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1.
J Cell Physiol ; 235(3): 2139-2148, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31392727

RESUMO

The development of specific and individualized training programs is a possible way to improve athletic performance and minimize injuries in professional athletes. The information regarding the sport's physical demands and the athletes' physical profile have been, so far, considered as exhaustive for the design of effective training programs. However, it is currently emerging that the genetic profile has to be also taken into consideration. By merging medical and genetic data, it is thus possible to identify the athlete's specific attitude to respond to training, diet, and physical stress. In this context, we performed a study in which 30 professional soccer players, subjected to standard sport medical evaluation and practices, were also screened for genetic polymorphism in five key genes (ACTN3, COL5A1, MCT1, VEGF, and HFE). This genetic analysis represents the central point of a multidisciplinary method that can be adopted by elite soccer teams to obtain an improvement in athletic performance and a concomitant reduction of injuries by tailoring training and nutritional programs. The genetic fingerprinting of single athletes led to the identification of two performance-enhancing polymorphisms (ACTN3 18705C>T, VEGF-634C>G) significantly enriched. Moreover, we derived a genetic model based on the gene set analyzed, which was tentatively used to reduce athletes' predisposition to injuries, by dictating a personalized nutrition and training program. The potential usefulness of this approach is concordant with data showing that this team has been classified as the healthiest and least injured team in Europe while covering the highest distance/match with the highest number of high-intensity actions/match.


Assuntos
Desempenho Atlético/fisiologia , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Futebol/fisiologia , Ferimentos e Lesões/genética , Atletas , Estudos de Associação Genética/métodos , Genômica , Genótipo , Humanos , Masculino
2.
J Cell Physiol ; 228(9): 1799-801, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23280577

RESUMO

Pin1 is a unique enzyme that can isomerize specific phospho-Ser/Thr-Pro peptide bonds, inducing a conformational change in the target protein. Such activity represents a novel and tightly controlled signaling mechanism regulating a spectrum of protein functions during the normal physiology of the cell and in pathological conditions. Our last study demonstrated that Pin1 interacts with the androgen receptor protein and that this interaction is important for its transcriptional activity. Here, we consider the activity that Pin1 plays on the N-terminal domain of different nuclear receptors and provide an interpretation of this phenomenon.


Assuntos
Peptídeos/metabolismo , Peptidilprolil Isomerase/metabolismo , Receptores Citoplasmáticos e Nucleares/química , Sítios de Ligação , Humanos , Peptidilprolil Isomerase de Interação com NIMA , Peptídeos/química , Peptidilprolil Isomerase/química , Peptidilprolil Isomerase/genética , Ligação Proteica , Conformação Proteica , Receptores Citoplasmáticos e Nucleares/metabolismo
3.
FASEB J ; 24(8): 2881-92, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20354138

RESUMO

Medulloblastoma is the most common malignant brain tumor in children, and despite improvements in the overall survival rate, it still lacks an effective treatment. Src plays an important role in cancer, and recently high Src activity was documented in medulloblastoma. In this report, we examined the effects of novel pyrazolo-[3,4-d]-pyrimidine derivative Src inhibitors in medulloblastoma. By MTS assay, we showed that the pyrimidine derivatives indicated as S7, S29, and SI163 greatly reduce the growth rate of medulloblastoma cells by inhibiting Src phosphorylation, compared with HT22 non-neoplastic nerve cells. These compounds also halt cells in the G(2)/M phase, and this effect likely occurs through the regulation of cdc2 and CDC25C phosphorylation, as shown by Western blot. Moreover, the exposure to pyrimidine derivatives induces apoptosis, assayed by the supravital propidium iodide assay, through modulation of the apoptotic proteins Bax and Bcl2, and inhibits tumor growth in vivo in a mouse model. Notably, S7, S29, and SI163 show major inhibitory effects on medulloblastoma cell growth compared with the chemotherapeutic agents cisplatin and etoposide. In conclusion, our results suggest that S7, S29, and SI163 could be novel attractive candidates for the treatment of medulloblastoma or tumors characterized by high Src activity.


Assuntos
Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Meduloblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Quinases da Família src/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Humanos , Meduloblastoma/patologia , Inibidores de Proteínas Quinases/química , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico
4.
Cancers (Basel) ; 12(3)2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32155756

RESUMO

Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease. To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the IGROV-CP20 ovarian carcinoma cells, whose resistance significantly relies on ATP7B. Using a synthetic lethality approach, we identified and validated three hits (Tranilast, Telmisartan, and Amphotericin B) that reduced cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these comprised key Pt-transporting proteins, including ATOX1, whose suppression affected ability of ATP7B to traffic in response to cisplatin. In summary, our findings reveal Tranilast, Telmisartan, and Amphotericin B as effective drugs that selectively promote cisplatin toxicity in Pt-resistant ovarian cancer cells and underscore the efficiency of HTS strategy for identification of biosafe compounds, which might be rapidly repurposed to overcome resistance of tumors to Pt-based chemotherapy.

