Conjugated linoleic acid downregulates Alzheimer's hallmarks in aluminum mouse model through an Nrf2-mediated adaptive response and increases brain glucose transporter levels.

Mitochondrial dysfunction, oxidative stress, inflammation and glucose dysmetabolism are pathological signs of Alzheimer's disease (AD). Dietary aluminum (Al) overload is often used to induce AD in rodents and trigger the onset of oxidative-stress hallmarks resembling those of the human disease. The Nuclear factor erythroid 2-related factor 2 (Nrf2), owing to its key role in redox homeostasis, mitochondrial function and inflammation, is a promising drug target for neurological disorders, but only a few data are available on its modulatory effects on glucose transporter expression levels. While it has been found that the protective effect of Conjugated linoleic acid (CLA) occurs through the activation of an Nrf2-mediated adaptive response, its beneficial effect on the considered pathological signs in the Al-induced model has not been established yet. Thirty-five male BalbC mice were divided into 5 groups: two Al-intoxicated groups were treated for 5 weeks with low or high Al doses (8 or 100 mg/kg/day in drinking water, respectively; L or H). Two groups of animals, orally supplemented with CLA (600 mg/kg bw/day) for 7 weeks (2 preliminary weeks plus the 5-week treatment with Al; CLA + L, CLA + H) were used to investigate its protective effect, while untreated mice were used as control (Cntr). We provide evidence that mitochondrial dysfunction, Nrf2 alteration, inflammation and Acetylcholinesterase (AChE) hyperactivation can occur even from L exposure. Interestingly, animal pre-treatment with an allometric CLA dose led to significant downregulation of the toxic effects elicited by L or H, likely through the activation of an adaptive response. In conclusion, CLA ability to increase the level of glucose transporters - along with its antioxidant and anti-inflammatory effect - expands the therapeutic targets of these molecules and comes out as an intriguing suitable candidate for the treatment of multifactorial disease.

Model predictive control for optimal social distancing in a type SIR-switched model.

Social distancing strategies have been adopted by governments to manage the COVID-19 pandemic, since the first outbreak began. However, further epidemic waves keep out the return of economic and social activities to their standard levels of intensity. Social distancing interventions based on control theory are needed to consider a formal dynamic characterization of the implemented SIR-type model to avoid unrealistic objectives and prevent further outbreaks. The objective of this work is twofold: to fully understand some dynamical aspects of SIR-type models under control actions (associated with second waves) and, based on it, to propose a switching non-linear model predictive control that optimize the non-pharmaceutical measures strategy. Opposite to other strategies, the objective here is not just to minimize the number of infected individuals at any time, but to minimize the final size of the epidemic while minimizing the time of social restrictions and avoiding the infected prevalence peak to overpass a maximum established by the healthcare system capacity. Simulations illustrate the benefits of the aforementioned proposal.

Application of response surface methodology (RSM) for the optimization of supercritical CO2 extraction of oil from patè olive cake: Yield, content of bioactive molecules and biological effects in vivo.

The two-phase technology for olive oil extraction generates large amounts of patè olive cake (POC), a by-product that is rich in bioactive health-promoting compounds. Here, response surface methodology (RSM) was used to maximize supercritical-CO2 oil extraction from POC, while minimizing operative temperature, pressure and time. Under the optimal parameters (40.2 °C, 43.8 MPa and time 30 min), the oil yield was 14.5 g·100 g-1 dw (~65% of the total oil content of the freeze-dried POC matrix), as predicted by RSM. Compared with freeze-dried POC, the oil contained more phytosterols (13-fold), tocopherols (6-fold) and squalene (8-fold) and was a good source of pentacyclic triterpenes. When the biological effects of POC oil intake (20-40 µL·die-1) were evaluated in the livers of BALB/c mice, no significant influence on redox homeostasis was observed. Notably, a decline in liver triglycerides alongside increased activities of NAD(P)H:Quinone Oxidoreductase 1, Carnitine Palmitoyl-CoA Transferase and mitochondrial respiratory complexes suggested a potential beneficial effect on liver fatty acid oxidation.

