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1.
Cortex ; 120: 394-418, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31419597

RESUMO

This paper examined the effects of treatment on both offline and online sentence processing and associated neuroplasticity within sentence processing and dorsal attention networks in chronic stroke-induced agrammatic aphasia. Twenty-three neurotypical adults and 19 individuals with aphasia served as participants. Aphasic individuals were randomly assigned to receive a 12-week course of linguistically-based treatment of passive sentence production and comprehension (N = 14, treatment group) or to serve as control participants (N = 5, natural history group). Both aphasic groups performed two offline tasks at baseline and three months following (at post-testing) to assess production and comprehension of trained passive structures and untrained syntactically related and unrelated structures. The aphasic participants and a healthy age-matched group also performed an online eyetracking comprehension task and a picture-verification fMRI task, which were repeated at post-testing for the aphasic groups. Results showed that individuals in the treatment, but not in the natural history, group improved on production and comprehension of both trained structures and untrained syntactically related structures. Treatment also resulted in a shift toward more normal-like eye movements and a significant increase in neural activation from baseline to post-testing. Upregulation encompassed right hemisphere regions homologs of left hemisphere regions involved in both sentence processing and domain-general functions and was positively correlated with treatment gains, as measured by offline comprehension accuracy, and with changes in processing strategies during sentence comprehension, as measured by eyetracking. These findings provide compelling evidence in favor of the contribution of both networks within the right hemisphere to the restoration of normal-like sentence processing patterns in chronic aphasia.

2.
Clin Breast Cancer ; 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31427171

RESUMO

In the last decade, several clinical trials have investigated novel endocrine combinations for the first-line treatment of hormone receptor-positive metastatic breast cancer. Nevertheless, the use of combinations for the first-line treatment of bone-only disease is widely discussed as a result of its indolent natural history. We performed a comprehensive search of phase 3 randomized clinical trials published in the literature through September 2018. Our aim was to explore the role of the new endocrine approaches in bone-only metastatic breast cancer, suggesting a possible strategy for their selection. In particular, we evaluated the comparative risk of adverse event occurrence during these treatments. A total of 6 studies were deemed suitable for meta-analysis: the Monaleesa-2, Monaleesa-7, Monarch-3, Paloma-2, SWOG, and Alliance trials. Overall, the novel strategies were shown to improve progression-free survival in bone-only disease (hazard ratio = 0.65; 95% confidence interval, 0.49-0.86; P = .003). Combinations with cyclin-dependent kinase inhibitors improved progression-free survival (hazard ratio = 0.54; 95% confidence interval, 0.39-0.75; P < .001) with an acceptable toxicity profile. Abemaciclib was associated with increased anemia and gastrointestinal toxicity (especially diarrhea), whereas palbociclib was associated with increased leukopenia (but not neutropenia) compared to the other compounds. Increased aspartate aminotransferase levels were reported for both ribociclib and abemaciclib. The combination of cyclin-dependent kinase 4/6 inhibitors and endocrine therapy represents an effective and well-tolerated approach for first-line treatment in bone-only disease settings. Because no direct comparison between the 3 cyclin-dependent kinase 4/6 inhibitors is available, the selection of the most appropriate treatment should be based on toxicity profile as well as patient preference and copathologies.

3.
J Invertebr Pathol ; 166: 107222, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31356818

RESUMO

Ostreid herpesvirus 1 (OsHV-1) is a DNA virus of the genus Ostreavirus (Malacoherpesviridae family, Herpesvirales order). Worldwide, OsHV-1 and its microvariants have been associated with increased mortality of Pacific oysters, Crassostrea gigas. Adult asymptomatic oysters also have shown a high prevalence of viral infection. As a consequence, surveillance is needed to better describe OsHV-1 diversity, pathogenicity, clinical signs, and geographical distribution. We examined Crassostrea gigas sampled in October 2017 from the inner zone of the Bahía Blanca Estuary, Argentina, and found that 8 of 30 specimens (26.7%) presented macroscopic lesions in mantle tissues. Histological analysis revealed abnormal presentation of mantle epithelial cells and connective tissues. Conventional and real-time PCR conducted on the oyster samples revealed 70% to be positive for presence of OsHV-1 DNA. The nucleotide sequence of the amplicon obtained from one sample using the primer pair IA1/IA2 (targeting ORF 42/43) was 99% identical to OsHV-1 reference as well as µVar strains B and A (KY271630, KY242785.1), sequenced from France and Ireland. This finding represents the first detection of OsHV-1 DNA in a wild population of C. gigas in Argentina in association with gross mantle lesions.

