Critical Roles of the Cysteine-Glutathione Axis in the Production of γ-Glutamyl Peptides in the Nervous System.

γ-Glutamyl moiety that is attached to the cysteine (Cys) residue in glutathione (GSH) protects it from peptidase-mediated degradation. The sulfhydryl group of the Cys residue represents most of the functions of GSH, which include electron donation to peroxidases, protection of reactive sulfhydryl in proteins via glutaredoxin, and glutathione conjugation of xenobiotics, whereas Cys-derived sulfur is also a pivotal component of some redox-responsive molecules. The amount of Cys that is available tends to restrict the capacity of GSH synthesis. In in vitro systems, cystine is the major form in the extracellular milieu, and a specific cystine transporter, xCT, is essential for survival in most lines of cells and in many primary cultivated cells as well. A reduction in the supply of Cys causes GPX4 to be inhibited due to insufficient GSH synthesis, which leads to iron-dependent necrotic cell death, ferroptosis. Cells generally cannot take up GSH without the removal of γ-glutamyl moiety by γ-glutamyl transferase (GGT) on the cell surface. Meanwhile, the Cys-GSH axis is essentially common to certain types of cells; primarily, neuronal cells that contain a unique metabolic system for intercellular communication concerning γ-glutamyl peptides. After a general description of metabolic processes concerning the Cys-GSH axis, we provide an overview and discuss the significance of GSH-related compounds in the nervous system.

Biological Action of Singlet Molecular Oxygen from the Standpoint of Cell Signaling, Injury and Death.

Energy transfer to ground state triplet molecular oxygen results in the generation of singlet molecular oxygen (1O2), which has potent oxidizing ability. Irradiation of light, notably ultraviolet A, to a photosensitizing molecule results in the generation of 1O2, which is thought to play a role in causing skin damage and aging. It should also be noted that 1O2 is a dominant tumoricidal component that is generated during the photodynamic therapy (PDT). While type II photodynamic action generates not only 1O2 but also other reactive species, endoperoxides release pure 1O2 upon mild exposure to heat and, hence, are considered to be beneficial compounds for research purposes. Concerning target molecules, 1O2 preferentially reacts with unsaturated fatty acids to produce lipid peroxidation. Enzymes that contain a reactive cysteine group at the catalytic center are vulnerable to 1O2 exposure. Guanine base in nucleic acids is also susceptible to oxidative modification, and cells carrying DNA with oxidized guanine units may experience mutations. Since 1O2 is produced in various physiological reactions in addition to photodynamic reactions, overcoming technical challenges related to its detection and methods used for its generation would allow its potential functions in biological systems to be better understood.

Serum Cholinesterase Levels to Predict All-Cause Mortality in a Community-Based Study: The Takahata Study.

INTRODUCTION: Serum albumin (Alb) levels have been found to be independent predictors of all-cause mortality in a community-based population, but whether this is the case for serum cholinesterase (ChE) levels is uncertain. This study aimed to determine whether serum ChE levels are independent predictors of all-cause mortality in a community-based population. METHODS: A total of 3,504 subjects (mean age 62.5 years) from Takahata, Japan, participated and were followed up for 13.5 years (median 13.2 years). Based on baseline serum Alb and ChE levels, subjects were stratified by interquartile range as low, middle, and high. The correlation between serum Alb and ChE levels was examined by calculating correlation coefficients. The association between each group and all-cause mortality was examined by Kaplan-Meier and Cox proportional hazards analyses. RESULTS: During follow-up, 568 subjects died. There was a positive correlation between serum Alb and ChE levels (r = 0.30). Kaplan-Meier analysis showed that all-cause mortality in the low group was significantly higher for both serum Alb and ChE levels (log-rank p < 0.01). Adjusted Cox proportional hazards analysis showed that the serum Alb level was not an independent predictor of all-cause mortality (hazard ratio [HR] 1.18, 95% confidence interval [CI], 0.95-1.46 for all-cause mortality in the low group compared to the middle group), whereas the serum ChE level was an independent predictor of all-cause mortality (HR 1.30, 95% CI, 1.06-1.59 for all-cause mortality in the low group compared to the middle group). CONCLUSION: The serum ChE level is an independent predictor of all-cause mortality in the general community-based population.

