scholarly journals Aerobic Exercise Improves Mitochondrial Function in Sarcopenia Mice Through Sestrin2 in an AMPKα2-Dependent Manner

2021 ◽  
Author(s):  
Sujuan Liu ◽  
Chunxia Yu ◽  
Lingjian Xie ◽  
Yanmei Niu ◽  
Li Fu
Keyword(s):  
Aerobic Exercise ◽  
Molecular Mechanism ◽  
Muscle Mass ◽  
Mitochondrial Function ◽  
High Morbidity ◽  
Dependent Manner ◽  
Cross Sectional ◽  
Age Related

Abstract Sarcopenia, the age-related loss of skeletal muscle mass and function, contributes to high morbidity and mortality in the older population. Regular exercise is necessary to avoid the initiation and progression of sarcopenia, in which the underlying molecular mechanism is still not clear. Our data revealed that the outcomes induced by sarcopenia, including muscle mass and strength loss, decreased cross-sectional area of gastrocnemius fiber, chronic inflammation, and increased dysfunctional mitochondria, were reversed by regulation exercise. Knockout or silencing of Sestrin2 (Sesn2) resulted in imbalanced mitochondrial fusion and fission, mitochondrial biogenesis, and mitophagy damage in vivo and in vitro, which was attenuated by aerobic exercise or overexpression of Sesn2. Moreover, we found that the effects of Sesn2 on mitochondrial function are dependent on AMP-activated protein kinase α2 (AMPKα2). This study indicates that aerobic exercise alleviates the negative effects resulting from sarcopenia via the Sesn2/AMPKα2 pathway and provides new insights into the molecular mechanism by which the Sesn2/AMPKα2 signaling axis mediates the beneficial impact of exercise on sarcopenia.

scholarly journals Damaging Effects of Bisphenol A on the Kidney and the Protection by Melatonin: Emerging Evidences from In Vivo and In Vitro Studies

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Anongporn Kobroob ◽  
Wachirasek Peerapanyasut ◽  
Nipon Chattipakorn ◽  
Orawan Wongmekiat
Keyword(s):  
Oxidative Stress ◽  
Bisphenol A ◽  
Mitochondrial Function ◽  
Dependent Manner ◽  
Redox Equilibrium ◽  
Membrane Potential Change ◽  
Kidney Mitochondria ◽  
Dose Dependent

This study investigates the effects of bisphenol A (BPA) contamination on the kidney and the possible protection by melatonin in experimental rats and isolated mitochondrial models. Rats exposed to BPA (50, 100, and 150 mg/kg, i.p.) for 5 weeks demonstrated renal damages as evident by increased serum urea and creatinine and decreased creatinine clearance, together with the presence of proteinuria and glomerular injuries in a dose-dependent manner. These changes were associated with increased lipid peroxidation and decreased antioxidant glutathione and superoxide dismutase. Mitochondrial dysfunction was also evident as indicated by increased reactive oxygen species production, decreased membrane potential change, and mitochondrial swelling. Coadministration of melatonin resulted in the reversal of all the changes caused by BPA. Studies using isolated mitochondria showed that BPA incubation produced dose-dependent impairment in mitochondrial function. Preincubation with melatonin was able to sustain mitochondrial function and architecture and decreases oxidative stress upon exposure to BPA. The findings indicated that BPA is capable of acting directly on the kidney mitochondria, causing mitochondrial oxidative stress, dysfunction, and subsequently, leading to whole organ damage. Emerging evidence further suggests the protective benefits of melatonin against BPA nephrotoxicity, which may be mediated, in part, by its ability to diminish oxidative stress and maintain redox equilibrium within the mitochondria.

scholarly journals Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1

2016 ◽  
Vol 113 (11) ◽  
pp. 3036-3041 ◽  
Author(s):  
Pooja Singhmar ◽  
XiaoJiao Huo ◽  
Niels Eijkelkamp ◽  
Susana Rojo Berciano ◽  
Faiza Baameur ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Molecular Mechanism ◽  
Inflammatory Pain ◽  
Critical Role ◽  
Specific Inhibitor ◽  
Mechanical Hyperalgesia ◽  
Dependent Manner ◽  
Phosphorylation Event

