Vismodegib Suppresses TRAIL-mediated Liver Injury in a Mouse Model of Nonalcoholic Steatohepatitis

Hedgehog signaling pathway activation has been implicated in the pathogenesis of NASH. Despite this concept, hedgehog pathway inhibitors have not been explored. Thus, we examined the effect of vismodegib, a hedgehog signaling pathway inhibitor, in a diet-induced model of NASH. C57BL/6 mice were placed on 3-month chow or FFC (high saturated fats, fructose, and cholesterol) diet. One week prior to sacrifice, mice were treated with vismodegib or vehicle. Mice fed the FFC diet developed significant steatosis, which was unchanged by vismodegib therapy. In contrast, vismodegib significantly attenuated FFC-induced liver injury as manifested by reduced serum ALT and hepatic TUNEL-positive cells. In line with the decreased apoptosis, vismodegib prevented FFC-induced strong upregulation of death receptor DR5 and its ligand TRAIL. In addition, FFC-fed mice, but not chow-fed animals, underwent significant liver injury and apoptosis following treatment with a DR5 agonist; however, this injury was prevented by pre-treatment with vismodegib. Consistent with a reduction in liver injury, vismodegib normalized FFC-induced markers of inflammation including mRNA for TNF-α, IL-1β, IL-6, monocyte chemotactic protein-1 and a variety of macrophage markers. Furthermore, vismodegib in FFC-fed mice abrogated indices of hepatic fibrogenesis. In conclusion, inhibition of hedgehog signaling with vismodegib appears to reduce TRAIL-mediated liver injury in a nutrient excess model of NASH, thereby attenuating hepatic inflammation and fibrosis. We speculate that hedgehog signaling inhibition may be salutary in human NASH.     

Competition and overlap of Oryzaephilus surinamensis and Plodia interpunctella populations under condition of stored date fruits

Plodia interpunctella and Oryzaephilus surinamensis are found in food storehouses including dates and palm storages. The current study aimed to determine competition and overlap potentials of the two pests of date fruits. Time series models were used to study two species populations and logistic growth model to estimate the effect of density of the species. The results revealed the environmental capacities of O. surinamensis and P. interpunctella were 433 and 1610 (maximum number per 20 g), respectively, and the population growth rates (r) were 1.2 and 1.3, respectively. Ecological balances of the two species were close to each other from the first to the third week. The population of O. surinamensis decreased in the fourth week of the competition. The highest population balance of the two species was in the 14th week. The potential of exploitable ecological niches (e_ij) and the amount of non-exploited ecological niches by any species (z_ij) for O. surinamensis was higher than for P. interpunctella from the 8th week untill the end of sampling period. The overlap of ecological niches in the two species (D) ranged from 0.94 to 1, indicating a complete overlap of temporal activity in the two populations on date palm. The current results of this study can be used by integrated pest management specialists. Information over the effects of species competition on population dynamics and their coexistence can be used to predict population status and to adopt simple pest control methods.     

ReviewIsoprostanes: Novel Bioactive Products of Lipid Peroxidation

Isoprostanes, are a novel group of prostaglandin-like compounds that are biosynthesised from esterified polyunsaturated fatty acid (PUFA) through a non-enzymatic free radical-catalysed reaction. Several of these compounds possess potent biological activity, as evidenced mainly through their pulmonary and renal vasoconstrictive effects, and have short half-lives. It has been shown that isoprostanes act as full or partial agonists through thromboxane receptors. Both human and experimental studies have indicated associations of isoprostanes and severe inflammatory conditions, ischemia-reperfusion, diabetes and atherosclerosis. Reports have shown that F²-isoprostanes are authentic biomarkers of lipid peroxidation and can be used as potential in vivo indicators of oxidant stress in various clinical conditions, as well as in evaluations of antioxidants or drugs for their free radical-scavenging properties.

Higher levels of F²-isoprostanes have been found in the normal human pregnancy compared to non-pregnancy, but their physiological role has not been well studied so far. Since bioactive F²-isoprostanes are continuously formed in various tissues and large amounts of these potent compounds are found unmetabolised in their free acid form in the urine in normal basal conditions with a wide inter-individual variation, their role in the regulation of normal physiological functions could be of further biological interest, but has yet to be disclosed. Their potent biological activity has attracted great attention among scientists, since these compounds are found in humans and animals in both physiological and pathological conditions and can be used as reliable biomarkers of lipid peroxidation.     

