A pan-cancer analysis of RNASEH1, a potential regulator of the tumor microenvironment

Background RNASEH1 (Ribonuclease H1) encodes an endonuclease that specifically degrades the RNA of RNA–DNA hybrids and acts in DNA replication and repair. Although there are many studies on RNASEH1, the research of RNASEH1 in cancers is still insufficient. Therefore, in order to clarify the physiological mechanism of RNASEH1 in tumor cells, we evaluated the role of RNASEH1 by combining The Cancer Genome Atlas (TCGA) pan-cancer data and Genotype-Tissue Expression (GTEx) normal tissue data. Methods RNASEH1 expression was analyzed by using RNAseq data from TCGA and the GTEx database. The Human Protein Atlas (HPA), GeneCards and STRING database were used to explore the protein information of RNASEH1. The prognostic value of RNASEH1 was analyzed by using the clinical survival data from TCGA. Differential analysis of RNASEH1 in different cancers was performed by using R package “DESeq2”, and enrichment analysis of RNASEH1 was conducted by using R package “clusterProfiler”. We downloaded the immune cell infiltration score of TCGA samples from published articles and online databases, and the correlation analysis between immune cell infiltration levels and RNASEH1 expression was performed. Not only that, we further evaluated the association of RNASEH1 with immune activating genes, immunosuppressive genes, chemokines and chemokine receptors. At the end of the article, the differential expression of RNASEH1 in pan-cancer was validated by using GSE54129, GSE40595, GSE90627, GSE106937, GSE145976 and GSE18672, and qRT-PCR was also performed for verification. Finding RNASEH1 was significantly overexpressed in 19 cancers and the overexpression was closely correlated with poor prognosis. Moreover, the expression of RNASEH1 was significantly correlated with the regulation of the tumor microenvironment (AU)

Liraglutide provides cardioprotection through the recovery of mitochondrial dysfunction and oxidative stress in aging hearts

Glucagon-like peptide-1 receptor (GLP-1R) agonists improve cardiovascular dysfunction via the pleiotropic effects behind their receptor action. However, it is unknown whether they have a cardioprotective action in the hearts of the elderly. Therefore, we examined the effects of GLP-1R agonist liraglutide treatment (LG, 4 weeks) on the systemic parameters of aged rats (24-month-old) compared to those of adult rats (6-month-old) such as electrocardiograms (ECGs) and systolic and diastolic blood pressure (SBP and DBP). At the cellular level, the action potential (AP) parameters, ionic currents, and Ca2+ regulation were examined in freshly isolated ventricular cardiomyocytes. The LG treatment of aged rats significantly ameliorated the prolongation of QRS duration and increased both SBP and DBP together with recovery in plasma oxidant and antioxidant statuses. The prolonged AP durations and depolarized membrane potentials of the isolated cardiomyocytes from the aged rats were normalized via recoveries in K+ channel currents with LG treatment. The alterations in Ca2+ regulation including leaky-ryanodine receptors (RyR2) could be also ameliorated via recoveries in Na+/Ca2+ exchanger currents with this treatment. A direct LG treatment of isolated aged rat cardiomyocytes could recover the depolarized mitochondrial membrane potential, the increase in both reactive oxygen and nitrogen species (ROS and RNS), and the cytosolic Na+ level, although the Na+ channel currents were not affected by aging. Interestingly, LG treatment of aged rat cardiomyocytes provided a significant inhibition of activated sodium-glucose co-transporter-2 (SGLT2) and recoveries in the depressed insulin receptor substrate 1 (IRS1) and increased protein kinase G (PKG). (AU)

Autophagy, a relevant process for metabolic health and type-2 diabetes / Autofagia, un proceso relevante para la salud y la diabetes tipo 2

Autophagy is a very active process that plays an important role in cell and organ differentiation and remodelling, being a crucial system to guarantee health. This physiological process is activated in starvation and inhibited in the presence of nutrients. This short review comments on the three types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy, as well as different aspects that control autophagy and its relationship with health and degenerative diseases. As autophagy is highly dependent on functional autophagy (ATG) proteins integrating the phagophore, the role of some key ATG genes and epigenes are briefly commented on. The manuscript deepens discussing some central aspects of type-2 diabetes mellitus and their relationship with the cell cleaning process and mitochondria homeostasis maintenance, as well as the mechanisms through which antidiabetic drugs affect autophagy. Well-designed studies are needed to elucidate whether autophagy plays a casual or causal role in T2DM. (AU)

