The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model

Background: The farnesoid X receptor (FXR) influences hepatic metabolism, inflammation and liver fibrosis as key components of non-alcoholic steatohepatitis (NASH). We studied the effects of the non-steroidal FXR agonist cilofexor (formerly GS-9674) on portal pressure and fibrosis in experimental NASH. Methods: NASH was induced in Wistar rats using a choline-deficient high-fat diet plus intraperitoneal sodium nitrite injections. First, a dose-finding study was performed with 10 mg/kg and 30 mg/kg of cilofexor, focusing on histological readouts. Liver fibrosis was assessed by Picro-Sirius-Red, desmin staining and hepatic hydroxyproline content. Gene expression was determined by RT-PCR. In a subsequent hemodynamic study, rats received 30 mg/kg cilofexor with or without propranolol (25 mg/kg). Portal pressure, systemic hemodynamics and splanchnic blood flow were measured. Results: Cilofexor dose-dependently induced FXR target genes shp, cyp7a1 and fgf15 in hepatic and ileal tissues, paralleled by a dose-dependent reduction in liver fibrosis area (Picro-Sirius-Red) of −41% (10 mg/kg) and −69% (30 mg/kg), respectively. The 30 mg/kg cilofexor dose significantly reduced hepatic hydroxyproline content (−41%), expression of col1a1 (−37%) and pdgfr-β (−36%), as well as desmin area (−42%) in NASH rats. Importantly, cilofexor decreased portal pressure (11.9 ± 2.1 vs. 8.9 ± 2.2 mmHg; p = 0.020) without affecting splanchnic blood-flow or systemic hemodynamics. The addition of propranolol to cilofexor additionally reduced splanchnic inflow (−28%) but also mean arterial pressure (−25%) and heart rate (−37%). Conclusion: The non-steroidal FXR agonist cilofexor decreased portal hypertension and reduced liver fibrosis in NASH rats. While cilofexor seems to primarily decrease sinusoidal resistance in cirrhotic portal hypertension, the combination with propranolol additionally reduced mesenteric hyperperfusion

Effects of Salt Stress on Three Ecologically Distinct Plantago Species

Comparative studies on the responses to salt stress of taxonomically related taxa should help to elucidate relevant mechanisms of stress tolerance in plants. We have applied this strategy to three Plantago species adapted to different natural habitats, P. crassifolia and P. coronopus both halophytes and P. major, considered as salt-sensitive since it is never found in natural saline habitats. Growth inhibition measurements in controlled salt treatments indicated, however, that P. major is quite resistant to salt stress, although less than its halophytic congeners. The contents of monovalent ions and specific osmolytes were determined in plant leaves after four-week salt treatments. Salt-treated plants of the three taxa accumulated Na+ and Cl- in response to increasing external NaCl concentrations, to a lesser extent in P. major than in the halophytes; the latter species also showed higher ion contents in the non-stressed plants. In the halophytes, K+ concentration decreased at moderate salinity levels, to increase again under high salt conditions, whereas in P. major K+ contents were reduced only above 400 mM NaCl. Sorbitol contents augmented in all plants, roughly in parallel with increasing salinity, but the relative increments and the absolute values reached did not differ much in the three taxa. On the contrary, a strong (relative) accumulation of proline in response to high salt concentrations (600 800 mM NaCl) was observed in the halophytes, but not in P. major. These results indicate that the responses to salt stress triggered specifically in the halophytes, and therefore the most relevant for tolerance in the genus Plantago are: a higher efficiency in the transport of toxic ions to the leaves, the capacity to use inorganic ions as osmotica, even under low salinity conditions, and the activation, in response to very high salt concentrations, of proline accumulation and K+ transport to the leaves of the plants.MAH was a recipient of an Erasmus Mundus pre-doctoral scholarship financed by the European Commission (Welcome Consortium). AP acknowledges the Erasmus mobility programme for funding her stay in Valencia to carry out her Master Thesis.Al Hassan, M.; Pacurar, AM.; López Gresa, MP.; Donat Torres, MDP.; Llinares Palacios, JV.; Boscaiu Neagu, MT.; Vicente Meana, Ó. (2016). Effects of Salt Stress on Three Ecologically Distinct Plantago Species. PLoS ONE. 11(8):1-21. doi:10.1371/journal.pone.0160236S12111

Spermidine affects the transcriptome responses to high temperature stress in ripening tomato fruit* #

Objective: High temperature adversely affects quality and yield of tomato fruit. Polyamine can alleviate heat injury in plants. This study is aimed to investigate the effects of polyamine and high temperature on transcriptional profiles in ripening tomato fruit. Methods: An Affymetrix tomato microarray was used to evaluate changes in gene expression in response to exogenous spermidine (Spd, 1 mmol/L) and high temperature (33/27 °C) treatments in tomato fruits at mature green stage. Results: Of the 10 101 tomato probe sets represented on the array, 127 loci were differentially expressed in high temperature-treated fruits, compared with those under normal conditions, functionally characterized by their involvement in signal transduction, defense responses, oxidation reduction, and hormone responses. However, only 34 genes were up-regulated in Spd-treated fruits as compared with non-treated fruits, which were involved in primary metabolism, signal transduction, hormone responses, transcription factors, and stress responses. Meanwhile, 55 genes involved in energy metabolism, cell wall metabolism, and photosynthesis were down-regulated in Spd-treated fruits. Conclusions: Our results demonstrated that Spd might play an important role in regulation of tomato fruit response to high temperature during ripening stage