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Migrasomes, the newly discovered cellular organelles that form large vesicle-like structures on the retraction fibers of migrating cells, are thought to be involved in communication between neighboring cells, cellular content transfer, unwanted material shedding, and information integration. Although their formation has been described previously, the molecular mechanisms of migrasome biogenesis are largely unknown. Here, we developed a cell line that overexpresses GFP-tetraspanin4, enabling observation of migrasomes. To identify compounds that regulate migrasome activity in retinal pigment epithelial (RPE) cells, we screened a fecal chemical library and identified cadaverine, a biogenic amine, as a potent migrasome formation inducer. Compared with normal migrating cells, those treated with cadaverine had significantly more migrasomes. Putrescine, another biogenic amine, also increased migrasome formation. Trace amine-associated receptor 8 (TAAR8) depletion inhibited migrasome increase in cadaverine-treated RPE cells, and cadaverine also inhibited protein kinase A phosphorylation. In RPE cells, cadaverine triggers migrasome formation via a TAAR8-mediated protein kinase A signaling pathway.
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Primary cilia are crucial for cellular balance, serving as sensors for external conditions. Nephronophthisis and related ciliopathies, which are hereditary and degenerative, stem from genetic mutations in cilia-related genes. However, the precise mechanisms of these conditions are still not fully understood. Our research demonstrates that downregulating PDIA6, leading to cilia removal, makes cells more sensitive to ferroptotic death caused by endoplasmic reticulum (ER) stress. The reduction of PDIA6 intensifies the ER stress response, while also impairing the regulation of primary cilia in various cell types. PDIA6 loss worsens ER stress, hastening ferroptotic death in proximal tubule epithelial cells, HK2 cells. Counteracting this ER stress can mitigate PDIA6 depletion effects, restoring both the number and length of cilia. Moreover, preventing ferroptosis corrects the disrupted primary ciliogenesis due to PDIA6 depletion in HK2 cells. Our findings emphasize the role of PDIA6 in primary ciliogenesis, and suggest its absence enhances ER stress and ferroptosis. These insights offer new therapeutic avenues for treating nephronophthisis and similar ciliopathies.
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Hypoxic responses have been implicated in critical pathologies, including inflammation, immunity, and tumorigenesis. Recently, efforts to identify effective natural remedies and health supplements are increasing. Previous studies have reported that the cell lysates and the cell wall-bound lipoteichoic acids of Lactiplantibacillus plantarum K8 (K8) exert anti-inflammatory and immunomodulative effects. However, the effect of K8 on cellular hypoxic responses remains unknown. In this study, we found that K8 lysates had a potent suppressive effect on gene expression under hypoxia. K8 lysates markedly downregulated hypoxia-induced HIF1α accumulation in the human bone marrow and lung cancer cell lines, SH-SY5Y and H460. Consequently, the transcription of known HIF1α target genes, such as p21, GLUT1, and ALDOC, was notably suppressed in the K8 lysate supplement and purified lipoteichoic acids of K8, upon hypoxic induction. Intriguingly, K8 lysates decreased the expression of PHD2 and VHL proteins, which are responsible for HIF1α destabilization under normoxic conditions, suggesting that K8 may regulate HIF1α stability in a non-canonical pathway. Overall, our results suggest that K8 lysates desensitize the cells to hypoxic stresses and suppress HIF1α-mediated hypoxic gene activation.
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Neuroblastoma , Humanos , Hipoxia de la Célula/genética , Línea Celular , Hipoxia/metabolismo , Expresión Génica , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismoRESUMEN
Autophagy is a pivotal biological process responsible for maintaining the homeostasis of intracellular organelles. Yet the molecular intricacies of peroxisomal autophagy (pexophagy) remain largely elusive. From a ubiquitin-related chemical library for screening, we identified several inhibitors of the Von Hippel-Lindau (VHL) E3 ligase, including VH298, thereby serving as potent inducers of pexophagy. In this study, we observed that VH298 stimulates peroxisomal degradation by ATG5 dependently and escalates the ubiquitination of the peroxisomal membrane protein ABCD3. Interestingly, the ablation of NBR1 is similar to the curtailed peroxisomal degradation in VH298-treated cells. We also found that the pexophagy induced by VH298 is impeded upon the suppression of gene expression by the translation inhibitor cycloheximide. Beyond VHL inhibition, we discovered that roxadustat, a direct inhibitor of HIF-α prolyl hydroxylase, is also a potent inducer of pexophagy. Furthermore, we found that VH298-mediated pexophagy is blocked by silencing HIF-1α. In conclusion, our findings suggest that VH298 promotes pexophagy by modulating VHL-mediated HIF-α transcriptional activity.