4.
Hum Mutat ; 40(9): 1557-1578, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31131967

RESUMO

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.

5.
Neuroscience ; 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31047977

RESUMO

Erythropoietin (EPO) is a hematopoietic growth factor that has an important role in the erythropoiesis. EPO and its receptor (EPO-R) are expressed all over in the mammalian brain. Furthermore, it has been reported that EPO may exert neuroprotective effect in animal models of brain disorders as ischemia and epilepsy. Here, we investigate whether EPO could modulate the GABA-evoked currents (IGABA) in both human epileptic and non-epileptic control brain tissues. Therefore, we transplanted in Xenopus oocytes cell membranes obtained from autoptic and surgical brain tissues (cortex) of seven temporal lope epilepsy (TLE) patients and of five control patients. Two microelectrodes voltage-clamp technique has been used to record IGABA. Moreover, qRT-PCR assay was performed in the same human tissues to quantify the relative gene expression levels of EPO/EPO-R. To further confirm experiments in oocytes, we performed additional experiments using patch-clamp recording in slices obtained from rat cerebellum. We show that exposure to EPO significantly increased the amplitude of the IGABA in all the patients analyzed. No differences in the expression of EPO and EPO-R in both TLE and control patients have been found. Notably, the increase of IGABA has been recorded also in rat cerebellar slices. Our findings show a new modulatory action of EPO on GABAA receptors (GABAA-Rs). This effect could be relevant to balance the GABAergic dysfunction in human TLE.

6.
J Commun Disord ; 79: 58-75, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30884288

RESUMO

We developed an Italian version of the Northwestern Assessment of Verbs and Sentences (NAVS, Thompson, 2011), a test assessing verb and sentence deficits typically found in aphasia, by focusing on verb-argument structure and syntactic complexity effects, rarely captured by standard language tests. Twenty-one young healthy individuals underwent a computerized experimental version of the NAVS, including three subtests assessing production/comprehension of verbs with different number (one, two, three) and type (obligatory or optional) of arguments, and two investigating production/comprehension of sentences with canonical/non-canonical word order. The number of verb arguments affected participants' reaction times (RTs) in verb naming and comprehension. Furthermore, verbs with optional arguments were processed faster than verbs with only obligatory arguments. Comprehension accuracy was lower for object-cleft vs. subject-cleft sentences. Object clefts and object relatives also elicited longer RTs than subject clefts and subject relatives, respectively. The study shows that the NAVS is sensitive to linguistic aspects of verb/sentence processing in Italian as in the English language. The study also highlights some differences between languages in the verb/sentence processing patterns of healthy individuals. Finally, the study contributes to the understanding of how information about verb-argument structure is represented and processed in healthy individuals, with reference to current models of verb processing.

