Deletion of the four phospholipid hydroperoxide glutathione peroxidase genes accelerates aging in Caenorhabditis elegans

The glutathione peroxidase (GPx) family is a major antioxidant enzyme family that catalyzes the reduction of a variety of hydroperoxides. GPxs are divided into selenium‐ and nonselenium‐containing GPxs. Because of their efficient antioxidant activity, which depends on the presence of the amino acid residue selenocysteine, selenium‐containing GPxs have been the subject of many studies. However, the physiological roles of the nonselenium GPxs remain unclear. Here, we report that the deletion of phospholipid hydroperoxide glutathione peroxidase (PHGPx) homologues causes accelerated aging that leads to a shortened lifespan in Caenorhabditis elegans. PHGPx is an antioxidant enzyme that directly reduces the phospholipid hydroperoxides generated in biomembranes. The quadruple phgpx mutant gpx‐1; gpx‐2; gpx‐6; gpx‐7 developed normally, reached adulthood and reproduced as well as the wild type. However, a lifespan analysis showed that the quadruple phgpx mutant had a short maximum lifespan, with an age‐related increase in its mortality rate. The intestine is the primary tissue expressing gpx‐1, gpx‐2, gpx‐6 and gpx‐7 in C. elegans, and the expression of gpx‐6 is greatly enhanced under starvation conditions. These results suggest that the C. elegans PHGPx homologues have important functions in the regulation of aging, probably by reducing oxidative damage in the intestine.     

Current status of drug therapies for osteoporosis and the search for stem cells adapted for bone regenerative medicine

A number of factors can lead to bone disorders such as osteoporosis, in which the balance of bone resorption vs. bone formation is upset (i.e., more bone is resorbed than is formed). The result is a loss of bone mass, with a concomitant decrease in bone density. Drugs for osteoporosis can be broadly classified as “bone resorption inhibitors”, which impede bone resorption by osteoclasts, and “bone formation accelerators”, which augment bone formation by osteoblasts. Here, we describe representative drugs in each class, i.e., the bisphosphonates and the parathyroid hormone. In addition, we introduce two novel bone formation accelerators, SST-VEDI and SSH-BMI, which are currently under investigation by our research group. On the other hand, regenerative therapy, characterized by (ideally) the use of a patient’s own cells to regenerate lost tissue, is now a matter of global interest. At present, candidate cell sources for regenerative therapy include embryonic stem cells (created from embryos based on the fertilization of oocytes), induced pluripotent stem cells (created artificially by using somatic cells as the starting material), and somatic stem cells (found in the tissues of the adult body). This review summarizes the identifying features and the therapeutic potential of each of these stem cell types for bone regenerative medicine. Although a number of different kinds of somatic stem cells have been reported, we turn our attention toward two that are of particular interest for prospective applications in bone repair: the dedifferentiated fat cell, and the deciduous dental pulp-derived stem cell.     

GET4 is a novel driver gene in colorectal cancer that regulates the localization of BAG6, a nucleocytoplasmic shuttling protein

Colorectal cancer (CRC) is one of the most common types of cancer and a significant cause of cancer mortality worldwide. Further improvements of CRC therapeutic approaches are needed. BCL2‐associated athanogene 6 (BAG6), a multifunctional scaffold protein, plays an important role in tumor progression. However, regulation of BAG6 in malignancies remains unclear. This study showed that guided entry of tail‐anchored proteins factor 4 (GET4), a component of the BAG6 complex, regulates the intercellular localization of BAG6 in CRC. Furthermore, GET4 was identified as a candidate driver gene on the short arm of chromosome 7, which is often amplified in CRC, by our bioinformatics approach using the CRC dataset from The Cancer Genome Atlas. Clinicopathologic and prognostic analyses using CRC datasets showed that GET4 was overexpressed in tumor cells due to an increased DNA copy number. High GET4 expression was an independent poor prognostic factor in CRC, whereas BAG6 was mainly overexpressed in the cytoplasm of tumor cells without gene alteration. The biological significance of GET4 was examined using GET4 KO CRC cells generated with CRISPR‐Cas9 technology or transfected CRC cells. In vitro and in vivo analyses showed that GET4 promoted tumor growth. It appears to facilitate cell cycle progression by cytoplasmic enrichment of BAG6‐mediated p53 acetylation followed by reduced p21 expression. In conclusion, we showed that GET4 is a novel driver gene and a prognostic biomarker that promotes CRC progression by inducing the cytoplasmic transport of BAG6. GET4 could be a promising therapeutic molecular target in CRC.     

Tannin-phytobezoars with Gastric Outlet Obstruction Treated by Dissolution with Administration and Endoscopic Injection of Coca-ColaⓇ, Endoscopic Crushing,and Removal (with Video)

A 77-year-old man complained of postmeal vomiting and sustained general fatigue. An abdominal computed tomography scan showed massive gastric expansion and fluid storage. Gastroscopy revealed four gastric bezoars that were considered to have caused pyloric ring obstruction. The patient was asked to drink 500 mL per day of Coca-Cola^Ⓡ for 4 days. On the fourth day, we performed endoscopic crushing and removal by injecting Coca-Cola^Ⓡ, cutting the softened bezoar with endoscopic snares, and collecting the pieces with endoscopic nets. We herein report (with a video presentation) a rare case of tannin-phytobezoars endoscopically removed with the administration and injection of Coca-Cola^Ⓡ.     

