There are two degradation systems in mammalian cells, autophagy/lysosomal pathway and ubiquitin-proteasome pathway. Proteasome is consist of multiple protein subunits and plays important roles in degradation of short-...There are two degradation systems in mammalian cells, autophagy/lysosomal pathway and ubiquitin-proteasome pathway. Proteasome is consist of multiple protein subunits and plays important roles in degradation of short-lived cellular proteins. Recent studies reveal that proteasomal degradation system is also involved in signal transduction and regulation of various cellular functions. Dysfunction or dysregulation of proteasomal function may thus be an important pathogenic mechanism in certain neurological disorders. This paper reviews the biological functions of proteasome in signal transduction and its potential roles in neurodegenerative diseases.展开更多
The research progress in molecular chaperones, unfolded protein response (UPR) and ER-associated degradation (ERAD) involved in the protein quality control was summarized in this paper, and then the existing probl...The research progress in molecular chaperones, unfolded protein response (UPR) and ER-associated degradation (ERAD) involved in the protein quality control was summarized in this paper, and then the existing problems and the future devel- opment prospect were also discussed. It was pointed out that the life process of protein experienced four stages including synthesizing, folding, assembling and degradation, while each stage required strict quality control. In endoplasmic reticulum (ER), a variety of proteins had been synthesized, folded and modified to form func- tional proteins with certain conformation. When the folding was blocked in ER, the unfolded proteins would aggregate and induce the UPR, which up-regulated the level of modification enzymes folded by a series of molecular chaperones and proteins to help them accomplish folding and assembling. If these proteins were still folded incorrectly, they would enter into ERAD for being degraded.展开更多
The discovery of intrinsically disordered proteins (IDP) (i.e., biologically active proteins that do not possess stable secondary and/or tertiary structures) came as an unexpected surprise, as the existence of suc...The discovery of intrinsically disordered proteins (IDP) (i.e., biologically active proteins that do not possess stable secondary and/or tertiary structures) came as an unexpected surprise, as the existence of such proteins is in contradiction to the traditional "sequence →structure →function" paradigm. Accurate prediction of a protein's predisposition to be intrinsically disordered is a necessary prerequisite for the further understanding of principles and mechanisms of protein folding and function, and is a key for the elaboration of a new structural and functional hierarchy of proteins. Therefore, prediction of IDPs has attracted the attention of many researchers, and a number of prediction tools have been developed. Predictions of disorder, in turn, are playing major roles in directing laboratory experiments that are leading to the discovery of ever more disordered proteins, and thereby leading to a positive feedback loop in the investigation of these proteins. In this review of algorithms for intrinsic disorder prediction, the basic concepts of various prediction methods for IDPs are summarized, the strengths and shortcomings of many of the methods are analyzed, and the difficulties and directions of future development of IDP prediction techniques are discussed.展开更多
Efficient functioning of the endoplasmic reticulum(ER) is very important for most cellular activities, such as protein folding and modification. The ER closely interacts with other organelles, including the Golgi body...Efficient functioning of the endoplasmic reticulum(ER) is very important for most cellular activities, such as protein folding and modification. The ER closely interacts with other organelles, including the Golgi body, endosome, membrane, and mitochondria, providing lipids and proteins for the repair of these organelles. ER stress can be induced by various abnormal materials in the cell. ER stress is a compensatory intracellular environment disorder that occurs during areaction. ER can sense the stress and respond to it through translational attenuation, upregulation of the genes for ER chaperones and related proteins, and degradation of unfolded proteins by a quality-control system, but excessive ER activation can cause cell death. The Pubmed and Web of Science databases were searched for full-text articles, and the terms "endoplasmic reticulum stress/unfolded protein response/gynecologic tumor cell apoptosis" were used as key words. Thirty-five studies of ER stress and unfolded protein response published from 2000 to 2016 were analyzed. Stress triggers apoptosis through a variety of signaling pathways. Increasing evidence has shown that the ER plays an important role in tumor cell diseases. The present review discusses the molecular mechanisms underlying unfolded protein response and its ability to promote survival and proliferation in gynecologic tumor cells.展开更多
