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1.
Sci Transl Med ; 16(750): eadk9811, 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38838134

RESUMEN

Clinical evidence indicates a close association between muscle dysfunction and bone loss; however, the underlying mechanisms remain unclear. Here, we report that muscle dysfunction-related bone loss in humans with limb-girdle muscular dystrophy is associated with decreased expression of folliculin-interacting protein 1 (FNIP1) in muscle tissue. Supporting this finding, murine gain- and loss-of-function genetic models demonstrated that muscle-specific ablation of FNIP1 caused decreased bone mass, increased osteoclastic activity, and mechanical impairment that could be rescued by myofiber-specific expression of FNIP1. Myofiber-specific FNIP1 deficiency stimulated expression of nuclear translocation of transcription factor EB, thereby activating transcription of insulin-like growth factor 2 (Igf2) at a conserved promoter-binding site and subsequent IGF2 secretion. Muscle-derived IGF2 stimulated osteoclastogenesis through IGF2 receptor signaling. AAV9-mediated overexpression of IGF2 was sufficient to decrease bone volume and impair bone mechanical properties in mice. Further, we found that serum IGF2 concentration was negatively correlated with bone health in humans in the context of osteoporosis. Our findings elucidate a muscle-bone cross-talk mechanism bridging the gap between muscle dysfunction and bone loss. This cross-talk represents a potential target to treat musculoskeletal diseases and osteoporosis.


Asunto(s)
Huesos , Factor II del Crecimiento Similar a la Insulina , Animales , Femenino , Humanos , Masculino , Ratones , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Huesos/metabolismo , Factor II del Crecimiento Similar a la Insulina/metabolismo , Músculo Esquelético/metabolismo , Músculos/metabolismo , Osteoclastos/metabolismo , Osteogénesis , Transducción de Señal
2.
Sci Adv ; 10(6): eadj2752, 2024 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-38324677

RESUMEN

Exercise-induced activation of adenosine monophosphate-activated protein kinase (AMPK) and substrate phosphorylation modulate the metabolic capacity of mitochondria in skeletal muscle. However, the key effector(s) of AMPK and the regulatory mechanisms remain unclear. Here, we showed that AMPK phosphorylation of the folliculin interacting protein 1 (FNIP1) serine-220 (S220) controls mitochondrial function and muscle fuel utilization during exercise. Loss of FNIP1 in skeletal muscle resulted in increased mitochondrial content and augmented metabolic capacity, leading to enhanced exercise endurance in mice. Using skeletal muscle-specific nonphosphorylatable FNIP1 (S220A) and phosphomimic (S220D) transgenic mouse models as well as biochemical analysis in primary skeletal muscle cells, we demonstrated that exercise-induced FNIP1 (S220) phosphorylation by AMPK in muscle regulates mitochondrial electron transfer chain complex assembly, fuel utilization, and exercise performance without affecting mechanistic target of rapamycin complex 1-transcription factor EB signaling. Therefore, FNIP1 is a multifunctional AMPK effector for mitochondrial adaptation to exercise, implicating a mechanism for exercise tolerance in health and disease.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Proteínas Portadoras , Ratones , Animales , Fosforilación/fisiología , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Portadoras/metabolismo , Mitocondrias/metabolismo , Músculo Esquelético/metabolismo
3.
Nat Commun ; 14(1): 7136, 2023 11 06.
Artículo en Inglés | MEDLINE | ID: mdl-37932296

RESUMEN

Ischaemia of the heart and limbs attributable to compromised blood supply is a major cause of mortality and morbidity. The mechanisms of functional angiogenesis remain poorly understood, however. Here we show that FNIP1 plays a critical role in controlling skeletal muscle functional angiogenesis, a process pivotal for muscle revascularization during ischemia. Muscle FNIP1 expression is down-regulated by exercise. Genetic overexpression of FNIP1 in myofiber causes limited angiogenesis in mice, whereas its myofiber-specific ablation markedly promotes the formation of functional blood vessels. Interestingly, the increased muscle angiogenesis is independent of AMPK but due to enhanced macrophage recruitment in FNIP1-depleted muscles. Mechanistically, myofiber FNIP1 deficiency induces PGC-1α to activate chemokine gene transcription, thereby driving macrophage recruitment and muscle angiogenesis program. Furthermore, in a mouse hindlimb ischemia model of peripheral artery disease, the loss of myofiber FNIP1 significantly improved the recovery of blood flow. Thus, these results reveal a pivotal role of FNIP1 as a negative regulator of functional angiogenesis in muscle, offering insight into potential therapeutic strategies for ischemic diseases.


