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Abstract Metabolic dysfunction-associated steatohepatitis (MASH), previously called non-alcoholic steatohepatitis (NASH), is a growing concern worldwide, with liver fibrosis being a critical determinant of its prognosis. Monocyte-derived macrophages have been implicated in MASH-associated liver fibrosis, yet their precise roles and the underlying differentiation mechanisms remain elusive. In this study, we unveil a key orchestrator of this process: long chain saturated fatty acid-Egr2 pathway. Our findings identify the transcription factor Egr2 as the driving force behind monocyte differentiation into hepatic lipid-associated macrophages (hLAMs) within MASH liver. Notably, Egr2-deficiency reroutes monocyte differentiation towards a macrophage subset resembling resident Kupffer cells, hampering hLAM formation. This shift has a profound impact, suppressing the transition from benign steatosis to liver fibrosis, demonstrating the critical pro-fibrotic role played by hLAMs in MASH pathogenesis. Long-chain saturated fatty acids that accumulate in MASH liver emerge as potent inducers of Egr2 expression in macrophages, a process counteracted by unsaturated fatty acids. Furthermore, oral oleic acid administration effectively reduces hLAMs in MASH mice. In conclusion, our work not only elucidates the intricate interplay between saturated fatty acids, Egr2, and monocyte-derived macrophages but also highlights the therapeutic promise of targeting the saturated fatty acid-Egr2 axis in monocytes for MASH management.

Introduction To date, there is limited evidence on the effects of bronchodilators on respiratory dynamics in chronic obstructive pulmonary disease (COPD). Dynamic chest radiography (DCR) is a novel radiographic modality that provides real-time, objective and quantifiable kinetic data, including changes in the lung area (Rs), tracheal diameter, diaphragmatic kinetics and pulmonary ventilation during respiration, at a lower radiation dose than that used by fluoroscopic or CT imaging. However, the therapeutic effect of dual bronchodilators on respiratory kinetics, such as chest wall dynamics and respiratory muscle function, has not yet been prospectively evaluated using DCR.Aim This study aims to evaluate the effects of bronchodilator therapy on respiratory kinetics in patients with COPD using DCR.Methods and analysis This is an open-label, prospective, single-centre, non-controlled, comparative study. A total of 35 patients with COPD, aged 40–85 years, with a forced expiratory volume in the first second of 30–80%, will be enrolled. After a 2–4 weeks washout period, patients will receive tiotropium/olodaterol therapy for 6 weeks. Treatment effects will be evaluated based on DCR findings, pulmonary function test results and patient-related outcomes obtained before and after treatment. The primary endpoint is the change in Rs after therapy. The secondary endpoints include differences in other DCR parameters (diaphragmatic kinetics, tracheal diameter change and maximum pixel value change rate), pulmonary function test results and patient-related outcomes between pre-therapy and post-therapy values. All adverse events will be reported.Ethics and dissemination Ethical approval for this study was obtained from the Ethics Committee of Chiba University Hospital. The results of this trial will be published in a peer-reviewed journal.Trial registration number jRCTs032210543.

Background Although living alone versus with others is a key social element for cardiovascular prevention in diabetes, evidence is lacking about whether the benefit of intensive glycemic and blood pressure (BP) control differs by living arrangements. We thus aim to investigate heterogeneity in the joint effect of intensive glycemic and BP control on cardiovascular events by living arrangements among participants with diabetes. Methods and Results This study included 4731 participants with diabetes in the ACCORD‐BP (Action to Control Cardiovascular Risk in Diabetes‐Blood Pressure) trial. They were randomized into 4 study arms, each with glycated hemoglobin target (intensive,

Abstract Background Pulmonary arterial hypertension is a serious medical condition. However, the condition is often misdiagnosed or a rather long delay occurs from symptom onset to diagnosis, associated with decreased 5-year survival. In this study, we developed and tested a deep-learning algorithm to detect pulmonary arterial hypertension using chest X-ray (CXR) images. Methods From the image archive of Chiba University Hospital, 259 CXR images from 145 patients with pulmonary arterial hypertension and 260 CXR images from 260 control patients were identified; of which 418 were used for training and 101 were used for testing. Using the testing dataset for each image, the algorithm outputted a numerical value from 0 to 1 (the probability of the pulmonary arterial hypertension score). The training process employed a binary cross-entropy loss function with stochastic gradient descent optimization (learning rate parameter, α = 0.01). In addition, using the same testing dataset, the algorithm’s ability to identify pulmonary arterial hypertension was compared with that of experienced doctors. Results The area under the curve (AUC) of the receiver operating characteristic curve for the detection ability of the algorithm was 0.988. Using an AUC threshold of 0.69, the sensitivity and specificity of the algorithm were 0.933 and 0.982, respectively. The AUC of the algorithm’s detection ability was superior to that of the doctors. Conclusion The CXR image-derived deep-learning algorithm had superior pulmonary arterial hypertension detection capability compared with that of experienced doctors.

Summary: The production of type 1 conventional dendritic cells (cDC1s) requires high expression of the transcription factor IRF8. Three enhancers at the Irf8 3′ region function in a differentiation stage-specific manner. However, whether and how these enhancers interact physically and functionally remains unclear. Here, we show that the Irf8 3′ enhancers directly interact with each other and contact the Irf8 gene body during cDC1 differentiation. The +56 kb enhancer, which functions from multipotent progenitor stages, activates the other 3′ enhancers through an IRF8-dependent transcription factor program, that is, in trans. Then, the +32 kb enhancer, which operates in cDC1-committed cells, reversely acts in cis on the other 3′ enhancers to maintain the high expression of Irf8. Indeed, mice with compound heterozygous deletion of the +56 and +32 kb enhancers are unable to generate cDC1s. These results illustrate how multiple enhancers cooperate to induce a lineage-determining transcription factor gene during cell differentiation.

Metabolic pathways are plastic and rapidly change in response to stress or perturbation. Current metabolic profiling techniques require lysis of many cells, complicating the tracking of metabolic changes over time after stress in rare cells such as hematopoietic stem cells (HSCs). Here, we aimed to identify the key metabolic enzymes that define differences in glycolytic metabolism between steady-state and stress conditions in murine HSCs and elucidate their regulatory mechanisms. Through quantitative 13C metabolic flux analysis of glucose metabolism using high-sensitivity glucose tracing and mathematical modeling, we found that HSCs activate the glycolytic rate-limiting enzyme phosphofructokinase (PFK) during proliferation and oxidative phosphorylation (OXPHOS) inhibition. Real-time measurement of ATP levels in single HSCs demonstrated that proliferative stress or OXPHOS inhibition led to accelerated glycolysis via increased activity of PFKFB3, the enzyme regulating an allosteric PFK activator, within seconds to meet ATP requirements. Furthermore, varying stresses differentially activated PFKFB3 via PRMT1-dependent methylation during proliferative stress and via AMPK-dependent phosphorylation during OXPHOS inhibition. Overexpression of Pfkfb3 induced HSC proliferation and promoted differentiated cell production, whereas inhibition or loss of Pfkfb3 suppressed them. This study reveals the flexible and multilayered regulation of HSC glycolytic metabolism to sustain hematopoiesis under stress and provides techniques to better understand the physiological metabolism of rare hematopoietic cells.