La autofagia es un proceso muy activo que juega un papel importante en la diferenciación y remodelación de células y órganos, siendo un sistema crucial para garantizar la salud. Este proceso fisiológico se activa en la inanición y se inhibe en presencia de nutrientes. En esta breve revisión se definen los tres tipos de autofagia: macroautofagia, microautofagia y autofagia mediada por chaperonas, y los diferentes aspectos que controlan la autofagia y su relación con la salud y las enfermedades degenerativas. Como la autofagia depende en gran medida de las proteínas funcionales de autofagia (ATG) que integran el fagóforo, se comenta brevemente el papel clave de algunos genes y epigenes de las ATG. El manuscrito profundiza discutiendo algunos aspectos centrales de la diabetes mellitus tipo 2 (DMT2) y su relación con el proceso de limpieza celular y el mantenimiento de la homeostasis mitocondrial, así como los mecanismos a través de cuales los fármacos antidiabéticos afectan a la autofagia. Se necesitan estudios bien diseñados para dilucidar si la autofagia juega un papel de casualidad o causalidad en el desarrollo de la DMT2. (AU)

Melatonin controls cell proliferation and modulates mitochondrial physiology in pancreatic stellate cells

We have investigated the effects of melatonin on major pathways related with cellular proliferation and energetic metabolism in pancreatic stellate cells. In the presence of melatonin (1 mM, 100 µM, 10 µM, or 1 µM), decreases in the phosphorylation of c-Jun N-terminal kinase and of p44/42 and an increase in the phosphorylation of p38 were observed. Cell viability dropped in the presence of melatonin. A rise in the phosphorylation of AMP-activated protein kinase was detected in the presence of 1 mM and 100 µM melatonin. Treatment with 1 mM melatonin decreased the phosphorylation of protein kinase B, whereas 100 µM and 10 µM melatonin increased its phosphorylation. An increase in the generation of mitochondrial reactive oxygen species and a decrease of mitochondrial membrane potential were noted following melatonin treatment. Basal and maximal respiration, ATP production by oxidative phosphorylation, spare capacity, and proton leak dropped in the presence of melatonin. The expression of complex I of the mitochondrial respiratory chain was augmented in the presence of melatonin. Conversely, in the presence of 1 mM melatonin, decreases in the expression of mitofusins 1 and 2 were detected. The glycolysis and the glycolytic capacity were diminished in cells treated with 1 mM or 100 µM melatonin. Increases in the expression of phosphofructokinase-1 and lactate dehydrogenase were noted in cells incubated with 100 µM, 10 µM, or 1 µM melatonin. The expression of glucose transporter 1 was increased in cells incubated with 10 µM or 1 µM melatonin. Conversely, 1 mM melatonin decreased the expression of all three proteins. Our results suggest that melatonin, at pharmacological concentrations, might modulate mitochondrial physiology and energy metabolism in addition to major pathways involved in pancreatic stellate cell proliferation. (AU)

Role of MST1 in the regulation of autophagy and mitophagy: implications for aging-related diseases

As a key mechanism to maintain cellular homeostasis under stress conditions, autophagy/mitophagy is related to the occurrence of metabolic disorders, neurodegenerative diseases, cancer, and other aging-related diseases, but the relevant signal pathways regulating autophagy have not been clarified. Mammalian sterile 20-like kinase 1 (MST1) is a central regulatory protein of many metabolic pathways involved in the pathophysiological processes of aging and aging-related diseases and has become a critical integrator affecting autophagic signaling. Recent studies show that MST1 not only suppresses autophagy through directly phosphorylating Beclin-1 and/or inhibiting the protein expression of silent information regulator 1 (SIRT1) in the cytoplasm, but also inhibits BCL2/adenovirus E1B protein-interacting protein 3 (BNIP3)–, FUN14 domain containing 1 (FUNDC1)–, and Parkin (Parkinson protein 2)–mediated mitophagy by interacting with factors such as Ras association domain family 1A (RASSF1A). Indeed, a common pharmacological strategy for anti-aging is to induce autophagy/mitophagy through MST1 inhibition. This article reviews the role and mechanism of MST1 in regulating autophagy during aging, to provide evidence for the development of drugs targeting MST1. (AU)

The mitochondrial DNA constitution shaping T-cell immunity in patients with rectal cancer at high risk of metastatic progression

