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Ectopic ACTH (adrenocorticotrophic hormone) syndrome (EAS) is rarely associated with small-cell lung cancer (SCLC). Although chemotherapy is initially effective for SCLC, complicated EAS scarcely improves. Recently, immune checkpoint inhibitors have been used to treat SCLC. Atezolizumab plus chemotherapy for SCLC improved progression-free survival compared to conventional chemotherapy. However, little has been reported on the efficacy of the combination therapy for SCLC with EAS. We report a 72-year-old male who presented with 4-week history of leg oedema, proximal myopathy, weight loss, and worsened symptoms of diabetes and hypertension. Laboratory findings revealed hypokalaemia, increased plasma ACTH, and serum cortisol levels. Cortisol levels were not suppressed by the high-dose dexamethasone test. Chest and abdominal CT revealed a right lower lobe tumour with multiple metastases on the hilar lymph nodes, liver, lumbar spine, and bilateral enlarged adrenal glands. The patient was diagnosed with stage 4B SCLC with EAS. Hypercortisolaemia was then treated with metyrapone and atezolizumab plus chemotherapy, which was started for SCLC. After 10 days, the tumour shrank noticeably, and the ACTH level drastically decreased concomitantly with low cortisol levels with symptoms of fever, appetite loss, and general fatigue. Hydrocortisone treatment was initiated, and the symptoms resolved immediately. We describe a case of SCLC with EAS treated with atezolizumab plus chemotherapy, presenting with adrenal insufficiency. Close observation is required for patients with adrenal insufficiency receiving atezolizumab plus chemotherapy because of its stronger effect. Furthermore, advances in cancer therapy and care for endocrine paraneoplastic syndrome needs to be adapted.

Pharmaceutical and food-related applications of lactoferrin, an 80-kDa iron-binding glycoprotein found predominantly in milk, have attracted interest lately, but the process of digestion of lactoferrin has been poorly characterized. The digestive fate of bovine lactoferrin in adult rats after oral administration of a single dose and after dietary supplementation was studied by (125)I-labeling and by surface-enhanced laser desorption/ionization (SELDI) affinity mass spectrometry. The latter method was designed to detect multiple forms of degraded lactoferrin as simple molecular ion peaks corresponding to one of the core regions of lactoferrin, namely, the lactoferricin region (Phe17-Ala42). Radioactive fragments with molecular masses of 42, 36, 33 and 29 kDa were observed at 20, 60 and 180 min postingestion in the contents of the lower small intestine. Rats were given free access to milk enriched with lactoferrin at 482 micromol/L (40 mg/mL). The concentrations of lactoferrin fragments in the contents of the stomach, small intestine and lower small intestine as determined by SELDI affinity mass spectrometry were approximately 200, 20 and 1 micromol/L, respectively. These data indicate that functional fragments of LF such as fragments containing glycosaminoglycan-binding site(s), as well as large fragments with a mass >20 kDa, indeed survive proteolytic degradation in the small intestine of adult rats. [ABSTRACT FROM AUTHOR]

Rosemary (Rosmarinus officinalis L.) is a rich source of dietary bioactive compounds such as rosmarinic acid and carnosol with a large repertoire of pharmacological properties, including anti-inflammatory and neuroprotective activities. In the present study, we investigated rosemary as a potential new therapeutic agent for cognitive function and other symptoms of aging. In this present study, we have aimed to investigate the effects of oral administration of rosemary extract (RME) on learning and memory in the context of other biomarkers-related cognitive function and neurotransmitter levels in senescent accelerated prone 8 (SAMP8) mouse, a model of accelerating aging and Alzheimer's disease. The Morris water maze (MWM) test showed improved spatial learning and memory behavior in RME treated SAMP8 mouse. Moreover, RME decreased Aβ 42 and inflammatory cytokine levels and increased BDNF, Sirt1, and neurotransmitter levels in SAMP8 mouse. Whole-genome microarray analysis revealed that RME significantly increased gene expression related to oligodendrocyte differentiation, myelination, and ATP production in the hippocampus and decreased gene expression related to stress, neuroinflammation, and apoptosis. Also, in the SAMP8 hippocampus, RME significantly increased Olig1 and Olig2 expression. Altogether, our study is the first to report improvement of spatial learning and memory of RME, modulation of genes important for oligodendrogenesis, and Anti-neuroinflammatory effect by suppressing Aβ 42 levels in mouse brain and thus highlights the prospects of RME in the treatment of cognitive dysfunction and aging., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Internal carotid artery stenosis is primarily attributed to atherosclerosis in the carotid artery bifurcation. Previous studies have detected oral bacteria in atherosclerotic lesions, suggesting an association between oral bacteria and atherosclerosis. In this study, we compared the bacterial flora of the atherosclerotic plaque in the carotid artery and dental plaque of patients with internal carotid artery stenosis using 16S ribosomal RNA (16S rRNA) metagenomic sequencing., Methods: Fifty-four patients who underwent internal carotid endarterectomy for internal carotid artery stenosis at the Showa University Hospital between April 2016 and February 2018 were included. Polymerase chain reaction targeting the 16S rRNA gene detected bacterial DNA in the carotid plaques of 11 cases, of which only 5 could be further analyzed. Thereafter, DNA extracted from the carotid and oral plaques of these 5 cases were analyzed using metagenomic sequencing targeting 16S rRNA. In addition, their general condition and oral conditions were evaluated. The patients were classified into symptomatic and asymptomatic groups based on the presence or absence of symptoms of transient ischemic attack, and their bacterial flora was evaluated., Results: The results demonstrated that the microflora of carotid plaques (n = 5) contained bacterial species from 55 families and 78 genera. In addition, 86.5% of the bacteria detected in the carotid plaques were also detected in oral plaques. Cariogenic and periodontopathic bacteria accounted for 27.7% and 4.7% of the bacteria in the carotid plaques, respectively., Conclusions: These results suggest that oral bacteria are directly or indirectly involved in the pathogenesis of atherosclerosis. More extensive studies of oral commensal bacteria detected in extra-oral lesions are warranted to comprehensively investigate the role of oral bacteria in the pathogenesis of systemic diseases., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Exposure to high-dose radiation causes life-threatening intestinal damage. Histopathology is the most accurate method of judging the extent of intestinal damage following death. However, it is difficult to predict the extent of intestinal damage. The present study investigated extracellular microRNAs (miRNAs or miRs) in serum and feces using a radiation-induced intestinal injury mouse model. A peak of 25-200 nucleotide small RNAs was detected in mouse serum and feces by bioanalyzer, indicating the presence of miRNAs. Microarray analysis detected four miRNAs expressed in the small intestine and increased by >2-fold in serum and 19 in feces following 10 Gy radiation exposure. Increased miR-375-3p in both serum and feces suggests leakage due to radiation-induced intestinal injury and may be a candidate for high-dose radiation biomarkers., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Chiba et al.)