Changes in pedicle pericardial fat tissue around the anastomotic site after tracheobronchoplasty.

PURPOSE: Pericardial fat is appropriate tissue to cover the bronchial anastomotic site because its harvesting is minimally invasive. We investigated the changes in pericardial fat tissue around the anastomotic site after pulmonary resection with tracheobronchoplasty. METHODS: The subjects of this study were 43 lung cancer patients who underwent pulmonary resection with tracheobronchoplasty. We measured the maximum cross-sectional area and average computed tomography (CT) values of the pedicle pericardial fat pad around the anastomotic site 1 week and then 6 months after the operation. RESULTS: The average volume of the residual pedicle pericardial fat pad 6 months postoperatively was 61%. A body mass index (BMI) < 21.2 kg/m2 (P = 0.031) and a blood albumin level < 3.4 g/dl (P = 0.005) were significant predictors of pedicle flap shrinkage. Patients with fat tissue shrinkage had significantly elevated CT values 6 months postoperatively (P = 0.029), whereas those without shrinkage maintained low CT values. CONCLUSIONS: Preoperative nutritional conditions, reflected in high BMI and blood albumin levels, correlated with a high residual pedicle pericardial fat pad. Conversely, patients with pedicle flap shrinkage had significantly increased CT values, suggesting that the fat might have taken on another form such as scar tissue.

[Status of Medical Assistance Techniques in Practice and Experiences of Problems in Home-Visit Nursing].

A questionnaire survey was administered to determine the status of medical assistance techniques in practice and experiences of problems in home-visit nursing.The frequencies of practice in and problems with the exchange and management of indwelling bladder catheters were the highest, whereas those of peritoneal dialysis and cancer chemotherapy were low, despite the difficulty level of practice being high.Many nurses feel anxious about judgment and practice in home-visit nursing, suggesting the necessity for measures to eliminate disparities in the regional home-visit nursing system and to improve homevisit nursing.

Brazilian propolis mitigates impaired glucose and lipid metabolism in experimental periodontitis in mice.

BACKGROUND: Periodontitis has been implicated as a risk factor for metabolic disorders associated with insulin resistance. Recently, we have demonstrated that orally administered Porphyromonas gingivalis, a representative periodontopathic bacterium, induces endotoxemia via reduced gut barrier function coupled with changes in gut microbiota composition, resulting in systemic inflammation and insulin resistance. Propolis, a resinous substance collected by honeybees from leaf buds and cracks in the bark of various plants, can positively affect metabolic disorders in various experimental models. In this study, we thus aimed to clarify the effect of propolis on impaired glucose and lipid metabolism induced by P. gingivalis administration. METHODS: Eight-week-old male C57BL/6 mice were orally administered P. gingivalis strain W83, propolis ethanol extract powder with P. gingivalis, or vehicle. We then analyzed the expression profile of glucose and lipid metabolism-related genes in the liver and adipose tissues. Serum endotoxin levels were also evaluated by a limulus amebocyte lysate test. In addition, we performed histological analysis of the liver and quantified alveolar bone loss by measuring the root surface area on the lower first molar. RESULTS: Oral administration of P. gingivalis induced downregulation of genes that improve insulin sensitivity in adipose tissue (C1qtnf9, Irs1, and Sirt1), but upregulation of genes associated with lipid droplet formation and gluconeogenesis (Plin2, Acox, and G6pc). However, concomitant administration of propolis abrogated these adverse effects of P. gingivalis. Consistent with gene expression, histological analysis showed that administered propolis suppressed hepatic steatosis induced by P. gingivalis. Furthermore, propolis inhibited the elevation of serum endotoxin levels induced by P. gingivalis administration. Contrary to the systemic effects, propolis had no beneficial effect on alveolar bone loss. CONCLUSION: These results suggest that administration of propolis may be effective in suppressing periodontopathic bacteria-induced metabolic changes that increase the risk of various systemic diseases.

[A Case of Long-Term Survival after Combination Therapy for Gastric Cancer with Synchronous Multiple Liver Metastasis].

