Linagliptin Ameliorates Hepatic Steatosis via Non-Canonical Mechanisms in Mice Treated with a Dual Inhibitor of Insulin Receptor and IGF-1 Receptor.

Abnormal hepatic insulin signaling is a cause or consequence of hepatic steatosis. DPP-4 inhibitors might be protective against fatty liver. We previously reported that the systemic inhibition of insulin receptor (IR) and IGF-1 receptor (IGF1R) by the administration of OSI-906 (linsitinib), a dual IR/IGF1R inhibitor, induced glucose intolerance, hepatic steatosis, and lipoatrophy in mice. In the present study, we investigated the effects of a DPP-4 inhibitor, linagliptin, on hepatic steatosis in OSI-906-treated mice. Unlike high-fat diet-induced hepatic steatosis, OSI-906-induced hepatic steatosis is not characterized by elevations in inflammatory responses or oxidative stress levels. Linagliptin improved OSI-906-induced hepatic steatosis via an insulin-signaling-independent pathway, without altering glucose levels, free fatty acid levels, gluconeogenic gene expressions in the liver, or visceral fat atrophy. Hepatic quantitative proteomic and phosphoproteomic analyses revealed that perilipin-2 (PLIN2), major urinary protein 20 (MUP20), cytochrome P450 2b10 (CYP2B10), and nicotinamide N-methyltransferase (NNMT) are possibly involved in the process of the amelioration of hepatic steatosis by linagliptin. Thus, linagliptin improved hepatic steatosis induced by IR and IGF1R inhibition via a previously unknown mechanism that did not involve gluconeogenesis, lipogenesis, or inflammation, suggesting the non-canonical actions of DPP-4 inhibitors in the treatment of hepatic steatosis under insulin-resistant conditions.

A Case of COVID-19 and Methicillin-Resistant Staphylococcus aureus (MRSA) Coinfection Resulting in MRSA Empyema.

Bacterial coinfections in patients with COVID-19 are rare; however, coinfection with Staphylococcus (S.) aureus is relatively common. No detailed report of patients with COVID-19 and methicillin-resistant S. aureus (MRSA) coinfection has been documented. Herein, we present a case of a patient with COVID-19 and MRSA coinfection who developed MRSA empyema after pneumonia and bacteremia. A 59-year-old man was admitted to the intensive care unit for treatment of COVID-19 and bacterial pneumonia with septic shock. He was initially treated with antibiotics, antiviral agents, and steroids. On the third day of admission, MRSA was detected in both sputum and blood cultures. Although he was treated with appropriate vancomycin doses with monitoring of renal function and serum vancomycin concentrations, he developed bilateral pleural effusions one week after starting treatment. Initially, the bilateral pleural effusions were thought to have been caused by hypoalbuminemia. However, bilateral chest drainage was performed due to the onset of left-sided chest pain. The left-sided pleural effusion was exudative, whereas the right-sided pleural effusion was transudative. MRSA was later detected on culture of the left-sided effusion but not the right-sided effusion. Based on the findings of the pleural fluid examination, the patient was diagnosed with left-sided empyema. His symptoms and radiographic findings improved after a repeat drainage of the left pleural effusion. Vancomycin was administered for 28 days, and the patient was discharged on the twenty-eighth day of admission. These findings highlight the importance of pleural fluid examination for the prompt diagnosis of pleural infection. Early diagnosis of empyema and prompt chest drainage may help avoid the need for surgery. This report could contribute to the clinical management of patients with COVID-19 and MRSA coinfection.

Acquired diaphragmatic hernia following a peritoneal biopsy for gastric cancer dissemination in the diaphragm: a case report.

BACKGROUND: Acute diaphragmatic hernia is a life-threatening condition caused by prolapse of an abdominal organ into the thoracic cavity through a defect in the diaphragm. We present herein a case of acquired diaphragmatic hernia following a peritoneal biopsy for gastric cancer dissemination in the diaphragm. CASE PRESENTATION: A 72-year-old, female patient presented with a complaint of acute abdomen 10 months after receiving a diagnosis of stage IV gastric cancer with peritoneal dissemination based on peritoneal biopsy findings during staging laparoscopy. Computed tomography demonstrated herniation of the small intestine into the thoracic cavity. Emergency surgery was performed, and a full-thickness diaphragmatic defect was found intraoperatively at the same location as the previous, peritoneal biopsy. The incarcerated small intestine was atraumatically repositioned into the abdominal cavity, and the defect was closed laparoscopically using an absorbable barbed suture. CONCLUSIONS: Although complications of staging laparoscopy are extremely rare, excising disseminated nodules from the diaphragm carries the risk of diaphragmatic hernia. For this reason, avoiding excision is desirable unless a diaphragmatic biopsy is needed.

Comprehensive circulating microRNA profile as a supersensitive biomarker for early-stage lung cancer screening.

