For the first time, the fertility of rice genic male sterile line was partially restored with the application of chemical regulators at Hainan Rice Breeding Nursery on Mar 1993. A single panicle of the rice plant coul...For the first time, the fertility of rice genic male sterile line was partially restored with the application of chemical regulators at Hainan Rice Breeding Nursery on Mar 1993. A single panicle of the rice plant could bear as many as 27 grains. The chemical agent that could modulate the growth of the rice plants of genic male sterile line was developed by Prof ZHOU Guangqia and his colleagues at the Biology Institute, Hunan Teachers University, China.展开更多
Liver fibrosis is an important health problem that can further progress into cirrhosis or liver cancer,and result in significant morbidity and mortality. Inhibiting proliferation and inducing apoptosis of hepatic stel...Liver fibrosis is an important health problem that can further progress into cirrhosis or liver cancer,and result in significant morbidity and mortality. Inhibiting proliferation and inducing apoptosis of hepatic stellate cells（HSCs） may be the key point to reverse liver fibrosis. At present,anti-fibrosis drugs are rare. Kinetin is a type of plant-derived cytokinin which has been reported to control differentiation and induce apoptosis of human cells. In this study,the HSCs were incubated with different concentrations of kinetin. The proliferation of rat HSCs was measured by MTT assay,cell cycle and apoptosis were analyzed by flow cytometry,and the apoptosis was examined by TUNEL method. The expression of Bcl-2 and Bax proteins was detected by immunocytochemistry staining. It was found that kinetin could markedly inhibit proliferation of HSCs. In a concentration range of 2 to 8 μg/m L,the inhibitory effects of kinetin on proliferation of HSCs were increased with the increased concentration and the extension of time（P〈0.01）. Flow cytometry indicated that kinetin could inhibit the DNA synthesis from G0/G1 to S phase in a dose-dependent manner（P〈0.01）. The apoptosis rates of the HSCs treated with 8,4 and 2 μg/m L kinetin（25.62%±2.21%,15.31%±1.9% and 6.18%±1.23%,respectively） were increased significantly compared with the control group（3.81%±0.93%）（P〈0.01）. All the DNA frequency histogram in kinetin-treated groups showed obvious hypodiploid peak（sub-G1 peak）,and with the increase of kinetin concentrations,the apoptosis rate of HSCs also showed a trend of increase. It was also found that kinetin could down-regulate the expression of Bcl-2,and up-regulate the expression of Bax,leading to the decreased ratio of Bcl-2/Bax significantly. The kinetin-induced apoptosis of HSCs was positively correlated with the expression of Bax,and negatively with the expression of Bcl-2. It was concluded that kinetin can inhibit activation and proliferation of HSCs by interrupting the cell cycle at G1/S restriction point and inducing apoptosis of HSCs via reducing the ratio of Bcl-2/Bax.展开更多
Studies on a variety of highly regenerative tissues, including the central nervous system（CNS） in non-mammalian vertebrates, have consistently demonstrated that tissue damage induces the formation of an ionic curren...Studies on a variety of highly regenerative tissues, including the central nervous system（CNS） in non-mammalian vertebrates, have consistently demonstrated that tissue damage induces the formation of an ionic current at the site of injury. These injury currents generate electric fields（EF） that are 100-fold increased in intensity over that measured for uninjured tissue. In vitro and in vivo experiments have convincingly demonstrated that these electric fields（by their orientation, intensity and duration） can drive the migration, proliferation and differentiation of a host of cell types. These cellular behaviors are all necessary to facilitate regeneration as blocking these EFs at the site of injury inhibits tissue repair while enhancing their intensity promotes repair. Consequently, injury-induced currents, and the EFs they produce, represent a potent and crucial signal to drive tissue regeneration and repair. In this review, we will discuss how injury currents are generated, how cells detect these currents and what cellular responses they can induce. Additionally, we will describe the growing evidence suggesting that EFs play a key role in regulating the cellular response to injury and may be a therapeutic target for inducing regeneration in the mammalian CNS.展开更多