A 63-year-old man was admitted to our hospital owing to weight loss and vertigo. Endoscopic examination revealed advanced gastric cancer type 2. Abdominal CT showed a 62mm liver tumor in segment 4 and a 26mm tumor in segment 8. Distal gastrectomy and D2 lymph node dissection were performed. After surgery, he was administered chemotherapy with S- 1. After 2 courses of treatment, the tumors' in segments 4 and 8 were reduced to 52mm and 16mm, respectively. No other metastases were detected. Left lobectomy and partial resection of segment 8 were performed. The pathological therapeutic effects were rated as Grade 1b for the tumor in segment 4 and Grade 3 for the tumor in segment 8. After hepatectomy, he was administered adjuvant chemotherapy with S-1 for 1 year. No recurrence has been detected for 4 years and 6months after hepatectomy.

Engaging in Action Research with Nurses: Overcoming Challenges and Gaining Positive Insights into End-of-Life Care.

The aim of this study was to qualitatively describe, from a practitioner's perspective, the process by which nurses struggle to support a patient with end-of-life cancer with frequent nurse calls and gain positive insights through two methodologies: AR and the case study method. The participants were four ward nurses who supported a patient receiving end-of-life cancer in his 80s. The participants engaged in monthly group work and practical training sessions, which included facilitators, to reflect on and develop care plans. Based on these activities, care was provided to the patient. After the intervention period, the patient's course and practice was documented and analysed qualitatively. The intervention significantly improved the nurses' ability to support inpatients with many needs through careful observation, enhancement, and practical skill improvement. This process resulted in a better understanding of patient needs, proactive skill development, enhanced team performance, and an innovative care-delivery system that resonated throughout the ward. This study demonstrated a successful strategy for nurses to improve support for high-need inpatients, emphasising the importance of attentive care, proactive skill improvement, and a team-based approach to healthcare innovation.

Measurement of serum hepcidin-25 by latex agglutination in healthy volunteers and patients with hematologic disorders.

Iron is an essential trace metal, vital for various physiologic processes, but excess levels can harm health. Maintaining iron homeostasis is critical, with hepcidin playing a key role. The isoform hepcidin-25 exerts the most significant influence on iron metabolism, making its serum levels a valuable diagnostic tool. However, mass-spectrometry and other conventional measurement methods can be difficult to perform, and some immunoassays lack reliability. In this study, we employed a recently developed latex agglutination method integrated with a readily available automated analyzer to quantify serum hepcidin-25 levels in both volunteers recruited from personnel of our hospital (n = 93) and patients with various hematological disorders (n = 112). Our findings unveiled a robust positive correlation between serum hepcidin-25 and ferritin, as well as C-reactive protein levels, in both volunteers and patients. Among the patients with hematological disorders, there was a noteworthy negative correlation between hepcidin-25 levels and hemoglobin concentrations, as well as reticulocyte counts. Interestingly, the hepcidin-25/ferritin ratio was remarkably low in patients with hemolytic anemia and myelodysplastic syndromes with ring sideroblasts. Our findings suggest that quantifying serum hepcidin-25 and the hepcidin-25/ferritin ratio using this method may be valuable for screening of hematopoietic diseases and other iron metabolism disorders.

Peripheral pulmonary mucous gland adenoma with a cavity mimicking lung cancer.

A 71-year-old woman presented to our hospital because of a 10 mm nodule with a cavity in right lower lobe on chest computed tomography. Fluorodeoxyglucose-positron emission tomography showed slight accumulation in the nodule (maximum standard uptake value 2.08). Her serum carcinoembryonic antigen concentration was 5.4 ng/mL. Wedge resection of the tumor was performed for diagnostic and treatment purposes. Findings on intraoperative pathological examination of a frozen section were suspicious for adenocarcinoma. We, therefore, performed a right lower lobectomy and mediastinal lymph node dissection. Postoperative histological examination revealed a mucous gland adenoma. The patient's postoperative course was favorable and she was discharged 7 days after surgery. Four months later, the serum carcinoembryonic antigen concentration had decreased to 3.1 ng/mL. Pulmonary mucous gland adenomas are rarely located peripherally. These benign tumors should be considered, even in the presence of high serum carcinoembryonic antigen concentrations or increased fluorodeoxyglucose uptake on fluorodeoxyglucose-positron emission tomography.

