RESUMO
The knowledge about cellular senescence expands dynamically, providing more and more conclusive evidence of its triggers, mechanisms, and consequences. Senescence-associated secretory phenotype (SASP), one of the most important functional traits of senescent cells, is responsible for a large extent of their context-dependent activity. Both SASP's components and signaling pathways are well-defined. A literature review shows, however, that a relatively underinvestigated aspect of senescent cell autocrine and paracrine activity is the change in the production of proteins responsible for the reception and transmission of SASP signals, i.e., receptors and binding proteins. For this reason, we present in this article the current state of knowledge regarding senescence-associated changes in cellular receptors and insulin-like growth factor binding proteins. We also discuss the role of these alterations in senescence induction and maintenance, pro-cancerogenic effects of senescent cells, and aging-related structural and functional malfunctions.
Assuntos
Senescência Celular , Humanos , Senescência Celular/fisiologia , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Animais , Fenótipo Secretor Associado à Senescência , Transdução de SinaisRESUMO
Carboplatin (CPT) and paclitaxel (PCT) are the optimal non-surgical treatment of epithelial ovarian cancer (EOC). Although their growth-restricting influence on EOC cells is well known, their impact on normal peritoneal cells, including mesothelium (PMCs) and fibroblasts (PFBs), is poorly understood. Here, we investigated whether, and if so, by what mechanism, CPT and PCT induce senescence of omental PMCs and PFBs. In addition, we tested whether PMC and PFB exposure to the drugs promotes the development of a pro-cancerogenic phenotype. The results showed that CPT and PCT induce G2/M growth arrest-associated senescence of normal peritoneal cells and that the strongest induction occurs when the drugs act together. PMCs senesce telomere-independently with an elevated p16 level and via activation of AKT and STAT3. In PFBs, telomeres shorten along with an induction of p21 and p53, and their senescence proceeds via the activation of ERK1/2. Oxidative stress in CPT + PCT-treated PMCs and PFBs is extensive and contributes causatively to their premature senescence. Both PMCs and PFBs exposed to CPT + PCT fuel the proliferation, migration, and invasion of established (A2780, OVCAR-3, SKOV-3) and primary EOCs, and this activity is linked with an overproduction of multiple cytokines altering the cancer cell transcriptome and controlled by p38 MAPK, NF-κB, STAT3, Notch1, and JAK1. Collectively, our findings indicate that CPT and PCT lead to iatrogenic senescence of normal peritoneal cells, which paradoxically and opposing therapeutic needs alters their phenotype towards pro-cancerogenic. It cannot be excluded that these adverse outcomes of chemotherapy may contribute to EOC relapse in the case of incomplete tumor eradication and residual disease initiation. © 2023 The Pathological Society of Great Britain and Ireland.
Assuntos
Neoplasias Ovarianas , Paclitaxel , Humanos , Feminino , Carboplatina/farmacologia , Paclitaxel/farmacologia , Linhagem Celular Tumoral , Apoptose , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Senescência Celular , Recidiva Local de Neoplasia/patologia , Epitélio/patologia , Carcinoma Epitelial do Ovário/patologia , Fibroblastos/patologiaRESUMO
Awakening and growth reinitiation by dormant cells may contribute to epithelial ovarian cancer (EOC) relapse. The links between these phenomena are loose because of the limited stock of compelling models of EOC dormancy. Here, we show a simple and convenient dormancy research protocol based on serum starvation. This study was conducted on established EOC cell lines A2780, OVCAR-3, and SKOV-3, as well as on primary EOC cells. Cell growth arrest and proliferation were monitored by assessing the Ki67 antigen, PKH26 fluorescence, and cell cycle distribution. In addition, cells were tested for ERK1/2/p38 MAPK activity ratio, apoptosis, and senescence. The study showed that 72-h serum starvation induces G0/G1 growth arrest of a significant fraction of cells, accompanied by reduced Ki67 and ERK1/2/p38 MAPK activity ratio, without signs of apoptosis or cellular senescence. Moreover, providing cells with 72 h of a medium enriched in 5% serum allows the culture to regain its proliferative potential. At the same time, we attempted to induce and terminate dormancy with Mitomycin C addition and withdrawal, which were unsuccessful. In conclusion, serum starvation is a convenient way to reliably induce dormancy in EOC cells, allowing them to be efficiently awakened for further mechanistic research in vitro.
