1,720,974 research outputs found
Involvement of a RAGE/p38MAPK/myogenin axis in cancer cachexia.
No full textCachexia is a highly debilitating multifactorial syndrome affecting more than 50% of patients with advanced
cancer, characterized by severe muscle wasting leading to pronounced weight loss, impaired quality of life,
reduced response to anti-cancer therapy, and premature death. Inflammatory cytokines, such as TNFα are
the main atrophy-inducing factors in cachexia causing excess catabolism of myofibrillary proteins through
activation of the ubiquitin-proteasome systems (UPS)1
.
An unexpected connection between the muscle-specific transcription factor, myogenin, and the induction of
atrogenes expression in different atrophying conditions (including TNFα-induced atrophy) has been
reported2,3. However, the receptor able to upregulate myogenin expression in atrophying conditions has not
been identified yet. We demonstrated that an appropriate recruitment of RAGE (receptor for advanced
glycation-end products) by its ligands, S100B and HMGB1, concurs to skeletal muscle development and
restoration of muscle homeostasis in physiological conditions and upon acute muscle injury4
. Here, we
investigated whether RAGE might up-regulate the expression of myogenin via p38 MAPK pathway in
atrophying conditions, as in the case of myoblasts, and lead to activation of the catabolic program. We found
that: i) Lewis lung carcinoma (LLC)-bearing mice re-express RAGE in myofibers and myogenin in myonuclei;
ii) muscles of LLC-bearing RAGE-null (Ager‒/‒) mice show reduced loss of mass and reduced Fbxo32
(atrogin1), Trim63 (MuRF1) and myogenin expression compared with LLC-bearing WT mice; iii) the
upregulation of Ager in atrophying C2C12 myotubes precedes the increase in Myog (myogenin), Fbxo32 and
Trim63 levels; iv) RAGE signaling is involved in the mechanism through which TNFα induces atrophy in vitro
(i.e., upregulation of myogenin via activation of the catabolic kinase, p38 MAPK); and v) high doses of S100B,
as found in the serum of cachectic mice, induce up-regulation of RAGE and myogenin expression with
concomitant activation of p38 MAPK and induction of the UPS in myotubes and in muscle tissue. Thus,
increased expression/activity of the RAGE/ p38 MAPK/myogenin axis in muscle tissue appears to concur to
cancer cachexia.
1. Porporato P.E., 2016, Oncogenesis 22(5): e200;
2. Moresi V. et al., 2010, Cell 143: 35-34;
3. Minetti G.C. et al., 2011, Sci Sign 4: ra80;
4. Riuzzi F. et al., 2012, J Cell Sci 125:1440-1454
Sertoli cell-secreted factors have promyogenic and antifibrotic properties on human DMD myoblasts with different mutations.
No full textDuchenne muscular dystrophy (DMD) is a recessive X-linked lethal disease affecting one over 5,000 live male births in which mutations in the dystrophin gene (DMD) lead to lack of a functional protein resulting in susceptibility of myofibers to rupture during contraction. Muscles of DMD patients or experimental models of DMD show progressive necrosis of the myofibers, chronic inflammation and reactive regeneration, which lead to exhaustion of muscle precursor cell pool and replacement of myofibers with fibrous and fatty tissues.1 Although multiple therapeutic approaches have been explored in the last decades and are still under investigation, the standard therapy to DMD remains the use of glucocorticoids despite their limited efficacy and undesired side effects.2 We set up a preclinical approach based on the peculiar properties of Sertoli cells (SeC)3,4 a cell type of the seminiferous tubules of the testis in which they favor the maturation of developing germ cells and protect them against the host immune system. Besides creating a physical barrier (the blood-testis barrier), SeC secrete a plethora of trophic and immunomodulatory factors that confer to these cells the ability to survive long time after engraftment, and protect allo- and xenogenic engraftments of tissues and organs.5 SeC isolated from specific pathogens free (SPF) pre-pubertal pigs were encapsulated in highly biocompatible alginate-based microcapsules (MC-SeC) and injected into the peritoneal cavity of mdx mice, an experimental model of DMD, in the absence of pharmacological immunosuppression.3,4A single i.p. injection of MC-SeC resulted in amelioration of muscle morphology and performance as a consequence of the secretion by SeC of anti-inflammatory factors and heregulin β1, an inducer of the dystrophin paralogue, utrophin, opening new routes in the treatment of DMD. However, information is lacking about possible direct effects of SeC on myoblasts/myotubes. Here, we show that SeC secrete factors able to stimulate cell proliferation in the early phase of the myogenic differentiation process in murine C2C12 and human (healthy and DMD) myoblasts. In DMD myoblasts, SeC-derived factors delayed the expression of the muscle-specific terminal differentiation markers, myogenin and myosin heavy chain (MyHC)-II in the early phase (24h) of the differentiation process; nevertheless, SeC stimulated terminal differentiation (6 days) in these cells, suggesting that the promitogenic activity of SeC does not affect the myogenic potential. Moreover, SeC inhibit the expression of the myofibroblast transdifferentiation markers, COL1A1, FN1 and CTGF/CCN2 in DMD myoblasts, suggesting an antifibrotic effect of the SeC-derived factors. Finally, SeC induced utrophin expression in preformed DMD myotubes regardless of the mutation, with the same mechanism reported in dystrophic mice. Altogether, these results further support the use of MC-SeC or SeC-derived factors in the treatment of DMD patients, and suggest that SeC-based approaches might be useful also in improving the early phase of muscle regeneration, during which myoblasts have to proliferate in order to reach the critical amount required to replace the damaged muscle mass.
