Linnea Hases  Madeleine Birgersson  Rajitha Indukuri  Amena Archer  Cecilia Williams 《International journal of molecular sciences》2022,23(18)

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Jorge Lopez-Tello  Maria Angeles Jimenez-Martinez  Esteban Salazar-Petres  Ritik Patel  Amy L. George  Richard G. Kay  Amanda N. Sferruzzi-Perri 《International journal of molecular sciences》2022,23(11)

Pregnancy is characterized by adaptations in the function of several maternal body systems that ensure the development of the fetus whilst maintaining health of the mother. The renal system is responsible for water and electrolyte balance, as well as waste removal. Thus, it is imperative that structural and functional changes occur in the kidney during pregnancy. However, our knowledge of the precise morphological and molecular mechanisms occurring in the kidney during pregnancy is still very limited. Here, we investigated the changes occurring in the mouse kidney during pregnancy by performing an integrated analysis involving histology, gene and protein expression assays, mass spectrometry profiling and bioinformatics. Data from non-pregnant and pregnant mice were used to identify critical signalling pathways mediating changes in the maternal kidneys. We observed an expansion of renal medulla due to proliferation and infiltration of interstitial cellular constituents, as well as alterations in the activity of key cellular signalling pathways (e.g., AKT, AMPK and MAPKs) and genes involved in cell growth/metabolism (e.g., Cdc6, Foxm1 and Rb1) in the kidneys during pregnancy. We also generated plasma and urine proteomic profiles, identifying unique proteins in pregnancy. These proteins could be used to monitor and study potential mechanisms of renal adaptations during pregnancy and disease.  相似文献   

    

Tatyana Strekalova  Dmitrii Pavlov  Alexander Trofimov  Daniel C. Anthony  Andrei Svistunov  Andrey Proshin  Aleksei Umriukhin  Alexei Lyundup  Klaus-Peter Lesch  Raymond Cespuglio 《International journal of molecular sciences》2022,23(4)

The phenomenon of individual variability in susceptibility/resilience to stress and depression, in which the hippocampus plays a pivotal role, is attracting increasing attention. We investigated the potential role of hippocampal cyclooxygenase-2 (COX-2), which regulates plasticity, neuroimmune function, and stress responses that are all linked to this risk dichotomy. We used a four-week-long chronic mild stress (CMS) paradigm, in which mice could be stratified according to their susceptibility/resilience to anhedonia, a key feature of depression, to investigate hippocampal expression of COX-2, a marker of microglial activation Iba-1, and the proliferation marker Ki67. Rat exposure, social defeat, restraints, and tail suspension were used as stressors. We compared the effects of treatment with either the selective COX-2 inhibitor celecoxib (30 mg/kg/day) or citalopram (15 mg/kg/day). For the celecoxib and vehicle-treated mice, the Porsolt test was used. Anhedonic (susceptible) but not non-anhedonic (resilient) animals exhibited elevated COX-2 mRNA levels, increased numbers of COX-2 and Iba-1-positive cells in the dentate gyrus and the CA1 area, and decreased numbers of Ki67-positive cells in the subgranular zone of the hippocampus. Drug treatment decreased the percentage of anhedonic mice, normalized swimming activity, reduced behavioral despair, and improved conditioned fear memory. Hippocampal over-expression of COX-2 is associated with susceptibility to stress-induced anhedonia, and its pharmacological inhibition with celecoxib has antidepressant effects that are similar in size to those of citalopram.  相似文献   

    

Chris S. Mesnard  Cody L. Barta  Asia L. Sladek  David Zenisek  Wallace B. Thoreson 《International journal of molecular sciences》2022,23(12)

Glutamate release from rod and cone photoreceptor cells involves presynaptic ribbons composed largely of the protein RIBEYE. To examine roles of ribbons in rods and cones, we studied mice in which GCamP3 replaced the B-domain of RIBEYE. We discovered that ribbons were absent from rods and cones of both knock-in mice possessing GCamP3 and conditional RIBEYE knockout mice. The mice lacking ribbons showed reduced temporal resolution and contrast sensitivity assessed with optomotor reflexes. ERG recordings showed 50% reduction in scotopic and photopic b-waves. The readily releasable pool (RRP) of vesicles in rods and cones measured using glutamate transporter anion currents (I_A(glu)) was also halved. We also studied the release from cones by stimulating them optogenetically with ChannelRhodopsin2 (ChR2) while recording postsynaptic currents in horizontal cells. Recovery of the release from paired pulse depression was twofold slower in the rods and cones lacking ribbons. The release from rods at −40 mV in darkness involves regularly spaced multivesicular fusion events. While the regular pattern of release remained in the rods lacking ribbons, the number of vesicles comprising each multivesicular event was halved. Our results support conclusions that synaptic ribbons in rods and cones expand the RRP, speed up vesicle replenishment, and augment some forms of multivesicular release. Slower replenishment and a smaller RRP in photoreceptors lacking ribbons may contribute to diminished temporal frequency responses and weaker contrast sensitivity.  相似文献   

