Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 17 de 17
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Cancer ; 22(1): 40, 2023 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-36810079

RESUMO

Lung cancer is the primary cause of mortality in the United States and around the globe. Therapeutic options for lung cancer treatment include surgery, radiation therapy, chemotherapy, and targeted drug therapy. Medical management is often associated with the development of treatment resistance leading to relapse. Immunotherapy is profoundly altering the approach to cancer treatment owing to its tolerable safety profile, sustained therapeutic response due to immunological memory generation, and effectiveness across a broad patient population. Different tumor-specific vaccination strategies are gaining ground in the treatment of lung cancer. Recent advances in adoptive cell therapy (CAR T, TCR, TIL), the associated clinical trials on lung cancer, and associated hurdles are discussed in this review. Recent trials on lung cancer patients (without a targetable oncogenic driver alteration) reveal significant and sustained responses when treated with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint blockade immunotherapies. Accumulating evidence indicates that a loss of effective anti-tumor immunity is associated with lung tumor evolution. Therapeutic cancer vaccines combined with immune checkpoint inhibitors (ICI) can achieve better therapeutic effects. To this end, the present article encompasses a detailed overview of the recent developments in the immunotherapeutic landscape in targeting small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Additionally, the review also explores the implication of nanomedicine in lung cancer immunotherapy as well as the combinatorial application of traditional therapy along with immunotherapy regimens. Finally, ongoing clinical trials, significant obstacles, and the future outlook of this treatment strategy are also highlighted to boost further research in the field.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Imunoterapia , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Recidiva Local de Neoplasia , Carcinoma de Pequenas Células do Pulmão/terapia
2.
Acta Pharmacol Sin ; 43(11): 2759-2776, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35379933

RESUMO

Three major approaches of cancer therapy can be enunciated as delivery of biotherapeutics, tumor image analysis, and immunotherapy. Liposomes, artificial fat bubbles, are long known for their capacity to encapsulate a diverse range of bioactive molecules and release the payload in a sustained, stimuli-responsive manner. They have already been widely explored as a delivery vehicle for therapeutic drugs as well as imaging agents. They are also extensively being used in cancer immunotherapy. On the other hand, exosomes are naturally occurring nanosized extracellular vesicles that serve an important role in cell-cell communication. Importantly, the exosomes also have proven their capability to carry an array of active pharmaceuticals and diagnostic molecules to the tumor cells. Exosomes, being enriched with tumor antigens, have numerous immunomodulatory effects. Much to our intrigue, in recent times, efforts have been directed toward developing smart, bioengineered, exosome-liposome hybrid nanovesicles, which are augmented by the benefits of both vesicular systems. This review attempts to summarize the contemporary developments in the use of exosome and liposome toward cancer diagnosis, therapy, as a vehicle for drug delivery, diagnostic carrier for tumor imaging, and cancer immunotherapy. We shall also briefly reflect upon the recent advancements of the exosome-liposome hybrids in cancer therapy. Finally, we put forward future directions for the use of exosome/liposome and/or hybrid nanocarriers for accurate diagnosis and personalized therapies for cancers.


Assuntos
Exossomos , Vesículas Extracelulares , Neoplasias , Humanos , Lipossomos , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos
3.
Drug Discov Today ; 27(1): 82-101, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34252612

RESUMO

WNT/ß-catenin signaling orchestrates various physiological processes, including embryonic development, growth, tissue homeostasis, and regeneration. Abnormal WNT/ß-catenin signaling is associated with various cancers and its inhibition has shown effective antitumor responses. In this review, we discuss the pathway, potential targets for the development of WNT/ß-catenin inhibitors, available inhibitors, and their specific molecular interactions with the target proteins. We also discuss inhibitors that are in clinical trials and describe potential new avenues for therapeutically targeting the WNT/ß-catenin pathway. Furthermore, we introduce emerging strategies, including artificial intelligence (AI)-assisted tools and technology-based actionable approaches, to translate WNT/ß-catenin inhibitors to the clinic for cancer therapy.


