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BACKGROUND: The Coronavirus 2019 disease (COVID-19) caused drastic changes in people's lifestyle that affected TMD characteristics through its physical and psychological influences. The aim of this study was to define the clinical and psychological characteristics of a large group of well-defined TMD patients and seek their differences between before and during the COVID-19 pandemic to establish points of care to be emphasized in the post-pandemic era. METHODS: TMD patients diagnosed by the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) aged ≥ 18 were analyzed. Samples between September, 2017 to July, 2019 (n = 455) and March, 2021 to June, 2022 (n = 338) were collected to represent before and during COVID-19, respectively. The Graded Chronic Pain Scale (GCPS) and Symptom Checklist-90-Revision (SCL-90-R) were used to evaluate disability levels and psychological status. Clinical indices were compared between COVID periods and factors related to higher pain levels were investigated according to pandemic period. RESULTS: More patients reported pain on palpation of the masticatory muscles during the pandemic (p = 0.021) while the number decreased for neck muscles (p = 0.001) and TMJ (p < 0.001) areas. Patients reporting nocturnal bruxism (23.3-29.6%) and clenching (45.1-54.7%) significantly increased during the pandemic. TMD patients with pain without disability were more common during the pandemic regardless of pain intensity (p < 0.001). The number of patients expressing interference in daily activities decreased drastically during COVID-19 regardless of disability level (p < 0.001). Factors associated with higher than moderate pain intensity (CPI ≥ 50) were insomnia (odds ratio [OR] = 1.603, p = 0.047) and somatization (OR = 1.082, p < 0.001) before the pandemic. During the pandemic, age (OR = 1.024, p = 0.007), somatization (OR = 1.070, p = 0.006), and paranoid ideation (OR = 1.117, p = 0.003) were significantly associated with higher pain intensity. CONCLUSIONS: The results of our study underline the importance of evaluating psychological profiles of TMD patients, especially somatization, paranoid ideation and psychoticism, in exceptional situations that may cause a change in individual mental status. This will lead to a better understanding of the individual TMD patient and help in planning personalized treatment strategies that will assist the patient in adjusting to changes occurring in special environments such as the COVID-19 pandemic.
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COVID-19 , Dolor Crónico , Trastornos de la Articulación Temporomandibular , Humanos , Pandemias , Estilo de VidaRESUMEN
Lysophosphatidic acid (LPA), a bioactive lipid produced extracellularly by autotaxin (ATX), has been known to induce various pathophysiological events, including cancer cell invasion and metastasis. Discoidin domain receptor 2 (DDR2) expression is upregulated in ovarian cancer tissues, and is closely associated with poor clinical outcomes in ovarian cancer patients. In the present study, we determined a critical role and signaling cascade for the expression of DDR2 in LPA-induced ovarian cancer cell invasion. We also found ectopic expression of ATX or stimulation of ovarian cancer cells with LPA-induced DDR2 expression. However, the silencing of DDR2 expression significantly inhibited ATX- and LPA-induced ovarian cancer cell invasion. In addition, treatment of the cells with pharmacological inhibitors of phosphoinositide 3-kinase (PI3K), Akt, and mTOR abrogated LPA-induced DDR2 expression. Moreover, we observed that HIF-1α, located downstream of the mTOR, is implicated in LPA-induced DDR2 expression and ovarian cancer cell invasion. Finally, we provide evidence that LPA-induced HIF-1α expression mediates Twist1 expression to upregulate DDR2 expression. Collectively, the present study demonstrates that ATX, and thereby LPA, induces DDR2 expression through the activation of the PI3K/Akt/mTOR/HIF-1α/Twist1 signaling axes, aggravating ovarian cancer cell invasion.
