ABSTRACT
The function of mitochondrial fusion and fission is one of the important factors causing ischemia-reperfusion (I/R) injury in diabetic myocardium. Aldehyde dehydrogenase 2 (ALDH2) is abundantly expressed in heart, which involved in the regulation of cellular energy metabolism and stress response. However, the mechanism of ALDH2 regulating mitochondrial fusion and fission in diabetic myocardial I/R injury has not been elucidated. In the present study, we found that the expression of ALDH2 was downregulated in rat diabetic myocardial I/R model. Functionally, the activation of ALDH2 resulted in the improvement of cardiac hemodynamic parameters and myocardial injury, which were abolished by the treatment of Daidzin, a specific inhibitor of ALDH2. In H9C2 cardiomyocyte hypoxia-reoxygenation model, ALDH2 regulated the dynamic balance of mitochondrial fusion and fission and maintained mitochondrial morphology stability. Meanwhile, ALDH2 reduced mitochondrial ROS levels, and apoptotic protein expression in cardiomyocytes, which was associated with the upregulation of phosphorylation (p-PI3KTyr458, p-AKTSer473, p-mTOR). Moreover, ALDH2 suppressed the mitoPTP opening through reducing 4-HNE. Therefore, our results demonstrated that ALDH2 alleviated the ischemia and reperfusion injury in diabetic cardiomyopathy through inhibition of mitoPTP opening and activation of PI3K/AKT/mTOR pathway.
Subject(s)
Diabetes Mellitus , Diabetic Cardiomyopathies , Myocardial Reperfusion Injury , Rats , Animals , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Aldehyde Dehydrogenase, Mitochondrial/genetics , Aldehyde Dehydrogenase, Mitochondrial/metabolism , Diabetic Cardiomyopathies/genetics , Diabetic Cardiomyopathies/metabolism , Mitochondrial Dynamics/genetics , Myocytes, Cardiac/metabolism , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Myocardial Reperfusion Injury/metabolism , Ischemia/metabolism , Apoptosis , Diabetes Mellitus/metabolismABSTRACT
BACKGROUND: Schizophrenia is a psychiatric disorder including multiple clinical symptoms such as severe psychosis and cognitive dysfunction. DHF-7 is a novel dihydroflavanone derivative that was designed and synthesized to treat schizophrenia. This study aimed to investigate the effects and mechanisms of DHF-7 in a mouse model of schizophrenia induced by a combination of cuprizone and MK-801. METHODS: After intragastric administration of DHF-7 for 7 weeks, open field, Y-maze, and novel object recognition tests were performed to detect behavioral changes in the mouse model. White matter lesions and myelin loss were determined using transmission electron microscopy and oil red O staining. Western blotting and immunohistochemistry were used to detect the expression of the related proteins. RESULTS: The results showed that DHF-7 treatment significantly improved cognitive impairment and positive symptoms in the model mice. Moreover, DHF-7 alleviated white matter lesions and demyelination and promoted the differentiation and maturation of oligodendrocytes for remyelination in the corpus callosum of model mice. The mechanistic study showed that DHF-7 increased the expression of brain-derived neurotrophic factor and phosphorylated Fyn, thus activating the tyrosine kinase receptor B (Trk B)/Fyn/N-methyl-D-aspartate receptor subunit 2 B (NMDAR2B) and Raf/mitogen-activated protein kinase (MEK)/ extracellular signal-related kinase (ERK) signaling pathways. CONCLUSIONS: Our results provide an experimental basis for the development of DHF-7 as a novel therapeutic agent for schizophrenia.
Subject(s)
Brain-Derived Neurotrophic Factor , Proto-Oncogene Proteins c-fyn , Schizophrenia , White Matter , Animals , Brain-Derived Neurotrophic Factor/metabolism , Cuprizone/toxicity , Disease Models, Animal , Dizocilpine Maleate/toxicity , Humans , Mice , Mice, Inbred C57BL , Proto-Oncogene Proteins c-fyn/metabolism , Schizophrenia/chemically induced , Schizophrenia/drug therapy , Schizophrenia/metabolism , White Matter/metabolismABSTRACT
Glioblastomas (GBM) is the most common primary malignant brain tumor, and radiotherapy plays a critical role in its therapeutic management. Unfortunately, the development of radioresistance is universal. Here, we identified calcium-regulated heat-stable protein 1 (CARHSP1) as a critical driver for radioresistance utilizing genome-wide CRISPR activation screening. This is a protein with a cold-shock domain (CSD)-containing that is highly similar to cold-shock proteins. CARHSP1 mRNA level was upregulated in irradiation-resistant GBM cells and knockdown of CARHSP1 sensitized GBM cells to radiotherapy. The high expression of CARHSP1 upon radiation might mediate radioresistance by activating the inflammatory signaling pathway. More importantly, patients with high levels of CARHSP1 had poorer survival when treated with radiotherapy. Collectively, our findings suggested that targeting the CARHSP1/TNF-α inflammatory signaling activation induced by radiotherapy might directly affect radioresistance and present an attractive therapeutic target for GBM, particularly for patients with high levels of CARHSP1.
