Genetic disruption of the RAS binding domain(RBD)of Phosphoinositide 3-kinase alpha(PI3Kα)impairs the growth of tumors driven by the small guanosine triphosphatase RAS in mice and does not impact PI3Kα's role in...Genetic disruption of the RAS binding domain(RBD)of Phosphoinositide 3-kinase alpha(PI3Kα)impairs the growth of tumors driven by the small guanosine triphosphatase RAS in mice and does not impact PI3Kα's role in insulin mediated control of glucose homeostasis.Selectively blocking the RAS-PI3Kαinteraction may represent a strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3Kαlipid kinase activity.We developed compounds that bind covalently to cysteine 242 in the RBD of PI3K p110αand block RAS activation of PI3Kαactivity.In mice,inhibitors slow the growth of RAS mutant tumors and Human Epidermal Growth Factor Receptor 2(HER2)overexpressing tumors,particularly when combined with other inhibitors of the RAS/Mitogen-activated protein kinase pathway,without causing hyperglycemia.Oncogenic mutations in the small guanosine triphosphatase RAS occur in 20%of human cancers,with RAS proteins activating both the mitogen-activated protein kinase(MAPK)and Phosphoinositide 3-kinase(PI3K)pathways(1-3).As each of these pathways has oncogenic potential,simultaneous activation,as occurs in mutant RAS driven cancers,generates aggressive disease.In RAS-driven cell and animal models,inhibition of both the MAPK and PI3K pathways is more efficacious than targeting the individual pathways(4);however,dose-limiting toxicities in humans prevent clinical success of this strategy.展开更多
OBJECTIVE:To compare and observe the effects of three kinds of cephalic acupuncture therapies commonly used in the clinic on promoting nerve function rehabilitation in the brain microenvironment of rats with cerebral ...OBJECTIVE:To compare and observe the effects of three kinds of cephalic acupuncture therapies commonly used in the clinic on promoting nerve function rehabilitation in the brain microenvironment of rats with cerebral palsy.METHODS:A negative control group,positive control group,and three cephalic acupuncture groups based on the administration of three cephalic acupuncture therapies were established.Ten experimental rats were selected from each group at 1,2,and 3 weeks after modeling.Neuromotor function after treatment was rated according to the Basso,Beattie,and Bresnahan method.White matter fiber bundles were evaluated by head diffusion tensor imaging.The expression levels of neuron-specific enolase,microtubule-associated protein 2,and myelin basic protein in the brain tissue extract were detected by Western blot analysis and the activities of ATPases were determined using a fixed phosphorus method.RESULTS:The pathological changes in brain tissue were restored and motor function scores were increased in the mice in each cephalic acupuncture group,and the expression of neuronal growth-related proteins in the brain tissue extract was significantly increased.Additionally,the activities of ATPases in the lesion area were significant enhanced(P<0.05).Diffusion tensor imaging revealed that the white matter fiber bundles of mice in each cephalic acupuncture group gradually increased and recovered.The nervous system structure was significantly improved.CONCLUSIONS:All three acupuncture methods promoted the rehabilitation of nerve function damaged by cerebral palsy.These effects are likely related to the improved expression of nerve growth-related proteins,enhancement of ATPase activities,and regulation of the brain microenvironment.展开更多
BACKGROUND Hereditary spastic paraplegia(HSP)is a group of neurogenetic diseases of the corticospinal tract,accompanied by distinct spasticity and weakness of the lower extremities.Mutations in the spastic paraplegia ...BACKGROUND Hereditary spastic paraplegia(HSP)is a group of neurogenetic diseases of the corticospinal tract,accompanied by distinct spasticity and weakness of the lower extremities.Mutations in the spastic paraplegia type 4(SPG4)gene,encoding the spastin protein,are the major cause of the disease.This study reported a Chinese family with HSP caused by a novel mutation of the SPG4 gene.CASE SUMMARY A 44-year-old male was admitted to our hospital for long-term right lower limb weakness,leg stiffness,and unstable walking.His symptoms gradually worsened,while no obvious muscle atrophy in the lower limbs was found.Neurological examinations revealed that the muscle strength of the lower limbs was normal,and knee reflex hyperreflexia and bilateral positive Babinski signs were detected.Members of his family also had the same symptoms.Using mutation analysis,a novel heterozygous duplication mutation,c.1053dupA,p.(Gln352Thrfs*15),was identified in the SPG4 gene in this family.CONCLUSION A Chinese family with HSP had a novel mutation of the SPG4 gene,which is autosomal dominant and inherited as pure HSP.The age of onset,sex distribution,and clinical manifestations of all existing living patients in this family were analyzed.The findings may extend the current knowledge on the existing mutations in the SPG4 gene.展开更多
