Blankenshipvinding8064

Despite the crucial role of glucocorticoid receptor (GR) in proper immune responses, the effect of GR hypersensitivity on inflammation is rarely reported. To fill this knowledge gap, we exploited the natural gain-of-function substitution in the porcine glucocorticoid receptor (GRAla610Val) and challenged pigs carrying normal or hypersensitive GR using 50 µg/kg lipopolysaccharide (LPS) following pretreatment with either saline or single bolus of 60 µg/kg dexamethasone (DEX). The GRAla610Val substitution reduced baseline cortisol, adrenocorticotropic hormone (ACTH), and triglyceride concentration and granulocyte proportion whereas baseline platelet counts were elevated. Val-carriers, i.e. AlaVal as well as ValVal pigs, showed less LPS-induced cortisol rise but the cortisol fold change was similar in all genotypes. Differently, ACTH response to LPS was most significant in GRAla610Val heterozygotes (AlaVal). LPS-induced disorders, including sickness behaviors, anorexia, thrombocytopenia, cytokine production, and metabolic alterations were more intense in Val-carriers. On the other hand, Val-carriers were more sensitive to DEX effect than wild types (AlaAla) during endotoxemia, but not under unchallenged conditions. This is the first report revealing aggravated responses to endotoxemia by GR gain-of-function. Tofacitinib chemical structure Together, these results imply that GR hypersensitivity is difficult to diagnose but may represent a risk factor for endotoxemia and sepsis.Aberrant microRNA expression implicates on hepatocellular carcinoma (HCC) development. Conversely, coffee consumption reduces by ~40% the risk for fibrosis/cirrhosis and HCC, while decaffeinated coffee does not. It is currently unknown whether these protective effects are related to caffeine (CAF), or to its combination with other common and/or highly bioavailable coffee compounds, such as trigonelline (TRI) and chlorogenic acid (CGA). We evaluated whether CAF individually or combined with TRI and/or CGA alleviates fibrosis-associated hepatocarcinogenesis, examining the involvement of miRNA profile modulation. Then, male C3H/HeJ mice were submitted to a diethylnitrosamine/carbon tetrachloride-induced model. Animals received CAF (50 mg/kg), CAF+TRI (50 and 25 mg/kg), CAF+CGA (50 and 25 mg/kg) or CAF+TRI+CGA (50, 25 and 25 mg/kg), intragastrically, 5×/week, for 10 weeks. Only CAF+TRI+CGA combination reduced the incidence, number and proliferation (Ki-67) of hepatocellular preneoplastic foci while enhanced apoptosis (cleaved caspase-3) in adjacent parenchyma. CAF+TRI+CGA treatment also decreased hepatic oxidative stress and enhanced the antioxidant Nrf2 axis. CAF+TRI+CGA had the most pronounced effects on decreasing hepatic pro-inflammatory IL-17 and NFκB, contributing to reduce CD68-positive macrophage number, stellate cell activation, and collagen deposition. In agreement, CAF+TRI+CGA upregulated tumor suppressors miR-144-3p, miR-376a-3p and antifibrotic miR-15b-5p, frequently deregulated in human HCC. CAF+TRI+CGA reduced the hepatic protein levels of pro-proliferative EGFR (miR-144-3p target), antiapoptotic Bcl-2 family members (miR-15b-5p targets), and the number of PCNA (miR-376a-3p target) positive hepatocytes in preneoplastic foci. Our results suggest that the combination of most common and highly bioavailable coffee compounds, rather than CAF individually, attenuates fibrosis-associated hepatocarcinogenesis by modulating miRNA expression profile.Obese subjects of all ages and sex have reduced plasma SHBG levels. Whether these low plasma SHBG levels play a role in obesity development is unknown. In the present work we wanted to explore if SHBG overexpression could prevent obesity development induced by high fat diet (HFD). To do so, we fed humanized SHBG transgenic male mice and their wild-type littermates with control diet (CD) or HFD over the course of 8 weeks. The results showed that SHBG overexpression protected against body weight gain and fat accumulation induced by HFD. In addition, SHBG overexpression also abrogated the increase in insulin, leptin and resistin levels, as well as the reduction in adiponectin, induced by HFD. Mechanistically, the SHBG protection against HFD-induced obesity was achieved by stimulating lipolysis in white adipose tissue. Furthermore, we have demonstrated the SHBG cell-autonomous effect using human primary visceral adipocytes. Taking together, our results demonstrate that SHBG overexpression protects against diet-induced obesity and improves the metabolic profile of male mice fed a HFD diet.

To describe a dedicated technique used in fenestrated endografting (FEVAR) for juxtarenal aneurysm (JAAA) to avoid intraoperative bridging stentgraft crushing in case of adjacent origin of left renal (LRA) and superior mesenteric (SMA) artery.

A 78-year-old male, at high surgical risk, underwent FEVAR for JAAA. SMA and LRA fenestrations were adjacent, at 1230 and 245 o'clock evaluation, respectively. The fenestrated endograft and the bridging stentgrafts for target visceral vessels (TVVs) were deployed without complications. The completion angiography and the cone-beam CT showed patency of TVVs, except for LRA, which showed crushing of its stentgraft. SMA and LRA were re-cannulated, and the renal stentgraft was dilated with a 4×40mm balloon. Finally, "Flaring-Kissing ballooning" of SMA and LRA stentgrafts was performed using two 10×20mm balloon under fluoroscopy rotational guidance, to ensure the patency of both arteries. The completion angiography and the postoperative CT-angiography showed the resolution of the crushing and the patency of TVVs. The postoperative course was uneventful; the patient was discharged home after 5 days. CT-angiography at 12months showed patency of TVVs and no endoleaks.

The "Flaring-Kissing ballooning" of adjacent stentgrafts is a valid, safe and effective intra-procedural maneuver to preserve the patency of the TVVs.

The "Flaring-Kissing ballooning" of adjacent stentgrafts is a valid, safe and effective intra-procedural maneuver to preserve the patency of the TVVs.

Commonly, but not exclusively, the celiac trunk (CT) trifurcates into the left gastric (LGA), common hepatic (CHA) and splenic (SA) arteries. Additional branches of the CT are scarcely reported in the literature. Less than ten reports were found presenting patterns of pentafurcation of the CT (pCT), all being resulted after anatomic dissections.

We hereby report such a rare pCT, which was found on the computed tomography angiograms of a 71-year-old female patient.

From that pCT were branching off three collateral branches, two ascending and one descending, and two terminal branches. The ascending ones were the left inferior phrenic artery and a secondary hepatogastric trunk, further divided into a replaced left hepatic artery and the left gastric artery. The dorsal pancreatic artery was the descending collateral branch of the pCT. The pCT ended by dividing into the CHA and SA. The CHA reached the anterior side of the portal vein to divide into the gastroduodenal and right hepatic arteries. An accessory right hepatic artery left the superior mesenteric artery (SMA) and ascended posterior to the portal vein.