Abstract Recent studies have shown that D-allose, a rare sugar, elicits antitumor effects on different types of solid cancers, such as hepatocellular carcinoma, non-small-cell lung cancer, and squamous cell carcinoma of the head and neck. In this study, we examined the effects of D-allose on the proliferation of human glioblastoma (GBM) cell lines (i.e., U251MG and U87MG) in vitro and in vivo and the underlying mechanisms. D-allose treatment inhibited the proliferation of U251MG and U87MG cells in a dose-dependent manner (3–50 mM). However, D-allose treatment did not affect cell cycles or apoptosis in these cells but significantly decreased the cell division frequency in both GBM cell lines. In a subcutaneous U87MG cell xenograft model, intraperitoneal injection of D-allose (100 mg/kg/day) significantly reduced the tumor volume in 28 days. These data indicate that D-allose-induced reduction in cell proliferation is associated with a subsequent decrease in the number of cell divisions, independent of cell-cycle arrest and apoptosis. Thus, D-allose could be an attractive additive to therapeutic strategies for GBM.

Key message Although intrathoracic extramedullary haematopoiesis (EMH) is rare, its nodular lesions should be differentiated from malignancy. 111In‐bone marrow scintigraphy can be useful for the non‐invasive diagnosis of intrathoracic EMH because extramedullary accumulation of 111In can be determined as EMH.

Abstract This study aimed to investigate whether phosphate contributes to the pathogenesis of chronic kidney disease (CKD) in dolphins. Renal necropsy tissue of an aged captive dolphin was analyzed and in vitro experiments using cultured immortalized dolphin proximal tubular (DolKT-1) cells were performed. An older dolphin in captivity died of myocarditis, but its renal function was within the normal range until shortly before death. In renal necropsy tissue, obvious glomerular and tubulointerstitial changes were not observed except for renal infarction resulting from myocarditis. However, a computed tomography scan showed medullary calcification in reniculi. Micro area X-ray diffractometry and infrared absorption spectrometry showed that the calcified areas were primarily composed of hydroxyapatite. In vitro experiments showed that treatment with both phosphate and calciprotein particles (CPPs) resulted in cell viability loss and lactate dehydrogenase release in DolKT-1 cells. However, treatment with magnesium markedly attenuated this cellular injury induced by phosphate, but not by CPPs. Magnesium dose-dependently decreased CPP formation. These data support the hypothesis that continuous exposure to high phosphate contributes to the progression of CKD in captive-aged dolphins. Our data also suggest that phosphate-induced renal injury is mediated by CPP formation in dolphins, and it is attenuated by magnesium administration.

Abstract Glioblastoma is characterized by a strong self-renewal potential and poor differentiated state. We have reported previously that the (pro)renin receptor [(P)RR] is a potential target for glioma therapy by silencing the (P)RR gene. Here, we have examined the effects of a monoclonal antibody against (P)RR on gliomagenesis. Human glioma cell lines (U251MG and U87MG) and a glioma stem cell line (MGG23) were used for the in vitro study. The expressions of the Wnt/β-catenin signaling pathway (Wnt signaling pathway) components and stemness markers were measured by Western blotting. The effects of the (P)RR antibody on cell proliferation, sphere formation, apoptosis and migration were also examined. Subcutaneous xenografts were also examined in nude mice. Treatment with the (P)RR antibody reduced expression of Wnt signaling pathway components and stemness markers. Furthermore, the (P)RR antibody reduced cell proliferation and decreased sphere formation significantly. The treatment also suppressed migration and induced apoptosis. In a subcutaneous xenograft model, systemic administration of the (P)RR antibody reduced tumor volume significantly. These data show that treatment with the (P)RR antibody is a potential therapeutic strategy for treating glioblastoma.

Abstract Macrophages are a major population of immune cells in solid cancers, especially colorectal cancers. Tumor-associated macrophages (TAMs) are commonly divided into M1-like (tumor suppression) and M2-like (tumor promotion) phenotypes. Vasoactive intestinal peptide (VIP) is an immunoregulatory neuropeptide with a potent anti-inflammatory function. Inhibition of VIP signaling has been shown to increase CD8+ T cell proliferation and function in viral infection and lymphoma. However, the role of VIP in macrophage polarization and function in solid tumors remains unknown. Here, we demonstrated that conditioned medium from CT26 (CT26-CM) cells enhanced M2-related marker and VIP receptor (VPAC) gene expression in RAW264.7 macrophages. VIP hybrid, a VIP antagonist, enhanced M1-related genes but reduced Mrc1 gene expression and increased phagocytic ability in CT26-CM-treated RAW264.7 cells. In immunodeficient SCID mice, VIP antagonist alone or in combination with anti-PD-1 antibody attenuated CT26 tumor growth compared with the control. Analysis of tumor-infiltrating leukocytes found that VIP antagonist increased M1/M2 ratios and macrophage phagocytosis of CT26-GFP cells. Furthermore, Vipr2 gene silencing or VPAC2 activation affected the polarization of CT26-CM-treated RAW264.7 cells. In conclusion, the inhibition of VIP signaling enhanced M1 macrophage polarization and macrophage phagocytic function, resulting in tumor regression in a CT26 colon cancer model.

Abstract Background We previously found that (pro)renin receptor ((P)RR) augments Wnt3 protein without affecting Wnt3 gene transcription in colorectal cancer (CRC) cells, thus contributes to CRC initiation. The present study aims to investigate whether (P)RR further promotes CRC progression following oncogenesis and the related mechanisms. Notably, we deeply elaborate how (P)RR affects Wnt3 protein level and the key enzyme that mediates this process. Methods Immunohistochemistry, western blotting and immunofluorescence were performed to detect protein expression status. A kind of gastrointestinal epithelium-specific ATP6AP2 ((P)RR encoding gene) knock-in mice were generated using Crispr/Cas9 system. Results We found that increased (P)RR expression in primary CRC lesions is positively associated with higher Wnt3 protein level and disease progression. Progressive CRC presents less colocalization of Wnt3 and an E3 ubiquitin ligase NEDD4L in primary lesions than non-progressive CRC. In colon cancer cells, (P)RR dramatically inhibits the NEDD4L-mediated Wnt3 protein ubiquitination. ATP6AP2 knock-in mice show more diminished Wnt3-NEDD4L colocalization in their gut epithelium in comparison to wildtype mice. They also have abnormal gut bacterial flora distribution. Especially, Lachnospiraceae_NK4A136 and Bacteroides genus, which are generally protective against CRC, are suppressed in guts of ATP6AP2 knock-in mice. Conclusions Collectively, (P)RR promotes CRC progression through inhibiting the NEDD4L-mediated Wnt3 ubiquitination and modulating gut microbiota. Video Abstract

Abstract Non-invasive blood glucose sensing can be achieved using mid-infrared spectroscopy, although no practical device based on this method has yet been developed. Here, we propose mid-infrared passive spectroscopic imaging for glucose measurements from a distance. Spectroscopic imaging of thermal radiation from the human body enabled, for the first time in the world, the detection of glucose-induced luminescence from a distance. In addition, glucose emission spectra of the wrist acquired at regular intervals up to 60 min showed that there was a strong correlation between the glucose emission intensity and blood glucose level measured using an invasive sensor. Thus, the new technology proposed here is expected to be applied to real-time monitoring of diabetic patients to detect hypoglycemic attacks during sleep and to detect hyperglycemia in a population. Moreover, this technology could lead to innovations that would make it possible to remotely measure a variety of substances.