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Receptor con Dominio Discoidina 2/metabolismo , Lisofosfolípidos/farmacología , Neoplasias Ováricas/inducido químicamente , Neoplasias Ováricas/metabolismo , Línea Celular Tumoral , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Invasividad Neoplásica/patología , Neoplasias Ováricas/patología , Fosfatidilinositol 3-Quinasa/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Background: Colistin (polymyxin E) is an important constituent of the polymyxin class of cationic polypeptide antibiotics. Intrarenal oxidative stress can contribute to colistin-induced nephrotoxicity. Nicotinamide adenine dinucleotide 3-phosphate oxidases (Noxs) are important sources of reactive oxygen species. Among the various types of Noxs, Nox4 is predominantly expressed in the kidney. Objectives: We investigated the role of Nox4 and benefit of Nox4 inhibition in colistin-induced acute kidney injury using in vivo and in vitro models. Methods: Human proximal tubular epithelial (HK-2) cells were treated with colistin with or without NOX4 knockdown, or GKT137831 (most specific Nox1/4 inhibitor). Effects of Nox4 inhibition on colistin-induced acute kidney injury model in Sprague-Dawley rats were examined. Results: Nox4 expression in HK-2 cells significantly increased following colistin exposure. SB4315432 (transforming growth factor-ß1 receptor I inhibitor) significantly inhibited Nox4 expression in HK-2 cells. Knockdown of NOX4 transcription reduced reactive oxygen species production, lowered the levels of pro-inflammatory markers (notably mitogen-activated protein kinases) implicated in colistin-induced nephrotoxicity and attenuated apoptosis by altering Bax and caspase 3/7 activity. Pretreatment with GKT137831 replicated these effects mediated by downregulation of mitogen-activated protein kinase activities. In a rat colistin-induced acute kidney injury model, administration of GKT137831 resulted in attenuated colistin-induced acute kidney injury as indicated by attenuated impairment of glomerulus function, preserved renal structures, reduced expression of 8-hydroxyguanosine and fewer apoptotic cells. Conclusions: Collectively, these findings identify Nox4 as a key source of reactive oxygen species responsible for kidney injury in colistin-induced nephrotoxicity and highlight a novel potential way to treat drug-related nephrotoxicity.
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Lesión Renal Aguda/inducido químicamente , Antibacterianos/efectos adversos , Colistina/efectos adversos , NADPH Oxidasa 4/metabolismo , Estrés Oxidativo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Línea Celular , Modelos Animales de Enfermedad , Células Epiteliales/efectos de los fármacos , Células Epiteliales/fisiología , Humanos , Modelos Biológicos , Ratas Sprague-DawleyRESUMEN
Recent studies revealed that Tonicity-responsive enhancer binding protein (TonEBP) directly regulates the transcription of aldose reductase (AR), which catalyzes the first step of the polyol pathway of glucose metabolism. Activation of protein kinase C δ (PKCδ) is dependent on AR and it has been linked to diabetic complications. However, whether TonEBP affects expressions of AR and PKCδ in diabetic retinopathy was not clearly shown. In this study, we used TonEBP heterozygote mice to study the role of TonEBP in streptozotocin (STZ)-induced diabetic retinopathy. We performed immunofluorescence staining and found that retinal expressions of AR and PKCδ were significantly reduced in the heterozygotes compared to wild type littermates, particularly in ganglion cell layer. To examine further the effect of TonEBP reduction in retinal tissues, we performed intravitreal injection of TonEBP siRNA and confirmed the decrease in AR and PKCδ levels. In addition, we found that a proapoptotic factor, Bax level was reduced and a survival factor, Bcl2 level was increased after injection of TonEBP siRNA, indicating that TonEBP mediates apoptotic cell death. In parallel, TonEBP siRNA was applied to the in vitro human retinal pigment epithelial (ARPE-19) cells cultured in high glucose media. We have consistently found the decrease in AR and PKCδ levels and changes in apoptotic factors for survival. Together, these results clearly demonstrated that hyperglycemia-induced TonEBP plays a crucial role in increasing AR and PKCδ levels and leading to apoptotic death. Our findings suggest that TonEBP reduction is an effective therapeutic strategy for diabetic retinopathy.