Taking advantage of the fast-growing knowledge of RNA-binding proteins(RBPs)we review the signature of downregulated genes for RBPs in the transcriptome of induced pluripotent stem cell neurons(iNeurons)modelling the ...Taking advantage of the fast-growing knowledge of RNA-binding proteins(RBPs)we review the signature of downregulated genes for RBPs in the transcriptome of induced pluripotent stem cell neurons(iNeurons)modelling the neurodevelopmental Rubinstein Taybi Syndrome(RSTS)caused by mutations in the genes encoding CBP/p300 acetyltransferases.We discuss top and functionally connected downregulated genes sorted to“RNA processing”and“Ribonucleoprotein complex biogenesis”Gene Ontology clusters.The first set of downregulated RBPs includes members of hnRNHP(A1,A2B1,D,G,H2-H1,MAGOHB,PAPBC),core subunits of U small nuclear ribonucleoproteins and Serine-Arginine splicing regulators families,acting in precursor messenger RNA alternative splicing and processing.Consistent with literature findings on reduced transcript levels of serine/arginine repetitive matrix 4(SRRM4)protein,the main regulator of the neural-specific microexons splicing program upon depletion of Ep300 and Crebbp in mouse neurons,RSTS iNeurons show downregulated genes for proteins impacting this network.We link downregulated genes to neurological disorders including the new HNRNPH1-related intellectual disability syndrome with clinical overlap to RSTS.The set of downregulated genes for Ribosome biogenesis includes several components of ribosomal subunits and nucleolar proteins,such NOP58 and fibrillarin that form complexes with snoRNAs with a central role in guiding post-transcriptional modifications needed for rRNA maturation.These nucleolar proteins are“dual”players as fibrillarin is also required for epigenetic regulation of ribosomal genes and conversely NOP58-associated snoRNA levels are under the control of NOP58 interactor BMAL1,a transcriptional regulator of the circadian rhythm.Additional downregulated genes for“dual specificity”RBPs such as RUVBL1 and METTL1 highlight the links between chromatin and the RBP-ome and the contribution of perturbations in their cross-talk to RSTS.We underline the hub position of CBP/p300 in chromatin regulation,the impact of its defect on neurons’post-transcriptional regulation of gene expression and the potential use of epidrugs in therapeutics of RBP-caused neurodevelopmental disorders.展开更多
Objective:To dig deeper into the traditional Chinese medicine treatment rules of chemotherapy-induced diarrhea with traditional Chinese medicine(TCM)inheritance computing platform system.Methods:Taking“traditional Ch...Objective:To dig deeper into the traditional Chinese medicine treatment rules of chemotherapy-induced diarrhea with traditional Chinese medicine(TCM)inheritance computing platform system.Methods:Taking“traditional Chinese medicine”,“chemotherapy”and“diarrhea”as the theme words,comprehensive search of the database of CNKI,Wanfang and VIP from its inception to November 2020 was conduct-ed.The formulas of external treatment of traditional Chinese medicine for chemotherapy-induced diarrhea were included and the association rule,clustering and factor analysis were carried out.Results:A total of 145 papers,57 prescriptions meeting the inclusion criteria were collected,among which high-frequency drugs including Baizhu(Atractylodis macrocephalae rhizoma),Fuling(Poria),Dangshen(Codonopsisradix),Huanglian(Coptidis rhizoma),Zhigancao(Glycyrrhizae radix et rhizoma praeparata cum melle)were the most commonly used.The confidence level was set as 0.7 and the support level was set as 10,12 core compatibility groups were obtained,and 6 categories were cluster analyzed.Conclusion:The principle of external treatment of chemotherapy-induced diarrhea is mainly“restore deficiency and benefiting qi”,“benefiting water infiltration and dampness”,“clearing heat”and“inducing astringency”.Prescription combination and new prescription combination based on traditional Chinese medicine(TCM)inheritance computing platform system can be used as reference for clinicians and applied in primary hospitals.展开更多
Objective To study the changes of prodynorphin （PDyn） gene expression and dopamine and cAMPregulated phosphoprotein of 32 kDa （DARPP-32） phosphorylation in rats with levodopa-induced dyskinesias （LID）, and to ex...Objective To study the changes of prodynorphin （PDyn） gene expression and dopamine and cAMPregulated phosphoprotein of 32 kDa （DARPP-32） phosphorylation in rats with levodopa-induced dyskinesias （LID）, and to explore the mechanism of over-activation in direct pathway mediated by dopamine D1 receptor. Methods Parkinson＇s disease （PD） rats were received levodopa （10 mg/kg, i.p.） for 28 d to get the LID rats. According to the behavior scale, LID rats were divided into mild （n=8） and severe （n=16） groups. On day 29, 8 rats in severe LID group were given an acute intraperitoneal injection of MK-801 （0.1 mg/kg） 15 min before levodopa treatment （MK-801 group, n=8）. The normal rats received same course and dosage of levodopa as the control group （n=8）. Hybridization in situ was used to measure the expression of PDyn mRNA in striatum. Protein and mRNA levels of total DARPP-32 and phospho-Thr-34 DARPP-32 level were measured by immunoblotting and RT-PCR, respectively. Results The levels of PDyn mRNA and phospho-Thr-34 DARPP-32 increased significantly in LID rats compared with control rats （P〈0.01）, and they also increased markedly in severe LID group compared with mild group （P〈0.01）. Conclusion Phospho-Thr-34 DARPP-32 level was increased in LID rats, which contributed to the over-activation of direct pathway mediated by dopamine D1 receptor.展开更多