Abstract The objective of this study was to explore intracellular molecular changes during the differentiation of human-induced pluripotent stem cells (iPSCs) into erythropoietin (EPO)-producing cells using Raman spectroscopy and imaging. Raman imaging data of fixed cells at four stages of cell differentiation were analyzed by a partial least squares (PLS) regression model, and the variations in the intracellular molecular compositions with cell differentiation were investigated. As a result, three biomarkers characterizing the cell phases were identified: dimethyl sulfoxide (DMSO), fatty acids with a low grade of unsaturation, and glycoproteins. The uptake of DMSO by EPO-producing cells, which was added into a culture medium as an inducer for cell differentiation, was detected, and the increase in unsaturated fatty acid concentrations was revealed that lipid metabolism changed over the course of cell differentiation. The decrease in the glycoprotein concentration after the cell phase during which iPSCs differentiated into EPO-producing cells was also made clear. Raman imaging successfully visualized chemical images of these three biomarkers in two dimensions, where the biomarker concentrations independently varied during cell differentiation. These results demonstrated the application potential of the proposed method to regenerative medicine for monitoring cell differentiation and discriminating cell maturation in situ at the molecular level.

This systematic review aimed to update the management of sleep bruxism (SB) in adults, as diagnosed using polysomnography (PSG) and/or electromyography (EMG). Management methods covered were oral appliance therapy (OAT) with stabilization splints, cognitive-behavioral therapy (CBT), biofeedback therapy (BFT), and pharmacological therapy. A comprehensive search was conducted on MEDLINE, Cochrane Library, and Web of Science up to October 1st, 2021. Reference list searches and hand searches were also performed by an external organization. Two reviewers for each therapy independently performed article selection, data extraction, and risk of bias assessment. The reviewers resolved any disagreements concerning the assortment of the articles by discussion. Finally, 11, 3, 14, and 22 articles were selected for each therapy. The results suggested that OAT tended to reduce the number of SB events, although there was no significant difference compared to other types of splints, that the potential benefits of CBT were not well supported, and that BFT, rabeprazole, clonazepam, clonidine, and botulinum toxin type A injection showed significant reductions in specific SB parameters, although several side effects were reported. It can be concluded that more methodologically rigorous randomized large-sample long-term follow-up clinical trials are needed to clarify the efficacy and safety of management for SB.

We have recently reported that the urea osmolyte-associated water conservation system is activated in fluid loss models such as high salt-induced natriuresis, renal injury-induced impaired renal concentrating ability, or skin barrier dysfunction-induced transepidermal water loss. The system consists of the interaction of multiple organs including renal urea recycling, hepato-muscular ureagenesis, and suppression of cardiovascular energy expenditure. Here, we determined the effect of pharmacological fluid loss induced by tolvaptan, a selective vasopressin V2 receptor antagonist, on water conservation. We evaluated the water conservation system in rats that consumed a control diet or a diet containing 0.1% tolvaptan. Tolvaptan increased urine volume on day 1, but this renal water loss then gradually decreased. Body water and osmolyte content were decreased by tolvaptan on day 1 but had normalized by day 7. Tolvaptan induced fluid loss on day 1, and the following restoration of body fluid on day 7 was associated with an increase in urea transporter A1-associated renal urea recycling. Tolvaptan did not affect hepato-muscular ureagenesis on day 1 and day 7, or cardiovascular energy expenditure during treatment. Thus, tolvaptan-induced fluid loss leads to activation of the water conservation system via renal urea recycling.

Treatment with a sodium glucose cotransporter 2 (SGLT2) inhibitor in patients with chronic kidney disease reduces the renal risk independent of changes in blood glucose concentrations and blood pressure. However, the precise mechanism responsible for this SGLT2 inhibitor-induced renoprotective effect is unclear. We have previously shown that SGLT2 inhibitors induce antihypertensive effects with decreased sympathetic nerve activity, which is associated with transient natriuresis. Furthermore, treatment with an SGLT2 inhibitor improves renal ischemia by producing vascular endothelial growth factor-a in the renal tubules. Other studies have suggested that ketone body production, changes in glomerular hemodynamics, and intrarenal metabolic changes and a reduction in oxidative stress due to decreased tubulointerstitial glucose levels may also be involved in the renoprotective effects of SGLT2 inhibitors. In this review, we summarize the mechanism responsible for the SGLT2 inhibitor-induced renoprotective effects, including our recent hypothesis regarding an “aestivation-like response,” which is a biological defense response to starvation.

Summary: Inflammatory stimuli cause a state of emergency myelopoiesis leading to neutrophil-like monocyte expansion. However, their function, the committed precursors, or growth factors remain elusive. In this study we find that Ym1+Ly6Chi monocytes, an immunoregulatory entity of neutrophil-like monocytes, arise from progenitors of neutrophil 1 (proNeu1). Granulocyte-colony stimulating factor (G-CSF) favors the production of neutrophil-like monocytes through previously unknown CD81+CX3CR1lo monocyte precursors. GFI1 promotes the differentiation of proNeu2 from proNeu1 at the cost of producing neutrophil-like monocytes. The human counterpart of neutrophil-like monocytes that also expands in response to G-CSF is found in CD14+CD16− monocyte fraction. The human neutrophil-like monocytes are discriminated from CD14+CD16− classical monocytes by CXCR1 expression and the capacity to suppress T cell proliferation. Collectively, our findings suggest that the aberrant expansion of neutrophil-like monocytes under inflammatory conditions is a process conserved between mouse and human, which may be beneficial for the resolution of inflammation.