Green fluorescent protein (GFP) and its variants /homolog proteins are generally called as GFP-like fluorescent proteins (FPs), which are widely used as visible molecular tools for monitoring a wide range of biologica...Green fluorescent protein (GFP) and its variants /homolog proteins are generally called as GFP-like fluorescent proteins (FPs), which are widely used as visible molecular tools for monitoring a wide range of biological processes due to their capability of simple, accurate and real time quantification. The FPs-based molecular and visible quantification tools are giving more impact on bioprocess engineering, enabling the biomolecule-level dynamic information to be linked with the process-level events. In this review, different applications of FPs in biological engineering with emphasis on rapid molecular bioprocess quantification, such as quantification of the transcription efficiency, the protein production, the protein folding efficiency, the cell concentration, the intracellular microenvironments and so on, would be first introduced. The challenges of using FPs with respect to actual bioprocess applications for the precise quantification including the interaction of FPs and the fused partner proteins, the maturation of FPs, the inner filter effect and sensing technology were then discussed. Finally, the future development for the FPs used in molecular bioprocess quantification would be proposed.展开更多
Members of the Dna J family are proteins that play a pivotal role in various cellular processes, such as protein folding, protein transport and cellular responses to stress. In the present study, we identified and cha...Members of the Dna J family are proteins that play a pivotal role in various cellular processes, such as protein folding, protein transport and cellular responses to stress. In the present study, we identified and characterized the full-length Dna J c DNA sequence from expressed sequence tags of Pyropia yezoensis( Py Dna J) via rapid identification of c DNA ends. This c DNA encoded a protein of 429 amino acids, which shared high sequence similarity with other identified Dna J proteins, such as a heat shock protein 40/Dna J from Pyropia haitanensis. The relative m RNA expression level of Py Dna J was investigated using real-time PCR to determine its specific expression during the algal life cycle and during desiccation. The relative m RNA expression level in sporophytes was higher than that in gametophytes and significantly increased during the whole desiccation process. These results indicate that Py Dna J is an authentic member of the Dna J family in plants and red algae and might play a pivotal role in mitigating damage to P. yezoensis during desiccation.展开更多
Molecular kinetics underlies all biological phenomena and, like many other biological processes, may best be understood in terms of networks. These networks, called Markov state models (MSMs), are typically built fr...Molecular kinetics underlies all biological phenomena and, like many other biological processes, may best be understood in terms of networks. These networks, called Markov state models (MSMs), are typically built from physical simulations. Thus, they are capable of quantitative prediction of experiments and can also provide an intuition for complex couformational changes. Their primary application has been to protein folding; however, these technologies and the insights they yield are transferable. For example, MSMs have already proved useful in understanding human diseases, such as protein misfolding and aggregation in Alzheimer's disease.展开更多
We study a three-dimensional off-lattice protein folding model, which involves two species of residues interacting through Lennard-Jones potentials. By incorporating an extra energy contribution into the original pote...We study a three-dimensional off-lattice protein folding model, which involves two species of residues interacting through Lennard-Jones potentials. By incorporating an extra energy contribution into the original potential function, we replace the original constrained problem with an unconstrained minimization of a mixed potential function. As such an efficient quasi-physical algorithm for solving the protein folding problem is presented. We apply the proposed algorithm to sequences with up to 55 residues and compare the computational results with the putative lowest energy found by several of the most famous algorithms, showing the advantages of our method. The dynamic behavior of the quasi-physlcal algorithm is also discussed.展开更多
Peripheral neuropathies refer to a group of conditions in which the peripheral nervous system(PNS)is damaged.These pathological state are are associated with weakness,pain,and loss of motor and sensory control.More th...Peripheral neuropathies refer to a group of conditions in which the peripheral nervous system(PNS)is damaged.These pathological state are are associated with weakness,pain,and loss of motor and sensory control.More than 100 types of peripheral neuropathies have been identified,with distinct symptoms and prognosis classified according to the type of damage to the nerves.Injury to peripheral nerves results in disabling loss of sensory and motor func-展开更多