AIM: To study the mechanism underlying carbon tetrachloride (CCl4)-induced alterations of protein synthesis in liver. METHODS: Male Sprague-Dawley rats were given CCl4 (1 mL/100 g body weight) and 3H-leucine incorpora...AIM: To study the mechanism underlying carbon tetrachloride (CCl4)-induced alterations of protein synthesis in liver. METHODS: Male Sprague-Dawley rats were given CCl4 (1 mL/100 g body weight) and 3H-leucine incorporation. Malondialdehyde (MDA) level in the liver, in vitro response of hepatocyte nuclei nucleotide triphosphatase (NTPase) to free radicals, and nuclear export of total mRNA with 3'-poly A+ were measured respectively. Survival response of HepG2 cells to CCl4 treatment was assessed by methyl thiazolyl tetrazolium. Km and Vmax values of nuclear envelope NTPase activity in liver of rats treated with CCl4 were assayed by a double-reciprocal plot. RESULTS: The protein synthesis was inhibited while the MDA level was signif icantly increased in liver of rats treated with CCl4. In addition, CCl4 decreased the NTPase binding capacity of nuclear envelope (Km value) in cultured HepG2 cells. Moreover, in vitro ferrous radicals from Fenton's system suppressed the NTPase activity of liver nuclear envelope in a dose-dependent manner. Down-regulation of the nuclear envelope NTPase activity indicated a lower energy provision for nucleocytoplasmic transport of mRNA molecules, an evidence in CCl4-treated HepG2 cells correspondingly supported by the nuclear sequestration of poly (A)+ mRNA molecules in morphological hybridization research. CONCLUSION: Inhibition of mRNA transport, suggestive of decreased NTPase activity of the nuclear envelope, may be involved in carbon tetrachloride-inhibited protein synthesis in liver.展开更多
The 5′-cap structures of eukaryotic m RNAs are important for RNA stability, pre-m RNA splicing,m RNA export, and protein translation. Many viruses have evolved mechanisms for generating their own cap structures with ...The 5′-cap structures of eukaryotic m RNAs are important for RNA stability, pre-m RNA splicing,m RNA export, and protein translation. Many viruses have evolved mechanisms for generating their own cap structures with methylation at the N7 position of the capped guanine and the ribose 2′-Oposition of the first nucleotide, which help viral RNAs escape recognition by the host innate immune system. The RNA genomes of coronavirus were identified to have 5′-caps in the early1980 s. However, for decades the RNA capping mechanisms of coronaviruses remained unknown.Since 2003, the outbreak of severe acute respiratory syndrome coronavirus has drawn increased attention and stimulated numerous studies on the molecular virology of coronaviruses. Here, we review the current understanding of the mechanisms adopted by coronaviruses to produce the 5′-cap structure and methylation modification of viral genomic RNAs.展开更多
Retinal ischemia causes several vision-threatening diseases, including diabetic retinopathy, retinal artery occlusion, and retinal vein occlusion. Intracellular adenosine triphosphate（ATP） depletion and subsequent i...Retinal ischemia causes several vision-threatening diseases, including diabetic retinopathy, retinal artery occlusion, and retinal vein occlusion. Intracellular adenosine triphosphate（ATP） depletion and subsequent induced endoplasmic reticulum（ER） stress are proposed to be the underlying mechanisms of ischemic retinal cell death. Recently, we found that a naphthalene derivative can inhibit ATPase activity of valosin-containing protein, universally expressed within various types of cells, including retinal neural cells, with strong cytoprotective activity. Based on the chemical structure, we developed novel valosin-containing protein modulators, Kyoto University Substances（KUSs）, that not only inhibit intracellular ATP depletion, but also ameliorate ER stress. Suppressing ER stress by KUSs is associated with neural cell survival in animal models of several neurodegenerative diseases, such as glaucoma and retinal degeneration. Given that a major pathology of ischemic retinal diseases, other than intracellular ATP depletion, is ER stress-induced cell death, KUSs may provide a novel strategy for cell protection in ischemic conditions. Hence, we investigated the efficacy of KUS121 in a rat model of retinal ischemic injury. Intravitreal injections of KUS121, which is clinically preferable route of drug administration in retinal diseases, significantly suppressed inner retinal thinning and retinal cell death, and maintained visual functions. Valosin-containing protein modulation by KUS is a promising novel therapeutic strategy for ischemic retinal diseases.展开更多
AIM: To investigate if the presence of relevant genetic polymorphisms has effect on the effectual clearance of bacteria by monocytes and granulocytes in patients with Crohn’s disease (CD).
