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Electrocatalytic properties for oxygen reduction reaction (ORR) of Pt (111) epitaxial layers on a Pdf (111) substrate are investigated. Scanning tunneling microscopy images of the as-prepared 0.6-nm- and 1.2-nm-thick Pt(111) epitaxial layers on Pd (111) (Pt0.6nm/Pd(111) and Pt1.2nm/Pd(111)) revealed that the topmost surface has atomically flat, 50-100-nm-wide terraces. Remarkable current features due to hydrogen storage and emission by the P d (111) substrate dominated the cyclic voltammograms of Pt0.6nm/Pd(111) in the potential range of 0.15-0.4 V vs. a reversible hydrogen electrode. In contrast, the curve of Pt1.2nm/P d (111) exhibited a shrinkage in the hydrogen charges (QH) in the potential range of 0.25-0.4 V, accompanied by the emergence of symmetrical redox features at 15 mV on the positive potential side, relative to Pt (111) "butterfly" feature. Both Pto.6nm/Pd(l 11) and Ptl,2nm/Pd( 111) showed ca. four times higher ORR activity than clean Pt(111), although their hydrogen-related behaviors and activity changes during applying potential cycles were much different. The results suggest that shrinkage in QH and positive shift in the onset potential of hydroxyl species are common features of the CV of highly ORR-active well-defined Pt-M(l 11) bimetallic surfaces and that the activity enhancements and the structural stabilities fairly depend on the surface structure of the epitaxial Pt(111) lattice. [ABSTRACT FROM AUTHOR]

Although oral candidiasis is frequently seen in the elderly, the factors determining candidal growth have insufficiently been explored. Hence, we examined the influence of aging on candidal adhesion and growth-inhibitory agents in saliva in 45 healthy volunteers and 60 patients with oral candidiasis. Both non-stimulated and stimulated salivary flow rates (SFRs) in the healthy controls decreased with aging. A gradual decrease of SFRs with aging was also observed in the patients, and the SFR levels were markedly lower than those in the controls. Although the salivary glucose levels were almost constant in all age groups, secretory immunoglobulin A and lactoferrin levels in saliva were significantly decreased statistically with age, and a marginal age-associated decrease in transferrin levels was also observed. In addition, the generation of superoxide from neutrophils in saliva and their Candida killing activity decreased with age, and these phenomena were more apparent in the patients. Furthermore, a larger number of Candida adhered to oral keratinocytes obtained from the elderly healthy controls than to those obtained from young controls. Correspondingly, keratinocytes from the aged controls showed more concanavalin-A binding sites than those from the young controls. However, oral Candida did not increase with increasing age in the controls, although an age-associated increase of oral Candida was observed in the patients. Taken together, these results indicate that the decreases of SFRs and salivary anti-candidal factors, suppression of salivary neutrophil function and the increase of candidal adhesion sites on keratinocytes predispose elderly individuals to oral candidiasis. [ABSTRACT FROM AUTHOR]

Salivary polymorphonuclear leukocyte (SPMN) functions were examined in 18 patients with oral squamous cell carcinoma and in 20 healthy individuals. SPMN obtained from patients before therapy exhibited significantly less FMLP-stimulated chemotactic activity (132.4 +/- 17.5 cells/0.26 mm2) than that in SPMN from controls (177.1 +/- 11.6 cells/0.26 mm2), although no difference in phagocytosis was observed. When stimulated with PMA or FMLP, control SPMN generated superoxide (O2-) at levels of 50.3 +/- 10.5 pmol/min/10(4) cells and 88.4 +/- 15.4 pmol, respectively, while SPMN from untreated patients generated significantly reduced O2- in the presence of PMA or FMLP (24.3 +/- 3.5 pmol and 59.5 +/- 9.8 pmol, respectively). Only slightly lower chemiluminescence was observed in SPMN from untreated patients however, compared to controls, values being 68.0 +/- 18.9 vs 81.3 +/- 14.9 peak mV by PMA and 62.4 +/- 13.7 vs 64.4 +/- 12.9 peak mV by FMLP. Compared to Candida killing in control subjects (24.9 +/- 3.1%). SPMN from patients before treatment exhibited significantly reduced activity (18.7 +/- 4.9%). Further suppression of the SPMN functions examined was observed after chemoradio-therapy. Suppressed SPMN function in cancer patients, especially that associated with chemoradiotherapy, may therefore play a part in oral candidiasis. [ABSTRACT FROM AUTHOR]

