scholarly journals Age-related sex differences in the expression of important disease-linked mitochondrial proteins in mice

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Michael Moschinger ◽  
Karolina E. Hilse ◽  
Anne Rupprecht ◽  
Ute Zeitz ◽  
Reinhold G. Erben ◽  
...  
Keyword(s):  
Protein Expression ◽  
Western Blot ◽  
Expression Patterns ◽  
Mitochondrial Proteins ◽  
List Type ◽  
Dependent Manner ◽  
Age Cohorts ◽  
Brown Adipose ◽  
Age Dependent ◽  
The Brain

Abstract The prevalence and progression of many illnesses, such as neurodegenerative and cardiovascular diseases, obesity, and cancer, vary between women and men, often in an age-dependent manner. A joint hallmark of these diseases is some type of mitochondrial dysfunction. While several mitochondrial proteins are known to be regulated by sex hormones, the levels of those proteins have not been systematically analyzed with regard to sex and age, and studies that consider sex and/or age differences in the protein expression are very rare. In this study, we compared the expression patterns of physiologically important mitochondrial proteins in female and male C57BL/6N mice of age cohorts frequently used in experiments. We found that sex-related differences in the expression of uncoupling proteins 1 and 3 (UCP1 and UCP3) occur in an age-dependent manner. The sex-specific expression of UCP1 and UCP3 in brown adipose tissue (BAT) was inversely correlated with differences in body weight. Expression of UCP4 in the brain, Complex I in the spleen, and Complex II in the brain and BAT was least affected by the sex of the mouse. We further demonstrated that there are serious limitations in using VDAC1 and actin as markers in western blot analyses, due to their sex- and age-specific fluctuations. Our results confirm that sex and age are important parameters and should be taken into account by researchers who examine the mechanistic aspects of diseases. Highlights The levels of UCP1 and UCP3 protein expression differ between females and males in an age-dependent manner.Pre-pubertal expression of almost all proteins tested in this study does not depend on the sex of the mouse.Expression of VDAC1 and actin, which are often used as loading control proteins in western blot analysis, is tissue-specifically influenced by sex and age.

Deletion of murine tau gene increases tau aggregation in a human mutant tau transgenic mouse model

2010 ◽  
Vol 38 (4) ◽  
pp. 1001-1005 ◽  
Author(s):  
Kunie Ando ◽  
Karelle Leroy ◽  
Céline Heraud ◽  
Anna Kabova ◽  
Zehra Yilmaz ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mouse ◽  
Double Mutant ◽  
Transgenic Mouse Model ◽  
Tau Proteins ◽  
Dependent Manner ◽  
Age Dependent ◽  
Ad Alzheimer’S Disease ◽  
Tau Aggregation ◽  
The Brain

We have reported previously a tau transgenic mouse model (Tg30tau) overexpressing human 4R1N double-mutant tau (P301S and G272V) and that develops AD (Alzheimer's disease)-like NFTs (neurofibrillary tangles) in an age-dependent manner. Since murine tau might interfere with the toxic effects of human mutant tau, we set out to analyse the phenotype of our Tg30tau model in the absence of endogenous murine tau with the aim to reproduce more faithfully a model of human tauopathy. By crossing the Tg30tau line with TauKO (tau-knockout) mice, we have obtained a new mouse line called Tg30×TauKO that expresses only exogenous human double-mutant 4R1N tau. Whereas Tg30×TauKO mice express fewer tau proteins compared with Tg30tau, they exhibit augmented sarkosyl-insoluble tau in the brain and an increased number of Gallyas-positive NFTs in the hippocampus. Taken together, exclusion of murine tau causes accelerated tau aggregation during aging of this mutant tau transgenic model.