Assuntos
Produtos Biológicos/farmacologia , Terapia de Alvo Molecular , Neoplasias , Via de Sinalização Wnt , Desenho de Fármacos , Humanos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/fisiologia
4.
Ann Biomed Eng ; 49(4): 1128-1150, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33674908

RESUMO

The need for bone grafts is tremendous, and that leads to the use of autograft, allograft, and bone graft substitutes. The biology of the bone is quite complex regarding cellular composition and architecture, hence developing a mineralized connective tissue graft is challenging. Traditionally used bone graft substitutes including metals, biomaterial coated metals and biodegradable scaffolds, suffer from persistent limitations. With the advent and rise of additive manufacturing technologies, the future of repairing bone trauma and defects seems to be optimistic. 3D printing has significant advantages, the foremost of all being faster manipulation of various biocompatible materials and live cells or tissues into the complex natural geometries necessary to mimic and stimulate cellular bone growth. The advent of new-generation bioprinters working with high-precision, micro-dispensing and direct digital manufacturing is aiding in ground-breaking organ and tissue printing, including the bone. The future bone replacement for patients holds excellent promise as scientists are moving closer to the generation of better 3D printed bio-bone grafts that will be safer and more effective. This review aims to summarize the advances in scaffold fabrication techniques, emphasizing 3D printing of biomimetic bone grafts.


Assuntos
Substitutos Ósseos , Impressão Tridimensional , Alicerces Teciduais , Animais , Biomimética , Transplante Ósseo , Osso e Ossos , Humanos
5.
Cell Stem Cell ; 27(3): 413-429.e4, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32721381

RESUMO

Our understanding of dynamic interactions between airway basal stem cells (ABSCs) and their signaling niches in homeostasis, injury, and aging remains elusive. Using transgenic mice and pharmacologic studies, we found that Wnt/ß-catenin within ABSCs was essential for proliferation post-injury in vivo. ABSC-derived Wnt ligand production was dispensable for epithelial proliferation. Instead, the PDGFRα+ lineage in the intercartilaginous zone (ICZ) niche transiently secreted Wnt ligand necessary for ABSC proliferation. Strikingly, ABSC-derived Wnt ligand later drove early progenitor differentiation to ciliated cells. We discovered additional changes in aging, as glandular-like epithelial invaginations (GLEIs) derived from ABSCs emerged exclusively in the ICZ of aged mice and contributed to airway homeostasis and repair. Further, ABSC Wnt ligand secretion was necessary for GLEI formation, and constitutive activation of ß-catenin in young mice induced their formation in vivo. Collectively, these data underscore multiple spatiotemporally dynamic Wnt-secreting niches that regulate functionally distinct phases of airway regeneration and aging.


Assuntos
Células-Tronco , beta Catenina , Envelhecimento , Animais , Diferenciação Celular , Proliferação de Células , Camundongos , Camundongos Transgênicos , Células-Tronco/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo
6.
Am J Transl Res ; 12(2): 409-427, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32194893

RESUMO

Oncogenic KRAS mutations are frequently found in non-small cell lung carcinoma (NSCLC) and cause constitutive activation of the MEK-ERK pathway. Many cancer types have been shown to overexpress PD-L1 to escape immune surveillance. FRA1 is a MEK/ERK-dependent oncogenic transcription factor and a member of the AP-1 transcriptional factor superfamily. This study assesses the hypothesis that KRAS mutation directly regulates PD-L1 expression through the MEK-ERK pathway mediated by FRA1. Premalignant human bronchial epithelial cell (HBEC) lines harboring the KRAS mutationV12, EGFR mutation, p53 knock-down, or both KRAS mutation and p53 knock-down were tested for levels of PD-L1, FRA1, and ERK activation (pERK). Our results showed that KRAS mutation alone, but not other genetic alterations, induced significantly higher expression of PD-L1 compared to its vector counterparts. The increased PD-L1 expression in the KRAS mutated cells was dramatically reduced by inhibition of ERK activation. Furthermore, the MEK-ERK pathway-dependent PD-L1 expression was markedly reduced by FRA1 silencing. Interestingly, FRA1 silencing led to inhibition of ERK activation, indicating that FRA1 plays a role in PD-L1 regulation via positive feedback of ERK activation. Correlation of PD-L1 and FRA1 mRNA expression was validated using human lung cancer specimens from The Cancer Genome Atlas (TCGA) and established NSCLC cell lines from Cancer Cell Line Encyclopedia (CCLE). FRA1 expression was significantly associated with PD-L1 expression, and high FRA1 expression was correlated with poor overall survival. Our findings suggest that oncogenic KRAS-driven PD-L1 expression is dependent on MEK-ERK and FRA1 in high risk, premalignant HBEC.