Cytokine generation by tissue-infiltrating mononuclear cells (TIMC) and by keratinocytes (KC) was investigated in material obtained from the oral mucosal tissues of patients with oral lichen planus (OLP). Peripheral blood mononuclear cells (PBMC) and chronically inflamed and noninflamed gingival KC (CIG-KC, NOR-KC, respectively) were used as the controls. Compared to NOR-KC and CIG-KC, KC from OLP patients (OLP-KC) produced much more interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and granulocyte-macrophage colony- stimulating factor (GM-CSF). The OLP-KC superiority in the production of these cytokines was more prominent when the KC were cultured in the presence of interleukin-l beta (IL-1β), lipopolysaccharide and phorbol myristate acetate. OLP-KC also produced more monocyte-chemotactic factor(s) which were not inactivated by the antibodies against GM-CSF, macrophage colony-stimulating factor and monocyte chemoattractant protein-1. TIMC in OLP tissues (OLP- TIMC) were superior to PBMC in the generation of IL-6 and GM-CSF. OLP- TIMC were stimulated to produce more TNF-α by IL-1β, IL-6 and GM-CSF, more IL-6 by IL-1f3 and GM-CSF, and more GM-CSF by IL-1β and IL-6 than PBMC. When compared to cytokine generation in TIMC from the chronically inflamed gingivae, more interferon-gamma, IL-6 and TNF-α were generated by OLP-TIMC. These results indicate that KC play a critical role in OLP, producing cytokines including monocyte-chemotactic factor(s), and that the cytokines produced by TIMC and OLP-KC through autocrine and paracrine processes enhance the local inflammatory response. [ABSTRACT FROM AUTHOR]

Azelastine (azelastine hydrochloride) was orally administered to 43 patients with recurrent aphthous ulcers (RAU), and its clinical effects and in vitro influence on leukocytes were examined. During at least 6 months after drug treatment, no oral ulcers occurred in 7 patients, and an improvement of the oral condition was exhibited in all except 4 or the remaining patients. The frequency of occurrence of RAU was significantly reduced, from 1.7 ± 0.9 to 0.9 ± 0.5 times/month. and ulcer duration and oral irritation were also significantly reduced from 12.5± 2.5 and 7.5 ± 2.4 days to 9.8 ± 2.6 and 5.3±2.4 days. respectively. Neutrophils from patients treated with Azelastine generated a suppressed volume of superoxide (O[SUB2]). Suppression or O[SUB2] generation and chemiluminescence by in vitro Azelastine was also confirmed to occur in a dose-dependent manner. Furthermore, the production of TNF-α and GM-CSF in lymphocytes was suppressed in the presence of Azelastine, and the drug protected sheep red blood cells and epithelial tumor cell lines against hydrogen peroxide impairment and hypotonic shock. These clinical and experimental results lead to the conclusion that improvement of RAU by Azelastine depends on the protection of cell membranes and the suppression or leukocyte-function, including reactive oxygen generation. [ABSTRACT FROM AUTHOR]