Long-chain acyl-CoA synthetase (ACSL) 4 converts polyunsaturated fatty acids (PUFAs) into their acyl-CoAs and plays an important role in maintaining PUFA-containing membrane phospholipids. Here we demonstrated decreases in various kinds of PUFA-containing phospholipid species in ACSL4-deficient murine lung. We then examined the effects of ACSL4 gene deletion on lung injury by treating mice with two pulmonary toxic chemicals: paraquat (PQ) and methotrexate (MTX). The results showed that ACSL4 deficiency attenuated PQ-induced acute lung lesion and decreased mortality. PQ-induced lung inflammation and neutrophil migration were also suppressed in ACSL4-deficient mice. PQ administration increased the levels of phospholipid hydroperoxides in the lung, but ACSL4 gene deletion suppressed their increment. We further found that ACSL4 deficiency attenuated MTX-induced pulmonary fibrosis. These results suggested that ACSL4 gene deletion might confer protection against pulmonary toxic chemical-induced lung injury by reducing PUFA-containing membrane phospholipids, leading to the suppression of lipid peroxidation. Inhibition of ACSL4 may be promising for the prevention and treatment of chemical-induced lung injury., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest associated with this manuscript., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Carnosic acid (CA) is a phenolic diterpene widely distributed in herbal plants, rosemary and sage. Although its medicinal properties, such as antioxidant, antimicrobial, and neuroprotective effects, have been well-documented, its relevant biochemical processes and molecular targets have not been fully explored yet. In the present study, we conducted an untargeted whole-genome transcriptomics analysis to investigate CA-induced early biological and molecular events in human amniotic epithelial stem cells (hAESCs) with the aim of exploring its multiple tissue-specific functionalities and potential molecular targets. We found that seven days of CA treatment in hAESCs could induce mesoderm-lineage-specific differentiation. Tissue enrichment analysis revealed that CA significantly enriched lateral plate mesoderm-originated cardiovascular and adipose tissues. Further tissue-specific PPI analysis and kinase and transcription factor enrichment analyses identified potential upstream regulators and molecular targets of CA in a tissue-specific manner. Gene ontology enrichment analyses revealed the metabolic, antioxidant, and antifibrotic activities of CA. Altogether, our comprehensive whole-genome transcriptomics analyses offer a thorough understanding of the possible underlying molecular mechanism of CA.

