of benzimidazole compounds., Effects of 4-methyl-2-mercaptobenzimidazole (4-MeMBI) and 5-methyl-2- mercaptobenzimidazole (5-MeMBI) on cytochrome P450 (CYP) activity were examined in primary cultured rat hepatocytes. Hepatocytes from male Wistar rats were cultured in the presence of 4-MeMBI or 5-MeMBI (0−400 μM), and the activity of CYPs 3A2/4 (48 and 96 h) and 1A1/2 (48 h) was determined by measuring the activity of testosterone 6β-hydroxylation and 7-ethoxyresorufin O-deethylation, respectively. As a result, 4-MeMBI and 5-MeMBI (≥12.5 μM) inhibited CYP3A2 activity. On the other hand, 4-MeMBI (≥25 μM) and 5-MeMBI (≥100 μM) induced CYP1A1/2 activity, being consistent with the previous in vivo results. In a comparative metabolism study using primary cultured human hepatocytes from two Caucasian donors, 4-MeMBI and 5-MeMBI induced the activity of CYPs 3A4 and 1A1/2 with individual variability. It was concluded from these results that 4-MeMBI, 5-MeMBI and MBI caused inhibition of CYP3A2 activity in primary cultured rat hepatocytes, suggesting their potential for metabolic drug-drug interactions. Primary cultured rat and human hepatocytes were considered to be useful for the evaluation of effects of the benzimidazole compounds on their inducibility and inhibitory activities of cytochrome P450 forms.

Pancreatic cancer (PC) is highly aggressive with multiple oncogenic mutations. The efficacy of current chemotherapy is poor, and new therapeutic targets are needed. The forkhead box (FOX) proteins are multidirectional transcriptional factors strongly implicated in malignancies. Their expression is consistently suppressed by several oncogenic pathways such as PI3K/AKT signaling activated in PC. A recent study showed that class IIa histone deacetylases (HDAC) can act as a transcriptional suppressor. In this study, we hypothesized that HDAC class IIa inhibition would upregulate FOXO3a expression, thereby inducing its transcription-dependent antitumor effects.We confirmed the change of FOXO3a expression and the effect of the cell growth inhibition by HDAC class IIa inhibition in AsPC-1 cells. Because FOXO3a is subject to ubiquitylation-mediated proteasome degradation, we examined the synergistic activation of FOXO3a by HDAC class IIa selective inhibitor TMP269 combined with proteasome inhibitor carfilzomib.We observed that TMP269 induced FOXO3a expression in a dose-dependent manner and inhibited cell growth in AsPC-1 cells. G1/S arrest was observed. FOXO3a expression was further increased and cell growth inhibition was dramatically enhanced by TMP269 combined with carfilzomib.Dual inhibition of class IIa HDACs and proteasome could be a promising new strategy for modifying FOXO3a activity against PC.

The differentiation of adipose tissue-derived stem cells (ASCs) to neuronal cells is greatly promoted by valproic acid (VPA), and is synergistically enhanced by the following treatment with neuronal induction medium (NIM) containing cAMP-elevating agents. In the present study, we investigated the synergism between VPA and NIM in neuronal differentiation of ASCs, assessed by the expression of neurofilament medium polypeptide (NeFM), with respect to Ca

Backgroundaims : We investigated the contributing factors of hyponatremia in patients on nutrition support using bioelectrical impedance analysis (BIA). Methods : Thirty patients administered enteral or parenteral nutrition support for at least 72 hours were studied. We collected nutritional and electrolyte intake, serum biochemical parameters, and body composition measured by BIA. Patients were classified into two groups according to their serum sodium levels : (1) Normanatremia group, 135-145 mEq / L (n = 18) and (2) Hyponatremia group, less than 135 mEq / L (n = 12), and their characteristics were analyzed. Results : There were no significant differences between the Normonatremia and Hyponatremia groups in terms of energy, protein, and sodium intake. Serum biochemical parameters other than serum sodium and chloride levels were comparable between the two groups. On the other hand, the ratio of extracellular water to total body water (ECW / TBW) obtained by BIA was significantly higher in the Hyponatremia group than in the Normonatremia group. Further, an elevated ECW / TBW significantly and negatively correlated with serum albumin level. Conclusions : Regardless of sodium intake, higher ECW / TBW was associated with hyponatremia in patients on nutrition support. ECW / TBW may be an important clinical parameter relevant to the nutritional care of hyponatremia. J. Med. Invest. 68 : 112-118, February, 2021.