Perfluoro-octanoic acid impairs sperm motility through the alteration of plasma membrane.

CONTEXT: Perfluoroalkyl-substances (PFAS) are chemical additives considered harmful for humans. We recently showed that accumulation of perfluoro-octanoic acid (PFOA) in human semen of exposed subjects was associated with altered motility parameters of sperm cells, suggesting direct toxicity. OBJECTIVES: To determine whether direct exposure of human spermatozoa to PFOA was associated to impairment of cell function. PATIENTS AND METHODS: Spermatozoa isolated from semen samples of ten normozoospermic healthy donors were exposed up to 2 h to PFOA, at concentrations from 0.1 to 10 ng/mL. Viability and motility parameters were evaluated by Sperm Class Analyser. Cell respiratory function was assessed by both mitochondrial probe JC-1 and respiratory control ratio (RCR) determination. Sperm accumulation of PFOA was quantified by liquid chromatography-mass spectrometry. Expression of organic ion-transporters OATP1 and SLCO1B2 was assessed by immunofluorescence and respective role in PFOA accumulation was evaluated by either blockade with probenecid or membrane scavenging through ß-cyclodextrin (ß-CD). Plasma membrane fluidity and electrochemical potential (ΔΨp) were evaluated, respectively, with Merocyanine-540 and Di-3-ANEPPDHQ fluorescent probes. RESULTS: Compared to untreated controls, a threefold increase of the percentage of non-motile sperms was observed after 2 h of exposure to PFOA regardless of the concentration of PFOA, whilst RCR was significantly reduced. Only scavenging with ß-CD was effective in reducing PFOA accumulation, suggesting membrane involvement. Altered membrane fluidity, reduced ΔΨp and sperm motility loss associated with exposure to PFOA were reverted by ß-CD treatment. CONCLUSION: PFOA alters human sperm motility through plasma-membrane disruption, an effect recovered by incubation with ß-CD.

Dietary fatty acids influence sperm quality and function.

Recently, obesity has been linked to male infertility. In animal models the administration of a high-fat diet caused a reduction in sperm quality, by impairing gamete energy metabolism. The aim of this study was to investigate a possible effect of dietary fatty acids supplementation in the modulation of sperm energy metabolism and, in turn, in the improvement of sperm quality in rats fed a high-fat diet. Sexually mature male Sprague-Dawley rats were divided into four groups and fed for 4 weeks a standard diet (control group), a high-fat diet (enriched in 35% of fat and 15% sucrose), a high-fat diet supplemented with 2.5% olive oil (a source of monounsaturated fatty acids) or a high-fat diet supplemented with 2.5% krill oil (a source of n-3 polyunsaturated fatty acids). Liver and adipose tissue weight, plasma glucose, insulin and lipid concentrations were determined. Activities of enzymes involved in sperm energetic metabolism were evaluated by spectrophotometric assays. Sperm mitochondrial respiratory efficiency was also assayed. The obtained results suggest that olive oil partially counteracts the negative effects of a high-fat diet on sperm quality, by increasing gamete motility, by reducing oxidative stress and slightly improving mitochondrial respiration efficiency. On the other hand, krill oil determines an increase in sperm concentration and motility, an increase in the activities of lactate dehydrogenase, Krebs cycle enzymes and respiratory chain complexes; a parallel increase in the cellular levels of ATP and a reduction in oxidative damage were also observed. These results suggest that dietary fatty acids are able to positively influence sperm quality and function.

A high-fat diet negatively affects rat sperm mitochondrial respiration.