β-Crystallins are the major structural proteins existing in the vertebrate lens, and their conformational stability is critical in maintaining the life-long transparency and refraction index of the lens. Seven subuni...β-Crystallins are the major structural proteins existing in the vertebrate lens, and their conformational stability is critical in maintaining the life-long transparency and refraction index of the lens. Seven subunits of β-crystallins naturally assemble into various heteroge- neous oligomers with different sizes. Here, we systematically investigated the thermal sta- bility of the different secondary structures present in β-Crystallins and then the dynamic process for the thermal-induced unfolding of β-crystallins by Fourier transform infrared spectroscopy-monitored thermal titration and temperature-jump nanosecond time-resolved IR difference absorbance spectra. Our results show that the N-terminal anti-parallel β-sheets in β-crystallin are the most unstable with a transition midpoint temperature at 36.0-2.1℃, leading to the formation of an intermediate consisting vastly of random coil structures. This intermediate structure is temporally assigned to that of the monomer generated by the thermal-induced disassembly of β-crystallin oligomers with a transition midpoint tempera- ture of 40.4-0.7℃. The global unfolding of β-crystallins that leads to denaturation and aggregation indicated by the formation of intermolecular anti-parallel β-sheets has a transi- tion midpoint temperature determined as 72.4-0.2 ℃. Temperature-jump time-resolved IR absorbance difference spectroscopy analysis further reveals that thermal-induced unfolding of β-crystallins occurs firstly in the anti-parallel β-sheets in the N-terminal domains with a time constant of 50 ns.展开更多
The response to endoplasmic reticulum(ER)stress has been noted in both human depression cases and depression models in rodents.Wuling powder,derived from the mycelium of the esteemed fungus Xylaria Nigripes(Kl.)Sacc,h...The response to endoplasmic reticulum(ER)stress has been noted in both human depression cases and depression models in rodents.Wuling powder,derived from the mycelium of the esteemed fungus Xylaria Nigripes(Kl.)Sacc,has demonstrated efficacy in alleviating depressive symptoms.The purpose of this research was to explore the antidepressant properties of Wuling powder and its basic molecular effects,particularly regarding alterations in ER stress.A model of social defeat stress was created by introducing a mouse to the cage of an unfamiliar,hostile mouse for intervals of 5–10 min daily over a span of 10 d.Subsequently,the mice received oral doses of Wuling powder for 2 weeks.The social approach-avoidance assay was employed to evaluate signs of depression-like behaviors.Moreover,protein and gene expressions linked to ER stress triggered by social defeat were analyzed through Western blotting analysis and quantitative real-time PCR.The behavioral tests indicated that Wuling powder ameliorated behaviors associated with depression due to social defeat stress.Treatment with Wuling powder markedly reduced the increased levels of the 78-k Da glucose-regulated protein and protein disulfide isomerase caused by social defeat stress.It also diminished the expression of inositol-requiring enzyme 1α(IRE1α)and spliced X box-binding protein-1(s XBP1)at the protein and m RNA levels.Furthermore,Wuling treatment notably decreased the levels of phosphorylated eukaryotic initiation factor 2 alpha kinase(P-e IF2α),activating transcription factor 4(ATF4)and C/EBP homologous protein(CHOP),simultaneously enhancing the ratio of B-cell lymphoma 2(Bcl-2)to Bcl-2-associated X protein(Bax).These results suggested that Wuling powder could alleviate ER stress and inhibit cell apoptosis in the hippocampus by inhibiting protein translation and synthesis,thereby attenuating depressive-like behavior.展开更多
Within the cell, several mechanisms exist to maintain homeostasis of the endoplasmic reticulum (ER). One of the primary mechanisms is the unfolded protein response (UPR). In this review, we primarily focus on the ...Within the cell, several mechanisms exist to maintain homeostasis of the endoplasmic reticulum (ER). One of the primary mechanisms is the unfolded protein response (UPR). In this review, we primarily focus on the latest signal webs and regulation mechanisms of the UPR. The relationships among ER stress, apoptosis, and cancer are also discussed. Under the normal state, binding immunoglobulin protein (BiP) interacts with the three sensors (protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme la (IREla)) Under ER stress, misfolded proteins interact with BiP, resulting in the release of BiP from the sensors. Subsequently, the three sensors dimerize and autophosphorylate to