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Autofagia , Ciclopropanos , Macroautofagia , Pirrolidinas , Tiazoles , Humanos , Células HeLa , Homeostasis , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genéticaRESUMEN
The primary cilium, an antenna-like structure on the cell surface, acts as a mechanical and chemical sensory organelle. Primary cilia play critical roles in sensing the extracellular environment to coordinate various developmental and homeostatic signaling pathways. Here, we showed that the depletion of heat shock protein family A member 9 (HSPA9)/mortalin stimulates primary ciliogenesis in SH-SY5Y cells. The downregulation of HSPA9 enhances mitochondrial stress by increasing mitochondrial fragmentation and mitochondrial reactive oxygen species (mtROS) generation. Notably, the inhibition of either mtROS production or mitochondrial fission significantly suppressed the increase in primary ciliogenesis in HSPA9-depleted cells. In addition, enhanced primary ciliogenesis contributed to cell survival by activating AKT in SH-SY5Y cells. The abrogation of ciliogenesis through the depletion of IFT88 potentiated neurotoxicity in HSPA9-knockdown cells. Furthermore, both caspase-3 activation and cell death were increased by MK-2206, an AKT inhibitor, in HSPA9-depleted cells. Taken together, our results suggest that enhanced primary ciliogenesis plays an important role in preventing neurotoxicity caused by the loss of HSPA9 in SH-SY5Y cells.
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Neuroblastoma , Proteínas Proto-Oncogénicas c-akt , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Línea Celular Tumoral , Apoptosis , Estrés Oxidativo , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas Mitocondriales/metabolismoRESUMEN
Although autophagy regulates the quality and quantity of cellular compartments, the regulatory mechanisms underlying peroxisomal autophagy (pexophagy) remain largely unknown. In this study, we identified several BRD4 inhibitors, including molibresib, a novel pexophagy inducer, via chemical library screening. Treatment with molibresib promotes loss of peroxisomes selectively, but not mitochondria, ER, or Golgi apparatus in HeLa cells. Consistently, depletion of BRD4 expression also induced pexophagy in RPE cells. In addition, the inhibition of BRD4 by molibresib increased autophagic degradation of peroxisome ATG7-dependency. We further found that molibresib produced reactive oxygen species (ROS), which potentiates ATM activation. Inhibition of ROS or ATM suppressed the loss of peroxisomes in molibresib-treated cells. Taken together, our data suggest that inhibition of BRD4 promotes pexophagy by increasing ROS and ATM activation.
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Macroautofagia , Proteínas Nucleares , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de Ciclo Celular/metabolismo , Células HeLa , Humanos , Proteínas Nucleares/metabolismo , Peroxisomas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Primary cilia help to maintain cellular homeostasis by sensing conditions in the extracellular environment, including growth factors, nutrients, and hormones that are involved in various signaling pathways. Recently, we have shown that enhanced primary ciliogenesis in dopamine neurons promotes neuronal survival in a Parkinson's disease model. Moreover, we performed fecal metabolite screening in order to identify several candidates for improving primary ciliogenesis, including L-carnitine and acetyl-L-carnitine. However, the role of carnitine in primary ciliogenesis has remained unclear. In addition, the relationship between primary cilia and neurodegenerative diseases has remained unclear. In this study, we have evaluated the effects of carnitine on primary ciliogenesis in 1-methyl-4-phenylpyridinium ion (MPP+)-treated cells. We found that both L-carnitine and acetyl-L-carnitine promoted primary ciliogenesis in SH-SY5Y cells. In addition, the enhancement of ciliogenesis by carnitine suppressed MPP+-induced mitochondrial reactive oxygen species overproduction and mitochondrial fragmentation in SH-SY5Y cells. Moreover, carnitine inhibited the production of pro-inflammatory cytokines in MPP+-treated SH-SY5Y cells. Taken together, our findings suggest that enhanced ciliogenesis regulates MPP+-induced neurotoxicity and inflammation.