Aims/introduction: This study was designed and carried out to investigate the association of dipeptidyl peptidase-4 inhibitor (DPP-4i) use with pancreatic cancer (PC) in individuals with diabetes in Japan., Materials and Methods: The JMDC Claims Database, which contains the medical and prescription information of Japanese employment-based health insurance programs, was used. The primary outcome was duration to the first occurrence of PC (International Classification of Diseases 10th Revision code C25), both all and hospitalized, from prescription of DPP-4is or other oral glucose-lowering agents (GLAs)., Results: Individuals with diabetes who received DPP-4is (n = 61,430) or other oral GLAs (n = 83,304) were analyzed. Follow-up periods (median [interquartile range]) were 17 months (8-33) for DPP-4is and 14 months (7-28) for other oral GLAs. Kaplan-Meier curve analysis to determine the duration of first use of DPP4i or other oral GLA to diagnosis of PC disclosed no differences between the two groups in duration to all or hospitalized PC (log-rank test: all, P = 0.7140; hospitalized, P = 0.3446). Cox proportional hazards models showed that use of DPP-4is did not affect the PC risk adjusted for medications, age, sex and risk comorbidities (all, hazard ratio 1.1, 95% confidence interval 0.8-1.3, P = 0.6518; hospitalized, hazard ratio 1.1, 95% confidence interval 0.8-1.4, P = 0.6662). Similar results were obtained when individuals with ≥2 years oral GLA treatment and those with medical checkup data (e.g., smoking or drinking habit) available were analyzed., Conclusion: This database study shows that there is not a significant PC risk due to DPP-4i treatment in individuals with diabetes in Japan, but larger studies with longer follow up are required to confirm these findings., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims/introduction: The aim of this study was to develop a scale to evaluate disease stigma in patients with lifestyle-related chronic non-communicable diseases (LCNCDs), which we named the Kanden Institute Stigma Scale (KISS), and to consider its possible clinical application for patients with diabetes., Materials and Methods: An initial 90 questions were drafted and categorized into six subscales according to the manifestations of stigma. The final version of the KISS was developed as a 24-item questionnaire comprising four items for each subscale., Results: A total of 539 outpatients including 452 patients with diabetes and 87 patients without diabetes were recruited. Construct validity was confirmed by assessing the correlation with previously established measures. Confirmatory factor analysis showed the KISS to have good model fitness (adjusted goodness-of-fit index = 0.856). Test-retest reproducibility analysis showed that the intraclass coefficient of the first and a second KISS was 0.843 (P < 0.001), indicating excellent reproducibility. The KISS showed higher scores for patients with diabetes than for patients without diabetes (12.23 ± 0.49 vs 5.76 ± 0.73, P < 0.05). The KISS score was significantly higher in type 1 and type 2 diabetes patients taking insulin therapy than in type 2 diabetes patients not taking insulin (P < 0.05)., Conclusion: The KISS is a validated and reliable questionnaire for assessment of stigma among patients with diabetes as well as other lifestyle-related chronic non-communicable diseases, and might contribute to identifying and rectifying diabetes stigma, as well promoting awareness among health care professionals of this very consequential health problem., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Members of the mitis group streptococci are the most abundant inhabitants of the oral cavity and dental plaque. Influenza A virus (IAV), the causative agent of influenza, infects the upper respiratory tract, and co-infection with Streptococcus pneumoniae is a major cause of morbidity during influenza epidemics. S. pneumoniae is a member of mitis group streptococci and shares many features with oral mitis group streptococci. In this study, we investigated the effect of viable Streptococcus oralis, a representative member of oral mitis group, on the infectivity of H1N1 IAV. The infectivity of IAV was measured by a plaque assay using Madin-Darby canine kidney cells. When IAV was incubated in growing culture of S. oralis, the IAV titer decreased in a time- and dose-dependent manner and became less than 100-fold, whereas heat-inactivated S. oralis had no effect. Other oral streptococci such as Streptococcus mutans and Streptococcus salivarius also reduced the viral infectivity to a lesser extent compared to S. oralis and Streptococcus gordonii, another member of the oral mitis group. S. oralis produces hydrogen peroxide (H2O2) at a concentration of 1-2 mM, and its mutant deficient in H2O2 production showed a weaker effect on the inactivation of IAV, suggesting that H2O2 contributes to viral inactivation. The contribution of H2O2 was confirmed by an inhibition assay using catalase, an H2O2-decomposing enzyme. These oral streptococci produce short chain fatty acids (SCFA) such as acetic acid as a by-product of sugar metabolism, and we also found that the inactivation of IAV was dependent on the mildly acidic pH (around pH 5.0) of these streptococcal cultures. Although inactivation of IAV in buffers of pH 5.0 was limited, incubation in the same buffer containing 2 mM H2O2 resulted in marked inactivation of IAV, which was similar to the effect of growing S. oralis culture. Taken together, these results reveal that viable S. oralis can inactivate IAV via the production of SCFAs and H2O2. This finding also suggests that the combination of mildly acidic pH and H2O2 at low concentrations could be an effective method to inactivate IAV., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Okahashi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Bovine lactoferrin (BLF) reportedly lowers blood pressure and induces vasorelaxation, but its effect on nitric oxide (NO) production has not been established. Accordingly, we aimed to determine whether BLF induces NO production in bovine aortic endothelial cells, and the effects of extracellular free magnesium (Mg) ion concentrations on this NO production. BLF induced NO production time-dependently. NO production was markedly inhibited by the NO synthase inhibitor, N G -nitro-L-arginine methyl ester, in an effect abolished by L-arginine, but not D-arginine. NO production was suppressed at low concentrations, and enhanced at high concentrations, of Mg ions in culture medium. These results suggest that BLF has an important role in hypotensive effects. Mg ions may affect BLF-induced NO production.