Effect of Auraptene on angiogenesis in Xenograft model of breast cancer

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Mohammad Reza Shiran ◽  
Elham Mahmoudian ◽  
Abolghasem Ajami ◽  
Seyed Mostafa Hosseini ◽  
Ayjamal Khojasteh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Animal Model ◽  
Protein Expression ◽  
Western Blot ◽  
Xenograft Model ◽  
Dependent Manner ◽  
Concentration Dependent Manner

Abstract Objectives Angiogenesis is the most important challenge in breast cancer treatment. Recently, scientists become interesting in rare natural products and intensive researches was performed to identify their pharmacological profile. Auraptene shows helpful effects such as cancer chemo-preventive, anti-inflammatory, anti-oxidant, immuno-modulatory. In this regard, we investigated the anti-angiogenesis effect of Auraptene in in-vitro and in-vivo model of breast cancer. Methods In this study, 4T, MDA-MB-231 and HUVEC cell lines were used. The proliferation study was done by MTT assay. For tube formation assay, 250 matrigel, 1 × 104 HUVEC treated with Auraptene, 20 ng/mL EGF, 20 ng/mL bFGF and 20 ng/mL VEGF were used. Gene expression of important gene related to angiogenesis in animal model of breast cancer was investigated by Real-time PCR. Protein expression of VCAM-1 and TNFR-1 gene related to angiogenesis in animal model of breast cancer was investigated by western-blot. Results Auraptene treatment led to reduction in cell viability of MDA-MB-231 in a concentration-dependent manner. Also, we observed change in the number of tubes or branches formed by cells incubated with 40 and 80 μM Auraptene. Auraptene effect the gene expression of important gene related to angiogenesis (VEGF, VEGFR2, COX2, IFNɣ). Moreover, the western blot data exhibited that Auraptene effect the protein expression of VCAM-1 and TNFR-1. Conclusions Overall, this study shows that Auraptene significantly suppressed angiogenesis via down-regulation of VEGF, VEGFR2, VCAM-1, TNFR-1, COX-2 and up-regulation of IFNγ.

In Vitro Antihepatoma Activity of Novel 3D-Copper Cyanide Supramolecular Coordination Polymers

2016 ◽  
Vol 99 (5) ◽  
pp. 1240-1246
Author(s):  
Noura M Darwish ◽  
Ahmed S Sultan ◽  
Ahmed M Malki ◽  
Hossam Khamis ◽  
Mohamed El-Ziady
Keyword(s):  
Protein Expression ◽  
Western Blot ◽  
Coordination Polymers ◽  
Hepg2 Cells ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Invasive Potential ◽  
Dna Ladder ◽  
Supramolecular Coordination

Abstract This study aimed to investigate the inhibitory effect of novel 3D-organocopper supramolecular coordination polymers (SCPs) on the invasive potential of HepG2 cells. Chemoprevention could represent an important means to inhibit the process of hepatocarcinogenesis. The inhibitory effect of an SCP compound on the proliferation of HepG2 hepatoma cells was evaluated by cell vibility assay. DNA ladder bands were observed by DNA agarose gel electrophoresis. The influence of the SCP compound on phosphorylated ERK1/2, Bcl-2, and β-catenin protein expression of HepG2 cells was analyzed by Western blot. The SCP compound exerted an inhibitory effect on HepG2 cell proliferation in a dose-dependent manner. This inhibitory effect was confirmed by examination of cell morphology and DNA fragmentation. Furthermore, Western blot analysis revealed that phosphorylated ERK1/2 and β-catenin protein expression was inhibited after 24 h of treatment with the SCP compound, and that this event was associated with decreased Bcl-2 expression. We concluded that SCP can effectively inhibit the invasive potential of the ERK signaling pathway in HepG2 cells by altering apoptosis and by inhibiting Bcl-2 and β-catenin, which may play a significant role in this process.

scholarly journals Machine Learning Reveals Modules of Economic Behavior from Foraging Mice

2018 ◽  
Author(s):  
Cornelia N Stacher Hörndli ◽  
Eleanor Wong ◽  
Elliott Ferris ◽  
Alexis Nikole Rhodes ◽  
P. Thomas Fletcher ◽  
...  
Keyword(s):  
Machine Learning ◽  
Building Blocks ◽  
Economic Behavior ◽  
Mouse Strains ◽  
Parental Effects ◽  
List Type ◽  
Prader Willi Syndrome ◽  
Dependent Manner ◽  
Foraging Patterns ◽  
Age Dependent