Asunto(s)
Macrófagos , Músculo Esquelético , Ratones , Animales , Ratones Noqueados , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Macrófagos/metabolismo , Modelos Animales de Enfermedad , Isquemia , Miembro Posterior/irrigación sanguínea , Neovascularización Fisiológica , Proteínas Portadoras/metabolismo
4.
Nat Cell Biol ; 25(6): 848-864, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37217599

RESUMEN

Mitochondrial proteases are emerging as key regulators of mitochondrial plasticity and acting as both protein quality surveillance and regulatory enzymes by performing highly regulated proteolytic reactions. However, it remains unclear whether the regulated mitochondrial proteolysis is mechanistically linked to cell identity switching. Here we report that cold-responsive mitochondrial proteolysis is a prerequisite for white-to-beige adipocyte cell fate programming during adipocyte thermogenic remodelling. Thermogenic stimulation selectively promotes mitochondrial proteostasis in mature white adipocytes via the mitochondrial protease LONP1. Disruption of LONP1-dependent proteolysis substantially impairs cold- or ß3 adrenergic agonist-induced white-to-beige identity switching of mature adipocytes. Mechanistically, LONP1 selectively degrades succinate dehydrogenase complex iron sulfur subunit B and ensures adequate intracellular succinate levels. This alters the histone methylation status on thermogenic genes and thereby enables adipocyte cell fate programming. Finally, augmented LONP1 expression raises succinate levels and corrects ageing-related impairments in white-to-beige adipocyte conversion and adipocyte thermogenic capacity. Together, these findings reveal that LONP1 links proteolytic surveillance to mitochondrial metabolic rewiring and directs cell identity conversion during adipocyte thermogenic remodelling.


Asunto(s)
Adipocitos , Mitocondrias , Adipocitos Marrones/metabolismo , Mitocondrias/metabolismo , Péptido Hidrolasas/metabolismo , Proteolisis , Succinatos/metabolismo , Proteínas Mitocondriales/metabolismo
5.
Sci Adv ; 8(30): eabo0340, 2022 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-35895846

RESUMEN

Mitochondrial quality in skeletal muscle is crucial for maintaining energy homeostasis during metabolic stresses. However, how muscle mitochondrial quality is controlled and its physiological impacts remain unclear. Here, we demonstrate that mitoprotease LONP1 is essential for preserving muscle mitochondrial proteostasis and systemic metabolic homeostasis. Skeletal muscle-specific deletion of Lon protease homolog, mitochondrial (LONP1) impaired mitochondrial protein turnover, leading to muscle mitochondrial proteostasis stress. A benefit of this adaptive response was the complete resistance to diet-induced obesity. These favorable metabolic phenotypes were recapitulated in mice overexpressing LONP1 substrate ΔOTC in muscle mitochondria. Mechanistically, mitochondrial proteostasis imbalance elicits an unfolded protein response (UPRmt) in muscle that acts distally to modulate adipose tissue and liver metabolism. Unexpectedly, contrary to its previously proposed role, ATF4 is dispensable for the long-range protective response of skeletal muscle. Thus, these findings reveal a pivotal role of LONP1-dependent mitochondrial proteostasis in directing muscle UPRmt to regulate systemic metabolism.

7.
J Exp Med ; 219(5)2022 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-35412553

RESUMEN

Metabolically beneficial beige adipocytes offer tremendous potential to combat metabolic diseases. The folliculin interacting protein 1 (FNIP1) is implicated in controlling cellular metabolism via AMPK and mTORC1. However, whether and how FNIP1 regulates adipocyte browning is unclear. Here, we demonstrate that FNIP1 plays a critical role in controlling adipocyte browning and systemic glucose homeostasis. Adipocyte-specific ablation of FNIP1 promotes a broad thermogenic remodeling of adipocytes, including increased UCP1 levels, high mitochondrial content, and augmented capacity for mitochondrial respiration. Mechanistically, FNIP1 binds to and promotes the activity of SERCA, a main Ca2+ pump responsible for cytosolic Ca2+ removal. Loss of FNIP1 resulted in enhanced intracellular Ca2+ signals and consequential activation of Ca2+-dependent thermogenic program in adipocytes. Furthermore, mice lacking adipocyte FNIP1 were protected against high-fat diet-induced insulin resistance and liver steatosis. Thus, these findings reveal a pivotal role of FNIP1 as a negative regulator of beige adipocyte thermogenesis and unravel an intriguing functional link between intracellular Ca2+ dynamics and adipocyte browning.