Melatonin, a sleep hormone derived from the pineal gland, has an anti-inflammatory effect on the immune system in addition to modulating the brain nervous system. Previous studies have shown that melatonin suppresses signaling pathways downstream of multiple pattern recognition receptors on the innate immune cells during pathogen infection, but the specific mechanism of suppression has not been well understood. Using an encephalomyocarditis virus (EMCV) infection model in macrophages, we investigated the effects of melatonin on the antiviral response in innate immunity and found that melatonin attenuated the uptake of viral particles into macrophages. Furthermore, melatonin suppressed cytoskeletal regulation by decreasing ATP production by mitochondria. Finally, in an in vivo infection experiment, we also found that melatonin administration partially exacerbated the infection in the mouse brain. These results suggest that melatonin may have an inhibitory effect on excessive inflammation by suppressing cytoskeletal regulation in the innate immune system, but also suggest that suppression of inflammation may lead to insufficient protection against EMCV infection in vivo ., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Fe-Si-B-P-Cu nanocrystalline alloy were treated with ball-mill using a lubricant as a process control agent (PCA). The resulting alloy powder is a strong candidate material for soft magnetic composites. Two ball milling methods (continuous and interval) were employed to control the interactions between the PCA and the alloy surface, and their effect on the microstructure of the prepared alloy particles was investigated. The alloy sheet was broken into small pieces and deformed plastically into flake-shaped particles regardless of the ball milling method implemented. Friction-force microscopy of the alloy immersed in the PCA revealed that the friction coefficient of the alloy surface exposed to air for a certain period was higher than that of the unexposed alloy surface (immediately after polishing). During ball milling, the ratio of the newly generated surface to the oxidized surfaces of the alloy subjected to interval milling was smaller than that of the alloy subjected to continuous milling. Therefore, the friction coefficient of the surface of the alloy subjected to interval milling was higher than that of the alloy subjected to continuous milling. Synchrotron radiation analysis revealed that the alloy subjected to interval milling exhibited enhanced surface friction, showing an obvious steepness and inflection in the diffraction intensity as a function of the tilt angle based on the Schulz reflection method. This indicates formation of crystallographic texture in α-Fe grains in an amorphous matrix. Hence, we demonstrated successfully that the ball milling process induced a crystallographic texture in the Fe-based nanocrystalline alloy due to plastic deformation due to the enhanced surface friction. The surface of the alloy was prepared based on the effect of the interfacial interactions between the alloy surface and the PCA., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Recently, it has been demonstrated that dysbiosis, an alteration in commensal microflora composition, is intimately involved in the onset of a variety of diseases. It is becoming increasingly evident that the composition of commensal microflora in the oral cavity is closely connected to oral diseases, such as periodontal disease, and systemic diseases, such as inflammatory bowel disease. Next-generation sequencing techniques are used as a method to examine changes in bacterial flora, but additional analytical methods to assess bacterial flora are needed to understand bacterial activity in more detail. In addition, the oral environment is unique because of the role of secretory antibodies contained in saliva in the formation of bacterial flora. The present study aimed to develop a new method for evaluating the compositional change of microbiota using flow cytometry (FCM) with specific antibodies against the bacterial surface antigen, as well as salivary antibodies. Using specific antibodies against Streptococcus mutans , a causative agent of dental caries, and human IgA, bacterial samples from human saliva were analyzed via FCM. The results showed that different profiles could be obtained depending on the oral hygiene status of the subjects. These results suggest that changes in the amount and type of antibodies that bind to oral bacteria may be an indicator for evaluating abnormalities in the oral flora. Therefore, the protocol established in this report could be applied as an evaluation method for alterations in the oral microbiota., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Aims/introduction: We assessed the association between dipeptidyl peptidase-4 inhibitors (DPP-4is) and bullous pemphigoid (BP) and time-dependent changes in the risk for developing BP after DPP-4i initiation., Materials and Methods: The present population-based, real-world study was carried out using the Japanese National Database dataset collected between 2013 and 2018. To assess independent correlations between DPP-4is and the development of BP, the self-controlled case series method was used., Results: Among the cohort followed up for a median of 1,540 days, 53,027 patients were likely to develop BP. The possible incidence rate of BP in all 150,328,339 patients was 10.4/100,000 person-years. Among the 9,705,814 patients with type 2 diabetes, 15,634 were likely to develop BP. The possible incidence rate of BP in patients with type 2 diabetes was 38.1/100,000 person-years, whereas that in patients with type 2 diabetes who did and did not use DPP-4is was 40.7 and 30.0/100,000 person-years, respectively. Analysis of the 28,705 patients with type 2 diabetes likely to develop BP after initial DPP-4i use showed a risk ratio of 2.15 (95% confidence interval [CI] 1.75-2.63), 1.70 (95% CI 1.37-2.11), 1.44 (95% CI 1.15-1.82), 1.25 (95% CI 0.98-1.59), 0.84 (95% CI 0.63-1.10), 0.84 (95% CI 0.64-1.11) and 1.05 (95% CI 0.92-1.20), for the risk period of ≤30, 31-60, 61-90, 91-120, 121-150, 151-180 and 181-365 days, respectively., Conclusions: Although DPP-4is were associated with increased risk for BP, the risk was particularly significant within 3 months from first use., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Acyl-CoA synthetase long-chain family member 4 (ACSL4) activates polyunsaturated fatty acids (PUFAs) to produce PUFA-derived acyl-CoAs, which are utilised for the synthesis of various biological components, including phospholipids (PLs). Although the roles of ACSL4 in non-apoptotic programmed cell death ferroptosis are well-characterised, its role in the other types of cell death is not fully understood. In the present study, we investigated the effects of ACSL4 knockdown on the levels of acyl-CoA, PL, and ferroptosis in the human normal kidney proximal tubule epithelial (HK-2) cells. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses revealed that the knockdown of ACSL4 markedly reduced the levels of PUFA-derived acyl-CoA, but not those of other acyl-CoAs. In contrast with acyl-CoA levels, the docosahexaenoic acid (DHA)-containing PL levels were preferentially decreased in the ACSL4-knockdown cells compared with the control cells. Cell death induced by the ferroptosis inducers RSL3 and FIN56 was significantly suppressed by treatment with ferrostatin-1 or ACSL4 knockdown, and, unexpectedly, upon treating with a necroptosis inhibitor. In contrast, ACSL4 knockdown failed to suppress the other oxidative stress-induced cell deaths initiated by cadmium chloride and sodium arsenite. In conclusion, ACSL4 is involved in the biosynthesis of DHA-containing PLs in HK-2 cells and is specifically involved in the cell death induced by ferroptosis inducers., (© 2022 The Author(s).)