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Neuroblastoma , Síndromes de Neurotoxicidad , 1-Metil-4-fenilpiridinio/toxicidad , Acetilcarnitina/farmacología , Apoptosis , Carnitina/farmacología , Línea Celular Tumoral , Neuronas Dopaminérgicas , Humanos , InflamaciónRESUMEN
In recent decades, dopant-free Si-based solar cells with a transition metal oxide layer have gained noticeable research interest as promising candidates for next-generation solar cells with both low manufacturing cost and high power conversion efficiency. Here, we report the effect of the substrate temperature for the deposition of vanadium oxide (V2O5-x, 0 ≤ X ≤ 5) thin films (TFs) for enhanced Si surface passivation. The effectiveness of SiOx formation at the Si/V2O5-x interface for Si surface passivation was investigated by comparing the results of minority carrier lifetime measurements, X-ray photoelectron spectroscopy, and atomic force microscopy. We successfully demonstrated that the deposition temperature of V2O5-x has a decisive effect on the surface passivation performance. The results confirmed that the aspect ratio of the V2O5-x islands that are initially deposited is a crucial factor to facilitate the transport of oxygen atoms originating from the V2O5-x being deposited to the Si surface. In addition, the stoichiometry of V2O5-x TFs can be notably altered by substrate temperature during deposition. As a result, experimentation with the fabricated Si/V2O5-x heterojunction solar cells confirmed that the power conversion efficiency is the highest at a V2O5-x deposition temperature of 75 °C.
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Autophagy plays a key role in eliminating and recycling cellular components in response to stress, including starvation. Dysregulation of autophagy is observed in various diseases, including neurodegenerative diseases, cancer, and diabetes. Autophagy is tightly regulated by autophagy-related (ATG) proteins. Autophagy-related 4 (ATG4) is the sole cysteine protease, and four homologs (ATG4A-D) have been identified in mammals. These proteins have two domains: catalytic and short fingers. ATG4 facilitates autophagy by promoting autophagosome maturation through reversible lipidation and delipidation of seven autophagy-related 8 (ATG8) homologs, including microtubule-associated protein 1-light chain 3 (LC3) and GABA type A receptor-associated protein (GABARAP). Each ATG4 homolog shows a preference for a specific ATG8 homolog. Post-translational modifications of ATG4, including phosphorylation/dephosphorylation, O-GlcNAcylation, oxidation, S-nitrosylation, ubiquitination, and proteolytic cleavage, regulate its activity and ATG8 processing, thus modulating its autophagic activity. We reviewed recent advances in our understanding of the effect of post-translational modification on the regulation, activity, and function of ATG4, the main protease that controls autophagy.
