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High-altitude exposure has been linked to cardiac dysfunction. Silent information regulator factor 2-related enzyme 1 (sirtuin 1, SIRT1), a nicotinamide adenine dinucleotide-dependent deacetylase, plays a crucial role in regulating numerous cardiovascular diseases. However, the relationship between SIRT1 and cardiac dysfunction induced by hypobaric hypoxia (HH) remains unexplored. This study aims to assess the impact of SIRT1 on HH-induced cardiac dysfunction and delve into the underlying mechanisms, both in vivo and in vitro. In this study, we have demonstrated that exposure to HH results in cardiomyocyte injury, along with the downregulation of SIRT1 and mitochondrial dysfunction. Upregulating SIRT1 significantly inhibits mitochondrial fission, improves mitochondrial function, reduces cardiomyocyte injury, and consequently enhances cardiac function in HH-exposed rats. Additionally, HH exposure triggers aberrant expression of mitochondrial fission-regulated proteins, with a decrease in PPARγ coactivator 1 alpha (PGC-1α) and mitochondrial fission factor (MFF) and an increase in mitochondrial fission 1 (FIS1) and dynamin-related protein 1 (DRP1), all of which are mitigated by SIRT1 upregulation. Furthermore, inhibiting PGC-1α diminishes the positive effects of SIRT1 regulation on the expression of DRP1, MFF, and FIS1, as well as mitochondrial fission. These findings demonstrate that SIRT1 alleviates HHinduced cardiac dysfunction by preventing mitochondrial fission through the PGC-1α-DRP1/FIS1/MFF pathway.
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About 140 million people worldwide live at an altitude above 2500 m. Studies have showed an increase of the incidence of hyperuricemia among plateau populations, but little is known about the possible mechanisms. This study aims to assess the effects of high altitude on hyperuricemia and explore the corresponding mechanisms at the histological, inflammatory and molecular levels. This study finds that intermittent hypobaric hypoxia (IHH) exposure results in an increase of serum uric acid level and a decrease of uric acid clearance rate. Compared with the control group, the IHH group shows significant increases in hemoglobin concentration (HGB) and red blood cell counts (RBC), indicating that high altitude hyperuricemia is associated with polycythemia. This study also shows that IHH exposure induces oxidative stress, which causes the injury of liver and renal structures and functions. Additionally, altered expressions of organic anion transporter 1 (OAT1) and organic cation transporter 1 (OCT1) of kidney have been detected in the IHH exposed rats. The adenosine deaminase (ADA) expression levels and the xanthione oxidase (XOD) and ADA activity of liver of the IHH exposure group have significantly increased compared with those of the control group. Furthermore, the spleen coefficients, IL-2, IL-1ß and IL-8, have seen significant increases among the IHH exposure group. TLR/MyD88/NF-κB pathway is activated in the process of IHH induced inflammatory response in joints. Importantly, these results jointly show that IHH exposure causes hyperuricemia. IHH induced oxidative stress along with liver and kidney injury, unusual expression of the uric acid synthesis/excretion regulator and inflammatory response, thus suggesting a potential mechanism underlying IHH-induced hyperuricemia.
Assuntos
Hiperuricemia , Hipóxia , Rim , Fígado , Estresse Oxidativo , Hiperuricemia/metabolismo , Animais , Masculino , Ratos , Fígado/metabolismo , Fígado/patologia , Hipóxia/metabolismo , Hipóxia/complicações , Rim/metabolismo , Rim/patologia , Altitude , Ácido Úrico/sangue , Ácido Úrico/metabolismo , Ratos Sprague-Dawley , Xantina Oxidase/metabolismo , Doença da Altitude/metabolismo , Doença da Altitude/complicações , Doença da Altitude/fisiopatologiaRESUMO
Hypoxia at high-altitude leads to osteoporosis. Resveratrol (RES), as an antioxidant, has been reported to promote osteoblastogenesis and suppress osteoclastogenesis. However, the therapeutic effect of RES against osteoporosis induced by high-altitude hypoxia remains unclear. Thus, this study was intended to investigate the potential effects of RES on high-altitude hypoxia-induced osteoporosis both in vivo and in vitro. Male Wistar rats were given RES (400 mg/kg) once daily for nine weeks under hypoxia, while the control was allowed to grow under normoxia. Bone mineral density (BMD), the levels of bone metabolism-related markers, and the changes on a histological level were measured. Bone marrow-derived mesenchymal stem cells (BMSCs) and RAW264.7 were incubated with RES under hypoxia, with a control growing under normoxia, followed by the evaluation of proliferation and differentiation. The results showed that RES inhibited high-altitude hypoxia-induced reduction in BMD, enhanced alkaline phosphatase (ALP), osteocalcin (OCN), calcitonin (CT) and runt-related transcription factor 2 (RUNX2) levels, whereas it reduced cross-linked carboxy-terminal telopeptide of type I collagen (CTX-I) levels and tartrate-resistant acid phosphatase (TRAP) activity in vivo. In addition, RES attenuated histological deteriorations in the femurs. In vitro, RES promoted osteoblastogenesis and mineralization in hypoxia-exposed BMSCs, along with promotion in RUNX2, ALP, OCN and osteopontin (OPN) levels, and inhibited the proliferation and osteoclastogenesis of RAW264.7. The promotion effects of RES on osteoblastogenesis were accompanied by the down-regulation of reactive oxygen species (ROS) and hypoxia inducible factor-1α (HIF-1α) induced by hypoxia. These results demonstrate that RES can alleviate high-altitude hypoxia-induced osteoporosis via promoting osteoblastogenesis by suppressing the ROS/HIF-1α signaling pathway. Thus, we suggest that RES might be a potential treatment with minimal side effects to protect against high-altitude hypoxia-induced osteoporosis.