Peripheral blood mononuclear cell parameters were examined in 17 adult patients with primary herpes simplex virus-1 (HSV-1) infection. Two-color flow cytometry revealed an increase in HLA-DR[SUP+] T cell and Leu8[SUP+] T cell subsets, and a decrease in CD57 CD16 subset in the patients. In the symptomatic phase of HSV-I infection, serum interferon gamma (IFN-γ) level increased in many patients, and the mean serum level in the patients (0.26 ± 0.12 U/ml was significantly higher than the mean control level (0.14 ± 0.06 U / mi). Soluble intercellular adhesion molecule-I (slCAM-I) in patients' serum also was increased to a mean level of 398 ± 130 ng/ml at the first visit. Both the IFN-γ and slCAM-I levels fell to near the control levels after the disappearance of oral inflammation. Natural killer (NK) activity was at first increased (mean 46.1 ± 17.9%), and later decreased to the control level (mean 31,1.4 ± 10.6&). In contrast, lymphokine activated killer (LAK) activity at the first visit (mean 53.2 ± 15.7%) was significantly lower than the control level (mean 69.5 ± 10.3%). PHA- or ConA-stimulated lymphocytes from the patients incorporated less thymidine than control lymphocytes. These reduced lymphocyte reactivities recovered to the control levels after the disappearance of the acute infection. These results indicate some of the characteristics of lymphocyte pathophysiology in primary HSV-I infection. [ABSTRACT FROM AUTHOR]

The prevalence of diabetes mellitus (DM) in odontogenic infections and oral candidiasis was examined, and influences of DM on the clinical manifestations of the infections and neutrophil functions were investigated. Among 21 severe and 221 mild odontogenic infections, DM was detected in 5 cases in each group. Of 64 cases of symptomatic oral candidiasis, 8 cases were complicated with DM which was detected by blood examination during treatment. During the period of infection, the mean fasting blood sugar level was 16.0 +/- 4.4 and 9.8 +/- 1.2 mmol/l in the DM-complicated odontogenic infections and candidiasis, respectively. All white blood counts, C-reactive protein levels and erythrocyte sedimentation rates were more elevated in DM(+) odontogenic infection cases than in DM(-) ones. In DM(+) candidiasis, hyposalivation (0.79 +/- 0.54 ml/10 min) was observed. The polymorphonuclear leukocytes from diabetic patients, especially those with candidiasis, produced less free oxygen radicals and exhibited reduced phagocytosis and intracellular killing of Candida cells associated with this reduced O2- generation during the infection. These suppressed neutrophil functions increased after treatment but did not reach control levels. These results indicate that DM is a predisposing condition for odontogenic infections and oral candidiasis, that DM-complicated infections become severe because of neutrophil suppression, and that examination of blood sugar level should be essential for patients with oral infections. [ABSTRACT FROM AUTHOR]

Serum cytokine levels were examined in 18 oral squamous cell carcinoma (SCC), 26 lichen planus (OLP), 20 recurrent aphthous stomatitis (RAS), 8 herpetic gingivostomatitis (HGS), 16 pseudomembrane candidiasis (PMC) and 19 acute bacterial infection (ABI) cases. All SCC and most PMC patients possessed clear serum IL-3. No clear increase of IL-4 was observed in most cases though over 20 pg/ml were found in a few OLP, RAS and ABI. ABI exhibited the highest IL-6, and the cytokine level was lower in RAS, PMC, HGS and OLP in this order. Suppressed IL-6 activity was elevated with improvement of HGS lesion. TNF-alpha increased in 9 OLP, but the levels were below 100 pg/ml in all cases. Most SCC possessed higher GM-CSF activity than the controls. Increase of the cytokine corresponding with improvement of the oral lesion was seen in HGS, but not in OLP. From these results, each serum cytokine seems to reflect a characteristic pathophysiology of individual oral disorder. [ABSTRACT FROM AUTHOR]