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Autofagia , Proteínas Asociadas a Microtúbulos , Animales , Autofagia/fisiología , Familia de las Proteínas 8 Relacionadas con la Autofagia/metabolismo , Proteínas Relacionadas con la Autofagia/metabolismo , Mamíferos/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Péptido Hidrolasas/metabolismo , Procesamiento Proteico-PostraduccionalRESUMEN
In the last decades, the conductive polymer PEDOT:PSS has been introduced in Si-based hybrid solar cells, gaining noticeable research interest and being considered a promising candidate for next generation solar cells which can achieve both of low manufacturing cost and high power conversion efficiency. This study succeeded in improving the electrical conductivity of PEDOT:PSS to 937 S/cm through a simple process of adding hydroquinone (HQ) to the pristine PEDOT:PSS solution. The results also showed that the addition of HQ to PEDOT:PSS(HQ-PEDOT:PSS) could not only dramatically improve the conductivity but also well-sustain the work function characteristics of PEDOT:PSS by promoting the formation of more continuous conductive-PEDOT channels without removing the insulating PSS. In this report, we reveal that the application of the HQ-PEDOT:PSS to the Si/PEDOT:PSS HSC could significantly improve the short-circuit current and open-circuit voltage characteristics to increase the power conversion efficiency of the HSCs compared to the conventional approaches. Moreover, we also treated the Si surface with the organic monomer, benzoquinone (BQ) to (1) passivate the excess Si surface defect states and (2) to improve the properties of the Si/PEDOT:PSS interface. We show that BQ treatment is able to dramatically increase the minority carrier lifetime induced by effective chemical and field-effect passivation in addition to enhancing the wettability of the Si surface with the PEDOT:PSS solution. As a result, the power conversion efficiency was increased by 10.6% by introducing HQ and BQ into the fabrication process of the Si/PEDOT:PSS HSC.
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Ir is one of the most efficient oxygen evolution reaction (OER) catalysts; however, it is also one of the rarest and most expensive elements. Therefore, it is highly desirable to develop Ir catalysts with nanostructures that reduce Ir consumption by maximizing the surface-to-volume ratio without limiting the mass transport of reactants and products of reactions. Ir OER catalysts on a template that consisted of porous nanotubes (PNTs) based on Ni are fabricated. The Ir/Ni PNTs offer multiple benefits, including high catalytic performance (potential of 1.500 V vs. reversible hydrogen electrode (RHE) at an operating current density of 10 mA cm-2 and Tafel slope of 44.34 mV decade-1 ), minimal use of Ir (mass activity of 3273 A g-1 at 1.53 V vs RHE), and facile mass transport through the NT-sidewall pores (stable operation for more than 10 h). The Ir/Ni PNTs are also applied to a tandem device, consisting of a Cu(In,Ga)Se2 -based photocathode and halide perovskite photovoltaic cell, for unassisted water splitting. A solar-to-hydrogen conversion efficiency that exceeded 10% is also demonstrated, which is nearly 1% point greater than when a planar Ir film is used as the anode instead of Ir/Ni PNTs.
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Selective autophagy controls cellular homeostasis by degrading unnecessary or damaged cellular components. Melanosomes are specialized organelles that regulate the biogenesis, storage, and transport of melanin in melanocytes. However, the mechanisms underlying melanosomal autophagy, known as the melanophagy pathway, are poorly understood. To better understand the mechanism of melanophagy, we screened an endocrine-hormone chemical library and identified nalfurafine hydrochlorides, a κ-opioid receptor agonist, as a potent inducer of melanophagy. Treatment with nalfurafine hydrochloride increased autophagy and reduced melanin content in alpha-melanocyte-stimulating hormone (α-MSH)-treated cells. Furthermore, inhibition of autophagy blocked melanosomal degradation and reversed the nalfurafine hydrochloride-induced decrease in melanin content in α-MSH-treated cells. Consistently, treatment with other κ-opioid receptor agonists, such as MCOPPB or mianserin, inhibited excessive melanin production but induced autophagy in B16F1 cells. Furthermore, nalfurafine hydrochloride inhibited protein kinase A (PKA) activation, which was notably restored by forskolin, a PKA activator. Additionally, forskolin treatment further suppressed melanosomal degradation as well as the anti-pigmentation activity of nalfurafine hydrochloride in α-MSH-treated cells. Collectively, our data suggest that stimulation of κ-opioid receptors induces melanophagy by inhibiting PKA activation in α-MSH-treated B16F1 cells.