Assuntos
Doença da Altitude , Osteoporose , Fosfatase Alcalina/metabolismo , Animais , Diferenciação Celular , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Hipóxia/complicações , Hipóxia/tratamento farmacológico , Masculino , Osteocalcina/metabolismo , Osteogênese , Osteoporose/tratamento farmacológico , Osteoporose/etiologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Transdução de SinaisRESUMO
OBJECTIVE: To investigate the effects of activation of mitochondrial aldehyde dehydrogenase 2(ALDH2) on high glucose-induced inflammasome production in alveolar epithelial A549 cells. METHODS: The alveolar epithelial A549 cells were cultured with 25 mmol/L high glucose complete medium and divided into 4 groups: Control group, ALDH2 agonist 20 µmol/L Alda-1 group, ALDH2 antagonist 60 µmol/L Daidzin group, 20 µmol/L Alda-1 + 60 µmol/L Daidzin group. After the cells treated for 24 h, the cell proliferation activity was measured by thiazolyl blue tetrazolium bromide(MTT) colorimetric assaymethod, and the cellular reactive oxygen species(ROS) level were detected by dihydroethidium(DHE) fluorescent staining method, the cell migration ability was performed by cell scratching experiments, the protein expressions of ALDH2 and the core components of inflammasome, nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3), apoptosis-associated speck-like protein containing CARD(ASC) and cysteinyl aspartate specific protease-1(caspase-1) were detected by western blot. RESULTS: Compared with the control group, after Alda-1 activated ALDH2 specifically, the cell proliferation activity did not change significantly, but the oxidative stress level and cell migration rate were significantly decreased(P<0.05). ALDH2 protein expression was significantly increased(P<0.05), the protein expressions of NLRP3, ASC and caspase-1 were significantly decreased(P<0.05). After Daidzin blocked ALDH2 specifically, there were no significant changes in cell proliferation, oxidative stress, cell migration rate, ALDH2 and ASC protein expressions, while NLRP3 protein expression was significantly increased(P<0.05), and caspase-1 protein expression was significantly decreased(P<0.05). Compared with Alda-1 group, there was no significant changes in cell proliferation and oxidative stress in Alda-1+Daidzin group, cell migration rate was significantly increased(P<0.05), ALDH2 protein expression was decreased(P<0.05), and the protein expressions of NLRP3, ASC and caspase-1 were significantly increased(P<0.05). CONCLUSION: Increasing ALDH2 expression in alveolar epithelial A549 cells may attenuate high glucose-induced cellular inflammatory reaction, possibly through reducing cellular ROS level and reducing inflammasome expression.