Background Concomitant chemoradiotherapy (CCRT) produces severe mucositis and swallowing dysfunction, often resulting in malnutrition. Intensive nutrition support (INS) in addition to percutaneous endoscopic gastrostomy (PEG) is reported to decrease adverse effects during CCRT. Patients and Methods Fifty-eight patients with oropharyngeal cancer treated by CDDP-based CCRT were retrospectively analyzed. Twenty-nine patients treated with INS in addition to PEG were classified as INS group, and other 29 patients treated with PEG but without INS were classified as control group. Results INS in addition to PEG significantly increased calorie intake in the second half of CCRT and reduced adverse events including mucositis (p=0.0019), leukopenia (p=0.04), and renal function (p=0.006). Moreover, 21 out of 29 patients had successfully administration of 200mg/m2 or more of CDDP, while only 10 out of 29 patients had enough amount of CDDP in control group. Conclusions These results suggest that INS in addition to prophylactic PEG not only decreases adverse effects but also may potentially improve oncological outcome of the patients with oropharyngeal cancer treated by CCRT.

Hemodialysis patients often become constipated. We analyzed the effect of prebiotics on the defecation status due to the intestinal environment in hemodialysis patients. Fifteen patients received prebiotics as partially hydrolyzed guar gum for four weeks. The defecation status was assessed using both the Bristol Stool Form Scale and the Japanese version of the Constipation Assessment Scale. The fecal status, microbiota measured by a terminal restriction fragment length polymorphism analysis, and fecal short-chain fatty acid concentrations by gas chromatography were compared before and after prebiotics ingestion. Prebiotics ingestion improved the individual stool form and decreased the constipation score from 5.1 to 3.0. The ratio of short-chain fatty acid-producing microbiota, such as Bifidobacterium and Bacteroides, increased after ingestion (2.35- and 3.17-fold, respectively). Furthermore, the concentration of short-chain fatty acids significantly increased (1.58-fold). The individual dendrogram distribution after ingestion was changed in 8 participants (53.3% of the subjects). In 5 participants (33.3% of the subjects), the clusters were even more noticeably different. Prebiotics improved the defecation status in hemodialysis patients due in part to the composition of intestinal microbiota and short-chain fatty acid concentrations.

Valproic acid (VPA) remarkably promotes the differentiation of adipose tissue-derived stem cells (ASCs) to mature neuronal cells through nitric oxide (NO) signaling due to up-regulated inducible NO synthase (iNOS) as early as within 3 days. Here, we investigated mechanisms of VPA-promoted neuronal differentiation of ASCs concerning the NO-citrulline cycle, the metabolic cycle producing NO. Cultured rat ASCs were differentiated to mature neuronal cells rich in dendrites and expressing a neuronal marker by treatments with VPA at 2 mM for 3 days and subsequently with the neuronal induction medium for 2 h. Inhibitor (α-methyl- d, l -aspartic acid, MDLA) of arginosuccinate synthase (ASS), a key enzyme of the NO-citrulline cycle, abolishes intracellular NO increase and VPA-promoted neuronal differentiation in ASCs. l -Arginine, the substrate of iNOS, restores the promotion effect of VPA, being against MDLA. Immunocytochemistry showed that ASS and iNOS were increased in ASCs expressing neurofilament medium polypeptide (NeFM), a neuronal marker, by VPA and NIM synergistically. Real-time RT-PCR analysis showed that mRNAs of Ass and arginosuccinate lyase (Asl) in the NO-citrulline cycle were increased by VPA. Chromatin immunoprecipitation assay indicated that Ass and Asl were up-regulated by VPA through the acetylation of their associated histone. From these results, it was considered that VPA up-regulated the whole NO-citrulline cycle, which enabled continuous NO production by iNOS in large amounts for potent iNOS-NO signaling to promote neuronal differentiation of ASCs. This may also indicate a mechanism enabling short-lived NO to function conveniently as a potent signaling molecule that can disappear quickly after its role.

