Early heart and skeletal muscle mitochondrial response to a moderate hypobaric hypoxia environment.

In eukaryotic cells, aerobic energy is produced by mitochondria through oxygen uptake. However, little is known about the early mitochondrial responses to moderate hypobaric hypoxia (MHH) in highly metabolic active tissues. Here, we describe the mitochondrial responses to acute MHH in the heart and skeletal muscle. Rats were randomly allocated into a normoxia control group (n = 10) and a hypoxia group (n = 30), divided into three groups (0, 6, and 24 h post-MHH). The normoxia situation was recapitulated at the University of Granada, at 662 m above sea level. The MHH situation was performed at the High-Performance Altitude Training Centre of Sierra Nevada located in Granada at 2320 m above sea level. We found a significant increase in mitochondrial supercomplex assembly in the heart as soon as the animals reached 2320 m above sea level and their levels are maintained 24 h post-exposure, but not in skeletal muscle. Furthermore, in skeletal muscle, at 0 and 6 h, there was increased dynamin-related protein 1 (Drp1) expression and a significant reduction in Mitofusin 2. In conclusion, mitochondria from the muscle and heart respond differently to MHH: mitochondrial supercomplexes increase in the heart, whereas, in skeletal muscle, the mitochondrial pro-fission response is trigged. Considering that skeletal muscle was not actively involved in the ascent when the heart was beating faster to compensate for the hypobaric, hypoxic conditions, we speculate that the different responses to MHH are a result of the different energetic requirements of the tissues upon MHH. KEY POINTS: The heart and the skeletal muscle showed different mitochondrial responses to moderate hypobaric hypoxia. Moderate hypobaric hypoxia increases the assembly of the electron transport chain complexes into supercomplexes in the heart. Skeletal muscle shows an early mitochondrial pro-fission response following exposure to moderate hypobaric hypoxia.

Health-related fitness in medical students: a curricular intervention in Bogota, Colombia.

OBJECTIVE: To evaluate the impact of a curricular intervention to promote health-related fitness (HRF) among medical students in Bogota, Colombia. METHOD: The study was conducted between May 2014 and December 2015 as part of the medical physiology course, in which 208 medical students were enrolled.The curricular intervention included two lectures on physical activity (PA) and student-led group presentations on the physiological effects of exercise on human physiology. An academic incentive (10% of final grade) was given to students who reported and documented regular PA practice during the semester. This study assessed students' HRF variables, perceptions of the curriculum intervention, and PA practices using quantitative and qualitative approaches. RESULTS: 55% of the students were female, with a mean age of 19.5 years. Body fat, estimated maximum oxygen consumption (VO2max), handgrip, and sit-up strength showed statistically significant improvements at the end of the intervention. Students reported that PA practice was positively influenced by the curriculum intervention, particularly the academic incentive and the HRF tests. Students reported a wide variety of PA practices, which were mainly done with friends, classmates, or family members. Lack of time was the main reported barrier to PA practice. CONCLUSION: The curricular intervention was effective in improving HRF and promoting PA. It remains to be investigated whether these gains are sustained over time.

Coenzyme Q10 modulates sulfide metabolism and links the mitochondrial respiratory chain to pathways associated to one carbon metabolism.

Abnormalities of one carbon, glutathione and sulfide metabolisms have recently emerged as novel pathomechanisms in diseases with mitochondrial dysfunction. However, the mechanisms underlying these abnormalities are not clear. Also, we recently showed that sulfide oxidation is impaired in Coenzyme Q10 (CoQ10) deficiency. This finding leads us to hypothesize that the therapeutic effects of CoQ10, frequently administered to patients with primary or secondary mitochondrial dysfunction, might be due to its function as cofactor for sulfide:quinone oxidoreductase (SQOR), the first enzyme in the sulfide oxidation pathway. Here, using biased and unbiased approaches, we show that supraphysiological levels of CoQ10 induces an increase in the expression of SQOR in skin fibroblasts from control subjects and patients with mutations in Complex I subunits genes or CoQ biosynthetic genes. This increase of SQOR induces the downregulation of the cystathionine ß-synthase and cystathionine γ-lyase, two enzymes of the transsulfuration pathway, the subsequent downregulation of serine biosynthesis and the adaptation of other sulfide linked pathways, such as folate cycle, nucleotides metabolism and glutathione system. These metabolic changes are independent of the presence of sulfur aminoacids, are confirmed in mouse models, and are recapitulated by overexpression of SQOR, further proving that the metabolic effects of CoQ10 supplementation are mediated by the overexpression of SQOR. Our results contribute to a better understanding of how sulfide metabolism is integrated in one carbon metabolism and may explain some of the benefits of CoQ10 supplementation observed in mitochondrial diseases.

