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1.
Adv Exp Med Biol ; 1232: 169-176, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893407

RESUMO

Inhospitable conditions within the tumor microenvironment (TME) are a characteristic feature ('hallmark') of most solid malignancies. Regional tumor hypoxia is a primary deficiency since it plays a key role in malignant progression. Severe hypoxia is often associated with other detrimental conditions in the TME as a consequence of hypoxia-/HIF-1α-induced (with/without oncogene-direction and/or reciprocal interaction of cancer cells with TME cells) metabolic re-programming, exorbitant extracellular adenosine (ADO) generation and VEGF overexpression/VEGF-R activation. Re-programming of the tumor metabolism inter alia includes a 'selfish' upregulation of aerobic glycolysis/glycolytic flux ('Warburg effect'), a strongly enhanced glutaminolysis in tumor cells, ketogenesis in cancer-associated fibroblasts, and an acceleration of the tryptophan uptake/intensified catabolism yielding kynurenine, which can support the malignant phenotype. Aerobic glycolysis and glutaminolysis result in lactate accumulation (up to 40 mM), and together with the enhanced ketogenesis and CO2/carbonic acid production lead to extracellular acidosis (pHe < 6.8). These traits of the TME individually or collectively operate towards cancer progression via e.g. promotion of genetic instability and mutation, resistance to apoptosis, clonal selection, limitless cell survival and sustained proliferation, continuous angiogenesis and tumor growth, local invasion and distant metastasis, anti-tumor immunosuppression and resistance to therapy.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia , Neoplasias , Hipóxia Tumoral , Microambiente Tumoral , Linhagem Celular Tumoral , Progressão da Doença , Glicólise , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias/fisiopatologia , Fenótipo
2.
Adv Exp Med Biol ; 1131: 605-623, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646527

RESUMO

Transient receptor potential (TRP) cation channel superfamily plays important roles in a variety of cellular processes such polymodal cellular sensing, adhesion, polarity, proliferation, differentiation and apoptosis. The expression of TRP channels is strictly regulated and their de-regulation can stimulate cancer development and progression.In human cancers, specific miRNAs are expressed in different tissues, and changes in the regulation of gene expression mediated by specific miRNAs have been associated with carcinogenesis. Several miRNAs/TRP channel pairs have been reported to play an important role in tumor biology. Thus, the TRPM1 gene regulates melanocyte/melanoma behaviour via TRPM1 and microRNA-211 transcripts. Both miR-211 and TRPM1 proteins are regulated through microphthalmia-associated transcription factor (MIFT) and the expression of miR-211 is decreased during melanoma progression. Melanocyte phenotype and melanoma behaviour strictly depend on dual TRPM1 activity, with loss of TRPM1 protein promoting melanoma aggressiveness and miR-211 expression supporting tumour suppressor. TRPM3 plays a major role in the development and progression of human clear cell renal cell carcinoma (ccRCC) with von Hippel-Lindau (VHL) loss. TRPM3, a direct target of miR-204, is enhanced in ccRCC with inactivated or deleted VHL. Loss of VHL inhibits miR-204 expression that lead to increased oncogenic autophagy. Therefore, the understanding of specific TRP channels/miRNAs molecular pathways in distinct tumors could provide a clinical rationale for target therapy in cancer.


Assuntos
Carcinogênese , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Neoplasias , Canais de Receptores Transientes de Potencial , Carcinogênese/genética , Carcinogênese/patologia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias/fisiopatologia , Canais de Receptores Transientes de Potencial/genética , Canais de Receptores Transientes de Potencial/metabolismo
3.
Adv Exp Med Biol ; 1131: 747-770, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646533

