scholarly journals Icariin Treatment Protects Against Gentamicin-Induced Ototoxicity via Activation of the AMPK-SIRT3 Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Yue Hu ◽  
Xiulan Ma
Keyword(s):  
Protective Effect ◽  
Organ Of Corti ◽  
Cell Loss ◽  
Ros Production ◽  
Auditory Hair Cells ◽  
Compound C ◽  
Ampk Phosphorylation ◽  
Apoptotic Effect ◽  
Gentamicin Ototoxicity ◽  
Sirt3 Expression

Ototoxicity is a serious health problem that greatly affects millions of people worldwide. This condition is caused by the entry of aminoglycosides into auditory hair cells, subsequently inducing reactive oxygen species (ROS) production and accumulation. Several strategies have been adopted to overcome irreversible ROS-induced hair cell loss in mammals. In recent years, icariin, a major active component of the traditional herb Epimedium, has been widely studied and revealed to have antioxidant, anti-inflammatory, and anti-apoptotic properties. In this study, we found that icariin pretreatment improved the survival rate of gentamicin-treated House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and cochlear explants. Icariin remarkably suppressed HEI-OC1 cell apoptosis and inhibited ROS production in cells. Notably, icariin upregulated PGC-1α (SIRT3 promoter) and SIRT3 expression in HEI-OC1 cells. In addition, SIRT3 inhibition significantly attenuated the anti-apoptotic effect of icariin. We also found that icariin can increase AMPK phosphorylation. Further studies showed that inhibition of SIRT3 activity had no significant effect on AMPK phosphorylation. Furthermore, the AMPK inhibitor compound C significantly suppressed SIRT3 expression, meaning that AMPK, as an upstream molecule, regulates SIRT3 expression. Meanwhile, inhibition of AMPK activity significantly reduced the protective effect of icariin on gentamicin ototoxicity. Based on these results, icariin exerts its protective effect on gentamicin-induced ototoxicity via activation of the AMPK-SIRT3 signaling pathway, thus providing a new strategy for treating ototoxicity caused by aminoglycoside antibiotics.

scholarly journals Resveratrol Improves Boar Sperm Quality via 5′AMP-Activated Protein Kinase Activation during Cryopreservation

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Zhendong Zhu ◽  
Rongnan Li ◽  
Xiaoteng Fan ◽  
Yinghua Lv ◽  
Yi Zheng ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Sperm Quality ◽  
Membrane Integrity ◽  
Mitochondrial Activity ◽  
Enzymatic Antioxidants ◽  
Ros Production ◽  
Compound C ◽  
Ampk Phosphorylation ◽  
Boar Sperm ◽  
Amp Activated Protein Kinase

Mammalian sperm is highly susceptible to the reactive oxygen species (ROS) stress caused by biochemical and physical modifications during the cryopreservation process. 5′AMP-activated protein kinase (AMPK) is involved in regulating both cell metabolism and cellular redox status. The aim of the present study was to investigate whether the resveratrol protects boar sperm against ROS stress via activation of AMPK during cryopreservation. Boar sperm was diluted with the freezing medium supplemented with resveratrol at different concentrations (0, 25, 50, 75, 100, and 125 μM). It was observed that the addition of 50 μM resveratrol significantly improved the postthaw sperm progressive motility, membrane integrity, acrosome integrity, mitochondrial activity, glutathione (GSH) level, activities of enzymatic antioxidants (glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase), and the phosphorylation of AMPK. Meanwhile, the lipid peroxidation, ROS levels, and apoptosis of postthaw sperm were reduced in the presence of 50 μM resveratrol. Furthermore, when fresh boar sperm was incubated with the medium in the presence of 50 μM resveratrol and 30 μM Compound C (an AMPK inhibitor), the effects of the resveratrol were partly counteracted by the Compound C. These observations suggest that the resveratrol protects boar sperm via promoting AMPK phosphorylation. In conclusion, the addition of resveratrol to the freezing extenders protects boar sperm against ROS damage via promoting AMPK phosphorylation for decreasing the ROS production and improving the antioxidative defense system of postthaw sperm. These findings provide novel insights into understanding the mechanisms of resveratrol on how to protect boar sperm quality contrary to the ROS production during cryopreservation.

scholarly journals Brimonidine Protects Auditory Hair Cells from in vitro-Induced Toxicity of Gentamicin

