Neuronal inclusions of hyperphosphorylated and aggregated tau protein are a pathological hallmark of several neurodegenerative tauopathies, including Alzheimer's disease (AD). The hypothesis of tau ...transmission in AD has emerged from histopathological studies of the spatial and temporal progression of tau pathology in postmortem patient brains. Increasing evidence in cellular and animal models supports the phenomenon of intercellular spreading of tau. However, the molecular and cellular mechanisms of pathogenic tau transmission remain unknown. The studies described herein investigate tau pathology propagation using human neurons derived from induced pluripotent stem cells. Neurons were seeded with full-length human tau monomers and oligomers and chronic effects on neuronal viability and function were examined over time. Tau oligomer-treated neurons exhibited an increase in aggregated and phosphorylated pathological tau. These effects were associated with neurite retraction, loss of synapses, aberrant calcium homeostasis, and imbalanced neurotransmitter release. In contrast, tau monomer treatment did not produce any measureable changes. This work supports the hypothesis that tau oligomers are toxic species that can drive the spread of tau pathology and neurodegeneration.
Several independent studies have implicated tau protein as central to Alzheimer's disease progression and cell-to-cell pathology propagation. In this study, we investigated the ability of different tau species to propagate pathology in human neurons derived from induced pluripotent stem cells, which to date has not been shown. We demonstrated that tau oligomers, but not monomers, induce accumulation of pathological, hyperphosphorylated tau. This effect was accompanied with neurite degeneration, loss of synapses, aberrant calcium homeostasis, imbalanced neurotransmitter release, and ultimately with neuronal death. This study bridges various tau pathological phenotypes into a single and relevant induced pluripotent stem cell neuronal model of human disease that can be applied to the discovery of the mechanisms of tau-induced neurodegeneration.
Brown adipose tissue (BAT) has been encouraged as a potential treatment for obesity and comorbidities due to its thermogenic activity capacity and contribution to energy expenditure. Some ...interventions such as cold and β-adrenergic drugs are able to activate BAT thermogenesis as well as promote differentiation of white adipocytes into brown-like cells (browning), enhancing the thermogenic activity of these cells. In this mini-review, we discuss new mechanisms related to BAT and energy expenditure. In this regard, we will also discuss recent studies that have revealed the existence of important secretory molecules from BAT "batokines" that act in autocrine, paracrine, and endocrine mechanisms, which in turn may explain some of the beneficial roles of BAT on whole body glucose and fat metabolism. Finally, we will discuss new insights related to BAT thermogenesis with an additional focus on the distinct features of BAT metabolism between rodents and humans.
Reprogramming metabolism is of great therapeutic interest for reducing morbidity and mortality during sepsis-induced critical illness. Disappointing results from randomized controlled trials ...targeting glutamine and antioxidant metabolism in patients with sepsis have begged a deeper understanding of the tissue-specific metabolic response to sepsis. The current study sought to fill this gap. We analyzed skeletal muscle transcriptomics of critically ill patients, versus elective surgical controls, which revealed reduced expression of genes involved in mitochondrial metabolism and electron transport, with increases in glutathione cycling, glutamine, branched chain, and aromatic amino acid transport. We then performed untargeted metabolomics and 13C isotope tracing to analyze systemic and tissue specific metabolic phenotyping in a murine polymicrobial sepsis model. We found an increased number of correlations between the metabolomes of liver, kidney, and spleen, with loss of correlations between the heart and quadriceps and all other organs, pointing to a shared metabolic signature within vital abdominal organs, and unique metabolic signatures for muscles during sepsis. A lowered GSH:GSSG and elevated AMP:ATP ratio in the liver underlie the significant upregulation of isotopically labeled glutamine's contribution to TCA cycle anaplerosis and glutamine-derived glutathione biosynthesis; meanwhile, the skeletal muscle and spleen were the only organs where glutamine's contribution to the TCA cycle was significantly suppressed. These results highlight tissue-specific mitochondrial reprogramming to support liver energetic demands and antioxidant synthesis, rather than global mitochondrial dysfunction, as a metabolic consequence of sepsis.