Asunto(s)
Adipocitos Beige , Calcio , Adipocitos/metabolismo , Adipocitos Beige/metabolismo , Animales , Calcio/metabolismo , Proteínas Portadoras/metabolismo , Glucosa/metabolismo , Ratones , Ratones Endogámicos C57BL , Termogénesis
8.
Nat Commun ; 13(1): 894, 2022 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-35173176

RESUMEN

Mitochondrial proteolysis is an evolutionarily conserved quality-control mechanism to maintain proper mitochondrial integrity and function. However, the physiological relevance of stress-induced impaired mitochondrial protein quality remains unclear. Here, we demonstrate that LONP1, a major mitochondrial protease resides in the matrix, plays a role in controlling mitochondrial function as well as skeletal muscle mass and strength in response to muscle disuse. In humans and mice, disuse-related muscle loss is associated with decreased mitochondrial LONP1 protein. Skeletal muscle-specific ablation of LONP1 in mice resulted in impaired mitochondrial protein turnover, leading to mitochondrial dysfunction. This caused reduced muscle fiber size and strength. Mechanistically, aberrant accumulation of mitochondrial-retained protein in muscle upon loss of LONP1 induces the activation of autophagy-lysosome degradation program of muscle loss. Overexpressing a mitochondrial-retained mutant ornithine transcarbamylase (ΔOTC), a known protein degraded by LONP1, in skeletal muscle induces mitochondrial dysfunction, autophagy activation, and cause muscle loss and weakness. Thus, these findings reveal a role of LONP1-dependent mitochondrial protein quality-control in safeguarding mitochondrial function and preserving skeletal muscle mass and strength, and unravel a link between mitochondrial protein quality and muscle mass maintenance during muscle disuse.


Asunto(s)
Proteasas ATP-Dependientes/metabolismo , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Músculo Esquelético/patología , Atrofia Muscular/patología , Proteasas ATP-Dependientes/genética , Animales , Autofagia/fisiología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Mitocondriales/genética , Fuerza Muscular/fisiología , Ornitina Carbamoiltransferasa/metabolismo , Proteolisis , Proteostasis/fisiología
9.
PLoS Genet ; 17(3): e1009488, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33780446

RESUMEN

Mitochondria are essential for maintaining skeletal muscle metabolic homeostasis during adaptive response to a myriad of physiologic or pathophysiological stresses. The mechanisms by which mitochondrial function and contractile fiber type are concordantly regulated to ensure muscle function remain poorly understood. Evidence is emerging that the Folliculin interacting protein 1 (Fnip1) is involved in skeletal muscle fiber type specification, function, and disease. In this study, Fnip1 was specifically expressed in skeletal muscle in Fnip1-transgenic (Fnip1Tg) mice. Fnip1Tg mice were crossed with Fnip1-knockout (Fnip1KO) mice to generate Fnip1TgKO mice expressing Fnip1 only in skeletal muscle but not in other tissues. Our results indicate that, in addition to the known role in type I fiber program, FNIP1 exerts control upon muscle mitochondrial oxidative program through AMPK signaling. Indeed, basal levels of FNIP1 are sufficient to inhibit AMPK but not mTORC1 activity in skeletal muscle cells. Gain-of-function and loss-of-function strategies in mice, together with assessment of primary muscle cells, demonstrated that skeletal muscle mitochondrial program is suppressed via the inhibitory actions of FNIP1 on AMPK. Surprisingly, the FNIP1 actions on type I fiber program is independent of AMPK and its downstream PGC-1α. These studies provide a vital framework for understanding the intrinsic role of FNIP1 as a crucial factor in the concerted regulation of mitochondrial function and muscle fiber type that determine muscle fitness.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Mitocondrias Musculares/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Animales , Femenino , Perfilación de la Expresión Génica , Masculino , Ratones , Ratones Transgénicos , Mitocondrias Musculares/ultraestructura , Fibras Musculares Esqueléticas/ultraestructura , Especificidad de Órganos , Oxidación-Reducción , Estrés Oxidativo
10.
Biochem Biophys Res Commun ; 537: 43-49, 2021 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-33383563