We examined the effects of thyrotoxic rubber antioxidants, 2-mercaptobenzimidazole (MBI, 0.3 mmol/kg/day) and its methyl derivatives, methyl-MBIs [4-methyl-MBI (4-MeMBI, 0.6 mmol/kg/day), 5-methyl-MBI (5-MeMBI, 0.6 mmol/kg/day), and 4(or 5)-methyl-MBI (4(5)-MeMBI, 0.6 or 1.2 mmol/kg/day)], on the drug-metabolizing activity in male rat liver microsomes by 8-day repeated oral administration. The weight of liver and thyroid were increased by all the test chemicals; MBI was most potent, and there was no additive or synergistic effect between 4-MeMBI and 5-MeMBI. MBI decreased the cytochrome P450 (CYP) content, NADPH-cytochrome P450 reductase (POR) activity, 7-ethoxycoumarin O-deethylation (ECOD) activity, and flavin-containing monooxygenase (FMO) activity, but increased the 7-pentoxyresorufin O-depentylation (PROD) activity, suggesting inhibition of the drug-metabolizing activity on the whole but induce some activities such as the CYP2B activity. On the contrary, all the methyl-MBIs increased the CYP content, CYB5 content, ECOD activity, 7-ethoxyresorufin O-deethylation (EROD) activity, and PROD activity, indicating that they are mostly inducible of the CYP activity. However, the methyl-MBIs decreased the FMO activity, and 5-MeMBI and 4(5)-MeMBI appeared inhibitory for CYPs 2C11 and 2C13. Between 4-MeMBI and 5-MeMBI, there was no additive or synergistic effect on the drug-metabolizing activity, but was counteraction. It was concluded that MBI and methyl-MBIs had both inhibitory and inducible effects on the drug-metabolizing activity in rat liver microsomes at thyrotoxic doses. The effects of 4(5)-MeMBI indicated that the increased liver weight alone can be a hepatotoxic sign but not an adaptive no-adverse response in toxicity studies. The present results were related to the toxicokinetic profiles of MBI and 4(5)-MeMBI in the repeated toxicity studies.

Aim To evaluate the antifibrogenic effects of butyrate or phenylbutyrate, a chemical derivative of butyrate, in human pterygium fibroblasts. Methods Human pterygium fibroblasts obtained from patient pterygium tissue were treated with butyrate or phenylbutyrate for 48h. Expression of α-smooth muscle actin, collagen I, collagen III and matrix metalloproteinase-1 mRNA was measured by quantitative real-time reverse transcription polymerase chain reaction, and acetylated histone was evaluated by Western blotting. Results Butyrate inhibited α-smooth muscle actin, type III collagen and matrix metalloproteinase-1 expressions, and phenylbutyrate inhibited types I and III collagen and matrix metalloproteinase-1 expressions without changing cell viability as well as both of these increased histone acetylation. These results suggested that butyrate and phenylbutyrate suppress fibrosis through a mechanism involving histone deacetylase inhibitor. Conclusion This indicates that butyrate or phenylbutyrate have antifibrogenic effects in human pterygium fibroblasts and could be novel types of prophylactic and/or therapeutic drugs for pterygium, especially phenylbutyrate, which does not have the unpleasant smell associated with butyrate.

Objective Serum diamine oxidase (DAO) activity varies to a greater extent in women than in men. DAO activity during the luteal phase was higher than that during the follicular phase in healthy women. Recent reports have indicated that duodenal lipid infusion increased DAO activity in the intestinal lymph in rats. The aim of this study was to elucidate the effect of dietary nutrient intake on serum DAO activity in healthy women. Methods Thirty-four healthy Japanese women were recruited. Food surveys were performed using dietary records for 3 d during both the follicular and luteal phases. Nutrient intake was calculated and expressed as the energy intake ratio. The correlation between DAO activity and nutrient intake was analyzed. Results Serum DAO activity in both phases was positively correlated with intake of long-chain fatty acids, saturated fatty acids, and monounsaturated fatty acids (P

Background Dysregulation of glucose metabolism, including hyperglycemia with insulin resistance, is commonly observed in critically ill patients. Interleukin-18 (IL-18) improves the insulin resistance associated with obesity, but the relationship between IL-18 and glucose metabolism in sepsis was unclear. The purpose of this study was to investigate the influence of IL-18 on hyperglycemia during sepsis. Methods Sepsis was induced using cecal ligation and puncture (CLP) in wild-type (WT) mice, IL-18 knockout (KO) mice, and IL-18 KO mice pretreated with recombinant IL-18. Blood glucose and plasma insulin, glucagon, and corticosterone were measured. The mRNAs for gluconeogenic enzymes (g6pc, pck1) and activation of insulin signaling were also analyzed. Results In both WT and IL-18 KO mice, CLP operation led to hyperglycemia that lasted longer (18 h) than after sham operation (6 h). Blood glucose levels in IL-18 KO mice were significantly higher than in WT mice, without alteration of insulin or glucagon levels. In IL-18 KO mice, insulin signaling in the liver and skeletal muscle was decreased during hyperglycemia as compared with WT mice without suppression of hepatic glucose production enzymes. Pretreatment with recombinant IL-18 reduced blood glucose levels after CLP. Additionally, corticosterone levels were higher after CLP in the presence of either endogenous or exogenous IL-18. Conclusion IL-18 may reduce blood glucose by modulating insulin signaling in the liver during sepsis-induced hyperglycemia. IL-18 is an important factor associated with alterations in blood glucose during sepsis.