We have previously demonstrated that KS-133 is a specific and potent antagonist of vasoactive intestinal peptide receptor 2 (VIPR2). We have also shown that vasoactive intestinal peptide-VIPR2 signaling affects the polarity and activation of tumor-associated macrophages, which is another strategy for cancer immunotherapy apart from the activation of effector T cells. In this study, we aimed to examine whether the selective blockade of VIPR2 by KS-133 changes the polarization of macrophages and induces anti-tumor effects. In the presence of KS-133, genetic markers indicative of tumor-aggressive M1-type macrophages were upregulated, and conversely, those of tumor-supportive M2-type macrophages were downregulated. Daily subcutaneous administration of KS-133 tended to suppress the growth of CT26 tumors (murine colorectal cancer-derived cells) implanted subcutaneously in Balb/c mice. To improve the pharmacological efficacy and reduce the number of doses, we examined a nanoformulation of KS-133 using the US Food and Drug Administration-approved pharmaceutical additive surfactant Cremophor® EL. KS-133 nanoparticles (NPs) were approximately 15 nm in size and stable at 4°C after preparation. Meanwhile, KS-133 was gradually released from the NPs as the temperature was increased. Subcutaneous administration of KS-133 NPs once every 3 days had stronger anti-tumor effects than daily subcutaneous administration of KS-133. Furthermore, KS-133 NPs significantly enhanced the pharmacological efficacy of an immune checkpoint-inhibiting anti-PD-1 antibody. A pharmacokinetic study suggested that the enhancement of anti-tumor activity was associated with improvement of the pharmacokinetic profile of KS-133 upon nanoformulation. Our data have revealed that specific blockade of VIPR2 by KS-133 has therapeutic potential for cancer both alone and in combination with immune checkpoint inhibitors.

Abstract Sexual reproduction involves the creation of sex-dependent gametes, oocytes and sperm. In mammals, sexually dimorphic differentiation commences in the primordial germ cells (PGCs) in embryonic gonads; PGCs in ovaries and testes differentiate into meiotic primary oocytes and mitotically quiescent prospermatogonia, respectively. Here, we show that the transition from PGCs to sex-specific germ cells was abrogated in conditional knockout mice carrying a null mutation of Smarcb1 (also known as Snf5) gene, which encodes a core subunit of the SWI/SNF chromatin remodeling complex. In female mutant mice, failure to upregulate meiosis-related genes resulted in impaired meiotic entry and progression, including defects in synapsis formation and DNA double strand break repair. Mutant male mice exhibited delayed mitotic arrest and DNA hypomethylation in retrotransposons and imprinted genes, resulting from aberrant expression of genes related to growth and de novo DNA methylation. Collectively, our results demonstrate that the SWI/SNF complex is required for transcriptional reprogramming in the initiation of sex-dependent differentiation of germ cells.

Sodium/glucose cotransporter 2 (SGLT2) is a renal low-affinity high-capacity sodium/glucose cotransporter expressed in the apical membrane of the early segment of proximal tubules. SGLT2 reabsorbs filtered glucose in the kidney, and its inhibitors represent a new class of oral medications used for type 2 diabetes mellitus, which act by increasing glucose and sodium excretion in urine, thereby reducing blood glucose levels. However, clinical trials showed marked improvement of renal outcomes, even in nondiabetic kidney diseases, although the underlying mechanism of this renoprotective effect is unclear. We showed that long-term excretion of salt by the kidneys, which predisposes to osmotic diuresis and water loss, induces a systemic body response for water conservation. The energy-intensive nature of water conservation leads to a reprioritization of systemic body energy metabolism. According to current data, use of SGLT2 inhibitors may result in similar reprioritization of energy metabolism to prevent dehydration. In this review article, we discuss the beneficial effects of SGLT2 inhibition from the perspective of energy metabolism and water conservation.

Abstract Chronic myeloid leukemia (CML) is a form of myeloproliferative neoplasm caused by the oncogenic tyrosine kinase BCR-ABL. Although tyrosine kinase inhibitors have dramatically improved the prognosis of patients with CML, several problems such as resistance and recurrence still exist. Immunological control may contribute to solving these problems, and it is important to understand why CML patients fail to spontaneously develop anti-tumor immunity. Here, we show that differentiation of conventional dendritic cells (cDCs), which are vital for anti-tumor immunity, is restricted from an early stage of hematopoiesis in CML. In addition, we found that monocytes and basophils, which are increased in CML patients, express high levels of PD-L1, an immune checkpoint molecule that inhibits T cell responses. Moreover, RNA-sequencing analysis revealed that basophils express genes related to poor prognosis in CML. Our data suggest that BCR-ABL not only disrupts the “accelerator” (i.e., cDCs) but also applies the “brake” (i.e., monocytes and basophils) of anti-tumor immunity, compromising the defense against CML cells.

IRF5 is a potential target for therapy in systemic lupus erythematosus (SLE). Here the authors show using mouse SLE-like models that genetic or chemical inhibition of IRF5 after SLE onset could be more effective than, or an add on for, currently utilised type I interferon inhibition.

OBJECTIVES Using a dataset from a survey on national health and productivity management, we identified health and productivity factors associated with organizational profitability. METHODS The Ministry of Economy, Trade and Industry conducted an annual survey on Health and Productivity Management between 2014 and 2021. We assessed the associations of organizational health and productivity management using survey questions collected in 2017 and 2018, with the rate of change in profits from 2017 and 2018 to 2020. We identified factors associated with organizational profitability using eXtreme Gradient Boosting, and calculated SHapley Additive exPlanation (SHAP) values for each factor. RESULTS Among 1,593 companies (n= 4,359,834 employees), the mean age of employees at baseline was 40.3 years and the proportion of women was 25.8%. A confusion matrix for evaluating model performance had an accuracy of 0.997, precision of 0.993, recall of 0.997, and area under the precision-recall curve of 0.999. The most important factors related to an increase in corporate profits were the percentage of current smokers (SHAP value, 0.121), per-employee cost of health services (0.084) and medical services (0.050); the percentage of full-time employees working in sales departments (0.074) and distribution or customer service departments (0.054); the percentage of employees who slept well (0.055); and the percentage of employees within a company who regularly exercised (0.043). CONCLUSIONS Employees’ lifestyle-related health risk factors and organizations’ management systems were associated with organizational profitability. Lifestyle medicine professionals may demonstrate a significant return on investment by creating a healthier and more productive workforce.

It has been our pleasure to have been able to develop two special issues within the International Journal of Molecular Sciences: (1) Renin-Angiotensin-Aldosterone System in Pathologies and (2) Renin-Angiotensin-Aldosterone System in Metabolism & Disease [...]

