Phosphodiesterase 4 inhibitor and phosphodiesterase 5 inhibitor combination therapy has antifibrotic and anti-inflammatory effects in mdx mice with Duchenne muscular dystrophy [Research]
In this study, we showed beneficial effects of the PDE4 inhibitor piclamilast in the DMD mdx mouse. Piclamilast reduced the mRNA level of profibrotic genes, including collagen 1A1, in the gastrocnemius and diaphragm, in the mdx mouse, and significantly reduced the Sirius red staining area. The PDE5 inhibitors sildenafil and tadalafil ameliorated functional muscle ischemia in boys with DMD, and sildenafil reversed cardiac dysfunction in the mdx mouse. Single-treatment piclamilast or sildenafil showed similar antifibrotic effects on the gastrocnemius; combination therapy showed a potent antifibrotic effect, and piclamilast a...
Source: FASEB Journal - November 30, 2017 Category: Biology Authors: Nio, Y., Tanaka, M., Hirozane, Y., Muraki, Y., Okawara, M., Hazama, M., Matsuo, T. Tags: Research Source Type: research
Amyloid-induced {beta}-cell dysfunction and islet inflammation are ameliorated by 4-phenylbutyrate (PBA) treatment [Research]
Human islet amyloid polypeptide (hIAPP) aggregation is associated with β-cell dysfunction and death in type 2 diabetes (T2D). we aimed to determine whether in vivo treatment with chemical chaperone 4-phenylbutyrate (PBA) ameliorates hIAPP-induced β-cell dysfunction and islet amyloid formation. Oral administration of PBA in hIAPP transgenic (hIAPP Tg) mice expressing hIAPP in pancreatic β cells counteracted impaired glucose homeostasis and restored glucose-stimulated insulin secretion. Moreover, PBA treatment almost completely prevented the transcriptomic alterations observed in hIAPP Tg islets, including the...
Source: FASEB Journal - November 30, 2017 Category: Biology Authors: Montane, J., de Pablo, S., Castano, C., Rodriguez-Comas, J., Cadavez, L., Obach, M., Visa, M., Alcarraz-Vizan, G., Sanchez-Martinez, M., Nonell-Canals, A., Parrizas, M., Servitja, J.-M., Novials, A. Tags: Research Source Type: research
Impaired liver regeneration after hepatectomy and bleeding is associated with a shift from hepatocyte proliferation to hypertrophy [Research]
Extensive liver resections are common, and bleeding is frequent in these operations. Impaired regeneration after partial hepatectomy (PHx) may contribute to liver failure. We thus assessed the impact of acute bleeding on the liver regeneration progress after PHx and explored possible contributing molecular mechanisms. In rats, the regeneration progress was delayed and attenuated with PHx and bleeding and was not restored with colloid resuscitation. Livers restored their initial volume by postoperative day (POD) 2 after PHx through hepatocyte proliferation vs. POD 4 in the PHx and bleeding group, primarily by hepatocyte hyp...
Source: FASEB Journal - November 30, 2017 Category: Biology Authors: Matot, I., Nachmansson, N., Duev, O., Schulz, S., Schroeder-Stein, K., Frede, S., Abramovitch, R. Tags: Research Source Type: research
Transcriptomic and epigenetic regulation of disuse atrophy and the return to activity in skeletal muscle [Research]
We report that silencing the tibialis anterior muscle in rats with tetrodotoxin (TTX)—administered to the common peroneal nerve—resulted in reductions in muscle mass of 7, 29, and 51% with corresponding reductions in muscle fiber cross-sectional area of 18, 42, and 69% after 3, 7, and 14 d of TTX, respectively. Of importance, 7 d of recovery, during which rodents resumed habitual physical activity, restored muscle mass from a reduction of 51% after 14 d TTX to a reduction of only 24% compared with sham control. Returning muscle mass to levels observed at 7 d TTX administration (29% reduction). Transcriptome-wid...
Source: FASEB Journal - November 30, 2017 Category: Biology Authors: Fisher, A. G., Seaborne, R. A., Hughes, T. M., Gutteridge, A., Stewart, C., Coulson, J. M., Sharples, A. P., Jarvis, J. C. Tags: Research Source Type: research
Fluorescent probes for selective protein labeling in lysosomes: a case of {alpha}-galactosidase A [Research]
Fluorescence-based live-cell imaging (LCI) of lysosomal glycosidases is often hampered by unfavorable pH and redox conditions that reduce fluorescence output. Moreover, most lysosomal glycosidases are low-mass soluble proteins that do not allow for bulky fluorescent protein fusions. We selected α-galactosidase A (GALA) as a model lysosomal glycosidase involved in Anderson-Fabry disease (AFD) for the current LCI approach. Examination of the subcellular localization of AFD-causing mutants can reveal the mechanism underlying cellular trafficking deficits. To minimize genetic GALA modification, we employed a biarsenical ...
