Deregulated neddylation in liver fibrosis.

Hepatic fibrosis is a global health problem currently without effective therapeutic approaches. Even though the ubiquitin-like posttranslational modification of neddylation, that conjugates Nedd8 (neural precursor cell expressed developmentally downregulated) to specific targets, is aberrant in many pathologies, its relevance in liver fibrosis (LF) remained unexplored. Our results show deregulated neddylation in clinical fibrosis and both in mouse bileductligation- and CCl4 -induced fibrosis. Importantly, neddylation inhibition, by using the pharmacological inhibitor, MLN4924, reduced liver injury, apoptosis, inflammation, and fibrosis by targeting different hepatic cell types. On one hand, increased neddylation was associated with augmented caspase 3 activity in bile-acid-induced apoptosis in mouse hepatocytes whereas neddylation inhibition ameliorated apoptosis through reduction of expression of the Cxcl1 and Ccl2 chemokines. On the other hand, chemokine receptors and cytokines, usually induced in activated macrophages, were reduced after neddylation inhibition in mouse Kupffer cells. Under these circumstances, decreased hepatocyte cell death and inflammation after neddylation inhibition could partly account for reduction of hepatic stellate cell (HSC) activation. We provide evidence that augmented neddylation characterizes activated HSCs, suggesting that neddylation inhibition could be important for resolving LF by directly targeting these fibrogenic cells. Indeed, neddylation inhibition in activated HSCs induces apoptosis in a process partly mediated by accumulation of c-Jun, whose cullin-mediated degradation is impaired under these circumstances. CONCLUSION: Neddylation inhibition reduces fibrosis, suggesting neddylation as a potential and attractive therapeutic target in liver fibrosis. (Hepatology 2017;65:694-709).

COX2 expression and Erk1/Erk2 activity mediate Cot-induced cell migration.

The MAPKKK8 Cot/tpl-2, identified as an oncogene (Cot-T), participates in the intracellular signaling activated by members of the TLR and TNFalpha receptor superfamilies. Here we demonstrate that Cot promotes cell migration by regulating different steps involved in this process, such as cell adhesion and metalloproteinase activity. Indeed, Cot also regulates the cytoskeleton and Cot-T overexpression provokes the polarization of microtubules and the loss of stress fibers. Moreover, and in accordance with the increased Rac-GTP levels observed, Cot-T overexpressing cells develop more lamellipodia than control cells. Conversely, depletion of endogenous Cot increases the formation of stress fibers which is correlated with the high levels of Rho-GTP observed in these cells. In addition, the increase in COX2 expression and the activation of Erk1/2 regulated by Cot are essential for the induction of cell migration. Together, these data provide evidence of a new role for both proto-oncogenic and oncogenic Cot.

Changes in lipid profile after biliopancreatic diversion.

BACKGROUND: Bariatric operations have varying degrees of effectiveness and different mechanisms of action. Our objective was to evaluate the efficacy of the biliopancreatic diversion (BPD) in reduction of weight and serum lipids. METHODS: A prospective study was conducted with follow-up from 12 to 72 months (average 39.4 months) of 58 patients with morbid obesity (10 men, 48 women, mean BMI 49.4 kg/m2). Their lipid levels were generally normal or slightly high. All the patients were subjected to subtotal gastrectomy and BPD with jejunoileostomy 50 cm proximal to the ileocecal valve, and they were instructed to maintain the same hypocaloric diet as before BPD. Serum lipoproteins and apolipoproteins B and A1 were measured before BPD and every 6 months during follow-up. RESULTS: Early and very significant reduction (P<0.001) of total cholesterol (32.8%), LDL (46.3%), total cholesterol/HDL ratio (29.7%) and apolipoprotein B (37%), with more moderate decrease of triglycerides (21.3%, P=0.004), were observed. This lipid decrease was maximum at 1 year after BPD. Important and persistent weight reduction that did not correlate with changes in lipids was observed. The youngest patients and those with high basal lipid levels proved to benefit most from BPD. There were no important side-effects. CONCLUSION: BPD, with careful selection of patients, is a well tolerated procedure that offers excellent results in the short- and mid-term in reduction in weight and blood levels of most atherogenic lipoproteins.

Ultrasonic value is not useful to detect bone changes following a biliopancreatic diversion.

To study the evolution of the bone mass by ultrasonic transmission after biliopancreatic diversion. Forty eight morbid obese patients were prospectively studied during 36 months following the Larrad biliopancreatic diversion. The bone metabolism was studied by PTHi and the urinary pirydinolines. The bone mass by echography and bone densitometry, which correlate to the levels of PTHi and pyridinolines. After 3 years the bone mass decreased from 50.15 +/- 7.31 kg/m(2), preoperatively, to 34.03 +/- 4.53 kg/m2 (p < 0.001). There was an increase of the PTHi value (from 71.4 +/- 79.6 to 91.65 +/- 43.06 pg/ml) (p = 0.01), and the urinary pirydinolines (from 7.93 +/- 4.06 an 11.4 +/- 10.12 nM/mM) (p < 0.05). The ultrasonic transmission speed increased (from 1,990.93 +/- 62.38 to 2,035.25 +/- 53.98 m/s). However, the bone mineral content (BMC) did not show changes (from 3,016.5 +/- 562.8 to 2,909.6 +/- 304.2 g), as well as the Bone Mineral Density (BMD) (of 1,174.2 +/- 98.8 g/cm2). Neither correlation was found between the BMD (r = 0.212; p = 0.6), the BMC (r =-0.125; p = 0.768), and the T-score (r = 0.592, p = 0.093). The study of the bone mass through ultrasonic transmission speed revealed low sensitivity during the assessment of the morbid obese patients. A percentage of cases of osteopenia were observed despite the fact that they are not reflected in the bone content or in the bone mass. Ultrasonic evaluation of bone mass has no value in the morbidly obese, by the clear negative correlation between ultrasound velocity and thickness of soft tissue.