Inflammatory Glycoprotein 130 Signaling Links Changes in Microtubules and Junctophilin-2 to Altered Mitochondrial Metabolism and Right Ventricular Contractility

2021 ◽  
Author(s):  
Sasha Z. Prisco ◽  
Lynn M. Hartweck ◽  
Lauren Rose ◽  
Patricia D.A. Lima ◽  
Thenappan Thenappan ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Fatty Acid ◽  
Pulmonary Artery ◽  
Right Ventricular ◽  
Interleukin 6 ◽  
Acid Oxidation ◽  
Mitochondrial Morphology ◽  
Interacting Proteins ◽  
Transmission Electron

Background: Right ventricular dysfunction (RVD) is the leading cause of death in pulmonary arterial hypertension (PAH), but no RV-specific therapy exists. We showed microtubule-mediated junctophilin-2 dysregulation (MT-JPH2 pathway) causes t-tubule disruption and RVD in rodent PAH, but the druggable regulators of this critical pathway are unknown. GP130 (glycoprotein 130) activation induces cardiomyocyte microtubule remodeling in vitro; however, the effects of GP130 signaling on the MT-JPH2 pathway and RVD resulting from PAH are undefined. Methods: Immunoblots quantified protein abundance, quantitative proteomics defined RV microtubule-interacting proteins (MT-interactome), metabolomics evaluated the RV metabolic signature, and transmission electron microscopy assessed RV cardiomyocyte mitochondrial morphology in control, monocrotaline, and monocrotaline-SC-144 (GP130 antagonist) rats. Echocardiography and pressure-volume loops defined the effects of SC-144 on RV-pulmonary artery coupling in monocrotaline rats (8–16 rats per group). In 73 patients with PAH, the relationship between interleukin-6, a GP130 ligand, and RVD was evaluated. Results: SC-144 decreased GP130 activation, which normalized MT-JPH2 protein expression and t-tubule structure in the monocrotaline RV. Proteomics analysis revealed SC-144 restored RV MT-interactome regulation. Ingenuity pathway analysis of dysregulated MT-interacting proteins identified a link between microtubules and mitochondrial function. Specifically, SC-144 prevented dysregulation of electron transport chain, Krebs cycle, and the fatty acid oxidation pathway proteins. Metabolomics profiling suggested SC-144 reduced glycolytic dependence, glutaminolysis induction, and enhanced fatty acid metabolism. Transmission electron microscopy and immunoblots indicated increased mitochondrial fission in the monocrotaline RV, which SC-144 mitigated. GP130 antagonism reduced RV hypertrophy and fibrosis and augmented RV-pulmonary artery coupling without altering PAH severity. In patients with PAH, higher interleukin-6 levels were associated with more severe RVD (RV fractional area change 23±12% versus 30±10%, P =0.002). Conclusions: GP130 antagonism reduces MT-JPH2 dysregulation, corrects metabolic derangements in the RV, and improves RVD in monocrotaline rats.

scholarly journals Quercetin ameliorates mitochondrial dysfunction and mitigates methamphetamine-induced anxiety-like behavior

2021 ◽  
Author(s):  
Fengrong Chen ◽  
Jiaxue Sun ◽  
Yongjin Zhang ◽  
Yicong Dai ◽  
Zherui Zhang ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Oxygen Consumption ◽  
Mitochondrial Dysfunction ◽  
Consumption Rate ◽  
Mitochondrial Morphology ◽  
Transmission Electron ◽  
Anxiety Behavior ◽  
And Function

Methamphetamine (MA) abuse results in neurotoxic outcomes, including increased anxiety and depression, during both MA use and withdrawal. Although numerous studies have reported an association between MA exposure and anxiety, the underlying mechanism remains elusive. In this study, escalating dose of MA was used to establish an MA-treated mouse model presenting anxiety behavior. RNA seq was then performed to profile the gene expression patterns in the hippocampus (HIPP). Differentially expressed genes (DEGs) were identified and function enrichment analysis was conducted to explore the underlying mechanisms. Quercetin as an mitochondria protector was used in vivo and in vitro. The C57BL/6J mice were co-treated with 50 mg/kg Quercetin and escalating MA. Anxiety behavior was evaluated by utilizing the elevated plus maze and the open field test. Transmission electron microscopy and immunohistochemistry were conducted to study the pathology of MA-inducced anxiety . The effects of MA and Quercetin on astrocytes were investigated by fluorescence staining, transmission electron microscopy, flow cytometry, and oxygen consumption rate. Western blot and qPCR were performed to analyze altered protein and gene levels of HIPP in mice and astrtocytes. The results demonstrated that forteen upregulated differentially expressed genes were identified and significantly enriched in signaling pathways related to psychiatric disorders and mitochondrial function. Interestingly, we found that quercetin was able to alleviate MA-induced anxiety-like behavior by improving neuron number and mitochondria injury. Mechanistically, quercetin can mitigate aberrant mitochondrial morphology and mitochondrial dysfunction not only by decreasing the levels of total cytoplasmic reactive oxygen species (ROS), mitochondria-derived ROS (mtROS), and mitochondrial membrane potential (MMP), but also increasing the oxygen consumption rate (OCR) and mitochondrial ATP production in vitro, indicating Quercetin ameliorated MA-induced anxiety-like behavior by modifying mitochondrial morphology and function. Furthermore, quercetin reversed OPA1 and DRP1 expression in astrocytes, and mitigated astrocyte activation and the release of inflammatory factors, which can trigger neuronal apoptosis and synaptic loss. Taken together, we provided evidence showing that MA can induce anxiety-like behavior via the induction of oxidative stress and mitochondrial dysfunction. Quercetin exerted antipsychotic activity through mitochondrial modulation, suggesting its potential for further therapeutic development in MA-induced anxiety.

