ABSTRACT
The treatment for tropical neglected diseases, such as Chagas disease (CD) and leishmaniasis, is extremely limited to a handful of drugs that suffer from unacceptable toxicity, tough administration routes, like parenteral, and increasing treatment failures due to the parasite resistance. Consequently, there is urgency for the development of new therapeutic options to treat such diseases. Since peptidases from these parasites are responsible for crucial functions in their biology, these molecules have been explored as alternative targets. In this context, a myriad of proteolytic inhibitors has been developed against calcium-dependent cysteine-type peptidases, collectively called calpains, which are implicated in several human pathophysiological diseases. These molecules are highly expanded in the genome of trypanosomatids and they have been reported participating in several parasite biological processes. In the present perspective, we discuss our almost two decades of experience employing the calpain inhibitors as an interesting shortcut to a possible repurpose strategy to treat CD and leishmaniasis.
ABSTRACT
Objective To investigate the expression of calpains and calpastatin in diaphragm of a rat model of chronic obstructive pulmonary disease(COPD). Methods Fotry male Wistar rats were randomly divided into the control group and the COPD group. Rats in the COPD group were copied by expo -sing to cigarettes smoking and dripping lipopolysaccharide into trachea. Pathological changes of lung and diaphragm were deteted. Immunohis-tochemistry and RT-PCR were performed to determine protein and mRNA expression of calapins and calpastatin. Results Diaphragmatic atrophy was observed in rats in the COPD group instead of the control group. The protein and mRNA expression of calpains in diaphrag-m of COPD group were Increased than those in the control group(P < 0.05). On the contrary ,the expression of calpastatin was significantly reduced in rats in the COPD group(t =-9.38 and-2.97;P < 0.001 ,P = 0.005). Conclusions An imbalance in the expression of calpains/calpastatin in diaphragm was observed in COPD rats ,and this imbalance may be responsible for diaphragm atrophy.
ABSTRACT
The transcription factor Pax7 negatively regulates the activity of the muscle regulatory transcription factor MyoD, preventing muscle precursor cells from undergoing terminal differentiation. In this context, the ratio between Pax7 and MyoD protein levels is thought to be critical in allowing myogenesis to proceed or to maintain the undifferentiated muscle precursor state. We have previously shown that Pax7 is subject to rapid down regulation in differentiating myoblasts, via a proteasome-dependent pathway. Here we present evidence indicating that Pax7 is also subject to caspase-3-dependent regulation. Furthermore, simultaneous inhibition of caspase-3 and proteasome activity induced further accumulation of Pax7 protein in differentiating myoblasts. These results suggest that at early stages of muscle differentiation, Pax7 levels are regulated by at least two independent mechanisms involving caspase-3 and proteasome activity.
Subject(s)
Animals , /physiology , Cell Differentiation/physiology , Muscle Development/physiology , MyoD Protein/metabolism , Myoblasts, Skeletal/physiology , /metabolism , Proteasome Endopeptidase Complex/physiology , Down-Regulation , Horses , Myoblasts, Skeletal/enzymologyABSTRACT
Calpains are calcium-modulated proteases which respond to Ca2+ signals by removing limited portions of protein substrates,thereby irreversibly modifying their functions.Members of calpains are present in a variety of organisms in human.Calpains mediates crucial cellular functions,including rearrangement of cytoskeletal proteins and protein cleavage to activate various receptors and pro-enzymes.The abnormal activation of calpains is one of the important mechanisms in several pathogenesis,including neurodegenerative diseases,traumatic brain and spinal cord injuries,cataracts and ischemia-associated injuries.The recent findings on the role of calpains and its inhibitors in the liver injury will be reviewed in this paper.