RESUMO

The pioneering work of Richard Altman on the presence of mitochondria in cells set in motion a field of research dedicated to uncovering the secrets of the mitochondria. Despite limitations in studying the structure and function of the mitochondria, advances in our understanding of this organelle prompted the development of potential treatments for various diseases, from neurodegenerative conditions to muscular dystrophy and cancer. As the powerhouses of the cell, the mitochondria represent the essence of cellular life and as such, a selective advantage for cancer cells. Much of the function of the mitochondria relies on Ca2+ homeostasis and the presence of effective Ca2+ signaling to maintain the balance between mitochondrial function and dysfunction and subsequently, cell survival. Ca2+ regulates the mitochondrial respiration rate which in turn increases ATP synthesis, but too much Ca2+ can also trigger the mitochondrial apoptosis pathway; however, cancer cells have evolved mechanisms to modulate mitochondrial Ca2+ influx and efflux in order to sustain their metabolic demand and ensure their survival. Therefore, targeting the mitochondrial Ca2+ signaling involved in the bioenergetic and apoptotic pathways could serve as potential approaches to treat cancer patients. This chapter will review the role of Ca2+ signaling in mediating the function of the mitochondria and its involvement in health and disease with special focus on the pathophysiology of cancer.


Assuntos
Sinalização do Cálcio , Cálcio , Mitocôndrias , Neoplasias , Apoptose , Cálcio/metabolismo , Sinalização do Cálcio/fisiologia , Homeostase , Humanos , Mitocôndrias/fisiologia , Neoplasias/fisiopatologia
4.
Adv Exp Med Biol ; 1131: 1013-1030, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646543

RESUMO

Endothelial colony forming cells (ECFCs) represent the only known truly endothelial precursors. ECFCs are released in peripheral circulation to restore the vascular networks dismantled by an ischemic insult or to sustain the early phases of the angiogenic switch in solid tumors. A growing number of studies demonstrated that intracellular Ca2+ signaling plays a crucial role in driving ECFC proliferation, migration, homing and neovessel formation. For instance, vascular endothelial growth factor (VEGF) triggers intracellular Ca2+ oscillations and stimulates angiogenesis in healthy ECFCs, whereas stromal derived factor-1α promotes ECFC migration through a biphasic Ca2+ signal. The Ca2+ toolkit endowed to circulating ECFCs is extremely plastic and shows striking differences depending on the physiological background of the donor. For instance, inositol-1,4,5-trisphosphate-induced Ca2+ release from the endoplasmic reticulum is downregulated in tumor-derived ECFCs, while agonists-induced store-operated Ca2+ entry is up-regulated in renal cellular carcinoma and is unaltered in breast cancer and reduced in infantile hemangioma. This remodeling of the Ca2+ toolkit prevents VEGF-induced pro-angiogenic Ca2+ oscillations in tumor-derived ECFCs. An emerging theme of research is the dysregulation of the Ca2+ toolkit in primary myelofibrosis-derived ECFCs, as this myeloproliferative disorder may depend on a driver mutation in the calreticulin gene. In this chapter, I provide a comprehensive, but succinct, description on the architecture and role of the intracellular Ca2+ signaling toolkit in ECFCs derived from umbilical cord blood and from peripheral blood of healthy donors, cancer patients and subjects affected by primary myelofibrosis.


Assuntos
Sinalização do Cálcio , Células Endoteliais , Cálcio , Proliferação de Células , Células Cultivadas , Células Endoteliais/citologia , Células Endoteliais/patologia , Células Endoteliais/fisiologia , Humanos , Neoplasias/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
Nat Med ; 25(12): 1822-1832, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31806905

RESUMO

Although intermittent increases in inflammation are critical for survival during physical injury and infection, recent research has revealed that certain social, environmental and lifestyle factors can promote systemic chronic inflammation (SCI) that can, in turn, lead to several diseases that collectively represent the leading causes of disability and mortality worldwide, such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and neurodegenerative disorders. In the present Perspective we describe the multi-level mechanisms underlying SCI and several risk factors that promote this health-damaging phenotype, including infections, physical inactivity, poor diet, environmental and industrial toxicants and psychological stress. Furthermore, we suggest potential strategies for advancing the early diagnosis, prevention and treatment of SCI.