Assuntos
Inflamassomos , Estresse Oxidativo , Células A549 , Aldeído Desidrogenase , Aldeído-Desidrogenase Mitocondrial , Glucose , HumanosRESUMO
Background: Oral squamous cell carcinoma (OSCC) is a common malignant tumor. Recently, Laminin Gamma 2 (LAMC2) has been shown to be abnormally expressed in OSCC; however, how LAMC2 signaling contributes to the occurrence and development of OSCC and the role of autophagy in OSCC has not been fully explored. This study aimed to analyze the role and mechanism of LAMC2 signaling in OSCC and the involvement of autophagy in OSCC. Methods: To explore the mechanism by which LAMC2 is highly expressed in OSCC, we used small interfering RNA (siRNA) to knock down LAMC2 to further observe the changes in the signaling pathway. Furthermore, we used cell proliferation assays, Transwell invasion assays, and wound-healing assays to observe the changes in OSCC proliferation, invasion, and metastasis. RFP-LC3 was used to detect the level of autophagy intensity. A cell line-derived xenograft (CDX) model was used to detect the effect of LAMC2 on tumor growth in vivo. Results: This study found that the level of autophagy was correlated with the biological behavior of OSCC. The downregulation of LAMC2 activated autophagy and inhibited OSCC proliferation, invasion, and metastasis via inhibiting the PI3K/AKT/mTOR pathway. Moreover, autophagy has a dual effect on OSCC, and the synergistic downregulation of LAMC2 and autophagy can inhibit OSCC metastasis, invasion, and proliferation via the PI3K/AKT/mTOR pathway. Conclusions: LAMC2 interacts with autophagy to regulate OSCC metastasis, invasion, and proliferation via the PI3K/AKT/mTOR pathway. LAMC2 down-regulation can synergistically modulate autophagy to inhibit OSCC migration, invasion, and proliferation.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Carcinoma de Células Escamosas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proliferação de Células/genética , Linhagem Celular Tumoral , Neoplasias Bucais/patologia , Serina-Treonina Quinases TOR/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço , RNA Interferente Pequeno , Movimento Celular/genética , Laminina/farmacologiaRESUMO
Objective: To study the protective effects of resveratrol (RSV) on cardiac function in rats with high altitude hypobaric hypoxia and its mechanisms. Methods: Thirty-six rats were randomly divided into control group, hypobaric hypoxia group (HH) and hypobaric hypoxia + RSV group (HH+RSV) according to the random number, 12 rats in each group. Rats in the HH and HH+RSV groups were subjected to chronic long-term high altitude hypobaric hypoxia intervention for 8 weeks in a hypobaric chamber at a simulated altitude of 6 000 m for 20 h / d. The rats of HH + RSV were fed with RSV at a dose of 400 mg/(kg·d). The rats were tested once a week for body weight and twice a week for food intake. Before execution, the rats were tested by blood cell analyzer for routine blood parameters and echocardiogram for cardiac function parameters in each group. The routine blood indexes of each group were measured by blood cell analyzer, the cardiac function indexes of each group were measured by echocardiography, myocardial hypertrophy was evaluated by HE staining, myocardial tissue reactive oxygen levels were evaluated by dihydroethidium (DHE) staining. Oxidative stress was evaluated by serum and myocardial tissue total antioxidant capacity (T-AOC), superoxide dismutase activity (SOD) and malondialdehyde (MDA) content. Results: Compared with the C group, the body mass and food intake of rats were decreased significantly (Pï¼0.05) in HH group, while compared with the C group, RSV had no significant effects on the body mass and food intake of rats in the HH+RSV group (Pï¼0.05). Compared with the C group, the levels of erythrocytes and hemoglobin of rats in the HH group were increased significantly (Pï¼0.05), while the platelet concentration was decreased significantly(Pï¼0.05); compared with the HH group, the erythrocyte and hemoglobin levels were decreased significantly (Pï¼0.05) and platelet concentration was increased significantly(Pï¼0.05) in rats of the HH+RSV group. Compared with the C group, the cardiac coefficient, myocardial fiber diameter and thickness were significantly increased in the HH group (Pï¼0.05); compared with the HH group, the cardiac coefficient and myocardial fiber thickness were significantly decreased in the HH+RSV group (Pï¼0.05). Echocardiographic analysis showed a significant increase in ventricular wall thickness (Pï¼0.05) and a significant decrease in ejection fraction and cardiac output (Pï¼0.05) in the HH group compared with the C group, and a significant decrease in ventricular wall thickness and a significant improvement in cardiac function (Pï¼0.05) in the HH+RSV group compared with the HH group. The results of DHE staining showed that myocardial tissue reactive oxygen levels were increased significantly in the HH group compared with the C group (Pï¼0.05); myocardial tissue reactive oxygen levels were significantly restored in the HH+RSV group compared with the HH group (Pï¼0.05). The oxidative/antioxidant results showed that the serum and myocardial T-AOC and SOD activities were decreased significantly (Pï¼0.05) and the MDA level was increased significantly (Pï¼0.05) in the HH group compared with the C group; the serum and myocardial T-AOC and SOD activities were increased significantly (Pï¼0.05) and the MDA level was decreased significantly(Pï¼0.05) in the HH+RSV group compared with the HH group. Conclusion: Long-term plateau hypobaric hypoxia exposure leads to myocardial hypertrophy and reduced cardiac function in rats. Resveratrol intervention significantly improves myocardial hypertrophy and cardiac function in rats caused by altitude hypobaric hypoxia exposure, which is closely related to reducing of reactive oxygen species and improving myocardial oxidative stress levels.