RESUMEN

Oxidative stress and endoplasmic reticulum (ER) stress are the key contributing factors for cataract progression. In our previous studies, we demonstrated that the nuclear factor erythroid 2-like-2 (Nrf-2)/heme oxygenase-1 (HO-1)/carbon monoxide (CO) axis protects lens epithelial cells (LECs) against oxidants and ER stress. In the present study, transgenic FVB/N mice overexpressing the negative dominant mutant HO-1 G143H (TgHO-1 G143H) were generated to evaluate the crosstalk among HO-1, oxidative stress and ER stress in maintaining lens transparency. Slit-lamp examination revealed that nuclear cataracts occurred at 4 months in the TgHO-1 G143H mice, which was 5 months earlier than that of the control mice. The lenses of the transgenic mice showed an accumulation of malondialdehyde and protein carbonyl with a decrease in glutathione and protein sulfhydryl levels. Elevated concentrations of ER stress biomarkers (Bip, PERK, ATF6, IRE1, CHOP, caspase-12 and caspase-3) in the lenses of the TgHO-1 G143H mice were identified by western blotting. Furthermore, we confirmed that overexpressed HO-1 G143H in LECs resulted in oxidative insult and apoptosis in vitro. All of these data suggested that HO-1 enzymatic activity loss induces early-onset nuclear cataracts by activating oxidative stress and ER stress.


Asunto(s)
Catarata/patología , Estrés del Retículo Endoplásmico , Hemo-Oxigenasa 1/metabolismo , Estrés Oxidativo , Envejecimiento/patología , Animales , Apoptosis , Biomarcadores/metabolismo , Proliferación Celular , Células Epiteliales/metabolismo , Espacio Intracelular/metabolismo , Cristalino/patología , Ratones Mutantes , Ratones Transgénicos , Especies Reactivas de Oxígeno/metabolismo
11.
J Clin Invest ; 130(9): 4710-4725, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32544095

RESUMEN

Skeletal muscle depends on the precise orchestration of contractile and metabolic gene expression programs to direct fiber-type specification and to ensure muscle performance. Exactly how such fiber type-specific patterns of gene expression are established and maintained remains unclear, however. Here, we demonstrate that histone monomethyl transferase MLL4 (KMT2D), an enhancer regulator enriched in slow myofibers, plays a critical role in controlling muscle fiber identity as well as muscle performance. Skeletal muscle-specific ablation of MLL4 in mice resulted in downregulation of the slow oxidative myofiber gene program, decreased numbers of type I myofibers, and diminished mitochondrial respiration, which caused reductions in muscle fatty acid utilization and endurance capacity during exercise. Genome-wide ChIP-Seq and mRNA-Seq analyses revealed that MLL4 directly binds to enhancers and functions as a coactivator of the myocyte enhancer factor 2 (MEF2) to activate transcription of slow oxidative myofiber genes. Importantly, we also found that the MLL4 regulatory circuit is associated with muscle fiber-type remodeling in humans. Thus, our results uncover a pivotal role for MLL4 in specifying structural and metabolic identities of myofibers that govern muscle performance. These findings provide therapeutic opportunities for enhancing muscle fitness to combat a variety of metabolic and muscular diseases.


Asunto(s)
Regulación de la Expresión Génica , N-Metiltransferasa de Histona-Lisina/metabolismo , Factores de Transcripción MEF2/metabolismo , Músculo Esquelético/metabolismo , Miofibrillas/metabolismo , Transcripción Genética , Adolescente , Animales , Niño , Femenino , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Factores de Transcripción MEF2/genética , Masculino , Ratones , Ratones Noqueados , Miofibrillas/genética , Estrés Oxidativo
12.
Cancer Biother Radiopharm ; 34(10): 666-670, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31596614

RESUMEN

Background: It is known that LINC00974 is an oncogenic long noncoding RNA in liver cancer. Results: The authors observed in this study that LINC00974 was upregulated in gastric cancer (GC) and positively correlated with CDK6. Survival analysis showed that high levels of LINC00974 and CDK6 predicted poor survival. In GC tissues, LINC00974 and CDK6 were positively correlated. In GC cells, LINC00974 overexpression led to upregulated, whereas LINC00974 siRNA silencing led to downregulated CDK6. Analysis of cell cycle progression and proliferation showed that LINC00974 and CDK6 overexpression promoted and siRNA silencing inhibited G1-S transition and cell proliferation. Conclusion: Therefore, LINC00974 upregulates CDK6 to promote cell cycle progression in GC.