Melatonin drives apoptosis in head and neck cancer by increasing mitochondrial ROS generated via reverse electron transport.

The oncostatic effects of melatonin correlate with increased reactive oxygen species (ROS) levels, but how melatonin induces this ROS generation is unknown. In the present study, we aimed to elucidate the two seemingly opposing actions of melatonin regarding its relationship with free radicals. We analyzed the effects of melatonin on head and neck squamous cell carcinoma cell lines (Cal-27 and SCC-9), which were treated with 0.5 or 1 mM melatonin. We further examined the potential effects of melatonin to induce ROS and apoptosis in Cal-27 xenograft mice. Here we report that melatonin mediates apoptosis in head and neck cancer by driving mitochondrial reverse electron transport (RET) to induce ROS production. Melatonin-induced changes in tumoral metabolism led to increased mitochondrial activity, which, in turn, induced ROS-dependent mitochondrial uncoupling. Interestingly, mitochondrial complex inhibitors, including rotenone, abolished the ROS elevation indicating that melatonin increased ROS generation via RET. Melatonin also increased membrane potential and CoQ10 H2 /CoQ10 ratio to elevate mitochondrial ROS production, which are essential conditions for RET. We found that genetic manipulation of cancer cells with alternative oxidase, which transfers electrons from QH2 to oxygen, inhibited melatonin-induced ROS generation, and apoptosis. RET restored the melatonin-induced oncostatic effect, highlighting the importance of RET as the site of ROS production. These results illustrate that RET and ROS production are crucial factors in melatonin's effects in cancer cells and establish the dual effect of melatonin in protecting normal cells and inducing apoptosis in cancer cells.

Deepint.net: A Rapid Deployment Platform for Smart Territories.

This paper presents an efficient cyberphysical platform for the smart management of smart territories. It is efficient because it facilitates the implementation of data acquisition and data management methods, as well as data representation and dashboard configuration. The platform allows for the use of any type of data source, ranging from the measurements of a multi-functional IoT sensing devices to relational and non-relational databases. It is also smart because it incorporates a complete artificial intelligence suit for data analysis; it includes techniques for data classification, clustering, forecasting, optimization, visualization, etc. It is also compatible with the edge computing concept, allowing for the distribution of intelligence and the use of intelligent sensors. The concept of smart cities is evolving and adapting to new applications; the trend to create intelligent neighbourhoods, districts or territories is becoming increasingly popular, as opposed to the previous approach of managing an entire megacity. In this paper, the platform is presented, and its architecture and functionalities are described. Moreover, its operation has been validated in a case study where the bike renting service of Paris-Vélib' Métropole has been managed. This platform could enable smart territories to develop adapted knowledge management systems, adapt them to new requirements and to use multiple types of data, and execute efficient computational and artificial intelligence algorithms. The platform optimizes the decisions taken by human experts through explainable artificial intelligence models that obtain data from IoT sensors, databases, the Internet, etc. The global intelligence of the platform could potentially coordinate its decision-making processes with intelligent nodes installed in the edge, which would use the most advanced data processing techniques.

Melatonin administration to wild-type mice and nontreated NLRP3 mutant mice share similar inhibition of the inflammatory response during sepsis.