cAMP signaling plays a key role in regulating pain sensitivity. Here, we uncover a previously unidentified molecular mechanism in which direct phosphorylation of the exchange protein directly activated by cAMP 1 (EPAC1) by G protein kinase 2 (GRK2) suppresses Epac1-to-Rap1 signaling, thereby inhibiting persistent inflammatory pain. Epac1−/− mice are protected against inflammatory hyperalgesia in the complete Freund’s adjuvant (CFA) model. Moreover, the Epac-specific inhibitor ESI-09 inhibits established CFA-induced mechanical hyperalgesia without affecting normal mechanical sensitivity. At the mechanistic level, CFA increased activity of the Epac target Rap1 in dorsal root ganglia of WT, but not of Epac1−/−, mice. Using sensory neuron-specific overexpression of GRK2 or its kinase-dead mutant in vivo, we demonstrate that GRK2 inhibits CFA-induced hyperalgesia in a kinase activity-dependent manner. In vitro, GRK2 inhibits Epac1-to-Rap1 signaling by phosphorylation of Epac1 at Ser-108 in the Disheveled/Egl-10/pleckstrin domain. This phosphorylation event inhibits agonist-induced translocation of Epac1 to the plasma membrane, thereby reducing Rap1 activation. Finally, we show that GRK2 inhibits Epac1-mediated sensitization of the mechanosensor Piezo2 and that Piezo2 contributes to inflammatory mechanical hyperalgesia. Collectively, these findings identify a key role of Epac1 in chronic inflammatory pain and a molecular mechanism for controlling Epac1 activity and chronic pain through phosphorylation of Epac1 at Ser-108. Importantly, using the Epac inhibitor ESI-09, we validate Epac1 as a potential therapeutic target for chronic pain.

Automated rodent in situ muscle contraction assay and myofiber organization analysis in sarcopenia animal models

2012 ◽  
Vol 112 (12) ◽  
pp. 2087-2098 ◽  
Author(s):  
H. Weber ◽  
A. Rauch ◽  
S. Adamski ◽  
K. Chakravarthy ◽  
A. Kulkarni ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Force Measurement ◽  
Muscle Performance ◽  
Area Measurement ◽  
Micro Ct ◽  
Cross Sectional ◽  
Muscle Aging ◽  
Age Related

Age-related sarcopenia results in frailty and decreased mobility, which are associated with increased falls and long-term disability in the elderly. Given the global increase in lifespan, sarcopenia is a growing, unmet medical need. This report aims to systematically characterize muscle aging in preclinical models, which may facilitate the development of sarcopenia therapies. Naïve rats and mice were subjected to noninvasive micro X-ray computed tomography (micro-CT) imaging, terminal in situ muscle function characterizations, and ATPase-based myofiber analysis. We developed a Definiens (Parsippany, NJ)-based algorithm to automate micro-CT image analysis, which facilitates longitudinal in vivo muscle mass analysis. We report development and characterization of translational in situ skeletal muscle performance assay systems in rat and mouse. The systems incorporate a custom-designed animal assay stage, resulting in enhanced force measurement precision, and LabVIEW (National Instruments, Austin, TX)-based algorithms to support automated data acquisition and data analysis. We used ATPase-staining techniques for myofibers to characterize fiber subtypes and distribution. Major parameters contributing to muscle performance were identified using data mining and integration, enabled by Labmatrix (BioFortis, Columbia, MD). These technologies enabled the systemic and accurate monitoring of muscle aging from a large number of animals. The data indicated that longitudinal muscle cross-sectional area measurement effectively monitors change of muscle mass and function during aging. Furthermore, the data showed that muscle performance during aging is also modulated by myofiber remodeling factors, such as changes in myofiber distribution patterns and changes in fiber shape, which affect myofiber interaction. This in vivo muscle assay platform has been applied to support identification and validation of novel targets for the treatment of sarcopenia.

scholarly journals Essential role of p21/waf1 in the mediation of the anti-proliferative effects of GHRH antagonist JMR-132

2008 ◽  
Vol 41 (5) ◽  
pp. 389-392 ◽  
Author(s):  
Aspasia-Athina Volakaki ◽  
Daniel Lafkas ◽  
Eva Kassi ◽  
Andrew V Schally ◽  
Athanasios G Papavassiliou ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Molecular Mechanism ◽  
A549 Cells ◽  
Significant Inhibition ◽  
Human Lung Cancer ◽  
Dependent Manner ◽  
Ghrh Antagonists ◽  
P21 Waf1