2017 ◽  
Vol 22 (3) ◽  
pp. 125-134 ◽  
Author(s):  
Maurizio Cortada ◽  
Soledad Levano ◽  
Daniel Bodmer
Keyword(s):  
Protein Expression ◽  
Protective Effect ◽  
Hair Cells ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Neuroprotective Effects ◽  
Auditory Hair Cells ◽  
Expression Levels ◽  
Ganglion Neurons

Brimonidine, an alpha-2 adrenergic receptor (α2-AR) agonist, has neuroprotective effects in the visual system and in spiral ganglion neurons. Auditory hair cells (HCs) express all 3 α2-AR subtypes, but their roles in HCs remain unknown. This study investigated the effects of brimonidine on auditory HCs that were also exposed to gentamicin, which is toxic to HCs. Organ of Corti explants were exposed to gentamicin in the presence or absence of brimonidine, and the α2-AR protein expression levels and Erk1/2 and Akt phosphorylation levels were determined. Brimonidine had a protective effect on auditory HCs against gentamicin-induced toxicity that was blocked by yohimbine. This suggested that the protective effect of brimonidine on HCs was mediated by the α2-AR. None of the treatments altered α2-AR protein expression levels, and brimonidine did not significantly change the activation levels of the Erk1/2 and Akt proteins. These observations indicated that brimonidine, acting directly via α2-AR, protects HCs from gentamicin-induced toxicity. Therefore, brimonidine shows potential for preventing or treating sensorineural hearing loss.

scholarly journals Canagliflozin protects against cisplatin-induced acute kidney injury by AMPK-mediated autophagy in renal proximal tubular cells

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Cheol Ho Park ◽  
Bin Lee ◽  
Myeonggil Han ◽  
Woo Joong Rhee ◽  
Man Sup Kwak ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Protective Effect ◽  
Kidney Injury ◽  
Proximal Tubular Cells ◽  
Cell Viability Assay ◽  
Tubular Cells ◽  
Compound C ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular

AbstractSodium-glucose cotransporter 2 inhibitors, which are recently introduced as glucose-lowering agents, improve cardiovascular and renal outcomes in patients with diabetes mellitus. These drugs also have beneficial effects in various kidney disease models. However, the effect of SGLT2 inhibitors on cisplatin-induced acute kidney injury (AKI) and their mechanism of action need to be elucidated. In this study, we investigated whether canagliflozin protects against cisplatin-induced AKI, depending on adenosine monophosphate-activated protein kinase (AMPK) activation and following induction of autophagy. In the experiments using the HK-2 cell line, cell viability assay and molecular analysis revealed that canagliflozin protected renal proximal tubular cells from cisplatin, whereas addition of chloroquine or compound C abolished the protective effect of canagliflozin. In the mouse model of cisplatin-induced AKI, canagliflozin protected mice from cisplatin-induced AKI. However, treatment with chloroquine or compound C in addition to administration of cisplatin and canagliflozin eliminated the protective effect of canagliflozin. Collectively, these findings indicate that canagliflozin protects against cisplatin-induced AKI by activating AMPK and autophagy in renal proximal tubular cells.

scholarly journals Spirulina Extract Enhanced a Protective Effect in Type 1 Diabetes by Anti-Apoptosis and Anti-ROS Production

Nutrients ◽  
2017 ◽  
Vol 9 (12) ◽  
pp. 1363 ◽  
Author(s):  
Jiyeong Lee ◽  
Arum Park ◽  
Mi Kim ◽  
Hee-Joung Lim ◽  
Young-Ah Rha ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Protective Effect ◽  
Ros Production

scholarly journals Role of PKC and AMPK in hypertonicity-stimulated water reabsorption in rat inner medullary collecting ducts

2019 ◽  
Vol 316 (2) ◽  
pp. F253-F262 ◽  
Author(s):  
Josephine K. Liwang ◽  
Joseph A. Ruiz ◽  
Lauren M. LaRocque ◽  
Fitra Rianto ◽  
Fuying Ma ◽  
...  
Keyword(s):  
Water Permeability ◽  
Collecting Duct ◽  
Adenosine Monophosphate ◽  
Osmotic Water Permeability ◽  
Water Reabsorption ◽  
Compound C ◽  
Ampk Phosphorylation ◽  
Osmotic Water ◽  
Medullary Collecting Duct