promote the signal cascades of ER stress. ER stress includes a series of positive and negative feedback signals, such as those regulating the stabilization of the sensors/BiP complex, activating and inactivating the sensors by autophosphorylation and dephosphorylation, activating specific transcription factors to enable selective transcription, and augmenting the ability to refold and export. Apart from the three basic pathways, vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR)-phospholipase C-~ (PLCy)-mammalian target of rapamycin complex 1 (mTORC1) pathway, induced only in solid tumors, can also activate ATF6 and PERK signal cascades, and IREla also can be activated by activated RAC-alpha serine/threonine-protein kinase (AKT). A moderate UPR functions as a pro-survival signal to return the cell to its state of homeostasis. However, persistent ER stress will induce cells to undergo apoptosis in response to increasing reactive oxygen species (ROS), Ca2+ in the cytoplasmic matrix, and other apoptosis signal cascades, such as c-Jun N-terminal kinase (JNK), signal transducer and activator of transcription 3 (STAT3), and P38, when cellular damage exceeds the capacity of this adaptive response.展开更多
Porcine circovirus type 2(PCV2)has recently been reported to elicit the unfolded protein response(UPR)via activation of the PERK/e IF2α(RNA-activated protein kinase-like endoplasmic reticulum(ER)kinase/eukaryo...Porcine circovirus type 2(PCV2)has recently been reported to elicit the unfolded protein response(UPR)via activation of the PERK/e IF2α(RNA-activated protein kinase-like endoplasmic reticulum(ER)kinase/eukaryotic initiation factor 2α)pathway.This study attempted to examine which viral protein might be involved in inducing UPR and whether this cellular event would lead to apoptosis of the cells expressing the viral protein.By transient expression,we found that both replicase(Rep)and capsid(Cap)proteins of PCV2 could induce ER stress as shown by increased phosphorylation of PERK with subsequent activation of the eI F2α-ATF4(activating transcription factor 4)-CHOP(CCAAT/enhancer-binding protein homologous protein)axis.Cap expression,but not Rep,significantly reduced antiapoptotic B-cell lymphoma-2(Bcl-2)and increased caspase-3 cleavage,possibly due to increased expression of CHOP.Since knockdown of PERK by RNA interference clearly reduced Cap-induced CHOP expression,caspase-3cleavage,and apoptotic cell death possibly by partially rescuing Bcl-2 expression,we propose that there is connection between Cap-induced UPR and apoptosis via the PERK/eI F2α/ATF4/CHOP/Bcl-2 pathway.This study,together with our earlier studies,provides insight into the mechanisms underlying PCV2 pathogenesis.展开更多
基金This work was supported by the National Natural Science Foundation of China (No. 30470587, No. 30600197).
文摘There are two degradation systems in mammalian cells, autophagy/lysosomal pathway and ubiquitin-proteasome pathway. Proteasome is consist of multiple protein subunits and plays important roles in degradation of short-lived cellular proteins. Recent studies reveal that proteasomal degradation system is also involved in signal transduction and regulation of various cellular functions. Dysfunction or dysregulation of proteasomal function may thus be an important pathogenic mechanism in certain neurological disorders. This paper reviews the biological functions of proteasome in signal transduction and its potential roles in neurodegenerative diseases.
基金Supported by National Natural Science Foundation of China (Grant No.30840002,30970223)Science Foundation for Returned Chinese Scholars in Heilongjiang (Grant No.LC08C03)+3 种基金Specialized Fund for Basic Scientific Research in Higher Education Institutions of China (Grant No.DL09DA02)Scientific Research Starting Foundation for Introduced Talents in Northeast Forestry University (Grant No.015-602042)National Science Foundation for Post-doctoral Scientists of China (Grant No.200902365)Preferred Foundation of Science-Technology Program for Returned Chinese Scholars in Heilongjiang (Grant No.2009-HLJLixinLi)~~
文摘The research progress in molecular chaperones, unfolded protein response (UPR) and ER-associated degradation (ERAD) involved in the protein quality control was summarized in this paper, and then the existing problems and the future devel- opment prospect were also discussed. It was pointed out that the life process of protein experienced four stages including synthesizing, folding, assembling and degradation, while each stage required strict quality control. In endoplasmic reticulum (ER), a variety of proteins had been synthesized, folded and modified to form func- tional proteins with certain conformation. When the folding was blocked in ER, the unfolded proteins would aggregate and induce the UPR, which up-regulated the level of modification enzymes folded by a series of molecular chaperones and proteins to help them accomplish folding and assembling. If these proteins were still folded incorrectly, they would enter into ERAD for being degraded.