PurposeA significant percentage of colorectal cancer patients proceeds to metastatic disease. We hypothesised that mitochondrial DNA (mtDNA) polymorphisms, generated by the high mtDNA mutation rate of energy-demanding clonal immune cell expansions and assessable in peripheral blood, reflect how efficiently systemic immunity impedes metastasis.Patients and methodsWe studied 44 rectal cancer patients from a population-based prospective biomarker study, given curative-intent neoadjuvant radiation and radical surgery for high-risk tumour stage and followed for metastatic failure. Blood specimens were sampled at the time of diagnosis and analysed for the full-length mtDNA sequence, composition of immune cell subpopulations and damaged serum mtDNA.ResultsWhole blood total mtDNA variant number above the median value for the study cohort, coexisting with an mtDNA non-H haplogroup, was representative for the mtDNA of circulating immune cells and associated with low risk of a metastatic event. Abundant mtDNA variants correlated with proliferating helper T cells and cytotoxic effector T cells in the circulation. Patients without metastatic progression had high relative levels of circulating tumour-targeting effector T cells and, of note, the naïve (LAG-3+) helper T-cell population, with the proportion of LAG-3+ cells inversely correlating with cell-free damaged mtDNA in serum known to cause antagonising inflammation.ConclusionNumerous mtDNA polymorphisms in peripheral blood reflected clonal expansion of circulating helper and cytotoxic T-cell populations in patients without metastatic failure. The statistical associations suggested that patient’s constitutional mtDNA manifests the helper T-cell capacity to mount immunity that controls metastatic susceptibility.

Schizosaccharomyces pombe Fzo1 is subjected to the ubiquitin–proteasome-mediated degradation during the stationary phase / Schizosaccharomyces pombe Fzo1 está sujeto a la degradación mediada por ubiquitina-proteasoma durante la fase estacionaria

Mitochondria are highly dynamic organelles that undergo fission and fusion to adapt to the metabolic needs of the cell. Mitofusins are dynamin-like GTPases that play a key role in the regulation of mitochondrial fusion and metabolism. In Saccharomyces cerevisiae, mitofusin Fzo1 levels are controlled by post-translational ubiquitination and degradation. However, it is not clear whether the levels of the Schizosaccharomyces pombe mitofusin Fzo1 are similarly regulated. In this study, we examined the expression S. pombe Fzo1 during normal growth. We showed that Fzo1 protein levels but not mRNA expression levels were reduced during the stationary phase. The protein was stabilized by the proteasome inhibitor bortezomib. Disruption of ubc8 encoding a ubiquitin-conjugating enzyme and rsv2 encoding an S. pombe homolog of S. cerevisiae RPN4 known for activating the expression of genes required for proteasomal biogenesis suppresses the proteasomal degradation of Fzo1 during the stationary phase. Overexpression of fzo1 prevents its degradation. Our results suggest that like S. pombe Fzo1 expression is not regulated by transcription but rather by proteolytic degradation during the stationary phase. Our findings also suggest that although S. cerevisiae and S. pombe Fzo1 proteins are regulated by ubiquitin-proteasomal degradation, different ubiquitin-conjugating enzymes (E2) and ubiquitin ligases (E3) are involved in their degradation.(AU)

Calorie restriction changes lipidomic profiles and maintains mitochondrial function and redox balance during isoproterenol-induced cardiac hypertrophy

Typically, healthy cardiac tissue utilizes more fat than any other organ. Cardiac hypertrophy induces a metabolic shift leading to a preferential consumption of glucose over fatty acids to support the high energetic demand. Calorie restriction is a dietary procedure that induces health benefits and lifespan extension in many organisms. Given the beneficial effects of calorie restriction, we hypothesized that calorie restriction prevents cardiac hypertrophy, lipid content changes, mitochondrial and redox dysregulation. Strikingly, calorie restriction reversed isoproterenol-induced cardiac hypertrophy. Isolated mitochondria from hypertrophic hearts produced significantly higher levels of succinate-driven H2O2 production, which was blocked by calorie restriction. Cardiac hypertrophy lowered mitochondrial respiratory control ratios, and decreased superoxide dismutase and glutathione peroxidase levels. These effects were also prevented by calorie restriction. We performed lipidomic profiling to gain insights into how calorie restriction could interfere with the metabolic changes induced by cardiac hypertrophy. Calorie restriction protected against the consumption of several triglycerides (TGs) linked to unsaturated fatty acids. Also, this dietary procedure protected against the accumulation of TGs containing saturated fatty acids observed in hypertrophic samples. Cardiac hypertrophy induced an increase in ceramides, phosphoethanolamines, and acylcarnitines (12:0, 14:0, 16:0, and 18:0). These were all reversed by calorie restriction. Altogether, our data demonstrate that hypertrophy changes the cardiac lipidome, causes mitochondrial disturbances, and oxidative stress. These changes are prevented (at least partially) by calorie restriction intervention in vivo. This study uncovers the potential for calorie restriction to become a new therapeutic intervention against cardiac hypertrophy, and mechanisms in which it acts. (AU)