The NLRP3 inflammasome is involved in the innate immune response during inflammation. Moreover, melatonin blunts the NF-κB/NLRP3 connection during sepsis. Thus, we compared the roles of the NLRP3 inflammasome and/or melatonin treatment in the septic response of wild-type and NLRP3-/- mice. Mouse myocardial tissue was used for this purpose. The nuclear turnover of NF-κB was enhanced during sepsis, with an increase in TNFα, iNOS, and pro-IL-1ß. The lack of inflammasome in NLRP3-/- mice significantly reduced that response and blunted IL-1ß maturation due to the lack of caspase-1. Clock and Bmal1 did not change in both mouse strains, enhancing Chrono expression in mutants. RORα, which positively regulates Bmal1, was enhanced at a similar extend in both mouse strains, whereas the expression of the Bmal1 repressor, Rev-Erbα, increased in WT but was depressed in NLRP3-/- mice. Nampt, transcriptionally controlled by Bmal1, increased in WT mice together with Sirt1, whereas they remained unchanged in NLRP3-/- mice. Melatonin treatment reduced the septic response in a comparable manner as did the lack of NLRP3, but unlike the latter, it normalized the clock genes turnover through the induction of RORα and repression of Rev-Erbα and Per2, leading to enhanced Nampt and Sirt1. The lack of NLRP3 inflammasome converts sepsis to a moderate inflammatory disease and identifies NLRP3 as a main target for the treatment of sepsis. The efficacy of melatonin in counteracting the NLRP3 inflammasome activation further confirms the indoleamine as a useful therapeutic drug against this serious condition.

Charged solvatochromic dyes as signal transducers in pH independent fluorescent and colorimetric ion selective nanosensors.

Ionophore-based ion selective optical nanosensors that operate independently of the sample pH are developed here by the use of electrically charged solvatochromic dyes as signal transducers. A series of dye molecules with a D-π-A structure was synthesized and characterized in various solvents and incorporated into ion selective nanospheres for K(+), Na(+), and H(+). Since dye leakage was greatly suppressed when the solvatochromic dyes were encapsulated in the nanosphere core, ion sensing nanospheres were explored for cellular ion imaging in Dictyostelium discoideum live cells but spontaneous dye loss resulted in undesired staining of cells. The in vitro analysis of potassium in human plasma was successfully demonstrated with this approach. A theoretical model was developed for the response of the ion selective nanosensors containing charged solvatochromic dyes. The nanosensors exhibited a tunable response range, high sensitivity, and good stability.

Potassium Sensitive Optical Nanosensors Containing Voltage Sensitive Dyes.

lonophore-based ion-selective optical nanosensors have been explored for a number of years. Voltage sensitive dyes (VSDs) have been introduced into this type of sensors only very recently, forming a new class of analytical tools. Here, K(+)-sensitive nanospheres incorporating a lipophilic VSD were successfully fabricated and characterized. The nanosensors were readily delivered into the social amoeba Dictyostelium discoideum in a non-invasive manner, forming a promising new platform for intracellular ion quantification and imaging.

Oral ß-RA induces metabolic rewiring leading to the rescue of diet-induced obesity.

Obesity represents a significant health challenge, intricately linked to conditions such as type II diabetes, metabolic syndrome, and hepatic steatosis. Several existing obesity treatments exhibit limited efficacy, undesirable side effects or a limited capability to maintain therapeutics effects in the long-term. Recently, modulation Coenzyme Q (CoQ) metabolism has emerged as a promising target for treatment of metabolic syndrome. This potential intervention could involve the modulation of endogenous CoQ biosynthesis by the use of analogs of the precursor of its biosynthesis, such as ß-resorcylic acid (ß-RA). Here, we show that oral supplementation with ß-RA, incorporated into the diet of diet-induced obese (DIO) mice, leads to substantial weight loss. The anti-obesity effects of ß-RA are partially elucidated through the normalization of mitochondrial CoQ metabolism in white adipose tissue (WAT). Additionally, we identify an HFN4α/LXR-dependent transcriptomic activation of the hepatic lipid metabolism that contributes to the anti-obesity effects of ß-RA. Consequently, ß-RA mitigates WAT hypertrophy, prevents hepatic steatosis, counteracts metabolic abnormalities in WAT and liver, and enhances glucose homeostasis by reducing the insulin/glucagon ratio and plasma levels of gastric inhibitory peptide (GIP). Moreover, pharmacokinetic evaluation of ß-RA supports its translational potential. Thus, ß-RA emerges as an efficient, safe, and translatable therapeutic option for the treatment and/or prevention of obesity, metabolic dysfunction-associated steatotic liver disease (MASLD).

Rhombencephalitis by Listeria monocytogenes in a cirrhotic patient: a case report and literature review.