Introduction: While recent investigations show that klotho exerts reno-protective actions, it has not been fully addressed whether klotho protein supplementation reverses renal damage. Methods: The impacts of subcutaneous klotho supplementation on rats with subtotal nephrectomy were examined. Animals were divided into 3 groups: group1 (short remnant, SR): remnant kidney for 4 weeks, group 2 (long remnant, LR): remnant kidney for 12 weeks and group 3 (klotho supplementation: KL): klotho protein (20 μg/kg/day) supplementation on the remnant kidney. Blood pressure, blood and urine compositions with conventional methods such as enzyme-linked immunosorbent assay and radioimmunoassay, kidney histology and renal expressions of various genes were analyzed. In vitro studies were also performed to support in vivo findings. Results: Klotho protein supplementation decreased albuminuria (-43%), systolic blood pressure (-16%), fibroblast growth factor (FGF) 23 (-51%) and serum phosphate levels (-19%), renal angiotensin II concentration (-43%), fibrosis index (-70%), renal expressions of collagen I (-55%) and transforming growth factor β (-59%) (p

Hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors were developed for treatment of renal anemia. Patients applicable for HIF-PHD inhibitor treatment experience complications such as chronic kidney disease, whereby water and electrolyte homeostasis is disrupted. The effects of hypoxia-inducible factor stabilization on salt accumulation in the setting of reduced renal function remain unclear. In the present study, we investigated the effect of a HIF-PHD inhibitor, molidustat, on salt distribution and excretion in rats with subtotal nephrectomy-induced chronic kidney disease. Male Wistar rats were subjected to 5/6 nephrectomy. After confirming blood pressure elevation (>150 mmHg, at 4 weeks after surgery), rats were treated with molidustat. After 1 week of treatment, molidustat did not significantly improve blood cell volume or blood pressure. Distribution of sodium, potassium, and water in skin, carcass, and bone samples was not affected by molidustat. Furthermore, molidustat had no significant effect on urinary sodium excretion or concentration in response to acute oral salt loading (1 g/kg). In conclusion, molidustat did not affect distribution or excretion of salt in rats subjected to a model of nephron loss.

Abstract Tumor spread through air spaces (STAS) in non-small-cell lung cancer (NSCLC) is known to influence a poor patient outcome, even in patients presenting with early-stage disease. However, the pre-operative diagnosis of STAS remains challenging. With the progress of radiomics-based analyses several attempts have been made to predict STAS based on radiological findings. In the present study, patients with NSCLC which is located peripherally and tumors ≤ 2 cm in size on computed tomography (CT) that were potential candidates for sublobar resection were enrolled in this study. The radiologic features of the targeted tumors on thin-section CT were extracted using the PyRadiomics v3.0 software package, and a predictive model for STAS was built using the t-test and XGBoost. Thirty-five out of 226 patients had a STAS histology. The predictive model of STAS indicated an area under the receiver-operator characteristic curve (AUC) of 0.77. There was no significant difference in the overall survival (OS) for lobectomy between the predicted-STAS (+) and (−) groups (p = 0.19), but an unfavorable OS for sublobar resection was indicated in the predicted-STAS (+) group (p

Summary: Our understanding of how each hereditary kidney cancer adapts to its tissue microenvironment is incomplete. Here, we present single-cell transcriptomes of 108,342 cells from patient specimens including from six hereditary kidney cancers. The transcriptomes displayed distinct characteristics of the cell of origin and unique tissue microenvironment for each hereditary kidney cancer. Of note, hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated kidney cancer retained some characteristics of proximal tubules, which were completely lost in lymph node metastases and present as an avascular tumor with suppressed T cells and TREM2-high macrophages, leading to immune tolerance. Birt-Hogg-Dubé (BHD)-associated kidney cancer exhibited transcriptomic intratumor heterogeneity (tITH) with increased characteristics of intercalated cells of the collecting duct and upregulation of FOXI1-driven genes, a critical transcription factor for collecting duct differentiation. These findings facilitate our understanding of how hereditary kidney cancers adapt to their tissue microenvironment.

Community-acquired bacterial bloodstream infections are caused by diverse pathogens with changing antimicrobial-resistance patterns. In low-middle income countries in Southeast Asia, where dengue fever is endemic and a leading cause of fever, limited information is available about bacterial bloodstream infections due to challenges of implementing a blood culture service. This study describes bacterial bloodstream pathogens and antimicrobial-resistance patterns in Metro Manila, the Philippines. We aimed to identify the proportion of patients with a positive blood culture, the bacteria isolated and their antimicrobial resistance patterns, and the clinical characteristics of these patients, in this dengue endemic area. We conducted a prospective observational study in a single hospital enrolling febrile patients clinically suspected of having a community-acquired bacterial bloodstream infection between 1st July 2015 and 30th June 2019. Each patient had a blood culture and additional diagnostic tests according to their clinical presentation. We enrolled 1315 patients and a significant positive blood culture was found in 77 (5.9%) including Staphylococcus aureus (n = 20), Salmonella enterica Typhi (n = 18), Escherichia coli (n = 16), Streptococcus pneumoniae (n = 3) and Burkholderia pseudomallei (n = 2). Thirty-four patients had meningococcal disease diagnosed by culture (n = 8) or blood PCR (n = 26). Additional confirmed diagnoses included leptospirosis (n = 177), dengue virus infection (n = 159) and respiratory diphtheria (n = 50). There were 79 (6.0%, 95%CI 4.8%-7.4%) patients who died within 28 days of enrollment. Patients with a positive blood culture were significantly more likely to die than patients with negative culture (15.2% vs 4.4%, P

IntroductionWind instrument players sometimes suffer from erosion of the mucous membrane of the lip. This is caused by the action and pressure of the mouthpiece of the wind instrument against teeth. To address this problem, a lip shield is fitted over the dental arch to prevent direct contact between the lips and teeth. However, there are a few studies on the influence of the lip shield on the acoustics of wind instruments. The purpose of this study was to analyze the psychoacoustics of a clarinet performance with the player wearing a custom-made soft lip shield to prevent mucosal erosion of the lower lip.Case DescriptionA lip shield was custom-made with a soft thermoplastic material for a female clarinetist who complained of mucosal erosion and pain of the lower lip. The psychoacoustics of her musical performance played in different dynamics, fortissimo, mezzo forte and pianissimo were analyzed, including loudness and sharpness. A self-evaluation questionnaire with items rated on a 10-point scale was administered. After wearing the lip shield, the patient reported that the mucosal erosion and pain of her lower lip when playing clarinet resolved. The lip shield had little effect on the loudness. There was a slight decrease in sharpness when the lip shield was worn compared to when it was not, describing the reduction of high frequencies. Furthermore, fewer variations in sharpness between the tones were observed.ConclusionThe results suggest that lip shields made of soft materials can eliminate mucosal erosion and pain of the lower lip while having little effect on performance, although, a slight change in timbre is possible.

Abstract Erythropoietin (EPO) is a crucial hormone for erythropoiesis and produced by adult kidneys. Insufficient EPO production in chronic kidney disease (CKD) can cause renal anemia. Although hypoxia-inducible factors (HIFs) are known as a main regulator, the mechanisms of EPO production have not been fully elucidated. In this study, we aimed to examine the roles of retinoic acid (RA) in EPO production using EPO-producing cells derived from human induced pluripotent stem cells (hiPSC-EPO cells) that we previously established. RA augmented EPO production by hiPSC-EPO cells under hypoxia or by treatment with prolyl hydroxylase domain-containing protein (PHD) inhibitors that upregulate HIF signals. Combination treatment with RA and a PHD inhibitor improved renal anemia in vitamin A-depleted CKD model mice. Our findings using hiPSC-EPO cells and CKD model mice may contribute to clarifying the EPO production mechanism and developing efficient therapies for renal anemia.