Assuntos
Doença Crônica/epidemiologia , Inflamação/fisiopatologia , Longevidade/genética , Doenças Autoimunes/etiologia , Doenças Autoimunes/fisiopatologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus/etiologia , Diabetes Mellitus/fisiopatologia , Humanos , Inflamação/complicações , Inflamação/epidemiologia , Estilo de Vida , Longevidade/fisiologia , Neoplasias/etiologia , Neoplasias/fisiopatologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco
6.
Adv Exp Med Biol ; 1206: 435-452, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31776997

RESUMO

Protein homeostasis is essential for maintaining cell survival. Protein synthesis and degradation coordinately regulate protein homeostasis. Chaperone-mediated autophagy (CMA) was the first lysosomal process to be discovered by which intracellular components are selectively degraded. This process involves the recognition of the substrate, the unfolding and translocation of the substrate, and the degradation of the substrate. By degrading specific target proteins in a timely manner, CMA is involved in a variety of cellular activities. In the past few years, we have acquired a better understanding of how CMA is regulated. It has been reported that peroxide accumulation, aging and/or other pathological signals interfere with CMA function, which in turn induces neurodegenerative diseases, cancer, and other diseases. Combining results from the current research, we summarize the basic processes, regulatory mechanisms, and physiological functions of CMA and discuss its critical role in the development of diseases.


Assuntos
Autofagia , Chaperonas Moleculares , Humanos , Lisossomos/metabolismo , Chaperonas Moleculares/metabolismo , Neoplasias/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia
7.
Adv Exp Med Biol ; 1168: 1-7, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31713161

RESUMO

The diagnosis, prognosis and treatment of cancer has had a great improvement due to the "omics" technologies such as genomics, proteomics, epigenomics, pharmacogenomics, and metabolomics. The technological progress of these technologies has allowed precision medicine to become a clinical reality. The study of different biomolecules such as DNA, RNA and proteins has helped to detect alterations in genes, changes in gene expression profiles and loss or gain of protein function, which allows us to make associations and better understand the cancer biology. Data obtained from different "omics" technologies gives a complementary spectrum of information that helps us to understand and unveil new information for a better diagnosis, prognosis, prediction of new molecular targets of anticancer therapies, etc. This chapter presents a general landscape of the interaction between the Pharmaco-Geno-Proteo-Metabolomic and translational medicine research in cancer.


Assuntos
Metabolômica , Neoplasias , Farmacogenética , Proteômica , Pesquisa Médica Translacional , Humanos , Metabolômica/tendências , Neoplasias/fisiopatologia , Farmacogenética/tendências , Proteômica/tendências , Pesquisa Médica Translacional/tendências
8.
Adv Exp Med Biol ; 1168: 31-42, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31713163

RESUMO

Epigenomics refers to the study of genome-wide changes in epigenetic mechanisms including DNA methylation, histone modifications and non-coding RNAs expression. The alterations in normal DNA methylation and histone acetylation/deacetylation patterns lead to deregulated transcription and chromatin organization resulting in altered gene expression profiles that facilitates tumor development and progression. In consequence, novel therapeutic strategies aimed at reversing aberrant epigenetic marks in cancer cells have been developed and used in recent molecular studies and clinical trials. Pharmaco-epigenomics is a research area, which refers to the study of epigenome changes in cancer development and how chemotherapeutic agents can reverse these aberrant epigenetic marks by targeting the epigenetic machinery. Besides, the effects of genome-wide polymorphisms in populations leading to variations in drug response are also study subject of pharmaco-epigenomics and are being studied extensively in cancer. Recent findings showed that drug response could be largely influenced by the presence of aberrant epigenetic marks of the whole genome. This implies that biological pathways and cellular processes are under the impact of epigenome status. However, data about the relationship between drug response and the epigenomic variations is still scarce mainly because the epigenome is highly variable between individuals. The present chapter reviewed the advances on the epigenetics changes mainly DNA methylation and histones modifications on cervical and breast human cancers. A special emphasis in how they could be used as targets for the development and use of novel drugs in cancer therapy is delineated.