We report a case of rhombencephalitis infection by Listeria monocytogenes in a 66-year-old man with cirrhosis. The CSF analysis indicated L. monocytogenes as the most likely pathogen. Blood and CSF culture were positive to L. monocytogenes and MRI findings were suggestive of rhomboencephalitis. The treatment was started empirically and then modified when the culture results were available. The patient had a full clinical recovery without neurologic sequelae. Clinicians should remember that L. monocytogenes most often presents as acute bacterial meningitis, particularly in the elderly, the immunosuppressed, and those with malignancies. L. monocytogenes CNS the infections may present as acute bacterial meningitis, meningoencephalitis, or acute encephalitis.

Ambulatory non-convulsive status epilepticus evolving into a malignant form.

We retrospectively analysed the clinical characteristics, electroencephalogram (EEG) records, brain magnetic resonance imaging (MRI) scans, antiepileptic therapy and prognosis of a case series with ambulatory non-convulsive status epilepticus (NCSE) which evolved into a malignant form (mNCSE). mNCSE was defined as NCSE that continues or recurs five days or more after the onset of general anaesthesia, including those cases where NCSE recurs upon reduction or withdrawal of anaesthetic therapy. Four women and two men were studied. The mean age was 42.8 years (range: 19-63 years). Two of six patients had a previous diagnosis of epilepsy. Four patients died. Two patients had a good outcome with return to consciousness and activities of daily life, and one of these subjects developed temporal lobe epilepsy. In four patients, the cause of mNCSE was encephalitis. Clinical presentation was complex partial status epilepticus (CPSE) in three patients and generalised NCSE (GNCSE) in the other three. Two of the latter had encephalitis and one was diagnosed with progressive myoclonus epilepsy (PME) of Lafora type. The mean duration of the NCSE episode was 47.5 days (range: 9-139 days; SD: 53.1). In three patients, continuous or rhythmic focal epileptiform discharges were the EEG pattern at onset. In the other three, continuous rhythmic generalised spike-wave, polyspike-wave or sharp slow-wave complexes were observed. Antiepileptic treatment was heterogeneous and patients were treated with an average of 6.0 AEDs (range: 3-10; SD: 3.0). In summary, mNCSE is a severe epileptic condition that occurs often in the context of encephalitis or pre-existing epilepsy. Both CPSE and GNCSE may occur. Although high mortality is associated with mNCSE, some patients may survive with normal or good recovery.

[Penetrating spinal injury with glass fragments causing CSF leak: case report]. / Fístula de líquido cefalorraquídeo secundaria a traumatismo medular por cristales: a propósito de un caso.

Penetrating injuries to the spine are important causes of spinal cord traumatism. There are two varieties: gunshot or stab wounds. Within the second category, sharp knifelike objects and, rarely, glass are found. This article presents a case of penetrating glass injury to the lumbar spine in an 18-year-old girl, with the migration of pieces of glass within muscles and spinous process until reaching the dural sac.

Mechanisms and Therapeutic Effects of Benzoquinone Ring Analogs in Primary CoQ Deficiencies.

Coenzyme Q (CoQ) is a conserved polyprenylated lipid composed of a redox-active benzoquinone ring and a long polyisoprenyl tail that serves as a membrane anchor. CoQ biosynthesis involves multiple steps, including multiple modifications of the precursor ring 4-hydroxybenzoic acid. Mutations in the enzymes involved in CoQ biosynthesis pathway result in primary coenzyme Q deficiencies, mitochondrial disorders whose clinical heterogenicity reflects the multiple biological function of CoQ. Patients with these disorders do not always respond to CoQ supplementation, and CoQ analogs have not been successful as alternative approaches. Progress made in understanding the CoQ biosynthesis pathway and studies of supplementation with 4-hydroxybenzoic acid ring analogs have opened a new area in the field of primary CoQ deficiencies treatment. Here, we will review these studies, focusing on efficacy of the different 4-hydroxybenzoic acid ring analogs, models in which they have been tested, and their mechanisms of action. Understanding how these compounds ameliorate biochemical, molecular, and/or clinical phenotypes of CoQ deficiencies is important to develop the most rational treatment for CoQ deficient patients, depending on their molecular defects.

The Q-junction and the inflammatory response are critical pathological and therapeutic factors in CoQ deficiency.