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Aldehído Reductasa/metabolismo , Retinopatía Diabética/enzimología , Modelos Animales de Enfermedad , Proteína Quinasa C/metabolismo , Factores de Transcripción/fisiología , Animales , Apoptosis , Western Blotting , Células Cultivadas , Diabetes Mellitus Experimental/enzimología , Retinopatía Diabética/patología , Retinopatía Diabética/prevención & control , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción NFATC/fisiología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Interferente Pequeño/genética , Retina/enzimología , Células Ganglionares de la Retina/enzimología , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Rasrelated protein 25 (Rab25) is a member of small GTPase and is implicated in cancer cell progression of various types of cancer. Growing evidence suggests the contextdependent role of Rab25 in cancer invasiveness. Claudin7 is a tight junction protein and has been known to suppress cancer cell invasion. Although Rab25 was reported to repress cancer aggressiveness through recycling ß1 integrin to the plasma membrane, the detailed underlying mechanism remains to be elucidated. The present study identified the critical role of claudin7 in Rab25induced suppression of colon cancer invasion. 3D Matrigel system and modified Boyden chamber analysis showed that enforced expression of Rab25 attenuated colon cancer cell invasion. In addition, Rab25 inactivated epidermal growth factor receptor (EGFR) and increased Ecadherin expression. Unexpectedly, it was observed that Rab25 induces claudin7 expression through protein stabilization. In addition, ectopic claudin7 expression reduced EGFR activity and Snail expression as well as colon cancer cell invasion. However, silencing of claudin7 expression reversed the tumor suppressive role of Rab25, thereby increasing colon cancer cell invasiveness. Collectively, the present data indicated that Rab25 inactivates EGFR and colon cancer cell invasion by upregulating claudin7 expression.
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Neoplasias del Colon , Receptores ErbB , Humanos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Neoplasias del Colon/genética , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Claudinas/genética , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab/metabolismo , Línea Celular TumoralRESUMEN
The degradation of mechanical properties caused by grain coarsening or the formation of brittle phases during welding reduces the longevity of products. Here, we report advances in the weld quality of ultra-high strength steels by utilizing Nb and Cr instead of Ni. Sole addition of Cr, as an alternative to Ni, has limitations in developing fine weld microstructure, while it is revealed that the coupling effects of Nb and Cr additions make a finer interlocking weld microstructures with a higher fraction of retained austenite due to the decrease in austenite to acicular ferrite and bainite transformation temperature and carbon activity. As a result, an alloying design with Nb and Cr creates ultrastrong and ductile steel welds with enhanced tensile properties, impact toughness, and fatigue strength, at 45% lower material costs and lower environmental impact by removing Ni.
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Lactobionic acid (LBA) is a specialty organic acid that is widely employed in the food, cosmetic, and pharmaceutical industries. In the present study, we screened new LBA-producing bacteria from the soil of a poultry farm. Among the 700 bacterial colonies, five that exhibited LBA-producing ability were successfully isolated. Phylogenetic analysis based on 16 S rRNA sequences identified strain 2-15 as an Acinetobacter sp., strains 3-13 and 3-15 as Pseudomonas spp., and strains 7-7 and 7-8 as Psychrobacter spp. The LBA-producing abilities of the five strains were compared in flask culture, whereupon Psychrobacter sp. 7-8 showed the highest LBA titer (203.7 g/L), LBA yield from lactose (97.3%), and LBA productivity (2.83 g/L/h). To our best knowledge, this is the first study showing that Acinetobacter and Psychrobacter spp. can produce LBA from lactose. Our results would help broaden the spectrum of workhorse bacteria available for the industrially important microbial production of LBA. In addition, we improved the LBA-production ability of the three isolated bacteria, namely Acinetobacter sp. 2-15, Pseudomonas spp. strains 3-13 and 3-15, by heterologously expressing quinoprotein glucose dehydrogenase from Pseudomonas taetrolens. In particular, the LBA-production ability of the recombinant Pseudomonas sp. 3-13 were highly improved that the LBA titer and productivity were 19.2- (205.6 vs. 10.7 g/L, respectively) and 17.8-fold (1.07 vs. 0.06 g/L/h, respectively) higher, respectively, than those of the wild-type strain. These values were almost identical to those of the wild-type Psychrobacter sp. 7-8, which showed the highest LBA productivity among the five isolated strains. This result demonstrated that the expression of lactose-oxidizing enzyme in LBA-producing microorganisms was highly effective to enhance their LBA-production ability. Our study presents a practical method to screen for efficient LBA-producing microorganisms and to improve their production ability by genetic engineering for industrial LBA production.