La interacción vitamina D-mitocondria podría modular el camino de señalización involucrado en el desarrollo de la hipertensión: una visión integrativa translacional / Vitamin D-mitochondria cross-talk could modulate the signaling pathway involved in hypertension development: a translational integrative overview

El déficit de vitamina D es una pandemia a nivel mundial y trae como consecuencia osteoporosis, hipertensión arterial (HTA) y otras enfermedades cardiovasculares. A nivel celular produce mayor carga oxidativa, marcadores inflamatorios y daño mitocondrial. Existe cada vez más evidencia sobre el protagonismo de la vitamina D en la regulación del sistema renina-angiotensina-aldosterona (RAAS), con posibles implicancias cardiovasculares así como para el sistema inmunológico. Valores de vitamina D inferiores a 25 ng/mL se relacionan con un aumento de tono vascular mediado por la contracción del músculo liso, ya sea a través de efectos directos sobre las células vasculares del músculo liso, sobrerregulación del RAAS, y/o a través de la modulación del metabolismo del calcio con hiperparatiroidismo secundario; lo cual predispone en los pacientes a desarrollar hipertrofia del ventrículo izquierdo y de la pared vascular originando HTA. En este trabajo se realizó una revisión de los principales mecanismos involucrados en el desarrollo de la HTA asociados al déficit de vitamina D. Entre ellos se destaca el vínculo que se establece entre los niveles de fosfato inorgánico extramitocondrial, sus principales hormonas reguladoras -como la vitamina D-, el aparato cardiovascular, las especies reactivas del oxígeno y el metabolismo mitocondrial. El papel del receptor de vitamina D a nivel mitocondrial y la regulación de la cadena respiratoria influirían en el remodelamiento arterial, ya que su activación reduciría el daño oxidativo y preservaría la vida celular. No obstante, existen aspectos aún no comprendidos sobre la intrincada red de señalización que resultan simples en ensayos experimentales, pero complejos en los estudios clínicos. En este sentido, la concreción de nuevos estudios como el VITAL podría clarificar, y así apoyar o refutar, los posibles beneficios de la vitamina D en la enfermedad cardiovascular hipertensiva

Vitamin D deficiency is a worldwide pandemic and results in osteoporosis, hypertension, and other cardiovascular diseases. At the cellular level, it produces significant oxidative stress, inflammatory markers, and mitochondrial damage. There is increasing evidence about the role of vitamin D in the regulation of the renin-angiotensin-aldosterone system (RAAS). Moreover, there is evidence of involvement in cardiovascular complications, as well as in the immune system disorders. Vitamin D values below 25 ng/mL are related to an increase in vascular tone mediated by smooth muscle contraction. Furthermore, it can produce direct effects on vascular smooth muscle cells, RAAS over-regulation, modulation of calcium metabolism, and secondary hyperparathyroidism. All this predisposes patients to develop hypertrophy of the left ventricle and vascular wall, causing hypertension. In this work, a review is presented of the main mechanisms involved in the development of hypertension due to vitamin D deficiency. Among them are the link established between the levels of extra-mitochondrial inorganic phosphate, its main regulatory hormones -such as vitamin D-, the cardiovascular system, reactive oxygen species, and mitochondrial metabolism. The role of the mitochondrial vitamin D receptor and the regulation of the respiratory chain could influence arterial remodelling since its activation would reduce oxidative damage and preserve cell life. However, there are aspects not yet understood about the intricate signalling network that appeared simple in experimental trials, but complex in clinical studies. In this way, the completion of new studies as VITAL, could clarify, and thus support or refute the possible benefits of vitamin D in hypertensive cardiovascular disease

Melatonin ameliorates the drug induced nephrotoxicity: Molecular insights / La melatonina mejora la nefrotoxicidad inducida por medicamentos: datos moleculares

BACKGROUND: Drug-induced nephrotoxicity is a frequent adverse event that can lead to acute or chronic kidney disease and increase the healthcare expenditure. It has high morbidity and mortality incidence in 40-70% of renal injuries and accounts for 66% cases of renal failure in elderly population. OBJECTIVE: Amelioration of drug-induced nephrotoxicity has been long soughed to improve the effectiveness of therapeutic drugs. This study was conducted to review the melatonin potential to prevent the pathogenesis of nephrotoxicity induced by important nephrotoxic drugs. METHODS: We analyzed the relevant studies indexed in Pubmed, Medline, Scielo and Web of science to explain the molecular improvements following melatonin co-administration with special attention to oxidative stress, inflammation and apoptosis as key players of drug-induced nephrotoxicity. RESULTS: A robust consensus among researchers of these studies suggested that melatonin efficiently eradicate the chain reaction of free radical production and induced the endogenous antioxidant enzymes which attenuate the lipid peroxidation of cellular membranes and subcellular oxidative stress in drug-induced nephrotoxicity. This agreement was further supported by the melatonin role in disintegration of inflammatory process through inhibition of principle pro-inflammatory or apoptotic cytokines such as TNF-alfa and NF-κB. These studies highlighted that alleviation of drug-induced renal toxicity is a function of melatonin potential to down regulate the cellular inflammatory and oxidative injury process and to stimulate the cellular repair or defensive mechanisms. CONCLUSION: The comprehensive nephroprotection and safer profile suggests the melatonin to be a useful adjunct to improve the safety of nephrotoxic drugs