Defects in Coenzyme Q (CoQ) metabolism have been associated with primary mitochondrial disorders, neurodegenerative diseases and metabolic conditions. The consequences of CoQ deficiency have not been fully addressed, and effective treatment remains challenging. Here, we use mice with primary CoQ deficiency (Coq9R239X), and we demonstrate that CoQ deficiency profoundly alters the Q-junction, leading to extensive changes in the mitochondrial proteome and metabolism in the kidneys and, to a lesser extent, in the brain. CoQ deficiency also induces reactive gliosis, which mediates a neuroinflammatory response, both of which lead to an encephalopathic phenotype. Importantly, treatment with either vanillic acid (VA) or ß-resorcylic acid (ß-RA), two analogs of the natural precursor for CoQ biosynthesis, partially restores CoQ metabolism, particularly in the kidneys, and induces profound normalization of the mitochondrial proteome and metabolism, ultimately leading to reductions in gliosis, neuroinflammation and spongiosis and, consequently, reversing the phenotype. Together, these results provide key mechanistic insights into defects in CoQ metabolism and identify potential disease biomarkers. Furthermore, our findings clearly indicate that the use of analogs of the CoQ biosynthetic precursor is a promising alternative therapy for primary CoQ deficiency and has potential for use in the treatment of more common neurodegenerative and metabolic diseases that are associated with secondary CoQ deficiency.

ß-RA Targets Mitochondrial Metabolism and Adipogenesis, Leading to Therapeutic Benefits against CoQ Deficiency and Age-Related Overweight.

Primary mitochondrial diseases are caused by mutations in mitochondrial or nuclear genes, leading to the abnormal function of specific mitochondrial pathways. Mitochondrial dysfunction is also a secondary event in more common pathophysiological conditions, such as obesity and metabolic syndrome. In both cases, the improvement and management of mitochondrial homeostasis remain challenging. Here, we show that beta-resorcylic acid (ß-RA), which is a natural phenolic compound, competed in vivo with 4-hydroxybenzoic acid, which is the natural precursor of coenzyme Q biosynthesis. This led to a decrease in demethoxyubiquinone, which is an intermediate metabolite of CoQ biosynthesis that is abnormally accumulated in Coq9R239X mice. As a consequence, ß-RA rescued the phenotype of Coq9R239X mice, which is a model of primary mitochondrial encephalopathy. Moreover, we observed that long-term treatment with ß-RA also reduced the size and content of the white adipose tissue (WAT) that is normally accumulated during aging in wild-type mice, leading to the prevention of hepatic steatosis and an increase in survival at the elderly stage of life. The reduction in WAT content was due to a decrease in adipogenesis, an adaptation of the mitochondrial proteome in the kidneys, and stimulation of glycolysis and acetyl-CoA metabolism. Therefore, our results demonstrate that ß-RA acted through different cellular mechanisms, with effects on mitochondrial metabolism; as such, it may be used for the treatment of primary coenzyme Q deficiency, overweight, and hepatic steatosis.

Metabolic Targets of Coenzyme Q10 in Mitochondria.

Coenzyme Q10 (CoQ10) is classically viewed as an important endogenous antioxidant and key component of the mitochondrial respiratory chain. For this second function, CoQ molecules seem to be dynamically segmented in a pool attached and engulfed by the super-complexes I + III, and a free pool available for complex II or any other mitochondrial enzyme that uses CoQ as a cofactor. This CoQ-free pool is, therefore, used by enzymes that link the mitochondrial respiratory chain to other pathways, such as the pyrimidine de novo biosynthesis, fatty acid ß-oxidation and amino acid catabolism, glycine metabolism, proline, glyoxylate and arginine metabolism, and sulfide oxidation metabolism. Some of these mitochondrial pathways are also connected to metabolic pathways in other compartments of the cell and, consequently, CoQ could indirectly modulate metabolic pathways located outside the mitochondria. Thus, we review the most relevant findings in all these metabolic functions of CoQ and their relations with the pathomechanisms of some metabolic diseases, highlighting some future perspectives and potential therapeutic implications.

Animal Models of Coenzyme Q Deficiency: Mechanistic and Translational Learnings.