Cold-inducible RNA-binding protein（CIRP）, a key regulatory protein, could be facilitated by mild hypothermia in the brain, heart and liver. This study observed the effects of mild hypothermia at 31 ± 0.5℃ on t...Cold-inducible RNA-binding protein（CIRP）, a key regulatory protein, could be facilitated by mild hypothermia in the brain, heart and liver. This study observed the effects of mild hypothermia at 31 ± 0.5℃ on traumatic brain injury in rats. Results demonstrated that mild hypothermia suppressed apoptosis in the cortex, hippocampus and hypothalamus, facilitated CIRP m RNA and protein expression in these regions, especially in the hypothalamus. The anti-apoptotic effect of mild hypothermia disappeared after CIRP silencing. There was no correlation between mitogen-activated extracellular signal-regulated kinase activation and CIRP silencing. CIRP silencing inhibited extracellular signal-regulated kinase-1/2 activation. These indicate that CIRP inhibits apoptosis by affecting extracellular signal-regulated kinase-1/2 activation, and exerts a neuroprotective effect during mild hypothermia for traumatic brain injury.展开更多
Plasmid expressing small interfering RNA （siRNA） against HIF-1α （pSilence-2.1-U6-siRNA） was constructed and transfected into LS174T cells in hypoxia condition.After expression of siRNA against HIF-1 α in LS174T ...Plasmid expressing small interfering RNA （siRNA） against HIF-1α （pSilence-2.1-U6-siRNA） was constructed and transfected into LS174T cells in hypoxia condition.After expression of siRNA against HIF-1 α in LS174T cells, expressions of HIF-1 α and N-myc downstream regulated gene 1 （NDRG1） gene were inhibited significantly. HIF-1 cta transcripts were positive in 67.7% （42/62） and 44.4% （8/18） of colorectal adenocarcinoma and adenoma, re- spectively. The mean percentage of cells with positive hybridization of HIF-1 α mRNA increases with the development from Duke stage A to stage C＋D （p〈 0.05）. The positive staining rate of NDRG1 protein was significant higher in than that in colorectal adenoma colorectal adenocarcinoma group group （p〈 0.05）. The level of HIF-1 a transcripts was positively correlated with the level of NDRG1 protein （p 〈 0.05） during colorectal tumor progression. HIF-1α and its down stream gene NDRG1 may play roles in tumor progression of human colorectal carcinoma.展开更多
AIM:To analyze the effect of chemotherapeutic drugs and specific kinase inhibitors,in combination with the death receptor ligand tumor necrosis factor-related apoptosis inducing ligand(TRAIL),on overcoming TRAIL resis...AIM:To analyze the effect of chemotherapeutic drugs and specific kinase inhibitors,in combination with the death receptor ligand tumor necrosis factor-related apoptosis inducing ligand(TRAIL),on overcoming TRAIL resistance in hepatocellular carcinoma(HCC)and to study the efficacy of agonistic TRAIL antibodies,as well as the commitment of antiapoptotic BCL-2 proteins, in TRAIL-induced apoptosis. METHODS:Surface expression of TRAIL receptors (TRAIL-R1-4)and expression levels of the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL were analyzed by flow cytometry and Western blotting,respectively. Knock-down of MCL-1 and BCL-xL was performed by transfecting specific small interfering RNAs.HCC cellswere treated with kinase inhibitors and chemotherapeutic drugs.Apoptosis induction and cell viability were analyzed via flow cytometry and 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. RESULTS:TRAIL-R1 and-R2 were profoundly expressed on the HCC cell lines Huh7 and Hep-G2. However,treatment of Huh7 and Hep-G2 with TRAIL and agonistic antibodies only induced minor apoptosis rates.Apoptosis resistance towards TRAIL could be considerably reduced by adding the chemotherapeutic drugs 5-fluorouracil and doxorubicin as well as the kinase inhibitors LY294002[inhibition of phosphoinositol- 3-kinase(PI3K)],AG1478(epidermal growth factor receptor kinase),PD98059(MEK1),rapamycin(mam- malian target of rapamycin)and the multi-kinase inhibitor Sorafenib.Furthermore,the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL play a major role in TRAIL resistance:knock-down by RNA interference increased TRAIL-induced apoptosis of HCC cells.Additionally, knock-down of MCL-1 and BCL-xL led to a significant sensitization of HCC cells towards inhibition of both c-Jun N-terminal kinase and PI3K.CONCLUSION:Our data identify the blockage of survival kinases,combination with chemotherapeutic drugs and targeting of antiapoptotic BCL-2 proteins as promising ways to overcome TRAIL resistance in HCC.展开更多
