Objective:The present study examines whether a long-term high salt diet causes hypertension and renal injury in normal subjects [Sprague-Dawley(SD) rats] and alters renal cytokine-related gene expression profiles.Meth...Objective:The present study examines whether a long-term high salt diet causes hypertension and renal injury in normal subjects [Sprague-Dawley(SD) rats] and alters renal cytokine-related gene expression profiles.Methods: Four 10 week old male SD rats received a high salt diet(HS,8%) and the other 4 SD rats received a normal salt diet(NS,0.5 %) for 8 weeks.Mean arterial pressure(MAP) and renal damages such as albuminuria and histological renal injury were determined.The relative mRNA levels of 514 cytokine-related genes(normalized by β-actin) in rat kidneys following NS or HS were determined quantitatively through analysis of 4 sets of gene expression profiles using the mouse cDNA membrane microarrays.Results: We demonstrated that 8 weeks of HS diet increased MAP [(140.0±5.3) vs(112.0±2.2) mmHg;1 mmHg=0.133 kPa,P<0.01],albuminuria [(41.4±3.2) vs(20.1±4.5) mg/d;P<0.01],and caused histological renal injury in SD rats,compared to NS group.Of the 514 genes in the array,there were 27(5.25%) genes with significantly different expression in the kidney of SD rats with HS compared to those of SD rats with NS.Functional clustering analysis indicated the following functional pathways related to high salt diet-induced hypertension:(1) pro-inflammatory response(↑IL-17,CCL28;↓NFκbib);(2) endothelial dysfunction(↓VEGF-A,VEGF-B,endoglin);(3) pro-matrix formation(↑osteopontin,IGFBP-5;↓IFN-γ);and(4) attenuated cell survival and differentiation(↓CNTF,IGF-Ⅱ R,ephrin-B1).Northern blot confirmed that 8 weeks of HS diet significantly decreased renal expression of VEGF mRNA,compared to NS group(P<0.01).ELISA showed that HS diet significantly decreased renal protein levels of VEGF and CCL28.Conclusion: These findings support the hypothesis that hypertension can be induced in normal rats by a long-term high salt diet,which is associated with increased renal injury and marked changes in renal cytokine gene expression profiles that are closely related to the pro-inflammatory response,pro-matrix formation,endothelial dysfunction,and attenuated cell survival and differentiation.展开更多
Nutlin-3a is a MDM2 antagonist and preclinical drug that activates p53. Cells with MDM2 gene amplification are especially prone to Nutlin-3a-induced apoptosis, though the basis for this is unclear. Glucose metabolism ...Nutlin-3a is a MDM2 antagonist and preclinical drug that activates p53. Cells with MDM2 gene amplification are especially prone to Nutlin-3a-induced apoptosis, though the basis for this is unclear. Glucose metabolism can inhibit apoptosis in response to Nutlin-3a through mechanisms that are incompletely understood. Glucose metabolism through the pentose phosphate pathway （PPP） produces NADPH that can protect cells from potentially lethal reactive oxygen species （ROS）. We compared apoptosis and glucose metabolism in cancer cells with and without MDM2 gene amplification treated with Nutlin-3a. Apoptosis in MDM2-amplified cells was associated with a reduction in glycolysis and the PPP, reduced NADPH, increased ROS, and depletion of the transcription factor SP1, which normally promotes PPP gene expression. In contrast, glycolysis and the PPP were maintained or increased in MDM2 non-amplified cells treated with Nutlin-3a. This was dependent on p53-mediated AKT activation and was associated with maintenance of SP1 and continued expression of PPP genes. Knockdown or inhibition of AKT, SP1, or the PPP sensitized MDM2-non-amplified cells to apoptosis. The data indicate that p53 promotes AKT and SP1-dependent activation of the PPP that protects cells from Nutlin-3a-induced apoptosis. These findings provide insight into how glucose metabolism reduces Nutlin-3a-induced apoptosis, and also provide a mechanism for the heightened sensitivity of MDM2-amplified cells to apoptosis in response to Nutlin-3a.展开更多
Olfactory impairment is a well-established sequela of head injury. The presence and degree of olfactory dysfunction is dependent on severity of head trauma, duration of post-traumatic amnesia, injuries obtained, and a...Olfactory impairment is a well-established sequela of head injury. The presence and degree of olfactory dysfunction is dependent on severity of head trauma, duration of post-traumatic amnesia, injuries obtained, and as more recently established, age. Deficits in smell can be conductive or neurosensory, contingent on location of injury. The former may be amenable to medical or surgical treatment, whereas the majority of patients with neurosen-sory deficits will not recover. Many patients will not seek treatment for such deficits until days, weeks, or even months after the traumatic event due to focus on more pressing injuries. Eval-uation should start with a comprehensive history and physical exam. Determination of the site of injury can be aided by CT and MRI scanning. Verification of the presence of olfactory deficit, and assessment of its severity requires objective olfactory testing, which can be accomplished with a number of methods. The prognosis of posttraumatic olfactory dysfunction is unfortu-nate, with approximately only one third improving. Emphasis must be placed on identification of reversible causes, such as nasal bone fractures, septal deviation, or mucosal edema/hema-toma. Olfactory loss is often discounted as an annoyance, rather than a major health concern by both patients and many healthcare providers. Patients with olfactory impairment have diminished quality of life, decreased satisfaction with life, and increased risk for personal injury. Paramount to the management of these patients is counseling with regard to adoption of compensatory strategies to avoid safety risks and maximize quality of life. Practicing otolar-yngologists should have a thorough understanding of the mechanisms of traumatic olfactory dysfunction in order to effectively diagnose, manage, and counsel affected patients.展开更多