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Glucosa 1-Deshidrogenasa , Pseudomonas , Disacáridos , Filogenia , Pseudomonas/genéticaRESUMEN
Rab coupling protein (RCP) has been known to induce cancer invasion and metastasis, and STAT3 is one of major oncogenic factors. In the present study, we identify the critical role of STAT3 in RCP-induced cancer cell invasion. Immunohistochemical data of ovarian cancer tissues presented that levels of RCP expression are closely correlated with those of phospho-STAT3 (p-STAT3). In addition, ovarian cancer patients with high expression of both RCP and p-STAT3 had significantly lower progress-free and overall survival rates compared to those with low either RCP or p-STAT3 expression. Mechanistically, RCP induced STAT3 phosphorylation in both ovarian and breast cancer cells. Silencing or pharmacological inhibition of STAT3 significantly inhibited RCP-induced cancer cell invasion. In addition, we provide evidence that the ß1 integrin/EGFR axis is important for RCP-induced STAT3 phosphorylation. Furthermore, STAT3 activated NF-κB for Slug expression that in turn upregulated MT1-MMP expression for cancer cell invasion. Collectively, our present data demonstrate that STAT3 is located downstream of the ß1 integrin/EGFR axis and induces Slug and MT1-MMP expression for cancer cell invasion.
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FN-kappa B , Neoplasias Ováricas , Línea Celular Tumoral , Receptores ErbB/metabolismo , Femenino , Humanos , Integrina beta1/metabolismo , Metaloproteinasa 14 de la Matriz/metabolismo , FN-kappa B/metabolismo , Invasividad Neoplásica , Neoplasias Ováricas/metabolismo , Factor de Transcripción STAT3/metabolismo , Factores de Transcripción de la Familia SnailRESUMEN
Cancer-associated fibroblasts (CAFs) are key structural components of the tumor microenvironment and are closely associated with tumor invasion and metastasis. Lysophosphatidic acid (LPA) is a biolipid produced extracellularly and involved in tumorigenesis and metastasis. LPA has recently been implicated in the education and transdifferentiation of normal fibroblasts (NFs) into CAFs. However, little is known about the effects of LPA on CAFs and their participation in cancer cell invasion. In the present study, we identified a critical role of LPA-induced amphiregulin (AREG) secreted from CAFs in cancer invasiveness. CAFs secrete higher amounts of AREG than NFs, and LPA induces AREG expression in CAFs to augment their invasiveness. Strikingly, knocking out the AREG gene in CAFs attenuates cancer invasiveness and metastasis. Mechanistically, LPA induces Yes-associated protein (YAP) activation and Zinc finger E-box binding homeobox 1 (Zeb1) expression through the LPAR1 and LPAR3/Gi/Rho signaling axes, leading to AREG expression. Furthermore, we provide evidence that metformin, a biguanide derivative, significantly inhibits LPA-induced AREG expression in CAFs to attenuate cancer cell invasiveness. Collectively, the present data show that LPA induces AREG expression through YAP and Zeb1 in CAFs to promote cancer cell invasiveness, with the process being inhibited by metformin, providing potential biomarkers and therapeutic avenues to interdict cancer cell invasion.
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Rab coupling protein (RCP) is upregulated in head and neck squamous cell carcinoma (HNSCC) and is correlated with the progression and survival of patients. However, the role of RCP in one of the aggressive types of HNSCC, oral squamous cell carcinoma (OSCC), remains elusive. In the present study, we identified the important role of Zeb1 in RCP-induced OSCC epithelial-to-mesenchymal transition (EMT) and invasion. RCP induces Zeb1 expression, and silencing Zeb1 expression significantly inhibits RCP-induced OSCC invasion. In addition, Zeb1 upregulates MT1-MMP expression to promote OSCC EMT and invasion. Furthermore, we observed that the ß1 integrin/EGFR/ß-catenin signaling cascade mediates RCP-induced Zeb1 expression to promote OSCC invasion. Notably, we provide evidence that resveratrol (REV) strongly inhibits RCP-induced Zeb1 expression through blocking ß1 integrin endosome recycling and EGFR activation, leading to suppression of RCP-induced OSCC invasion, demonstrating the important role of RCP in OSCC invasion and its reversion by REV. Collectively, the present study provides evidence for the first time that RCP aggravates OSCC invasion through increasing Zeb1 expression and subsequently upregulating MT1-MMP expression and that this process is reversed by REV, providing novel biomarkers and indicating the therapeutic potential of REV in OSCC.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Transición Epitelial-Mesenquimal , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Proteínas de la Membrana/metabolismo , Resveratrol/farmacología , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/efectos de los fármacos , Receptores ErbB/metabolismo , Humanos , Integrina beta1/metabolismo , Metaloproteinasa 14 de la Matriz/metabolismo , Modelos Biológicos , Invasividad Neoplásica , Transducción de Señal/efectos de los fármacos , Factor de Transcripción 4/metabolismoRESUMEN