Recent evidences have linked abdominal obesity, insulin resistance, and dyslipidemia to male infertility. Since a defective energy metabolism may play an important role in the impairment of sperm quality, the aim of this study is to investigate the sperm energetic metabolism in rats fed with a high-fat diet, an animal model associated with metabolic syndrome development. Sexually mature male Sprague-Dawley rats were divided into two groups and fed for 4 weeks a standard diet (control group) or a diet enriched in 35% of fat (high fat group). Liver and adipose tissue weight, plasma glucose, insulin, and lipid concentrations were determined. Activities of enzymes involved in sperm energetic metabolism were evaluated by spectrophotometric assays. Sperm mitochondrial respiratory activity was evaluated with a polarographic assay of oxygen consumption. The administration of a high-fat diet caused a significant increase in body weight of rats and provoked hyperglycemia, hyperinsulinemia, and dyslipidemia. In these animals, we also observed a reduction in sperm concentration and motility. The investigation of sperm energetic metabolism in animals fed a high-fat diet revealed an impairment in the activity of pyruvate and lactate dehydrogenase, citrate synthase, and respiratory chain complexes. A parallel reduction in the cellular levels of adenosine triphosphate (ATP) and an increase in oxidative damage were also observed. A defective energy metabolism may play an important role in the impairment of sperm quality in the high-fat diet fed rats.

The role of mitochondria in energy production for human sperm motility.

Mitochondria of spermatozoa are different from the corresponding organelles of somatic cells, in both their morphology and biochemistry. The biochemical differences are essentially related to the existence of specific enzyme isoforms, which are characterized by peculiar kinetic and regulatory properties. As mitochondrial energy metabolism is a key factor supporting several sperm functions, these organelles host critical metabolic pathways during germ cell development and fertilization. Furthermore, spermatozoa can use different substrates, and therefore activate different metabolic pathways, depending on the available substrates and the physico-chemical conditions in which they operate. This versatility is critical to ensure fertilization success. However, the most valuable aspect of mitochondria function in all types of cells is the production of chemical energy in the form of ATP which can be used, in the case of spermatozoa, for sustaining sperm motility. The latter, on the other hand, represents one of the major determinants of male fertility. Accordingly, the presence of structural and functional alterations in mitochondria from asthenozoospermic subjects confirms the important role played by these organelles in energy maintenance of sperm motility. The present study gives an overview of the current knowledge on the energy-producing metabolic pathways operating inside human sperm mitochondria and critically analyse the differences with respect to somatic mitochondria. Such a comparison has also been carried out between the functional characteristics of human sperm mitochondria and those of other mammalian species. A deeper understanding of mitochondrial energy metabolism could open up new avenues of investigation in bioenergetics of human sperm mitochondria, both in physiological and pathological conditions.

A krill oil supplemented diet reduces the activities of the mitochondrial tricarboxylate carrier and of the cytosolic lipogenic enzymes in rats.

The mitochondrial tricarboxylate carrier supplies cytosol with the carbon units necessary for hepatic lipogenesis. The activities of cytosolic acetyl-CoA carboxylase and fatty acid synthetase are therefore strictly connected to the function of mitochondrial tricarboxylate carrier. Dietary polyunsaturated fatty acids (PUFA) are potent modulators of hepatic lipogenesis. In rats fed with a diet enriched with 2.5% krill oil (KO), a novel source of dietary n-3 PUFA, a time-dependent decrease in the activities of the mitochondrial tricarboxylate carrier and of the lipogenic enzymes was found. The KO induced inhibition of hepatic lipogenesis was more pronounced than that found in fish oil (FO)-fed rats, at least at short feeding times. The decrease in the activity of the mitochondrial tricarboxylate carrier caused by KO was due to a reduced expression of the protein. Furthermore, in the KO-fed animals a greater reduction in the levels of hepatic triglycerides and cholesterol was found in comparison to FO-fed rats.

Evaluation of mitochondrial respiratory efficiency during in vitro capacitation of human spermatozoa.