Hepatitis C virus(HCV)infection is a global health problem that affects more than 170 million people worldwide.It is a major cause of cirrhosis and hepatocellular carcinoma,making the virus the most common cause of li...Hepatitis C virus(HCV)infection is a global health problem that affects more than 170 million people worldwide.It is a major cause of cirrhosis and hepatocellular carcinoma,making the virus the most common cause of liver failure and transplantation.The standardof-care treatment for chronic hepatitis C(CHC)has been changed during the last decade and direct acting antiviral drugs have already been used.Besides,understanding of the pathogenesis of CHC has evolved rapidly during the last years and now several host factors are known to affect the natural history and response to treatment.Recent genome-wide association studies have shown the important role of interleukin-28B and inosine triphosphatase in HCV infection.The present review article attempts to summarize the current knowledge on the role of host factors towards individualization of HCV treatment.展开更多
AIM:To analyzed the association between inosine triphosphatase(ITPA)(rs1127354) genotypes and sustained virological response(SVR) rates in peginterferon(Peg-IFN)α + ribavirin(RBV) treatment.METHODS:Patients who under...AIM:To analyzed the association between inosine triphosphatase(ITPA)(rs1127354) genotypes and sustained virological response(SVR) rates in peginterferon(Peg-IFN)α + ribavirin(RBV) treatment.METHODS:Patients who underwent Peg-IFNα + RBV combination therapy were enrolled(n = 120) and they had no history of other IFN-based treatments.Variation in hemoglobin levels during therapy,cumulative reduction of RBV dose,frequency of treatment withdrawal,and SVR rates were investigated in each ITPA genotype.RESULTS:In patients with ITPA CC genotype,hemoglobin decline was significantly greater and the percentage of patients in whom total RBV dose was < 60% of standard and/or treatment was withdrawn was significantly higher compared with CA/AA genotype.However,SVR rates were equivalent between CC and CA/AA genotypes,and within a subset of patients with Interleukin 28B(IL28B)(rs8099917) TT genotype,SVR rates tended to be higher in patients with ITPA CC genotype,although the difference was not significant.CONCLUSION:ITPA CC genotype was a disadvantageous factor for Peg-IFNα + RBV treatment in relation to completion rates and RBV dose.However,CC genotype was not inferior to CA/AA genotype for SVR rates.When full-length treatment is accomplished,it is plausible that more SVR is achieved in patients with ITPA CC variant,especially in a background of IL28B TT genotype.展开更多
Aim: To study the effect of mercuric chloride on the membrane-bound enzymes. Methods: The effect of mercuric chloride at two different doses, 1 mg/kg (low dose) and 2 mg/kg (high dose), orally for 30 days, was observe...Aim: To study the effect of mercuric chloride on the membrane-bound enzymes. Methods: The effect of mercuric chloride at two different doses, 1 mg/kg (low dose) and 2 mg/kg (high dose), orally for 30 days, was observed on the membrane-bound enzymes in the testis of adult albino rats. Results: Mercuric chloride significantly decreased the body weight and testis weight in the high dose group (P<0.05), but not in the low dose group. The activities of 5' nucleotidase and adenosine triphosphatases were markedly decreased (P<0.01) in the testis of both groups. Alkaline phosphatase and γ-glutamyl transferase activities were significantly increased (P<0.01) in both groups. However, the effect was more pronounced in the high than in the low dose groups. Conclusion: The dose dependent effect of mercuric chloride on these enzymes may affect the membrane characteristics and thereby the fertility of the animal. (Asian J Androl 2002 Dec; 4:309-311)展开更多