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Melaninas , alfa-MSH , alfa-MSH/farmacología , Colforsina , Melaninas/metabolismo , Receptores Opioides kappa/agonistas , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Animales , RatonesRESUMEN
Particulate matters (PMs) increase oxidative stress and inflammatory response in different tissues. PMs disrupt the formation of primary cilia in various skin cells, including keratinocytes and melanocytes. In this study, we found that 2-isopropylmalic acid (2-IPMA) promoted primary ciliogenesis and restored the PM2.5-induced dysgenesis of primary cilia in dermal fibroblasts. Moreover, 2-IPMA inhibited the generation of excessive reactive oxygen species and the activation of stress kinase in PM2.5-treated dermal fibroblasts. Further, 2-IPMA inhibited the production of pro-inflammatory cytokines, including IL-6 and TNF-α, which were upregulated by PM2.5. However, the inhibition of primary ciliogenesis by IFT88 depletion reversed the downregulated cytokines by 2-IPMA. Moreover, we found that PM2.5 treatment increased the MMP-1 expression in dermal fibroblasts and a human 3-D-skin model. The reduced MMP-1 expression by 2-IPMA was further reversed by IFT88 depletion in PM2.5-treated dermal fibroblasts. These findings suggest that 2-IPMA ameliorates PM2.5-induced inflammation by promoting primary ciliogenesis in dermal fibroblasts.
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Citocinas/metabolismo , Activación Enzimática/efectos de los fármacos , Malatos/farmacología , Metaloproteinasa 1 de la Matriz/metabolismo , Técnicas de Cultivo de Célula , Línea Celular , Cilios/metabolismo , Cilios/patología , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , Interleucina-6/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Metaloproteinasa 1 de la Matriz/genética , Modelos Biológicos , Estrés Oxidativo/efectos de los fármacos , Material Particulado/toxicidad , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Primary cilia mediate the interactions between cells and external stresses. Thus, dysregulation of primary cilia is implicated in various ciliopathies, e.g., degeneration of the retina caused by dysregulation of the photoreceptor primary cilium. Particulate matter (PM) can cause epithelium injury and endothelial dysfunction by increasing oxidative stress and inflammatory responses. Previously, we showed that PM disrupts the formation of primary cilia in retinal pigment epithelium (RPE) cells. In the present study, we identified 2-isopropylmalic acid (2-IPMA) as a novel inducer of primary ciliogenesis from a metabolite library screening. Both ciliated cells and primary cilium length were increased in 2-IPMA-treated RPE cells. Notably, 2-IPMA strongly promoted primary ciliogenesis and restored PM2.5-induced dysgenesis of primary cilia in RPE cells. Both excessive reactive oxygen species (ROS) generation and activation of a stress kinase, JNK, by PM2.5 were reduced by 2-IPMA. Moreover, 2-IPMA inhibited proinflammatory cytokine production, i.e., IL-6 and TNF-α, induced by PM2.5 in RPE cells. Taken together, our data suggest that 2-IPMA ameliorates PM2.5-induced inflammation by promoting primary ciliogenesis in RPE cells.
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Inflamación/metabolismo , Material Particulado/metabolismo , Epitelio Pigmentado de la Retina/metabolismo , Cilios/metabolismo , Cilios/ultraestructura , Citocinas/metabolismo , Activación Enzimática , Técnicas de Silenciamiento del Gen , Humanos , MAP Quinasa Quinasa 4/metabolismo , Malatos/metabolismo , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , RetinaRESUMEN
The maintenance of lysosomal integrity is essential for lysosome function and cell fate. Damaged lysosomes are degraded by lysosomal autophagy, lysophagy. The mechanism underlying lysophagy remains largely unknown; this study aimed to contribute to the understanding of this topic. A cell-based screening system was used to identify novel lysophagy modulators. Triamterene (6-phenylpteridine-2,4,7-triamine) was identified as one of the most potent lysophagy inducers from the screening process. We found that triamterene causes lysosomal rupture without affecting other cellular organelles and increases autophagy flux in HepG2 cells. Damaged lysosomes in triamterene-treated cells were removed by autophagy-mediated pathway, which was inhibited by depletion of the autophagy regulator, ATG5 or SQSTM1. In addition, treatment of triamterene decreased the integrity of lysosome and cell viability, which were rescued by removing the triamterene treatment in HepG2 cells. Hence, our data suggest that triamterene is a novel lysophagy inducer through the disruption of lysosomal integrity.