Assuntos
Epigenômica , Farmacogenética , Pesquisa Médica Translacional , Metilação de DNA , Epigenômica/tendências , Humanos , Neoplasias/fisiopatologia , Neoplasias/terapia , Farmacogenética/tendências , Pesquisa Médica Translacional/tendências
9.
Adv Exp Med Biol ; 1168: 103-115, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31713167

RESUMO

The past two decades have seen unprecedented advances in the field of oncogenomics. The ongoing characterization of neoplastic tissues through genomic techniques has transformed many aspects of cancer research, diagnosis, and treatment. However, identifying sequence variants with biological and clinical significance is a challenging endeavor. In order to accomplish this task, variants must be annotated and interpreted using various online resources. Data on protein structure, functional prediction, variant frequency in relevant populations, and multiple other factors have been compiled in useful databases for this purpose. Thus, understanding the available online resources for the annotation and interpretation of sequence variants is critical to aid molecular pathologists and researchers working in this space.


Assuntos
Bases de Dados Genéticas , Privacidade Genética , Neoplasias , Farmacogenética , Privacidade Genética/tendências , Variação Genética , Recursos em Saúde , Humanos , Internet , Neoplasias/fisiopatologia , Neoplasias/terapia , Análise de Sequência de DNA/normas , Análise de Sequência de DNA/tendências
10.
Adv Exp Med Biol ; 1168: 157-168, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31713171

RESUMO

Cancer is a complex group of diseases where different signaling pathways have been found to be deregulated, mainly related to cell proliferation, angiogenesis, metastasis, evasion of apoptosis and insensitivity to anti-growth sings among others. Diet plays a fundamental role in the treatment of the oncological patients, we must be aware that food can interact with certain types of cancer therapy. On the other hand, cancer therapies sometimes affect the patient's sense of smell, taste, appetite, gastric capacity or nutrient absorption, which often results in malnutrition due to the lack of essential nutriments. In this chapter we will review the effect of different metabolic disorders in cancer and mechanisms of action of some phytochemicals found in different foods like resveratrol, EGCG, curcumin and lycopene.


Assuntos
Neoplasias , Fenômenos Fisiológicos da Nutrição , Medicina de Precisão , Apoptose , Proliferação de Células , Humanos , Neoplasias/fisiopatologia , Neoplasias/terapia , Compostos Fitoquímicos/metabolismo , Medicina de Precisão/tendências
11.
BMC Complement Altern Med ; 19(1): 266, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31601198

RESUMO

BACKGROUND: Propolis is a natural bee product with a wide range of biological activities that are related to its chemical composition. The present study investigated the quantification of quercetin (Q) in Ardabil ethanol extract of propolis (AEEP), and then compared its anti-bacterial, anti- biofilm and cytotoxic effects on cancer and normal cell lines. METHOD: In the present study, the chemical composition of AEEP was determined through the high-performance liquid chromatography (HPLC). The AEEP and its main component, quercetin (Q), were evaluated in vitro against 57 oral streptococci by a broth micro-dilution method. The biofilm formation was assessed through the crystal violet staining and MTT assays. The impact of AEEP and Q anti-proliferative effect were evaluated on the fibroblast as normal and cancer cell lines (KB and A431). RESULTS: The Q concentration in the composition of AEEP was 6.9% of all its components. The findings indicated that the AEEP and Q were efficient against the cariogenic bacteria and were able to inhibit the S.mutans biofilm adherence at a sub-MIC concentration. Moreover, electron micrographs indicated the inhibition of biofilms compared to control biofilms. In addition, the AEEP and Q indicated a dose-dependent cytotoxic effect on A431 and KB cell lines. On the contrary, they had no cytotoxic effect on fibroblast cells. CONCLUSION: The results indicated that the synergistic impact of main components of AEEP was related to the inhibition of the cancer cell proliferation, cariogenic bacteria and oral biofilm formation. It may play a promising role in the complementary medicine and, it is suggested to be used as food additives.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Neoplasias/fisiopatologia , Própole/química , Streptococcus/efeitos dos fármacos , Animais , Antibacterianos/análise , Antineoplásicos/análise , Abelhas , Biofilmes/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Irã (Geográfico) , Testes de Sensibilidade Microbiana , Boca/microbiologia , Neoplasias/tratamento farmacológico , Quercetina/análise , Quercetina/farmacologia , Streptococcus/crescimento & desenvolvimento
12.
Adv Exp Med Biol ; 1164: 199-206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576550

