Hypocretins/orexins are crucial for the regulation of wakefulness by the excitatory actions on multiple subcortical arousal systems. In prefrontal cortex,
Alzheimer's disease(AD) is a growing health problem. It has enormous public health impact. Sleep problems show an early component of this disease. Hypocretin hasa major function in sleep-wake cycle. The total numb...Alzheimer's disease(AD) is a growing health problem. It has enormous public health impact. Sleep problems show an early component of this disease. Hypocretin hasa major function in sleep-wake cycle. The total number of hypocretin neurons in the normal humans ranges from 51000-83000, located exclusively in the hypothalamus. Deficiency in hypocretins neurotransmission results in narcolepsy, Parkinson's disease, and other neurological and psychological disorders. Cerebrospinal fluid(CSF) hypocretin levels were directly related with t-tau protein amount in AD. Increased hypocretin CSF in AD suggest that hypocretin is involved in the mechanism of AD pathology.展开更多
Recent studies suggest that Hypocretin (HCRT, Orexin) are involved in stress regulation of depression through the hypothalamic-pituitary-adrenal (HPA) axis. However, the molecular mechanism by which Hypocretin regulat...Recent studies suggest that Hypocretin (HCRT, Orexin) are involved in stress regulation of depression through the hypothalamic-pituitary-adrenal (HPA) axis. However, the molecular mechanism by which Hypocretin regulate neurobiological responses is unknown. Herein, the effects of chronic stress on the epigenetic modification of HCRT and its association with depression were explored with regard to a potential role in cancer progression. In the study, Sprague Dawley (SD) rats were used to establish an animal model of cancer with depression by administrating n-nitrosodiethylamine (DEN) and chronic unpredictable mild stress (CUMS). RNA-sequencing was used to detect differentially expressed genes in the hippocampus of rats and quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the results of RNA-sequencing. The status of HCRT promoter methylation was assessed by methylation specific polymerase chain reaction. Behavioral tests showed that rats exposed to CUMS had significant depressive-like behaviors. The number of liver tumors and tumor load in depressed rats exposed to CUMS was higher than in SD rats without CUMS. RNA-sequencing revealed that HCRT was one of the most siginificantly downregulated gene in the hippocampus of SD rats with CUMS compared to non-stressed group, which was validated by qRT-PCR. HCRT mRNA expression was downregulated and the promoter for HCRT was hyper-methylated in those with depression. These results identified a critical role for chronic psychological stressors in tumorigenesis and cancer progression, via epigenetic HCRT downregulation. Such epigenetic downregulation may be the molecular basis for the association of cancer with depression.展开更多
Background：Hypocretin （HCRT） signaling plays an important role in the pathogenesis of narcolepsy and can be significantly influenced by Chinese herbal therapy.Our previous study showed that xingshentongqiao decocti...Background：Hypocretin （HCRT） signaling plays an important role in the pathogenesis of narcolepsy and can be significantly influenced by Chinese herbal therapy.Our previous study showed that xingshentongqiao decoction （XSTQ） is clinically effective for the treatment of narcolepsy.To determine whether XSTQ improves narcolepsy by modulating HCRT signaling,we investigated its effects on SH-SY5Y cell proliferation,apoptosis,and HCRT receptor 1/2 （orexin receptor 1 [OXl R] and orexin receptor 2 [OX2R]） expression.The signaling pathways involved in these processes were also assessed.Methods：The effects of XSTQ on proliferation and apoptosis in SH-SY5Y cells were assessed using cell counting kit-8 and annexin V-fluorescein isothiocyanate assays.OX1R and OX2R expression was assessed by quantitative real-time polymerase chain reaction analysis.Western blotting for mitogen-activated protein kinase （MAPK） pathway activation was performed to further assess the signaling mechanism of XSTQ.Results：XSTQ reduced the proliferation and induced apoptosis of SH-SY5Y cells.This effect was accompanied by the upregulation of OX 1R and OX2R expression and the reduced phosphorylation of extracellular signal-regulated kinase （Erk） 1/2,p38 MAPK and c-Jun N-terminal kinase （JNK）.Conclusions：XSTQ inhibits proliferation and induces apoptosis in SH-SY5Y cells.XSTQ also promotes OX1R and OX2R expression.These effects are associated with the repression of the Erkl/2,p38 MAPK,and JNK signaling pathways.These results define a molecular mechanism for XSTQ in regulating HCRT and MAPK activation,which may explain its ability to treat narcolepsy.展开更多
文摘Hypocretins/orexins are crucial for the regulation of wakefulness by the excitatory actions on multiple subcortical arousal systems. In prefrontal cortex,
文摘Alzheimer's disease(AD) is a growing health problem. It has enormous public health impact. Sleep problems show an early component of this disease. Hypocretin hasa major function in sleep-wake cycle. The total number of hypocretin neurons in the normal humans ranges from 51000-83000, located exclusively in the hypothalamus. Deficiency in hypocretins neurotransmission results in narcolepsy, Parkinson's disease, and other neurological and psychological disorders. Cerebrospinal fluid(CSF) hypocretin levels were directly related with t-tau protein amount in AD. Increased hypocretin CSF in AD suggest that hypocretin is involved in the mechanism of AD pathology.