Functions of peripheral blood lymphocytes and neutrophils from 30 oral lichen planus (OLP) patients were examined using healthy persons as controls. Two- color flow cytometry of lymphocytes revealed no proportional difference, in CD3 or CD4 cells between OLP and controls. CD8CDI lb (suppressor T) and CD3HLA-DR[SUP+] cell populations increased significantly in OLP when compared with controls, and, CD4JCD8 cell ratio decreased in OLP. Mitogenic response of patients' CD8 and CD4Leu8 cells was similar to that in controls. However, weaker blastogenesis of CD4Leu[SUP+] cells, the most excellent responders in T cell subsets, was observed in OLP. Serum IFNβ level in OLP (8.4±4.8 LU/mI) was significantly lower than in controls (13.7 ± 5.0 lU/mi) whereas no difference between the two groups could be found in IFNα or γ. As for in vitro cytokine production by IL-2-stimulated lymphocytes, there was no difference in GM-CSF generation between the two groups, but, LFNγ and IL1β production of patients' lymphocytes was less than that in healthy donors (57.6 ± 50.7 VS 78.7 ± 39.6 U ! ml, 152.3±93.5 VS 258.7±65.4 pg/mI, respectively). Moreover, superoxide generation of patients' neutrophils by PMA stimulation was significantly insufficient as compared with controls' (84.9±30.9 VS 110.8±24.1 pmol/min/104 cells). Nevertheless, natural killer cell activities of both groups distributed in the same range. These results suggest that OLP patients' lymphocyte and neutrophil functions are impaired, and that cellular immunosuppression is a pathologic characteristic of OLP. [ABSTRACT FROM AUTHOR]

Four cases of lateral cervical cysts were reported. All cyst walls were lined with keratinized stratified squamous epithelium, and contained lymph follicles with well-defined germinal centers. Ectopic salivary gland tissue was found in one case. Histochemical examination by the immunoperoxidase method revealed the existence of carcinoembryonic antigen (CEA). However, alpha-feto protein (AFP) and amylase were not detected in any of the cysts. The cyst fluid contained high levels of CEA and high titers of salivary type amylase, but AFP was negative. These results do not support any one of the theories concerning the etiology of cervical lymphoepithelial cysts. It seems likely that cysts derive from both epithelial remnants of the branchial apparatus and from salivary gland inclusions in lymph nodes. [ABSTRACT FROM AUTHOR]