5.
Int J Cancer ; 125(1): 235-43, 2009 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-19358275

RESUMO

Abacavir is one of the most efficacious nucleoside analogues, with a well-characterized inhibitory activity on reverse transcriptase enzymes of retroviral origin, and has been clinically approved for the treatment of AIDS. Recently, Abacavir has been shown to inhibit also the human telomerase activity. Telomerase activity seems to be required in essentially all tumours for the immortalization of a subset of cells, including cancer stem cells. In fact, many cancer cells are dependent on telomerase for their continued replication and therefore telomerase is an attractive target for cancer therapy. Telomerase expression is upregulated in primary primitive neuroectodermal tumours and in the majority of medulloblastomas suggesting that its activation is associated with the development of these diseases. Therefore, we decided to test Abacavir activity on human medulloblastoma cell lines with high telomerase activity. We report that exposure to Abacavir induces a dose-dependent decrease in the proliferation rate of medulloblastoma cells. This is associated with a cell accumulation in the G(2)/M phase of the cell cycle in the Daoy cell line, and with increased cell death in the D283-MED cell line, and is likely to be dependent on the inhibition of telomerase activity. Interestingly, both cell lines showed features of senescence after Abacavir treatment. Moreover, after Abacavir exposure we detected, by immunofluorescence staining, increased protein expression of the glial marker glial fibrillary acidic protein and the neuronal marker synaptophysin in both medulloblastoma cell lines. In conclusion, our results suggest that Abacavir reduces proliferation and induces differentiation of human medulloblastoma cells through the downregulation of telomerase activity. Thus, using Abacavir, alone or in combination with current therapies, might be an effective therapeutic strategy for the treatment of medulloblastoma.


Assuntos
Fármacos Anti-HIV/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Cerebelares/patologia , Didesoxinucleosídeos/farmacologia , Meduloblastoma/patologia , Neoplasias Peritoneais/secundário , Ciclo Celular/efeitos dos fármacos , Neoplasias Cerebelares/tratamento farmacológico , Criança , Pré-Escolar , Imunofluorescência , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Masculino , Meduloblastoma/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sinaptofisina/metabolismo , Telomerase/genética , Telomerase/metabolismo , Células Tumorais Cultivadas
6.
J Cell Biol ; 218(3): 783-797, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30659099

RESUMO

Phosphatidylinositol-4-phosphate (PI4P), a phosphoinositide with key roles in the Golgi complex, is made by Golgi-associated phosphatidylinositol-4 kinases and consumed by the 4-phosphatase Sac1 that, instead, is an ER membrane protein. Here, we show that the contact sites between the ER and the TGN (ERTGoCS) provide a spatial setting suitable for Sac1 to dephosphorylate PI4P at the TGN. The ERTGoCS, though necessary, are not sufficient for the phosphatase activity of Sac1 on TGN PI4P, since this needs the phosphatidyl-four-phosphate-adaptor-protein-1 (FAPP1). FAPP1 localizes at ERTGoCS, interacts with Sac1, and promotes its in-trans phosphatase activity in vitro. We envision that FAPP1, acting as a PI4P detector and adaptor, positions Sac1 close to TGN domains with elevated PI4P concentrations allowing PI4P consumption. Indeed, FAPP1 depletion induces an increase in TGN PI4P that leads to increased secretion of selected cargoes (e.g., ApoB100), indicating that FAPP1, by controlling PI4P levels, acts as a gatekeeper of Golgi exit.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Proteínas de Membrana/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Retículo Endoplasmático/genética , Complexo de Golgi/genética , Células HeLa , Células Hep G2 , Humanos , Proteínas de Membrana/genética , Camundongos , Fosfatos de Fosfatidilinositol/genética
7.
J Cell Biochem ; 105(4): 956-64, 2008 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-18821585

RESUMO

The adipocyte-derived peptide leptin acts through binding to specific membrane receptors, of which six isoforms (obRa-f) have been identified up to now. Binding of leptin to its receptor induces activation of different signaling pathways, including the JAK/STAT, MAPK, IRS1, and SOCS3 signaling pathways. Since the circulating levels of leptin are elevated in obese individuals, and excess body weight has been shown to increase breast cancer risk in postmenopausal women, several studies addressed the role of leptin in breast cancer. Expression of leptin and its receptors has been demonstrated to occur in breast cancer cell lines and in human primary breast carcinoma. Leptin is able to induce the growth of breast cancer cells through activation of the Jak/STAT3, ERK1/2, and/or PI3K pathways, and can mediate angiogenesis by inducing the expression of vascular endothelial growth factor (VEGF). In addition, leptin induces transactivation of ErbB-2, and interacts in triple negative breast cancer cells with insulin like growth factor-1 (IGF-1) to transactivate the epidermal growth factor receptor (EGFR), thus promoting invasion and migration. Leptin can also affect the growth of estrogen receptor (ER)-positive breast cancer cells, by stimulating aromatase expression and thereby increasing estrogen levels through the aromatization of androgens, and by inducing MAPK-dependent activation of ER. Taken together, these findings suggest that the leptin system might play an important role in breast cancer pathogenesis and progression, and that it might represent a novel target for therapeutic intervention in breast cancer.