基金Supported by NIH/National Heart,Lung,and Blood Institute Grant(HL-51971)NIH/National Institute on Alcohol Abuse and Alcoholism Grant(AA-012821)~~
文摘Objective:The present study examines whether a long-term high salt diet causes hypertension and renal injury in normal subjects [Sprague-Dawley(SD) rats] and alters renal cytokine-related gene expression profiles.Methods: Four 10 week old male SD rats received a high salt diet(HS,8%) and the other 4 SD rats received a normal salt diet(NS,0.5 %) for 8 weeks.Mean arterial pressure(MAP) and renal damages such as albuminuria and histological renal injury were determined.The relative mRNA levels of 514 cytokine-related genes(normalized by β-actin) in rat kidneys following NS or HS were determined quantitatively through analysis of 4 sets of gene expression profiles using the mouse cDNA membrane microarrays.Results: We demonstrated that 8 weeks of HS diet increased MAP [(140.0±5.3) vs(112.0±2.2) mmHg;1 mmHg=0.133 kPa,P<0.01],albuminuria [(41.4±3.2) vs(20.1±4.5) mg/d;P<0.01],and caused histological renal injury in SD rats,compared to NS group.Of the 514 genes in the array,there were 27(5.25%) genes with significantly different expression in the kidney of SD rats with HS compared to those of SD rats with NS.Functional clustering analysis indicated the following functional pathways related to high salt diet-induced hypertension:(1) pro-inflammatory response(↑IL-17,CCL28;↓NFκbib);(2) endothelial dysfunction(↓VEGF-A,VEGF-B,endoglin);(3) pro-matrix formation(↑osteopontin,IGFBP-5;↓IFN-γ);and(4) attenuated cell survival and differentiation(↓CNTF,IGF-Ⅱ R,ephrin-B1).Northern blot confirmed that 8 weeks of HS diet significantly decreased renal expression of VEGF mRNA,compared to NS group(P<0.01).ELISA showed that HS diet significantly decreased renal protein levels of VEGF and CCL28.Conclusion: These findings support the hypothesis that hypertension can be induced in normal rats by a long-term high salt diet,which is associated with increased renal injury and marked changes in renal cytokine gene expression profiles that are closely related to the pro-inflammatory response,pro-matrix formation,endothelial dysfunction,and attenuated cell survival and differentiation.
文摘Nutlin-3a is a MDM2 antagonist and preclinical drug that activates p53. Cells with MDM2 gene amplification are especially prone to Nutlin-3a-induced apoptosis, though the basis for this is unclear. Glucose metabolism can inhibit apoptosis in response to Nutlin-3a through mechanisms that are incompletely understood. Glucose metabolism through the pentose phosphate pathway （PPP） produces NADPH that can protect cells from potentially lethal reactive oxygen species （ROS）. We compared apoptosis and glucose metabolism in cancer cells with and without MDM2 gene amplification treated with Nutlin-3a. Apoptosis in MDM2-amplified cells was associated with a reduction in glycolysis and the PPP, reduced NADPH, increased ROS, and depletion of the transcription factor SP1, which normally promotes PPP gene expression. In contrast, glycolysis and the PPP were maintained or increased in MDM2 non-amplified cells treated with Nutlin-3a. This was dependent on p53-mediated AKT activation and was associated with maintenance of SP1 and continued expression of PPP genes. Knockdown or inhibition of AKT, SP1, or the PPP sensitized MDM2-non-amplified cells to apoptosis. The data indicate that p53 promotes AKT and SP1-dependent activation of the PPP that protects cells from Nutlin-3a-induced apoptosis. These findings provide insight into how glucose metabolism reduces Nutlin-3a-induced apoptosis, and also provide a mechanism for the heightened sensitivity of MDM2-amplified cells to apoptosis in response to Nutlin-3a.
文摘Olfactory impairment is a well-established sequela of head injury. The presence and degree of olfactory dysfunction is dependent on severity of head trauma, duration of post-traumatic amnesia, injuries obtained, and as more recently established, age. Deficits in smell can be conductive or neurosensory, contingent on location of injury. The former may be amenable to medical or surgical treatment, whereas the majority of patients with neurosen-sory deficits will not recover. Many patients will not seek treatment for such deficits until days, weeks, or even months after the traumatic event due to focus on more pressing injuries. Eval-uation should start with a comprehensive history and physical exam. Determination of the site of injury can be aided by CT and MRI scanning. Verification of the presence of olfactory deficit, and assessment of its severity requires objective olfactory testing, which can be accomplished with a number of methods. The prognosis of posttraumatic olfactory dysfunction is unfortu-nate, with approximately only one third improving. Emphasis must be placed on identification of reversible causes, such as nasal bone fractures, septal deviation, or mucosal edema/hema-toma. Olfactory loss is often discounted as an annoyance, rather than a major health concern by both patients and many healthcare providers. Patients with olfactory impairment have diminished quality of life, decreased satisfaction with life, and increased risk for personal injury. Paramount to the management of these patients is counseling with regard to adoption of compensatory strategies to avoid safety risks and maximize quality of life. Practicing otolar-yngologists should have a thorough understanding of the mechanisms of traumatic olfactory dysfunction in order to effectively diagnose, manage, and counsel affected patients.