We introduce our technique to treat dural arteriovenous fistulae (dAVFe) under sinus balloon protection. The Kaneka Shoryu 7 × 7 mm balloon was used for sinus occlusion. Initially, the balloon was inflated slowly using 1.5–2.0 mL of saline on the table. A 6F guiding catheter was navigated into the proximal portion of the lesion from the jugular vein of the affected side. The balloon catheter was introduced to the point occluding the shunt. The balloon was temporarily inflated to determine the occlusion point without occluding the outlet of the vein of Labbe. ONYX injection was started from the microcatheter located at just proximal to the shunt point under sinus balloon occlusion. ONYX penetrated the feeding arteries in an antegrade and retrograde manner. After the penetration of ONYX into each feeding artery, the inflated balloon was temporarily deflated to examine the residual shunt. If a small shunt remained, the balloon was inflated again and ONYX injection was continued. To cure dAVF, the location of the balloon is important. The guiding catheter should be placed just proximal to the shunt and the balloon catheter should be gently pulled to stabilize the balloon position.

Inappropriate mineralocorticoid receptor (MR) activation in different cardiovascular cell types has deleterious effects on cardiac remodeling and function. Therefore, MR inhibition is a crucial pharmacological strategy to overcome cardiovascular dysfunction. Despite efficient blockade of MR with steroidal MR antagonists (MRAs), their clinical application is unsatisfactory due to the adverse effects. Newer non-steroidal MRAs with greater potency could be suitable for clinical application, especially in patients with type 2 diabetes mellitus and chronic kidney disease. Although clinical evidence has shown the beneficial effects of non-steroidal MRAs on cardiovascular outcomes in patients with heart failure with reduced ejection fraction, clinical trials are ongoing to evaluate the efficacy of heart failure with preserved ejection fraction. Therefore, comparative pharmacological characterization of non-steroidal MRAs over classic steroidal MRAs is crucial. Here, we summarize the pre-clinical evidence of non-steroidal MRAs, which suggests an improvement in cardiac dysfunction, as well as the underlying molecular mechanisms in animal models mimicking different clinical conditions. In addition, we discuss up-to-date information from clinical trials regarding the beneficial effects of non-steroidal MRAs on meaningful cardiovascular outcomes. Both pre-clinical and clinical evidence support treatment with non-steroidal MRAs in patients with cardiovascular disease.

The kidneys are the major organs for erythropoietin (EPO) production in adults, and thus, kidney damage results in reduced EPO levels and anemia. Inhibitors of Hypoxia-inducible factor-prolyl hydroxylase domain-containing protein (HIF-PHD) are awaited as new therapeutic options for renal anemia. It can be predicted that most patients who receive HIF-PHD inhibitors have renal dysfunction as a cause of anemia. Therefore, in the present study, we investigated the effects of the HIF-PHD inhibitor molidustat on anemia and renal dysfunction when initiated after the onset of renal anemia. Male C57BL/6J mice received adenine orally to induce nephropathy. After the onset of nephropathy, the mice were treated with either vehicle or molidustat. After 4 weeks of administration, vehicle-treated mice displayed significant anemia, and molidustat ameliorated this anemia. Vehicle-treated mice exhibited reduced creatinine clearance and body weight, increased blood urea nitrogen levels, histopathological changes, immune cell infiltration, and dehydration. Molidustat reversed immune cell infiltration, dehydration, and renal fibrosis without improving renal functional parameters. In conclusion, molidustat treatment initiated after the onset of nephropathy and renal anemia reversed anemia in mice. Molidustat improved some parameters of renal abnormality, but it did not restore renal function.

Objective: Transarterial embolization under intrasinus balloon protection is an efficient treatment strategy for intracranial arteriovenous fistula. Ordinary balloon protection methods using the Copernic RC balloon may occlude the normal drainage route, and the occurrence of venous complications is concerning. The aim of this study was to report the efficacy of the supercompliant SHOURYU balloon catheter for intrasinus balloon protection while preserving the normal venous outlet. Methods: Eighteen patients with dural arteriovenous fistulas who were treated with transarterial embolization under intrasinus balloon protection between April 2011 and July 2020 were included. All lesions were treated with transarterial embolization under intrasinus balloon protection using the SHOURYU balloon catheter. Clinical and angiographic data were retrospectively collected, and the occlusion rate, complications, and clinical outcomes were analyzed. Results: Nine men and nine women were treated, and their average age was 61.1 years. Fistulas were located at the transverse-sigmoid sinus (n = 13), superior sagittal sinus (n = 3), tentorial sinus (n = 1), and around the torcular Herophili (n = 1). Ten patients were classified as Borden typeⅠand eight as Borden type Ⅱ. Complete (n = 9) or near-complete (n = 4) occlusion was achieved in 72.2% of the patients. Periprocedural complications, but no venous complications were observed in two patients. Symptoms were not aggravated after treatment. Conclusions: Transarterial embolization under intrasinus balloon protection using the SHOURYU balloon catheter is effective and safe for treatment of dural arteriovenous fistulas while maintaining the patency of the venous sinus.

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease with no decisive treatment. The sodium glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin was developed as a new oral hypoglycemic drug, which can improve NASH via an insulin-independent glucose-lowering effect by inhibiting glucose reabsorption in the renal proximal tubules. However, ipragliflozin appears to modulate steatosis or inflammation via different pathways. To elucidate the new mechanism of ipragliflozin for the treatment of NASH, we evaluated its effects in a NASH mouse model (STAM mice) with beta cell depletion, and compared the expression of microRNAs (miRNAs) in STAM mice treated with or without ipragliflozin (16.7 μg/day for 5 weeks). Ipragliflozin reduced aspartate transaminase and alanine aminotransferase levels, along with reduced hepatic steatosis, hepatocyte ballooning, lobular inflammation, and liver fibrosis. In addition, ipragliflozin upregulated mitochondrial transport-related and antioxidant defensive system-related genes in the liver. Among 2555 mouse miRNA probes, miR-19b-3p was commonly differentially expressed with ipragliflozin treatment for 5 weeks in both the liver and serum but in different directions, with a decrease in the liver and increase in the serum. Therefore, ipragliflozin can improve NASH development likely through the antioxidative stress pathway and by regulating miR-19b-3p.