Asunto(s)
Quinasa 6 Dependiente de la Ciclina/metabolismo , ARN Largo no Codificante/metabolismo , Neoplasias Gástricas/metabolismo , Adulto , Anciano , Ciclo Celular/fisiología , Línea Celular Tumoral , Proliferación Celular/fisiología , Quinasa 6 Dependiente de la Ciclina/genética , Progresión de la Enfermedad , Fase G1/fisiología , Humanos , Persona de Mediana Edad , ARN Largo no Codificante/genética , Fase S/fisiología , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Regulación hacia Arriba
13.
Proc Natl Acad Sci U S A ; 116(24): 11776-11785, 2019 06 11.
Artículo en Inglés | MEDLINE | ID: mdl-31123148

RESUMEN

The cytoplasmic coat protein complex-II (COPII) is evolutionarily conserved machinery that is essential for efficient trafficking of protein and lipid cargos. How the COPII machinery is regulated to meet the metabolic demand in response to alterations of the nutritional state remains largely unexplored, however. Here, we show that dynamic changes of COPII vesicle trafficking parallel the activation of transcription factor X-box binding protein 1 (XBP1s), a critical transcription factor in handling cellular endoplasmic reticulum (ER) stress in both live cells and mouse livers upon physiological fluctuations of nutrient availability. Using live-cell imaging approaches, we demonstrate that XBP1s is sufficient to promote COPII-dependent trafficking, mediating the nutrient stimulatory effects. Chromatin immunoprecipitation (ChIP) coupled with high-throughput DNA sequencing (ChIP-seq) and RNA-sequencing analyses reveal that nutritional signals induce dynamic XBP1s occupancy of promoters of COPII traffic-related genes, thereby driving the COPII-mediated trafficking process. Liver-specific disruption of the inositol-requiring enzyme 1α (IRE1α)-XBP1s signaling branch results in diminished COPII vesicle trafficking. Reactivation of XBP1s in mice lacking hepatic IRE1α restores COPII-mediated lipoprotein secretion and reverses the fatty liver and hypolipidemia phenotypes. Thus, our results demonstrate a previously unappreciated mechanism in the metabolic control of liver protein and lipid trafficking: The IRE1α-XBP1s axis functions as a nutrient-sensing regulatory nexus that integrates nutritional states and the COPII vesicle trafficking.


Asunto(s)
Vesículas Cubiertas por Proteínas de Revestimiento/metabolismo , Endorribonucleasas/metabolismo , Nutrientes/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transporte de Proteínas/fisiología , Transducción de Señal/fisiología , Proteína 1 de Unión a la X-Box/metabolismo , Animales , Movimiento Celular/fisiología , Inmunoprecipitación de Cromatina/métodos , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico/fisiología , Lípidos/fisiología , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Regiones Promotoras Genéticas/fisiología
14.
J Surg Res ; 226: 150-156, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29661281

RESUMEN

BACKGROUND: Uncontrolled hemorrhage (UH) remains the most common cause of death on the battlefield. This study examined the pathophysiological characteristics of UH in rats acutely exposed to high altitude. MATERIAL AND METHODS: Rats raised at sea level were randomly divided into two groups. Rats in the high-altitude group were exposed to hypobaric hypoxia in a hypobaric chamber (simulating 4000 m above sea level) for 2 d and then were performed a hemorrhagic shock protocol in the hypobaric chamber. Rats that underwent the same hemorrhage procedure at sea level were used as control. Anesthetized rats were bled to maintain their mean arterial pressure at 45 mmHg for 1 h. The distal quarter of the tail was amputated to allow free blood loss. After 1 h, the tail cut was ligated to induce hemostasis. mean arterial pressure, acid-base balance, blood loss, and survival were recorded. Rats were killed, and tissues were obtained for histological analysis. RESULTS: Rats in the high-altitude group suffered less uncontrolled blood loss, more severe acidosis (lower pH and base excess), and inferior tissue oxygen supply (lower oxygen saturation and higher arterial lactate concentration) during the hemorrhage periods compared with the control group. Survival rates were significantly lower in the high-altitude group than those in the control group (P < 0.05), which was consistent with the results of pathological tissue injury. CONCLUSIONS: In this rat model of hemorrhagic shock, acute high-altitude exposure resulted in decreased UH but more serious hemorrhagic shock injuries than that at sea level.