ANTECEDENTES: La nefrotoxicidad inducida por medicamentos es un acontecimiento adverso frecuente que puede conducir a una nefropatía aguda o crónica, e incrementar los costes sanitarios. Presenta una incidencia elevada de morbimortalidad en el 40-70% de las lesiones renales y es responsable del 66% de los casos de insuficiencia renal entre la población de edad avanzada. OBJETIVO: La mejora de la nefrotoxicidad inducida por medicamentos es un objetivo anhelado desde hace mucho tiempo, para mejorar la eficacia de los fármacos terapéuticos. Este estudio se llevó a cabo con el propósito de revisar el potencial de la melatonina para prevenir la patogenia de la nefrotoxicidad inducida por medicamentos nefrotóxicos importantes. MÉTODOS: Analizamos los estudios relevantes indexados en Pubmed, Medline, Scielo y Web of Science, para explicar las mejoras moleculares posteriores a la administración concomitante de melatonina; prestando especial atención al estrés oxidativo, la inflamación y la apoptosis como actores fundamentales de la nefrotoxicidad inducida por medicamentos. RESULTADOS: Un sólido consenso entre los investigadores de estos estudios sugirió que la melatonina erradica de forma eficiente la reacción en cadena de producción de radicales libres e induce las enzimas antioxidantes endógenas que atenúan la peroxidación lipídica de las membranas celulares y el estrés oxidativo subcelular en la nefrotoxicidad inducida por medicamentos. Este consenso se vio respaldado por el papel de la melatonina en la desintegración del proceso inflamatorio a través de la inhibición de las principales citocinas proinflamatorias o apoptóticas, como el TNF-α y el NF-κB. Estos estudios subrayan que la mitigación de la nefrotoxicidad inducida por medicamentos se deriva del potencial de la melatonina para regular a la baja el proceso celular de lesión inflamatoria y oxidativa, y estimular la reparación celular o los mecanismos defensivos de las células. CONCLUSIÓN: La nefroprotección exhaustiva y el perfil de seguridad más favorable sugieren que la melatonina es un complemento útil para mejorar la seguridad de los fármacos nefrotóxicos

Melatonin and mitochondrial dysfunction are key players in the pathophysiology of sepsis / La melatonina y la disfunción mitocondrial son elementos claves en la patofisiología de la sepsis

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Lower mitochondrial dysfunction in survivor septic patients with mitochondrial DNA haplogroup JT / Menor disfunción mitocondrial en pacientes septicos supervivientes con haplogrupo JT del ADN mitocondrial

OBJECTIVE: The comparison on mitochondrial function between severe septic patients and healthy control subjects according to mitochondrial deoxyribonucleic acid (mtDNA) haplogroup has not been previously reported; and this was the objective of the current study. METHODS: Prospective, multicenter, observational study. We obtained blood samples from 198 severe septic patients at days 1, 4 and 8 of severe sepsis diagnosis and from 96 sex- and age-matched healthy controls to determine mtDNA haplogroup and platelet respiratory complex IV (CIV) specific activity. The endpoint of the study was 30-day mortality. RESULTS: We included 198 severe septic patients (38 with mtDNA haplogroup JT and 160 with mtDNA haplogroup non-JT) and 96 healthy control subjects (16 with mtDNA haplogroup JT and 80 with mtDNA haplogroup non-JT). We have no found statistically significant differences in platelet CIV specific activity between healthy controls and survivor severe septic patients with mtDNA haplogroup JT at days 1, 4 and 8 of severe sepsis diagnosis; and the remaining severe septic patients showed lower platelet CIV specific activity than healthy controls with the same mtDNA haplogroup. CONCLUSIONS: The new finding of our study was that survivor severe septic patients and healthy controls with mtDNA haplogroup JT showed no different platelet Civ specific activity

