RESUMEN
The evolutionary pressure for life transitioning from extended periods of hypoxia to an increasingly oxygenated atmosphere initiated drastic selections for a variety of biochemical pathways supporting the robust life currently present on the planet. First, we discuss how fermentative glycolysis, a primitive metabolic pathway present at the emergence of life, is instrumental for the rapid growth of cancer, regenerating tissues, immune cells but also bacteria and viruses during infections. The 'Warburg effect', activated via Myc and HIF-1 in response to growth factors and hypoxia, is an essential metabolic and energetic pathway which satisfies nutritional and energetic demands required for rapid genome replication. Second, we present the key role of lactic acid, the end-product of fermentative glycolysis able to move across cell membranes in both directions via monocarboxylate transporting proteins (i.e., MCT1/4) contributing to cell-pH homeostasis but also to the complex immune response via acidosis of the tumor microenvironment. Importantly lactate is recycled in multiple organs as a major metabolic precursor of gluconeogenesis and energy source protecting cells and animals from harsh nutritional or oxygen restrictions. Third, we revisit the Warburg effect via CRISPR-Cas9 disruption of glucose-6-phosphate isomerase (GPI-KO) or lactate dehydrogenases (LDHA/B-DKO) in two aggressive tumors (melanoma B16-F10, human adenocarcinoma LS174T). Full suppression of lactic acid production reduces but does not suppress tumor growth due to reactivation of OXPHOS. In contrast, disruption of the lactic acid transporters MCT1/4 suppressed glycolysis, mTORC1, and tumor growth as a result of intracellular acidosis. Finally, we briefly discuss the current clinical developments of an MCT1 specific drug AZ3965, and the recent progress for a specific in vivo MCT4 inhibitor, two drugs of very high potential for future cancer clinical applications.
Asunto(s)
Simportadores , Virosis , Animales , Humanos , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Simportadores/genética , Simportadores/metabolismo , Línea Celular Tumoral , Ácido Láctico/metabolismo , Ácido Láctico/farmacología , Bacterias/metabolismo , HipoxiaRESUMEN
Ferroptosis is a recently described form of regulated cell death characterized by intracellular iron accumulation and severe lipid peroxidation due to an impaired cysteine-glutathione-glutathione peroxidase 4 antioxidant defence axis. One of the hallmarks of ferroptosis is a specific morphological phenotype characterized by extensive ultrastructural changes of mitochondria. Increasing evidence suggests that mitochondria play a significant role in the induction and execution of ferroptosis. The present review summarizes existing knowledge about the mitochondrial impact on ferroptosis in different pathological states, primarily cancer, cardiovascular diseases, and neurodegenerative diseases. Additionally, we highlight pathologies in which the ferroptosis/mitochondria relation remains to be investigated, where the process of ferroptosis has been confirmed (such as liver- and kidney-related pathologies) and those in which ferroptosis has not been studied yet, such as diabetes. We will bring attention to avenues that could be followed in future research, based on the use of mitochondria-targeted approaches as anti- and proferroptotic strategies and directed to the improvement of existing and the development of novel therapeutic strategies.
Asunto(s)
Ferroptosis/genética , Mitocondrias/metabolismo , HumanosRESUMEN
Infertility is a global problem that is on the rise, especially during the last decade. Currently, infertility affects approximately 10-15% of the population worldwide. The frequency and origin of different forms of infertility varies. It has been shown that reactive oxygen and nitrogen species (ROS and RNS) are involved in the aetiology of infertility, especially male infertility. Various strategies have been designed to remove or decrease the production of ROS and RNS in spermatozoa, in particular during in vitro fertilization. However, in recent years it has been shown that spermatozoa naturally produce a variety of ROS/RNS, including superoxide anion radical (O2 (â -)), hydrogen peroxide and NO. These reactive species, in particular NO, are essential in regulating sperm capacitation and the acrosome reaction, two processes that need to be acquired by sperm in order to achieve fertilization potential. In addition, it has recently been shown that mitochondrial function is positively correlated with human sperm fertilization potential and quality and that NO and NO precursors increase sperm motility by increasing energy production in mitochondria. We will review the new link between sperm NO-driven redox regulation and infertility herein. A special emphasis will be placed on the potential implementation of new redox-active substances that modulate the content of NO in spermatozoa to increase fertility and promote conception.
