Insulin deprivation decreases insulin degrading enzyme levels in primary cultured cortical neurons and in the cerebral cortex of rats with streptozotocin-induced diabetes

Background

Many studies have indicated a relationship between diabetes and Alzheimer’s disease (AD). However, the molecular mechanism underlying this association has not been clarified. Among several factors, insulin degrading enzyme (IDE), which plays roles in the degradation of both insulin and amyloid β (Aβ), has gained interest as a potential target in efforts to solve this puzzle. This study sought to examine the effects of varying insulin and/or glucose concentrations on IDE expression.

β‐adrenergic Receptor Blocker ICI 118,551 Selectively Increases Intermediate‐Conductance Calcium‐Activated Potassium Channel (IKCa)‐Mediated Relaxations in Rat Main Mesenteric Artery

Endothelial IK_Ca and/or SK_Ca channels play an important role in the control of vascular tone by participating in endothelium‐dependent relaxation. Whether β‐AR antagonists, mainly used in hypertension, affect endothelial K_Ca channel function is unknown. In this study, we examined the effect of the β2‐AR antagonist and inverse agonist ICI 118,551 on the IK_Ca/SK_Ca channel activity by assessing functional relaxation responses to several agonists that stimulate these channels. Mesenteric arterial rings isolated from male Sprague Dawley mounted to organ baths. Acetylcholine elicited IK_Ca‐ and SK_Ca‐mediated relaxations that were abolished by TRAM‐34 and apamin, respectively. ICI 118,551, which did not dilate the arteries per se, increased the IK_Ca‐mediated relaxations, whereas SK_Ca‐mediated relaxations remained unaltered. Same potentiating effect was also detected on the IK_Ca‐mediated relaxations to carbachol and A23187, but not to NS309. Neither acetylcholine‐induced nitric oxide‐mediated relaxations nor SNP relaxations changed with ICI 118,551. The PKA inhibitor KT‐5720, the selective β2‐AR agonist salbutamol, the selective β2‐AR antagonist butoxamine, the non‐selective β‐AR antagonist propranolol, and the inverse agonists carvedilol or nadolol failed to affect the IK_Ca‐mediated relaxations. ICI 118,551‐induced increase was not reversed by salbutamol or propranolol as well. Besides, low potassium‐induced relaxations in endothelium‐removed arteries remained the same in the presence of ICI 118,551. These data demonstrate a previously unrecognized action of ICI 118,551, the ability to potentiate endothelial IK_Ca channel‐mediated vasodilation, through a mechanism independent of β2‐AR antagonistic or inverse agonistic action. Instead, the enhancement of acetylcholine relaxation seems likely to occur by a mechanism secondary to endothelial calcium increase.     

Protective Effect of Gymnema sylvestre Ethanol Extract on High Fat Diet-induced Obese Diabetic Wistar Rats

Obesity is associated with numerous co-morbidities such as cardiovascular diseases, type 2 diabetes, hypertension and others. Therefore, the present study was planned to investigate the effect of water- soluble fraction of Gymnema sylvestre ethanol extract on biochemical and molecular alterations in obese diabetic rats. Diabetes was induced by single i.v. injection of streptozotocin (45 mg/kg) via tail vein. Obesity was induced by oral feeding of high fat diet for a period of 28 days in diabetic rats. Body weight gain, food intake, water intake, hemodynamic parameters (systolic, diastolic, mean arterial blood pressures and heart rate), serum biochemical parameters (leptin, insulin, lipid levels, apolipoprotein B and glucose), cardiomyocyte apoptosis (cardiac caspase-3, Na⁺/K⁺ ATPase activity and DNA fragmentation) organs and visceral fat pad weight and oxidative stress parameters were measured. Oral treatment with water soluble fraction of Gymnema sylvestre ethanol extracts (120 mg/kg/p.o.) for a period of 21 days, resulted in significant reduction in heart rate, mean arterial pressure, serum leptin, insulin, apolipoprotein B, lipids, glucose, cardiac caspase-3 levels, Na⁺/K⁺ ATPase activity and DNA laddering, visceral fat pad and organ''s weight and improved the antioxidant enzymes levels in the high fat diet induced obesity in diabetic rats. The results of present study reveal that water soluble fraction of Gymnema sylvestre ethanol extract could be useful intervention in the treatment of obesity and type-2 diabetes mellitus.     

Proteomic analysis of RAW macrophages treated with cGAMP or c-di-GMP reveals differentially activated cellular pathways

Global and quantitative analysis of the proteome help to reveal how host cells sense invading bacteria and respond to bacterial signaling molecules. Here, we performed label free quantitative proteomic analysis of RAW macrophages treated with host-derived cGAMP and bacterial-derived c-di-GMP, in an attempt to identify cellular pathways impacted by these dinucleotides and determine if the host responds differentially to these two cyclic dinucleotides. We identified a total of 3811 proteins of which abundances of 404 proteins in cGAMP and 236 proteins in c-di-GMP treated cells were significantly different compared to the control. Many of the proteins that were strongly and commonly upregulated, such as interferon-induced proteins 47, 202 and 204 (Ifi47, Ifi202, Ifi204), ubiquitin-activating enzyme E7 (Uba7), interferon-induced protein with tetratricopeptide repeats 1, 2 or 3 (Ifit1, Ifit2, Ifit3), ubiquitin-like protein ISG15 (ISG15), might be due to the fact that both dinucleotides promote the production of interferons, which induce the expression of many proteins. However, there were also other proteins that were differentially affected by cGAMP or c-di-GMP treatment, including probable ATP-dependent RNA helicase DHX58 (Dhx58), nuclear autoantigen Sp-100 (Sp100), MARCKS-related protein (Marcksl1) and antigen peptide transporter 2 (Tap2). This is probably due to the differential levels of IFNs produced by the dinucleotides or may indicate that non-STING activation might also contribute to the host''s response to c-di-GMP and cGAMP. Interestingly Trex1, a nuclease that degrades DNA (an activator of cGAS to produce cGAMP), was upregulated (3.22 fold) upon cGAMP treatment, hinting at a possible feedback loop to regulate cGAMP synthesis. These results lay a foundation for future studies to better characterize and understand the complex c-di-GMP and cGAMP signaling network.

cGAMP modulates proteins involved in antigen presentation and inflammation.     