Right upper lobectomy for lung cancer with a displaced right bronchus: Two case reports.

Case 1 describe a 73-year-old man with an abnormal opacity in the upper lobe of the right lung on chest computed tomography (CT), which was done during the postoperative follow-up for bile duct cancer. The chest CT scan showed a ground glass nodule (GGN) measuring 1.0 cm and another one measuring 0.6 cm of the right lung. Case 2 involved a 79-year-old woman with an abnormal opacity in the upper lobe of the right lung on a chest CT that was obtained after she fell down the stairs. The CT scan showed a solid mass measuring 3.0 cm in the right upper lung. Both the patients underwent bronchoscopy before surgery and showed bronchial branching abnormalities. The surgical procedures could be performed accurately since sufficient information had been acquired pre-operatively and they diagnosed lung cancer. Both the patients were able to undergo radical surgery for lung cancer and are currently doing well with no postoperative complications or recurrence of lung cancer.

Metachronous multiple pulmonary nodules 9 years after esophagectomy: a case report.

A 79-year-old man was referred to our hospital for further examination. He had undergone radical esophagectomy with right thoracotomy 9 years ago. Four cycles of chemotherapy (CDDP +5-FU) were also performed for him. Eight years after esophagectomy, two nodules were identified in the upper lobe of the right lung on chest computed tomography (CT). Owing to the possibility of new primary lung cancer, partial resection was performed. Histopathological examination revealed squamous cell carcinoma. One year and two months later, follow-up chest CT scan revealed a nodule shadow of 1.5 cm in the left apex and a nodule shadow of 0.9 cm below the S9 pleura. Hence, partial left lung resection was performed. Five months after left lung resection, a metastatic liver tumor was found on abdominal CT and left lobectomy of the liver was performed. One year after hepatectomy, the patient died due to peritoneal dissemination.

Surgical Outcomes in Patients With Centrally Located Non-small Cell Lung Cancer.

BACKGROUND/AIM: Identification of prognostic factors is helpful in selecting optimal treatment for centrally-located non-small cell lung cancer (NSCLC). This study aimed to detect prognostic factors in patients with centrally-located NSCLC. PATIENTS AND METHODS: NSCLCs in the hilar area requiring pneumonectomy or sleeve lobectomy for complete removal are defined as centrally-located NSCLCs. We retrospectively investigated the clinical courses of 45 patients with such lesions. RESULTS: Sleeve lobectomies were performed on 33 patients and pneumonectomies on 12. Three and five-year survival rates were 72% and 62%, respectively. Presence of comorbidities (p=0.013), severe symptoms (p=0.001), high white cell count (p=0.001), and pathological T3-4 stage (p=0.004) were identified as independent predictors of poor prognosis. Operative procedures did not correlate with outcomes (p=0.722). CONCLUSION: Presence of comorbidities, severe symptoms, high white cell counts, and pathological T stage are independent predictors of poor prognosis. These data can contribute in selecting appropriate treatments for such lesions.

Development of clinical application for a nutritional prescription support system for total parenteral/enteral nutrition.

One of the important roles of pharmacists as members of a nutrition support team is nutritional prescription support. We developed a nutritional prescription support system (NPSS) that facilitates prescription support and analysis and evaluated its usefulness in nutritional therapy. An NPSS for prescription support and the management of patient information was created. With this NPSS, the nutritional status was assessed, and, on the basis of the results, such variables as the total energy expenditure were calculated. This system allows prescription support for parenteral nutrition (PN) therapy, enteral nutrition (EN) therapy, and the transition period between them. This system was used for 2 representative patients and evaluated. In a malnourished patient receiving oral warfarin, EN solutions were compared by means of the NPSS, and an appropriate EN solution was selected. In addition, the prothrombin time-international normalized ratio was monitored, and favorable results were obtained regarding the adjustment of the warfarin dose and nutritional management. In a patient with aspiration pneumonia, continuous nutritional management to EN from PN therapy was straightforwardly performed with the NPSS. This NPSS allows rapid, comprehensive nutritional management during the transition period to EN from PN therapy, despite these therapies being considered separately in conventional nutritional management. The NPSS is useful for simplifying prescription support and facilitating information sharing among members of a nutrition support team.