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Doença da Altitude , Antioxidantes , Animais , Ratos , Resveratrol , Hipóxia , Oxigênio , Hipertrofia , Superóxido DismutaseRESUMO
BACKGROUNDS: Numerous studies have revealed that hypobaric hypoxia exposure elicited imbalance of homeostasis. However, the effects of intermittent hypobaric hypoxia (IHH) exposure on the female reproductive system have been rarely reported. This study aims to assess the effects of IHH on rat female reproductive system and explore the corresponding mechanism at the histological, endocrine and molecular levels. METHODS: The female rats were randomly divided into control and IHH groups. Multiple pathophysiological parameters, including body weight gain, organ coefficients, estrus cycle, and health signs were measured. Also, the reproductive hormones, hormone receptor mRNA expression and oxidant/antioxidant level were evaluated. RESULTS: Significant increases of the heart, liver and lung coefficients were observed after IHH exposure. There were no statistically significant differences in ovarian and uterine coefï¬cients, but changes were found in the morphology of the ovary and uterus. Additionally, the diestrus phase duration was significantly increased during IHH exposure. Furthermore, estrogen increased and the Luteinizing hormone and progesterone decreased after IHH exposure. Altered expression of ER, PR and LHR were also found in the IHH exposed rats. Importantly, IHH exposure significantly repressed the activities of GSH-Px and T-SOD and improved the contents of MDA. CONCLUSIONS: Our results evince that IHH exposure caused estrus cycle irregularity. IHH induced oxidative stress along with ovarian and uterine structure damages, reproductive hormone disturbances and unusual expression of hormone receptors, thus suggesting a potential mechanism underlying IHH-induced reproductive system dysfunction.
Assuntos
Genitália Feminina/fisiopatologia , Hipóxia/fisiopatologia , Animais , Estro/fisiologia , Feminino , Expressão Gênica , Genitália Feminina/patologia , Hormônios Esteroides Gonadais/metabolismo , Hipóxia/patologia , Ratos Sprague-Dawley , Útero/patologiaRESUMO
Porous carbon particles have been widely used in many areas including energy storage. Production of carbon microspheres in an efficient, controlled, and low-cost manner, however, is challenging. Here, we demonstrate a microfluidic approach to generate porous carbon particles using inexpensive precursors and show that the size of the particle and pores can be tuned by adjusting the deionized (DI) water content in droplets and preheating temperature. The developed strategy offers an effective approach to control the production of porous carbon spheres with a well-defined diameter, narrow size distribution and pore size.
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AIM: The aim of this study was to determine the clinicopathological features, surgical management, and prognosis of solid pseudopapillary neoplasms (SPNs) of the pancreas. METHODS: This study conducted a retrospective analysis of 97 patients who underwent surgery for a pathologically confirmed SPN in five hospitals between January 1996 and December 2014. RESULTS: The 97 cases included 93 female and 4 male patients, and the average age was 31.2 years. The tumor was located in the body or tail (70.1%), the head (20.6%), and the neck (9.3%). All patients underwent surgical exploration, including distal pancreatectomy (63.9%), pancreaticoduodenectomy (20.6%) (partial portal vein or superior mesenteric vein resection and artificial vascular graft reconstruction performed in 4.1% of the patients), central pancreatectomy (10.3%), enucleation (5.2%), and liver resection (1.0%). 16.5% of the patients had malignant tumors. The positive rate of Ki-67 was 66.7% in patients diagnosed with a malignant neoplasm and was comparable to 8.4% of the patients diagnosed to have a benign neoplasm (p < 0.001). After a median follow-up of 70.1 months, three patients had recurrence and one patient died of liver metastasis. CONCLUSIONS: SPN is a rare neoplasm with low malignant potential. Surgical resection is warranted even in the presence of local invasion or metastases as patients demonstrate excellent long-term survival. Positive immunoreactivity for Ki-67 may predict the malignant potential and poor outcome of SPNs.