The role of mitochondria in sperm motility was the subject of several investigations. However, different views on this topic emerged among scientists. In particular, very little is known on the mechanisms of energy production occurring during human sperm capacitation and related processes. In this study, we have investigated the mitochondrial respiratory efficiency in human sperm samples from normozoospermic subjects before and after swim-up selection and incubation under capacitating condition. Sperm cells, selected by swim-up treatment, were incubated up to 24 h and then demembranated by hypotonic swelling at selected times. The oxygen uptake rate was measured in both basal and swim-up selected samples by a polarographic assay. Mitochondria of swim-up selected cells showed an impressive oxygen consumption rate, which was about 20 times higher than that measured in basal samples. The high mitochondrial respiratory efficiency remained stable up to 24 h after the swim-up treatment. The respiration control ratio, the substrate specificity and the inhibitor sensitivity in the swim-up selected samples were similar to those of basal samples thereby suggesting that the physiology of mitochondria was preserved after the swim-up treatment. Furthermore, the remarkably high mitochondrial respiration in swim-up selected samples allowed the oxygraphic analysis of just 200,000 sperm cells. Sperm selection and incubation under capacitating condition are therefore associated with a high activity of the mitochondrial respiratory chain. The sperm oxygen consumption rate could be useful to exclude mitochondria malfunctioning in male infertility.

Oxygen uptake by mitochondria in demembranated human spermatozoa: a reliable tool for the evaluation of sperm respiratory efficiency.

In this work we report a relatively simple and fast method for analysing oxygen consumption and therefore mitochondrial functionality, in individual human ejaculates. This oxygraphic method requires a low number of cells, is highly reproducible and linearly correlates with sperm concentration. Our results have shown that oxygen uptake by mitochondria of demembranated sperm cells from normozoospermic subjects is significantly stimulated by a large set of respiratory substrates and ADP. The respiratory control ratio (RCR) values indicate a good coupling between respiration and phosphorylation by sperm mitochondria and thus a well preserved integrity of the mitochondria themselves. Interestingly, whereas the rates of oxygen uptake, as expected, changed with different sperm concentrations, the RCR values remained constant, thus demonstrating a linear response of the assay. In asthenozoospermic subjects, however, a significant decrease in the sperm respiratory efficiency was found. The results obtained suggest that this method, besides its potential clinical application, could be useful for a deeper understanding of the biochemical properties of sperm mitochondria and their role in ATP production in human spermatozoa.

The mitochondrial tricarboxylate carrier: unexpected increased activity in starved silver eels.

The tricarboxylate carrier was purified to homogeneity from liver mitochondria of European eel at the silver and the yellow stage and functionally reconstituted into liposomes. Unexpectedly, the molecular activity of the tricarboxylate carrier obtained from silver eel was about twofold higher than that of the same protein from yellow eel, although eels at the silver stage stop feeding. Parallel changes were found in the activities of the lipogenic enzymes in silver eels. This suggests a functional coordination between all these proteins sequentially involved in hepatic lipogenesis. Cardiolipin added to proteoliposomes strongly stimulated the activity of the purified tricarboxylate carrier from yellow eels, whereas it slightly reduced the activity of the same protein from silver eels. The higher activity of the tricarboxylate carrier from silver eels could therefore be ascribed, at least in part, to a different composition of the lipid domain surrounding the carrier protein, possibly in response to the hormonal alterations accompanying metamorphosis from yellow to silver stage.

[Possibilities of control of regulation of the function of arteriovenous anastomoses and of capillary blood flow by means of acupuncture]. / Possibilità di controllo della regolazione della funzione delle anastomosi artero-venose e del flusso capillare mediante agopuntura.

Acupuncture was carried out on a patient with rheumatoid arthritis and microangiopathy of the lower limbs. Photoplethysmographic waves appeared at the right inferior limb where before they had been absent; at the left inferior limb normalization of postural reflexes was achieved, suggesting that acupuncture is effective in vasodilatation of capillaries and preterminal arterioles and in the reactivation of the arterio-venous blood flow.