GHRH, besides its neuroendocrine action in controlling the release of GH from the pituitary, stimulates the growth of various cancers in vivo and in vitro by direct mechanism(s). However, the molecular mechanism that mediates these proliferative effects of GHRH in extrapituitary tissues remains poorly characterized. In the present study, we investigated whether the tumor suppressor p21/waf1 is involved in the mediation of the proliferative effects of GHRH in A549 human lung cancer epithelial cells. Exposure of A549 cells to the GHRH antagonist JMR-132 caused a significant inhibition in the rate of cell proliferation. In A549 cells, GHRH suppressed while JMR-132 increased the levels of p21 expression in a dose-dependent manner. This suggests that GHRH could regulate p21 levels. We then evaluated whether p21 is required in A549 cells for the regulation of cell proliferation by GHRH. To this end, we knocked-down p21 expression in A549 cells by siRNA and assessed the effects of antagonist JMR-132 on cell proliferation. We found that the loss of p21 expression abolished the anti-proliferative effects of JMR-132. Suppression of p21 expression by siRNA in human HT29 colon cancer cells and non-transformed mouse osteoblasts KS483 also blocked the anti-proliferative effects of JMR-132 suggesting that the regulation of cell proliferation by GHRH is p21 dependent. These results shed light on the molecular mechanism of action of GHRH antagonists in tumor tissues and suggest that the antineoplastic activity of GHRH antagonists could be considered for the treatment of cancers expressing p21.

scholarly journals Streptozotocin induces G2 arrest in skeletal muscle myoblasts and impairs muscle growth in vivo

2007 ◽  
Vol 292 (3) ◽  
pp. C1033-C1040 ◽  
Author(s):  
Adam P. W. Johnston ◽  
Jonathan E. Campbell ◽  
Jeremy G. Found ◽  
Michael C. Riddell ◽  
Thomas J. Hawke
Keyword(s):  
Skeletal Muscle ◽  
Muscle Growth ◽  
Phase Cell ◽  
Saline Control ◽  
Dependent Manner ◽  
Β Cell ◽  
Cross Sectional ◽  
M Phase

Streptozotocin (STZ) is used extensively to induce pancreatic β-cell death and ultimately diabetes mellitus in animal models. However, the direct effects of STZ on muscle are largely unknown. To delineate the effects of STZ from the effects of hypoinsulinemia/hyperglycemia, we injected young rats with 1) saline (control), 2) STZ (120 mg/kg) or 3) STZ and insulin (STZ-INS; to maintain euglycemia). STZ rats demonstrated significantly elevated blood glucose throughout the 48-h protocol, while control and STZ-INS rats were euglycemic. Body mass increased in control (13 ± 4 g), decreased by 19 ± 2 g in STZ and remained unchanged in STZ-INS rats (−0.3 ± 2 g). Cross-sectional areas of gastrocnemius muscle fibers were smaller in STZ vs. control (1,480 ± 149 vs. 1,870 ± 40 μm2, respectively; P < 0.05) and insulin treatment did not rescue this defect (STZ-INS: 1,476 ± 143 μm2). Western blot analysis revealed a detectable increase in ubiquitinated proteins in the STZ skeletal muscles compared with control and STZ-INS. To further define the effects of STZ on skeletal muscle, independent of hyperglycemia, myoblasts were exposed to varying doses of STZ (0.25–3.0mg/ml) in vitro. Both acute and chronic exposures of STZ significantly impaired proliferative capacity in a dose-dependent manner. Within STZ-treated myoblasts, increased reactive oxygen species was associated with significant G2/M phase cell-cycle arrest. Taken together, our findings show that the effects of STZ are not β-cell specific and reveal that STZ should not be used for studies examining diabetic myopathy.

scholarly journals The Novel Arylamidine T-2307 Selectively Disrupts Yeast Mitochondrial Function by Inhibiting Respiratory Chain Complexes

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Kohei Yamashita ◽  
Taiga Miyazaki ◽  
Yoshiko Fukuda ◽  
Junichi Mitsuyama ◽  
Tomomi Saijo ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Mitochondrial Function ◽  
Yeast Cells ◽  
Dependent Manner ◽  
The Novel ◽  
Respiratory Chain Complexes ◽  
Content Type ◽  
Chain Complexes