SUMMARYComplex ethological behaviors could be constructed from modules that are discrete functional units of behavior with a genetic basis. Here, we test this idea for foraging, and develop a paradigm to dissect foraging patterns in mice. We uncover discrete behavioral modules linked to round trip excursions from the home. Machine learning reveals 59 modules across different genetic backgrounds and ages. Different modules develop at different ages and are linked to different aspects of economic behavior, including memory, reward, risk and effort responses. Crosses of distant mouse strains reveal that parental and genetic effects shape foraging differently, and parental effects grow stronger with age. Specific behavioral modules, genes and pathways are found to be sensitive to parental effects. One candidate gene, Magel2, is linked to Prader-Willi Syndrome and shaped the expression of discrete modules in an age-dependent manner. Our results reveal building blocks for normal and abnormal economic behavior patterns.HIGHLIGHTSIdentification of 59 economic behavior modules underlying foragingDiscrete modules are linked to memory, reward, risk and effort responsesGenetic and parental effects shape foraging by changing module expressionMagel2, a Prader-Willi Syndrome gene, affects specific modules at specific ages

scholarly journals FGF21 Ameliorates Hepatic Fibrosis by Multiple Mechanisms

2021 ◽  
Author(s):  
Fanrui Meng ◽  
Mir Hassan Khoso ◽  
Kai Kang ◽  
Qi He ◽  
Yukai Cao ◽  
...  
Keyword(s):  
Protein Expression ◽  
Western Blot ◽  
Hepatic Fibrosis ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Cell Model ◽  
Dependent Manner ◽  
Rt Pcr ◽  
Mrna And Protein Expression ◽  
Dose Dependent

Abstract Previous study reports that FGF21 could ameliorate hepatic fibrosis, but its mechanisms have not been fully investigated. In this study, three models were used to investigate the mechanism by which FGF21 alleviates liver fibrosis. CCL4 and DMN were respectively used to induce hepatic fibrosis animal models. Our results demonstrated that liver index and liver function were deteriorated in both models. HE and Masson’s staining showed that the damaged tissue architectonics were observed in the mice of both models. Treatment with FGF21 significantly ameliorated these changes. ELISA analysis showed that the serum levels of IL-1β, IL-6 and TNF-α were significantly elevated in both models. However, administration of FGF21 significantly reduced these inflammatory cytokines. RT-PCR and Western blot analysis showed that mRNA and protein expression of collagenI, α-SMA and TGF-β were significantly decreased by treatment with FGF21. PDGF-BB stimulant was used to establish the experimental cell model in HSCs. RT-PCR and Western blot analysis demonstrated that the expression of collagenI and α-SMA were significantly upregulated by this stimulant in model group. Interestingly, our results showed that mRNA and protein expression of leptin were also significantly induced in PDGF-BB treated HSCs. Administration of FGF21 could significantly reduce leptin expression in a dose dependent manner and these effects were reversed in siRNA (against β-klotho) transfected HSCs. Furthermore, the leptin signaling pathways related protein p-ERK/t-ERK, p-STAT3/STAT3 and TGF-β were significantly downregulated by FGF21 treatment in a dose dependent manner. The expression of SOCS3 and Nrf-2 were enhanced by treatment with FGF21. The underlying mechanism may be that FGF21 regulates leptin-STAT3 axis via Nrf-2 and SOCS3 pathway in activated HSCs.

scholarly journals The hypothalamus to brainstem circuit suppresses late-onset body weight gain

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yuko Maejima ◽  
Shigeki Kato ◽  
Shoichiro Horita ◽  
Yoichi Ueta ◽  
Seiichi Takenoshita ◽  
...  
Keyword(s):  
Body Weight ◽  
Neural Circuits ◽  
Late Onset ◽  
Body Weight Gain ◽  
Growth Period ◽  
Underlying Mechanism ◽  
Dependent Manner ◽  
Aged Rats ◽  
Age Dependent ◽  
The Brain

AbstractBody weight (BW) is regulated in age-dependent manner; it continues to increase during growth period, and reaches a plateau once reaching adulthood. However, its underlying mechanism remains unknown. Regarding such mechanisms in the brain, we here report that neural circuits from the hypothalamus (paraventricular nucleus: PVN) to the brainstem (dorsal vagal complex: DVC) suppress late-onset BW gain without affecting food intake. The genetic suppression of the PVN-DVC circuit induced BW increase only in aged rats, indicating that this circuit contributes to suppress the BW at a fixed level after reaching adulthood. PVN neurons in the hypothalamus were inactive in younger rats but active in aged rats. The density of neuropeptide Y (NPY) terminal/fiber is reduced in the aged rat PVN area. The differences in neuronal activity, including oxytocin neurons in the PVN, were affected by the application of NPY or its receptor inhibitor, indicating that NPY is a possible regulator of this pathway. Our data provide new insights into understanding age-dependent BW regulation.