7.
J Cancer Res Clin Oncol ; 145(4): 821-828, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30603906

RESUMO

PURPOSE: Hormone receptors (HR) status in HER2 + breast cancer (BC) is a recognized stratification factor with relevant clinical implication. According to HR expression, HER2 + BC show different clinical characteristics, treatment sensitivity and prognosis. The interaction between HR and HER2 pathways remains incompletely understood. METHODS: Thirty-four HER2 + BC were included: 18 tumors with HER2+/HR + and 16 with HER2+/HR-. The expression of 770 genes and 13 molecular pathways were evaluated using Nanostring PanCancer Pathway panel performed on FFPE BC biopsies. RESULTS: Gene expression analysis identified 127 genes with significantly different expression between the two cohorts. 83% of these genes were overexpressed in HER2+/HR- cohort. Globally, 23% of them belonged to PI3K pathway (41 genes), 15% to Trascriptional regulation (26 genes) and 12% to MAPK (22 genes). Regarding pathway expression, PI3K, MAPK and NOTCH were significantly differently expressed between the two groups (p = 0.003, p = 0.0018 and p = 0.02, respectively), all of them were overexpressed in HER2+/HR- tumors. CONCLUSIONS: According to HR status, HER2 + tumors express different pathways profiles: the overexpression of PI3K, MAPK and NOTCH pathways in HER2+/HR- group could justify different survival outcomes and treatment sensitivity. The identification of tumor driver pathways may be a useful instrument for individualized pathway-directed therapies. Further clinical implications are warranted.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Receptor ErbB-2/biossíntese , Receptores Estrogênicos/biossíntese , Receptores de Progesterona/biossíntese , Biópsia , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/biossíntese , Proteínas Quinases Ativadas por Mitógeno/genética , Inclusão em Parafina , Receptor ErbB-2/genética , Receptores Estrogênicos/genética , Receptores de Progesterona/genética , Estudos Retrospectivos
8.
Fungal Biol ; 122(12): 1134-1141, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30449351

RESUMO

Tuber magnatum Pico, the delectable white truffle, is the most prized truffle species. In this study, we examined the reddish pigmentation that frequently occurs in T. magnatum ascomata for the presence of pigment-producing bacteria. The inner part of the reddish-pigmented region of three T. magnatum ascomata collected in North-Central Italy was analysed. This reddish part was used to establish a bacterial culture collection and to extract the total genomic DNA in order to obtain a library of 16S rRNA genes representative of the bacterial community. The molecular approach revealed limited microbial diversity within the reddish-pigmented regions compared to the wider range of bacterial species commonly found at the same maturation stage and season in T. magnatum ascomata. The pigmented regions showed a prevalence of specific bacterial species belonging to α-, ß- and γ- Proteobacteria, Actinobacteria and Firmicutes. From the tandem mass spectrometry analysis of the extracted pigment, four compounds were identified: i) bixin, ii) ß-carotene, iii) cis-1-glycosyl-apo-8'- lycopene and iv) the fucoxanthin. Carotenoid producing species such as Microbacterium and Chryseobacterium emerged as the most likely cause of the peculiar reddish pigment production. Indeed, our findings suggest that the peculiar reddish pigment might be produced by these bacterial species.

9.
Oxid Med Cell Longev ; 2018: 5896786, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30363988

RESUMO

Triple-negative breast cancer (TNBC) does not express estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 and is characterized by its aggressive nature, lack of targets for targeted therapies, and early peak of recurrence. Due to these specific characteristics, chemotherapy does not usually yield substantial improvements and new target therapies and alternative strategies are needed. The beneficial responses of TNBC survivors to regular exercise, including a reduction in the rate of tumor growth, are becoming increasingly apparent. Physiological adaptations to exercise occur in skeletal muscle but have an impact on the entire body through systemic control of energy homeostasis and metabolism, which in turn influence the TNBC tumor microenvironment. Gaining insights into the causal mechanisms of the therapeutic cancer control properties of regular exercise is important to improve the prescription and implementation of exercise and training in TNBC survivors. Here, we provide new evidence of the effects of exercise on TNBC prevention, control, and outcomes, based on the inhibition of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (PKB also known as Akt)/mammalian target of rapamycin (mTOR) (PI3K-Akt-mTOR) signaling. These findings have wide-ranging clinical implications for cancer treatment, including recurrence and case management.


