1,721,022 research outputs found
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
Microencapsulation of cells and molecular therapy of type 1 diabetes mellitus: The actual state and future perspectives between promise and progress
No full textThe history of microencapsulation of live cells started with an idea of Thomas MS Chang in 1964, thereafter applied to isolated pancreatic islets by Anthony M Sun in 1980. The original aim was to provide isolated cells with an immune-protective shield, to prevent physical contact between the transplanted cells and the host’s immune system, with retention of the microcapsules’ biocompatibility and physical–chemical properties over time. In particular, this revolutionary approach essentially applied to islet grafts, in diabetic recipients who are not immunosuppressed, at a preclinical (rodents) and, subsequently, clinical level. Among the different chemistries potentially suitable for microencapsulation of live cells, alginic acid-based polymers, originally proposed by Sun, proved to be superior to all others in the following decades. In fact, only alginic acid-based microcapsules, containing allogeneic islets, ultimately entered pilot human clinical trials in patients with type 1 diabetes mellitus, as immuno-selectiveness and biocompatibility of alginic acid-hydrogels were never matched by other biopolymers. With problems related to human islet procurement coming into a sharper focus, in conjunction with technical limits of the encapsulated islet grafting procedures, new challenges are actually being pursued, with special regard to developing both new cellular systems – able to release immunomodulatory molecules and insulin itself – and new microencapsulation methods, with the use of novel polymeric formulations, under actual scrutiny. The use of embryonic and adult stem cells, within microcapsules, should address the restricted availability of cadaveric human donor-derived islets, whereas a new generation of newly-engineered microcapsules could better fulfill issues with graft site and long-term retention of biopolymer properties
GLP-1 RAs and SGLT2i: two antidiabetic agents associated with immune and inflammation modulatory properties through the common AMPK pathway
No full textImmune cells and other cells respond to nutrient deprivation by the classic catabolic pathway of AMPK (Adenosine monophosphate kinase). This kinase is a pivotal regulator of glucose and fatty acids metabolism, although current evidence highlights its role in immune regulation. Indeed AMPK, through activation of Foxo1 (Forkhead box O1) and Foxo3 (Forkhead box O3), can regulate FOXP3, the key gene for differentiation and homeostasis of Tregs (T regulators lymphocytes). The relevance of Tregs in the onset of T1D (Type 1 diabetes) is well-known, while their role in the pathogenesis of T2D (Type 2 diabetes) is not fully understood yet. However, several studies seem to indicate that Tregs may oppose the progression of diabetic complications by mitigating insulin resistance, atherosclerosis, and damage to target organs (as in kidney disease). Hence, AMPK and AMPK-activating agents may play a role in the regulation of the immune system. The connection between metformin and AMPK is historically known; however, this link and the possible related immune effects are less studied about SGLT2i (Sodium-glucose co-transport 2 inhibitors) and GLP1-RAs (Glucagon-like peptide-1 receptor agonists). Actual evidence shows that the negative caloric balance, induced by SGLT2i, can activate AMPK. Conversely and surprisingly, an anabolizing agent like GLP-1RAs can also upregulate this kinase through cAMP (Cyclic adenosine monophosphate) accumulation. Therefore, both these drugs can likely lead to the activation of the AMPK pathway and consequential proliferation of Tregs. These observations seem to confirm not only the metabolic but also the immunoregulatory effects of these new antidiabetic agents
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
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
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
The Inferto-Sex Syndrome (ISS): sexual dysfunction in fertility care setting and assisted reproduction
Full text linkpurpose Infertility represents a peculiar social burden affecting more than 15% of couples, provoking it a real threat to the general quality of life and to the sexual health. the medicalization (diagnosis, therapy and follow up) of the lack of fertility is frequently a challenge in term of personal and couple's involvement. In particular, while the assisted reproductive technology (ART) has allowed many infertile couples to achieve pregnancy, the therapeutic process faced by the couple bears a strong psychological stress that can affect the couple's quality of life, relationship and sexuality. despite infertility affects both female and male sexual health, only recently the interest in the effects of ART on the couple's sexuality has grown, especially for women. methods a literature research on the sexual dysfunction in fertility care and particularly in ART setting was performed. results literature largely found that intimacy and sexuality appear specifically impaired by intrusiveness of treatments and medical prescriptions. moreover, there is a close relationship between emotional, psychological and sexual aspects, which can be integrated in the new concept of Inferto-sex syndrome (ISS) that can impair the ART treatment outcomes. evidence demonstrates that the assessment of sexual function is necessary in couples undergoing diagnosis of infertility and ART. conclusion a close relationship between infertility and sexuality, both in the female and male partners, was detected. ART treatments may heavily impact on the couple's psychosexual health. a couple-centred program for the integrated management of psychological and sexual dysfunction should be considered in the context of ART programs
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