Hypoxia-inducible factor 1, a nuclear transcription factor, is induced by hypoxia. Hypoxia-inducible factor 1, a heterodimeric DNA-binding protein, is composed of hypoxia-inducible factor 1α and hypoxia-inducible fac...Hypoxia-inducible factor 1, a nuclear transcription factor, is induced by hypoxia. Hypoxia-inducible factor 1, a heterodimeric DNA-binding protein, is composed of hypoxia-inducible factor 1α and hypoxia-inducible factor 1βsubunits, which are family members of the basic helix-loop-helix-PER, ARNT, SIM （PAS） protein. O2 concentration regulates hypoxia-inducible factor 1 activity via this subunit. Hypoxia-inducible factor 1α plays a major role in response to hypoxia and transcriptional activation, as well as in the target gene specificity of the DNA enhancer. Hypoxia-inducible factor 1β cannot be induced by hypoxia. This effect may be due to hypoxia-inducible factor 1 stability and activated conformation due to dimerization. Previous studies have shown that hypoxia-inducible factor 1 mRNA expression increases in the penumbra following ischemia/hypoxia. Hypoxia-inducible factor 1 plays an important role in brain tissue injury after ischemia by affecting a series of target genes, elevating tolerance to hypoxia, and ensuring survival of neural cells. This article summarizes the structure, function, expression, regulatory mechanisms, biological effects, and significance of hypoxia-inducible factor 1 in patients with ischemic cerebrovascular disease. As a transcriptional activator, hypoxia- inducible factor 1 plays a key role in hypoxic responses by stabilizing the internal environment. It also has been shown to regulate the expression of several genes. The regulatory effects of hypoxia-inducible factor 1 in patients with ischemic cerebrovascular disease have been described. The present review re-examined the concept of brain protection at the level of gene regulation.展开更多
文摘For the first time, the fertility of rice genic male sterile line was partially restored with the application of chemical regulators at Hainan Rice Breeding Nursery on Mar 1993. A single panicle of the rice plant could bear as many as 27 grains. The chemical agent that could modulate the growth of the rice plants of genic male sterile line was developed by Prof ZHOU Guangqia and his colleagues at the Biology Institute, Hunan Teachers University, China.
基金supported by a grant from Hubei Natural Science Foundation of China(No.2013CFB135)
文摘Liver fibrosis is an important health problem that can further progress into cirrhosis or liver cancer,and result in significant morbidity and mortality. Inhibiting proliferation and inducing apoptosis of hepatic stellate cells（HSCs） may be the key point to reverse liver fibrosis. At present,anti-fibrosis drugs are rare. Kinetin is a type of plant-derived cytokinin which has been reported to control differentiation and induce apoptosis of human cells. In this study,the HSCs were incubated with different concentrations of kinetin. The proliferation of rat HSCs was measured by MTT assay,cell cycle and apoptosis were analyzed by flow cytometry,and the apoptosis was examined by TUNEL method. The expression of Bcl-2 and Bax proteins was detected by immunocytochemistry staining. It was found that kinetin could markedly inhibit proliferation of HSCs. In a concentration range of 2 to 8 μg/m L,the inhibitory effects of kinetin on proliferation of HSCs were increased with the increased concentration and the extension of time（P〈0.01）. Flow cytometry indicated that kinetin could inhibit the DNA synthesis from G0/G1 to S phase in a dose-dependent manner（P〈0.01）. The apoptosis rates of the HSCs treated with 8,4 and 2 μg/m L kinetin（25.62%±2.21%,15.31%±1.9% and 6.18%±1.23%,respectively） were increased significantly compared with the control group（3.81%±0.93%）（P〈0.01）. All the DNA frequency histogram in kinetin-treated groups showed obvious hypodiploid peak（sub-G1 peak）,and with the increase of kinetin concentrations,the apoptosis rate of HSCs also showed a trend of increase. It was also found that kinetin could down-regulate the expression of Bcl-2,and up-regulate the expression of Bax,leading to the decreased ratio of Bcl-2/Bax significantly. The kinetin-induced apoptosis of HSCs was positively correlated with the expression of Bax,and negatively with the expression of Bcl-2. It was concluded that kinetin can inhibit activation and proliferation of HSCs by interrupting the cell cycle at G1/S restriction point and inducing apoptosis of HSCs via reducing the ratio of Bcl-2/Bax.