•Oral wound leads to increased neutrophilia and decreasedneutropoietic potential.•Washing the oral cavity with chlorhexidine abolished the bone-marrow neutrophilia.•Matched treatment is important to ...reduce neutrophilia.•Endogenous Glucocorticoids aren’t involved in this model.
The oral cavity undergoes frequent stress caused by repeated mechanical trauma, and the constant contact of the injured oral mucosa with bacteria leads to the production of various pro-inflammatory cytokines and chemokines. Neutrophils play essential roles in the acute inflammation against the invasive microbiota, and compromised neutrophil recruitment hinders the bacterial clearance and worsens periodontitis. In this study, we aimed to explore whether wounding at the oral cavity would have an impact on the neutrophil lineage, and, if so, whether microbial contamination of the wounded surface plays significant roles.
We developed a surgical model of an oral wound (palate wound), by a small incision in the hard palate of the mice. We also evaluated the effect of chlorhexidine on oral wound-induced neutrophilia of bone-marrow.
We demonstrated an increased neutrophilia in the bone-marrow of the oral wound group, as well as decreasedex vivoneutropoietic potential, in both IL-3 and GM-CSF-driven bone-marrow cultures. Washing of the entire oral cavity with chlorhexidine before surgery abolished the bone-marrow neutrophilia in the oral wound group and increased neutropoiesis in culture, relative to the saline-treated oral wound control group. Co-located treatment (both chlorhexidine treatment and wound on the right side of the palate) resulted in significantly reduced bone-marrow neutrophilia, compared to the mismatched treatment (chlorhexidine treatment and wound on opposite sides of the palate). Neither neutrophilia nor decreased neutropoiesis were dependent on glucocorticoid signaling.
The prophylactic use of chlorhexidine ameliorates the neutrophilic response on the bone marrow, restoring the neutrophil numbers.
In the last years, the use of probiotics, including
Lactobacillus
species, has received much attention to prevent and treat vaginal disorders. These species have been described as having the ability ...to colonize the epithelial surface and produce antimicrobial metabolites that are able to control the remaining vaginal microflora. This study aimed to identify and characterize, for the first time, a bacteriocin natively produced by
Lactobacillus acidophilus
KS400 (probiotic strain from Gynoflor
®
-Medinova AG, Switzerland) and its antimicrobial activity against relevant urogenital pathogens. After organic acids and hydrogen peroxide neutralization in the fermented
Lactobacillus acidophilus
KS400 culture medium, bacteriocin activity was tested against the indicator microorganism
Lactobacillus delbrueckii
ATCC9649. The fermentation of
Lactobacillus acidophilus
KS400 for bacteriocin production was carried out in batch mode, and its antimicrobial activity, optical density and pH were monitored. After production and extraction, the bacteriocin molecular weight was estimated by electrophoresis and tested against vaginal pathogenic microorganisms. As described for other bacteriocins, batch fermentation profiles indicated that bacteriocin production occurs during the exponential growth phase of the lactobacilli, and declines during their stationary growth phase. The molecular weight of the bacteriocin is approximately 7.5 kDa. The bacteriocin containing protein extract was shown to inhibit the growth of
Gardnerella vaginalis
,
Streptococcus agalactiae
,
Pseudomonas aeruginosa
and the indicator strain
Lactobacillus delbrueckii
ATCC9649. We conclude that
L. acidophilus
KS400 produces bacteriocin with antimicrobial activity against relevant urogenital pathogens.
Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the ...hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n = 142; 122 males and 20 females) or SCZ (n = 143; 95 males and 48 females). We identified >200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).
Cystic fibrosis (CF) is a complex inherited disease which affects many organs, including the pancreas and liver, gastrointestinal tract and reproductive system, sweat glands and, particularly, the ...respiratory system.
