Adverse psychosocial experiences have been shown to modulate individual responses to immune challenges and affect mitochondrial functions. The aim of this study was to investigate inflammation and ...immune responses as well as mitochondrial bioenergetics in an experimental model of Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS). Starting in adolescence (postnatal day 28), male SJL/J mice were exposed to five injections (interspaced by two weeks) with Group-A beta-haemolytic streptococcus (GAS) homogenate. Mice were exposed to chronic psychosocial stress, in the form of protracted visual exposure to an aggressive conspecific, for four weeks. Our results indicate that psychosocial stress exacerbated individual response to GAS administrations whereby mice exposed to both treatments exhibited altered cytokine and immune-related enzyme expression in the hippocampus and hypothalamus. Additionally, they showed impaired mitochondrial respiratory chain complexes IV and V, and reduced adenosine triphosphate (ATP) production by mitochondria and ATP content. These brain abnormalities, observed in GAS-Stress mice, were associated with blunted titers of plasma corticosterone. Present data support the hypothesis that challenging environmental conditions, in terms of chronic psychosocial stress, may exacerbate the long-term consequences of exposure to GAS processes through the promotion of central immunomodulatory and oxidative stress.
The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic calls for rapid actions, now principally oriented to a world‐wide vaccination campaign. In this study we verified if, in ...individuals with a previous SARS‐CoV‐2 infection, a single dose of messenger RNA (mRNA) vaccine would be immunologically equivalent to a full vaccine schedule in naïve individuals. Health care workers (184) with a previous SARS‐CoV‐2 infection were sampled soon before the second dose of vaccine and between 7 and 10 days after the second dose, the last sampling time was applied to SARS‐CoV‐2 naïve individuals, too. Antibodies against SARS‐CoV‐2 were measured using Elecsys Anti‐SARS‐CoV‐2 S immunoassay. The study was powered for non‐inferiority. We used non parametric tests and Pearson correlation test to perform inferential analysis. After a single vaccine injection, the median titer of specific antibodies in individuals with previous coronavirus disease 2019 was 30.527 U/ml (interquartile range IQR: 19.992–39.288) and in subjects with previous SARS‐CoV‐2 asymptomatic infection was 19.367.5 U/ml (IQR: 14.688–31.353) (p = .032). Both results were far above the median titer in naïve individuals after a full vaccination schedule: 1974.5 U/ml (IQR: 895–3455) (p < .0001). Adverse events after vaccine injection were more frequent after the second dose of vaccine (mean: 0.95; 95% confidence interval CI: 0.75–1.14 vs. mean: 1.91; 95% CI: 1.63–2.19) (p < .0001) and in exposed compared to naïve (mean: 1.63; 95% CI: 1.28–1.98 vs. mean: 2.35; 95% CI: 1.87–2.82) (p = .015). In SARS‐CoV‐2 naturally infected individuals a single mRNA vaccine dose seems sufficient to reach immunity. Modifying current dosing schedules would speed‐up vaccination campaigns.
Highlights
1) Individuals COVID 19 positive shows a single dose antibody titers 10 fold higher than naive individuals with full vaccination schedule
2) In SARS‐CoV‐2 naturally infected individuals a single mRNA vaccine dose seems sufficient to reach immunity.
Information about severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection in HIV‐infected individuals is scarce. In this prospective study, we included HIV (human immunodefeciency ...virus)‐infected individuals (people living with HIV PLWHIV) with confirmed SARS‐CoV‐2 infection and compared them with PLWHIV negative for SARS‐CoV‐2. We compared 55 cases of SARS‐CoV‐2 infection with 69 asymptomatic PLWHIV negative for SARS‐CoV‐2 reverse transcription‐polymerase chain reaction and/or serology. There was no significant difference between SARS‐CoV‐2 positive or negative patients for age distribution, gender, time with HIV infection, nadir CD4‐cell counts, type and number of co‐morbidities, current CD4 and CD8 counts and type of anti‐HIV therapy. Positive patients presented with a median of three symptoms (interquartile range, 1‐3). Most common symptoms were fever (76%), dyspnea (35%), anosmia (29%) non‐productive cough (27%), fatigue 22%), and ageusia (20%). Ten patients (18%) were completely asymptomatic. Four (7.2%) subjects died of coronavirus disease 2019. Factors significantly (P < .05) associated with death included age and number of co‐morbidities, while time from HIV infection and lower current CD4 counts were significant only in univariate analysis. HIV‐infected individuals are not protected from SARS‐CoV‐2 infection or have a lower risk of severe disease. Indeed, those with low CD4 cell counts might have worse outcomes. Infection is asymptomatic in a large proportion of subjects and this is relevant for epidemiological studies.