OBJETIVO: La comparación en la función mitocondrial entre pacientes con sepsis grave y sujetos sanos según el haplogrupo del ácido desoxirribonucleico mitocondrial (ADNmt) no se ha reportado previamente; y este fue el objetivo del estudio. MÉTODOS: Estudio prospectivo, multicéntrico y observacional. Obtuvimos muestras sanguíneas de 198 pacientes con sepsis grave en los días 1, 4 y 8 del diagnóstico de la sepsis grave y de 96 sujetos sanos para determinar el haplogrupo del ADNmt y la actividad del complejo respiratorio mitocondrial IV (CIV) en plaquetas circulantes. La variable resultado principal del estudio fue la mortalidad a los 30 días. RESULTADOS: Se incluyeron 198 pacientes con sepsis grave (38 con haplogrupo JT del ADNmt y 160 con otro haplogrupo del ADNmt) y 96 sujetos sanos (16 con haplogrupo JT del ADNmt y 80 con otro haplogrupo del ADNmt). No encontramos diferencias estadísticamente significativas en la actividad de CIV plaquetaria entre los sujetos sanos y los pacientes sépticos supervivientes con haplogrupo JT del ADNmt en los días 1, 4 y 8 del diagnóstico de la sepsis grave; y el resto de los pacientes sépticos presentaron menor actividad de CIV plaquetaria que los sujetos sanos con su mismo haplogrupo del ADNmt. CONCLUSIONES: El nuevo hallazgo de nuestro estudio fue que los pacientes sépticos y sujetos sanos con haplogrupo JT del ADNmt no tenían diferencias en la actividad de CIV plaquetaria

CypD-mPTP axis regulates mitochondrial functions contributing to osteogenic dysfunction of MC3T3-E1 cells in inflammation

Bone is a dynamic organ, the bone-forming osteoblasts and bone-resorbing osteoclasts form the physiological basis of bone remodeling process. During pathological process of numerous inflammatory diseases, these two aspects are uncoupled and the balance is usually tipped in favor of bone destruction. Evidence suggests that the inflammatory destruction of bone is mainly attributed to oxidative stress and is closely related to mitochondrial dysfunction. The mechanisms underlying osteogenic dysfunction in inflammation still need further investigation. Reactive oxygen species (ROS) is associated with mitochondrial dysfunction and cellular damage. Here, we reported an unexplored role of cyclophilin D (CypD), the major modulator of mitochondrial permeability transition pore (mPTP), and the CypD-mPTP axis in inflammation-induced mitochondrial dysfunction and bone damage. And the protective effects of knocking down CypD by siRNA interference or the addition of cyclosporin A (CsA), an inhibitor of CypD, were evidenced by rescued mitochondrial function and osteogenic function of osteoblast under tumor necrosis factor-alfa (TNF-alfa) treatment. These findings provide new insights into the role of CypD-mPTP-dependent mitochondrial pathway in the inflammatory bone injury. The protective effect of CsA or other moleculars affecting the mPTP formation may hold promise as a potential novel therapeutic strategy for inflammation-induced bone damage via mitochondrial pathways

Changes in the activity of some metabolic enzymes in the heart of SHR rat incurred by transgenic expression of CD36

Hypertension, dyslipidemia, and insulin resistance in the spontaneously hypertensive rat (SHR) can be alleviated by rescuing CD36 fatty acid translocase. The present study investigated whether transgenic rescue of CD36 in SHR could affect mitochondrial function and activity of selected metabolic enzymes in the heart. These analyses were conducted on ventricular preparations derived from SHR and from transgenic strain SHR-Cd36 that expresses a functional wild-type CD36. Our respirometric measurements revealed that mitochondria isolated from the left ventricles exhibited two times higher respiratory activity than those isolated from the right ventricles. Whereas, we did not observe any significant changes in functioning of the mitochondrial respiratory system between both rat strains, enzyme activities of total hexokinase, and both mitochondrial and total malate dehydrogenase were markedly decreased in the left ventricles of transgenic rats, compared to SHR. We also detected downregulated expression of the succinate dehydrogenase subunit SdhB (complex II) and 70 kDa peroxisomal membrane protein in the left ventricles of SHR-Cd36. These data indicate that CD36 may affect in a unique fashion metabolic substrate flexibility of the left and right ventricles

Effect of fish and olive oil on mitochondrial ATPase activity and membrane fluidity in patients with relapsing-remitting multiple sclerosis treated with interferon beta 1-b / Efecto del aceite de pescado en la actividad hidrolítica de la ATPasa y en la fluidez de la membrana mitocondrial en pacientes con esclerosis múltiple remitente-recurrente tratados con interferón beta 1-b

