54 research outputs found
Glucocorticoid-Treated Mice Are an Inappropriate Positive Control for Long-Term Preclinical Studies in the mdx Mouse
Dmd(mdx) (mdx) mice are used as a genetic and biochemical model of dystrophin deficiency. The long-term consequences of glucocorticoid (GC) treatment on dystrophin-deficient skeletal and heart muscle are not yet known. Here we used systematic phenotyping to assess the long-term consequences of GC treatment in mdx mice. Our investigation addressed not only the effects of GC on the disease phenotype but also the question of whether GCs can be used as a positive control for preclinical drug evaluations.We performed nine pre-clinical efficacy trials (treated N = 129, untreated N = 106) of different durations in 9-to-50-week-old dystrophic mdx mice over a 3-year time period using standardized methods. In all these trials, we used either 1 mg/kg body weight of prednisone or 5 mg/kg body weight of prednisolone as positive controls to compare the efficacy of various test drugs. Data from untreated controls and GC-treated mice in the various trials have been pooled and analyzed to assess the effects of GCs on dystrophin-deficient skeletal and cardiac muscles of mdx mice. Our results indicate that continuous GC treatment results in early (e.g., at 50 days) improvements in normalized parameters such as grip strength, motor coordination and maximal in vitro force contractions on isolated EDL muscle, but these initial benefits are followed by a progressive loss of muscle strength after 100 days. We also found a significant increase in heart fibrosis that is reflected in a significant deterioration in cardiac systolic function after 100 days of treatment.Continuous administration of prednisone to mdx mice initially improves skeletal muscle strength, but further therapy result in deterioration of muscle strength and cardiac function associated with enhanced cardiac fibrosis. These results suggest that GCs may not serve as an appropriate positive control for long-term mdx mouse preclinical trials
The ER-Bound RING Finger Protein 5 (RNF5/RMA1) Causes Degenerative Myopathy in Transgenic Mice and Is Deregulated in Inclusion Body Myositis
Growing evidence supports the importance of ubiquitin ligases in the pathogenesis of muscular disorders, although underlying mechanisms remain largely elusive. Here we show that the expression of RNF5 (aka RMA1), an ER-anchored RING finger E3 ligase implicated in muscle organization and in recognition and processing of malfolded proteins, is elevated and mislocalized to cytoplasmic aggregates in biopsies from patients suffering from sporadic-Inclusion Body Myositis (sIBM). Consistent with these findings, an animal model for hereditary IBM (hIBM), but not their control littermates, revealed deregulated expression of RNF5. Further studies for the role of RNF5 in the pathogenesis of s-IBM and more generally in muscle physiology were performed using RNF5 transgenic and KO animals. Transgenic mice carrying inducible expression of RNF5, under control of β-actin or muscle specific promoter, exhibit an early onset of muscle wasting, muscle degeneration and extensive fiber regeneration. Prolonged expression of RNF5 in the muscle also results in the formation of fibers containing congophilic material, blue-rimmed vacuoles and inclusion bodies. These phenotypes were associated with altered expression and activity of ER chaperones, characteristic of myodegenerative diseases such as s-IBM. Conversely, muscle regeneration and induction of ER stress markers were delayed in RNF5 KO mice subjected to cardiotoxin treatment. While supporting a role for RNF5 Tg mice as model for s-IBM, our study also establishes the importance of RNF5 in muscle physiology and its deregulation in ER stress associated muscular disorders
Ubiquitous LEA29Y Expression Blocks T Cell Co-Stimulation but Permits Sexual Reproduction in Genetically Modified Pigs
We have successfully established and characterized a genetically modified pig line with ubiquitous expression of LEA29Y, a human CTLA4-Ig derivate. LEA29Y binds human B7.1/CD80 and B7.2/CD86 with high affinity and is thus a potent inhibitor of T cell co-stimulation via this pathway. We have characterized the expression pattern and the biological function of the transgene as well as its impact on the porcine immune system and have evaluated the potential of these transgenic pigs to propagate via assisted breeding methods. The analysis of LEA29Y expression in serum and multiple organs of CAG-LEA transgenic pigs revealed that these animals produce a biologically active transgenic product at a considerable level. They present with an immune system affected by transgene expression, but can be maintained until sexual maturity and propagated by assisted reproduction techniques. Based on previous experience with pancreatic islets expressing LEA29Y, tissues from CAG-LEA29Y transgenic pigs should be protected against rejection by human T cells. Furthermore, their immune-compromised phenotype makes CAG-LEA29Y transgenic pigs an interesting large animal model for testing human cell therapies and will provide an important tool for further clarifying the LEA29Y mode of action
Applications of lignin in the agri-food industry
Of late, valorization of agri-food industrial by-products and their sustainable utilization is
gaining much contemplation world-over. Globally, 'Zero Waste Concept' is promoted with
main emphasis laid towards generation of minimal wastes and maximal utilization of plantbased
agri-food raw materials. One of the wastes/by-products in the agri-food industry are the
lignin, which occurs as lignocellulosic biomass. This biomass is deliberated to be an
environmental pollutant as they offer resistance to natural biodegradation. Safe disposal of this
biomass is often considered a major challenge, especially in low-income countries. Hence, the
application of modern technologies to effectively reduce these types of wastes and maximize
their potential use/applications is vital in the present day scenario. Nevertheless, in some of the
high-income countries, attempts have been made to efficiently utilize lignin as a source of fuel, as a raw material in the paper industry, as a filler material in biopolymer based packaging and
for producing bioethanol. However, as of today, agri-food industrial applications remains
significantly underexplored. Chemically, lignin is heterogeneous, bio-polymeric, polyphenolic
compound, which is present naturally in plants, providing mechanical strength and rigidity.
Reports are available wherein purified lignin is established to possess therapeutic values; and
are rich in antioxidant, anti-microbial, anti-carcinogenic, antidiabetic properties, etc.
This chapter is divided into four sub-categories focusing on various technological
aspects related to isolation and characterization of lignin; established uses of lignin; proved
bioactivities and therapeutic potentials of lignin, and finally on identifying the existing research
gaps followed by future recommendations for potential use from agri-food industrial wastes.Theme of this chapter is based on our ongoing project- Valortech,
which has received funding from the European Union’s Horizon 2020 research and innovation
program under grant agreement No 810630
Breast cancer survival among young women: a review of the role of modifiable lifestyle factors
Determination of sofosbuvir with two co-administered drugs;Â paracetamol and DL-methionine by two chromatographic methods. Application to a pharmacokinetic study
Fabrication of Al-doped ZnO nanoparticles and their application as a semiconductor-based gas sensor for the detection of ammonia
Enhancement of heat transfer in solar air heater duct having different pitch of triangular protrusions as roughness elements on absorber plate
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