文摘The discovery of intrinsically disordered proteins (IDP) (i.e., biologically active proteins that do not possess stable secondary and/or tertiary structures) came as an unexpected surprise, as the existence of such proteins is in contradiction to the traditional "sequence →structure →function" paradigm. Accurate prediction of a protein's predisposition to be intrinsically disordered is a necessary prerequisite for the further understanding of principles and mechanisms of protein folding and function, and is a key for the elaboration of a new structural and functional hierarchy of proteins. Therefore, prediction of IDPs has attracted the attention of many researchers, and a number of prediction tools have been developed. Predictions of disorder, in turn, are playing major roles in directing laboratory experiments that are leading to the discovery of ever more disordered proteins, and thereby leading to a positive feedback loop in the investigation of these proteins. In this review of algorithms for intrinsic disorder prediction, the basic concepts of various prediction methods for IDPs are summarized, the strengths and shortcomings of many of the methods are analyzed, and the difficulties and directions of future development of IDP prediction techniques are discussed.
文摘Efficient functioning of the endoplasmic reticulum(ER) is very important for most cellular activities, such as protein folding and modification. The ER closely interacts with other organelles, including the Golgi body, endosome, membrane, and mitochondria, providing lipids and proteins for the repair of these organelles. ER stress can be induced by various abnormal materials in the cell. ER stress is a compensatory intracellular environment disorder that occurs during areaction. ER can sense the stress and respond to it through translational attenuation, upregulation of the genes for ER chaperones and related proteins, and degradation of unfolded proteins by a quality-control system, but excessive ER activation can cause cell death. The Pubmed and Web of Science databases were searched for full-text articles, and the terms "endoplasmic reticulum stress/unfolded protein response/gynecologic tumor cell apoptosis" were used as key words. Thirty-five studies of ER stress and unfolded protein response published from 2000 to 2016 were analyzed. Stress triggers apoptosis through a variety of signaling pathways. Increasing evidence has shown that the ER plays an important role in tumor cell diseases. The present review discusses the molecular mechanisms underlying unfolded protein response and its ability to promote survival and proliferation in gynecologic tumor cells.
基金Supported by the National Natural Science Foundation of China (20836004 20806046) the Special Fund for Major State Basic Research Program of China (2009CB724702) the National High Technology Research and Development Program ofChina (2009AA062903)
文摘Green fluorescent protein (GFP) and its variants /homolog proteins are generally called as GFP-like fluorescent proteins (FPs), which are widely used as visible molecular tools for monitoring a wide range of biological processes due to their capability of simple, accurate and real time quantification. The FPs-based molecular and visible quantification tools are giving more impact on bioprocess engineering, enabling the biomolecule-level dynamic information to be linked with the process-level events. In this review, different applications of FPs in biological engineering with emphasis on rapid molecular bioprocess quantification, such as quantification of the transcription efficiency, the protein production, the protein folding efficiency, the cell concentration, the intracellular microenvironments and so on, would be first introduced. The challenges of using FPs with respect to actual bioprocess applications for the precise quantification including the interaction of FPs and the fused partner proteins, the maturation of FPs, the inner filter effect and sensing technology were then discussed. Finally, the future development for the FPs used in molecular bioprocess quantification would be proposed.
基金Supported by the National Natural Science Foundation of China(No.41476091)
文摘Members of the Dna J family are proteins that play a pivotal role in various cellular processes, such as protein folding, protein transport and cellular responses to stress. In the present study, we identified and characterized the full-length Dna J c DNA sequence from expressed sequence tags of Pyropia yezoensis( Py Dna J) via rapid identification of c DNA ends. This c DNA encoded a protein of 429 amino acids, which shared high sequence similarity with other identified Dna J proteins, such as a heat shock protein 40/Dna J from Pyropia haitanensis. The relative m RNA expression level of Py Dna J was investigated using real-time PCR to determine its specific expression during the algal life cycle and during desiccation. The relative m RNA expression level in sporophytes was higher than that in gametophytes and significantly increased during the whole desiccation process. These results indicate that Py Dna J is an authentic member of the Dna J family in plants and red algae and might play a pivotal role in mitigating damage to P. yezoensis during desiccation.
文摘Molecular kinetics underlies all biological phenomena and, like many other biological processes, may best be understood in terms of networks. These networks, called Markov state models (MSMs), are typically built from physical simulations. Thus, they are capable of quantitative prediction of experiments and can also provide an intuition for complex couformational changes. Their primary application has been to protein folding; however, these technologies and the insights they yield are transferable. For example, MSMs have already proved useful in understanding human diseases, such as protein misfolding and aggregation in Alzheimer's disease.