A peptide derived from rice inhibits alveolar bone resorption via suppression of inflammatory cytokine production.

BACKGROUND: Periodontitis is an inflammatory disease that results in alveolar bone resorption due to inflammatory cytokine production induced by bacterial antigens such as lipopolysaccharides (LPS). Here, the preventive effect of the Amyl-1-18 peptide derived from rice in an experimental model of periodontitis and the effect on the anti-inflammatory response were assessed. METHODS: Alveolar bone resorption, gene transcription of proinflammatory cytokines in the gingiva, and the endotoxin level in the oral cavity were evaluated after oral administration of the Amyl-1-18 peptide for 14 days using a ligature-induced periodontitis model in mice. Additionally, murine macrophages were incubated with LPS of Escherichia coli or Porphyromonas gingivalis in the presence of Amyl-1-18 to analyze the suppressive effects of Amyl-1-18 on the cell signaling pathways associated with proinflammatory cytokine production, including inflammasome activities. RESULTS: Oral administration of Amyl-1-18 suppressed alveolar bone resorption and gene transcription of interleukin (il)6 in the gingiva of the periodontitis model, and decreased endotoxin levels in the oral cavity, suggesting modulation of periodontal inflammation by inhibition of endotoxin activities in vivo. Also, Amyl-1-18 suppressed IL-6 production induced by LPS and recombinant IL-1ß in macrophages in vitro but had no effect on inflammasome activity. CONCLUSIONS: The Amyl-1-18 peptide from rice inhibited alveolar bone destruction in mouse periodontitis model via suppressing inflammatory cytokine production induced by LPS. It was suggested that Amyl-1-18 peptide has anti-inflammatory property against LPS, not only by neutralization of LPS and subsequent inhibition of nuclear factor-κB signaling but also by inhibition of the IL-1R-related signaling cascade.

A bacterial metabolite ameliorates periodontal pathogen-induced gingival epithelial barrier disruption via GPR40 signaling.

Several studies have demonstrated the remarkable properties of microbiota and their metabolites in the pathogenesis of several inflammatory diseases. 10-Hydroxy-cis-12-octadecenoic acid (HYA), a bioactive metabolite generated by probiotic microorganisms during the process of fatty acid metabolism, has been studied for its protective effects against epithelial barrier impairment in the intestines. Herein, we examined the effect of HYA on gingival epithelial barrier function and its possible application for the prevention and treatment of periodontal disease. We found that GPR40, a fatty acid receptor, was expressed on gingival epithelial cells; activation of GPR40 by HYA significantly inhibited barrier impairment induced by Porphyromonas gingivalis, a representative periodontopathic bacterium. The degradation of E-cadherin and beta-catenin, basic components of the epithelial barrier, was prevented in a GPR40-dependent manner in vitro. Oral inoculation of HYA in a mouse experimental periodontitis model suppressed the bacteria-induced degradation of E-cadherin and subsequent inflammatory cytokine production in the gingival tissue. Collectively, these results suggest that HYA exerts a protective function, through GPR40 signaling, against periodontopathic bacteria-induced gingival epithelial barrier impairment and contributes to the suppression of inflammatory responses in periodontal diseases.

Expression, cellular localization, and functional role of monocarboxylate transporter 4 (MCT4) in the gastrointestinal tract of ruminants.

This is the first study to determine the precise cellular localization of monocarboxylate transporter 4 (MCT4), along with its co-existence with its chaperone, CD147 in the ruminant gastrointestinal tract. Quantitative Western blot analysis demonstrated that the abundance of MCT4 protein was in the order of forestomach > large intestine > abomasum >or= small intestine. Immunohistochemistry and immunofluorescence confocal laser microscopy showed that MCT4 in the forestomach was confined to the cell membranes of strata corneum and granulosum, while diffuse cytoplasmic staining for MCT4 was visualized in strata spinosum and basale. In the epithelium cells lining the abomasum, MCT4 immunoreactive positivities were predominantly localized on the basolateral membranes. In the small intestine, MCT4 was localized at the brush borders and the basolateral membranes of the epithelial cells lining the villi, however it was mostly found on the apical membranes of the crypt cells. In the large intestine, the immunoreactivity for MCT4 differed between the surface epithelium and the crypts; in the surface epithelium, MCT4 was mainly localized at the apical membranes, whereas in the crypts it was predominantly expressed on the basolateral membranes of the lining epithelial cells. MCT4 was remarkably co-existed with CD147 along the bovine gastrointestinal tract. Our results suggest that MCT4 can play an important role in the transport of SCFA. The study also explored the potential functional collaboration between MCT1 and MCT4 and provided new insights into the mechanisms that mediate the transport of SCFA and other monocarboxylates in the different segments of the ruminant gastrointestinal tract.

