Comprehensive lipid profiling of bleomycin‐induced lung injury

Drug‐induced lung injury is an adverse effect of drug treatment that can result in respiratory failure. Because lipid profiling could provide cutting‐edge understanding of the pathophysiology of toxicological responses, we performed lipidomic analyses of drug‐induced lung injury. We used a mouse model of bleomycin‐induced lung injury and followed the physiological responses at the acute inflammatory (day 2), inflammatory‐to‐fibrosis (day 7) and fibrosis (day 21) phases. The overall lipid profiles of plasma, lung and bronchoalveolar lavage fluid (BALF) revealed that drastic changes in lipids occurred in the lung and BALF, but not in the plasma, after 7 and 21 days of bleomycin treatment. In the lung, the levels of ether‐type phosphatidylethanolamines decreased, while those of phosphatidylcholines, bismonophosphatidic acids and cholesterol esters increased on days 7 and 21. In BALF, the global lipid levels increased on days 7 and 21, but only those of some lipids, such as phosphatidylglycerols/bismonophosphatidic acids and phosphatidylinositols, increased from day 2. The lung levels of prostaglandins, such as prostaglandin D₂, were elevated on day 2, and those of 5‐ and 15‐lipoxygenase metabolites of docosahexaenoic acid were elevated on day 7. In BALF, the levels of 12‐lipoxygenase metabolites of polyunsaturated fatty acids were elevated on day 7. Our comprehensive lipidomics approach suggested anti‐inflammatory responses in the inflammatory phase, phospholipidosis and anti‐inflammatory responses in the inflammatory‐to‐fibrosis phase, and increased oxidative stress and/or cell phenotypic transitions in the fibrosis phase. Understanding these molecular changes and potential mechanisms will help develop novel drugs to prevent or treat drug‐induced lung injury.     

Requirement of apelin-apelin receptor system for oxidative stress-linked atherosclerosis

The recently identified endogenous peptide apelin and its specific apelin receptor (APJ) are currently being considered as potential regulators in vascular tissue. Previously, we reported apelin mediates phosphorylation of myosin light chain and elicits vasoconstriction in vascular smooth muscle. In this study, physiological roles of the apelin-APJ system were investigated on atherosclerosis. In APJ and apolipoprotein E double-knockout (APJ(-/-)ApoE(-/-)) mice fed a high-cholesterol diet, atherosclerotic lesions were dramatically reduced when compared with APJ(+/+) ApoE(-/-) mice, in the absence of an effect of cholesterol levels. Immunohistochemical detection of smooth muscle cells, using a smooth muscle alpha-actin antibody, showed greatly reduced staining for these cells in lesions of APJ(-/-)ApoE(-/-) mice fed a high-cholesterol diet. Vascular production of superoxide radicals and the expression of nicotinamide-adenine dinucleotide phosphate oxidase subunits were decreased in APJ(-/-)ApoE(-/-) mice compared with APJ(+/+)ApoE(-/-) mice fed a standard normal diet. In vascular smooth muscle cells, apelin induced nicotinamide-adenine dinucleotide phosphate oxidase subunit expression. Apelin also induced vascular smooth muscle cell proliferation, which was inhibited by superoxide dismutase or diphenylene iodonium. The apelin-APJ system is a mediator of oxidative stress in vascular tissue, and thus we propose it to be a critical factor in atherogenesis under high-cholesterol dietary conditions. APJ deficiency is preventative against oxidative stress-linked atherosclerosis.     

Bacillus Calmette–Guérin-unresponsive non-muscle-invasive bladder cancer: Its definition and future therapeutic strategies

Bacillus Calmette–Guérin induction with or without maintenance is the gold standard therapy for intermediate-/high-risk non-muscle-invasive bladder cancer; however, one-third of patients treated with adequate bacillus Calmette–Guérin therapy do not achieve sufficient responses, and this is referred to as “bacillus Calmette–Guérin failure.” The term, bacillus Calmette–Guérin failure, is ambiguous and includes a very heterogeneous population of patients. By strictly focusing on patients who are unlikely to benefit from additional bacillus Calmette–Guérin therapy and who need to be treated with radical cystectomy, the new concept of “bacillus Calmette–Guérin unresponsive” was recently proposed, and might accelerate the development of novel therapeutic options for bacillus Calmette–Guérin-unresponsive disease. A promising therapeutic strategy for bacillus Calmette–Guérin-unresponsive disease is the blockade of the programmed cell death-1/programmed cell death-ligand 1 pathway, which is considered to be activated by bacillus Calmette–Guérin therapy. Several large clinical trials have been carried out to assess the potential of programmed cell death-1/programmed cell death-ligand 1 blockade in bacillus Calmette–Guérin-naïve high-risk non-muscle-invasive bladder cancer and bacillus Calmette–Guérin-unresponsive disease. Furthermore, clinical trials that are targeting bacillus Calmette–Guérin-unresponsive disease with other strategies, such as vaccines, gene therapy, and targeted and cytotoxic therapies, are ongoing. The findings of these trials are awaited in order to establish appropriate bladder-sparing approaches for patients with bacillus Calmette–Guérin-unresponsive disease.     