7.
Cell Rep ; 30(7): 2055-2064.e5, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32075752

RESUMO

Mechanisms underpinning airway epithelial homeostatic maintenance and ways to prevent its dysregulation remain elusive. Herein, we identify that ß-catenin phosphorylated at Y489 (p-ß-cateninY489) emerges during human squamous lung cancer progression. This led us to develop a model of airway basal stem cell (ABSC) hyperproliferation by driving Wnt/ß-catenin signaling, resulting in a morphology that resembles premalignant lesions and loss of ciliated cell differentiation. To identify small molecules that could reverse this process, we performed a high-throughput drug screen for inhibitors of Wnt/ß-catenin signaling. Our studies unveil Wnt inhibitor compound 1 (WIC1), which suppresses T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) activity, reduces ABSC proliferation, induces ciliated cell differentiation, and decreases nuclear p-ß-cateninY489. Collectively, our work elucidates a dysregulated Wnt/p-ß-cateninY489 axis in lung premalignancy that can be modeled in vitro and identifies a Wnt/ß-catenin inhibitor that promotes airway homeostasis. WIC1 may therefore serve as a tool compound in regenerative medicine studies with implications for restoring normal airway homeostasis after injury.


Assuntos
Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Proteínas Wnt/antagonistas & inibidores , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Brônquios/citologia , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Brônquios/patologia , Diferenciação Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Ensaios de Triagem em Larga Escala/métodos , Homeostase/efeitos dos fármacos , Humanos , Pulmão/citologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Bibliotecas de Moléculas Pequenas/farmacologia , Células-Tronco/citologia , Células-Tronco/patologia , Transfecção , Proteínas Wnt/metabolismo , beta Catenina/antagonistas & inibidores , beta Catenina/metabolismo
8.
Anat Cell Biol ; 52(3): 226-235, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31598350

RESUMO

The human quest to master the anatomy and physiology of living systems started as early as 1600 BC, with documents from the Greeks, Indians, and Romans presenting the earliest systematic studies and advances. Following the fall of the Roman Empire, the progress slowed until the Renaissance renewed scientific interest in anatomy and physiology, ushering in an era of spectacular advances. Alongside the discoveries of modern science, innovations in media such as printing, photography and color reproduction, improved the accuracy of communicating science. Techniques for noninvasively viewing the human body, such as magnetic resonance imaging, opened up new ways of exploring and understanding anatomy, physiology, and disease pathogenesis. Advances in three-dimensional (3D)-technologies, including computer graphics and animation are directly linked to many advances in medicine and surgery. Anatomy education has come a long way from papyrus leaf inscriptions to computerized 3D modeling, holographic representation, and virtual reality-based software. The future presents unlimited options for studying and understanding anatomy as Google glasses, bioprinting, virtual reality, and allied technologies transform the world into a classroom. This review summarizes the journey of mankind to master anatomy and physiology.