Abstract Background The (pro) renin receptor ((P)RR) plays important roles in various pathways, such as the Wnt/β-catenin, renin-angiotensin system (RAS), MAPK/ERK and PI3K/AKT/mTOR pathways, that are involved in a wide range of physiological and pathological processes incorporating the tumorigenesis. However, our knowledge about (P) RR was mostly limited to its roles in cardiovascular and renal physiological functions and diseases. In the past 5 years, however, compelling evidence has revealed that (P) RR is aberrantly expressed in and contributes to the development of various cancers by different means. For instance, (P) RR was recently demonstrated to induce the oncogenesis of pancreatic, colorectal and brain cancers via the Wnt signaling, while promote the endometrial cancer and glioblastoma through the RAS. Methods Combining with the deep analysis of big data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, this review updates and summarizes the recent studies about the newly recognized roles of (P) RR in the pathophysiological processes of cancer development and its detailed functions through related pathways, as well as the novel research progress of (P) RR in related fields including the development and application of soluble (P) RR detection kit and monoclonal (P) RR antibody. Results This review provides an overview of the essential roles of (P) RR in the tumorigenesis and progression of various cancers and offers a translational outlook for the future research and clinical practices. Conclusion (P) RR in the tumor tissues and/or body fluids of patients may be a novel and promising biomarker and potential therapeutic target for diagnosis, treatment and prognosis prediction in various cancers. Video Abstract Graphical abstract

Renal anemia in chronic kidney disease is treated with recombinant human erythropoietin (rhEPO). However, some patients with anemia do not respond well to rhEPO, emphasizing the need for a more biocompatible EPO. Differentiation protocols for hepatic lineages have been modified to enable production from human induced pluripotent stem cell (hiPSC)‐derived EPO‐producing cells (EPO cells). However, markers for hiPSC‐EPO cells are lacking, making it difficult to purify hiPSC‐EPO cells and therefore to optimize EPO production and cell counts for transplantation. To address these issues, we investigated whether CD140b and CD73 could be used as markers for hiPSC‐EPO cells. We measured the expression of EPO, CD140b, and CD73 in hiPSC‐EPO cells and the EPO concentration in the cell supernatant by immunohistochemistry and enzyme‐linked immunosorbent assays on culture day 13, revealing that expression levels of CD140b and CD73 are correlated with the level of EPO. In addition, rates of CD140b+ CD73+ cells were observed to be correlated with the concentration of EPO. Thus, our results suggest that CD140b and CD73 may be markers for hiPSC‐EPO cells.

Background Studies of the association of hypertension with incident colorectal cancer (CRC) may have been confounded by including individuals taking antihypertensive medication, at high risk for CRC (ie, colorectal polyps and inflammatory bowel disease), or with shared risk factors (eg, obesity and diabetes). We assessed whether adults with untreated hypertension are at higher risk for incident CRC compared with those with normal blood pressure (BP), and whether any association is evident among individuals without obesity or metabolic abnormalities. Methods and Results Analyses were conducted using a nationwide health claims database collected in the JMDC Claims Database between 2005 and 2018 (n=2 220 112; mean age, 44.1±11.0 years; 58.4% men). Participants who were taking antihypertensive medications or had a history of CRC, colorectal polyps, or inflammatory bowel disease were excluded. Each participant was categorized as having normal BP (systolic BP [SBP]

Abstract Pulmonary hypertension (PH) is a life‐threatening disorder, which originates from various aetiologies. Ventilation–perfusion (V/Q) scanning is commonly used to evaluate the differential diagnosis of PH. Meanwhile, previous studies have shown that single‐photon emission computed tomography (SPECT)/CT imaging can provide a more detailed analysis for the assessment of pulmonary blood flow. However, there is insufficient evidence supporting the merits of V/Q SPECT/CT image data in detecting pulmonary vascular disease. Here, we report a case of pulmonary arterial hypertension with localized accumulation and peculiar distribution just below the pleura on V/Q SPECT/CT. Our finding is unique, and it suggests that V/Q SPECT/CT image data might be useful to detect blood flow not only in cases of pulmonary embolism, but also in the more commonly encountered PH.

Non-alcoholic fatty liver disease (NAFLD) affects up to 20% of the world’s population. Overactivation of the angiotensin receptor type 1 (AT1) contributes to metabolic dysfunction and increased oxidant production, which are associated with NAFLD and impaired hepatic lipid metabolism. Nuclear factor erythroid-2-related factor 2 (Nrf2) regulates the expression of antioxidant phase II genes by binding to the antioxidant response element (ARE); however, the mechanisms by which AT1 contributes to this pathway during the progression of NAFLD remain unresolved. To investigate hepatic Nrf2 response to a hyperglycemic challenge, we studied three groups of rats (male, 10-weeks-old): (1) untreated, lean Long Evans Tokushima Otsuka (LETO), (2) untreated, obese Otsuka Long Evans Tokushima Fatty (OLETF), and (3) OLETF + angiotensin receptor blocker (OLETF + ARB; 10 mg olmesartan/kg/d × 6 weeks). Livers were collected after overnight fasting (T0; baseline), and 1 h and 2 h post-oral glucose load. At baseline, chronic AT1 blockade increased nuclear Nrf2 content, reduced expression of glutamate-cysteine ligase catalytic (GCLC) subunit, glutathione peroxidase 1 (GPx1), and superoxide dismutase 2 (SOD2), mitochondrial catalase activity, and hepatic 4-hydroxy-2-nonenal (4-HNE) content. The expression of hepatic interleukin-1 beta (IL-1β) and collagen type IV, which are associated with liver fibrosis, were decreased with AT1 blockade. Glucose increased Nrf2 translocation in OLETF but was reduced in ARB, suggesting that glucose induces the need for antioxidant defense that is ameliorated with ARB. These results suggest that overactivation of AT1 promotes oxidant damage by suppressing Nrf2 and contributing to hepatic fibrosis associated with NAFLD development.

Background: The nonsteroidal mineralocorticoid receptor blocker esaxerenone is effective in reducing blood pressure (BP). Objective: In this study, we investigated esaxerenone-driven sodium homeostasis and its association with changes in BP in Dahl salt-sensitive (DSS) hypertensive rats. Methods: In the different experimental setups, we evaluated BP by a radiotelemetry system, and sodium homeostasis was determined by an approach of sodium intake (food intake) and excretion (urinary excretion) in DSS rats with a low-salt diet (0.3% NaCl), high-salt diet (HSD, 8% NaCl), HSD plus 0.001% esaxerenone (w/w), and HSD plus 0.05% furosemide. Results: HSD-fed DSS rats showed a dramatic increase in BP with a non-dipper pattern, while esaxerenone treatment, but not furosemide, significantly reduced BP with a dipper pattern. The cumulative sodium excretion in the active period was significantly elevated in esaxerenone- and furosemide-treated rats compared with their HSD-fed counterparts. Sodium content in the skin, skinned carcass, and total body tended to be lower in esaxerenone-treated rats than in their HSD-fed counterparts, while these values were unchanged in furosemide-treated rats. Consistently, sodium balance tended to be reduced in esaxerenone-treated rats during the active period. Histological evaluation showed that esaxerenone, but not furosemide, treatment attenuated glomerulosclerosis, tubulointerstitial fibrosis, and urinary protein excretion induced by high salt loading. Conclusions: Collectively, these findings suggest that an esaxerenone treatment-induced reduction in BP and renoprotection are associated with body sodium homeostasis in salt-loaded DSS rats.

