Hyper-responsiveness of IPF/UIP fibroblasts: interplay between TGFbeta1, IL-13 and CCL2

One of the hallmarks of idiopathic pulmonary fibrosis with a usual interstitial pneumonia histological pathology (IPF/UIP) is excess collagen deposition, due to enhanced fibroblast extracellular matrix synthetic activity. Studies using murine models of lung fibrosis have elucidated a pro-fibrotic pathway involving IL-13 driving CCL2, which in turn drives TGFbeta1 in lung fibroblasts. Therefore, we sought to determine whether this pathway exists in the human fibrotic setting by evaluating human IPF/UIP fibroblasts. IPF/UIP fibroblasts have an increased baseline fibrotic phenotype compared to non-fibrotic fibroblasts. Interestingly, non-fibrotic fibroblasts responded in a pro-fibrotic manner to TGFbeta1 but were relatively non-responsive to IL-13 or CCL2, whereas, IPF/UIP cells were hyper-responsive to TGFbeta1, IL-13 and CCL2. Interestingly, TGFbeta1, CCL2 and IL-13 all upregulated TGFbeta receptor and IL-13 receptor expression, suggesting an ability of the mediators to modulate the function of each other. Furthermore, in vivo, neutralization of both JE and MCP5, the two functional orthologs of CCL2, during bleomycin-induced pulmonary fibrosis significantly reduced collagen deposition as well as JE and CCR2 expression. Also in the bleomycin model, CTGF, which is highly induced following TGFbeta stimulation, was attenuated with anti-JE/anti-MCP5 treatment. Overall this study demonstrates an interplay between TGFbeta1, IL-13 and CCL2 in IPF/UIP, where these three mediators feedback on each other, promoting the fibrotic response.     

Upregulation of telomerase function during tissue regeneration

Telomerase plays a primary role in the maintenance of telomeres in immortal, germ, and tumor cells in humans but is lacking in most somatic cells and tissues. However, many species, including fish and inbred mice, express telomerase in most cells and tissues. Little is known about the expression of telomerase in aquatic species, although the importance of telomerase for longevity has been suggested. We compared telomerase activity and telomere lengths among a broad range of tissues from aquatic species and found telomerase at significant levels in both long- and short-lived aquatic species, suggesting constitutive telomerase expression has an alternative function. Telomere lengths in these aquatic species were comparable to those observed in normal human tissues and cell strains. Given that a host of aquatic species with short life spans have telomerase and a tremendous capacity to regenerate, we tested the hypothesis that telomerase upregulation is important for tissue regeneration. During regeneration, telomerase activity was upregulated and telomere lengths are maintained with the shortest telomeres being elongated, indicating the importance for maintaining telomere length and integrity during tissue regeneration. Thus, the expression of telomerase in aquatic animals is likely not related to longevity but to their ability to regenerate injured tissue.     

High population connectivity across the Indo-Pacific: Congruent lack of phylogeographic structure in three reef fish congeners

We used the mitochondrial control region and a comparative approach to study the genetic population structure of two surgeonfishes, Naso brevirostris and Naso unicornis, across their Indo-central Pacific ranges. Our purpose was to compare our results with those of a previous study of Naso vlamingii [Klanten, S.O., van Herwerden, L., Choat J.H., 2007. Extreme genetic diversity and temporal rather than spatial partitioning in a widely distributed coral reef fish. Mar. Biol. 150, 659-670] another widely distributed Indo-central Pacific Naso species. We found no evidence of a barrier to gene flow between the Indian and Pacific Oceans for either species, consistent with what was shown for N. vlamingii. Overall, both target species lacked spatial population partitions and probably have complex patterns of gene flow on several spatial scales. Despite the lack of geographic population structure distinct clades were observed in N. brevirostris, similar to those found in N. vlamingii. Coalescence times for intraspecific clades of N. brevirostris and N. vlamingii approximate each other, suggesting parallel evolutionary histories. A bimodal mismatch distribution in N. brevirostris indicates that a biogeographic barrier separated N. brevirostris populations sometime during its species history. Naso unicornis, in contrast, lacked genetic structure of any kind, although it has what could represent a single surviving clade. Congruent lack of spatial population structure among all three species suggest that such patterns are not due to stochastic processes of DNA mutation and are most likely driven by ecological and environmental factors.     

