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Anesthetic sevoflurane induces mitochondrial dysfunction, impairment of neurogenesis, and cognitive impairment in young mice, but the underlying mechanism remains to be determined. Cyclophilin D (CypD) is a modulatory factor for the mitochondrial permeability transition pore (mPTP). We, therefore, set out to evaluate the role of CypD in these sevoflurane-induced changes in vitro and in young mice. Wild-type (WT) and CypD knockout (KO) young (postnatal day 6, 7, and 8) mice received 3% sevoflurane 2 h daily and the neural progenitor cells (NPCs) harvested from the WT or CypD KO mice received 4.1% sevoflurane. We used immunohistochemistry and immunocytochemistry imaging, flow cytometry, Western blot, RT-PCR, co-immunoprecipitation, and Morris Water Maze to assess the interaction of sevoflurane and CypD on mitochondria function, neurogenesis, and cognition in vitro and in WT or CypD KO mice. We demonstrated that the sevoflurane anesthesia induced accumulation of CypD, mitochondrial dysfunction, impairment of neurogenesis, and cognitive impairment in WT mice or NPCs harvested from WT mice, but not in CypD KO mice or NPCs harvested from CypD KO mice. Furthermore, the sevoflurane anesthesia reduced the binding of CypD with Adenine nucleotide translocator, the other component of mPTP. These data suggest that the sevoflurane anesthesia might induce a CypD-dependent mitochondria dysfunction, impairment of neurogenesis, and cognitive impairment in young mice and NPCs.

Gel-forming mucins are the main organic component responsible for physical properties of the mucus hydrogels. While numerous biological functions of these mucins are well documented, specific physiological functions of each mucin are largely unknown. To investigate in vivo functions of the gel-forming mucin Muc5b, which is one of the major secreted airway mucins, along with Muc5ac, we generated mice in which Muc5b was disrupted and maintained in the absence of environmental stress. Adult Muc5b-deficient mice displayed bronchial hyperplasia and metaplasia, interstitial thickening, alveolar collapse, immune cell infiltrates, fragmented and disorganized elastin fibers and collagen deposits that were, for approximately one-fifth of the mice, associated with altered pulmonary function leading to respiratory failure. These lung abnormalities start early in life, as demonstrated in one-quarter of 2-day-old Muc5b-deficient pups. Thus, the mouse mucin Muc5b is essential for maintaining normal lung function., Summary: The gelling mucin MUC5B is essential for the mucociliary clearance at adulthood. Here we show that Muc5b-deficient mice exhibit an early lung inflammation that may lead to respiratory distress.

Tau phosphorylation is associated with cognitive impairment in young mice. However, the underlying mechanism and targeted interventions remain mostly unknown. We set out to determine the potential interactions of Tau, interleukin 6 (IL-6) and mitochondria following treatment of anesthetic sevoflurane and to assess their influences on synapse number and cognition in young mice. Sevoflurane (3% for 2 ​h) was given to wild-type, Tau knockout, IL-6 knockout, and cyclophilin D (CypD) knockout mice on postnatal (P) day 6, 7 and 8. We measured amounts of phosphorylated Tau, IL-6, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), ATP, postsynaptic density 95 (PSD-95), synaptophysin, N-cadherin, synapse number, and cognitive function in the mice, employing Western blot, electron microscope and Morris water maze among others. Here we showed that sevoflurane increased Tau phosphorylation and caused IL-6 elevation, mitochondrial dysfunction, synaptic loss and cognitive impairment in young wild-type, but not Tau knockout, mice. In young IL-6 knockout mice, sevoflurane increased Tau phosphorylation but did not cause mitochondrial dysfunction, synaptic loss or cognitive impairment. Finally, sevoflurane increased Tau phosphorylation and IL-6 amount, but did not induce synaptic loss and cognitive impairment, in young CypD knockout mice or WT mice pretreated with idebenone, an analog of co-enzyme Q10. In conclusion, sevoflurane increased Tau phosphorylation, which caused IL-6 elevation, leading to mitochondrial dysfunction in young mice. Such interactions caused synaptic loss and cognitive impairment in the mice. Idebenone mitigated sevoflurane-induced cognitive impairment in young mice. These studies would promote more research to study Tau in young mice., Highlights • Research in context.•Evidence before this studya.Tau, a microtubule-associated protein that is predominantly expressed inside neurons, is associated with microtubule assembly and function. Tau phosphorylation, aggregation and spread all serve as the pathogenesis of age-dependent neurodegeneration in the old brain, as well as the neuropathogenesis of Alzheimer’s disease. However, the effects of Tau on the cellular changes and the function of the young brain are undetermined. Our previous studies showed that anesthetic sevoflurane induced Tau phosphorylation, IL-6 elevation, mitochondrial dysfunction and synaptic loss in brain tissues of neonatal mice, as well as cognitive impairment in the mice. However, the potential interactions of the Tau phosphorylation, IL-6 elevation and mitochondrial dysfunction and the influences of these interactions on synapse number and cognitive function in neonatal mice remains largely unknown.•Added value of studyb.Employing sevoflurane as a clinically relevant tool, and using the approaches including wild-type, Tau, IL-6, and CypD knockout neonatal mice, the present studies showed that Tau phosphorylation caused IL-6 elevation, which induced mitochondrial dysfunction, leading to synaptic loss and cognitive impairment in the neonatal mice. Idebenone, a synthetic analog of coenzyme Q10, mitigated the sevoflurane-induced cognitive impairment in the neonatal mice.•Implications of all the available evidencec.These findings demonstrated the role of Tau phosphorylation in cognitive impairment in neonatal mice, revealed the effects of the interactions of Tau phosphorylation, IL-6 elevation and mitochondrial dysfunction on the synapse number and cognitive function in the mice, and identified potential targeted intervention of the cognitive impairment in the neonatal mice.