(1) Background: Protein stimulates the secretion of glucagon (GCG), which can affect glucose metabolism. This study aimed to analyze the metabolic effect of a high-protein diet (HPD) in the presence or absence of proglucagon-derived peptides, including GCG and GLP-1. (2) Methods: The response to HPD feeding for 7 days was analyzed in mice deficient in proglucagon-derived peptides (GCGKO). (3) Results: In both control and GCGKO mice, food intake and body weight decreased with HPD and intestinal expression of Pepck increased. HPD also decreased plasma FGF21 levels, regardless of the presence of proglucagon-derived peptides. In control mice, HPD increased the hepatic expression of enzymes involved in amino acid metabolism without the elevation of plasma amino acid levels, except branched-chain amino acids. On the other hand, HPD-induced changes in the hepatic gene expression were attenuated in GCGKO mice, resulting in marked hyperaminoacidemia with lower blood glucose levels; the plasma concentration of glutamine exceeded that of glucose in HPD-fed GCGKO mice. (4) Conclusions: Increased plasma amino acid levels are a common feature in animal models with blocked GCG activity, and our results underscore that GCG plays essential roles in the homeostasis of amino acid metabolism in response to altered protein intake.

The global outbreak of coronavirus disease 2019 (COVID-19) has raised concerns about the risk of airborne infection during dental treatment. Aerosol-generating dental procedures (AGDP) produce droplets and aerosols, but the details of the risks of COVID-19 transmission in AGDP are not well-understood. By discriminating between droplets and aerosols, we devised a method to measure particle size using laser diffraction analysis and evaluated aerosols generated from dental devices for providing a basis for proper infection control procedures. The droplets and aerosols generated from dental devices were characterized by multimodal properties and a wide range of droplet sizes, with the majority of droplets larger than 50 μm. AGDP emitted few aerosols smaller than 5 μm, which are of concern for pulmonary infections due to airborne transmission. In addition, the use of extraoral suction was found to prevent the spread of aerosols from high-speed dental engines. This study suggests that the risk of aerosol infections is considerably limited in regular dental practice and that current standard precautions, such as mainly focusing on protection against droplet and contact infections, are sufficient. While several cases of airborne transmission of COVID-19 in general clinics and emergency hospitals have been reported, cluster outbreaks in dental clinics have not yet been reported, which may indicate that AGDP does not pose a significant threat in contributing to the spread of SARS-CoV-2., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Onoyama, Matsui, Kikuchi, Sato, Fukamachi, Kadena, Funatsu, Maruoka, Baba, Maki and Kuwata.)

Aims/introduction: This 6-month, single-center, prospective, open-labeled, randomized trial was designed to investigate whether physicians' diabetes self-management education using an education tool developed by the Japan Association of Diabetes Education and Care and a self-monitoring of blood glucose (SMBG) analyzer improves glycemic control in individuals with type 2 diabetes receiving insulin and SMBG., Materials and Methods: Participants were randomized into intervention (I) and control (C) groups. Both groups received physicians' diabetes self-management education at each hospital visit, whereas the Japan Association of Diabetes Education and Care education tool and the SMBG readings analyzer was used in group I, but not group C. All participants filled out a diabetes treatment-related quality of life form and an original questionnaire on SMBG use with five questions (Q1-Q5) before and after the study period., Results: A total of 76 individuals were recruited and randomized. Glycated hemoglobin (HbA1c) was significantly improved during the study period in group I, whereas no significant change was observed in group C. The change in HbA1c was greater in group I, although it did not reach statistical significance. The diabetes treatment-related quality of life total score was not changed in either group. Interestingly, the score of Q1 ("How important is SMBG to you?") in the SMBG questionnaire was unchanged in group I, whereas it was significantly decreased in group C. HbA1c change was independently associated with changes in insulin dose and SMBG Q1 score., Conclusion: Greater HbA1c-lowering by physicians' diabetes self-management education using the Japan Association of Diabetes Education and Care education tool and SMBG analyzer in individuals with type 2 diabetes receiving insulin and SMBG was suggested, but not confirmed., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims/introduction: Differences in the glucose-lowering mechanisms of glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been noted. Clarifying these differences could facilitate the choice of optimal drugs for individuals with type 2 diabetes and requires investigation in a clinical setting., Materials and Methods: A single-arm, prospective, observational study was conducted to evaluate the effects of various GLP-1RAs on postprandial glucose excursion, secretions of insulin and glucagon as well as on the gastric emptying rate. Participants were subjected to meal tolerance tests before and 2 weeks and 12 weeks after GLP-1RA initiation. Effects on postprandial secretions of glucose-dependent insulinotropic polypeptide (GIP) and apolipoprotein B48 were also investigated., Results: Eighteen subjects with type 2 diabetes received one of three GLP-1RAs, i.e., lixisenatide, n = 7; liraglutide, n = 6; or dulaglutide, n = 5. While 12-week administration of all of the GLP-1RAs significantly reduced HbA1c, only lixisenatide and liraglutide, but not dulaglutide, significantly reduced body weight. Postprandial glucose elevation was improved by all of the GLP-1RAs. Postprandial insulin levels were suppressed by lixisenatide, while insulin levels were enhanced by liraglutide. Postprandial glucagon levels were suppressed by lixisenatide. The gastric emptying rate was significantly delayed by lixisenatide, while liraglutide and dulaglutide had limited effects on gastric emptying. GIP secretion was suppressed by lixisenatide and liraglutide. Apolipoprotein B48 secretion was suppressed by all of the GLP-1RAs., Conclusions: All of the GLP-1RAs were found to improve HbA1c in a 12-week prospective observational study in Japanese individuals with type 2 diabetes. However, differences in the mechanisms of the glucose-lowering effects and body weight reduction were observed., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Oxytocin (OXT), a neuropeptide involved in mammal reproductive and prosocial behaviors, has been reported to interact with various stressor-provoked neurobiological changes, including neuroendocrine, neurotransmitter, and inflammatory processes. In view of disturbances in psychosocial relationships due to social isolation and physical distancing measures amid the COVID-19 pandemic, being one of the triggering factors for the recent rise in depression and anxiety, OXT is a potential candidate for a new antidepressant., Methods: In this present study, we have aimed to investigate the effects of oral administration of Rosmarinus officinalis extract (RE), extracted from distillation residue of rosemary essential oil, on central OXT level in the context of other stress biomarkers and neurotransmitter levels in mice models. Tail suspension test (TST) and elevated plus maze test (EPMT) following LPS injection were employed to assess depressive- and anxiety-like behavior in mice, respectively., Findings: Pretreatment with RE for seven days significantly improved behavior in TST and EPMT. Whole-genome microarray analysis reveals that RE significantly reversed TST stress-induced alterations in gene expressions related to oxytocinergic and neurotransmitter pathways and inflammatory processes. In both models, RE significantly increased central Oxt and Oxtr expressions, as well as OXT protein levels. RE also significantly attenuated stress-induced changes in serum corticosterone, brain and serum BDNF levels, and brain neurotransmitters levels in both models., Interpretation: Altogether, our study is the first to report antidepressant- and anxiolytic-like activities of RE through modulating oxytocinergic system in mice brain and thus highlights the prospects of RE in the treatment of depressive disorders of psychosocial nature., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