Asunto(s)
Infertilidad Masculina/fisiopatología , Óxido Nítrico/metabolismo , Espermatozoides/fisiología , Diseño de Fármacos , Fertilidad/fisiología , Humanos , Infertilidad Masculina/tratamiento farmacológico , Masculino , Mitocondrias/metabolismo , Oxidación-Reducción , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Motilidad Espermática/fisiologíaRESUMEN
Mitochondria are key organelles maintaining cellular bioenergetics and integrity, and their regulation of [Ca2+]i homeostasis has been investigated in many cell types. We investigated the short-term Ca-SANDOZ® treatment on brown adipocyte mitochondria, using imaging and molecular biology techniques. Two-month-old male Wistar rats were divided into two groups: Ca-SANDOZ® drinking or tap water (control) drinking for three days. Alizarin Red S staining showed increased Ca2+ level in the brown adipocytes of treated rats, and potassium pyroantimonate staining localized electron-dense regions in the cytoplasm, mitochondria and around lipid droplets. Ca-SANDOZ® decreased mitochondrial number, but increased their size and mitochondrial cristae volume. Transmission electron microscopy revealed numerous enlarged and fusioned-like mitochondria in the Ca-SANDOZ® treated group compared to the control, and megamitochondria in some brown adipocytes. The Ca2+ diet affected mitochondrial fusion as mitofusin 1 (MFN1) and mitofusin 2 (MFN2) were increased, and mitochondrial fission as dynamin related protein 1 (DRP1) was decreased. Confocal microscopy showed a higher colocalization rate between functional mitochondria and endoplasmic reticulum (ER). The level of uncoupling protein-1 (UCP1) was elevated, which was confirmed by immunohistochemistry and Western blot analysis. These results suggest that Ca-SANDOZ® stimulates mitochondrial fusion, increases mitochondrial-ER contacts and the thermogenic capacity of brown adipocytes.
Asunto(s)
Adipocitos Marrones/efectos de los fármacos , Calcio/farmacología , Retículo Endoplásmico/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Animales , Electroforesis en Gel de Poliacrilamida , Inmunohistoquímica , Masculino , Microscopía Electrónica de Transmisión , Ratas , Coloración y EtiquetadoRESUMEN
The aim of the present study was to investigate whether hyperinsulinaemia, which frequently precedes insulin resistance syndrome (obesity, diabetes), induces apoptosis of endothelial cells (ECs) in brown adipose tissue (BAT) and causes BAT atrophy and also, to investigate the possible mechanisms underlying ECs death. In order to induce hyperinsulinaemia, adult male rats of Wistar strain were treated with high dose of insulin (4 U/kg, intraperitonealy) for one or three days. Examinations at ultrastructural level showed apoptotic changes of ECs, allowing us to point out that changes mainly but not exclusively, occur in nuclei. Besides different stages of condensation and alterations of the chromatin, nuclear fragmentation was also observed. Higher number of ECs apoptotic nuclei in the BAT of hyperinsulinaemic rats was also confirmed by propidium iodide staining. Immunohistochemical localization of tumor necrosis factor-alpha (TNF-α) revealed increased expression in ECs of BAT of hyperinsulinaemic animals, indicating its possible role in insulin-induced apoptotic changes. These results suggest that BAT atrophy in hyperinsulinaemia is a result of endothelial and adipocyte apoptosis combined, rather than any of functional components alone.