Assuntos
Exercício/fisiologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/fisiopatologia , Autofagia , Ingestão de Energia , Feminino , Humanos
10.
Nutrients ; 10(8)2018 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-30115856

RESUMO

Menopause is an age-dependent physiological condition associated with a natural decline in oestrogen levels, which causes a progressive decrease of muscle mass and strength and bone density. Sarcopenia and osteoporosis often coexist in elderly people, with a prevalence of the latter in elderly women. The profound interaction between muscle and bone induces a negative resonance between the two tissues affected by these disorders worsening the quality of life in the postmenopausal period. It has been estimated that at least 1 in 3 women over age 50 will experience osteoporotic fractures, often requiring hospitalisation and long-term care, causing a large financial burden to health insurance systems. Hormonal replacement therapy is effective in osteoporosis prevention, but concerns have been raised with regard to its safety. On the whole, the increase in life expectancy for postmenopausal women along with the need to improve their quality of life makes it necessary to develop specific and safe therapeutic strategies, alternative to hormonal replacement therapy, targeting both sarcopenia and osteoporosis progression. This review will examine the rationale and the effects of dietary protein, vitamin D and calcium supplementation combined with a specifically-designed exercise training prescription as a strategy to counteract these postmenopausal-associated disorders.


Assuntos
Proteínas na Dieta , Exercício/fisiologia , Músculo Esquelético/fisiologia , Osteoporose/prevenção & controle , Pós-Menopausa , Vitamina D/administração & dosagem , Feminino , Humanos
11.
Sci Rep ; 8(1): 8919, 2018 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-29891966

RESUMO

Insulin-like growth factor-1 (IGF-1) is synthesised as a prohormone (proIGF-1) requiring enzymatic activity to yield the mature IGF-1. Three proIGF-1s are encoded by alternatively spliced IGF-1 mRNAs: proIGF-1Ea, proIGF-1Eb and proIGF-1Ec. These proIGF-1s have a common IGF-1 mature sequence but different E-domains. The structure of the E-domains has not been resolved, and their molecular functions are still unclear. Here, we show that E-domains are Intrinsically Disordered Regions that have distinct regulatory functions on proIGF-1s production. In particular, we identified a highly conserved N-glycosylation site in the Ea-domain, which regulated intracellular proIGF-1Ea level preventing its proteasome-mediated degradation. The inhibition of N-glycosylation by tunicamycin or glucose starvation markedly reduced proIGF-1Ea and mature IGF-1 production. Interestingly, 2-deoxyglucose, a glucose and mannose analogue, increased proIGF-1Ea and mature IGF-1 levels, probably leading to an accumulation of an under-glycosylated proIGF-1Ea that was still stable and efficiently secreted. The proIGF-1Eb and proIGF-1Ec were devoid of N-glycosylation sites, and hence their production was unaffected by N-glycosylation inhibitors. Moreover, we demonstrated that alternative Eb- and Ec-domains controlled the subcellular localisation of proIGF-1s, leading to the nuclear accumulation of both proIGF-1Eb and proIGF-1Ec. Our results demonstrated that E-domains are regulatory elements that control IGF-1 production and secretion.

12.
Am J Alzheimers Dis Other Demen ; 33(5): 292-300, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29544341

RESUMO

Prototypical items within a semantic category are processed faster than atypical items within the same category. This typicality effect reflects normal representation and processing of semantic categories and when absent may be reflective of lexical-semantic deficits. We examined typicality effects in individuals with semantic and nonsemantic variants of primary progressive aphasia (PPA; semantic-PPA-S, agrammatic-PPA-G), a neurodegenerative disorder characterized by specific decline in language function, and age-matched controls. Using a semantic category verification task, where participants were asked to decide whether visual or auditory words (category typical, atypical, or nonmembers) belonged within a specified superordinate category, we found a typicality effect (ie, faster response times for typical vs atypical items) for all participant groups. However, participants with more severe PPA-S did not show a typicality effect in either modality. Findings may reflect increased intracategory semantic blurring as the disease progresses and semantic impairment becomes more severe.