Highlights
This study addresses the question if specific characteristics of HIV infection may raise the risk of SARS‐CoV‐2 infection by comparing infected persons living with HIV (PLWHIV), either symptomatic or not, with other PLWHIV who tested negative for SARS‐CoV‐2 infection. None of the parameters classically used to define immune suppression or risk of immune impairment in HIV positive subjects does correlate with the risk of acquiring SARS‐CoV‐2 infection. Although low CD4 counts were not associated with the positivity for SARS‐CoV‐2, relative immunosuppression did seem to affect disease severity, and it might be associated with adverse outcomes. By contrast, there was no evidence that any specific antiretroviral drug affected SARS‐CoV‐2 infection or COVID‐19 severity.
The disease may cover a vast range of clinical pictures, being almost one fifth of infected individuals asymptomatic and variables already described for the general population as risk factors for a more severe disease such as advanced age and the presence of multiple co‐morbidities do apply to PLWHIV, too.
HIV‐infected individuals should not be considered protected from SARS‐CoV‐2 infection or as having lower risk of severe disease. Indeed, those with low CD4 cell counts might have worse outcomes than individuals with restored immunity. Infection may be asymptomatic in a large proportion of subjects and this variable must be counted when epidemiological studies are implemented in PLWHIV.
In the light of the occurrence of L-lactate dehydrogenase inside the mitochondrial matrix, we looked at whether isolated rat liver mitochondria can take up and metabolize L-lactate, and provide ...oxaloacetate outside mitochondria, thus contributing to a partial reconstruction of gluconeogenesis in vitro. We found that: (1) L-lactate (10 mM), added to mitochondria in the presence of a cocktail of glycolysis/gluconeogenesis enzymes and cofactors, can lead to synthesis of glyceraldehyde-3-phosphate at a rate of about 7 nmol/min per mg mitochondrial protein. (2) Three novel translocators exist to mediate L-lactate traffic across the inner mitochondrial membrane. An L-lactate/H+ symporter was identified by measuring fluorimetrically the rate of endogenous pyridine nucleotide reduction. Consistently, L-lactate oxidation was found to occur with P/O ratio=3 (where P/O ratio is the ratio of mol of ATP synthesized to mol of oxygen atoms reduced to water during oxidative phosphorylation) and with generation of membrane potential. Proton uptake, which occurred as a result of addition of L-lactate to RLM together with electron flow inhibitors, and mitochondrial swelling in ammonium L-lactate solutions were also monitored. L-Lactate/oxaloacetate and L-lactate/pyruvate anti-porters were identified by monitoring photometrically the appearance of L-lactate counter-anions outside mitochondria. These L-lactate translocators, which are distinct from the monocarboxylate carrier, were found to differ from each other in V(max) values and in inhibition and pH profiles, and proved to regulate mitochondrial L-lactate metabolism in vitro. The role of lactate/mitochondria interactions in gluconeogenesis is discussed.