Asunto(s)
Adipocitos/citología , Tejido Adiposo Pardo , Apoptosis , Células Endoteliales/citología , Hiperinsulinismo , Factor de Necrosis Tumoral alfa/metabolismo , Adipocitos/metabolismo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/ultraestructura , Animales , Proliferación Celular , Células Endoteliales/metabolismo , Inmunohistoquímica , Masculino , Ratas , Ratas WistarRESUMEN
AIM: To examine the success of the one-appointment pulpotomy technique with three different medicaments on primary molar teeth. METHODS: The study was conducted on 104 primary molars in 104 children with an indication for pulpotomy treatment on at least one primary molar. Primary teeth were treated with either formocresol (FC) (34 teeth), calcium hydroxide (CA) (33 teeth) or ferric sulphate (FS) (37 teeth) using standardised criteria for the pulpotomy procedures. Teeth were clinically and radiographically evaluated during the examination period of 18 months. RESULTS: The clinical success rate at 18 months for the FC and FS groups was 90.9% and 89.2%, respectively. The CA showed an overall clinical success rate of 82.3%, with no statistical difference compared with either the FC or FS groups. The overall radiographic success for each technique was: FC 84.8%, CA 76.5%, and FS 81.1%. The presence of a dentine bridge above the pulp amputation site was observed radiographically for CA (47%), and FS (40.5%) pulpotomies without any statistical difference. Radiographic examination did not reveal the presence of a dentine bridge for any of the teeth treated with FC pulpotomy. CONCLUSION: Favourable clinical and radiographic success rates of ferric sulphate pulpotomy, comparable to formocresol were obtained. Therefore, ferric sulphate can be recommended as a pulpotomy medicament.
Asunto(s)
Recubrimiento de la Pulpa Dental/métodos , Compuestos Férricos/uso terapéutico , Pulpotomía/métodos , Hidróxido de Calcio/uso terapéutico , Niño , Preescolar , Dentina Secundaria/crecimiento & desarrollo , Dentina Secundaria/metabolismo , Formocresoles/uso terapéutico , Humanos , Tablas de Vida , Diente Molar , Diente PrimarioRESUMEN
AIMS: To quantify retinal vascular change during and after hyperbaric oxygenation (HO) for 6x5 weekly 90 minute treatments. METHODS: Fundus photographs were taken before, during, and after HO at 2.5 atmospheres absolute pressure (ATA) on days 1, 2, 3, 10, 20, 29, and 30 of treatment on three patients using a specially developed hand held ophthalmoscope with a digital colour camera. Blood vessel diameter was estimated on red free retinal images. The mean of three measurements of arterioles and venoles close to the optic disc was calculated. Consistency and repeatability of the method was verified by estimating the diameter of the vessels by three measurements in each of seven images taken within 70 seconds on the same person. Analysis of variance with Bonferroni correction for multiple comparisons was conducted to ascertain whether significant intergroup differences existed. RESULTS: Breathing 100% oxygen at 2.5 ATA constricts retinal arterioles by 9.6% (standard deviation 0.3%) and venoles by 20.6% (SD 0.3%) of their size in air at ambient pressure. Constriction escalates during treatment. Ten minutes after the HO, arterioles dilate to 94.5% (SD 0.3%) and venoles to 89.0% (SD 0.3%) of their primary size. This pattern is the same for each day of measurement. Heart frequency falls continually during HO. Systolic, diastolic, and mean arterial pressures stay constant. CONCLUSION: Exposure to hyperbaric oxygen causes constriction of the retinal vessels. It is found that this constriction is constant through the series of treatments. This suggests that oxygen or products thereof are responsible for the vascular changes during and after hyperbaric oxygenation probably through autoregulation of the retinal vessels.
Asunto(s)
Oxigenoterapia Hiperbárica , Vasos Retinianos/anatomía & histología , Anciano , Análisis de Varianza , Arteriolas/anatomía & histología , Densitometría , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Masculino , Persona de Mediana Edad , Oftalmoscopios , Vasoconstricción , Vénulas/anatomía & histologíaRESUMEN
Fructosamine, HbAlc, glucose, albumins and total proteins were estimated in 40 healthy pregnant women and 80 pregnant women with insulin dependent diabetes mellitus. Fructosamine was estimated by the NBT method with "Fructosamine test" commercially available kit on Technicom automatic analyser RA-1000. Glucose was determined on Beckman glucose analyser. HbAlc was assayed by the Bio-Rad test, while albumin and total proteins by Beckman tests. For all estimated parameters no significant differences were found between healthy pregnant women and pregnant women with insulin dependent diabetes mellitus.