Lysophosphatidic acid (LPA) has been known to induce epithelial-mesenchymal transition (EMT) to stimulate cancer cell invasion, and resveratrol (3,5,4'-trans-trihydroxystilbene; REV) suppresses the invasion and metastasis of various cancers. The current study aimed to identify the underlying mechanism by which LPA aggravates breast cancer cell invasion and the reversal of this phenomenon. Immunoblotting and quantitative RT-PCR analysis revealed that LPA induces amphiregulin (AREG) expression. Silencing of Y-box binding protein 1 (YB-1) or enhancer of zeste homolog 2 (EZH2) expression efficiently inhibited LPA-induced AREG expression. In addition, transfection of the cells with YB-1 siRNA abrogated LPA-induced EZH2 and AREG expression, leading to attenuation of breast cancer cell invasion. Furthermore, we observed that both REV and 5-fluorouracil (5-Fu) significantly reduce LPA-induced YB-1 phosphorylation and subsequent breast cancer invasion. Importantly, combined treatment of REV with 5-Fu showed more significant inhibition of LPA-induced breast cancer invasion compared to single treatment. Therefore, our data demonstrate that the YB-1/EZH2 signaling axis mediates LPA-induced AREG expression and breast cancer cell invasion and its inhibition by REV and 5-Fu, providing potential therapeutic targets and inhibition of breast cancer.
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Antimetabolitos Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Lisofosfolípidos/metabolismo , Transducción de Señal/efectos de los fármacos , Anfirregulina/metabolismo , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , Invasividad Neoplásica/patología , Fosforilación/efectos de los fármacos , ARN Interferente Pequeño/metabolismo , Resveratrol/farmacología , Resveratrol/uso terapéutico , Proteína 1 de Unión a la Caja Y/antagonistas & inhibidores , Proteína 1 de Unión a la Caja Y/genética , Proteína 1 de Unión a la Caja Y/metabolismoRESUMEN
Hypoxia is an important cause of acute kidney injury (AKI) in various conditions because kidneys are one of the most susceptible organs to hypoxia. In this study, we investigated whether nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidase 4 (Nox4) plays a role in hypoxia induced AKI in a cellular and animal model. Expression of Nox4 in cultured human renal proximal tubular epithelial cells (HK-2) was significantly increased by hypoxic stimulation. TGF-ß1 was endogenously secreted by hypoxic HK-2 cells. SB4315432 (a TGF-ß1 receptor I inhibitor) significantly inhibited Nox4 expression in HK-2 cells through the Smad-dependent cell signaling pathway. Silencing of Nox4 using Nox4 siRNA and pharmacologic inhibition with GKT137831 (a specific Nox1/4 inhibitor) reduced the production of ROS and attenuated the apoptotic pathway. In addition, knockdown of Nox4 increased cell survival in hypoxic HK-2 cells and pretreatment with GKT137831 reproduce these results. This study demonstrates that hypoxia induces HK-2 cell apoptosis through a signaling pathway involving TGF-ß1 via Smad pathway induction of Nox4-dependent ROS generation. In an ischemia/reperfusion rat model, pretreatment of GKT137831 attenuated ischemia/reperfusion induced acute kidney injury as indicated by preserved kidney function, attenuated renal structural damage and reduced apoptotic cells. Therapies targeting Nox4 may be effective against hypoxia-induced AKI.
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Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , NADPH Oxidasa 4/metabolismo , Transducción de Señal , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Lesión Renal Aguda/fisiopatología , Animales , Apoptosis/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Pruebas de Función Renal , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Modelos Biológicos , NADPH Oxidasa 4/antagonistas & inhibidores , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Pirazoles/farmacología , Pirazolonas , Piridinas/farmacología , Piridonas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Factor de Crecimiento Transformador beta1/farmacologíaRESUMEN
The small GTP-binding protein Rab25 is associated with tumor formation and progression. However, recent studies have shown discordant effects of Rab25 on cancer cell progression depending on cell lineage. In the present study, we elucidate the underlying mechanisms by which Rab25 induces cellular invasion. We demonstrate that Rab25 increases ß1 integrin levels and subsequent activation of EGFR and upregulation of VEGF-A expression, leading to increased Snail expression, epithelial-to-mesenchymal transition and cancer cell invasiveness. Strikingly, we identify that Snail mediates Rab25-induced cancer cell invasiveness through fascin expression and that ectopic expression of Rab25 aggravates metastasis of ovarian cancer cells to the lung. We thus demonstrate a novel role of a ß1 integrin/EGFR/VEGF-A/Snail signaling cascade in Rab25-induced cancer cell aggressiveness through induction of fascin expression, thus providing novel biomarkers and potential therapeutic targets for Rab25-expressing cancer cells.