13.
BMC Cancer ; 17(1): 722, 2017 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-29115937

RESUMO

BACKGROUND: Trastuzumab-related cardiotoxicity has been reported in patients receiving trastuzumab concurrently with other agents, especially with anthracyclines. Cardiac function damage is generally rare, precox and mild with trastuzumab alone. CASE PRESENTATION: We report the case of a 49 year-old woman affected by metastatic breast cancer who developed trastuzumab-related cardiogenic shock due to pump failure (with LVEF of about 15%) after three months of treatment. After a long hospitalization in the cardiac intensive care unit and a proper treatment, LVEF increased to 50% and, due to a severe progression of disease, trastuzumab was resumed and continued for more than one year. CONCLUSION: This is a case of particularly severe cardiotoxicity related to trastuzumab treatment, which was recovered with pharmacological treatment and the temporary discontinuation of the treatment. Trastuzumab was safely resumed after clinical and echocardiographic parameters improvement.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Choque Cardiogênico/induzido quimicamente , Trastuzumab/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Cardiotoxicidade , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Choque Cardiogênico/fisiopatologia , Choque Cardiogênico/terapia , Volume Sistólico , Trastuzumab/administração & dosagem
14.
Oxid Med Cell Longev ; 2017: 3937842, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28713486

RESUMO

Type 2 diabetes (T2D) is an age-related chronic disease associated with metabolic dysregulation, chronic inflammation, and activation of peripheral blood mononuclear cells (PBMC). The aim of this study was to assess the effects of a concurrent exercise training program on inflammatory status and metabolic parameters of T2D patients. Sixteen male patients (age range 55-70) were randomly assigned to an intervention group (n = 8), which underwent a concurrent aerobic and resistance training program (3 times a week; 16 weeks), or to a control group, which followed physicians' usual diabetes care advices. Training intervention significantly improved patients' body composition, blood pressure, total cholesterol, and overall fitness level. After training, plasma levels of adipokines leptin (-33.9%) and RBP4 (-21.3%), and proinflammatory markers IL-6 (-25.3%), TNF-α (-19.8%) and MCP-1 (-15.3%) decreased, whereas anabolic hormone IGF-1 level increased (+16.4%). All improvements were significantly greater than those of control patients. Plasma proteomic profile of exercised patients showed a reduction of immunoglobulin K light chain and fibrinogen as well. Training also induced a modulation of IL-6, IGF-1, and IGFBP-3 mRNAs in the PBMCs. These findings confirm that concurrent aerobic and resistance training improves T2D-related metabolic abnormalities and has the potential to reduce the deleterious health effects of diabetes-related inflammation.


Assuntos
Exercício/fisiologia , Fator de Crescimento Insulin-Like I/metabolismo , Treinamento de Resistência/métodos , Idoso , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade
15.
Neural Plast ; 2017: 5601509, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28573050

RESUMO

The role of the right hemisphere (RH) in recovery from aphasia is incompletely understood. The present study quantified RH grey matter (GM) volume in individuals with chronic stroke-induced aphasia and cognitively healthy people using voxel-based morphometry. We compared group differences in GM volume in the entire RH and in RH regions-of-interest. Given that lesion site is a critical source of heterogeneity associated with poststroke language ability, we used voxel-based lesion symptom mapping (VLSM) to examine the relation between lesion site and language performance in the aphasic participants. Finally, using results derived from the VLSM as a covariate, we evaluated the relation between GM volume in the RH and language ability across domains, including comprehension and production processes both at the word and sentence levels and across spoken and written modalities. Between-subject comparisons showed that GM volume in the RH SMA was reduced in the aphasic group compared to the healthy controls. We also found that, for the aphasic group, increased RH volume in the MTG and the SMA was associated with better language comprehension and production scores, respectively. These data suggest that the RH may support functions previously performed by LH regions and have important implications for understanding poststroke reorganization.