A novel epidermal growth factor receptor-signaling platform and its targeted translation in pancreatic cancer

Epidermal growth factor (EGF)-induced EGFR tyrosine kinase receptor activation in cancer cell survival responses has become a strategic molecular-targeting clinical therapeutic intent, but the failures of these targeted approaches in the clinical setting demand alternate strategies. Here, we uncover a novel neuraminidase-1 (Neu1) and matrix metalloproteinase-9 (MMP-9) cross-talk in alliance with GPCR neuromedin B, which is essential for EGF-induced receptor activation and cellular signaling. Neu1 and MMP-9 form a complex with EGFR on the cell surface. Tamiflu (oseltamivir phosphate), anti-Neu1 antibodies, broad range MMP inhibitor galardin (GM6001), neuromedin B GPCR specific antagonist BIM-23127, the selective inhibitor of whole heterotrimeric G-protein complex BIM-46174 and MMP-9 specific inhibitor dose-dependently inhibited Neu1 activity associated with EGF stimulated 3T3–hEGFR cells. Tamiflu, anti-Neu1 antibodies and MMP9i attenuated EGFR phosphorylation associated with EGF-stimulated cells. Preclinical data provide the proof-of-evidence for a therapeutic targeting of Neu1 with Tamiflu in impeding human pancreatic cancer growth and metastatic spread in heterotopic xenografts of eGFP-MiaPaCa-2 tumors growing in RAGxCγ double mutant mice. Tamiflu-treated cohort exhibited a reduction of phosphorylation of EGFR-Tyr1173, Stat1-Tyr701, Akt-Thr308, PDGFRα-Tyr754 and NFκBp65-Ser311 but an increase in phospho-Smad2-Ser465/467 and -VEGFR2-Tyr1175 in the tumor lysates from the xenografts of human eGFP-MiaPaCa-2 tumor-bearing mice. The findings identify a novel promising alternate therapeutic treatment of human pancreatic cancer.     

Field estimates of fitness costs of the pace‐of‐life in an endangered damselfly

Theory predicts that within‐population differences in the pace‐of‐life can lead to cohort splitting and produce marked intraspecific variation in body size. Although many studies showed that body size is positively correlated with fitness, many argue that selection for the larger body is counterbalanced by opposing physiological and ecological selective mechanisms that favour smaller body. When a population split into cohorts with different paces of life (slow or fast cohort), one would expect to detect the fitness–size relationship among and within cohorts, that is, (a) slower‐developing cohort has larger body size and higher fitness than faster‐developing cohort, and (b) larger individuals within each cohort show higher fitness than smaller individuals. Here, we test these hypotheses in capture–mark–recapture field surveys that assess body size, lifespan, survival and lifetime mating success in two consecutive generations of a partially bivoltine aquatic insect, Coenagrion mercuriale, where the spring cohort is slower‐developing than the autumn cohort. As expected, body size was larger in the slow‐developing cohort, which is consistent with the temperature‐size rule and also with the duration of development. Body size seasonal variation was greater in slow‐developing cohort most likely because of the higher variation in age at maturity. Concordant with theory, survival probability, lifespan and lifetime mating success were higher in the slow‐developing cohort. Moreover, individual body size was positively correlated with survival and mating success in both cohorts. Our study confirms the fitness costs of fast pace‐of‐life and the benefits of larger body size to adult fitness.     

Estrogenic regulation of skeletal muscle proteome: a study of premenopausal women and postmenopausal MZ cotwins discordant for hormonal therapy

Female middle age is characterized by a decline in skeletal muscle mass and performance, predisposing women to sarcopenia, functional limitations, and metabolic dysfunction as they age. Menopausal loss of ovarian function leading to low circulating level of 17β‐estradiol has been suggested as a contributing factor to aging‐related muscle deterioration. However, the underlying molecular mechanisms remain largely unknown and thus far androgens have been considered as a major anabolic hormone for skeletal muscle. We utilized muscle samples from 24 pre‐ and postmenopausal women to establish proteome‐wide profiles, associated with the difference in age (30–34 years old vs. 54–62 years old), menopausal status (premenopausal vs. postmenopausal), and use of hormone replacement therapy (HRT; user vs. nonuser). None of the premenopausal women used hormonal medication while the postmenopausal women were monozygotic (MZ) cotwin pairs of whom the other sister was current HRT user or the other had never used HRT. Label‐free proteomic analyses resulted in the quantification of 797 muscle proteins of which 145 proteins were for the first time associated with female aging using proteomics. Furthermore, we identified 17β‐estradiol as a potential upstream regulator of the observed differences in muscle energy pathways. These findings pinpoint the underlying molecular mechanisms of the metabolic dysfunction accruing upon menopause, thus having implications for understanding the complex functional interactions between female reproductive hormones and health.