RESUMO

Cancer cell heterogeneity is a universal feature of human tumors and represents a significant barrier to the efficacy and duration of anticancer therapies, especially targeted therapeutics. Among the heterogeneous cancer cell populations is a subpopulation of relatively quiescent cancer cells, which are in the G0/G1 cell-cycle phase and refractory to anti-mitotic drugs that target proliferative cells. These slow-cycling cells (SCCs) preexist in untreated tumors and frequently become enriched in treatment-failed tumors, raising the possibility that these cells may mediate therapy resistance and tumor relapse. Here we review several general concepts on tumor cell heterogeneity, quiescence, and tumor dormancy. We discuss the potential relationship between SCCs and cancer stem cells (CSCs). We also present our current understanding of how SCCs and cancer dormancy might be regulated. Increasing knowledge of SCCs and tumor dormancy should lead to identification of novel molecular regulators and therapeutic targets of tumor relapse, residual diseases, and metastasis.


Assuntos
Ciclo Celular , Neoplasias , Ciclo Celular/fisiologia , Humanos , Neoplasias/fisiopatologia , Células-Tronco Neoplásicas/citologia
13.
Adv Exp Med Biol ; 1141: 549-580, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571174

RESUMO

ATP-binding cassette (ABC) transporters are involved in active pumping of many diverse substrates through the cellular membrane. The transport mediated by these proteins modulates the pharmacokinetics of many drugs and xenobiotics. These transporters are involved in the pathogenesis of several human diseases. The overexpression of certain transporters by cancer cells has been identified as a key factor in the development of resistance to chemotherapeutic agents. In this chapter, the localization of ABC transporters in the human body, their physiological roles, and their roles in the development of multidrug resistance (MDR) are reviewed. Specifically, P-glycoprotein (P-GP), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP/ABCG2) are described in more detail. The potential of ABC transporters as therapeutic targets to overcome MDR and strategies for this purpose are discussed as well as various explanations for the lack of efficacy of ABC drug transporter inhibitors to increase the efficiency of chemotherapy.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Neoplasias , Transportadores de Cassetes de Ligação de ATP/metabolismo , Resistência a Múltiplos Medicamentos/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Neoplasias/fisiopatologia , Distribuição Tecidual
14.
Nat Rev Cancer ; 19(12): 686-697, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31519982

RESUMO

A research autopsy is a post-mortem medical procedure performed on a deceased individual with the primary goal of collecting tissue to support basic and translational research. This approach has increasingly been used to investigate the pathophysiological mechanisms of cancer evolution, metastasis and treatment resistance. In this Review, we discuss the rationale for the use of research autopsies in cancer research and provide an evidence-based discussion of the quality of post-mortem tissues compared with other types of biospecimens. We also discuss the advantages of using post-mortem tissues over other types of biospecimens, including the large amounts of tissue that can be obtained and the extent of multiregion sampling that is achievable, which is not otherwise possible in living patients. We highlight how the research autopsy has supported the identification of the clonal origins and modes of spread among metastases, the extent that selective pressures imposed by treatments cause bottlenecks leading to parallel and convergent tumour evolution, and the creation of rare tissue banks and patient-derived model systems. Finally, we comment on the future of the research autopsy as an integral component of precision medicine strategies.