Keywords: Duchenne muscular dystrophy; Sertoli cell; muscle differentiation; fibrosis.
References
1. Davies KE, Nowak KJ. Molecular mechanisms of muscular dystrophies: old and new players. Nat Rev Mol Cell Biol. 2006;10:762-73. doi: 10.1038/nrm 2024
2. Muntoni F, Fisher I, Morgan, JE, Abraham D. Steroids in Duchenne muscular dystrophy: from clinical trials to genomic research. Neuromuscul. Disord. 2002;1:S162-5. doi: 10.1016/s0960-8966 (02)00101-3
3. Chiappalupi S, Luca G, Mancuso F, Madaro L, Fallarino F, Nicoletti C, Calvitti M, Arato I, Falabella F, Salvadori L, Di Meo A, Bufalari A, Giovagnoli S, Calafiore R, Donato R, Sorci G. Intraperitoneal injection of microencapsulated Sertoli cells restores muscle morphology and performance in dystrophic mice. Biomaterials. 2016;75:313-26. doi:10.1016/j.biomaterials. 2015. 10.029
4. Chiappalupi S, Luca G, Mancuso F, Madaro L, Fallarino F, Nicoletti C, Calvitti M, Arato I, Falabella F, Salvadori L, Di Meo A, Bufalari A, Giovagnoli S, Calafiore R, Donato R, Sorci G. Effects of intraperitoneal injection of microencapsulated Sertoli cells on chronic and presymptomatic dystrophic mice. Data in Brief. 2015;5:1015-21. doi:10.1016/j.dib.2015.11.016
5. Chiappalupi S, Salvadori L, Luca G, Riuzzi F, Calafiore R, Donato R, Sorci G. Do porcine Sertoli cells represent an opportunity for Duchenne muscular dystrophy? Cell Proliferation. 2019;26:e12599; doi: 10.1111/cpr.12599
CAVEOLINS AND CAVINS IN MUSCLE-DERIVED TUMOURS
No full textRhabdomyosarcomas (RMS) are muscle-derived tumours with a significant incidence in children. RMS cells exhibit a widespread pattern of muscle-specific markers, the detection of which may be useful for discriminating the tumour grading in order to optimize the timing and doses of chemotherapy. By analyzing human RMS specimens and in vitro cell lines, we determined the time window of expression of Caveolins (Cav-1, -2 and -3) and some Cavins family members (i.e. PTRF/Cavin-1 and MURC/Cavin-4). In detail, the simultaneous expression of Cav-1, Cav-2 and PTRF/Cavin-1 defined a signature predictive of immature cells, whereas the expression of Cav-3 and MURC/Cavin-4 was restricted to cells more differentiated. In addition, in immature cells Cav-1 was tyrosine-phosphorylated in a Src-dependent manner, resulting in increased cell proliferation and migration. As a result, the subcutaneous injections into nude mice of RMS cells overexpressing the wild-type Cav-1 form promoted a significant tumour growth, which was instead prevented by the injection of cells expressing a non-phosphorylatable Cav-1 form.
Overall, it can be concluded that Caveolins and Cavins can be useful to identify the degree of cellular differentiation in RMS and that phosphorylation of Cav-1, in particular, plays a key role in tumour aggressiveness
Do porcine Sertoli cells represent an opportunity for Duchenne muscular dystrophy?