    

Rocio Alfaro-Ruiz  Carolina Aguado  Alejandro Martín-Belmonte  Ana Esther Moreno-Martínez  Jesús Merchn-Rubira  Flix Hernndez  Jesús vila  Yugo Fukazawa  Rafael Lujn 《International journal of molecular sciences》2022,23(21)

Tau pathology is a hallmark of Alzheimer’s disease (AD) and other tauopathies, but how pathological tau accumulation alters the glutamate receptor dynamics driving synaptic dysfunction is unclear. Here, we determined the impact of tau pathology on AMPAR expression, density, and subcellular distribution in the hippocampus of P301S mice using immunoblot, histoblot, and quantitative SDS-digested freeze-fracture replica labeling (SDS-FRL). Histoblot and immunoblot showed differential regulation of GluA1 and GluA2 in the hippocampus of P301S mice. The GluA2 subunit was downregulated in the hippocampus at 3 months while both GluA1 and GluA2 subunits were downregulated at 10 months. However, the total amount of GluA1-4 was similar in P301S mice and in age-matched wild-type mice. Using quantitative SDS-FRL, we unraveled the molecular organization of GluA1-4 in various synaptic connections at a high spatial resolution on pyramidal cell spines and interneuron dendrites in the CA1 field of the hippocampus in 10-month-old P301S mice. The labeling density for GluA1-4 in the excitatory synapses established on spines was significantly reduced in P301S mice, compared to age-matched wild-type mice, in the strata radiatum and lacunosum-moleculare but unaltered in the stratum oriens. The density of synaptic GluA1-4 established on interneuron dendrites was significantly reduced in P301S mice in the three strata. The labeling density for GluA1-4 at extrasynaptic sites was significantly reduced in several postsynaptic compartments of CA1 pyramidal cells and interneurons in the three dendritic layers in P301S mice. Our data demonstrate that the progressive accumulation of phospho-tau is associated with alteration of AMPARs on the surface of different neuron types, including synaptic and extrasynaptic membranes, leading to a decline in the trafficking and synaptic transmission, thereby likely contributing to the pathological events taking place in AD.  相似文献   

    

Grzegorz K. Przybylski  Dorota Korsak  Katarzyna Iykowska  Karina Nowicka  Tomasz Zalewski  Ma&#x;gorzata Tubacka  Maria Mosor  Danuta Januszkiewicz-Lewandowska  Magdalena Frydrychowicz  Maciej Boruczkowski  Grzegorz Dworacki  Jens van den Brandt  Piotr Grabarczyk  Christian A. Schmidt  Chengwu Zeng  Yangqiu Li 《International journal of molecular sciences》2022,23(9)

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Brigitte Potier  Louison Lallemant  Sandrine Parrot  Aline Huguet-Lachon  Genevive Gourdon  Patrick Dutar  Mrio Gomes-Pereira 《International journal of molecular sciences》2022,23(2)

Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disease mediated by a toxic gain of function of mutant RNAs. The neuropsychological manifestations affect multiple domains of cognition and behavior, but their etiology remains elusive. Transgenic DMSXL mice carry the DM1 mutation, show behavioral abnormalities, and express low levels of GLT1, a critical regulator of glutamate concentration in the synaptic cleft. However, the impact of glutamate homeostasis on neurotransmission in DM1 remains unknown. We confirmed reduced glutamate uptake in the DMSXL hippocampus. Patch clamp recordings in hippocampal slices revealed increased amplitude of tonic glutamate currents in DMSXL CA1 pyramidal neurons and DG granule cells, likely mediated by higher levels of ambient glutamate. Unexpectedly, extracellular GABA levels and tonic current were also elevated in DMSXL mice. Finally, we found evidence of synaptic dysfunction in DMSXL mice, suggestive of abnormal short-term plasticity, illustrated by an altered LTP time course in DG and in CA1. Synaptic dysfunction was accompanied by RNA foci accumulation in localized areas of the hippocampus and by the mis-splicing of candidate genes with relevant functions in neurotransmission. Molecular and functional changes triggered by toxic RNA may induce synaptic abnormalities in restricted brain areas that favor neuronal dysfunction.  相似文献   