Hypertonicity increases water permeability, independently of vasopressin, in the inner medullary collecting duct (IMCD) by increasing aquaporin-2 (AQP2) membrane accumulation. We investigated whether protein kinase C (PKC) and adenosine monophosphate kinase (AMPK) are involved in hypertonicity-regulated water permeability. Increasing perfusate osmolality from 150 to 290 mosmol/kgH2O and bath osmolality from 290 to 430 mosmol/kgH2O significantly stimulated osmotic water permeability. The PKC inhibitors chelerythrine (10 µM) and rottlerin (50 µM) significantly reversed the increase in osmotic water permeability stimulated by hypertonicity in perfused rat terminal IMCDs. Chelerythrine significantly increased phosphorylation of AQP2 at S261 but not at S256. Previous studies show that AMPK is stimulated by osmotic stress. We tested AMPK phosphorylation under hypertonic conditions. Hypertonicity significantly increased AMPK phosphorylation in inner medullary tissues. Blockade of AMPK with Compound C decreased hypertonicity-stimulated water permeability but did not alter phosphorylation of AQP2 at S256 and S261. AICAR, an AMPK stimulator, caused a transient increase in osmotic water permeability and increased phosphorylation of AQP2 at S256. When inner medullary tissue was treated with the PKC activator phorbol dibutyrate (PDBu), the AMPK activator metformin, or both, AQP2 phosphorylation at S261 was decreased with PDBu or metformin alone, but there was no additive effect on phosphorylation with PDBu and metformin together. In conclusion, hypertonicity regulates water reabsorption by activating PKC. Hypertonicity-stimulated water reabsorption by PKC may be related to the decrease in endocytosis of AQP2. AMPK activation promotes water reabsorption, but the mechanism remains to be determined. PKC and AMPK do not appear to act synergistically to regulate water reabsorption.

scholarly journals Synphilin-1 Interacts with AMPK and Increases AMPK Phosphorylation

2020 ◽  
Vol 21 (12) ◽  
pp. 4352 ◽  
Author(s):  
Tianxia Li ◽  
Jingnan Liu ◽  
Gongbo Guo ◽  
Bo Ning ◽  
Xueping Li ◽  
...  
Keyword(s):  
Energy Balance ◽  
Cultured Cells ◽  
Energy Status ◽  
Glutathione S Transferase ◽  
Cellular Functions ◽  
Ampk Signaling ◽  
Cellular Energy ◽  
Downstream Signaling ◽  
Compound C ◽  
Ampk Phosphorylation

A role for the cytoplasmic protein synphilin-1 in regulating energy balance has been demonstrated recently. Expression of synphilin-1 increases ATP levels in cultured cells. However, the mechanism by which synphilin-1 alters cellular energy status is unknown. Here, we used cell models and biochemical approaches to investigate the cellular functions of synphilin-1 on the AMP-activated protein kinase (AMPK) signaling pathway, which may affect energy balance. Overexpression of synphilin-1 increased AMPK phosphorylation (activation). Moreover, synphilin-1 interacted with AMPK by co-immunoprecipitation and GST (glutathione S-transferase) pull-down assays. Knockdown of synphilin-1 reduced AMPK phosphorylation. Overexpression of synphilin-1 also altered AMPK downstream signaling, i.e., a decrease in acetyl CoA carboxylase (ACC) phosphorylation, and an increase in p70S6K phosphorylation. Treatment of compound C (an AMPK inhibitor) reduced synphilin-1 binding with AMPK. In addition, compound C diminished synphilin-1-induced AMPK phosphorylation, and the increase in cellular ATP (adenosine triphosphate) levels. Our results demonstrated that synphilin-1 couples with AMPK, and they exert mutual effects on each other to regulate cellular energy status. These findings not only identify novel cellular actions of synphilin-1, but also provide new insights into the roles of synphilin-1 in regulating energy currency, ATP.

scholarly journals Pioglitazone Ameliorates Gentamicin Ototoxicity by Affecting the TLR and STAT Pathways in the Early Postnatal Organ of Corti

2020 ◽  
Vol 14 ◽  
Author(s):  
Marijana Sekulic-Jablanovic ◽  
Matthew B. Wright ◽  
Vesna Petkovic ◽  
Daniel Bodmer
Keyword(s):  
Organ Of Corti ◽  
Gentamicin Ototoxicity

scholarly journals AMPK-dependent regulation of GLP1 expression in L-like cells

2016 ◽  
Vol 57 (3) ◽  
pp. 151-160 ◽  
Author(s):  
Sushi Jiang ◽  
Hening Zhai ◽  
Danjie Li ◽  
Jiana Huang ◽  
Heng Zhang ◽  
...  
Keyword(s):  
Serum Starvation ◽  
Energy Status ◽  
Wild Type ◽  
High Concentration ◽  
Cellular Energy ◽  
Compound C ◽  
Ampk Phosphorylation ◽  
Evolutionarily Conserved ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