scholarly journals Transmission electron microscopy of the benzbromarone-induced change in mitochondrial morphology in HepG2 cells

2019 ◽  
Vol 6 (8) ◽  
pp. 281-286 ◽  
Author(s):  
Tomoyuki Sato ◽  
Akinori Takemura ◽  
Yugo Ikeyama ◽  
Yuriko Sakamaki ◽  
Ayako Mimata ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Hepg2 Cells ◽  
Mitochondrial Morphology ◽  
Transmission Electron

Secretion of Weibel-Palade bodies observed in extra-alveolar vessels of rabbit lung

1983 ◽  
Vol 54 (5) ◽  
pp. 1284-1286 ◽  
Author(s):  
J. M. McNiff ◽  
J. Gil
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Endothelial Cells ◽  
Pulmonary Artery ◽  
Rabbit Lung ◽  
Vascular Lumen ◽  
Cells In Culture ◽  
Transmission Electron ◽  
Specific Granules

We fixed rabbit lungs by perfusion of osmium into the pulmonary artery and examined in light and transmission electron microscopy a large number of extra-alveolar vessels with a diameter of 0.1–0.25 mm, with emphasis on Weibel-Palade bodies (endothelial specific granules). Weibel-Palade bodies are organelles specific to endothelial cells. Their function is unknown, but they are useful markers for identification of endothelial cells in culture. We were able to observe release of the content of these bodies into the vascular lumen; this indicates that they are secretory.

scholarly journals In Vitro Killing of Candida albicans by Fatty Acids and Monoglycerides

2001 ◽  
Vol 45 (11) ◽  
pp. 3209-3212 ◽  
Author(s):  
Gudmundur Bergsson ◽  
Jóhann Arnfinnsson ◽  
Ólafur Steingrı́msson ◽  
Halldor Thormar
Keyword(s):  
Electron Microscopy ◽  
Fatty Acids ◽  
Transmission Electron Microscopy ◽  
Candida Albicans ◽  
Fatty Acid ◽  
Saturated Fatty Acid ◽  
Capric Acid ◽  
Transmission Electron ◽  
Ultrathin Sections

ABSTRACT The susceptibility of Candida albicans to several fatty acids and their 1-monoglycerides was tested with a short inactivation time, and ultrathin sections were studied by transmission electron microscopy (TEM) after treatment with capric acid. The results show that capric acid, a 10-carbon saturated fatty acid, causes the fastest and most effective killing of all three strains of C. albicans tested, leaving the cytoplasm disorganized and shrunken because of a disrupted or disintegrated plasma membrane. Lauric acid, a 12-carbon saturated fatty acid, was the most active at lower concentrations and after a longer incubation time.

A Simple Dilution Method for Preparation of Different Aggregates from Oleic Acid/CHAPSO Bicelles

2021 ◽  
Vol 21 (12) ◽  
pp. 5993-5999
Author(s):  
Shogo Taguchi ◽  
Yasuaki Tachibana ◽  
Yuta Kimura ◽  
Takuji Yamamoto ◽  
Hiroshi Umakoshi
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Oleic Acid ◽  
Fatty Acid ◽  
Light Scattering ◽  
Packing Density ◽  
Dilution Method ◽  
Molar Ratios ◽  
Transmission Electron ◽  
Functional Membrane

We evaluated the effect of dilution on both the size and packing density of aggregates prepared from a fatty acid (oleic acid, OA)/detergent (3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxypropane sulfonate (CHAPSO)) bicelle as a parent for functional membrane materials. The sizes of the aggregates formed at different molar ratios, XOA(= [OA]/([OA]+[CHAPSO])), of 0.3 and 0.7 and their parent bicelles were measured by dynamic light scattering and transmission electron microscopy; their packing density was evaluated by deconvolution of the fluorescence spectrum, where Laurdan molecules were used as a probe. The experimental results showed that the bicelles formed aggregates upon dilution because of the hydration of CHAPSO. The packing density of the nano-ordered aggregate formed at XOA = 0.3 was much greater than that of the aggregate formed at XOA = 0.7, implying the formation of an ordered aggregate under the condition of XOA = 0.3

Sign in / Sign up

Export Citation Format

Share Document