基金The project partially supported by National Key Basic Research Project of China under Grant No. 2004GB318000 and National Natural Science Foundation of China under Grant No. 10471051
文摘We study a three-dimensional off-lattice protein folding model, which involves two species of residues interacting through Lennard-Jones potentials. By incorporating an extra energy contribution into the original potential function, we replace the original constrained problem with an unconstrained minimization of a mixed potential function. As such an efficient quasi-physical algorithm for solving the protein folding problem is presented. We apply the proposed algorithm to sequences with up to 55 residues and compare the computational results with the putative lowest energy found by several of the most famous algorithms, showing the advantages of our method. The dynamic behavior of the quasi-physlcal algorithm is also discussed.
基金funded by FONDAP program 15150012(to CH and FAC)Millennium Institute,No.P09-015-F+12 种基金the Frick Foundation 20014-15ALS Therapy Alliance 2014-F-059Muscular Dystrophy Association 382453CONICYT-USA 2013-0003Michael J Fox Foundation for Parkinson′s Research–Target Validation grant No.9277COPEC-UC Foundation 2013.R.40Ecos-Conicyt C13S02FONDECYT No.1140549Office of Naval Research-Global(ONR-G)N62909-16-1-2003ALSRP Therapeutic Idea Award AL150111(to CH)Millennium Nucleus-P-07-011-FFONDECYT,No.1110987(to FAC)PhD fellow supported by CONICYT,No.21130843(to MO)
文摘Peripheral neuropathies refer to a group of conditions in which the peripheral nervous system(PNS)is damaged.These pathological state are are associated with weakness,pain,and loss of motor and sensory control.More than 100 types of peripheral neuropathies have been identified,with distinct symptoms and prognosis classified according to the type of damage to the nerves.Injury to peripheral nerves results in disabling loss of sensory and motor func-
文摘β-Crystallins are the major structural proteins existing in the vertebrate lens, and their conformational stability is critical in maintaining the life-long transparency and refraction index of the lens. Seven subunits of β-crystallins naturally assemble into various heteroge- neous oligomers with different sizes. Here, we systematically investigated the thermal sta- bility of the different secondary structures present in β-Crystallins and then the dynamic process for the thermal-induced unfolding of β-crystallins by Fourier transform infrared spectroscopy-monitored thermal titration and temperature-jump nanosecond time-resolved IR difference absorbance spectra. Our results show that the N-terminal anti-parallel β-sheets in β-crystallin are the most unstable with a transition midpoint temperature at 36.0-2.1℃, leading to the formation of an intermediate consisting vastly of random coil structures. This intermediate structure is temporally assigned to that of the monomer generated by the thermal-induced disassembly of β-crystallin oligomers with a transition midpoint tempera- ture of 40.4-0.7℃. The global unfolding of β-crystallins that leads to denaturation and aggregation indicated by the formation of intermolecular anti-parallel β-sheets has a transi- tion midpoint temperature determined as 72.4-0.2 ℃. Temperature-jump time-resolved IR absorbance difference spectroscopy analysis further reveals that thermal-induced unfolding of β-crystallins occurs firstly in the anti-parallel β-sheets in the N-terminal domains with a time constant of 50 ns.
基金National Natural Science Foundation of China(Grant No.81100801 and 81050025)the foundation of Zhejiang Jolly Pharmaceutical Co.,Ltd.
文摘The response to endoplasmic reticulum(ER)stress has been noted in both human depression cases and depression models in rodents.Wuling powder,derived from the mycelium of the esteemed fungus Xylaria Nigripes(Kl.)Sacc,has demonstrated efficacy in alleviating depressive symptoms.The purpose of this research was to explore the antidepressant properties of Wuling powder and its basic molecular effects,particularly regarding alterations in ER stress.A model of social defeat stress was created by introducing a mouse to the cage of an unfamiliar,hostile mouse for intervals of 5–10 min daily over a span of 10 d.Subsequently,the mice received oral doses of Wuling powder for 2 weeks.The social approach-avoidance assay was employed to evaluate signs of depression-like behaviors.Moreover,protein and gene expressions linked to ER stress triggered by social defeat were analyzed through Western blotting analysis and quantitative real-time PCR.The behavioral tests indicated that Wuling powder ameliorated behaviors associated with depression due to social defeat stress.Treatment with Wuling powder markedly reduced the increased levels of the 78-k Da glucose-regulated protein and protein disulfide isomerase caused by social defeat stress.It also diminished the expression of inositol-requiring enzyme 1α(IRE1α)and spliced X box-binding protein-1(s XBP1)at the protein and m RNA levels.Furthermore,Wuling treatment notably decreased the levels of phosphorylated eukaryotic initiation factor 2 alpha kinase(P-e IF2α),activating transcription factor 4(ATF4)and C/EBP homologous protein(CHOP),simultaneously enhancing the ratio of B-cell lymphoma 2(Bcl-2)to Bcl-2-associated X protein(Bax).These results suggested that Wuling powder could alleviate ER stress and inhibit cell apoptosis in the hippocampus by inhibiting protein translation and synthesis,thereby attenuating depressive-like behavior.