This study examined whether AMPK, an evolutionarily conserved sensor of cellular energy status, determines the production of glucagon-like peptide-1 (GLP1). A negative relation existed between phosphorylation of AMPKα and the expression and secretion of GLP1 during changes in energy status in STC-1 cells, an L-like cell line. High concentration of glucose (25 mmol/L) decreased AMPKα phosphorylation, whereas it stimulated the expression and secretion of GLP1 relative to 5.6 mmol/L glucose. Serum starvation upregulated AMPKα phosphorylation, whereas it reduced GLP1 production significantly. Stimulation of AMPK phosphorylation by AICAR and overexpression of wild-type AMPKα1, constitutively active AMPKα1 plasmids, or AMPKα1 lentivirus particles suppressed proglucagon mRNA and protein contents in STC-1 cells. Inactivation of AMPK by Compound C, AMPKα1 siRNA or kinase-inactive AMPKα1 mutant increased the expression and secretion of GLP1. Our results suggest that AMPKα1 may link energy supply with the production of GLP1 in L-like cells.

The Proteasome Inhibitor Bortezomib and Histone Deacetylase Inhibitor SAHA Sinergistically Inhibit Proliferation and Induce Apoptosis of Megakaryoblastic MO7-e Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4389-4389
Author(s):  
Sara Galimberti ◽  
Martina Canestraro ◽  
Simone Pacini ◽  
Rita Fazzi ◽  
Enrico Orciuolo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Line ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Proteasome Inhibitor ◽  
Myeloproliferative Disorders ◽  
Ros Production ◽  
Deacetylase Inhibitor ◽  
Apoptotic Effect

Abstract PS-341 (Bortezomib) is a novel dipeptide boronic acid proteasome inhibitor with in vitro and in vivo antitumor activity that induces apoptosis in different human cancer cell lines. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, has been reported to induce apoptosis of leukemic cells by increasing the cyclin-dependent kinase inhibitor p21 or generating reactive oxygen species (ROS). Co-exposure of BCR/ABL-positive cells both sensitive and resistant to imatinib to these compounds has been previously reported resulting in an increased apoptotic rate. To extend this observation, we examined the effect of treatment with bortezomib or/and SAHA of a megakaryoblastic cell line (MO7-e). Cell proliferation, ROS production, cell cycle progression, induction of apoptosis and differentiation has been investigated. Bortezomib was shown to retain NF-kB in the cytoplasm and inhibit cell growth (IC50=20nM), in a dose/time-dependent way. This anti-proliferative activity resulted to be lineage-specific, because other leukemic cell lines were unaffected by the bortezomib treatment. Moreover, bortezomib in MO7-e cells increased ROS production and induced a significant pro-apoptotic effect (50% vs 5% in control). Finally, cell cycle was blocked in the G2 phase and bortezomib was able to down-regulate WT1 expression, gene that could play a relevant prognostic role in myeloproliferative disorders. Moreover, any significant effect on cell differentiation was found. SAHA also resulted able to inactivate NF-kB and to inhibit cell proliferation, at 1.5 uM. It did not increase significantly ROS production, blocked cell cycle in the G1 phase and down-regulated WT1 expression (10 fold minus than bortezomib). Neverthelles, SAHA also did not induce differentiation of megakaryoblatic cells. Co-exposure of this cell line to minimally toxic concentrations of bortezomib (5 nM) and SAHA (0.5 uM), resulted in a significant increase of anti-proliferative (50% of growth inhibition vs 15% with bortezomib and 10% with SAHA alone) and pro-apoptotic effect (45% vs 20% of bortezomib and 15% of SAHA alone). Interestingly, immunocitochemistry assays detecting the NF-kB p65 subunit showed that the co-exposure to bortezomib and SAHA resulted in a minor NF-kB inactivation than that achieved with single compounds. This finding was confirmed by the pre-incubation of MO7-e cells with SAHA in respect of the pre-incubation with bortezomib or the simultaneously addition of the two drugs. In fact, pre-incubating megakaryoblasts with SAHA, the anti-proliferative effect of bortezomib significantly decreased. In conclusion, this study supports the association of a proteasome with a histone deacetylase inhibitor, in a time-sequence-related way, especially in chronic myeloproliferative disorders where a spontaneous NF-kB activation and a WT1 over-expression have been reported.

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