RESUMO
Kisspeptin (KP, encoded by Kiss1, binding to the Gpr54 receptor) is a neuropeptide conveying information on the metabolic status to the hypothalamic-pituitary-gonadal axis. KP acts together with dynorphin A (encoded by Pdyn) and neurokinin B (encoded by Tac2) to regulate reproduction. KP is crucial for the onset of puberty and is under the control of sirtuin (encoded by Sirt1). We hypothesize that the maternal cafeteria (CAF) diet has adverse effects on the offspring's hormonal, metabolic, and reproductive functions due to sex-specific alterations in the expression of Kiss1, Gpr54, Pdyn, Tac2, and Sirt1 in the hypothalamus, and Kiss1, Gpr54, and Sirt1 in the liver. Rats were fed a CAF diet before pregnancy, during pregnancy, and during lactation. The vaginal opening was monitored. Offspring were sacrificed in three age points: PND 30, PND 35, and PND 60 (females) and PND 40, PND 45, and PND 60 (males). Their metabolic and hormonal status was assessed. mRNA for Kiss1, Gpr54, Pdyn, Tac2, and Sirt1 were measured by real-time PCR in the hypothalamus and/or livers. We found that CAF offspring had lower weight and altered body composition; increased cholesterol and triglyceride levels, sex-specific changes in glucose and insulin levels; sex-dependent changes in Sirt1/Kiss1 mRNA ratio in the hypothalamus; sex-specific alterations in Kiss1 and Sirt1 mRNA in the liver with more diversity in males; and a delayed puberty onset in females. We concluded that the mother's CAF diet leads to sex-specific alterations in metabolic and reproductive outcomes via Kiss1/Gpr54 and Sirt1 systems in offspring.
Assuntos
Kisspeptinas , Sirtuína 1 , Gravidez , Feminino , Masculino , Ratos , Animais , Kisspeptinas/genética , Kisspeptinas/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Maturidade Sexual/fisiologia , Receptores de Kisspeptina-1/genética , Receptores de Kisspeptina-1/metabolismo , Dieta , Metaboloma , RNA Mensageiro/metabolismoRESUMO
Oncologic patients are subjected to four major treatment types: surgery, radiotherapy, chemotherapy, and immunotherapy. All nonsurgical forms of cancer management are known to potentially violate the structural and functional integrity of the cardiovascular system. The prevalence and severity of cardiotoxicity and vascular abnormalities led to the emergence of a clinical subdiscipline, called cardiooncology. This relatively new, but rapidly expanding area of knowledge, primarily focuses on clinical observations linking the adverse effects of cancer therapy with deteriorated quality of life of cancer survivors and their increased morbidity and mortality. Cellular and molecular determinants of these relations are far less understood, mainly because of several unsolved paths and contradicting findings in the literature. In this article, we provide a comprehensive view of the cellular and molecular etiology of cardiooncology. We pay particular attention to various intracellular processes that arise in cardiomyocytes, vascular endothelial cells, and smooth muscle cells treated in experimentally-controlled conditions in vitro and in vivo with ionizing radiation and drugs representing diverse modes of anti-cancer activity.