文摘Studies on a variety of highly regenerative tissues, including the central nervous system（CNS） in non-mammalian vertebrates, have consistently demonstrated that tissue damage induces the formation of an ionic current at the site of injury. These injury currents generate electric fields（EF） that are 100-fold increased in intensity over that measured for uninjured tissue. In vitro and in vivo experiments have convincingly demonstrated that these electric fields（by their orientation, intensity and duration） can drive the migration, proliferation and differentiation of a host of cell types. These cellular behaviors are all necessary to facilitate regeneration as blocking these EFs at the site of injury inhibits tissue repair while enhancing their intensity promotes repair. Consequently, injury-induced currents, and the EFs they produce, represent a potent and crucial signal to drive tissue regeneration and repair. In this review, we will discuss how injury currents are generated, how cells detect these currents and what cellular responses they can induce. Additionally, we will describe the growing evidence suggesting that EFs play a key role in regulating the cellular response to injury and may be a therapeutic target for inducing regeneration in the mammalian CNS.
基金This work was supported by Italian Ministery of Health RC 08C921 to LL,Istituto Auxologico Italiano,IRCCs.
文摘Taking advantage of the fast-growing knowledge of RNA-binding proteins(RBPs)we review the signature of downregulated genes for RBPs in the transcriptome of induced pluripotent stem cell neurons(iNeurons)modelling the neurodevelopmental Rubinstein Taybi Syndrome(RSTS)caused by mutations in the genes encoding CBP/p300 acetyltransferases.We discuss top and functionally connected downregulated genes sorted to“RNA processing”and“Ribonucleoprotein complex biogenesis”Gene Ontology clusters.The first set of downregulated RBPs includes members of hnRNHP(A1,A2B1,D,G,H2-H1,MAGOHB,PAPBC),core subunits of U small nuclear ribonucleoproteins and Serine-Arginine splicing regulators families,acting in precursor messenger RNA alternative splicing and processing.Consistent with literature findings on reduced transcript levels of serine/arginine repetitive matrix 4(SRRM4)protein,the main regulator of the neural-specific microexons splicing program upon depletion of Ep300 and Crebbp in mouse neurons,RSTS iNeurons show downregulated genes for proteins impacting this network.We link downregulated genes to neurological disorders including the new HNRNPH1-related intellectual disability syndrome with clinical overlap to RSTS.The set of downregulated genes for Ribosome biogenesis includes several components of ribosomal subunits and nucleolar proteins,such NOP58 and fibrillarin that form complexes with snoRNAs with a central role in guiding post-transcriptional modifications needed for rRNA maturation.These nucleolar proteins are“dual”players as fibrillarin is also required for epigenetic regulation of ribosomal genes and conversely NOP58-associated snoRNA levels are under the control of NOP58 interactor BMAL1,a transcriptional regulator of the circadian rhythm.Additional downregulated genes for“dual specificity”RBPs such as RUVBL1 and METTL1 highlight the links between chromatin and the RBP-ome and the contribution of perturbations in their cross-talk to RSTS.We underline the hub position of CBP/p300 in chromatin regulation,the impact of its defect on neurons’post-transcriptional regulation of gene expression and the potential use of epidrugs in therapeutics of RBP-caused neurodevelopmental disorders.