Assuntos
Autopsia , Neoplasias/genética , Neoplasias/fisiopatologia , Neoplasias/terapia , Projetos de Pesquisa , Animais , Biomarcadores Tumorais/metabolismo , Carcinogênese , Resistencia a Medicamentos Antineoplásicos , Evolução Molecular , Humanos , Metástase Neoplásica , Medicina de Precisão , Manejo de Espécimes
15.
J Appl Oral Sci ; 27: e20180596, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31508793

RESUMO

Bone development and healing processes involve a complex cascade of biological events requiring well-orchestrated synergism with bone cells, growth factors, and other trophic signaling molecules and cellular structures. Beyond health processes, MMPs play several key roles in the installation of heart and blood vessel related diseases and cancer, ranging from accelerating metastatic cells to ectopic vascular mineralization by smooth muscle cells in complementary manner. The tissue inhibitors of MMPs (TIMPs) have an important role in controlling proteolysis. Paired with the post-transcriptional efficiency of specific miRNAs, they modulate MMP performance. If druggable, these molecules are suggested to be a platform for development of "smart" medications and further clinical trials. Thus, considering the pleiotropic effect of MMPs on mammals, the purpose of this review is to update the role of those multifaceted proteases in mineralized tissues in health, such as bone, and pathophysiological disorders, such as ectopic vascular calcification and cancer.


Assuntos
Remodelação Óssea/fisiologia , Matriz Extracelular/fisiologia , Metaloproteinases da Matriz/fisiologia , Doenças Ósseas/metabolismo , Doenças Ósseas/fisiopatologia , Progressão da Doença , Humanos , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Osteoblastos/fisiologia , Inibidores Teciduais de Metaloproteinases/fisiologia , Calcificação Vascular/metabolismo , Calcificação Vascular/fisiopatologia
16.
Adv Exp Med Biol ; 1161: 1-2, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31562616

RESUMO

In addition to this introduction, this book contains 18 outstanding chapters based on comprehensive and detailed reviews of timely topics presented at the 15th International Conference on Bioactive Lipids in Cancer, Inflammation and Related Diseases held in Puerto Vallarta, Mexico on October 22-25, 2017.


Assuntos
Inflamação , Lipídeos , Neoplasias , Congressos como Assunto , Humanos , Lipídeos/fisiologia , México , Neoplasias/fisiopatologia
17.
Adv Exp Med Biol ; 1161: 193-217, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31562631

RESUMO

Headache is a common complaint after mild traumatic brain injury (mTBI). Changes in the CNS lipidome were previously associated with acrolein-induced headache in rodents. mTBI caused similar headache-like symptoms in rats; therefore, we tested the hypothesis that mTBI might likewise alter the lipidome. Using a stereotaxic impactor, rats were given either a single mTBI or a series of 4 mTBIs 48 h apart. 72 h later for single mTBI and 7 days later for repeated mTBI, the trigeminal ganglia (TG), trigeminal nucleus (TNC), and cerebellum (CER) were isolated. Using HPLC/MS/MS, ~80 lipids were measured in each tissue and compared to sham controls. mTBI drove widespread alterations in lipid levels. Single mTBI increased arachidonic acid and repeated mTBI increased prostaglandins in all 3 tissue types. mTBI affected multiple TRPV agonists, including N-arachidonoyl ethanolamine (AEA), which increased in the TNC and CER after single mTBI. After repeated mTBI, AEA increased in the TG, but decreased in the TNC. Common to all tissue types in single and repeated mTBI was an increase the AEA metabolite, N-arachidonoyl glycine, a potent activator of microglial migration. Changes in the CNS lipidome associated with mTBI likely play a role in headache and in long-term neurodegenerative effects of repeated mTBI.