Source: FASEB Journal - November 30, 2017 Category: Biology Authors: Bohl, C., Pomorski, A., Seemann, S., Knospe, A.-M., Zheng, C., Krezel, A., Rolfs, A., Lukas, J. Tags: Research Source Type: research
A novel synthetic analogue of {omega}-3 17,18-epoxyeicosatetraenoic acid activates TNF receptor-1/ASK1/JNK signaling to promote apoptosis in human breast cancer cells [Research]
This study evaluated the apoptotic mechanism of C20E. Increased cytosolic cytochrome c expression and altered expression of pro- and antiapoptotic B-cell lymphoma-2 proteins indicated activation of the mitochondrial pathway. Caspase-3 activation by C20E was prevented by pharmacological inhibition and silencing of the JNK and p38 MAP kinases (MAPK), upstream MAPK kinases MKK4 and MKK7, and the upstream MAPK kinase kinase apoptosis signal-regulating kinase 1 (ASK1). Silencing of the death receptor TNF receptor 1 (TNFR1), but not Fas, DR4, or DR5, and the adapters TRADD and TNF receptor–associated factor 2, but not Fas-...
Source: FASEB Journal - November 30, 2017 Category: Biology Authors: Dyari, H. R. E., Rawling, T., Chen, Y., Sudarmana, W., Bourget, K., Dwyer, J. M., Allison, S. E., Murray, M. Tags: Research Source Type: research
Drosophila CHIP protects against mitochondrial dysfunction by acting downstream of Pink1 in parallel with Parkin [Research]
In this study, overexpression of Drosophila CHIP suppressed a range of Pink1 mutant phenotypes in flies, including abnormal wing posture, thoracic indentation, locomotion defects, muscle degeneration, and loss of dopaminergic neurons. Mitochondrial defects of Pink1 mutant, such as excessive fusion, reduced ATP content, and crista disorganization, were rescued by CHIP but not its ligase-dead mutants. Similar phenotypes and mitochondrial impairment were ameliorated in Parkin mutant flies by wild-type CHIP. Inactivation of CHIP with null fly mutants resulted in mitochondrial defects, such as reduced thoracic ATP content at 3 ...
Source: FASEB Journal - November 30, 2017 Category: Biology Authors: Chen, J., Xue, J., Ruan, J., Zhao, J., Tang, B., Duan, R. Tags: Research Source Type: research
EHD4 is a novel regulator of urinary water homeostasis [Research]
This study focused on EHD4, which we found to be expressed differentially across nephron segments with the highest expression in the inner medullary collecting duct. Under baseline conditions, Ehd4–/– [EHD4-knockout (KO)] mice on a C57Bl/6 background excreted a higher volume of more dilute urine than control C57Bl/6 wild-type (WT) mice while maintaining a similar plasma osmolality. Urine excretion after an acute intraperitoneal water load was significantly increased in EHD4-KO mice compared to WT mice, and although EHD4-KO mice concentrated their urine during 24-h water restriction, urinary osmolality remained ...
Source: FASEB Journal - November 30, 2017 Category: Biology Authors: Rahman, S. S., Moffitt, A. E. J., Trease, A. J., Foster, K. W., Storck, M. D., Band, H., Boesen, E. I. Tags: Research Source Type: research
Morphine alters the circulating proteolytic profile in mice: functional consequences on cellular migration and invasion [Research]
Opioids modulate the tumor microenvironment with potential functional consequences for tumor growth and metastasis. We evaluated the effects of morphine administration on the circulating proteolytic profile of tumor-free mice. Serum from morphine-treated (1 or 10 mg/kg, i.p. every 12 h) or saline-treated mice was collected at different time points and tested ex vivo in endothelial, lymphatic endothelial, and breast cancer cell migration assays. Serum from mice that were treated with 10 mg/kg morphine for 3 d displayed reduced chemotactic potential for endothelial and breast cancer cells, and elicited reduced cancer cell in...
Source: FASEB Journal - November 30, 2017 Category: Biology Authors: Xie, N., Khabbazi, S., Nassar, Z. D., Gregory, K., Vithanage, T., Anand-Apte, B., Cabot, P. J., Sturgess, D., Shaw, P. N., Parat, M.-O. Tags: Research Source Type: research
A dynamic ribosomal biogenesis response is not required for IGF-1-mediated hypertrophy of human primary myotubes [Research]
We examined the relationship between ribosomal RNA (rRNA) production and IGF-1–mediated myotube hypertrophy in vitro. Primary skeletal myotubes were treated with IGF-1 (50 ng/ml) with or without 0.5 µM CX-5461 (CX), an inhibitor of RNA polymerase I. Myotube diameter, total protein, and RNA and DNA levels were measured along with markers of RNA polymerase I regulatory factors and regulators of protein synthesis. CX treatment reduced 45S pre-rRNA expression (–64 ± 5% vs. IGF-1; P < 0.001) and total RNA content (–16 ± 2% vs. IGF-1; P < 0.001) in IGF-1-treated myotubes. IGF-1-mediate...