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Neoplasias de la Mama/patología , Integrina beta1/metabolismo , Neoplasias Ováricas/patología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteínas de Unión al GTP rab/metabolismo , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Ratones Desnudos , Proteínas de Microfilamentos/metabolismo , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/mortalidad , Transducción de Señal , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas de Unión al GTP rab/genéticaRESUMEN
After online publication of this article, the authors noticed an error in the Figure 4c and Figure 5c section.
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Unfortunately, there are some errors in Fig. 1b and Fig. 3a of the article.
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Contrast-induced acute kidney injury (CIAKI) is a leading cause of acute kidney injury following radiographic procedures. Intrarenal oxidative stress plays a critical role in CIAKI. Nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidases (Noxs) are important sources of reactive oxygen species (ROS). Among the various types of Noxs, Nox4 is expressed predominantly in the kidney in rodents. Here, we evaluated the role of Nox4 and benefit of Nox4 inhibition on CIAKI using in vivo and in vitro models. HK-2 cells were treated with iohexol, with or without Nox4 knockdown, or the most specific Nox1/4 inhibitor (GKT137831). Effects of Nox4 inhibition on CIAKI mice were examined. Expression of Nox4 in HK-2 cells was significantly increased following iohexol exposure. Silencing of Nox4 rescued the production of ROS, downregulated pro-inflammatory markers (particularly phospho-p38) implicated in CIAKI, and reduced Bax and caspase 3/7 activity, which resulted in increased cellular survival in iohexol-treated HK-2 cells. Pretreatment with GKT137831 replicated these effects by decreasing levels of phospho-p38. In a CIAKI mouse model, even though the improvement of plasma blood urea nitrogen was unclear, pretreatment with GKT137831 resulted in preserved structure, reduced expression of 8-hydroxy-2'-deoxyguanosine (8OHdG) and kidney injury molecule-1 (KIM-1), and reduced number of TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive cells. These results suggest Nox4 as a key source of reactive oxygen species responsible for CIAKI and provide a novel potential option for prevention of CIAKI.
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Lesión Renal Aguda/metabolismo , Medios de Contraste/efectos adversos , NADPH Oxidasa 4/metabolismo , Estrés Oxidativo , Lesión Renal Aguda/inducido químicamente , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Activación Enzimática , Silenciador del Gen , Humanos , Yohexol/farmacología , Túbulos Renales Proximales/citología , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , NADPH Oxidasa 4/genética , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Superóxidos/metabolismoRESUMEN
Stress hormone norepinephrine (NE) has been associated with acquisition of cancer progression, and naturally occurring phytoalexin resveratrol (REV) has been known to suppress cancer growth and progression. In the present study, we determine the effect of REV on NE-induced ovarian cancer invasiveness. Pretreatment of REV significantly inhibited NE-induced ovarian cancer cell epithelial-to-mesenchymal transition with concomitant recovery of E-cadherin expression. In addition, our data showed that REV downregulates NE-induced human telomerase reverse transcriptase (hTERT) expression through inhibiting Src phosphorylation and HIF-1α expression. Further, REV reduced NE-induced Slug expression and subsequent ovarian cancer invasion. More importantly, combined treatment of REV with a pharmacological inhibitor of beta adrenergic receptor significantly attenuated NE-induced ovarian cancer invasion compared to single treatment. Therefore, we demonstrate interference of a Src and HIF-1α/hTERT/Slug signaling cascade by REV, providing potential therapeutic targets and inhibition of ovarian cancer.