The influence of peplomycin (PLM) and azelastine hydrochloride (Azeptin) on reactive oxygen (RO) and cytokine generation was examined in human peripheral blood mononuclear leukocytes, polymorphonuclear leukocytes (PMN), and rabbit alveolar macrophages (RAM). In addition, the influence of these drugs on DNA and collagen synthesis was investigated in human gingival and rabbit pulmonary fibroblasts. In vitro, PLM increased the FMLP- and PMA-induced chemiluminescence and superoxide (O2-) generation in human PMN and RAM in a dose-dependent manner. In contrast to PLM, Azeptin dose-dependently suppressed RO generation. Such contrasting actions of PLM and Azeptin were also observed in RAM and PMN obtained from rabbits treated with PLM or Azeptin. Even when human PMN were preincubated with 10-100 micrograms/ml of PLM, the increase in RO generation was negligible in the presence of 10(-5) M Azeptin in the culture medium. No increases in RO generation were observed in RAM or PMN obtained from rabbits that had received PLM (0.1 mg/kg per day) and Azeptin (0.04 mg/kg per day) concomitantly. PLM suppressed superoxide dismutase activity in RAM and human PMN, while Azeptin did not affect this activity. In vitro, PLM up-regulated the release of interleukin-1 beta, interleukin-6, tumor necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor both from human cells and from RAM and pulmonary fibroblasts. In the generation of these cytokines, Azeptin abrogated the up-regulatory action of PLM. PLM and Azeptin also had contrasting actions in [3H]thymidine and [3H]proline incorporation in human and rabbit fibroblasts. Furthermore, protein tyrosine phosphorylation, in particular that of a 115-kDa protein in human PMN, was suppressed by Azeptin and enhanced by PLM. These results seem to indicate that up-regulated RO and collagen generation are the causative factors of PLM-induced pulmonary fibrosis and that Azeptin may suppress the adverse effect. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Fatty acid-binding protein 4 (FABP4) has been reported to act as a hepatic insulin resistance factor. We previously reported that fasting FABP4 was correlated with insulin resistance measurements derived from the glucose clamp, and another study reported that postprandial FABP4 levels were decreased in healthy volunteers but were not reported (or known) in participants with type 2 diabetes. We have limited knowledge about the direct effect of FABP4 on muscle cells. We investigated the postprandial FABP4 levels in participants with type 2 diabetes, and the basic mechanism of muscle insulin resistance and FABP4., Methods: We performed a meal tolerance test and hyperinsulinaemic-euglycaemic clamp in 22 participants with type 2 diabetes and 26 participants without diabetes. We measured fasting and postprandial serum FABP4. We cultured mouse C2C12 muscle cells, and investigated the effect of FABP4 on glucose uptake. We analysed insulin signalling by western blot and insulin binding assay., Results: The postprandial FABP4 level in participants with type 2 diabetes was higher than that in participants without diabetes. Participants without diabetes had lower postprandial FABP4 than fasting except for one participant, whereas one-third of participants with type 2 diabetes had higher postprandial FABP4 than fasting. Postprandial FABP4 was correlated with the muscle insulin resistance M/I value from a glucose clamp in participants without diabetes (r=-0.42, p<0.05). The increase in FABP4 after a meal correlated with the muscle insulin resistance M/I value (r=-0.44, p<0.05) and the difference between fasting and postprandial glucagon in participants with type 2 diabetes (r=0.36, p<0.05). FABP4 alone appears to increase glucose uptake, and the combination of FABP4 and insulin decreases glucose uptake when compared with insulin alone. FABP4 inhibits insulin signalling of muscle cells through decreases in phosphorylation of insulin receptor substrate 1 and Akt. The physiological concentration of FABP4 did not inhibit insulin binding to muscle cells., Conclusions/interpretation: These results suggested that the postprandial FABP4 level is associated with insulin resistance, and FABP4 may suppress insulin signals., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Gallbladder cancer incidence has been increasing globally, and it remains challenging to expect long prognosis with the current systemic chemotherapy. We identified a novel nucleic acid-mediated therapeutic target against gallbladder cancer by using innovative organoid-based gallbladder cancer models generated from Kras LSL-G12D/+ ; Trp53 f/f mice. Using comprehensive microRNA expression analyses and a bioinformatics approach, we identified significant microRNA-34a-5p downregulation in both murine gallbladder cancer organoids and resected human gallbladder cancer specimens. In three different human gallbladder cancer cell lines, forced microRNA-34a-5p expression inhibited cell proliferation and induced cell-cycle arrest at the G1 phase by suppressing direct target ( CDK6 ) expression. Furthermore, comprehensive RNA sequencing revealed the significant enrichment of gene sets related to the cell-cycle regulators after microRNA-34a-5p expression in gallbladder cancer cells. In a murine xenograft model, locally injected microRNA-34a-5p mimics significantly inhibited gallbladder cancer progression and downregulated CDK6 expression. These results provide a rationale for promising therapeutics against gallbladder cancer by microRNA-34a-5p injection, as well as a strategy to explore therapeutic targets against cancers using organoid-based models, especially for those lacking useful genetically engineered murine models, such as gallbladder cancer., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Background: Hepatic insulin clearance (HIC) is an important pathophysiology of type 2 diabetes mellitus (T2DM). HIC was reported to decrease in patients with type 2 diabetes and metabolic syndrome. HIC is originally calculated by post-load insulin and C-peptide from the oral glucose tolerance test (OGTT). However, OGTT or meal tolerance tests are a burden for patients, and OGTT is not suitable for overt diabetes due to the risk of hyperglycemia. If we can calculate the HIC from the fasting state, it is preferable. We hypothesized that fasting HIC correlates with postprandial HIC in both participants with T2DM and without diabetes. We investigated whether fasting HIC correlates with postprandial HIC in overt T2DM and nondiabetes subjects (non-DM) evaluated by using glucose clamp and meal load., Methods: We performed a meal tolerance test and hyperinsulinemic-euglycemic clamp in 70 subjects, 31 patients with T2DM and 39 non-DM subjects. We calculated the postprandial C-peptide AUC-to-insulin AUC ratio as the postprandial HIC and the fasting C-peptide-to-insulin ratio as the fasting HIC. We also calculated whole-body insulin clearance from the glucose clamp test., Results: The fasting HIC significantly correlated with postprandial HIC in T2DM (r&#95;S = 0.82, P < 0.001). Nondiabetes subjects also showed a significant correlation between fasting and postprandial HIC (r&#95;S = 0.71, P < 0.001). Fasting HIC in T2DM was correlated with BMI, HbA1c, gamma-glutamyl transpeptidase, HOMA-IR, HOMA-beta, M/I, and whole-body insulin clearance. Fasting HIC in nondiabetes subjects was correlated with HOMA-IR and HOMA-beta., Conclusions: These results suggest that fasting HIC is strongly correlated with postprandial HIC in both overt T2DM and non-DM patients, as evaluated by the meal test and glucose clamp method. Fasting HIC could be a convenient marker of HIC., (© 2023. The Author(s).)