Objectives Sodium butyrate, an inhibitor of histone deacetylase, has several therapeutic actions, including anti-inflammation. These actions depend on the concentration of sodium butyrate. In addition, lower concentrations have shown no effect on inflammation. Sonoporation by ultrasound can modify the permeability of the cell plasma membrane. Thus, the effects of sodium butyrate may be enhanced by the ultrasonic acoustics. Therefore, the facilitative effects of low-intensity ultrasound on histone acetylation and interleukin 6 (IL-6) regulation by sodium butyrate were investigated in this study. Methods Human dermal fibroblasts were treated with 1-mM sodium butyrate for 3 hours with 20 minutes of 0.1-W/cm2 pulsed or continuous ultrasound irradiation at the beginning of the sodium butyrate treatments. Results The combination of treatments with sodium butyrate and ultrasound significantly increased histone acetylation in fibroblasts (P

Hyperglycemia induces nonconcordant regulation of renal mitochondrial respiratory complexes, increases oxidative stress, and causes diabetic nephropathy. Hypertension is a complication associated with diabetes and involves glomerular hyperfiltration, the effects of which on mitochondrial respiratory complexes are not well understood. To investigate the effect of glomerular hyperfiltration on renal mitochondrial respiratory complexes, we used the 5/6 nephrectomized BKS. Cg-Dock7m+/+Leprdb/J, Dock7m+/+Leprdb mice (db/m-5/6Nx mice) as a model for glomerular hyperfiltration. The BKS. Cg-Dock7m+/+Leprdb/J, +Leprdb/+Leprdb mice (db/db mice), a model for type 2 diabetes, was used as the positive control. We investigated the activities and protein levels of the mitochondrial complex, and the mitochondrial DNA and adenosine triphosphate content in the kidneys of these models. Blood chemistry and renal histopathological examination were performed for characterization of the disease. Both models showed expansion of the mesangial matrix of the glomeruli, which is indicative of glomerular hyperfiltration. The activities of complexes I and IV and the protein levels of complexes I and III were nonconcordant in db/m-5/6Nx mice. In conclusion, we demonstrated that nonconcordant regulation of mitochondrial complexes in db/m-5/6Nx mice involved with glomerular hyperfiltration. The progression and/or severity of nephropathy might be affected through a synergistic effect of mitochondrial dysfunction in hyperglycemia and glomerular hyperfiltration. J. Med. Invest. 64: 255-261, August, 2017.

Nanomaterials have been extensively used in our daily life, and may also induce health effects and toxicity. Nanomaterials can translocate from the outside to internal organs, including the brain. For example, both nano-ZnO and nano-TiO2 translocate into the brain via the olfactory pathway in rodents, possibly leading to toxic effects on the brain. Although the effects of nano-ZnO and nano-TiO2 on neuronal viability or neuronal excitability have been studied, no work has focused on how these nanomaterials affect neuronal differentiation and development. In this study, we investigated the effects of nano-ZnO and nano-TiO2 on neurite outgrowth of PC12 cells, a useful model system for neuronal differentiation. Surprisingly, the number, length, and branching of differentiated PC12 neurites were significantly suppressed by the 7-day exposure to nano-ZnO (in the range of 1.0 × 10-4 to 1.0 × 10-1 µg/mL), at which the cell viability was not affected. The number and length were also significantly inhibited by the 7-day exposure to nano-TiO2 (1.0 × 10-3 to 1.0 µg/mL), which did not have cytotoxic effects. These results demonstrate that the neurite outgrowth in differentiated PC12 cells was suppressed by sub-cytotoxic concentrations of nano-ZnO or nano-TiO2.