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Células Endoteliais , Qualidade de Vida , Humanos , Miócitos Cardíacos , Imunoterapia , Miócitos de Músculo LisoRESUMO
The prenatal period, during which a fully formed newborn capable of surviving outside its mother's body is built from a single cell, is critical for human development. It is also the time when the foetus is particularly vulnerable to environmental factors, which may modulate the course of its development. Both epidemiological and animal studies have shown that foetal programming of physiological systems may alter the growth and function of organs and lead to pathology in adulthood. Nutrition is a particularly important environmental factor for the pregnant mother as it affects the condition of offspring. Numerous studies have shown that an unbalanced maternal metabolic status (under- or overnutrition) may cause long-lasting physiological and behavioural alterations, resulting in metabolic disorders, such as obesity and type 2 diabetes (T2DM). Various diets are used in laboratory settings in order to induce maternal obesity and metabolic disorders, and to alter the offspring development. The most popular models are: high-fat, high-sugar, high-fat-high-sugar, and cafeteria diets. Maternal undernutrition models are also used, which results in metabolic problems in offspring. Similarly to animal data, human studies have shown the influence of mothers' diets on the development of children. There is a strong link between the maternal diet and the birth weight, metabolic state, changes in the cardiovascular and central nervous system of the offspring. The mechanisms linking impaired foetal development and adult diseases remain under discussion. Epigenetic mechanisms are believed to play a major role in prenatal programming. Additionally, sexually dimorphic effects on offspring are observed. Therefore, further research on both sexes is necessary.
Assuntos
Diabetes Mellitus Tipo 2 , Hipernutrição , Adulto , Animais , Peso ao Nascer , Diabetes Mellitus Tipo 2/complicações , Feminino , Feto/metabolismo , Humanos , Masculino , Obesidade/metabolismo , Hipernutrição/metabolismo , GravidezRESUMO
"Western diet" containing high concentrations of sugar and fat consumed during pregnancy contributes to development of obesity and diabetes type 2 in offspring. To mimic effects of this diet in animals, a cafeteria (CAF) diet is used. We hypothesized that CAF diet given to rats before, and during pregnancy and lactation differently influences fat content, metabolic and inflammation profiles in offspring. Females were exposed to CAF or control diets before pregnancy, during pregnancy and lactation. At postnatal day 25 (PND 25), body composition, fat contents were measured, and blood was collected for assessment of metabolic and inflammation profiles. We have found that CAF diet lead to sex-specific alterations in offspring. At PND25, CAF offspring had: (1) higher percentage of fat content, and were lighter; (2) sex-specific differences in levels of glucose; (3) higher levels of interleukin 6 (IL-6), interleukin-10 (IL-10) and tumor necrosis factor (TNF-α); (4) sex-specific differences in concentration of IL-6 and TNF-α, with an increase in CAF females; (5) higher level of IL-10 in both sexes, with a more pronounced increase in females. We concluded that maternal CAF diet affects fat content, metabolic profiles, and inflammation parameters in offspring. Above effects are sex-specific, with female offspring being more susceptible to the diet.
Assuntos
Gorduras/metabolismo , Inflamação/metabolismo , Metaboloma , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Animais Recém-Nascidos , Composição Corporal , Dieta , Gorduras/análise , Feminino , Humanos , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , Fenômenos Fisiológicos da Nutrição Pré-Natal , Ratos , Ratos Wistar , Caracteres SexuaisRESUMO
Adropin (ADR) plays a role in metabolism regulation and its alterations in obesity and diabetes have been found. Treatment with ADR was beneficial in metabolic diseases, and physical exercise increased ADR concentrations in obese patients. However, data on the distribution of ADR in the brain are sparse. The role of metabolic status and physical exercise on its expression in the brain is undiscovered. We hypothesized that diabetes type 2 (DM2) and/or exercise will alter number of ADR-immunoractive (-ir) cells in the rat brain. Animals were divided into groups: diabetes type 2 (receiving high-fat diet and injections of streptozotocin) and control (fed laboratory chow diet; C). Rats were further divided into: running group (2 weeks of forced exercise on a treadmill) and non-running group. Body mass, metabolic and hormonal profiles were assessed. Immunohistochemistry was run to study ADR-ir cells in the brain. We found that: 1) in DM2 animals, running decreased insulin and increased glucose concentrations; 2) in C rats, running decreased insulin concentrations and had no effect on glucose concentration in blood; 3) running increased corticosterone (CORT) concentrations in DM2 and C rats; 4) ADR-ir cells were detected in the hippocampus and ADR-ir fibers in the arcuate nucleus of the hypothalamus, which is a novel location; 5) metabolic status and running, however, did not change number of these cells. We concluded that 2 weeks of forced moderate intensity locomotor training induced stress response present as increased concentration of CORT and did not influence number of ADR-ir cells in the brain.