9.
Am J Pathol ; 189(3): 648-664, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30593824

RESUMO

The Food and Drug Administration-approved clinical dose (1.5 mg/mL) of bone morphogenetic protein-2 (BMP2) has been reported to induce significant adverse effects, including cyst-like adipose-infiltrated abnormal bone formation. These undesirable complications occur because of increased adipogenesis, at the expense of osteogenesis, through BMP2-mediated increases in the master regulatory gene for adipogenesis, peroxisome proliferator-activated receptor-γ (PPARγ). Inhibiting PPARγ during osteogenesis has been suggested to drive the differentiation of bone marrow stromal/stem cells toward an osteogenic, rather than an adipogenic, lineage. We demonstrate that knocking down PPARγ while concurrently administering BMP2 can reduce adipogenesis, but we found that it also impairs BMP2-induced osteogenesis and leads to bone nonunion in a mouse femoral segmental defect model. In addition, in vitro studies using the mouse bone marrow stromal cell line M2-10B4 and mouse primary bone marrow stromal cells confirmed that PPARγ knockdown inhibits BMP2-induced adipogenesis; attenuates BMP2-induced cell proliferation, migration, invasion, and osteogenesis; and escalates BMP2-induced cell apoptosis. More important, BMP receptor 2 and 1B expression was also significantly inhibited by the combined BMP2 and PPARγ knockdown treatment. These findings indicate that PPARγ is critical for BMP2-mediated osteogenesis during bone repair. Thus, uncoupling BMP2-mediated osteogenesis and adipogenesis using PPARγ inhibition to combat BMP2's adverse effects may not be feasible.


Assuntos
Proteína Morfogenética Óssea 2/metabolismo , Regeneração Óssea , Fêmur , Osteogênese , PPAR gama/metabolismo , Adipogenia/genética , Animais , Proteína Morfogenética Óssea 2/farmacologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Fêmur/lesões , Fêmur/metabolismo , Fêmur/patologia , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Camundongos Transgênicos , PPAR gama/genética
10.
Cell Stem Cell ; 15(2): 199-214, 2014 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-24953182

RESUMO

Airways are exposed to myriad environmental and damaging agents such as reactive oxygen species (ROS), which also have physiological roles as signaling molecules that regulate stem cell function. However, the functional significance of both steady and dynamically changing ROS levels in different stem cell populations, as well as downstream mechanisms that integrate ROS sensing into decisions regarding stem cell homeostasis, are unclear. Here, we show in mouse and human airway basal stem cells (ABSCs) that intracellular flux from low to moderate ROS levels is required for stem cell self-renewal and proliferation. Changing ROS levels activate Nrf2, which activates the Notch pathway to stimulate ABSC self-renewal and an antioxidant program that scavenges intracellular ROS, returning overall ROS levels to a low state to maintain homeostatic balance. This redox-mediated regulation of lung stem cell function has significant implications for stem cell biology, repair of lung injuries, and diseases such as cancer.


Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Notch/metabolismo , Células-Tronco/citologia , Traqueia/citologia , Animais , Antioxidantes/metabolismo , Ciclo Celular , Diferenciação Celular , Proliferação de Células , Homeostase , Humanos , Camundongos , Oxirredução , Polidocanol , Polietilenoglicóis/química , Transdução de Sinais , Cicatrização
11.
Stem Cells Dev ; 23(6): 664-75, 2014 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-24171691

RESUMO

Both basal and submucosal gland (SMG) duct stem cells of the airway epithelium are capable of sphere formation in the in vitro sphere assay, although the efficiency at which this occurs is very low. We sought to improve this efficiency of sphere formation by identifying subpopulations of airway basal stem cells (ABSC) and SMG duct cells based on their aldehyde dehydrogenase (ALDH) activity. ALDH(hi) ABSCs and SMG duct cells were highly enriched for the population of cells that could make spheres, while the co-culture of ALDH(hi) differentiated cells with the ALDH(hi) ABSCs increased their sphere-forming efficiency. Specific ALDH agonists and antagonists were used to show that airway specific ALDH isozymes are important for ABSC proliferation. Pathway analysis of gene expression profiling of ALDH(hi) and ALDH(lo) ABSCs revealed a significant upregulation of the arachidonic acid (AA) metabolism pathway in ALDH(hi) ABSCs. We confirmed the importance of this pathway in the metabolism of proliferating ALDH(hi) ABSCs using bioenergetics studies as well as agonists and antagonists of the AA pathway. These studies could lead to the development of novel strategies for altering ABSC proliferation in the airway epithelium.