ABSTRACT The novel arylamidine T-2307 exhibits broad-spectrum in vitro and in vivo antifungal activities against clinically significant pathogens. Previous studies have shown that T-2307 accumulates in yeast cells via a specific polyamine transporter and disrupts yeast mitochondrial membrane potential. Further, it has little effect on rat liver mitochondrial function. The mechanism by which T-2307 disrupts yeast mitochondrial function is poorly understood, and its elucidation may provide important information for developing novel antifungal agents. This study aimed to determine how T-2307 promotes yeast mitochondrial dysfunction and to investigate the selectivity of this mechanism between fungi and mammals. T-2307 inhibited the respiration of yeast whole cells and isolated yeast mitochondria in a dose-dependent manner. The similarity of the effects of T-2307 and respiratory chain inhibitors on mitochondrial respiration prompted us to investigate the effect of T-2307 on mitochondrial respiratory chain complexes. T-2307 particularly inhibited respiratory chain complexes III and IV not only in Saccharomyces cerevisiae but also in Candida albicans, indicating that T-2307 acts against pathogenic fungi in a manner similar to that of yeast. Conversely, T-2307 showed little effect on bovine respiratory chain complexes. Additionally, we demonstrated that the inhibition of respiratory chain complexes by T-2307 resulted in a decrease in the intracellular ATP levels in yeast cells. These results indicate that inhibition of respiratory chain complexes III and IV is a key factor for selective disruption of yeast mitochondrial function and antifungal activity.

Up-Regulation of GATA4 Regulates Human Lens Epithelial Cell Function in Age-Related Cataract

2020 ◽  
Vol 63 (6) ◽  
pp. 564-571
Author(s):  
Xiaodong Xie ◽  
Xiaofei Song ◽  
Xin Liu ◽  
Xiaogang Luo ◽  
Maidina Nabijiang ◽  
...  
Keyword(s):  
Prolonged Exposure ◽  
Cell Function ◽  
Critical Role ◽  
Lens Epithelial Cell ◽  
Human Lens ◽  
Dependent Manner ◽  
Age Related

<b><i>Purpose:</i></b> GATA4 has emerged as a novel regulator that plays a critical role in mediating senescence. However, the role of GATA4 in age-related cataract (ARC), the leading cause of visual impairment, requires further elucidation. <b><i>Methods:</i></b> GATA4 expression was measured by quantitative RT-PCR and capillary Western immunoassay (WES). The MTT assay, EdU assay, and rhodamine-123/Hoechst and calcein-AM/propidium iodide double staining were used to investigate the role of GATA4 in the viability, proliferation, and apoptosis of cultured human lens epithelial cells (HLECs). <b><i>Results:</i></b> HLECs were subjected to 3 different treatment models, including prolonged exposure to low-dose H<sub>2</sub>O<sub>2</sub>, UVB irradiation, and mild heating, to simulate senescence and apoptosis. GATA4 expression was significantly increased in these models in a time- and dose-dependent manner. Overexpression of GATA4 reduced cell viability, accelerated apoptosis development, and reduced the proliferation of HLECs. Furthermore, the expression of GATA4 from ARC was up-regulated at both mRNA and at protein level compared with clear lenses. <b><i>Conclusion:</i></b> GATA4 is up-regulated in all 3 models of HLECs in vitro and the cells from ARC lenses in vivo. Up-regulation of GATA4 mediates HLEC dysfunction. GATA4-mediated effects in HLECs would provide a novel insight into the pathogenesis of ARC.

Synthesis, Antioxidant and Anticancer Activities of Efficient Glutathione Peroxidase Mimic

2011 ◽  
Vol 282-283 ◽  
pp. 317-321
Author(s):  
Ting Ting Lin ◽  
Jun Qiu Liu
Keyword(s):  
Glutathione Peroxidase ◽  
Oxidative Damage ◽  
Dependent Manner ◽  
Anticancer Activities ◽  
Peroxidase Mimic ◽  
Age Related ◽  
Tnf Α ◽  
Dose Dependent

Glutathione peroxidase (GPX) is a well-known selenoenzyme that can protect cells against oxidative damage. A novel dicyclodextrinyl ditelluride (2-TeCD) compound was devised as a functional mimic of the GPX. The antioxidant effect of 2-TeCD was evaluated by its ability to protect mitochondria from oxidative damage. 2-TeCD could also suppress the TNF-α induced inflammatory effect on HUVECs surface in a dose-dependent manner. Meanwhile, 2-TeCD exhibited anti-proliferative property both in vitro and in vivo. These results indicate that 2-TeCD may be useful for developing medical agents in many pathological conditions such as cataract­, age-related diseases­, atherosclerosis, cancer and so on.

scholarly journals Cartilage protective and anti-analgesic effects of ALM16 on monosodium iodoacetate induced osteoarthritis in rats