Assuntos
Lesões Encefálicas Traumáticas , Sistema Nervoso Central , Cefaleia , Inflamação , Lipídeos , Neoplasias , Animais , Lesões Encefálicas Traumáticas/fisiopatologia , Sistema Nervoso Central/fisiopatologia , Cefaleia/fisiopatologia , Inflamação/fisiopatologia , Lipídeos/química , Lipídeos/genética , Lipídeos/fisiologia , Neoplasias/fisiopatologia , Ratos
18.
Adv Gerontol ; 32(3): 311-315, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31512415

RESUMO

The mini-review is presented about contribution of estrogens and other hormones to the etiopathogeny of tumors, as well as in phenomena of perinatal programming / imprinting for various cancer types. In addition, the article considers the importance of endocrine disruptors in the ontopathogeny of some oncologic diseases. Special focus is made on important role of stress and glucocorticoids, as referred to neoplastic growth. The necessity is suggested for higher attention to the maintenance of balance between cellular proliferation, survival and apoptosis, as the basis for bioregulation of normal and pathologic growth.


Assuntos
Hormônios , Neoplasias , Hormônios/metabolismo , Humanos , Neoplasias/fisiopatologia
19.
PLoS Comput Biol ; 15(9): e1007361, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31545788

RESUMO

The co-evolutionary dynamics of competing populations can be strongly affected by frequency-dependent selection and spatial population structure. As co-evolving populations grow into a spatial domain, their initial spatial arrangement and their growth rate differences are important factors that determine the long-term outcome. We here model producer and free-rider co-evolution in the context of a diffusive public good (PG) that is produced by the producers at a cost but evokes local concentration-dependent growth benefits to all. The benefit of the PG can be non-linearly dependent on public good concentration. We consider the spatial growth dynamics of producers and free-riders in one, two and three dimensions by modeling producer cell, free-rider cell and public good densities in space, driven by the processes of birth, death and diffusion (cell movement and public good distribution). Typically, one population goes extinct, but the time-scale of this process varies with initial conditions and the growth rate functions. We establish that spatial variation is transient regardless of dimensionality, and that structured initial conditions lead to increasing times to get close to an extinction state, called ε-extinction time. Further, we find that uncorrelated initial spatial structures do not influence this ε-extinction time in comparison to a corresponding well-mixed (non-spatial) system. In order to estimate the ε-extinction time of either free-riders or producers we derive a slow manifold solution. For invading populations, i.e. for populations that are initially highly segregated, we observe a traveling wave, whose speed can be calculated. Our results provide quantitative predictions for the transient spatial dynamics of cooperative traits under pressure of extinction.


Assuntos
Biologia Computacional/métodos , Teoria do Jogo , Modelos Teóricos , Dinâmica Populacional , Bactérias/citologia , Humanos , Neoplasias/fisiopatologia , Dinâmica não Linear , Comportamento Espacial , Fatores de Tempo
20.
Nat Commun ; 10(1): 4224, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31530811

RESUMO

Mitotic catastrophe is a broad descriptor encompassing unclear mechanisms of cell death. Here we investigate replication stress-driven mitotic catastrophe in human cells and identify that replication stress principally induces mitotic death signalled through two independent pathways. In p53-compromised cells we find that lethal replication stress confers WAPL-dependent centromere cohesion defects that maintain spindle assembly checkpoint-dependent mitotic arrest in the same cell cycle. Mitotic arrest then drives cohesion fatigue and triggers mitotic death through a primary pathway of BAX/BAK-dependent apoptosis. Simultaneously, a secondary mitotic death pathway is engaged through non-canonical telomere deprotection, regulated by TRF2, Aurora B and ATM. Additionally, we find that suppressing mitotic death in replication stressed cells results in distinct cellular outcomes depending upon how cell death is averted. These data demonstrate how replication stress-induced mitotic catastrophe signals cell death with implications for cancer treatment and cancer genome evolution.


Assuntos
Apoptose , Proteínas de Transporte/metabolismo , Replicação do DNA , Mitose , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Telômero/metabolismo , Morte Celular , Linhagem Celular Tumoral , Humanos , Neoplasias/genética , Neoplasias/fisiopatologia , Telômero/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
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