Background: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system associated with increased oxidative stress (OS) and mitochondrial alterations. Fish oil consumption has neuroprotective, antioxidant and anti-inflammatory effects in patients with relapsing-recurrent MS (RR-MS). Objective: To evaluate changes in the hydrolytic activity of ATP synthase and mitochondrial membrane fluidity in patients with RR-MS who receive fish oil or olive oil as a dietary supplement. Methods: Clinical, controlled, randomized, double-blind trial. Patients consumed fish oil or olive oil for one year. The hydrolytic activity of ATPase and the fluidity of the mitochondrial membrane of platelets were quantified. Results: In patients with RR-MS, a decrease in the fluidity of mitochondrial membranes and an increase in the hydrolytic activity of ATP synthase was observed in comparison with healthy controls. After 6 or 9 months of treatment with fish oil or olive oil, respectively, these values were normalized. Conclusion: The consumption of fish oil and olive oil increases the fluidity of the mitochondrial membranes and decreases the catabolic activity of ATP synthase in platelets from patients with RR-MS (AU)

Introducción: la esclerosis multiple (EM) es una enfermedad inflamatoria del sistema nervioso central asociada con estrés oxidativo (EO) y alteraciones mitocondriales. El aceite de pescado tiene efectos neuroprotectores, antioxidantes y antiinflamatorios en pacientes con EM remitente-recurrente (EM-RR). Objetivo: evaluar los cambios en la actividad hidrolítica de la ATPasa y de la fluidez de membrana mitocondrial en pacientes con EM-RR que reciben aceite de pescado o aceite de oliva como suplemento alimenticio. Métodos: ensayo clínico, controlado, aleatorizado, doble ciego. Los pacientes consumieron aceite de pescado o aceite de oliva durante un año. Se cuantifico la actividad hidrolítica de la ATPasa y la fluidez de la membrana mitocondrial de plaquetas. Resultados: en pacientes con EM-RR hay una disminución de la fluidez de las membranas mitocondriales y un incremento de la actividad hidrolítica de la ATPasa en comparación con controles sanos. Después de 6 y 9 meses de tratamiento con aceite de oliva y de aceite de pescado, respectivamente, los valores se normalizaron y se mantuvieron así hasta el fin del estudio. Conclusión: el consumo de aceite de pescado y aceite de oliva incrementan la fluidez de membrana y disminuye la actividad catabólica de la ATP sintasa en pacientes con EM-RR (AU)

La expresión del complejo de síntesis de coenzima Q es regulada durante el envejecimiento / Regulation of the expression of coenzyme Q-synthesis complex during ageing

Introducción. El coenzima Q es un componente esencial para la actividad de la cadena de transporte de electrones mitocondrial. En su síntesis están implicados, al menos, 10 proteínas diferentes que conforman un complejo. Nuestro objetivo ha sido el de determinar la evolución de la expresión de los diferentes genes implicados en la síntesis de coenzima Q durante el envejecimiento en ratones. Material y métodos. El ARN mensajero (ARNm) de diferentes órganos (cerebro, hígado, riñón y músculo) de ratones jóvenes (8 meses), maduros (18 meses) y viejos (24 meses) fue extraído utilizando Trizol y analizado por PCR a tiempo real (qPCR) utilizando sondas específicas para los diferentes genes COQ que codifican para los miembros del complejo de síntesis del coenzima Q. Resultados. El hígado fue el órgano que presentó mayores cambios en cuanto a la expresión de ARNm respecto a la edad, afectando tanto a la amplitud de las variaciones como en la significatividad del cambio. En la mayoría de los genes, los niveles de ARNm fueron mayores en los animales maduros que en los jóvenes. Cuando comparamos los niveles de ARNm de los animales jóvenes y viejos solo se encontraron pequeñas reducciones de expresión. El riñón presentó un patrón similar al hígado en cuanto a la evolución de la expresión, aunque con menores incrementos en los animales maduros que los observados en el hígado. Cerebro y músculo esquelético presentaron las menores variaciones de expresión, siendo el músculo el que menores cambios presentó, aunque se observó un patrón similar al encontrado en hígado y riñón, con ligeros incrementos en animales maduros. Discusión. Nuestros resultados indican que la edad es un factor importante a tener en cuenta en el análisis de la expresión de los genes COQ. Además, la expresión de estos genes depende del órgano estudiado. Teniendo en cuenta la importancia del coenzima Q en el metabolismo celular y en el envejecimiento, es obligado un mayor estudio de la regulación génica de su maquinaria de síntesis (AU)