Asunto(s)
Altitud , Hipoxia/mortalidad , Choque Hemorrágico/mortalidad , Heridas Relacionadas con la Guerra/mortalidad , Animales , Presión Sanguínea , Modelos Animales de Enfermedad , Humanos , Hipoxia/etiología , Hipoxia/patología , Masculino , Distribución Aleatoria , Ratas , Ratas Wistar , Choque Hemorrágico/etiología , Choque Hemorrágico/patología , Tasa de Supervivencia , Heridas Relacionadas con la Guerra/complicaciones , Heridas Relacionadas con la Guerra/patología
15.
Zhongguo Fei Ai Za Zhi ; 20(12): 800-807, 2017 Dec 20.
Artículo en Chino | MEDLINE | ID: mdl-29277177

RESUMEN

BACKGROUND: It has been proven that circular RNAs (circRNAs) play an important role on the process of many types cancer and circUBAP2 was a cancer-promoting circRNA, however, the role and mechanism in lung cancer was not clear. The aim of this study is to investigate the effects of circUBAP2 on cell proliferation and invasion of human lung cancer A549 cells. METHODS: CCK-8 assay was employed to detect the effect of circUBAP2 sliencing on cell proliferation of A549 cells. Fow cytometry was applied to detect the impact of circUBAP2 sliencing on cell cycle and cell anoikis, and Transwell invasion assay was applied to determine cell invasion of A549 cells. We also employed Western blot and Real-time PCR to determine the expressions of CDK6, cyclin D1, p27 and c-IAP1, Bcl-2, Survivin, Bax, FAK, Rac1 and MMP2, and the activities of JNK and ERK1/2, luciferase report gene assay was used to detect the targets. RESULTS: CCK-8 assay showed that the inhibition of cell proliferation in the circUBAP2-siRNA group compared to untreated group and siRNA control group. Results of cell cycle detected by flow cytometry showed that cell cycle arrestd at G0/G1 after circUBAP2 silencing, cell apoptosis rate increased also. We also found that after circUBAP2 silencing, cell invasion of A549 cells was significantly inhibited. Western blot and Real-time PCR results showed that expression of CDK6, cyclin D1, c-IAP1, Bcl-2, Survivin, FAK, Rac1 and MMP2 were down-regulated, and the expression of p27 and Bax were up-regulated. Moreover, the activities of JNK and ERK1/2 were inhibited because of circUBAP2 silencing, the target genes were miR-339-5p, miR-96-3p and miR-135b-3p. CONCLUSIONS: CircUBAP2 plays an important role in the proliferation and invasion of human lung cancer. Silencing of circUBAP2 might be a novel target for molecular targeted therapy of patients with lung cancer.
.


Asunto(s)
Neoplasias Pulmonares/patología , Interferencia de ARN , ARN/genética , Células A549 , Apoptosis/genética , Proliferación Celular/genética , Humanos , MicroARNs/genética , Invasividad Neoplásica , ARN Circular
16.
Plant Physiol ; 175(4): 1878-1892, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29089392

RESUMEN

In Arabidopsis (Arabidopsis thaliana) plants growing under normal conditions, DEHYDRATION-RESPONSIVE ELEMENT BINDING PROTEIN2A (DREB2A) is present at low levels because it is ubiquitinated and destabilized by DREB2A INTERACTING PROTEIN1 (DRIP1) and DRIP2 through 26S proteasome-mediated proteolysis. Drought stress counteracts the ubiquitination and proteolysis of DREB2A, thus allowing the accumulation of sufficient amounts of DREB2A protein to activate downstream gene expression. The mechanisms leading to drought stress-mediated DREB2A accumulation are still unclear. Here, we report that the wheat (Triticum aestivum) TaSAP5 protein, which contains an A20/AN1 domain, acts as an E3 ubiquitin ligase to mediate DRIP degradation and thus increase DREB2A protein levels. Drought induces TaSAP5 expression in wheat, and TaSAP5 overexpression in Arabidopsis and wheat seedlings increased their drought tolerance, as measured by survival rate and grain yield under severe drought stress. TaSAP5 can interact with and ubiquitinate TaDRIP, as well as AtDRIP1 and AtDRIP2, leading to their subsequent degradation through the 26S proteasome pathway. Consistent with this, TaSAP5 overexpression enhances DRIP degradation and increases the levels of DREB2A protein and its downstream targets. These results suggest that TaSAP5 acts to link drought with DREB2A accumulation and illustrate the molecular mechanisms involved in this process.