    

Masanori Ono  Natsumi Toyoda  Kyosuke Kagami  Takashi Hosono  Takeo Matsumoto  Shin-ichi Horike  Rena Yamazaki  Mitsuhiro Nakamura  Yasunari Mizumoto  Tomoko Fujiwara  Hitoshi Ando  Hiroshi Fujiwara  Takiko Daikoku 《International journal of molecular sciences》2022,23(14)

Recently, it was demonstrated that the expression of BMAL1 was decreased in the endometrium of women suffering from recurrent spontaneous abortion. To investigate the pathological roles of uterine clock genes during pregnancy, we produced conditional deletion of uterine Bmal1 (cKO) mice and found that cKO mice could receive embryo implantation but not sustain pregnancy. Gene ontology analysis of microarray suggested that uterine NK (uNK) cell function was suppressed in cKO mice. Histological examination revealed the poor formation of maternal vascular spaces in the placenta. In contrast to WT mice, uNK cells in the spongiotrophoblast layer, where maternal uNK cells are directly in contact with fetal trophoblast, hardly expressed an immunosuppressive NK marker, CD161, in cKO mice. By progesterone supplementation, pregnancy could be sustained until the end of pregnancy in some cKO mice. Although this treatment did not improve the structural abnormalities of the placenta, it recruited CD161-positive NK cells into the spongiotrophoblast layer in cKO mice. These findings indicate that the uterine clock system may be critical for pregnancy maintenance after embryo implantation.  相似文献   

    

Joanna Szpotkowska  Kamil Szpotkowski  Jerzy Ciesio&#x;ka 《International journal of molecular sciences》2022,23(17)

A mouse model has often been used in studies of p53 gene expression. Detailed interpretation of functional studies is, however, hampered by insufficient knowledge of the impact of mouse p53 mRNA’s structure and its interactions with proteins in the translation process. In particular, the 5′-terminal region of mouse p53 mRNA is an important region which takes part in the regulation of the synthesis of p53 protein and its N-truncated isoform Δ41p53. In this work, the spatial folding of the 5′-terminal region of mouse p53 mRNA and its selected sub-fragments was proposed based on the results of the SAXS method and the RNAComposer program. Subsequently, RNA-assisted affinity chromatography was used to identify proteins present in mouse fibroblast cell lysates that are able to bind the RNA oligomer, which corresponds to the 5′-terminal region of mouse p53 mRNA. Possible sites to which the selected, identified proteins can bind were proposed. Interestingly, most of these binding sites coincide with the sites determined as accessible to hybridization of complementary oligonucleotides. Finally, the high binding affinity of hnRNP K and PCBP2 to the 5′-terminal region of mouse p53 mRNA was confirmed and their possible binding sites were proposed.  相似文献   

    

Alejandra Hernandez Pichardo  Francesco Amadeo  Bettina Wilm  Raphaël Lvy  Lorenzo Ressel  Patricia Murray  Violaine Se 《International journal of molecular sciences》2022,23(22)

Mesenchymal stromal cells (MSCs) injected intravenously are trapped in the capillaries of the lungs and die within the first 24 h. Studying the biodistribution and fate of labelled therapeutic cells in the 3D pulmonary context is important to understand their function in this organ and gain insights into their mechanisms of action. Optical tissue clearing enables volumetric cell tracking at single-cell resolution. Thus, we compared three optical tissue-clearing protocols (Clear, Unobstructed Brain/Body Imaging Cocktails and Computational analysis (CUBIC), modified stabilised 3D imaging of solvent-cleared organs (s-DISCO) and ethyl cinnamate (ECi)) to evaluate their potential to track the biodistribution of human umbilical cord MSCs expressing the tdTomato fluorescence reporter and investigate how they interact with host cells in the mouse lung. The results showed that although CUBIC clearing is the only method that enables direct imaging of fluorescently labelled MSCs, combining s-DISCO or ECi with immunofluorescence or dye labelling allows the interaction of MSCs with endothelial and immune cells to be studied. Overall, this comparative study offers guidance on selecting an optical tissue-clearing method for cell tracking applications.  相似文献