Introduction. Coenzyme Q is an essential component in the activity of the mitochondrial electron transport chain. Its synthesis involves, at least, a complex of ten different proteins. In this study, an attempt is made to determine the evolution of the expression of the genes involved in coenzyme Q synthesis during mouse ageing. Material and methods. The messenger RNA (mRNA) of different organs, such as brain, liver, kidney and skeletal muscle from young (8 months), mature (18 months), and old (24 months) mice was extracted by using Trizol and was then analysed by real time PCR (qPCR) using specific primers for all the known components of the coenzyme Q-synthesis complex (COQ genes). Results. Liver showed the highest age-dependent changes in mRNA levels of the different components of Q-synthesis complex, affecting the extent of the variation as well as the significance of the change. In most of the cases, mRNA levels of the different components were higher in mature animals compared to young and old animals. When mRNAs of young and old animals were compared, only minor reductions of mRNA levels were found. Kidney showed a pattern similar to that found in liver as regards the changes in expression, although with lower increases in mature animals than those observed in the liver. Brain and skeletal muscle showed low variations, with muscle being the tissue with less changes, although a pattern similar to that found in liver and kidney was found, with slight increases in mature animals. Discussion. The results of this study indicate that ageing is an important factor affecting COQ gene expression, but its effect depends on the organ, and that mature animals show higher levels of mRNA than young and old animals. Taken into consideration the importance of coenzyme Q in cell metabolism and ageing, a more detailed study is needed to understand the gene regulation of the coenzyme Q-synthesis mechanisms during ageing (AU)

A review of mitochondrial optic neuropathies: from inherited to acquired forms / Revisión de las neuropatías ópticas mitocondriales: de las formas hereditarias a las adquiridas

In recent years, the term mitochondrial optic neuropathy (MON) has increasingly been used within the literature to describe a group of optic neuropathies that exhibit mitochondrial dysfunction in retinal ganglion cells (RGCs). Interestingly, MONs include genetic aetiologies, such as Leber hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA), as well as acquired aetiologies resulting from drugs, nutritional deficiencies, and mixed aetiologies. Regardless of an inherited or acquired cause, patients exhibit the same clinical manifestations with selective loss of the RGCs due to mitochondrial dysfunction. Various novel therapies are being explored to reverse or limit damage to the RGCs. Here we review the pathophysiology, clinical manifestations, differential diagnosis, current treatment, and promising therapeutic targets of MON (AU)

En los últimos años, se ha incrementado el uso en la literatura del término neuropatía óptica mitocondrial (MON), para describir un grupo de neuropatías ópticas que presentan una disfunción mitocondrial en las células ganglionares de la retina (RGC). De manera interesante, las MON incluyen etiologías genéticas, tales como Neuropatía Óptica Hereditaria de Leber (LHON) y Atrofia Óptica Dominante (DOA), así como etiologías adquiridas derivadas del consumo de drogas, deficiencias nutricionales y etiologías mixtas. Independientemente de que la causa sea hereditaria o adquirida, los pacientes presentan las mismas manifestaciones clínicas, con pérdida selectiva de RGCs debido a la disfunción mitocondrial. Se están explorando diversas terapias novedosas para revertir o limitar el daño a las RGC. En este documento revisamos la patofisiología, las manifestaciones clínicas, los diagnósticos diferenciales, el tratamiento actual y los prometedores objetivos terapéuticos de las MON (AU)

Sodium butyrate protects against oxidative stress in HepG2 cells through modulating Nrf2 pathway and mitochondrial function

Sodium butyrate (NaBu) is a by-product of microbial fermentation of dietary fiber in the gastrointestinal tract and has been shown to increase the activity of antioxidant enzymes, such as catalase or heme oxidase-1, in vivo. However, the mechanism of this effect is still unclear. This study investigated the antioxidant effect of NaBu on HepG2 cells under H2O2-induced oxidative stress. NaBu (0.3 mM) attenuated cell death and accumulation of reactive oxygen species and improved multiple antioxidant parameters in H2O2-injured HepG2 cells. NaBu inhibited glycogen synthase kinase-3 beta (GSK-3Beta) by increasing the p-GSK-3 Beta (Ser9) level and promoted nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), which increased the expression of downstream antioxidant enzymes. Together with promotion of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and mitochondrial DNA copy number, NaBu modulated energy metabolism and mitochondrial function, decreasing glycolysis, increasing Beta -oxidation, and enhancing the tricarboxylic acid cycle and oxidative phosphorylation. NaBu increased mitochondrial manganese-superoxide dismutase and glutathione peroxidase activity. In conclusion, NaBu protected HepG2 cells against oxidative stress by modulating Nrf2 pathway activity and mitochondrial function