Antimicrobial susceptibility surveillance of obligate anaerobic bacteria in the Kinki area

Obligate anaerobes exist as resident flora in various sites in humans, but they are also emphasized as endogenous causative microorganism of infections. We performed surveillance to understand the trend of drug susceptibility in obligate anaerobic bacteria in the Kinki area of Japan. In the experiment, we used 156 obligate anaerobe isolates collected from 13 institutions that participated in the Study of Bacterial Resistance Kinki Region of Japan. MALDI Biotyper was used to identify the collected strains, and among the 156 test strains, those that could be identified with an accuracy of Score Value 2.0 or more included 6 genera, 30 species, and 144 strains (Bacteroides spp. 77 strains, Parabacteroides sp. 2 strains, Prevotella spp. 29 strains, Fusobacterium spp. 14 strains, Porphyromonas spp. 2 strains, and Clostridioides difficile 20 strains), and they were assigned as subject strains for drug susceptibility testing. The drug susceptibility test was carried out by broth microdilution method using Kyokuto Opt Panel MP ANA (Kyokuto Pharmaceutical Industrial Co., Ltd., Tokyo, Japan) and judged according to CLSI criteria. As a result, Bacteroides and Parabacteroides species showed good sensitivities to tazobactam-piperacillin, imipenem, metronidazole and chloramphenicol, and low sensitivities to ampicillin, cefoperazone and vancomycin. Prevotella species showed good sensitivities to sulbactam-ampicillin, tazobactam-piperacillin, cefmetazole, imipenem, doripenem and metronidazole. Susceptibility rates to other drugs were slightly different depending on the bacterial species. Both Fusobacterium spp. and Porphyromonas spp. showed high sensitivities to many drugs. C. difficile was highly sensitive to vancomycin and metronidazole, having MIC₉₀s of 0.5 μg/mL and ≤2 μg/mL, respectively.     

Evaluation of gastric motor activity in the elderly by electrogastrography and the (13)C-acetate breath test

BACKGROUND: Elderly people frequently have symptoms of fullness and appetite loss due to impaired gastric motor activity. These symptoms may cause malnutrition, immunosuppression and other complications. OBJECTIVE: The effects of aging and daily activity on gastric motility in the elderly were investigated by electrogastrography and the (13)C-acetate breath test. METHODS: We enrolled seven active elderly subjects (active elderly group), seven elderly subjects staying at a geriatric facility who had reduced mental and physical capacities (inactive elderly group) and seven healthy young volunteers (young group). Electrogastrography was recorded before and after ingestion of a (13)C-acetate-mixed liquid meal. Expired air was sampled every 10 min after the meal to measure the (13)CO(2) concentration. RESULTS: The ratio of the incidence of the 3-cpm wave (gastric intrinsic frequency) during the postprandial period compared to the fasting state was reduced in both elderly groups compared to young subjects, and the reduction was greater in the inactive elderly than in the active elderly group. The ratio of the amplitude of the peak frequency during the postprandial period to that in the fasting state (power ratio) was also lower in the elderly groups. The time of peak (13)CO(2) expiration was delayed in the active elderly and more so in the inactive elderly group. CONCLUSIONS: Postprandial peristalsis and gastric contractile force are reduced in the elderly, and gastric emptying is delayed indicating a reduction in gastric motor activity.     

Effects of cimetidine on the healing and recurrence of duodenal ulcers and gastric ulcers

The effects of cimetidine on the healing and recurrence of duodenal ulcers and gastric ulcers were compared. The extent of the acid secreting areas was examined by the endoscopic Congo red methylene blue test. Using the extent of acid secreting areas gastric ulcers were classified into ulcers with and without extensive acid secreting areas. Duodenal ulcers were all associated with extensive acid secreting areas. The gastric acid outputs in the basal state and after maximal stimulation with gastrin were highest in duodenal ulcers, and lowest in gastric ulcers without extensive acid secreting areas. Cimetidine treatment significantly promoted the healing of duodenal ulcers and gastric ulcers with extensive acid secreting areas when compared with placebo, but not of the gastric ulcers without extensive acid secreting areas. Cimetidine also significantly diminished the recurrence of duodenal ulcers, but not gastric ulcers with and without extensive acid secreting areas. These findings indicate that in Japan cimetidine promotes the healing of duodenal and gastric ulcers associated with high gastric acid production and prevents recurrence of duodenal ulcers, but has little or no influence on the healing and recurrence of gastric ulcers associated with low acid secretion.