Assuntos
Proteínas Sanguíneas/metabolismo , Corticosterona/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hipocampo/metabolismo , Movimento , Peptídeos/metabolismo , Condicionamento Físico Animal , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Peso Corporal , Encéfalo/metabolismo , Diabetes Mellitus Experimental , Glucose/metabolismo , Hipotálamo/metabolismo , Insulina/metabolismo , Masculino , Perfusão , Ratos , Ratos WistarRESUMO
Obesity, which reaches an epidemic, is characterized by alterations in metabolic and hormonal profiles. Moreover, uncontrolled obesity may lead to development of diabetes type 2, which accounts for about 90% of all diabetic cases. In obesity, besides changes in metabolism, numerous co-morbidities are reported, e.g. disruptions of reproductive functions. Additionally, sex differences in development of this disease occur. We hypothesized that short-term exposure to high-fat diet (HFD; containing 50% of total energy from fat) would alter histology of testes and ovaries, and thus contribute to reproductive disruptions in male and female rats. Adult rats were fed ad libitum with HFD for 6-7 weeks and its effects on histology of testes and ovaries (n = 4/sex and treatment group) were studied using hematoxylin-eosin staining followed by microscopic analysis and compared to control (laboratory chow fed) group. We have found that in male rats fed with HFD there were: 1) decrease in diameter of seminiferous tubules due to smaller luminar diameter, and no change in epithelium height; 2) decrease in number of Sertoli cells; 3) no changes in number of spermatogonia and in percentage of semen in seminiferous tubules. In female rats exposed to HFD we have seen: 1) decrease in diameters of corpora lutea; 2) decrease in diameter of ovarian follicles types 7 and 8, but no changes in their number; 3) no changes in number of early primary follicles, primary follicles, and secondary follicles. We concluded that relatively short-term exposure to HFD in rats leads to changes in histology of both testes and ovaries, thus affecting reproductive functions.
Assuntos
Dieta Hiperlipídica , Obesidade/patologia , Folículo Ovariano/patologia , Ovário/patologia , Animais , Diabetes Mellitus Tipo 2/patologia , Feminino , Masculino , Obesidade/metabolismo , Folículo Ovariano/metabolismo , Ovário/metabolismo , Ratos Wistar , Reprodução , Fatores de TempoRESUMO
Acquisition of reproductive maturity involves one of the most important series of developmental events in an organism's life. The beginning of adolescence is marked by the onset of puberty. Puberty is the continuum of physical changes through which an infantile body matures into an adult capable of reproduction. This is a period of increased brain plasticity, where processes of re-wiring, neuronal proliferation, and pruning are enhanced. The initiation of mammalian puberty requires an increased pulsatile release of gonadotropin-releasing hormone from the hypothalamus. Puberty is regulated by neuroendocrine, genetic, and epigenetic factors. The maturation and function of the reproductive axis are highly sensitive to the energy status of the organism and sophisticated mechanisms exist to inhibit the axis in unfavorable energetic or metabolic conditions.In this review, we will focus on the impact of alcohol and obesity on reproductive outcomes, with emphasis on their effects on the timing of puberty. In the case of obesity, conflictive data are found, and while in females the association of overnutrition with advanced onset of puberty is consistent, in males, discrepant results have been reported. Concerning alcohol exposure, compelling evidence has documented a delay in the onset of puberty. We will present here data from both clinical studies and research involving preclinical models, which do not only delineate the impact of these conditions on the timing of puberty and potential underlying mechanisms, but that may help to define better strategies for the rational management of puberty disorders, especially of metabolic origin.