Neuronal loss and abnormal BMP/Smad signaling in the myenteric plexus of diabetic rats

Bone morphogenetic proteins (BMPs) are critical molecules during gut morphogenesis. However, little is known about their participation in the homeostasis of adult gut and their possible role in diseases. Gastrointestinal complications occur during diabetes with loss of enteric neurons. In this study, we investigated the possible involvement of BMPs signaling pathway in diabetic enteric neuropathy in an experimental model of diabetes in rats. The expression of BMPs, BMPs receptors and intracellular Smad effectors were assessed in control and diabetic smooth muscle layer of jejunum by immunofluorescence, Western blot and RT-PCR methods. Myenteric neurons and glial cells were measured by immunofluorescence using specific markers. In addition, cell apoptosis was evaluated by means of direct and indirect techniques. We demonstrated that diabetic ganglia displayed a significant decrease in ganglion size due to enhanced apoptosis and loss of peripherin. A decrease in glial fibrillary acidic protein (GFAP protein) was also observed in enteric glial cells. BMP-2 was down-regulated in the myenteric plexus of diabetic rats at 3 and 9weeks. A loss of enteric neurons by apoptosis was correlated with an ectopic BMP-4, increased BMPR-Ia and nuclear p-Smad1 expression in the myenteric plexus. Insulin-treatment prevented the intestinal alterations observed. These findings suggest that diabetes is associated with an abnormal BMP/Smad signaling expression in the myenteric ganglia that affects the homeostasis of the enteric plexus

Kinetics of urinary cell cycle arrest markers for acute kidney injury following exposure to potential renal insults

Objectives:Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 predict the development of acute kidney injury following renal insults of varied aetiology. To aid clinical interpretation, we describe the kinetics of biomarker elevations around an exposure. Design:In an ancillary analysis of the multicenter SAPPHIRE study, we examined the kinetics of the urinary [tissue inhibitor of metalloproteinase-2]•[insulin-like growth factor binding protein 7] in association with exposure to common renal insults (major surgery, IV radiocontrast, vancomycin, nonsteroidal anti-inflammatory drugs, and piperacillin/tazobactam). Setting:Thirty-five sites in North America and Europe between September 2010 and June 2012. Patients:Seven hundred twenty-three critically ill adult patients admitted to the ICU. Interventions: None. Measurements and Main Results:We compared the urinary [tissue metalloproteinase-2]•[insulin growth factor binding protein 7] kinetics from the day prior to exposure up to 5 days after exposure in patients developing acute kidney injury stage 2–3, stage 1, or no acute kidney injury by Kidney Disease Improving Global Outcome criteria. Among the 723 patients, 679 (94%) had at least one, 70% had more than one, and 35% had three or more exposures to a known renal insult. There was a significant association between cumulative number of exposures up to study day 3 and risk of acute kidney injury (p = 0.02) but no association between the specific type of exposure and acute kidney injury (p = 0.22). With the exception of radiocontrast, patients who developed acute kidney injury stage 2–3 after one of the five exposures, had a clear rise and fall of urinary [tissue inhibitor of metalloproteinase-2]•[insulin-like growth factor binding protein 7] from the day of exposure to 24–48 hours later. In patients without acute kidney injury, there was no significant elevation in urinary [tissue inhibitor of metalloproteinase-2]•[insulinlike growth factor binding protein 7]. Conclusions:Exposure to potential renal insults is common. In patients developing acute kidney injury stage 2–3, the kinetics of urinary [tissue inhibitor of metalloproteinase-2]•[insulin-like growth factor binding protein 7] matched the exposure except in the case of radiocontrast.</p

Common PIEZO1 Allele in African Populations Causes RBCDehydration and Attenuates Plasmodium Infection

Host-parasite interactio

Colonic Dendritic Cells, Intestinal Inflammation, and T Cell-Mediated Bone Destruction Are Modulated by Recombinant Osteoprotegerin

AbstractAutoimmune associated bone disease and intestinal inflammation are closely linked with deregulation and hyperactivation of autoreactive CD4 T cells. How these T cells are activated and mediate disease is not clear. Here we show that in the Interleukin 2-deficient mouse model of autoimmunity spontaneous osteopenia and colitis are caused by increased production of the ligand for receptor activator of NFκB (RANKL). RANKL acting via its receptor, receptor activator of NFκB (RANK), increases bone turnover and promotes intestinal dendritic cell (DC) survival in vivo. Modulation of RANKL-RANK interactions with exogenous recombinant osteoprotegerin (Fc-OPG) reverses skeletal abnormalities and reduces colitis by decreasing colonic DC numbers. This study identifies a common causal link between bone disease and intestinal inflammation and establishes the importance of DC in mediating colonic inflammation in vivo

Control of uterine Ca2+ by membrane voltage toward understanding the excitation-contraction coupling in human myometrium

Myometrial contractility is a complex and dynamic physiological process that changes substantially during pregnancy and culminates in childbirth. Uterine contractions are initiated by transient rises in cytoplasmic Ca2+ concentration ([Ca2+](i)),which in turn are triggered and controlled by myometrial action potentials. The sequence of events between the action potential generation and the contraction initiation is referred to as excitation-contraction coupling. Hormones and other physiologically active substances affect myometrial contractility by modulating different steps in the excitation-con traction coupling process. It is therefore imperative that we understand that process to understand the regulation of myometrial contractility. The complex action potentials generated by human myometrium result from the activity of many ion channels, transporters, and pumps. Two types of myometrial action potential waveform have been described in the literature: a plateau type and a spike type. Parameters of the myometrial [Ca2+](i) transients and contractions differ depending on the type of action potential that triggers them. Some aspects of the excitation-contraction coupling are unique to human myometrium and cannot be found in animal models; some others are common between many species. This article reviews the current state and discusses future directions of physiological research on human myometrial excitation-contraction coupling