Background: Angiotensin converting enzyme inhibitors (ACEi) are the current standard of care treatment for cardiac dysfunction in Duchenne muscular dystrophy patients. We previously showed treatment with an ACEi plus mineralocorticoid receptor (MR) antagonist improves limb and respiratory skeletal muscles, in addition to cardiac muscles, in a dystrophic mouse model at 20 weeks-of-age. Objective: To determine whether previously observed preclinical benefits of an ACEi plus MR antagonist on dystrophic skeletal muscles can be reproduced by increasing ACEi dosage alone. We also compared functional and histological outcome measures at 10 and 20 weeks-of-age. Methods: Dystrophin deficient utrophin haplo-insufficient (utrn +/- ; mdx) “het” mice were treated with 10, 20, or 50 mg/kg × day of the ACEi lisinopril from 4 to 10 weeks-of-age via water bottles and compared with C57BL/10 wild-type control mice and untreated hets. Data from 10 week-old het mice were also compared to data collected from an untreated het group at 20 weeks-old. In vivo cardiac and grip strength measurements, in vitro diaphragm and extensor digitorum longus muscle force measurements, and histopathological analyses were performed. One-way ANOVA followed by Dunnett post hoc comparison was used to determine significance. Results: ACEi treatment reduced skeletal muscle damage but had no significant effect on muscle force. Body weight, heart rate, grip strength and blood pressure were unaffected by treatment. Limb muscle histopathology was more informative at 10 than 20 weeks-of-age. Conclusions: These results suggest increased ACEi dosage alone cannot improve all dystrophic parameters. Further optimization of MR antagonists in 20 week-old mice is warranted.

Background/Purpose: Oral immunization with Lactococcus lactis PppA (LPA+), a recombinant strain that is able to express the pneumococcal protective protein A, can improve the resistance to respiratory challenge with Streptococcus pneumoniae in adult mice. In this study, we investigated whether oral immunization protocols using LPA+ are able to protect young mice against pneumococcal respiratory infection. Methods: Young mice (aged, 3 weeks) were immunized orally with LPA+ for 5 consecutive days. Vaccination was performed once (non-boosted group), or twice with a 2-week interval between each immunization (boosted group). At the end of treatment, the specific immune responses and the resistance to pneumococcal infection were studied. Results: We found that the oral immunization with LPA+ was able to induce the production of specific antibodies in the respiratory and intestinal tracts as well as systemically. Analysis of IgG subtypes showed that LPA+ immunization stimulated a mixed Th1 and Th2 response. To assess whether the production of mucosal and systemic antibodies was able to afford protection against respiratory pneumococcal infection, challenge experiments with the pathogenic serotypes 3, 6B, 14, and 23F were carried out. Vaccination with LPA+ was able to increase resistance to infection with the four serotypes of S. pneumoniae, although the protective capacity of the experimental vaccine was different for each of them. Immunization decreased colonization in the lung, prevented bacteremia of serotypes 6B, 14, and 23F, and decreased colony counts of serotype 3. Conclusion: We have shown that the oral immunization of young mice with LPA+ effectively induces the production of specific antibodies against the antigen PppA, both in mucosae and at the systemic level. The antibodies produced may play an important role in the protection against pneumococcal disease, since the young mice immunized with the experimental vaccine showed an increased resistance to infection with different serotypes of the pathogen. Fil: Villena, Julio Cesar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Centro de Referencia para Lactobacilos; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Bioquímica Aplicada; Argentina Fil: Medina, Marcela Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Centro de Referencia para Lactobacilos; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Bioquímica Aplicada; Argentina Fil: Racedo, Silvia María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Centro de Referencia para Lactobacilos; Argentina Fil: Alvarez, Gladis Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Centro de Referencia para Lactobacilos; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Bioquímica Aplicada; Argentina