Assuntos
Afasia/patologia , Cérebro/patologia , Substância Cinzenta/patologia , Acidente Vascular Cerebral/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Afasia/complicações , Afasia/diagnóstico por imagem , Mapeamento Encefálico , Cérebro/diagnóstico por imagem , Compreensão , Feminino , Lateralidade Funcional , Substância Cinzenta/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
16.
Future Oncol ; 13(11s): 35-43, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28481188

RESUMO

The antimitotic agent eribulin, a synthetic analog of halichondrin B isolated from a marine sponge, resulted particularly effective in improving the overall survival of heavily pretreated metastatic breast cancer (MBC) patients in randomized Phase III clinical trials and real-life studies. However, only scant information is available on the clinical experiences of patients who underwent long-lasting eribulin treatment followed by a rechallenge. Here we presented two cases of MBC women previously treated with several lines of chemotherapy and hormonal therapies, who underwent long-lasting treatment and rechallenge with eribulin, showing a partial response in both periods. These anecdotal experiences suggest that rechallenge with eribulin could represent a treatment strategy for advanced MBC and it should be evaluated in a larger study.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Substituição de Medicamentos , Feminino , Furanos/administração & dosagem , Furanos/efeitos adversos , Humanos , Cetonas/administração & dosagem , Cetonas/efeitos adversos , Metástase Neoplásica , Estadiamento de Neoplasias , Retratamento , Tomografia Computadorizada por Raios X , Resultado do Tratamento
17.
Oxid Med Cell Longev ; 2016: 5152029, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27610211

RESUMO

Creatine (Cr) is a nutritional supplement promoting a number of health benefits. Indeed Cr has been shown to be beneficial in disease-induced muscle atrophy, improve rehabilitation, and afford mild antioxidant activity. The beneficial effects are likely to derive from pleiotropic interactions. In accord with this notion, we previously demonstrated that multiple pleiotropic effects, including preservation of mitochondrial damage, account for the capacity of Cr to prevent the differentiation arrest caused by oxidative stress in C2C12 myoblasts. Given the importance of mitochondria in supporting the myogenic process, here we further explored the protective effects of Cr on the structure, function, and networking of these organelles in C2C12 cells differentiating under oxidative stressing conditions; the effects on the energy sensor AMPK, on PGC-1α, which is involved in mitochondrial biogenesis and its downstream effector Tfam were also investigated. Our results indicate that damage to mitochondria is crucial in the differentiation imbalance caused by oxidative stress and that the Cr-prevention of these injuries is invariably associated with the recovery of the normal myogenic capacity. We also found that Cr activates AMPK and induces an upregulation of PGC-1α expression, two events which are likely to contribute to the protection of mitochondrial quality and function.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Creatina/farmacologia , Mitocôndrias Musculares/efeitos dos fármacos , Desenvolvimento Muscular/efeitos dos fármacos , Mioblastos Esqueléticos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Linhagem Celular , Citoproteção , DNA Mitocondrial/efeitos dos fármacos , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Proteínas de Ligação a DNA/metabolismo , Ativação Enzimática , Proteínas de Grupo de Alta Mobilidade/metabolismo , Peróxido de Hidrogênio/toxicidade , Peroxidação de Lipídeos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/ultraestrutura , Mioblastos Esqueléticos/metabolismo , Mioblastos Esqueléticos/ultraestrutura , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteômica/métodos , Transdução de Sinais/efeitos dos fármacos
18.
Biochim Biophys Acta ; 1859(5): 757-68, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27048986