Assuntos
Neoplasias da Mama/patologia , Leptina/metabolismo , Transdução de Sinais , Neoplasias da Mama/metabolismo , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Leptina/genética , Leptina/fisiologia , Receptores para Leptina/genética
8.
Peptides ; 29(11): 1878-86, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18721837

RESUMO

The proline-rich antimicrobial peptide dimer, A3-APO, was designed based on a statistical analysis of native antibacterial peptide and protein sequences. Analysis of a series of structural analogs failed to identify any single or multiple amino acid modification or architectural changes that would significantly improve its potential as a clinical therapeutic. However, a single chain Chex1-Arg20 version, a natural in vivo metabolite, showed a 2 to 8-fold increase in activity against test Enterobacteriaceae strains. In addition to bacterial species close to Escherichia coli in phylogeny, A3-APO analogs were able to effectively kill Pseudomonas aeruginosa and Staphylococcus saprophyticus. Antibacterial efficacy analysis together with biochemical experiments provided further evidence for a multiple mode of action of A3-APO that includes binding and inhibition of the bacterial heat shock protein DnaK. Through inactivating of resistance enzymes, A3-APO was able to recover the lost activity of conventional antibiotics including chloramphenicol, beta-lactams, sulfonamides or trimethoprim against multidrug resistant strains with partial or full synergy. However, the synergy appeared to be individual strain and small molecule drug combination-dependent.


Assuntos
Antibacterianos/química , Peptídeos/farmacologia , Sequência de Aminoácidos , Antibacterianos/farmacologia , Desenho de Fármacos , Sinergismo Farmacológico , Proteínas de Escherichia coli/antagonistas & inibidores , Proteínas de Escherichia coli/metabolismo , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Proteínas de Choque Térmico HSP70/metabolismo , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/enzimologia , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Peptídeos/química , Prolina/química , Ligação Proteica , Relação Estrutura-Atividade , beta-Galactosidase/antagonistas & inibidores
9.
Cell Cycle ; 11(18): 3415-20, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-22894932

RESUMO

Hormone-dependent tumors are characterized by deregulated activity of specific steroid receptors, allowing aberrant expression of many genes involved in cancer initiation, progression and metastasis. In prostate cancer, the androgen receptor (AR) protein has pivotal functions, and over the years it has been the target of different drugs. AR is a nuclear receptor whose activity is regulated by a phosphorylation mechanism controlled by hormone and growth factors. Following phosphorylation, AR interacts with many cofactors that closely control its function. Among such cofactors, Pin1 is a peptidyl-prolyl isomerase that is involved in the control of protein phosphorylation and has a prognostic value in prostate cancer. In the present study, we demonstrate that ARSer81 is involved in the interaction with Pin1, and that this interaction is important for the transcriptional activity of AR. Since Pin1 expression positively correlates with tumor grade, our results suggest that Pin1 can participate in this process by modulating AR function.


Assuntos
Peptidilprolil Isomerase/metabolismo , Receptores Androgênicos/química , Receptores Androgênicos/metabolismo , Serina/metabolismo , Linhagem Celular Tumoral , Di-Hidrotestosterona/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Peptidilprolil Isomerase de Interação com NIMA , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/genética
10.
Curr Top Med Chem ; 10(10): 1036-45, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20370654

RESUMO

Adenosine and its receptors play different roles in normal and patho-physiological conditions. For these reasons, many laboratories have focused their attention on dissecting the molecular pathway underlying the mechanism of action of this nucleoside with the final goal being to design new drugs. Wide expression and overlapping functions have been the major problems to designing specific adenosine agonists and antagonists with few associated negative side effects. Engineered mice have helped to dissect the single adenosine receptor function in specific tissues and pathological conditions. All these efforts in the last 20 years have led to the design of more than 2000 compounds, some of them now in clinical trials for treating different pathologies. In this review, we highlight the mouse animal models that have been of use in designing new selective drugs as well as discuss the main adenosine receptor ligands in clinical trials.


Assuntos
Adenosina/uso terapêutico , Receptores Purinérgicos P1/metabolismo , Adenosina/análogos & derivados , Adenosina/química , Adenosina/farmacologia , Animais , Ensaios Clínicos como Assunto , Humanos , Ligantes , Relação Estrutura-Atividade
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