Asunto(s)
Antineoplásicos/farmacología , Movimiento Celular/efectos de los fármacos , Norepinefrina/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Estilbenos/farmacología , Telomerasa/metabolismo , Antagonistas Adrenérgicos beta/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Invasividad Neoplásica , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Fosforilación , Resveratrol , Transducción de Señal/efectos de los fármacos , Factores de Transcripción de la Familia Snail/metabolismo , Telomerasa/genética , Transfección , Familia-src Quinasas/metabolismoRESUMEN
In the present study, we analyzed the central metabolic pathway of an Ashbya gossypii wild type strain and a riboflavin over-producing mutant strain developed in a previous study in order to characterize the riboflavin over-production pathway. (13)C-Metabolic flux analysis ((13)C-MFA) was carried out in both strains, and the resulting data were fit to a steady-state flux isotopomer model using OpenFLUX. Flux to pentose-5-phosphate (P5P) via the pentose phosphate pathway (PPP) was 9% higher in the mutant strain compared to the wild type strain. The flux from purine synthesis to riboflavin in the mutant strain was 1.6%, while that of the wild type strain was only 0.1%, a 16-fold difference. In addition, the flux from the cytoplasmic pyruvate pool to the extracellular metabolites, pyruvate, lactate, and alanine, was 2-fold higher in the mutant strain compared to the wild type strain. This result demonstrates that increased guanosine triphosphate (GTP) flux through the PPP and purine synthesis pathway (PSP) increased riboflavin production in the mutant strain. The present study provides the first insight into metabolic flux through the central carbon pathway in A. gossypii and sets the foundation for development of a quantitative and functional model of the A. gossypii metabolic network.
Asunto(s)
Eremothecium/genética , Eremothecium/metabolismo , Análisis de Flujos Metabólicos , Mutación/genética , Riboflavina/biosíntesis , Carbono/metabolismo , Purinas/biosíntesisRESUMEN
The effect of dietary lipid on the fatty acid composition of muscle, testis and ovary of cultured sweet smelt, Plecoglossus altivelis, was investigated and compared with that of wild sweet smelt. Cultured fish were fed three different diets for 12 weeks: a control diet rich in docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3) (CO group); a diet deficient in DHA and EPA (DP group); and a diet rich in alpha-linolenic acid (ALA, 18:3n-3), but deficient in DHA and EPA (LP group). The fatty acid composition of muscle and gonad lipids was related with dietary fatty acids. Despite the difference in DHA and EPA content in the diets, muscles and gonads, respectively, contained almost equal levels of DHA and EPA in each CO and DP group. However, the muscle and gonad of the LP group showed a lower level of DHA than other groups, due to having the highest level of ALA. In the wild fish muscle, the DHA content was similar to that of CO and DP groups, but the EPA content showed the highest level in all groups. There was no difference in the muscle fatty acid proportions between male and female. On the other hand, the testes of cultured and wild fish were rich in DHA, EPA, docosapentaenoic acid and arachidonic acid, while ovaries were rich in oleic, palmitoleic, linoleic acids and ALA. Moreover, of all the groups, the fish fatty acid composition of the LP group was closest to that of wild fish. These results indicate that in the sweet smelt, tissue n-3 polyunsaturated fatty acids (PUFAs) greater than C20 can be synthesized from dietary precursors and special fatty acids are preferentially accumulated to the testis or ovary, respectively, to play different physiological functions.
Asunto(s)
Animales Domésticos/metabolismo , Animales Salvajes/metabolismo , Ácidos Grasos/metabolismo , Peces/metabolismo , Ovario/metabolismo , Testículo/metabolismo , Animales , Constitución Corporal , Peso Corporal/efectos de los fármacos , Grasas de la Dieta/farmacología , Femenino , Masculino , Músculos/efectos de los fármacos , Músculos/metabolismo , Ovario/efectos de los fármacos , Testículo/efectos de los fármacosRESUMEN
Spontaneous bloody nipple discharge from a single duct is a significant clinical problem. When performing preoperative marking of the discharging duct, it is sometimes difficult to identify the duct owing to intermittent discharge. Precise preoperative marking of the discharging duct and intraductal lesions is very important to avoid unnecessary wide excision of breast tissue or failure to remove the cause of nipple discharge. We herein present a case of preoperative ultrasound-guided indigo carmine staining in a patient with no discharge on the day of surgery. When a dilated duct is visualized on ultrasound, the targeted duct can be localized using indigo carmine staining, and it is possible to perform a precise minimal volume microdochectomy.