PURPOSE:  Less-invasive early diagnosis of lung cancer is essential for improving patient survival rates. The purpose of this study is to demonstrate that serum comprehensive miRNA profile is high sensitive biomarker to early-stage lung cancer in direct comparison to the conventional blood biomarker using next-generation sequencing (NGS) technology combined with automated machine learning (AutoML). METHODS: We first evaluated the reproducibility of our measurement system using Pearson's correlation coefficients between samples derived from a single pooled RNA sample. To generate comprehensive miRNA profile, we performed NGS analysis of miRNAs in 262 serum samples. Among the discovery set (57 patients with lung cancer and 57 healthy controls), 1123 miRNA-based diagnostic models for lung cancer detection were constructed and screened using AutoML technology. The diagnostic faculty of the best performance model was evaluated by inspecting the validation samples (74 patients with lung cancer and 74 healthy controls). RESULTS: The Pearson's correlation coefficients between samples derived from the pooled RNA sample ≥ 0.98. In the validation analysis, the best model showed a high AUC score (0.98) and a high sensitivity for early stage lung cancer (85.7%, n = 28). Furthermore, in comparison to carcinoembryonic antigen (CEA), a conventional blood biomarker for adenocarcinoma, the miRNA-based model showed higher sensitivity for early-stage lung adenocarcinoma (CEA, 27.8%, n = 18; miRNA-based model, 77.8%, n = 18). CONCLUSION: The miRNA-based diagnostic model showed a high sensitivity for lung cancer, including early-stage disease. Our study provides the experimental evidence that serum comprehensive miRNA profile can be a highly sensitive blood biomarker for early-stage lung cancer.

E2F1 transcription factor mediates a link between fat and islets to promote ß cell proliferation in response to acute insulin resistance.

Prevention or amelioration of declining ß cell mass is a potential strategy to cure diabetes. Here, we report the pathways utilized by ß cells to robustly replicate in response to acute insulin resistance induced by S961, a pharmacological insulin receptor antagonist. Interestingly, pathways that include CENP-A and the transcription factor E2F1 that are independent of insulin signaling and its substrates appeared to mediate S961-induced ß cell multiplication. Consistently, pharmacological inhibition of E2F1 blocks ß-cell proliferation in S961-injected mice. Serum from S961-treated mice recapitulates replication of ß cells in mouse and human islets in an E2F1-dependent manner. Co-culture of islets with adipocytes isolated from S961-treated mice enables ß cells to duplicate, while E2F1 inhibition limits their growth even in the presence of adipocytes. These data suggest insulin resistance-induced proliferative signals from adipocytes activate E2F1, a potential therapeutic target, to promote ß cell compensation.

Influene of Pharmaceutical Excipients on the Membrane Transport of a P-glycoprotein Substrate in the Rat Small Intestine.

BACKGROUND AND OBJECTIVES: Generic drugs are generally used worldwide because of affordability compared to brand-name drugs. One of the main differences between brand-name and generic drugs is pharmaceutical excipients. We previously reported the effects of pharmaceutical excipients on the membrane permeation of drugs via the paracellular and transcellular routes, which are passive transport routes. P-glycoprotein (P-gp) is a typical ATP-binding cassette transporter and is mostly responsible for drug-drug interactions involving transporters. In the present study, rhodamine 123 (Rho123) was selected as the P-gp substrate, and the effects of pharmaceutical excipients on its membrane transport in the rat jejunum and ileum were examined. METHODS: Twenty major pharmaceutical excipients widely used in the pharmaceutical industry were selected. The in vitro diffusion chamber method using the rat jejunum and ileum was employed to investigate the effects of pharmaceutical excipients on the membrane permeation of Rho123. RESULTS: The results obtained showed that the membrane permeability of Rho123 significantly (P < 0.05) changed under certain dosage conditions of pharmaceutical excipients such as sodium carboxymethyl starch, pullulan, glyceryl monostearate and so on. Furthermore, the effects of pharmaceutical excipients were site specific in the small intestine. CONCLUSION: The present results demonstrated that some pharmaceutical excipients altered the membrane permeability of Rho123 in the rat small intestine.

Magnetic Resonance Imaging of Ovarian Activity in Microminipigs Showing Normal Estrous Cycles.

We investigated whether magnetic resonance imaging (MRI) might be applicable to evaluation of the ovarian activity of microminipigs. Firstly, using three mature microminipigs, we confirmed ovarian position and morphology by laparotomy or laparoscopy, and then acquired MRI images in various patterns to determine the most suitable condition for the acquisition. Next, using four microminipigs, we performed daily MRI, starting 10 days after ovulation and ending 10 days after the subsequent ovulation, as the starting day of standing estrus was taken as day 0. While the ovarian structure could not be discriminated on T1-weighted imaging, it was possible to confirm the follicles during estrus as hyperintense regions on T2-weighted imaging. With chronological MRI, 3-5 follicles were visible on T2-weighted imaging during the interval from day -2 to day 1, and their size immediately prior to ovulation was 3-5 mm. However, confirmation of the presence of small follicles and the corpus luteum was difficult.

Reproductive characteristics of female lesser mouse deers (Tragulus javanicus) based on fecal progestagens and breeding records.

Information about breeding and the reproductive biology of mouse deer is limited in the wild and captivity. No reports on reproductive endocrinology are available. The objective of the present study was to observe the reproductive biology based on breeding records, to validate the utility of the non-invasive endocrine monitoring technique using feces of the female lesser mouse deer (Tragulus javanicus), and thus to clarify the reproductive physiology. Breeding records from 2 females were investigated and the fecal progestagen profile was monitored in captivity. Fecal progestagens were extracted using methanol and measured by enzyme immunoassay. From the breeding records, many births occurred in May (spring) and November-December (winter); however, fecal progestagen profile showed cyclical changes throughout the year in a female mouse deer. Most mounting and mating behaviors were observed 2-3 days after the peak of progestagen concentration during luteal phase. The ovarian cycle length based on the fecal progestagen profile averaged 14.5±0.3 days. The fecal progestagen concentration remained high during pregnancy. Fecal progestagen monitoring is useful for evaluating ovarian activity and pregnancy in the lesser mouse deer.