Source: FASEB Journal - November 30, 2017 Category: Biology Authors: Crossland, H., Timmons, J. A., Atherton, P. J. Tags: Research Source Type: research
MiR-338 controls BPA-triggered pancreatic islet insulin secretory dysfunction from compensation to decompensation by targeting Pdx-1 [Research]
Bisphenol A (BPA) can disrupt glucose homeostasis and impair pancreatic islet function; however, the mechanisms behind these effects are poorly understood. Male mice (4 wk old) were treated with BPA (50 or 500 μg/kg/d) for 8 wk. Whole-body glucose homeostasis, pancreatic islet morphology and function, and miR-338-mediated molecular signal transduction analyses were examined. We showed that BPA treatment led to a disruption of glucose tolerance and a compensatory increase of pancreatic islets insulin secretion and pancreatic and duodenal homeobox 1 (Pdx1) expression in mice. Inhibition of Pdx1 reduced glucose-stimulated ...
Source: FASEB Journal - November 30, 2017 Category: Biology Authors: Wei, J., Ding, D., Wang, T., Liu, Q., Lin, Y. Tags: Research Source Type: research
A PP2A-mediated feedback mechanism controls Ca2+-dependent NO synthesis under physiological oxygen [Research]
Intracellular O2 is a key regulator of NO signaling, yet most in vitro studies are conducted in atmospheric O2 levels, hyperoxic with respect to the physiologic milieu. We investigated NO signaling in endothelial cells cultured in physiologic (5%) O2 and stimulated with histamine or shear stress. Culture of cells in 5% O2 (>5 d) decreased histamine- but not shear stress–stimulated endothelial (e)NOS activity. Unlike cells adapted to a hypoxic environment (1% O2), those cultured in 5% O2 still mobilized sufficient Ca2+ to activate AMPK. Enhanced expression and membrane targeting of PP2A-C was observed in 5% O2, res...
Source: FASEB Journal - November 30, 2017 Category: Biology Authors: Keeley, T. P., Siow, R. C. M., Jacob, R., Mann, G. E. Tags: Research Source Type: research
Unacylated ghrelin normalizes skeletal muscle oxidative stress and prevents muscle catabolism by enhancing tissue mitophagy in experimental chronic kidney disease [Research]
Unacylated ghrelin (UnAG) may lower skeletal muscle oxidative stress, inflammation, and insulin resistance in lean and obese rodents. UnAG-induced autophagy activation may contribute to these effects, likely involving removal of dysfunctional mitochondria (mitophagy) and redox state maintenance. In chronic kidney disease (CKD) oxidative stress, inflammation and insulin resistance may negatively influence patient outcome by worsening nutritional state through muscle mass loss. Here we show in a 5/6 nephrectomy (Nx) CKD rat model that 4 d s.c. UnAG administration (200 µg twice a day) normalizes CKD-induced loss of gast...
Source: FASEB Journal - November 30, 2017 Category: Biology Authors: Gortan Cappellari, G., Semolic, A., Ruozi, G., Vinci, P., Guarnieri, G., Bortolotti, F., Barbetta, D., Zanetti, M., Giacca, M., Barazzoni, R. Tags: Research Source Type: research
Impact of folic acid intake during pregnancy on genomic imprinting of IGF2/H19 and 1-carbon metabolism [Research]
Folic acid is an essential component of 1-carbon metabolism, which generates methyl groups for DNA methylation. Disruption of genomic imprinting leads to biallelic expression which may affect disease susceptibility possibly reflected in high levels of S-adenosyl-homocysteine (SAH) and low levels of S-adenosyl-methionine (SAM). We investigated the association between folic acid supplementation during pregnancy and loss of imprinting (LOI) of IGF2 and H19 genes in placentas and cord blood of 90 mother–child dyads in association with the methylenetetrahydrofolate reductase (MTHFR) genotype. Pyrosequencing was used to ev...
Source: FASEB Journal - November 30, 2017 Category: Biology Authors: Tserga, A., Binder, A. M., Michels, K. B. Tags: Research Source Type: research
Caenorhabditis elegans models of tauopathy [Alzheimer's Disease Review Series]
One of the hallmarks of the tauopathies, which include the neurodegenerative disorders, such as Alzheimer disease (AD), corticobasal degeneration, frontotemporal dementia, and progressive supranuclear palsy (PSP), is the abnormal accumulation of post-translationally modified, insoluble tau. The result is a loss of neurons, decreased mental function, and complete dependence of patients on others. Aggregation of tau, which under physiologic conditions is a highly soluble protein, is thought to be central to the pathogenesis of these diseases. Indeed one of the strongest lines of evidence is the MAPT gene polymorphisms that l...
Source: FASEB Journal - November 30, 2017 Category: Biology Authors: Pir, G. J., Choudhary, B., Mandelkow, E. Tags: Alzheimer ' s Disease Review Series Source Type: research