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Doo Jin Choi ◽  
Soo-Im Choi ◽  
Bo-Ram Choi ◽  
Young-Seob Lee ◽  
Dae Young Lee ◽  
...  
Keyword(s):  
Joint Disease ◽  
Control Group ◽  
Dependent Manner ◽  
Paw Edema ◽  
In Vivo Models ◽  
Age Related ◽  
Monosodium Iodoacetate ◽  
Anti Inflammatory

Abstract Background Osteoarthritis (OA) is an age-related joint disease with characteristics that involve the progressive degradation of articular cartilage and resulting chronic pain. Previously, we reported that Astragalus membranaceus and Lithospermum erythrorhizon showed significant anti-inflammatory and anti-osteoarthritis activities. The objective of this study was to examine the protective effects of ALM16, a new herbal mixture (7:3) of ethanol extracts of A. membranaceus and L. erythrorhizon, against OA in in vitro and in vivo models. Methods The levels of matrix metalloproteinase (MMP)-1, −3 and − 13 and glycosaminoglycan (GAG) in interleukin (IL)-1β or ALM16 treated SW1353 cells were determined using an enzyme-linked immunosorbent and quantitative kit, respectively. In vivo, the anti-analgesic and anti-inflammatory activities of ALM16 were assessed via the acetic acid-induced writhing response and in a carrageenan-induced paw edema model in ICR mice, respectively. In addition, the chondroprotective effects of ALM16 were analyzed using a single-intra-articular injection of monosodium iodoacetate (MIA) in the right knee joint of Wister/ST rat. All samples were orally administered daily for 2 weeks starting 1 week after the MIA injection. The paw withdrawal threshold (PWT) in MIA-injected rats was measured by the von Frey test using the up-down method. Histopathological changes of the cartilage in OA rats were analyzed by hematoxylin and eosin (H&E) staining. Results ALM16 remarkably reduced the GAG degradation and MMP levels in IL-1β treated SW1353 cells. ALM16 markedly decreased the thickness of the paw edema and writhing response in a dose-dependent manner in mice. In the MIA-induced OA rat model, ALM16 significantly reduced the PWT compared to the control group. In particular, from histological observations, ALM16 showed clear improvement of OA lesions, such as the loss of necrotic chondrocytes and cartilage erosion of more than 200 mg/kg b.w., comparable to or better than a positive drug control (JOINS™, 200 mg/kg) in the cartilage of MIA-OA rats. Conclusions Our results demonstrate that ALM16 has a strong chondroprotective effect against the OA model in vitro and in vivo, likely attributed to its anti-inflammatory activity and inhibition of MMP production.

scholarly journals PTK2 Promotes Uveal Melanoma Metastasis by Activating Epithelial-to-Mesenchymal Transition

2021 ◽  
Author(s):  
Zhongyi Fan ◽  
Jingjing Duan ◽  
Lei Zhang ◽  
Qiong Chen ◽  
Wen Xiao ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Uveal Melanoma ◽  
Epithelial To Mesenchymal Transition ◽  
The Cancer Genome Atlas ◽  
High Morbidity ◽  
Melanoma Metastasis ◽  
Mesenchymal Transition ◽  
Tyrosine Kinase 2

Abstract Background: Uveal melanoma (UM) is an aggressive primary intraocular tumor in adults, with high metastatic capacity and high morbidity. However, the mechanisms of UM metastasis have not been clearly elucidated.Methods: The PTK2 expression and activation were performed in the Cancer Genome Atlas (TCGA) database and 25 patients of UM. The role of PTK2 in promoting metastasis was explored in vitro and in vivo. Subsequently, we revealed the correlation between PTK2 expression and epithelial-to-mesenchymal transition (EMT). Finally, we explored the reason for the high expression of PTK2 in UM.Results: Our study found that protein tyrosine kinase 2 (PTK2) was overexpressed in UM specimens, and as a novel independent risk factor, its overexpression predicted the poor survival of UM patients. For the molecular mechanism, PTK2 promoted EMT phenotype, thus leading to tumor metastasis in UM cells. Subsequently, we have demonstrated that PTK2 was a functional gene of chromosome 8q gain accounting for UM metastasis, providing a novel molecular mechanism for the aberrantly expression and activation of PTK2 in UM.Conclusion: Our data reveal the important role and mechanism of PTK2 in the metastatic process of UM, which may clue to a new predictive biomarker for UM metastasis and a new therapeutic target for UM treatment.

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