基金Project supported by the National Basic Research Program(973)of China(No.2012CB518900)the National Natural Science Foundation of China(Nos.31160240 and 31260621)+2 种基金the National Major Scientific and Technological Special Project during the Twelfth Five-year Plan Period of China(No.2012ZX10002006)the Hangzhou Normal University Supporting Project(No.PE13002004042)the Natural Science Foundation of Jiangxi Province(No.20114BAB204016),China
文摘Within the cell, several mechanisms exist to maintain homeostasis of the endoplasmic reticulum (ER). One of the primary mechanisms is the unfolded protein response (UPR). In this review, we primarily focus on the latest signal webs and regulation mechanisms of the UPR. The relationships among ER stress, apoptosis, and cancer are also discussed. Under the normal state, binding immunoglobulin protein (BiP) interacts with the three sensors (protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme la (IREla)) Under ER stress, misfolded proteins interact with BiP, resulting in the release of BiP from the sensors. Subsequently, the three sensors dimerize and autophosphorylate to promote the signal cascades of ER stress. ER stress includes a series of positive and negative feedback signals, such as those regulating the stabilization of the sensors/BiP complex, activating and inactivating the sensors by autophosphorylation and dephosphorylation, activating specific transcription factors to enable selective transcription, and augmenting the ability to refold and export. Apart from the three basic pathways, vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR)-phospholipase C-~ (PLCy)-mammalian target of rapamycin complex 1 (mTORC1) pathway, induced only in solid tumors, can also activate ATF6 and PERK signal cascades, and IREla also can be activated by activated RAC-alpha serine/threonine-protein kinase (AKT). A moderate UPR functions as a pro-survival signal to return the cell to its state of homeostasis. However, persistent ER stress will induce cells to undergo apoptosis in response to increasing reactive oxygen species (ROS), Ca2+ in the cytoplasmic matrix, and other apoptosis signal cascades, such as c-Jun N-terminal kinase (JNK), signal transducer and activator of transcription 3 (STAT3), and P38, when cellular damage exceeds the capacity of this adaptive response.
基金supported by the National Natural Science Foundation of China(No.31272534)the Department of Education of Zhejiang Province(No.Y201635576),China
文摘Porcine circovirus type 2(PCV2)has recently been reported to elicit the unfolded protein response(UPR)via activation of the PERK/e IF2α(RNA-activated protein kinase-like endoplasmic reticulum(ER)kinase/eukaryotic initiation factor 2α)pathway.This study attempted to examine which viral protein might be involved in inducing UPR and whether this cellular event would lead to apoptosis of the cells expressing the viral protein.By transient expression,we found that both replicase(Rep)and capsid(Cap)proteins of PCV2 could induce ER stress as shown by increased phosphorylation of PERK with subsequent activation of the eI F2α-ATF4(activating transcription factor 4)-CHOP(CCAAT/enhancer-binding protein homologous protein)axis.Cap expression,but not Rep,significantly reduced antiapoptotic B-cell lymphoma-2(Bcl-2)and increased caspase-3 cleavage,possibly due to increased expression of CHOP.Since knockdown of PERK by RNA interference clearly reduced Cap-induced CHOP expression,caspase-3cleavage,and apoptotic cell death possibly by partially rescuing Bcl-2 expression,we propose that there is connection between Cap-induced UPR and apoptosis via the PERK/eI F2α/ATF4/CHOP/Bcl-2 pathway.This study,together with our earlier studies,provides insight into the mechanisms underlying PCV2 pathogenesis.