scholarly journals Quantitative and dynamic expression profile of premature and active forms of the regional ADAM proteins during chicken brain development

2011 ◽  
Vol 16 (3) ◽  
Author(s):  
Annett Markus ◽  
Xin Yan ◽  
Arndt Rolfs ◽  
Jiankai Luo
Keyword(s):  
Western Blot ◽  
Expression Patterns ◽  
Transmembrane Proteins ◽  
Tissue Formation ◽  
Chicken Brain ◽  
Dynamic Expression ◽  
Quantitative Western Blot ◽  
First Time ◽  
The Brain ◽  
Different Parts

AbstractThe ADAM (A Disintegrin and Metalloprotease) family of transmembrane proteins plays important roles in embryogenesis and tissue formation based on their multiple functional domains. In the present study, for the first time, the expression patterns of the premature and the active forms of six members of the ADAM proteins — ADAM9, ADAM10, ADAM12, ADAM17, ADAM22 and ADAM23 — in distinct parts of the developing chicken brain were investigated by quantitative Western blot analysis from embryonic incubation day (E) 10 to E20. The results show that the premature and the active forms of various ADAM proteins are spatiotemporally regulated in different parts of the brain during development, suggesting that the ADAMs play a very important role during embryonic development.

scholarly journals Differential regulation of the immune system in a brain-liver-fats organ network during short term fasting

2020 ◽  
Author(s):  
Susie S.Y. Huang ◽  
Melanie Makhlouf ◽  
Eman H. AbouMoussa ◽  
Mayra L. Ruiz Tejada Segura ◽  
Lisa S. Mathew ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Immune System ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Fine Tuning ◽  
Short Term ◽  
Interscapular Brown Adipose Tissue ◽  
Brown Adipose ◽  
Wide Range ◽  
The Brain

ABSTRACTDifferent fasting regimens are known to promote health, mitigate chronic immunological disorders, and improve age-related pathophysiological parameters in animals and humans. Indeed, several clinical trials are currently ongoing using fasting as a potential therapy for a wide range of conditions. Fasting alters metabolism by acting as a reset for energy homeostasis. However, the molecular mechanisms underlying the beneficial effects of short-term fasting (STF) are still not well understood, particularly at the systems or multi-organ level. Here, we investigated the dynamic gene expression patterns associated with six periods of STF in nine different mouse organs. We cataloged the transcriptional dynamics within and between organs during STF and discovered differential temporal effects of STF among organs. Using gene ontology enrichment analysis, we identified an organ network sharing 37 common biological pathways perturbed by STF. This network incorporates the brain, liver, interscapular brown adipose tissue, and posterior-subcutaneous white adipose tissue, hence we named it the brain-liver-fats organ network. Using Reactome pathways analysis, we identified the immune system, dominated by T cell regulation processes, as a central and prominent target of systemic modulations during STF in this organ network. The changes we identified in specific immune components point to the priming of adaptive immunity and parallel the fine-tuning of innate immune signaling. Our study provides a comprehensive multi-organ transcriptomic profiling of mice subjected to multiple periods of STF, and adds new insights into the molecular modulators involved in the systemic immuno-transcriptomic changes that occur during short-term energy loss.

scholarly journals Amyloid accumulation drives proteome-wide alterations in mouse models of Alzheimer’s disease like pathology

2017 ◽  
Author(s):  
Jeffrey N. Savas ◽  
Yi-Zhi Wang ◽  
Laura A. DeNardo ◽  
Salvador Martinez-Bartolome ◽  
Daniel B. McClatchy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Expression ◽  
Mouse Models ◽  
Ampa Receptor ◽  
Proteomic Analysis ◽  
Protein Networks ◽  
Causative Role ◽  
List Type ◽  
The Brain