Genetic System of Artemisia maritima L.: An Overexploited Medicinal Species Under Stress

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Artemisia maritima L., a potent source of Santonin (a drug used to expel roundworms), forms isolated...     

Review of stoma site and midline incisional hernias after stoma reversal

Background

The incidence of incisional hernias after stoma reversal is not well reported. The aim of this study was to systematically review the literature reporting data on incisional hernias after stoma reversal. We evaluated both the incidence of stoma site and midline incisional hernias.

Methods

A systematic review identified studies published between January 1, 1980, and December 31, 2012, reporting the incidence of incisional hernia after stoma reversal at either the stoma site or at the midline incision (in cases requiring laparotomy). Pediatric studies were excluded. Assessment of risk of bias, detection method, and essential study-specific characteristics (follow-up duration, stoma type, age, body mass index, and so forth) was done.

Results

Sixteen studies were included in the analysis; 1613 patients had 1613 stomas formed. Fifteen studies assessed stoma site hernias and five studies assessed midline incisional hernias. The median (range) incidence of stoma site incisional hernias was 8.3% (range 0%–33.9%) and for midline incisional hernias was 44.1% (range 8.7%–58.1%). When evaluating only studies with a low risk of bias, the incidence for stoma site incisional hernias is closer to one in three and for midline incisional hernias is closer to one in two.

Conclusion

Stoma site and midline incisional hernias are significant clinical complications of stoma reversals. The quality of studies available is poor and heterogeneous. Future prospective randomized controlled trials or observational studies with standardized follow-up and outcome definitions/measurements are needed.     

Safe Zone for Superolateral Entry Pin Into the Distal Humerus in Children: An MRI Analysis

Background

The radial nerve is at risk for iatrogenic injury during placement of pins, screws, or wires around the distal humerus. Unlike adults, detailed anatomic information about the relationship of the nerve to the distal humerus is lacking in children.

Question/purposes

This study evaluates the relationship of the radial nerve to the distal humerus in a pediatric population on conventional MRI and proposes an anatomic safe zone using easily identifiable bony landmarks on an AP elbow radiograph.

Methods

To determine the course of the radial nerve at the lateral distal humerus, we reviewed 23 elbow radiographs and MRIs of 22 children (mean age, 9 ± 4 years; range, 3–12 years) obtained as part of their workup for various elbow conditions. We described a technique using distance ratios calculated as a percentage of the patient’s own transepicondylar distance, defined as the distance measured between the apices of the medial and lateral epicondyles, on the AP elbow radiograph and the midcoronal MR image. The cross-reference tool on a Picture Archiving and Communication System was then used to identify axial MR image at the level where the transepicondylar distance was measured. On this axial image, a line was drawn connecting the medial and lateral epicondyles (the transepicondylar axis) and its midpoint was determined. The radial nerve angle was measured by a line from the radial nerve to the midpoint of the transepicondylar axis and a line along the lateral half of the transepicondylar axis. On this axial slice, the closest distance from the nerve to the underlying cortex of the distal humerus was measured. To further localize the nerve along the distal humerus, predetermined percentages of the transepicondylar distance were projected proximally from the level of the transepicondylar axis along the longitudinal axis of the humerus on the midcoronal MR image. At these designated heights, the corresponding axial MR image was identified using the cross-reference tool and the nerve was mapped in a similar fashion. We then proposed a simpler method using a best-fit line drawn along the lateral supracondylar ridge on the AP radiograph to define the safe zone for lateral pin entry.

Results

On axial MR images, the radial nerve was located in the anterolateral quadrant with a mean radial nerve angle of 54° (range, 35°–87) at 0% transepicondylar distance (23 MRIs), 41° (range, 24°–63°) at 50% transepicondylar distance (23 MRIs), and ≥ 10° at 75% transepicondylar distance (on the 13 MRIs that extended this far cephalad). The mean closest distance between the radial nerve and the underlying humeral cortex was 10 mm (range, 3–26 mm) at 0% transepicondylar distance and 7 mm (3–16 mm) at 50% transepicondylar distance. On the AP elbow radiograph, the height of the lateral supracondylar ridge, determined by a best-fit line drawn along the lateral cortex of the ridge, diverged from the most proximal extent of the ridge at a point located at 60% transepicondylar distance (range, 51%–76%). At the corresponding location on the axial MR image, the nerve was located anterolaterally with a mean radial nerve angle of 39° (range, 15°–61°) and a mean distance of 6 mm (range, 2–10 mm) from the underlying humerus.

Conclusions

Our data suggest that percutaneous direct lateral entry Kirschner wires and half-pins can be safely inserted in the distal humerus in children along the transepicondylar axis, either at or slightly posterior to the lateral supracondylar ridge, when placed caudal to the point located where the lateral supracondylar ridge line diverges from the proximal extent of the supracondylar ridge on AP elbow radiograph.