We examined the effects of the angiotensin receptor-neprilysin inhibitor LCZ696 on overt proteinuria and renal injury in type 2 diabetic Otsuka-Long- Evans-Tokushima-Fatty (OLETF) rats. Aged OLETF rats were also treated with either valsartan or valsartan plus hydralazine for comparison. LCZ696 caused greater attenuation of the progression of proteinuria than either valsartan alone or valsartan combined with hydralazine. Reduced glomerular injury and tubulointerstitial fibrosis were also observed in LCZ696-treated rats. Moreover, LCZ696 prevented increases in blood urea nitrogen (BUN) and creatinine levels. These data suggest that LCZ696 elicits a reno-protective effect against type 2 diabetes with overt proteinuria. Keywords: LCZ696, Proteinuria, Diabetic kidney disease (DKD)

Abstract The ischaemia-reperfusion (I/R) model is a widely used model of acute kidney injury (AKI) and renal fibrosis. However, the ischaemia duration that is long enough to cause broad fibrosis shows that a high mortality rate and a short ischaemia duration does not cause fibrosis, resulting in a large variation in fibrosis progression in this experimental model. Inter-operator variation occurs for I/R injury severity because the I/R procedure is complex, which results in poor reproducibility of subsequent fibrosis in the model. In the present study, we developed a renal fibrosis model in which the fibrosis progression for 8 weeks is predictable within 8 days. Three operators independently performed I/R followed by uninephrectomy at day 7 in mice. The aim was to create a model that would show a blood urea nitrogen (BUN) level >100 mg/dL at day 8 after I/R (day 1 after uninephrectomy). Although the ischaemia duration to satisfy this BUN criterion differed among operators, the mice developed anaemia, polyuria, and fibrosis in a similar manner under the same BUN criterion with a low mortality rate. Interstitial fibrosis had developed at week 8, which was strongly correlated with the BUN at day 8. This protocol allows operators to adjust the ischaemia duration based on the BUN criterion and to separate mice into the desired number of groups based on the BUN to study interventions against renal fibrosis.

New Findings What is the central question of this study? Can chymase inhibition prevent angiotensin I‐induced hypertension through inhibiting the conversion of angiotensin I to angiotensin II in the kidney? What is the main finding and its importance? Treatment with TEI‐F00806 decreased angiotensin II content of the kidney, renal cortical angiotensinogen protein levels and chymase mRNA expression, and attenuated the development of hypertension. Abstract The effects of the selective chymase inhibitor TEI‐F00806 were examined on angiotensin I (Ang I)‐induced hypertension and intrarenal angiotensin II (Ang II) production in salt‐treated mice. Twelve‐week‐old C57BL male mice were given a high‐salt diet (4% NaCl + saline (0.9% NaCl)), and divided into three groups: (1) sham + vehicle (5% acetic acid in saline), (2) Ang I (1 μg kg−1 min−1, s.c.) + vehicle, and (3) Ang I + TEI‐F00806 (100 mg kg−1 day−1, p.o.) (n = 8–10 per group). Systolic blood pressure was measured weekly using a tail‐cuff method. Kidney Ang II content was measured by radioimmunoassay. Chronic infusion of Ang I resulted in the development of hypertension (P

Background and study aims Exposed endoscopic full-thickness resection (EFTR) enables the operator to obtain a sufficient surgical margin. However, insufflation leakage and secure endoscopic full-thickness closure (EFTC) remain problematic. This study aimed to evaluate the safety and feasibility of a new exposed EFTR. Patients and methods Exposed EFTR was performed for 2-cm virtual lesions in different locations of the upper stomach in four dogs. EFTR mainly involved half-circumferential EFTR of the endpoint and clip-line traction. Pulley traction was applied with the forward approach for the greater curvature. EFTC involved endoscopic ligation with O-ring closure to diminish insufflation leakage, followed by over-the-scope clip closure. Results Complete resection and technical success were achieved in all four cases. One case of intraoperative bleeding was endoscopically managed. No postoperative complications occurred in any cases. The median maximum resected size was 27.5 mm. The median procedure time of the total operation, EFTR, and EFTC was 76, 37, and 35.5 minutes, respectively. The 1-month survival rate was 100 %. Conclusions This therapeutic strategy may lead to the establishment of exposed EFTR.

Caloric restriction (CR) is one of the most important behavioral interventions to reduce excessive abdominal adiposity, which is a risk factor for the development of insulin resistance. Previous metabolomics studies have characterized substrate metabolism during healthy conditions; however, the effects of CR and subsequent mass recovery on shifts in substrate metabolism during insulin resistance (IR) have not been widely investigated. To assess the effects of acute CR and the subsequent mass recovery on shifts in substrate metabolism, a cohort of 15-week old Long Evans Tokushima Otsuka (LETO) and Otsuka Long Evans Tokushima Fatty (OLETF) rats were calorie restricted (CR: 50% × 10 days) with or without partial body mass recovery (PR; 73% x 7 days), along with their respective ad libitum controls. End-of-study plasma samples were analyzed for primary carbon metabolites by gas chromatography (GC) time-of-flight (TOF) mass spectrometry (MS) data acquisition. Data analysis included PCA, Pearson correlation vs previously reported variables (adipose and body masses, and insulin resistance index, IRI), and metabolomics maps (MetaMapp) generated for the most significant group comparisons. All treatments elicited a significant group differentiation in at least one principal component. CR improved TCA cycle in OLETF, and increased lipolysis and proteolysis. These changes were reversed after PR except for gluconeogenesis. Plasma lipid concentrations were inversely correlated to IRI in LETO, but not OLETF. These shifts in substrate metabolism suggest that the CR-induced decreases in adipose may not be sufficient to more permanently alter substrate metabolism to improve IR status during metabolic syndrome.

Caloric restriction, among other behavioral interventions, has demonstrated benefits on improving glycemic control in obesity-associated diabetic subjects. However, an acute and severe intervention without proper maintenance could reverse the initial benefits, with additional metabolic derangements. To assess the effects of an acute caloric restriction in a metabolic syndrome model, a cohort of 15-week old Long Evans Tokushima Otsuka (LETO) and Otsuka Long Evans Tokushima Fatty (OLETF) rats were calorie restricted (CR: 50% × 10 days) with or without a 10-day body mass (BM) recovery period, along with their respective ad libitum controls. An oral glucose tolerance test (oGTT) was performed after CR and BM recovery. Both strains had higher rates of mass gain during recovery vs. ad lib controls; however, the regain was partial (ca. 50% of ad lib controls) over the measurement period. Retroperitoneal and epididymal adipose masses decreased 30% (8.8 g, P < 0.001) in OLETF; however, this loss only accounted for 11.5% of the total BM loss. CR decreased blood glucose AUC 16% in LETO and 19% in OLETF, without significant decreases in insulin. Following CR, hepatic expression of the gluconeogenic enzyme, PEPCK, was reduced 55% in OLETF compared to LETO, and plasma triglycerides (TG) decreased 86%. Acute CR induced improvements in glucose tolerance and TG suggestive of improvements in metabolism; however, partial recovery of BM following CR abolished the improvement in glucose tolerance. The present study highlights the importance of proper maintenance of BM after CR as only partial recovery of the lost BM reversed benefits of the initial mass loss.