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Autofagia/efectos de los fármacos , Bloqueadores del Canal de Sodio Epitelial/farmacología , Lisosomas/efectos de los fármacos , Triantereno/farmacología , Autofagia/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células HeLa , Células Hep G2 , Humanos , Lisosomas/metabolismoRESUMEN
Peroxisomes play an essential role in cellular homeostasis by regulating lipid metabolism and the conversion of reactive oxygen species (ROS). Several peroxisomal proteins, known as peroxins (PEXs), control peroxisome biogenesis and degradation. Various mutations in the PEX genes are genetic causes for the development of inheritable peroxisomal-biogenesis disorders, such as Zellweger syndrome. Among the peroxins, PEX1 defects are the most common mutations in Zellweger syndrome. PEX1 is an AAA-ATPase that regulates the recycling of PEX5, which is essential for importing peroxisome matrix proteins. However, the post-transcriptional regulation of PEX1 is largely unknown. Here, we showed that heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) controls PEX1 expression. In addition, we found that depletion of HNRNPA1 induces autophagic degradation of peroxisome, which is blocked in ATG5-knockout cells. In addition, depletion of HNRNPA1 increased peroxisomal ROS levels. Inhibition of the generation of peroxisomal ROS by treatment with NAC significantly suppressed pexophagy in HNRNPA1-deficient cells. Taken together, our results suggest that depletion of HNRNPA1 increases peroxisomal ROS and pexophagy by downregulating PEX1 expression.
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ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Ribonucleoproteína Nuclear Heterogénea A1/metabolismo , Macroautofagia/fisiología , Proteínas de la Membrana/metabolismo , Peroxisomas/metabolismo , ATPasas Asociadas con Actividades Celulares Diversas/genética , Proteína 5 Relacionada con la Autofagia/antagonistas & inhibidores , Proteína 5 Relacionada con la Autofagia/genética , Proteína 5 Relacionada con la Autofagia/metabolismo , Células Cultivadas , Regulación hacia Abajo , Técnicas de Inactivación de Genes , Células HCT116 , Células HeLa , Ribonucleoproteína Nuclear Heterogénea A1/deficiencia , Ribonucleoproteína Nuclear Heterogénea A1/genética , Humanos , Macroautofagia/genética , Proteínas de la Membrana/genética , Procesamiento Postranscripcional del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Síndrome de Zellweger/genética , Síndrome de Zellweger/metabolismoRESUMEN
Arsenic is reportedly a biphasic inorganic compound for its toxicity and anticancer effects in humans. Recent studies have shown that certain arsenic compounds including arsenic hexoxide (AS4O6; hereafter, AS6) induce programmed cell death and cell cycle arrest in human cancer cells and murine cancer models. However, the mechanisms by which AS6 suppresses cancer cells are incompletely understood. In this study, we report the mechanisms of AS6 through transcriptome analyses. In particular, the cytotoxicity and global gene expression regulation by AS6 were compared in human normal and cancer breast epithelial cells. Using RNA-sequencing and bioinformatics analyses, differentially expressed genes in significantly affected biological pathways in these cell types were validated by real-time quantitative polymerase chain reaction and immunoblotting assays. Our data show markedly differential effects of AS6 on cytotoxicity and gene expression in human mammary epithelial normal cells (HUMEC) and Michigan Cancer Foundation 7 (MCF7), a human mammary epithelial cancer cell line. AS6 selectively arrests cell growth and induces cell death in MCF7 cells without affecting the growth of HUMEC in a dose-dependent manner. AS6 alters the transcription of a large number of genes in MCF7 cells, but much fewer genes in HUMEC. Importantly, we found that the cell proliferation, cell cycle, and DNA repair pathways are significantly suppressed whereas cellular stress response and apoptotic pathways increase in AS6-treated MCF7 cells. Together, we provide the first evidence of differential effects of AS6 on normal and cancerous breast epithelial cells, suggesting that AS6 at moderate concentrations induces cell cycle arrest and apoptosis through modulating genome-wide gene expression, leading to compromised DNA repair and increased genome instability selectively in human breast cancer cells.