Assuntos
Aldeído Desidrogenase/metabolismo , Diferenciação Celular/fisiologia , Proliferação de Células , Células-Tronco/enzimologia , Animais , Células Cultivadas , Técnicas de Cocultura , Camundongos Endogâmicos C57BL , Células-Tronco/citologia
12.
Stem Cells Transl Med ; 1(10): 719-24, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23197663

RESUMO

Basal cells and submucosal gland (SMG) duct cells have been isolated and shown to be stem/progenitor cell populations for the murine airway epithelium. However, methods for the isolation of basal and SMG duct cells from human airways have not been defined. We used an optimized two-step enzyme digestion protocol to strip the surface epithelium from tracheal specimens separate from SMG cells, and we then sorted the basal and duct stem/progenitors using fluorescence-activated cell sorting. We used nerve growth factor receptor, as well as a combination of CD166 and CD44, to sort basal cells and also used CD166 to isolate SMG duct cells. Sorted stem/progenitor cells were cultured to characterize their self-renewal and differentiation ability. Both basal and SMG duct cells grew into spheres. Immunostaining of the spheres showed mostly dense spheres with little to no central lumen. The spheres expressed cytokeratins 5 and 14, with some mucus- and serous-secreting cells. The sphere-forming efficiency and the rate of growth of the spheres varied widely between patient samples and correlated with the degree of hyperplasia of the epithelium. We found that only aldehyde dehydrogenase (ALDH)(hi) basal and duct cells were capable of sphere formation. Global inhibition of ALDH, as well as specific inhibition of the ALDH2 isoform, inhibited self-renewal of both basal and duct cells, thereby producing fewer and smaller spheres. In conclusion, we have developed methods to isolate basal and SMG duct cells from the surface epithelium and SMGs of human tracheas and have developed an in vitro model to characterize their self-renewal and differentiation.


Assuntos
Dissecação/métodos , Glândulas Exócrinas/química , Mucosa Respiratória/química , Células-Tronco/citologia , Traqueia/química , Aldeído Desidrogenase/antagonistas & inibidores , Aldeído Desidrogenase/química , Aldeído-Desidrogenase Mitocondrial , Antígenos CD/química , Biomarcadores/química , Moléculas de Adesão Celular Neuronais/química , Diferenciação Celular , Proliferação de Células , Separação Celular , Forma Celular , Células Cultivadas , Glândulas Exócrinas/patologia , Proteínas Fetais/química , Citometria de Fluxo/métodos , Humanos , Receptores de Hialuronatos/química , Hiperplasia/patologia , Imuno-Histoquímica , Isoflavonas/farmacologia , Queratina-14/química , Queratina-5/química , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologia , Células-Tronco/química , Células-Tronco/efeitos dos fármacos , Traqueia/patologia
13.
Biochim Biophys Acta ; 1822(6): 1030-7, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22366060

RESUMO

Focal adhesion kinase (FAK), a non-receptor protein kinase, is known to be a phosphatidyl inositol 3-kinase (PI3K) pathway activator and thus widely implicated in regulation of cell survival and cancer. In recent years FAK has also been strongly implicated as a crucial regulator of insulin resistance in peripheral tissues like skeletal muscle and liver, where decrease in its expression/activity has been shown to lead to insulin resistance. However, in the present study we report an altogether different role of FAK in regulation of insulin/PI3K signaling in neurons, the post-mitotic cells. An aberrant increase in FAK tyrosine phosphorylation was observed in insulin resistant Neuro-2a (N2A) cells. Downregulation of FAK expression utilizing RNAi mediated gene silencing in insulin resistant N2A cells completely ameliorated the impaired insulin/PI3K signaling and glucose uptake. FAK silencing in primary cortical neurons also showed marked enhancement in glucose uptake. The results thus suggest that in neurons FAK acts as a negative regulator of insulin/PI3K signaling. Interestingly, the available literature also demonstrates cell-type specific functions of FAK in neurons. FAK that is well known for its cell survival effects has been shown to be involved in neurodegeneration. Along with these previous reports, present findings highlight a novel and critical role of FAK in neurons. Moreover, as this implicates differential regulation of insulin/PI3K pathway by FAK in peripheral tissues and neuronal cells, it strongly suggests precaution while considering FAK modulators as possible therapeutics.