基金The study was supported by the National Natural Science Foundation of China (NSFC) (No.#81872380)the Opening Foundation of Chongqing Key Laboratory of Molecular Oncology and Epigenetics.
文摘Recent studies suggest that Hypocretin (HCRT, Orexin) are involved in stress regulation of depression through the hypothalamic-pituitary-adrenal (HPA) axis. However, the molecular mechanism by which Hypocretin regulate neurobiological responses is unknown. Herein, the effects of chronic stress on the epigenetic modification of HCRT and its association with depression were explored with regard to a potential role in cancer progression. In the study, Sprague Dawley (SD) rats were used to establish an animal model of cancer with depression by administrating n-nitrosodiethylamine (DEN) and chronic unpredictable mild stress (CUMS). RNA-sequencing was used to detect differentially expressed genes in the hippocampus of rats and quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the results of RNA-sequencing. The status of HCRT promoter methylation was assessed by methylation specific polymerase chain reaction. Behavioral tests showed that rats exposed to CUMS had significant depressive-like behaviors. The number of liver tumors and tumor load in depressed rats exposed to CUMS was higher than in SD rats without CUMS. RNA-sequencing revealed that HCRT was one of the most siginificantly downregulated gene in the hippocampus of SD rats with CUMS compared to non-stressed group, which was validated by qRT-PCR. HCRT mRNA expression was downregulated and the promoter for HCRT was hyper-methylated in those with depression. These results identified a critical role for chronic psychological stressors in tumorigenesis and cancer progression, via epigenetic HCRT downregulation. Such epigenetic downregulation may be the molecular basis for the association of cancer with depression.
文摘Background：Hypocretin （HCRT） signaling plays an important role in the pathogenesis of narcolepsy and can be significantly influenced by Chinese herbal therapy.Our previous study showed that xingshentongqiao decoction （XSTQ） is clinically effective for the treatment of narcolepsy.To determine whether XSTQ improves narcolepsy by modulating HCRT signaling,we investigated its effects on SH-SY5Y cell proliferation,apoptosis,and HCRT receptor 1/2 （orexin receptor 1 [OXl R] and orexin receptor 2 [OX2R]） expression.The signaling pathways involved in these processes were also assessed.Methods：The effects of XSTQ on proliferation and apoptosis in SH-SY5Y cells were assessed using cell counting kit-8 and annexin V-fluorescein isothiocyanate assays.OX1R and OX2R expression was assessed by quantitative real-time polymerase chain reaction analysis.Western blotting for mitogen-activated protein kinase （MAPK） pathway activation was performed to further assess the signaling mechanism of XSTQ.Results：XSTQ reduced the proliferation and induced apoptosis of SH-SY5Y cells.This effect was accompanied by the upregulation of OX 1R and OX2R expression and the reduced phosphorylation of extracellular signal-regulated kinase （Erk） 1/2,p38 MAPK and c-Jun N-terminal kinase （JNK）.Conclusions：XSTQ inhibits proliferation and induces apoptosis in SH-SY5Y cells.XSTQ also promotes OX1R and OX2R expression.These effects are associated with the repression of the Erkl/2,p38 MAPK,and JNK signaling pathways.These results define a molecular mechanism for XSTQ in regulating HCRT and MAPK activation,which may explain its ability to treat narcolepsy.