To clarify the association between lifestyle changes as a result of coronavirus disease 2019 containment measures and changes in metabolic and glycemic status in patients with diabetes, a cross-sectional, single-center, observation study was carried out. A self-reported questionnaire was provided to ascertain the frequency of various lifestyle activities before and after the coronavirus disease 2019 containment measures in Japan. Among 463 patients, change in glycated hemoglobin was significantly associated with change in bodyweight. After stratification by age 65 years, binary logistic regression analysis showed that increased frequency of snack eating increased bodyweight (odds ratio 1.709, P = 0.007) and glycated hemoglobin (odds ratio 1.420, P = 0.025) in the younger group, whereas in the older patients, reduced walking activities resulted in weight gain (odds ratio 0.726, P = 0.010). In conclusion, changes in eating behavior and physical activity increased bodyweight and reduced glycemic control among diabetes patients, but by different processes depending on age under the coronavirus disease 2019 containment measures in Japan., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background/aim: Microsomal prostaglandin (PG) E synthase-1 (mPGES-1) is a terminal enzyme in PGE 2 synthesis and highly expressed in several cancers. In this study, to reveal the involvement of mPGES-1 in skin carcinogenesis, the effect of mPGES-1 deficiency on two-stage skin carcinogenesis in mice was investigated., Materials and Methods: A two-stage skin carcinogenesis model using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter was applied on mPGES-1 knockout (KO) mice and littermate wild-type mice of a Balb/c genetic background., Results: DMBA/TPA-induced skin carcinogenesis was suppressed in mPGES-1 KO mice. The induction of IL-17 and other inflammatory cytokines by TPA was also suppressed by mPGES-1 deficiency, although DMBA-induced apoptosis was not affected., Conclusion: mPGES-1 promotes chemically induced skin carcinogenesis and might play an important role in the TPA-induced promotion phase of the two-stage skin carcinogenesis model. mPGES-1 inhibition may be a therapeutic target for skin cancer., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Fractal dimensions and characteristic periodicities were evaluated in normal sentences, computer-generated word salads, and word salads from schizophrenia patients, in both Japanese and English, using the random walk patterns of vowels.　In normal sentences, the walking curves were smooth with gentle undulations, whereas computer-generated word salads were rugged with mechanical repetitions, and word salads from patients with schizophrenia were unreasonably winding with meaningless repetitive patterns or even artistic cohesion. These tendencies were similar in both languages. Fractal dimensions between normal sentences and word salads of schizophrenia were significantly different in Japanese [1.19 ± 0.09 (n = 90) and 1.15 ± 0.08 (n = 45), respectively] and English [1.20 ± 0.08 (n = 91), and 1.16 ± 0.08 (n = 42)] (p < 0.05 for both). Differences in long-range (>10) periodicities between normal sentences and word salads from schizophrenia patients were predominantly observed at 25.6 (p < 0.01) in Japanese and 10.7 (p < 0.01) in English. The differences in fractal dimension and characteristic periodicities of relatively long-range (>10) presented here are sensitive to discriminate between schizophrenia and healthy mental state, and could be implemented in social robots to assess the mental state of people in care., Competing Interests: The authors have declared that no competing interests exist.