基金National Natural Science Foundation of China Youth Science Foundation Project(No.81904001)Capital Health Development Scientific Research Project(No.first issue 2018-1-4061)+1 种基金State Administration of Traditional Chinese Medicine Clinical Collaboration Project of TCM and Western Medicine for Major and Intractable Diseases(No.2019-ZX-005)In-Hospital Project of China-Japan Friendship Hospital(No.2019-1-QN-56)。
文摘Objective:To dig deeper into the traditional Chinese medicine treatment rules of chemotherapy-induced diarrhea with traditional Chinese medicine(TCM)inheritance computing platform system.Methods:Taking“traditional Chinese medicine”,“chemotherapy”and“diarrhea”as the theme words,comprehensive search of the database of CNKI,Wanfang and VIP from its inception to November 2020 was conduct-ed.The formulas of external treatment of traditional Chinese medicine for chemotherapy-induced diarrhea were included and the association rule,clustering and factor analysis were carried out.Results:A total of 145 papers,57 prescriptions meeting the inclusion criteria were collected,among which high-frequency drugs including Baizhu(Atractylodis macrocephalae rhizoma),Fuling(Poria),Dangshen(Codonopsisradix),Huanglian(Coptidis rhizoma),Zhigancao(Glycyrrhizae radix et rhizoma praeparata cum melle)were the most commonly used.The confidence level was set as 0.7 and the support level was set as 10,12 core compatibility groups were obtained,and 6 categories were cluster analyzed.Conclusion:The principle of external treatment of chemotherapy-induced diarrhea is mainly“restore deficiency and benefiting qi”,“benefiting water infiltration and dampness”,“clearing heat”and“inducing astringency”.Prescription combination and new prescription combination based on traditional Chinese medicine(TCM)inheritance computing platform system can be used as reference for clinicians and applied in primary hospitals.
文摘Objective To study the changes of prodynorphin （PDyn） gene expression and dopamine and cAMPregulated phosphoprotein of 32 kDa （DARPP-32） phosphorylation in rats with levodopa-induced dyskinesias （LID）, and to explore the mechanism of over-activation in direct pathway mediated by dopamine D1 receptor. Methods Parkinson＇s disease （PD） rats were received levodopa （10 mg/kg, i.p.） for 28 d to get the LID rats. According to the behavior scale, LID rats were divided into mild （n=8） and severe （n=16） groups. On day 29, 8 rats in severe LID group were given an acute intraperitoneal injection of MK-801 （0.1 mg/kg） 15 min before levodopa treatment （MK-801 group, n=8）. The normal rats received same course and dosage of levodopa as the control group （n=8）. Hybridization in situ was used to measure the expression of PDyn mRNA in striatum. Protein and mRNA levels of total DARPP-32 and phospho-Thr-34 DARPP-32 level were measured by immunoblotting and RT-PCR, respectively. Results The levels of PDyn mRNA and phospho-Thr-34 DARPP-32 increased significantly in LID rats compared with control rats （P〈0.01）, and they also increased markedly in severe LID group compared with mild group （P〈0.01）. Conclusion Phospho-Thr-34 DARPP-32 level was increased in LID rats, which contributed to the over-activation of direct pathway mediated by dopamine D1 receptor.
基金supported by the National Natural Science Foundation of China,No.81303091
文摘Cold-inducible RNA-binding protein（CIRP）, a key regulatory protein, could be facilitated by mild hypothermia in the brain, heart and liver. This study observed the effects of mild hypothermia at 31 ± 0.5℃ on traumatic brain injury in rats. Results demonstrated that mild hypothermia suppressed apoptosis in the cortex, hippocampus and hypothalamus, facilitated CIRP m RNA and protein expression in these regions, especially in the hypothalamus. The anti-apoptotic effect of mild hypothermia disappeared after CIRP silencing. There was no correlation between mitogen-activated extracellular signal-regulated kinase activation and CIRP silencing. CIRP silencing inhibited extracellular signal-regulated kinase-1/2 activation. These indicate that CIRP inhibits apoptosis by affecting extracellular signal-regulated kinase-1/2 activation, and exerts a neuroprotective effect during mild hypothermia for traumatic brain injury.