Valproic acid (VPA) remarkably promotes the differentiation of adipose tissue-derived stem cells (ASCs) to mature neuronal cells, enabling neuronal induction within only three days. Here, we investigated the involvement of NO-signaling in the VPA-promoted neuronal differentiation of ASCs as a possible mechanism. Cultured rat ASCs were differentiated to matured neuronal cells rich in dendrites and expressing βIII-tubulin protein, a neuronal marker, by treatments with VPA at 2 mM for 3 days and subsequently with the neuronal induction medium (NIM) containing cAMP-elevating agents for 2 h. Increased intracellular NO was detected in neuronal cells differentiated from ASCs treated with VPA by a fluorescence NO-specific probe, diaminofluorescein-FM diacetate. However, a NO donor (NOC18) increased the incidence of neuronal cells only to a lesser extent than VPA, indicating the insufficiency of exogenous NO. RT-PCR analysis of ASCs treated with VPA showed increased mRNA expression of inducible nitric oxide synthase (iNOS) with the acetylation of its associated histone H3K9. iNOS inhibitors (1400 W and dexamethasone) or a soluble guanylate cyclase (sGC) inhibitor (ODQ) decreased the incidence of neuronal cells differentiated from ASCs treated with VPA. These inhibitors also decreased the mRNA expression of mature neuronal markers, neurofilament medium polypeptide (NeFM) and microtubule-associated protein 2 (MAP2), as well as βIII-tubulin (TUBB3), to various extents. It was considered from these results that VPA promoted mature neuronal differentiation of ASCs through the iNOS–NO–sGC signaling pathway. This provided insights into the regulated neuronal differentiation of ASCs in clinical applications.

Objective: Dermal fibroproliferative disorders impair patients’ quality of life. Although several therapeutic approaches exist for treatment of dermal scars, the development of effective ointments with few adverse effects could improve these therapeutic methods. Short-chain and ω-3 polyunsaturated fatty acids are reported to be immunomodulators with anti-inflammatory properties. Our aim was to evaluate anti-inflammatory and antifibrogenic effects of these fatty acids in human dermal fibroblasts. Methods: Cells were incubated with short-chain fatty acids (butyrate or propionate; 0-16 mM) and/or ω-3 polyunsaturated fatty acids (docosahexaenoic acid or eicosapentaenoic acid; 0-100 μM) for 24 hours to evaluate antifibrogenic effects and for 3 or 48 hours to evaluate anti-inflammatory effects after stimulation with lipopolysaccharide or without stimulation. Expression levels of α-smooth muscle actin, collagen I, collagen III, and IL-6 were evaluated, as were cell proliferation, stress fiber formation, and histone acetylation. Results: In the lipopolysaccharide-unstimulated group, butyrate inhibited mRNA expression of α-smooth muscle actin and collagen III more effectively than propionate and increased histone acetylation. Docosahexaenoic acid inhibited mRNA expression of α-smooth muscle actin and collagen III, whereas eicosapentaenoic acid did not. Combining butyrate with docosahexaenoic acid had stronger effects, downregulating α-smooth muscle actin, collagen I, and collagen III mRNA. As for cell proliferation and stress fiber formation, butyrate acted as a stronger inhibitor than docosahexaenoic acid and the combined administration had stronger effects. In the lipopolysaccharide-stimulated group, butyrate and docosahexaenoic acid attenuated IL-6 mRNA upregulation by lipopolysaccharide. Conclusion: Butyrate and docosahexaenoic acid may be a novel therapeutic approach to treatment of dermal fibroproliferative disorders.

Effects of additional physical treatments during vitrification of the bovine ovarian tissue were examined for increasing of permeability of ethylene glycol (EG) and dimethyl sulfoxide (Me2SO). The concentrations of EG and Me2SO and histological changes in the ovarian tissue were evaluated. In the first equilibration step (7.5% EG and 7.5% Me2SO), all the 10-min physical treatments, i.e., negative (679 hPa) or positive (1347 hPa) air pressure applied with a disposable syringe, and shaking (60 rpm) applied with a laboratory shaker, were comparable to 25-min non-physical treatment (plain) vitrification. When effects of the negative air pressure were examined in the second equilibration step (20% EG and 20% Me2SO), its 10-min treatment was equivalent to 15-min plain vitrification (140–170 mg/g tissue). It was thus indicated that the negative air pressure treatment accelerates the penetration of permeable cryoprotectants into the ovarian tissue slices. Histological examination showed that the cell density and the amount of pan-cadherin in the tunica albuginea of the ovary was reduced by the vitrification, but was improved by the negative air pressure treatment. The amount of pan-cadherin in the tunica albuginea was recommended as a biomarker for evaluation of effectiveness of protocol for cryopreservation of bovine ovarian tissue and considered to be a candidate biomarker for human ovarian tissue cryopreservation.