Asunto(s)
Proteínas de Plantas/metabolismo , Factores de Transcripción/metabolismo , Triticum/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Agua , Secuencia de Aminoácidos , Núcleo Celular , Citosol , Regulación Enzimológica de la Expresión Génica/fisiología , Regulación de la Expresión Génica de las Plantas/fisiología , Proteínas de Plantas/genética , Complejo de la Endopetidasa Proteasomal , Factores de Transcripción/genética , Triticum/genética , Ubiquitina-Proteína Ligasas/genética , Regulación hacia Arriba
17.
J Surg Res ; 216: 73-79, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28807216

RESUMEN

BACKGROUND: Oxidative stress induced by hemorrhagic shock (HS) is known to initiate a systemic inflammatory response, which leads to subsequent acute lung injury. This study is aimed to assess the efficacy of exendin-4 (Ex-4) in attenuating lung injury in a rat model of HS and resuscitation (HS/R). METHODS: HS was induced in sodium pentobarbital-anesthetized adult male Wistar rats by withdrawing blood to maintain a mean arterial pressure of 30-35 mm Hg for 50 min. Then, the animals received Ex-4 (5 µg/kg) or vehicle (saline) intravenously and were resuscitated with a volume of normal saline 1.5 times that of the shed blood volume. Mean arterial pressure was measured throughout the experiment, and acid-base status, oxidative stress, inflammation, and lung injury were evaluated at 2 h after resuscitation. RESULTS: Ex-4 infusion reduced the methemoglobin content, the malondialdehyde content, the myeloperoxidase activity, and the expression of tumor necrosis factor-α and interleukin-6 in the lungs. The histologic injury was also markedly decreased in the Ex-4 group compared with the vehicle group. CONCLUSIONS: Ex-4 ameliorates the oxidative stress, inflammatory response, and subsequent acute lung injury occurring after HS/R. Although future studies are required to elucidate the underlying mechanism, our results indicate that Ex-4 infusion may be a promising strategy for improving lung injury in the treatment of HS.


Asunto(s)
Lesión Pulmonar Aguda/prevención & control , Antioxidantes/uso terapéutico , Péptidos/uso terapéutico , Resucitación/métodos , Choque Hemorrágico/terapia , Ponzoñas/uso terapéutico , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Animales , Antioxidantes/farmacología , Biomarcadores/metabolismo , Terapia Combinada , Exenatida , Fluidoterapia , Infusiones Intravenosas , Masculino , Estrés Oxidativo/efectos de los fármacos , Péptidos/farmacología , Distribución Aleatoria , Ratas , Ratas Wistar , Choque Hemorrágico/complicaciones , Resultado del Tratamiento , Ponzoñas/farmacología
18.
Amino Acids ; 49(2): 347-354, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27913992

RESUMEN

Oxidative stress induced by hemorrhagic shock (HS) initiates a systemic inflammatory response, which leads to subsequent kidney injury. This study assessed the efficacy of c-type natriuretic peptide (CNP) in attenuating kidney injury in a rat model of hemorrhagic shock and resuscitation (HS/R). Sodium pentobarbital-anesthetized adult male Wistar rats underwent HS induced by the withdrawal of blood to a mean arterial pressure of 30-35 mmHg for 50 min. Then, the animals received CNP (25 µg/kg) or vehicle (saline) intravenously, followed byresuscitation with 1.5 times the shed blood volume in the form of normal saline. Mean arterial pressure was measured throughout the experiment, and acid-base status, oxidative stress, inflammation, tissue injury and kidney function were evaluated after resuscitation. CNP infusion reduced the malondialdehyde content, lowered the myeloperoxidase activity and decreased the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß in the kidney. The histologic injury score and the plasma creatinine concentration were also significantly decreased after CNP treatment compared to the vehicle group. CNP treatment ameliorates oxidative stress, the inflammatory response, and consequently acute kidney injury after HS/R. Thus, CNP may represent a promising strategy to improve resuscitation for the treatment of HS and deserves further investigation.