Subject(s)
Brain Neoplasms/genetics , CRISPR-Associated Protein 9/metabolism , CRISPR-Cas Systems/genetics , DNA-Binding Proteins/metabolism , Genome, Human , Glioblastoma/genetics , Phosphoproteins/metabolism , Radiation Tolerance/genetics , Transcription Factors/metabolism , Brain Neoplasms/pathology , Brain Neoplasms/radiotherapy , Cell Line, Tumor , DNA-Binding Proteins/genetics , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , Glioblastoma/pathology , Glioblastoma/radiotherapy , Humans , Phosphoproteins/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Transcription Factors/genetics , Tumor Necrosis Factor-alpha/metabolism , Up-Regulation/geneticsABSTRACT
Schizophrenia is a mental illness characterized by episodes of psychosis, apathy, social withdrawal, and cognitive impairment. White matter lesions and glutamatergic hypofunction are reported to be the key pathogeneses underlying the multiple clinical symptoms of schizophrenia. Cuprizone (CPZ) is a copper chelator that selectively injures oligodendrocytes, and MK-801 is an antagonist of the N-methyl d-aspartate (NMDA) receptor. To better mimic the psychosis and complicated pathogenesis of schizophrenia, a novel possible mouse model was established by the combination of CPZ and MK-801. After exposure to CPZ for 5 weeks, the mice received a daily intraperitoneal injection of MK-801 for 2-weeks. Behavioral changes in the mouse model were evaluated using Y-maze, object recognition, and open field tests. Pathological changes were observed by transmission electron microscopy, oil red O staining, immunohistochemistry, and western blotting. The results showed that the novel mouse model induced by CPZ plus MK-801 exhibited severe spatial and recognition memory deficits, hyperactivity, and anxiety disorder. Moreover, the mice showed obvious demyelination and white matter damage and decreased expression levels of myelin basic protein (MBP) and 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) in the corpus callosum. Furthermore, the phosphorylation levels of Fyn and NMDA receptor 2B in the corpus callosum and NMDA receptor 1 in the cerebral cortex were noticeably decreased. Taken together, the novel mouse model induced by the combination of cuprizone and MK-801 showed comprehensive behavioral and neurobiological changes, which might make it a suitable animal model for schizophrenia.
Subject(s)
Chelating Agents , Cuprizone , Dizocilpine Maleate , Schizophrenia/chemically induced , Schizophrenic Psychology , Animals , Anxiety/chemically induced , Anxiety/psychology , Behavior, Animal , Corpus Callosum/drug effects , Corpus Callosum/metabolism , Hyperkinesis/chemically induced , Hyperkinesis/psychology , Injections, Intraperitoneal , Male , Memory Disorders/chemically induced , Memory Disorders/psychology , Mice , Mice, Inbred C57BL , Recognition, Psychology , Schizophrenia/pathology , Spatial Memory/drug effects , White Matter/metabolism , White Matter/pathologyABSTRACT
Recent studies have shown that white matter lesions play an important role in the pathogenesis of schizophrenia. DHF-6 is a novel flavanone derivative synthesized in our laboratory. The purpose of the present study was to investigate the effects of DHF-6 on behavioral changes and white matter pathology in a 0.2% cuprizone-fed C57BL/6 mice model. The results showed that cuprizone induced a decrease in spontaneous alternations in the Y-maze test, an increase in locomotor activity in the open field test, demyelination determined by electron microscopy, a decline in the expression of myelin basic protein (MBP), a decrease in the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs), and an activation of microglia and astrocytes in the corpus callosum measured by western blot and/or immunocytochemical analyses. Intragastric administration of DHF-6 (25 and 50mg/kg) for 5-weeks increased the spontaneous alternations, reduced locomotor activity, reversed demyelination and MBP decrease, promoted OPCs differentiation into mature OLs, and inhibited the activation of microglia and astrocytes. These results suggest that DHF-6 may improve cognitive impairment and the positive symptoms of schizophrenia by alleviating white matter lesions via facilitating remyelination and inhibiting neuroinflammation, thus may be beneficial in the treatment of schizophrenia.
Subject(s)
Brain/pathology , Cuprizone/toxicity , Flavanones/pharmacology , Locomotion , White Matter/pathology , Animals , Brain/drug effects , Chelating Agents/toxicity , Corpus Callosum/drug effects , Corpus Callosum/pathology , Demyelinating Diseases/chemically induced , Demyelinating Diseases/drug therapy , Demyelinating Diseases/pathology , Flavanones/therapeutic use , Locomotion/drug effects , Male , Mice , Mice, Inbred C57BL , Myelin Sheath/drug effects , Myelin Sheath/pathology , Neurogenesis/drug effects , Oligodendroglia/drug effects , Oligodendroglia/pathology , Random Allocation , White Matter/drug effectsABSTRACT
The aim of this study was to investigate the relationship between 16-slice spiral CT perfusion imaging and tumor angiogenesis and cyclin D1 expression in patients with peripheral lung cancer. Fifty-eight patients with peripheral lung cancer underwent 16-slice spiral CT perfusion imaging. The CT perfusion imaging was analyzed for time density curve (TDC), perfusion parametric maps, and the respective perfusion parameters. Correlation between the respective perfusion parameters and immunohistochemical findings of microvessel density measurement and cyclin D1 expression was evaluated.