Mitochondrial dysfunctions critically impair nervous system development and are potentially involved in the pathogenesis of various neurodevelopmental disorders, including Down syndrome (DS), the ...most common genetic cause of intellectual disability. Previous studies from our group demonstrated impaired mitochondrial activity in peripheral cells from DS subjects and the efficacy of epigallocatechin-3-gallate (EGCG) – a natural polyphenol major component of green tea – to counteract the mitochondrial energy deficit. In this study, to gain insight into the possible role of mitochondria in DS intellectual disability, mitochondrial functions were analyzed in neural progenitor cells (NPCs) isolated from the hippocampus of Ts65Dn mice, a widely used model of DS which recapitulates many major brain structural and functional phenotypes of the syndrome, including impaired hippocampal neurogenesis. We found that, during NPC proliferation, mitochondrial bioenergetics and mitochondrial biogenic program were strongly compromised in Ts65Dn cells, but not associated with free radical accumulation. These data point to a central role of mitochondrial dysfunction as an inherent feature of DS and not as a consequence of cell oxidative stress. Further, we disclose that, besides EGCG, also the natural polyphenol resveratrol, which displays a neuroprotective action in various human diseases but never tested in DS, restores oxidative phosphorylation efficiency and mitochondrial biogenesis, and improves proliferation of NPCs. These effects were associated with the activation of PGC-1α/Sirt1/AMPK axis by both polyphenols. This research paves the way for using nutraceuticals as a potential therapeutic tool in preventing or managing some energy deficit-associated DS clinical manifestations.
•Neural progenitor cell (NPC) proliferation is affected in Ts65Dn model of DS.•Mitochondrial bioenergetics and biogenesis are impaired during NPC proliferation.•EGCG and RSV counteract mitochondrial dysfunctions and promote NPC proliferation.•EGCG and RSV activate PGC-1α/Sirt1/AMPK axis.
To find out whether and how proteasome is involved in plant programmed cell death (PCD) we measured proteasome function in tobacco cells undergoing PCD as a result of heat shock (HS-PCD). Reactive ...oxygen species (ROS) production, cytochrome
c levels and caspase-3-like protease activation were also measured in the absence or presence of MG132, a proteasome inhibitor. We show that proteasome activation occurs in early phase of HS-PCD upstream of the caspase-like proteases activation; moreover inhibition of proteasome function by MG132 results in prevention of PCD perhaps due to the prevention of ROS production, cytochrome
c release and caspase-3-like protease activation.
•Down syndrome is both a neurodevelopment and neurodegenerative disorder.•Genetic and metabolic alterations involved in Down syndrome neuropathology are discussed.•Drugs targeting altered genes and ...metabolic pathways for therapeutic challenge in DS are discussed.
Down syndrome (DS) is a genetic disease that occurs due to an aneuploidy of human chromosome 21. Trisomy of chromosome 21 is a primary genetic cause of developmental abnormalities leading to cognitive and learning deficits. Impairments in GABAergic transmission, noradrenergic neuronal loss, anomalous glutamatergic transmission and N-methyl-d-aspartate receptor signalling, mitochondrial dysfunction, increased oxidative stress and inflammation, differentially expressed microRNAs, increased expression of crucial chromosome 21 genes, and DNA hyper-methylation and hyperactive homocysteine trans-sulfuration pathway, are common incongruities that have been reported in DS and might contribute to cognitive impairment and intellectual disability. This review provides an update on metabolic and neurobiological alterations in DS. It also provides an overview of the currently available pharmacological therapies that may influence and/or reverse these alterations in DS.
•Mitochondrial dysfunctions and oxidative stress are hallmarks in DS and in ID-related diseases.•Polyphenols improve signalling pathways impaired in DS.•Polyphenols target mitochondria and reduce ...oxidative stress.•Polyphenols can suppress neuroinflammation and enhance memory and cognitive behaviour.•Dietary polyphenols may be a therapeutic supplementation for DS handling.
Polyphenols are secondary metabolites of plants largely found in fruits, vegetables, cereals and beverages, and therefore represent important constituents of the human diet. Increasing studies have demonstrated the potential beneficial effects of polyphenols on human health. Extensive reviews have discussed the protective effects of polyphenols against a series of diseases such as cancer, cardiovascular diseases, diabetes, and neurodegenerative disorders. Limited studies have investigated the potential therapeutic effects of these natural compounds on neurodevelopmental disorders associated with intellectual disability, such as Down syndrome (DS), for which mitochondrial dysfunctions and oxidative stress are hallmarks and contribute to the deleterious symptoms and cognitive decline. This review, starting from the structure, source, bioavailability and pharmacokinetics of relevant polyphenols, highlights recent studies on the effect and potential molecular mechanism(s) of action of the phenolic compounds epigallocatechin-3-gallate, resveratrol and hydroxytyrosol in restoring mitochondrial energy deficit and in reversing phenotypical alteration in DS. The clinical implications of plant polyphenol dietary supplements as therapeutic tools in managing DS and other intellectual disability-related diseases, is also discussed.