Pancreatic islet β-cells weaken under oxidative stress. In this study, human pancreatic islet-derived 1.1B4 cells were exposed to H 2 O 2 and analysed using a human microarray, which revealed that heme oxygenase 1 ( HMOX1) , glutamate-cysteine ligase , early growth response 1 , nuclear receptor subfamily 4 group A member 3 ( NR4A3 ) and jun B proto-oncogene were upregulated, whereas superoxide dismutase 1 and catalase were not. Expression of NR4A3 rapidly increased after H 2 O 2 addition, and the 1.1B4 cells treated with siRNA targeting NR4A3 became sensitive to H 2 O 2 ; further, HMOX1 expression was strongly inhibited, suggesting that NR4A3 is an oxidative stress-responsive transcription factor that functions through HMOX1 expression in pancreatic islet β-cells. Expression of cyclin E1 and cyclin-dependent kinase 1 was also inhibited by siRNAs targeting NR4A3 .

Gemcitabine is an effective chemotherapeutic agent for biliary tract cancers (BTCs), including gallbladder cancer (GBC) and cholangiocarcinoma (CCA). However, few other effective agents are currently available, particularly for GEM-refractory BTCs. We previously identified microRNA-451a (miR-451a) as a potential therapeutic target in GBC. To elucidate the antineoplastic effects of miR-451a and its underlying mechanisms, we transfected miR-451a into GBC, gemcitabine-resistant GBC (GR-GBC), and gemcitabine-resistant CCA (GR-CCA) cell lines. Furthermore, mimicking in vivo conditions, tumorigenic GBC organoids and three-dimensional (3D) cell culture systems were employed to investigate the anti-proliferative effects of miR-451a on BTCs, and its effect on stem cell properties. We found that miR-451a significantly inhibited cell proliferation, induced apoptosis, and reduced chemoresistant phenotypes, such as epithelial-mesenchymal transition, in both GBC and GR-GBC. The principal mechanism is probably the negative regulation of the phosphatidylinositol 3-kinase/AKT pathway, partially accomplished by directly downregulating macrophage migration inhibitory factor. The Gene Expression Omnibus database revealed that miR-451a was the most significantly downregulated microRNA in CCA tissues. The introduction of miR-451a resulted in similar antineoplastic effects in GR-CCA. Furthermore, miR-451a reduced cell viability in 3D spheroid models and tumorigenic GBC organoids. These findings suggest that the supplementation of miR-451a is a potential treatment strategy for GEM-refractory BTCs., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)