Dopamine modulates the optomotor response to unreliable visual stimuli in Drosophila melanogaster

State‐dependent modulation of sensory systems has been studied in many organisms and is possibly mediated through neuromodulators such as monoamine neurotransmitters. Among these, dopamine is involved in many aspects of animal behaviour, including movement control, attention, motivation and cognition. However, the precise neural mechanism underlying dopaminergic modulation of behaviour induced by sensory stimuli remains poorly understood. Here, we used Drosophila melanogaster to show that dopamine can modulate the optomotor response to moving visual stimuli including noise. The optomotor response is the head‐turning response to moving objects, which is observed in most sight‐reliant animals including mammals and insects. First, the effects of the dopamine system on the optomotor response were investigated in mutant flies deficient in dopamine receptors D1R1 or D1R2, which are involved in the modulation of sleep‐arousal in flies. We examined the optomotor response in D1R1 knockout (D1R1 KO) and D1R2 knockout (D1R2 KO) flies and found that it was not affected in D1R1 KO flies; however, it was significantly reduced in D1R2 KO flies compared with the wild type. Using cell‐type‐specific expression of an RNA interference construct of D1R2, we identified the fan‐shaped body, a part of the central complex, responsible for dopamine‐mediated modulation of the optomotor response. In particular, pontine cells in the fan‐shaped body seemed important in the modulation of the optomotor response, and their neural activity was required for the optomotor response. These results suggest a novel role of the central complex in the modulation of a behaviour based on the processing of sensory stimulations.     

Construction of Supramolecular Systems That Achieve Lifelike Functions

The Nobel Prize in Chemistry was awarded in 1987 and 2016 for research in supramolecular chemistry on the “development and use of molecules with structure-specific interactions of high selectivity” and the “design and production of molecular machines”, respectively. This confirmed the explosive development of supramolecular chemistry. In addition, attempts have been made in systems chemistry to embody the complex functions of living organisms as artificial non-equilibrium chemical systems, which have not received much attention in supramolecular chemistry. In this review, we explain recent developments in supramolecular chemistry through four categories: stimuli-responsiveness, time evolution, dissipative self-assembly, and hierarchical expression of functions. We discuss the development of non-equilibrium supramolecular systems, including the use of molecules with precisely designed properties, to achieve functions found in life as a hierarchical chemical system.     

Diagnostic criteria for acute‐onset type 1 diabetes mellitus (2012): Report of the Committee of Japan Diabetes Society on the Research of Fulminant and Acute‐onset Type 1 Diabetes Mellitus

Type 1 diabetes is a disease characterized by destruction of pancreatic β‐cells, which leads to absolute deficiency of insulin secretion. Depending on the manner of onset and progression, it is classified as fulminant, acute‐onset or slowly progressive type 1 diabetes. Here, we propose the diagnostic criteria for acute‐onset type 1 diabetes mellitus. Among the patients who develop ketosis or diabetic ketoacidosis within 3 months after the onset of hyperglycemic symptoms and require insulin treatment continuously after the diagnosis of diabetes, those with anti‐islet autoantibodies are diagnosed with ‘acute‐onset type 1 diabetes mellitus (autoimmune)’. In contrast, those whose endogenous insulin secretion is exhausted (fasting serum C‐peptide immunoreactivity <0.6 ng/mL) without verifiable anti‐islet autoantibodies are diagnosed simply with ‘acute‐onset type 1 diabetes mellitus’. Patients should be reevaluated after certain periods in case their statuses of anti‐islet autoantibodies and/or endogenous insulin secretory capacity are unknown.     

Association Between Pulse Wave Velocity and a Marker of Renal Tubular Damage (N‐Acetyl‐β‐D‐Glucosaminidase) in Patients Without Diabetes

The authors assessed the association between the ratio of urinary activity of N‐acetyl‐β‐D‐glucosaminidase (NAG) to creatinine and the brachial‐ankle pulse wave velocity (baPWV) in patients without overt diabetes mellitus (DM). This was a cross‐sectional study of 233 patients who had an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m² and no history of kidney disease. Patients were divided into two groups: high NAG group (>5.8 U/g creatinine) and low NAG group (≤5.8 U/g creatinine). Mean baPWVs of the high NAG group were significantly higher than those of the low NAG group in both the eGFR ≥30 and <60 tertiles and the eGFR ≥60 and <90 tertiles. The baPWV was positively correlated with NAG in all patients (r=0.341, P<.001). Stepwise multivariate regression analysis showed that the baPWV was significantly related with NAG, age, and systolic blood pressure. Elevated NAG is related to elevated arterial stiffness in patients without DM.     

Synergistic effect of adipose-derived stem cell therapy and bone marrow progenitor recruitment in ischemic heart

Human multipotent adipose-derived stem cells (hMADSCs) have recently been isolated featuring extensive expansion capacity ex vivo. We tested the hypothesis that hMADSC transplantation might contribute to cardiac functional recovery by its direct or indirect effect on myocardial infarction (MI). Nude rats were either transplanted with hMADSCs or PBS (control) in ischemic myocardium immediately following MI. Echocardiographical assessment of cardiac function after MI with hMADSCs showed significant improvement of each parameter compared to that with PBS. Histological analysis also showed significantly reduced infarct size and increased capillary density in peri-infarct myocardium by hMADSC treatment. However, remarkable transdifferentiation of hMADSCs into cardiac or vascular lineage cells was not observed. Despite the less transdifferentiation capacity, hMADSCs produced robust multiple pro-angiogenic growth factors and chemokines, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and stromal cell-derived factor-1α (SDF-1α). Specifically, hMADSC-derived SDF-1α had a crucial role for cooperative angiogenesis, with the paracrine effect of hMADSCs and Tie2-positive bone marrow (BM) progenitor recruitment in ischemic myocardium. hMADSCs exhibit a therapeutic effect on cardiac preservation following MI, with the production of VEGF, bFGF, and SDF-1α showing paracrine effects and endogenous BM stem/progenitor recruitment to ischemic myocardium rather than its direct contribution to tissue regeneration.