Asunto(s)
Lesión Renal Aguda/prevención & control , Péptido Natriurético Tipo-C/farmacología , Estrés Oxidativo/efectos de los fármacos , Choque Hemorrágico/tratamiento farmacológico , Lesión Renal Aguda/metabolismo , Animales , Análisis de los Gases de la Sangre , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Neutrófilos/efectos de los fármacos , Neutrófilos/patología , Ratas Wistar , Resucitación , Choque Hemorrágico/complicaciones
19.
Mediators Inflamm ; 2016: 3549207, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27746589

RESUMEN

RBCs undergo numerous changes during storage and stored RBCs may induce adverse effects, ultimately resulting in organ injury in transfusion recipients. We tested the hypothesis that the addition of SP to stored RBCs would improve the quality of the stored RBCs and mitigate liver injury after transfusion in a murine model. RBCs were harvested from C57BL/6J mice and stored for 14 days in CPDA-1 containing either a solution of SP in saline or saline alone. Haemolysis, the 24-hour posttransfusion recovery, the oxygen-carrying capacity, and the SOD activity of stored RBCs were evaluated. The plasma biochemistry, hepatic MDA level, MPO activity, IL-6, TNF-α concentrations, and histopathology were measured two hours after the transfusion of stored RBCs. Compared with RBCs stored in CPDA-1 and saline, the addition of SP to stored RBCs restored their oxygen-carrying capacity and SOD activity, reduced the AST activity, BUN concentrations, and LDH activity in the plasma, and decreased the MDA level, MPO activity, and concentrations of IL-6 and TNF-α in the liver. These data indicate that the addition of SP to RBCs during storage has a beneficial effect on storage lesions in vitro and subsequently alleviates liver injury after the transfusion of stored RBCs in vivo.


Asunto(s)
Transfusión Sanguínea/métodos , Eritrocitos/efectos de los fármacos , Hepatopatías/terapia , Ácido Pirúvico/farmacología , Sodio/farmacología , Animales , Conservación de la Sangre , Modelos Animales de Enfermedad , Hemoglobinas/química , Humanos , Interleucina-6/sangre , Ácido Láctico/sangre , Hepatopatías/patología , Masculino , Malondialdehído/sangre , Ratones , Ratones Endogámicos C57BL , Oxígeno/química , Peroxidasa/sangre , Superóxido Dismutasa/sangre , Superóxido Dismutasa/metabolismo , Factores de Tiempo , Factor de Necrosis Tumoral alfa/sangre
20.
Exp Biol Med (Maywood) ; 241(14): 1603-10, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27190249

RESUMEN

Gradually increased oxygen administration (GIOA) seems promising in hemorrhagic shock. However, the effects of GIOA on survival remain unclear, and details of GIOA are to be identified. After the induction of hemorrhagic shock, the rats were randomized into five groups (n = 9): normoxic group (Normo), hyperoxic group (Hypero), normoxic to hyperoxic group (GIOA1), long-time hypoxemic to hyperoxic group (GIOA2), and short-time hypoxemic to hyperoxic group (GIOA3). Survival was recorded for 96 h, plasma alanine transaminase, oxidative stress, hemodynamics, and blood gas were measured. The mean survival time of the GIOA3 was significantly longer than that of the Normo, Hypero, and GIOA2. Plasma alanine transaminase levels were significantly lower in the Normo, GIOA1, and GIOA3 compared to the Hypero and GIOA2 at 2 h post-resuscitation (PR). Plasma 3-nitrotyrosine levels at 2 h PR were significantly lower in the GIOA2 and GIOA3 compared to the Normo and Hypero. Central venous oxygen saturation at 2 h PR in the GIOA3 was significantly higher than the Normo; however, no significant difference was observed between GIOA1 and Normo. Besides, at 2 h PR, mean arterial pressure in the GIOA3 was significantly higher than the GIOA2; however, no significant difference was observed between GIOA1 and GIOA2. (1) GIOA could significantly prolong survival time compared to normoxemic resuscitation and hyperoxic resuscitation; (2) early moments of GIOA are critical to the benefits; and (3) hypoxemia at onset of resuscitation may be imperative, more works are needed to determine the optimal initial oxygen concentration of GIOA.


Asunto(s)
Oxígeno/administración & dosificación , Choque Hemorrágico/terapia , Alanina Transaminasa/sangre , Animales , Análisis de los Gases de la Sangre , Hemodinámica , Estrés Oxidativo , Oxígeno/uso terapéutico , Ratas , Análisis de Supervivencia , Factores de Tiempo , Tirosina/análogos & derivados , Tirosina/sangre
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