Assuntos
Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Resistência à Insulina , Neurônios/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Animais , Linhagem Celular Tumoral , Proteína-Tirosina Quinases de Adesão Focal/genética , Glucose/metabolismo , Insulina/metabolismo , Camundongos , Neuroblastoma , Fosforilação , Interferência de RNA , RNA Interferente Pequeno , Transdução de Sinais
14.
Stem Cells ; 29(8): 1283-93, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21710468

RESUMO

The airway epithelium is in direct contact with the environment and therefore constantly at risk for injury. Basal cells (BCs) have been found to repair the surface epithelium (SE), but the contribution of other stem cell populations to airway epithelial repair has not been identified. We demonstrated that airway submucosal gland (SMG) duct cells, in addition to BCs, survived severe hypoxic-ischemic injury. We developed a method to isolate duct cells from the airway. In vitro and in vivo models were used to compare the self-renewal and differentiation potential of duct cells and BCs. We found that only duct cells were capable of regenerating SMG tubules and ducts, as well as the SE overlying the SMGs. SMG duct cells are therefore a multipotent stem cell for airway epithelial repair This is of importance to the field of lung regeneration as determining the repairing cell populations could lead to the identification of novel therapeutic targets and cell-based therapies for patients with airway diseases.


Assuntos
Células-Tronco Multipotentes/patologia , Regeneração , Mucosa Respiratória/patologia , Traqueia/patologia , Animais , Diferenciação Celular , Linhagem da Célula , Separação Celular , Rastreamento de Células , Células Cultivadas , Epitélio/patologia , Perfilação da Expressão Gênica , Hipóxia/patologia , Isquemia/patologia , Queratina-14/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Multipotentes/metabolismo , Células-Tronco Multipotentes/transplante , Análise de Sequência com Séries de Oligonucleotídeos , Traqueia/irrigação sanguínea , Traqueia/fisiopatologia
15.
Neuropharmacology ; 60(6): 910-20, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21277873

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Pharmacological treatments presently available can slow down the progression of symptoms but can not cure the disease. Currently there is widening recognition that AD is closely associated with impaired insulin signaling and glucose metabolism in brain, suggesting it to be a brain-specific form of diabetes and so also termed as "type 3 diabetes". Hence investigating the role of pharmacological agents that could ameliorate neuronal insulin resistance merit attention in AD therapeutics, however the therapeutics for pathophysiological condition like neuronal insulin resistance itself is largely unknown. In the present study we have determined the effect of metformin on neuronal insulin resistance and AD-associated characteristics in an in vitro model of "type 3 diabetes" by differentiating neuronal cell line Neuro-2a under prolonged presence of insulin. We observed that prolonged hyperinsulinemic conditions in addition to generating insulin resistance also led to development of hallmark AD-associated neuropathological changes. Treatment with metformin sensitized the impaired insulin actions and also prevented appearance of molecular and pathological characteristics observed in AD. The results thus demonstrate possible therapeutic efficacy of peripheral insulin-sensitizer drug metformin in AD by its ability to sensitize neuronal insulin resistance. These findings also provide direct evidences linking hyperinsulinemia and AD and suggest a unique opportunity for prevention and treatment of "type 3 diabetes".


Assuntos
Doença de Alzheimer/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Hiperinsulinismo/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Metformina/uso terapêutico , Neurônios/metabolismo , Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Linhagem Celular , Colinesterases/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Glucose/metabolismo , Hiperinsulinismo/induzido quimicamente , Hiperinsulinismo/complicações , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Camundongos , Neurônios/patologia , Fragmentos de Peptídeos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo
16.
BMC Cell Biol ; 9: 48, 2008 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-18771597