Pseudomonas aeruginosa
is the main cause of chronic airway infection. In order to reduce morbidity and mortality due to lung infection by
P. aeruginosa
, aerosol antibiotics have been used to achieve high local concentrations in the airways and to reduce systemic toxicity. In the course of this review, the current treatments to control CF lung infections by
P. aeruginosa
are presented. Some innovative aerosol formulations such as liposomes and microspheres are herein reviewed, which may improve the efficiency of anti-pseudomonal agents, and ensure patients’ compliance to treatments, by reducing dosing frequency and/or drug dose, while maintaining therapeutic efficacy, preventing the occurrence of bacterial resistance and/or reducing adverse effects due to their controlled-release properties.
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•Intraperitoneal implants of egg white induced 5-lipoxygenase- and glucocorticoid-dependent eosinophilia in mice.•Highly purified eosinophil in preparative amounts can be efficiently ...obtained from peritoneal exudate of these mice.•The purified eosinophils are functionally intact in both in vivo and in vitro immunopharmacological assays.
Subcutaneous implants of heat–coagulated egg white (egg white implants, EWI) induce intense local eosinophilia and prime for hyperreactivity following airway ovalbumin challenge. The roles of allergen sensitization, surgical trauma–induced glucocorticoids, and the 5-lipoxygenase (5-LO) pathway were hitherto unexplored in this model, in which quantitative recovery and large-scale purification of the eosinophils from the inflammatory site for functional and immunopharmacological studies are difficult to achieve.
We overcame this limitation by shifting the implantation site to the peritoneal cavity (EWIp), thereby enabling quantitative leukocyte retrieval.
By day 7 post–surgery, eosinophil counts reached ~ 30% of all leukocytes recovered. Eosinophilia was prevented by: a) induction of allergen–specific oral tolerance to ovalbumin, the main allergen in egg white; b) inactivation of the 5–lipoxygenase pathway; c) blockade of endogenous glucocorticoid signaling by pretreatment with metirapone plus mifepristone before surgery. Highly purified eosinophils (~99% pure) could be obtained from the peritoneal exudate of EWIp–carrier mice in 2 simple, antibody–free steps. Preparative-scale yields, suitable for most biochemical, pharmacological, and molecular applications, were routinely obtained, and could be further enhanced through addition of pre–or post–surgery immunization steps (active or adoptive). The recovered eosinophils were fully functional in vivo, as demonstrated by the transfer of purified eosinophils into eosinophil–deficient Δdbl–GATA–1-KO mice, which upon subsequent challenge with eotaxin-1 present secondary accumulation of neutrophils, but not of mononuclear phagocytes.
These findings document glucocorticoid−, allergen– and 5–lipoxygenase–dependent eosinophilia, which makes EWIp carriers an abundant source of pure, nontransgenic eosinophils for immunopharmacological studies.
There is evidence for the involvement of peroxisome proliferator-activated receptors (PPARs) in pain, cognition, and anxiety. However, their role in pain-fear interactions is unknown. The amygdala ...plays a key role in pain, conditioned fear, and fear-conditioned analgesia (FCA). We investigated the effects of intra-basolateral amygdala (BLA) administration of PPARα, PPARβ/δ, and PPARγ antagonists on nociceptive behaviour, FCA, and conditioned fear in the presence or absence of nociceptive tone. Male Sprague-Dawley (SD) rats received footshock (FC) or no footshock (NFC) in a conditioning arena. Twenty-three and a half hours later, rats received an intraplantar injection of formalin or saline and, 15 min later, intra-BLA microinjections of vehicle, PPARα (GW6471) PPARβ/δ (GSK0660), or PPARγ (GW9662) antagonists before arena re-exposure. Pain and fear-related behaviour were assessed, and neurotransmitters/endocannabinoids measured post-mortem. Intra-BLA administration of PPARα or PPARγ antagonists potentiated freezing in the presence of nociceptive tone. Blockade of all PPAR subtypes in the BLA increased freezing and BLA dopamine levels in NFC rats in the absence of nociceptive tone. Administration of intra-BLA PPARα and PPARγ antagonists increased levels of dopamine in the BLA compared with the vehicle-treated counterparts. In conclusion, PPARα and PPARγ in the BLA play a role in the expression or extinction of conditioned fear in the presence or absence of nociceptive tone.
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