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Trióxido de Arsénico/toxicidad , Células MCF-7/efectos de los fármacos , Glándulas Mamarias Humanas/efectos de los fármacos , Apoptosis/efectos de los fármacos , Arsénico/metabolismo , Trióxido de Arsénico/metabolismo , Trióxido de Arsénico/farmacología , Arsenicales/farmacología , Neoplasias de la Mama/genética , Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Glándulas Mamarias Humanas/metabolismo , Cultivo Primario de Células , Células Tumorales CultivadasRESUMEN
In this report, we present a process for the fabrication and tapering of a silicon (Si) nanopillar (NP) array on a large Si surface area wafer (2-inch diameter) to provide enhanced light harvesting for Si solar cell application. From our N,N-dimethyl-formamide (DMF) solvent-controlled spin-coating method, silica nanosphere (SNS in 310 nm diameter) coating on the Si surface was demonstrated successfully with improved monolayer coverage (>95%) and uniformity. After combining this method with a reactive ion etching (RIE) technique, a high-density Si NP array was produced, and we revealed that controlled tapering of Si NPs could be achieved after introducing a two-step RIE process using (1) CHF3/Ar gases for SNS selective etching over Si and (2) Cl2 gas for Si vertical etching. From our experimental and computational study, we show that an effectively tapered Si NP (i.e., an Si nanotip (NT)) structure could offer a highly effective omnidirectional and broadband antireflection effect for high-efficiency Si solar cell application.
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As a dynamic organelle, mitochondria continuously fuse and divide with adjacent mitochondria. Imbalance in mitochondria dynamics leads to their dysfunction, which implicated in neurodegenerative diseases. However, how mitochondria alteration and glucose defect contribute to pathogenesis of Alzheimer's disease (AD) is still largely unknown. Dynamin-related protein 1 (Drp1) is an essential regulator for mitochondria fission. Among various posttranslational modifications, O-GlcNAcylation plays a role as a sensor for nutrient and oxidative stress. In this study, we identified that Drp1 is regulated by O-GlcNAcylation in AD models. Treatment of Aß as well as PugNAc resulted in mitochondrial fragmentation in neuronal cells. Moreover, we found that AD mice brain exhibits an upregulated Drp1 O-GlcNAcylation. However, depletion of OGT inhibited Drp1 O-GlcNAcylation in Aß-treated cells. In addition, overexpression of O-GlcNAc defective Drp1 mutant (T585A and T586A) decreased Drp1 O-GlcNAcylation and Aß-induced mitochondria fragmentation. Taken together, these finding suggest that Aß regulates mitochondrial fission by increasing O-GlcNAcylation of Drp1.
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Péptidos beta-Amiloides/metabolismo , Dinaminas/metabolismo , Dinámicas Mitocondriales , Neuronas/metabolismo , Animales , Células Cultivadas , Glicosilación , Humanos , Ratones TransgénicosRESUMEN
The melanosome is a specialized membrane-bound organelle that is involved in melanin synthesis, storage, and transportation. In contrast to melanosome biogenesis, the processes underlying melanosome degradation remain largely unknown. Autophagy is a process that promotes degradation of intracellular components' cooperative process between autophagosomes and lysosomes, and its role for process of melanosome degradation remains unclear. Here, we assessed the regulation of autophagy and its contributions to depigmentation associated with Melasolv (3,4,5-trimethoxycinnamate thymol ester). B16F1 cells-treated with Melasolv suppressed the α-MSH-stimulated increase of melanin content and resulted in the activation of autophagy. However, introduction of bafilomycin A1 strongly suppressed melanosome degradation in Melasolv-treated cells. Furthermore, inhibition of autophagy by ATG5 resulted in significant suppression of Melasolv-mediated depigmentation in α-MSH-treated cells. Taken together, our results suggest that treatment with Melasolv inhibits skin pigmentation by promoting melanosome degradation via autophagy activation.