基金Supported by the Fund for Key Technologies R and D Pro-gramme of Hubei Province(2006AA301A03 )
文摘Plasmid expressing small interfering RNA （siRNA） against HIF-1α （pSilence-2.1-U6-siRNA） was constructed and transfected into LS174T cells in hypoxia condition.After expression of siRNA against HIF-1 α in LS174T cells, expressions of HIF-1 α and N-myc downstream regulated gene 1 （NDRG1） gene were inhibited significantly. HIF-1 cta transcripts were positive in 67.7% （42/62） and 44.4% （8/18） of colorectal adenocarcinoma and adenoma, re- spectively. The mean percentage of cells with positive hybridization of HIF-1 α mRNA increases with the development from Duke stage A to stage C＋D （p〈 0.05）. The positive staining rate of NDRG1 protein was significant higher in than that in colorectal adenoma colorectal adenocarcinoma group group （p〈 0.05）. The level of HIF-1 a transcripts was positively correlated with the level of NDRG1 protein （p 〈 0.05） during colorectal tumor progression. HIF-1α and its down stream gene NDRG1 may play roles in tumor progression of human colorectal carcinoma.
基金Supported by Research grants from Merck KGaA,Darmstadt,Germany,to Schulze-Bergkamen H
文摘AIM:To analyze the effect of chemotherapeutic drugs and specific kinase inhibitors,in combination with the death receptor ligand tumor necrosis factor-related apoptosis inducing ligand(TRAIL),on overcoming TRAIL resistance in hepatocellular carcinoma(HCC)and to study the efficacy of agonistic TRAIL antibodies,as well as the commitment of antiapoptotic BCL-2 proteins, in TRAIL-induced apoptosis. METHODS:Surface expression of TRAIL receptors (TRAIL-R1-4)and expression levels of the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL were analyzed by flow cytometry and Western blotting,respectively. Knock-down of MCL-1 and BCL-xL was performed by transfecting specific small interfering RNAs.HCC cellswere treated with kinase inhibitors and chemotherapeutic drugs.Apoptosis induction and cell viability were analyzed via flow cytometry and 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. RESULTS:TRAIL-R1 and-R2 were profoundly expressed on the HCC cell lines Huh7 and Hep-G2. However,treatment of Huh7 and Hep-G2 with TRAIL and agonistic antibodies only induced minor apoptosis rates.Apoptosis resistance towards TRAIL could be considerably reduced by adding the chemotherapeutic drugs 5-fluorouracil and doxorubicin as well as the kinase inhibitors LY294002[inhibition of phosphoinositol- 3-kinase(PI3K)],AG1478(epidermal growth factor receptor kinase),PD98059(MEK1),rapamycin(mam- malian target of rapamycin)and the multi-kinase inhibitor Sorafenib.Furthermore,the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL play a major role in TRAIL resistance:knock-down by RNA interference increased TRAIL-induced apoptosis of HCC cells.Additionally, knock-down of MCL-1 and BCL-xL led to a significant sensitization of HCC cells towards inhibition of both c-Jun N-terminal kinase and PI3K.CONCLUSION:Our data identify the blockage of survival kinases,combination with chemotherapeutic drugs and targeting of antiapoptotic BCL-2 proteins as promising ways to overcome TRAIL resistance in HCC.
文摘Hypoxia-inducible factor 1, a nuclear transcription factor, is induced by hypoxia. Hypoxia-inducible factor 1, a heterodimeric DNA-binding protein, is composed of hypoxia-inducible factor 1α and hypoxia-inducible factor 1βsubunits, which are family members of the basic helix-loop-helix-PER, ARNT, SIM （PAS） protein. O2 concentration regulates hypoxia-inducible factor 1 activity via this subunit. Hypoxia-inducible factor 1α plays a major role in response to hypoxia and transcriptional activation, as well as in the target gene specificity of the DNA enhancer. Hypoxia-inducible factor 1β cannot be induced by hypoxia. This effect may be due to hypoxia-inducible factor 1 stability and activated conformation due to dimerization. Previous studies have shown that hypoxia-inducible factor 1 mRNA expression increases in the penumbra following ischemia/hypoxia. Hypoxia-inducible factor 1 plays an important role in brain tissue injury after ischemia by affecting a series of target genes, elevating tolerance to hypoxia, and ensuring survival of neural cells. This article summarizes the structure, function, expression, regulatory mechanisms, biological effects, and significance of hypoxia-inducible factor 1 in patients with ischemic cerebrovascular disease. As a transcriptional activator, hypoxia- inducible factor 1 plays a key role in hypoxic responses by stabilizing the internal environment. It also has been shown to regulate the expression of several genes. The regulatory effects of hypoxia-inducible factor 1 in patients with ischemic cerebrovascular disease have been described. The present review re-examined the concept of brain protection at the level of gene regulation.