The impact of individualised cardiovascular disease (CVD) risk estimates and lifestyle advice on physical activity in individuals at high risk of CVD: a pilot 2 × 2 factorial understanding risk trial

Background

Epidemiological studies have revealed a relationship between early growth restriction and the subsequent development of insulin resistance and type 2 diabetes. Ligation of the uterine arteries in rats mimics uteroplacental insufficiency and serves as a model of intrauterine growth restriction (IUGR) and subsequent developmental programming of impaired glucose tolerance, hyperinsulinemia and adiposity in the offspring. The objective of this study was to investigate the effects of uterine artery ligation on the skeletal muscle expression of insulin receptor and key enzymes of LCFA metabolism.

Methods

Bilateral uterine artery ligation was performed on day 19 of gestation in Sprague-Dawley pregnant rats. Muscle of the posterior limb was dissected at birth and processed by real-time RT-PCR to analyze the expression of insulin receptor, ACCα, ACCβ (acetyl-CoA carboxylase alpha and beta subunits), ACS (acyl-CoA synthase), AMPK (AMP-activated protein kinase, alpha2 catalytic subunit), CPT1B (carnitine palmitoyltransferase-1 beta subunit), MCD (malonyl-CoA decarboxylase) in 14 sham and 8 IUGR pups. Muscle tissue was treated with lysis buffer and Western immunoblotting was performed to assay the protein content of insulin receptor and ACC.

Results

A significant down regulation of insulin receptor protein (p < 0.05) and reduced expression of ACS and ACCα mRNA (p < 0.05) were observed in skeletal muscle of IUGR newborns. Immunoblotting showed no significant change in ACCα content.

Conclusion

Our data suggest that uteroplacental insufficiency may affect skeletal muscle metabolism down regulating insulin receptor and reducing the expression of key enzymes involved in LCFA formation and oxidation.     

Minimal seasonal alterations in the skeletal muscle of captive brown bears

Abstract Previous studies on wild black bears (Ursus americanus) have shown that skeletal muscle morphology, composition, and overall force-generating capacity do not differ drastically between seasons despite prolonged inactivity during hibernation. However, the amount and characteristics of the seasonal variations were not consistent in these studies. The goals of this study were to compare the amount of muscle atrophy in captive brown bears (Ursus arctos) with that observed in wild black bears and measure seasonal differences in twitch characteristics. Samples from the biceps femoris muscle were collected during the summer and winter. Protein concentration, fiber-type composition, and fiber cross-sectional area were measured along with twitch characteristics. The protein concentration of the winter samples was 8.2% lower than that of the summer samples; fiber cross-sectional area and the relative proportion of fast and slow fibers remained unchanged between seasons. Myosin heavy chain isoforms I, IIa, and IIx were identified by immunoblotting and electrophoresis, and the proportions did not change between seasons. The half-rise time in the twitch contractions increased in winter relative to summer samples, which is unexpected under disuse conditions. These results agreed with a study that showed minimal skeletal muscle atrophy between seasons in wild black bears.     

Mating‐induced ovulation in loggerhead sea turtles,Caretta caretta

Mating‐induced ovulation is common in mammals, but has been rarely described in other taxa. Observations of several mature female loggerhead sea turtles, Caretta caretta, held in captivity seemed to indicate that ovulation did not occur in the absence of a male. This study was designed to determine whether this was an effect of captivity or an effect of the absence of a male. Two mature female loggerheads were followed over six annual reproductive cycles. Ultrasound exams were performed approximately every 2 weeks to follow the development of follicles in the ovaries. During the first two seasons, no male was present, in the next two seasons, a mature male was present without mating, and in the final two seasons a mature male was present, mating with one or both females. When no male was present or when present without mating, ovarian follicles developed to full size, but ovulation did not occur and the follicles gradually began to decrease in diameter and undergo changes evident on ultrasound. In the fifth season, only one of the females mated, dropping two eggs after 7 days, and continued to oviposit throughout the following months (total 275 eggs). The unmated female did not ovulate, showing the same pattern as earlier seasons. In the final season, both females mated and ovulated, dropping eggs for the next four months (total 539 eggs). The following year, no males were present and neither female ovulated. This study provides clear evidence that ovulation in loggerhead sea turtles is induced by mating. Zoo Biol 27:213–225, 2008. © 2008 Wiley‐Liss, Inc.     

Carboxylic acid bioisosteres acylsulfonamides, acylsulfamides, and sulfonylureas as novel antagonists of the CXCR2 receptor

A series of novel acylsulfonamide, acylsulfamide, and sulfonylurea bioisosteres of carboxylic acids were prepared as CXCR2 antagonists. Structure-activity relationships are reported for these series. One potent orally bioavailable inhibitor had excellent PK properties and was active in a lung injury model in hyperoxia-exposed newborn rats.