Deregulated iron metabolism underlies the pathogenesis of many human cancers. Recently, low expression of ferroportin, which is the only identified non-heme iron exporter, has been associated with significantly reduced overall survival in multiple myeloma (MM); however, the altered iron metabolism in MM biology remains unclear. In this study we demonstrated, by live cell imaging, that MM cells have increased intracellular iron levels as compared with normal cells. In experiments to test the effect of iron chelation on the growth of MM cells, we found that deferasirox (DFX), an oral iron chelator used to treat iron overload in clinical practice, inhibits MM cell growth both in vivo and in vitro. Mechanistically, DFX was found to induce apoptosis of MM cells via the inhibition of proline-rich tyrosine kinase 2 (Pyk2), which is known to promote tumor growth in MM. Inhibition of Pyk2 is caused by the suppression of reactive oxygen species, and leads to downregulation of the Wnt/β-catenin signaling pathway. Taken together, our findings indicate that high levels of intracellular iron, which might be due to low ferroportin expression, play a role in MM pathophysiology. Therefore, DFX may provide a therapeutic option for MM that is driven by deregulated iron homeostasis and/or Pyk2/Wnt signaling.

近年の社会の高齢化に伴い、寝たきり患者数は200万人を超え、その10%以上に褥瘡の発生を見る。褥瘡の発生・増悪は直達力の他に、二次的なリスク因子が存在し、加齢に加え、栄養障害が強く相関している。この論文は、高齢者褥瘡患者についての臨床症例を通して、栄養と褥瘡治療の関連性について検討することである。今回、18名の高齢者褥瘡患者を対象に、栄養評価による栄養障害の程度、栄養管理法、および栄養療法を施行した後の褥瘡の治療反応性について検討した。その結果、対象患者は全例中等度～高度の栄養障害を有し、その半数以上に高度の褥瘡を認めた。チーム医療による栄養管理を行った結果、18例中12例に治療効果を認め、この治療反応性は、経口摂取群、経腸栄養投与群に多く見られた。以上より、褥瘡患者では栄養障害が存在するため、局所の創管理に加えて、チーム医療による全身的な栄養管理をより生理的な栄養投与ルートを介して行うことが必要であると考えられた。, With the recent advance of aging society in Japan, the number of the patients with pressure ulcers has been increasing over 10% of two million elderly who are bedridden.The primary cause of pressure ulcer is the disintegration of skin and subcutaneous tissue for pressure due to voluntary immobility of the patients. Moreover there are other risk factors for development of pressure ulcers, which are the old age and malnutrition. The purpose of this study is to survey the relevance of hospitalized aged patients with pressure ulcers and the role of nutrition therapy in the treatment.Eighteen elderly patients with pressure ulcer(s) were entered in this study, and their nutritional assessment, nutritional management, and the healing of the wound were investigated. All patients had moderate to severe malnutrition, and over the half of them had suffered from severe pressure ulcers. In our study, there was strong correlation between the healing of pressure ulcer and nutritional management.The patients with pressure ulcers have mostly been malnourished and needed not only the local wound treatment but the systemic nutritional care via physiological enteral route under the management by the interprofessional team.

The inhibition of neural crest cell (NCC) migration has been considered as a possible pathogenic mechanism underlying chemical developmental toxicity. In this study, we examined the effects of 13 developmentally toxic chemicals on the migration of rat cephalic NCCs (cNCCs) by using a simple in vitro assay. cNCCs were cultured for 48 h as emigrants from rhombencephalic neural tubes explanted from rat embryos at day 10.5 of gestation. The chemicals were added to the culture medium at 24 h of culture. Migration of cNCCs was measured as the change in the radius (radius ratio) calculated from the circular spread of cNCCs between 24 and 48 h of culture. Of the chemicals examined, 13-cis-retinoic acid, ethanol, ibuprofen, lead acetate, salicylic acid, and selenate inhibited the migration of cNCCs at their embryotoxic concentrations; no effects were observed for acetaminophen, caffeine, indium, phenytoin, selenite, tributyltin, and valproic acid. In a cNCC proliferation assay, ethanol, ibuprofen, salicylic acid, selenate, and tributyltin inhibited cell proliferation, suggesting the contribution of the reduced cell number to the inhibited migration of cNCCs. It was determined that several developmentally toxic chemicals inhibited the migration of cNCCs, the effects of which were manifested as various craniofacial abnormalities.