RESUMO

BACKGROUND: Focal Adhesion Kinase (FAK) is recently reported to regulate insulin resistance by regulating glucose uptake in C2C12 skeletal muscle cells. However, the underlying mechanism for FAK-mediated glucose transporter-4 translocation (Glut-4), responsible for glucose uptake, remains unknown. Recently actin remodeling was reported to be essential for Glut-4 translocation. Therefore, we investigated whether FAK contributes to insulin-induced actin remodeling and harbor Glut-4 for glucose transport and whether downregulation of FAK affects the remodeling and causes insulin resistance. RESULTS: To address the issue we employed two approaches: gain of function by overexpressing FAK and loss of function by siRNA-mediated silencing of FAK. We observed that overexpression of FAK induces actin remodeling in skeletal muscle cells in presence of insulin. Concomitant to this Glut-4 molecules were also observed to be present in the vicinity of remodeled actin, as indicated by the colocalization studies. FAK-mediated actin remodeling resulted into subsequent glucose uptake via PI3K-dependent pathway. On the other hand FAK silencing reduced actin remodeling affecting Glut-4 translocation resulting into insulin resistance. CONCLUSION: The data confirms that FAK regulates glucose uptake through actin reorganization in skeletal muscle. FAK overexpression supports actin remodeling and subsequent glucose uptake in a PI3K dependent manner. Inhibition of FAK prevents insulin-stimulated remodeling of actin filaments resulting into decreased Glut-4 translocation and glucose uptake generating insulin resistance. To our knowledge this is the first study relating FAK, actin remodeling, Glut-4 translocation and glucose uptake and their interrelationship in generating insulin resistance.


Assuntos
Citoesqueleto de Actina/ultraestrutura , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Resistência à Insulina/fisiologia , Insulina/farmacologia , Músculo Esquelético/enzimologia , Actinas/metabolismo , Animais , Células Cultivadas , Proteína-Tirosina Quinases de Adesão Focal/genética , Inativação Gênica , Glucose/metabolismo , Camundongos , Microscopia Confocal , Microscopia de Fluorescência , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestrutura , Fosfatidilinositol 3-Quinases/metabolismo , RNA Interferente Pequeno/metabolismo , Transfecção
17.
J Physiol ; 586(16): 3825-37, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18587052

RESUMO

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, has recently been implicated in the regulation of insulin resistance in vitro. However, its in vivo validation has not been attempted due to lethality of FAK knockout. Hence, to ascertain the role of FAK in the development of insulin resistance in vivo, we have down-regulated FAK expression by delivering FAK-specific small interfering RNA (siRNA) in mice using hydrodynamic tail vein injection. Here, we show for the first time that FAK silencing (57 +/- 0.05% in muscle and 80 +/- 0.08% in liver) exacerbates insulin signalling and causes hyperglycaemia (251.68 +/- 8.1 mg dl(-1)) and hyperinsulinaemia (3.48 +/- 0.06 ng ml(-1)) in vivo. FAK-silenced animals are less glucose tolerant and have physiological and biochemical parameters similar to that of high fat diet (HFD)-fed insulin-resistant animals. Phosphorylation and expression of insulin receptor substrate 1 (IRS-1) was attenuated by 40.2 +/- 0.03% and 35.2 +/- 0.6% in muscle and 52.3 +/- 0.04% and 40.2 +/- 0.03% in liver in FAK-silenced mice. Akt-Ser473-phosphorylation decreased in muscle and liver (50.3 +/- 0.03% and 70.2 +/- 0.02%, respectively) in FAK-silenced mice. This, in part, explains the mechanism of development of insulin resistance in FAK-silenced mice. The present study provides direct evidence that FAK is a crucial mediator of insulin resistance in vivo. Considering the lethality of FAK gene knockout the approach of this study will provide a new strategy for in vivo inhibition of FAK. Furthermore, the study should certainly motivate chemists to synthesize new chemical entities for FAK activation. This may shed light on new drug development against insulin resistance.


Assuntos
Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Hiperglicemia/enzimologia , Hiperinsulinismo/enzimologia , Resistência à Insulina , Animais , Proteína-Tirosina Quinases de Adesão Focal/genética , Masculino , Camundongos , Camundongos Knockout
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...