Long-chain acyl-CoA synthetases (ACSLs) are a family of enzymes that convert long-chain free fatty acids into their active form, acyl-CoAs. Recent knock-out mouse studies revealed that among ACSL isoenzymes, ACSL6 plays an important role in the maintenance of docosahexaenoic acid (DHA)-containing glycerophospholipids. Several transcript variants of the human ACSL6 gene have been found; the two major ACSL6 variants, ACSL6V1 and V2, encode slightly different short motifs that both contain a conserved structural domain, the fatty acid Gate domain. In the present study, we expressed recombinant human ACSL6V1 and V2 in Spodoptera frugiperda 9 (Sf9) cells using the baculovirus expression system, and then, using our novel ACSL assay system with liquid chromatography-tandem mass spectrometry (LC-MS/MS), we examined the substrate specificities of the recombinant human ACSL6V1 and V2 proteins. The results showed that both ACSL6V1 and V2 could convert various kinds of long-chain fatty acids into their acyl-CoAs. Oleic acid was a good common substrate and eicosapolyenoic acids were poor common substrates for both variants. However, ACSL6V1 and V2 differed considerably in their preferences for octadecapolyenoic acids, such as linoleic acid, and docosapolyenoic acids, such as DHA and docosapentaenoic acid (DPA): ACSL6V1 preferred octadecapolyenoic acids, whereas V2 strongly preferred docosapolyenoic acids. Moreover, our kinetic studies revealed that ACSL6V2 had a much higher affinity for DHA than ACSL6V1. Our results suggested that ACSL6V1 and V2 might exert different physiological functions and indicated that ACSL6V2 might be critical for the maintenance of membrane phospholipids bearing docosapolyenoic acids such as DHA.

While adjustment of total energy and nutritional balance is critically important, meal sequence, a relatively simple method of correcting postprandial hyperglycemia, is becoming established as a practical dietary approach for prevention and management of diabetes and obesity. Meal sequence, i.e., consumption of protein and/or fat before carbohydrate, promotes secretion of glucagon-like peptide-1 (GLP-1) from the gut and ameliorates secretions of insulin and glucagon and delays gastric emptying, thereby improving postprandial glucose excursion. GLP-1 is known to suppress appetite by acting on the hypothalamus via the afferent vagus nerve. Thus, enhancement of GLP-1 secretion by meal sequence is expected to reduce body weight. Importantly, consumption of a diet rich in saturated fatty acids such as meat dishes before carbohydrate increases secretions of not only GLP-1 but also glucose-dependent insulinotropic polypeptide (GIP), which promotes energy storage in adipose tissue and may lead to weight gain in the long term. Dietary fiber intake before carbohydrate intake significantly reduces postprandial glucose elevation and may have a weight loss effect, but this dietary strategy does not enhance the secretion of GLP-1. Thus, it is suggested that their combination may have additive effects on postprandial glucose excursion and body weight. Indeed, results of some clinical research supports the idea that ingesting dietary fiber together with meal sequence of protein and/or fat before carbohydrate benefits metabolic conditions of individuals with diabetes and obesity.

Accumulating evidence demonstrates that not only sustained elevation of blood glucose levels but also the glucose fluctuation represents key determinants for diabetic complications and mortality. Current closed-loop insulin therapy option is limited to the use of electronics-based systems, although it poses some technical issues with high cost. Here we demonstrate an electronics-free, synthetic boronate gel-based insulin-diffusion-control device technology that can cope with glucose fluctuations and potentially address the electronics-derived issues. The gel was combined with hemodialysis hollow fibers and scaled suitable for rats, serving as a subcutaneously implantable, insulin-diffusion-active site in a manner dependent on the subcutaneous glucose. Continuous glucose monitoring tests revealed that our device not only normalizes average glucose level of rats, but also markedly ameliorates the fluctuations over timescale of a day without inducing hypoglycemia. With inherent stability, diffusion-dependent scalability, and week-long & acute glucose-responsiveness, our technology may offer a low-cost alternative to current electronics-based approaches.

Mast cells and basophils are central players in allergic reactions triggered by immunoglobulin E (IgE). They have intracellular granules containing allergic mediators (e.g., histamine, serotonin, inflammatory cytokines, proteases and β-hexosaminidase), and stimulation by IgE-allergen complex leads to the release of such allergic mediators from the granules, that is, degranulation. Mast cells are residents of mucosal surfaces, including those of nasal and oral cavities, and play an important role in the innate defense system. Members of the mitis group streptococci such as Streptococcus oralis, are primary colonizers of the human oral cavity. They produce hydrogen peroxide (H2O2) as a by-product of sugar metabolism. In this study, we investigated the effects of streptococcal infection on RBL-2H3 mast cell/basophil cell line. Infection by oral streptococci did not induce degranulation of the cells. Stimulation of the RBL-2H3 cells with anti-dinitrophenol (DNP) IgE and DNP-conjugated human serum albumin triggers degranulation with the release of β-hexosaminidase. We found that S. oralis and other mitis group streptococci inhibited the IgE-triggered degranulation of RBL-2H3 cells. Since mitis group streptococci produce H2O2, we examined the effect of S. oralis mutant strain deficient in producing H2O2, and found that they lost the ability to suppress the degranulation. Moreover, H2O2 alone inhibited the IgE-induced degranulation. Subsequent analysis suggested that the inhibition of degranulation was related to the cytotoxicity of streptococcal H2O2. Activated RBL-2H3 cells produce interleukin-4 (IL-4); however, IL-4 production was not induced by streptococcal H2O2. Furthermore, an in vivo study using the murine pollen-induced allergic rhinitis model suggested that the streptococcal H2O2 reduces nasal allergic reaction. These findings reveal that H2O2 produced by oral mitis group streptococci inhibits IgE-stimulated degranulation by inducing cell death. Consequently, streptococcal H2O2 can be considered to modulate the allergic reaction in mucosal surfaces., Competing Interests: The authors have declared that no competing interests exist.