No full textSertoli cells (SeC) are responsible for the immunoprivileged status of the testis thanks
to which allogeneic or xenogeneic engraftments can survive without pharmacological
immune suppression if co‐injected with SeC. This peculiar ability of SeC is dependent
on secretion of a plethora of factors including maturation factors, hormones,
growth factors, cytokines and immunomodulatory factors. The anti‐inflammatory
and trophic properties of SeC have been largely exploited in several experimental
models of diseases, diabetes being the most studied. Duchenne muscular dystrophy
(DMD) is a lethal X‐linked recessive pathology in which lack of functional dystrophin
leads to progressive muscle degeneration culminating in loss of locomotion and premature
death. Despite a huge effort to find a cure, DMD patients are currently
treated with anti‐inflammatory steroids. Recently, encapsulated porcine SeC (MCSeC)
have been injected ip in the absence of immunosuppression in an animal model
of DMD resulting in reduction of muscle inflammation and amelioration of muscle
morphology and functionality, thus opening an additional avenue in the treatment of
DMD. The novel protocol is endowed with the advantage of being potentially applicable
to all the cohort of DMD patients regardless of the mutation. This mini‐review
addresses several issues linked to the possible use of MC‐SeC injected ip in dystrophic
people
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Reductive stress in striated muscle cells
No full textReductive stress is defined as a condition of sustained increase in cellular glutathione/glutathione disulfide and NADH/NAD+ ratios. Reductive stress is emerging as an important pathophysiological event in several diseased states, being as detrimental as is oxidative stress. Occurrence of reductive stress has been documented in several cardiomyopathies and is an important pathophysiological factor particularly in coronary artery disease and myocardial infarction. Excess activation of the transcription factor, Nrf2—the master regulator of the antioxidant response—, consequent in most cases to defective autophagy, can lead to reductive stress. In addition, hyperglycemia-induced activation of the polyol pathway can lead to increased NADH/NAD+ ratio, which might translate into increased levels of hydrogen sulfide—via enhanced activity of cystathionine β-synthase—that would fuel reductive stress through inhibition of mitochondrial complex I. Reductive stress may be either a potential weapon against cancer priming tumor cells to apoptosis or a cancer’s ally promoting tumor cell proliferation and making tumor cells resistant to reactive oxygen species-inducing drugs. In non-cancer pathological states reductive stress is definitely harmful paradoxically leading to reactive oxygen species overproduction via excess NADPH oxidase 4 activity. In face of the documented occurrence of reductive stress in several heart diseases, there is much less information about the occurrence and effects of reductive stress in skeletal muscle tissue. In the present review we describe relevant results emerged from studies of reductive stress in the heart and review skeletal muscle conditions in which reductive stress has been experimentally documented and those in which reductive stress might have an as yet unrecognized pathophysiological role. Establishing whether reductive stress has a (patho)physiological role in skeletal muscle will hopefully contribute to answer the question whether antioxidant supplementation to the general population, athletes, and a large cohort of patients (e.g. heart, sarcopenic, dystrophic, myopathic, cancer, and bronco-pulmonary patients) is harmless or detrimental
Targeting RAGE to prevent SARS-CoV-2-mediated multiple organ failure: Hypotheses and perspectives
No full textA novel infectious disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was detected in December 2019 and declared as a global pandemic by the World Health. Approximately 15% of patients with COVID-19 progress to severe pneumonia and eventually develop acute respiratory distress syndrome (ARDS), septic shock and/or multiple organ failure with high morbidity and mortality. Evidence points towards a determinant pathogenic role of members of the renin–angiotensin system (RAS) in mediating the susceptibility, infection, inflammatory response and parenchymal injury in lungs and other organs of COVID-19 patients. The receptor for advanced glycation end-products (RAGE), a member of the immunoglobulin superfamily, has important roles in pulmonary pathological states, including fibrosis, pneumonia and ARDS. RAGE overexpression/hyperactivation is essential to the deleterious effects of RAS in several pathological processes, including hypertension, chronic kidney and cardiovascular diseases, and diabetes, all of which are major comorbidities of SARS-CoV-2 infection. We propose RAGE as an additional molecular target in COVID-19 patients for ameliorating the multi-organ pathology induced by the virus and improving survival, also in the perspective of future infections by other coronaviruses
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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