SummaryAmyloid beta (Aβ) peptides impair multiple cellular pathways in the brain and play a causative role in Alzheimer’s disease (AD) pathology, but how the brain proteome is remodeled during this process is unknown. To identify new protein networks associated with AD-like pathology, we performed global quantitative proteomic analysis in three mouse models at pre- and post-symptomatic ages. Our analysis revealed a robust and consistent increase in Apolipoprotein E (ApoE) levels in nearly all transgenic brain regions with increased Aβ levels. Taken together with prior findings on ApoE driving Aβ accumulation, this analysis points to a pathological dysregulation of the ApoE-Aβ axis. We also found dysregulation of protein networks involved in excitatory synaptic transmission consistent with AD pathophysiology. Targeted analysis of the AMPA receptor complex revealed a specific loss of TARPγ-2, a key AMPA receptor trafficking protein. Expression of TARPγ-2 in vivo in hAPP transgenic mice led to a restoration of AMPA currents. This database of proteome alterations represents a unique resource for the identification of protein alterations responsible for AD.HighlightsProteomic analysis of mouse brains with AD-like pathology reveals stark remodelingProteomic evidence points to a dysregulation of ApoE levels associated with Aβ clearance rather than productionCo-expression analysis found distinctly impaired synapse and mitochondria modulesIn-depth analyses of AMPAR complex points to loss of TARPγ-2, which may compromise synapses in ADeTOC BlurbProteome-wide profiling of brain tissue from three mouse models of AD-like pathology reveals Aβ, brain region, and age dependent alterations of protein levels. This resource provides a new global protein expression atlas for the Alzheimer’s disease research community.

scholarly journals PDTM-18. COMBINED SUPPRESSION OF THE mTOR AND MAPK PATHWAYS INHIBITS GROWTH, DECREASES VASCULARITY AND INDUCES APOPTOSIS OR SENESCENCE IN PEDIATRIC LOW GRADE GLIOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi191-vi191
Author(s):  
Antje Arnold ◽  
Lauren Harris ◽  
Ming Yuan ◽  
Fausto Rodriguez ◽  
Charles Eberhart ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Combination Therapy ◽  
Protein Expression ◽  
Western Blot ◽  
Cell Line ◽  
Combination Treatment ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Dependent Manner

Abstract Pediatric low-grade glioma (pLGG) is the most common brain tumor in children. We and others have identified constitutive activation of the mTOR and MEK-pathway in pLGG. This led us to investigate TAK228, a mTORC1/2-inhibitor, and the FDA approved MEK-inhibitor, trametinib, in mono- and combination therapy in pLGG. We examined antitumor activity in four patient-derived pLGG cell models treated with TAK228, trametinib, and combination: JHH_NF1_PA1(NF1mut), BT40(BRAFV600E), Res186(PTEN-/-) and Res259(CDKN2A-/-). Treatment with TAK228 or trametinib reduced cell proliferation in a dose and time dependent manner (MTS-assay). The combination treatment exerted a synergistic effect at 5-20nM in JHH_NF1_PA1, Res186, and Res259 cells (Chou-Talay method). The combination of TAK228 and trametinib increased apoptosis by up to 127% (p< 0.001 by 1-way ANOVA) in Res186 and Res259 cells as measured by cleaved caspase 3 immunocytochemistry. Trametinib and combination treatment induces senescence in JHH_NF1_PA1 cell line verified through increase in p27 protein expression (Western Blot) and positive b-galactosidase staining. Mono-treatment with TAK228 or vehicle showed no signs of senescence. We tested trametinib and TAK228 against the mutant BT40BRAFV600E patient-derived cell line in immunodeficient mice. The combination treatment showed greater antitumor activity than that of either mono-treatment in vivo. BT40 tumor growth was significantly decreased in combination compared to vehicle or either agent alone (p< 0.01). Combination treatment strikingly reduced the vascularization in the tumor tissue after combination treatment analyzed by CD31 and CD34 protein expression (Western Blot), compared to vehicle and mono-treatment. Our study provides evidence that pLGG-derived cell lines in vitro and in vivo are sensitive to mTORC1/2 kinase inhibition and MEK inhibition. Combination treatment with TAK228 and trametinib had a significant anti-tumor activity in vivo shown in survival rate, decreased tumor size, and reduced vascularity. These results provide the first strong rationale for combination therapy with TAK228 and trametinib for clinical consideration in pLGG.

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