Little is known about the applicability of dual treatments based on integrase inhibitors. We explored the combination of lamivudine + dolutegravir as an option when switching from standard cART in ...virologically suppressed patients.
In this prospective cohort we enrolled patients previously switched to 3TC + DTG who were 18 years or older, with no previous resistance mutations to the used drugs, having a HIV-RNA <50 copies/ml for 6 months or longer, negative for HBsAg and on a stable (>6 months) cART.
Ninety-four individuals were included. They were mostly men (77.7%) with a mean age of 53 years. They presented 159 co-morbidities including cardiovascular, bone, hepatic, kidney, and CNS diseases. Because of these pathologies, they took 207 non-ARV drugs (mean 2.2 per patient). Median duration of viral suppression was 77.5 months (IQR 61). All subjects were prospectively followed up to week 24 and all remained on dual therapy during the whole period. Neither virological failure, nor viral blip was detected. The median CD4 count rose from 658 cells/mcl (IQR 403) to 724 cells/mcl (IQR 401) (P = 0.006) without a significant (P = 0.44) change in the CD4/CD8 ratio. A significant (P < 0.0001) increment of median creatinine from 0.87 mg/dl (IQR 0.34) to 0.95 mg/dl (IQR 0.29) was observed in the first 2 months but thereafter leveled on these values (1.00 mg/dl; IQR 0.35) (P = 0.111 compared to 2 months). The lipid profile slightly improved. The daily cost of cART was significantly (P < 0.0001) reduced of 6.89 euros (SD 6.10).
Switching to a dual cART regimen based on lamivudine + dolutegravir maintains virological efficacy up to week 24, and is associated to slight improvements of the immunologic and metabolic status. The strategy allows to freely using concomitant medications for associated pathologies. The dual therapy is less expensive in economic terms.
Although still limited evidence exists, a dolutegravir-based dual therapy in combination with lamivudine shows promising results to be confirmed in larger controlled trials.
Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than ...95% of classic cases, and currently there is no cure for this devastating disorder. Recently we have demonstrated that neurobehavioral and brain molecular alterations can be rescued in a RTT mouse model, by pharmacological stimulation of the brain serotonin receptor 7 (5-HT7R). This member of the serotonin receptor family, crucially involved in the regulation of brain structural plasticity and cognitive processes, can be stimulated by systemic repeated treatment with LP-211, a brain-penetrant selective agonist. The present study extends previous findings by demonstrating that LP-211 treatment (0.25 mg/kg, once per day for 7 days) rescues mitochondrial respiratory chain impairment, oxidative phosphorylation deficiency and the reduced energy status in the brain of heterozygous female mice from two highly validated mouse models of RTT (MeCP2-308 and MeCP2-Bird mice). Moreover, LP-211 treatment completely restored the radical species overproduction by brain mitochondria in the MeCP2-308 model and partially recovered the oxidative imbalance in the more severely affected MeCP2-Bird model. These results provide the first evidence that RTT brain mitochondrial dysfunction can be rescued targeting the brain 5-HT7R and add compelling preclinical evidence of the potential therapeutic value of LP-211 as a pharmacological approach for this devastating neurodevelopmental disorder.
•Pharmacological 5-HT7R stimulation rescues brain mitochondrial deficiency and radical species overproduction in Rett mice.•Brain mitochondrial respiratory chain impairment, radical species overproduction and reduced energy status in Rett mice.•Degree of brain mitochondrial dysfunction associates with the severity of the phenotype in two validated Rett mouse models.
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