Acetaminophen (APAP) overdose is a common cause of drug-induced acute liver failure. Although hepatocyte cell death is considered to be the critical event in APAP-induced hepatotoxicity, the underlying mechanism remains unclear. Ferroptosis is a newly discovered type of cell death that is caused by a loss of cellular redox homeostasis. As glutathione (GSH) depletion triggers APAP-induced hepatotoxicity, we investigated the role of ferroptosis in a murine model of APAP-induced acute liver failure. APAP-induced hepatotoxicity (evaluated in terms of ALT, AST, and the histopathological score), lipid peroxidation (4-HNE and MDA), and upregulation of the ferroptosis maker PTGS2 mRNA were markedly prevented by the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1). Fer-1 treatment also completely prevented mortality induced by high-dose APAP. Similarly, APAP-induced hepatotoxicity and lipid peroxidation were prevented by the iron chelator deferoxamine. Using mass spectrometry, we found that lipid peroxides derived from n-6 fatty acids, mainly arachidonic acid, were elevated by APAP, and that auto-oxidation is the predominant mechanism of APAP-derived lipid oxidation. APAP-induced hepatotoxicity was also prevented by genetic inhibition of acyl-CoA synthetase long-chain family member 4 or α-tocopherol supplementation. We found that ferroptosis is responsible for APAP-induced hepatocyte cell death. Our findings provide new insights into the mechanism of APAP-induced hepatotoxicity and suggest that ferroptosis is a potential therapeutic target for APAP-induced acute liver failure.

Adipogenic differentiation is a complex process by which fibroblast-like undifferentiated cells are converted into cells that accumulate lipid droplets. We here investigated the effect of gene deletion of calcium-independent phospholipase A 2 γ (iPLA 2 γ), a membrane-bound PLA 2 enzyme, on adipogenic differentiation in mice. Since iPLA 2 γ knockout (KO) mice showed reduced fat volume and weight, we prepared mouse embryonic fibroblasts (MEF) from wild-type (WT) and iPLA 2 γ KO mice and examined the effect of iPLA 2 γ deletion on in vitro adipogenic differentiation. iPLA 2 γ increased during adipogenic differentiation in WT mouse-derived MEFs, and the differentiation was partially abolished in iPLA 2 γ KO-derived MEFs. In KO-derived MEFs, the inductions of peroxisome proliferator activator receptor γ (PPARγ) and CAAT/enhancer-binding protein α (C/EBPα) were also reduced during adipogenic differentiation, and the reductions in PPARγ and C/EBPα expressions and the defect in adipogenesis were restored by treatment with troglitazone, a PPARγ ligand. These results indicate that iPLA 2 γ might play a critical role in adipogenic differentiation by regulating PPARγ expression.

Food allergy is a life-threatening response to specific foods, and microbiota imbalance (dysbiosis) in gut is considered a cause of this disease. Meanwhile, the host immune response also plays an important role in the disease. Notably, interleukin 33 (IL-33) released from damaged or necrotic intestinal epithelial cells facilitates IL-2-producing CD4 helper T (Th2) responses. However, causal relationships between the gut and oral dysbiosis and food allergy remain unknown. In this study, we analyzed effects of gut and oral dysbiosis on development of food allergy. A murine model of food allergy was established via ovalbumin (OVA) injection in BALB/c mice. Viable fecal bacteria were identified using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). il33 expression in colon-26 mouse colon cells stimulated by isolated fecal bacteria was quantified by real-time PCR. Intestinal T cells from the mice were analyzed by flow cytometry. Salivary IgA levels were quantified by enzyme-linked immunosorbent assay (ELISA), and IgA-bound oral bacteria were detected by flow cytometry. Among fecal bacteria, the abundance of Citrobacter sp. increased in the feces of allergic mice and induced il33 expression in colon-26 cells. Orally administered Citrobacter koseri JCM1658 exacerbated systemic allergic symptoms and reduced intestinal Th17 cells. Salivary IgA and IgA-bound oral bacteria increased in the allergic mice. Based on the results described above, food allergy induced both gut and oral dysbiosis. Citrobacter sp. aggravated allergy symptoms by inducing IL-33 release from intestinal epithelial cells., (Copyright © 2019 Matsui et al.)

Accumulating clinical data on incretin-based dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists in the past decade have clearly confirmed their safety and efficacy as antidiabetes drugs. However, the journey to understand the incretin system and its role in health and disease continues., (© 2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Mitochondrial uncoupling protein 1 (UCP1) is well known for its thermogenic function in brown adipose tissue (BAT). Since UCP1 expends energy on thermogenesis, UCP1 activation has been considered an approach to ameliorate obesity. As a tool for uncovering yet unknown mechanisms of UCP1 activation, we generated a transgenic mouse model in which UCP1 expression levels are reflected in fluorescence derived from monomeric red fluorescent protein 1 (mRFP1). In these UCP1-mRFP1 BAC transgenic mice, fluorescence intensity mimics the change in UCP1 expression levels evoked through physiological or pharmacological stimulation. This transgenic mouse model will be useful in the search for bioactive compounds with the ability to induce UCP1 and for revealing undiscovered mechanisms of BAT activation., (© 2019 Federation of European Biochemical Societies.)