Coenzyme Q (CoQ) is a vital lipophilic molecule that is endogenously synthesized in the mitochondria of each cell. The CoQ biosynthetic pathway is complex and not completely characterized, and it involves at least thirteen catalytic and regulatory proteins. Once it is synthesized, CoQ exerts a wide variety of mitochondrial and extramitochondrial functions thank to its redox capacity and its lipophilicity. Thus, low levels of CoQ cause diseases with heterogeneous clinical symptoms, which are not always understood. The decreased levels of CoQ may be primary caused by defects in the CoQ biosynthetic pathway or secondarily associated with other diseases. In both cases, the pathomechanisms are related to the CoQ functions, although further experimental evidence is required to establish this association. The conventional treatment for CoQ deficiencies is the high doses of oral CoQ10 supplementation, but this therapy is not effective for some specific clinical presentations, especially in those involving the nervous system. To better understand the CoQ biosynthetic pathway, the biological functions linked to CoQ and the pathomechanisms of CoQ deficiencies, and to improve the therapeutic outcomes of this syndrome, a variety of animal models have been generated and characterized in the last decade. In this review, we show all the animal models available, remarking on the most important outcomes that each model has provided. Finally, we also comment some gaps and future research directions related to CoQ metabolism and how the current and novel animal models may help in the development of future research studies.

Insular cortex thinning in first episode schizophrenia patients.

Overall and regional cortical thinning has been observed at the first break of schizophrenia. Due to the fact that structural abnormalities in the insular cortex have been described in schizophrenia, we investigated insular thickness anomalies in first episode schizophrenia. Participants comprised 118 schizophrenia patients and 83 healthy subjects. Magnetic resonance imaging brain scans (1.5T) were obtained, and images were analyzed by using BRAINS2. The contribution of sociodemographic, cognitive and clinical characterictics was controlled. Schizophrenia patients demonstrated a significant right insular thinning, and a significant group by gender interaction was found for left insular thickness. Post-hoc comparisons revealed that male schizophrenia patients had a significant left insular thinning compared with healthy male subjects. There were no significant associations between insular thickness, the severity of symptoms at baseline and cognitive measurements and premorbid variables. The fact that insular thinning is already present at early phases of the illness and is independent of intervening variables offers evidence for the potential of these changes to be a biological marker of the illness.

Temporal pole morphology in first-episode schizophrenia patients: clinical correlations.

Studies of the temporal pole (TP) in schizophrenia patients are not consistent. The aim of this study was to investigate morphometric anomalies of the TP in first-episode schizophrenia patients. Patients did not significantly differ from controls in the TP morphometric variables evaluated. Clinical variables were not significantly related to the TP.

Rapamycin administration is not a valid therapeutic strategy for every case of mitochondrial disease.

BACKGROUND: The vast majority of mitochondrial disorders have limited the clinical management to palliative care. Rapamycin has emerged as a potential therapeutic drug for mitochondrial diseases since it has shown therapeutic benefits in a few mouse models of mitochondrial disorders. However, the underlying therapeutic mechanism is unclear, the minimal effective dose needs to be defined and whether this therapy can be generally used is unknown. METHODS: We have evaluated whether low and high doses of rapamycin administration may result in therapeutic effects in a mouse model (Coq9R239X) of mitochondrial encephalopathy due to CoQ deficiency. The evaluation involved phenotypic, molecular, image (histopathology and MRI), metabolomics, transcriptomics and bioenergetics analyses. FINDINGS: Low dose of rapamycin induces metabolic changes in liver and transcriptomics modifications in midbrain. The high dose of rapamycin induces further changes in the transcriptomics profile in midbrain due to the general inhibition of mTORC1. However, neither low nor high dose of rapamycin were able to improve the mitochondrial bioenergetics, the brain injuries and the phenotypic characteristics of Coq9R239X mice, resulting in the lack of efficacy for increasing the survival. INTERPRETATION: These results may be due to the lack of microgliosis-derived neuroinflammation, the limitation to induce autophagy, or the need of a functional CoQ-junction. Therefore, the translation of rapamycin therapy into the clinic for patients with mitochondrial disorders requires, at least, the consideration of the particularities of each mitochondrial disease. FUND: Supported by the grants from "Fundación Isabel Gemio - Federación Española de Enfermedades Neuromusculares - Federación FEDER" (TSR-1), the NIH (P01HD080642) and the ERC (Stg-337327).