RESUMO

Insulin-like growth factor (IGF) -1 is a pleiotropic hormone exerting mitogenic and anti-apoptotic effects. Inclusion or exclusion of exon 5 into the IGF-1 mRNA gives rise to three transcripts, IGF-1Ea, IGF-1Eb and IGF-1Ec, which yield three different C-terminal extensions called Ea, Eb and Ec peptides. The biological significance of the IGF-1 splice variants and how the E-peptides affect the actions of mature IGF-1 are largely unknown. In this study we investigated the origin and conservation of the IGF-1 E-peptides and we compared the pattern of expression of the IGF-1 isoforms in vivo, in nine mammalian species, and in vitro using human and mouse IGF-1 minigenes. Our analysis showed that only IGF-1Ea is conserved among all vertebrates, whereas IGF-1Eb and IGF-1Ec are an evolutionary novelty originated from the exonization of a mammalian interspersed repetitive-b (MIR-b) element. Both IGF-1Eb and IGF-1Ec mRNAs were constitutively expressed in all mammalian species analyzed but their expression ratio varies greatly among species. Using IGF-1 minigenes we demonstrated that divergence in cis-acting regulatory elements between human and mouse conferred species-specific features to the exon 5 region. Finally, the protein-coding sequences of exon 5 showed low rate of synonymous mutations and contain disorder-promoting amino acids, suggesting a regulatory role for these domains. In conclusion, exonization of a MIR-b element in the IGF-1 gene determined gain of exon 5 during mammalian evolution. Alternative splicing of this novel exon added new regulatory elements at the mRNA and protein level potentially able to regulate the mature IGF-1 across tissues and species.


Assuntos
Evolução Molecular , Fator de Crescimento Insulin-Like I/genética , Isoformas de Proteínas/genética , Retroelementos/genética , Processamento Alternativo/genética , Animais , Éxons/genética , Humanos , Mamíferos , Camundongos , Especificidade da Espécie
19.
Amino Acids ; 48(8): 1897-911, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26724921

RESUMO

A growing body of scientific reports indicates that the role of creatine (Cr) in cellular biochemistry and physiology goes beyond its contribution to cell energy. Indeed Cr has been shown to exert multiple effects promoting a wide range of physiological responses in vitro as well as in vivo. Included in these, Cr promotes in vitro neuron and muscle cell differentiation, viability and survival under normal or adverse conditions; anabolic, protective and pro-differentiative effects have also been observed in vivo. For example Cr has been shown to accelerate in vitro differentiation of cultured C2C12 myoblasts into myotubes, where it also induces a slight but significant hypertrophic effect as compared to unsupplemented cultures; Cr also prevents the anti-differentiation effects caused by oxidative stress in the same cells. In trained adults, Cr increases the mRNA expression of relevant myogemic factors, protein synthesis, muscle strength and size, in cooperation with physical exercise. As to neurons and central nervous system, Cr favors the electrophysiological maturation of chick neuroblasts in vitro and protects them from oxidative stress-caused killing; similarly, Cr promotes the survival and differentiation of GABA-ergic neurons in fetal spinal cord cultures in vitro; in vivo, maternal Cr supplementation promotes the morpho-functional development of hippocampal neurons in rat offsprings. This article, which presents also some new experimental data, focuses on the trophic, pro-survival and pro-differentiation effects of Cr and examines the ensuing preventive and therapeutic potential in pathological muscle and brain conditions.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Creatina/farmacologia , Citoproteção/efeitos dos fármacos , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos , Animais , Diferenciação Celular/fisiologia , Creatina/metabolismo , Citoproteção/fisiologia , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Mioblastos Esqueléticos/metabolismo , Neurônios/metabolismo , Estresse Oxidativo/fisiologia
20.
Mini Rev Med Chem ; 16(1): 4-11, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26202198

RESUMO

Creatine (Cr) - along with the Cr kinase (CK) system - plays a fundamental role in muscle biochemistry and physiology not limited to its ergogenic role. Indeed, Cr has been shown to exert pleiotropic effects, which promote protein accretion, muscle-specific protein synthesis, growth in cultured myogenic cells and favour the myogenic process either in normal or stressing conditions. This review focuses on the effects of Cr supplementation on cellular and mitochondrial biochemistry and function in the course of skeletal muscle differentiation, either in normal or oxidatively stressing conditions, and on the ensuing nutraceutical/therapeutic perspectives.


Assuntos
Diferenciação Celular , Creatina/metabolismo , Músculo Esquelético/citologia , Mioblastos/citologia , Humanos , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Estresse Oxidativo/fisiologia
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