Detection of gamma-tubulin in spermatogonial cells of Bombyx mori (Lepidoptera) and Chortophaga viridifasciata (Orthoptera).

We detected a putative gamma-tubulin gene in silico and detected BACs containing the gene from a Bombyx mori BAC library. BAC-FISH mapping revealed that the gene is located on chromosome 5. To observe the distribution of gamma-tubulin, we employed antibodies against mammalian gamma-tubulin peptides. Western blot analysis disclosed a band very similar in size to gamma-tubulin protein in other species (approximately 48 kDa). In mitotic metaphase of B. mori spermatogonial cells, gamma-tubulin is exclusively localized in the spindle poles, where the centrosomes occur. We applied the same system to the grasshopper Chortophaga viridifasciata, as a representative of insect orders in which the gamma-tubulin distribution had not previously been studied. Gamma-tubulin was also found in the spindle poles during metaphase of spermatogonial cells in the grasshopper.

Aggravation of collagen-induced arthritis by orally administered Porphyromonas gingivalis through modulation of the gut microbiota and gut immune system.

Porhyromonas gingivalis, a causative bacterium of periodontitis, is implicated in the etiology of rheumatoid arthritis (RA), mainly because of expressing peptidyl arginine deiminase (PAD) that generates RA-related autoantigens. However, compared with other periodontopathic bacteria, the precise role of P. gingivalis in RA is largely unknown. We found that orally administered P. gingivalis changed the gut microbiome with concomitant elevation of serum endotoxin and inflammatory markers, and impairment of the gut barrier function. Based on findings showing a relationship between gut microbiota and RA, we investigated whether the change of gut microbiota induced by P. gingivalis and Prevotella intermedia, another periodontopathic bacterium without PAD, is associated with collagen-induced arthritis (CIA). DBA/1J mice were orally administered with or without bacteria followed by induction of CIA. P. gingivalis, but not P. intermedia, administration significantly aggravated arthritis with increased interleukin-17 levels in sera and culture supernatants, increased Th17 cell proportions among mesenteric lymphocytes, and a significant change in the gut microbiome. However, P. gingivalis administration did not elevate the level of anti-citrullinated protein antibody. These results suggest a unique role of P. gingivalis in the link between periodontitis and RA by affecting the gut immune system and the gut microbiota composition.

An ENU-induced splice site mutation of mouse Col1a1 causing recessive osteogenesis imperfecta and revealing a novel splicing rescue.

GU-AG consensus sequences are used for intron recognition in the majority of cases of pre-mRNA splicing in eukaryotes. Mutations at splice junctions often cause exon skipping, short deletions, or insertions in the mature mRNA, underlying one common molecular mechanism of genetic diseases. Using N-ethyl-N-nitrosourea, a novel recessive mutation named seal was produced, associated with fragile bones and susceptibility to fractures (spine and limbs). A single nucleotide transversion (T → A) at the second position of intron 36 of the Col1a1 gene, encoding the type I collagen, α1 chain, was responsible for the phenotype. Col1a1 seal mRNA expression occurred at greatly reduced levels compared to the wild-type transcript, resulting in reduced and aberrant collagen fibers in tibiae of seal homozygous mice. Unexpectedly, splicing of Col1a1 seal mRNA followed the normal pattern despite the presence of the donor splice site mutation, likely due to the action of a putative intronic splicing enhancer present in intron 25, which appeared to function redundantly with the splice donor site of intron 36. Seal mice represent a model of human osteogenesis imperfecta, and reveal a previously unknown mechanism for splicing "rescue."