Objectives.To observe if lysophosphatidic acid(LPA)can influence nuclear nucleoside triphos-phatase(NTPase)activity of isolated hepatocyte from rat,and to investigate the possible mechanisms by which LPA affects the N...Objectives.To observe if lysophosphatidic acid(LPA)can influence nuclear nucleoside triphos-phatase(NTPase)activity of isolated hepatocyte from rat,and to investigate the possible mechanisms by which LPA affects the NTPase.Method.Isolated and cultured hepatocytes from rat liver were exposed to LPA(1×10 -9 ,1×10 -8 and5×10 -8 mol/L)with or without inhibitors of protein kinase C(PKC)and mitogen activating protein kinase kinase(MAPKK),and the NTPase activity on nuclear envelope was assayed using ATP and GTP as substrate,respectively.Results.Nuclear NTPase activity of rat hepatocytes was potently stimulated by incubation of hepato-cytes with LPA in concentration?and time ?dependent manners.In hepatocytes incubated with LPA,nu-clear NTPase activity was significantly higher than that of the control(P<0.01).In hepatocytes preincu-bated with PKC inhibitor H-7or MAPKK inhibitor PD98059,LPA-stimulated activation of nuclear NT-Pase was obviously attenuated.In addition,direct incubation of isolated hepatic nuclei with LPA had no effect on nuclear NTPase activity.Conclusion.LPA is involved in modulating nuclear NTPase activity in hepatocytes.The stimulating effect of LPA on the nuclear NTPase is mediated at least partly by PKC and MAPK-dependent pathway.展开更多
The present study was carried out to investigate the effect of lead acetate on the ultrastructure of albino rat hepatocytes with special reference to its effect on the mitochondrial and lysosomal activity. Lead acetat...The present study was carried out to investigate the effect of lead acetate on the ultrastructure of albino rat hepatocytes with special reference to its effect on the mitochondrial and lysosomal activity. Lead acetate was given orally to albino rats at a dose of 1% lead acetate / 100 g body weight, three times / week for one month （Gila）, two months （Glib）, three months （GIIc）. Liver total protein, body / liver weight ratio and cytochrome P-450 value were calculated. Three parts of the liver samples were incubated in media containing adenosine triphosphate, p-nitrophenyl phosphate and 2% glutlraldehyde and prepared for electron microscopy to visualize adenosine triphosphatase, acid phosphatase and the fine structures ofhepatocytes respectively. The main changes of the fine structures was found in the nucleus, as irregularity of the nuclear membrane, clumped heterochromatin and sun radiation of lead inclusion bodies. The cytoplasm was characterized by shortened, dilated rough endoplasmic reticulum, destroyed and hazy mitochondria with increased number of lysosomes with storage secretion. Ultrastructure findings showed hepatocytes damage due to increased hydrolysis enzymes and decreased cytotoxic enzymes （cytochrome P-450） as well as oxidative enzymes that proved the toxic effect of lead according to the duration of exposure.展开更多
Background Organophosphate poisoning is an important health problem in developing countries which causes death mainly by inducing acute lung injury. In this study, we examined the effects of penehyclidine hydrochlori...Background Organophosphate poisoning is an important health problem in developing countries which causes death mainly by inducing acute lung injury. In this study, we examined the effects of penehyclidine hydrochloride （PHC）, a selective M-receptor inhibitor, on dichlorvos-induced acute lung injury in swine. Methods Twenty-two female swines were randomly divided into control （n=5）, dichlorvos （n=6）, atropine （n=6）, and PHC （n=5） groups. Hemodynamic data, extravascular lung water index （EVLWI）, and pulmonary vascular permeability index （PVPI） were monitored; blood gas analysis and acetylcholinesterase （AchE） levels were measured. PaO2/FiO2, cardiac index （CI）, and pulmonary vascular resistance indices （PVRI） were calculated. At termination of the study, pulmonary tissue was collected for ATPase activity determination and wet to dry weight ratio （W/D） testing 6 hours post-poisoning. TUNEL assay, and Bax, Bcl-2, and caspase-3 expression were applied to pulmonary tissue, and histopathology was observed. Results After poisoning, PHC markedly decreased PVRI, increased CI more effectively than atropine. Anticholinergic treatment reduced W/D, apoptosis index （AI）, and mitigated injury to the structure of lung; however, PHC reduced AI and caspase-3 expression and improved Bcl-2/Bax more effectively than atropine. Atropine and PHC improved ATPase activities; a significant difference between groups was observed in Ca2＋-ATPase activity, but not Na＋-K＋-ATPase activity. Conclusions The PHC group showed mild impairment in pathology, less apoptotic cells, and little impact on cardiac function compared with the atropine group in dichlorvos-induced acute lung injury.展开更多
Objective： To observe the effect of moxibustion on intestinal propulsion rate, content of serum D-xylose, content of adenosine triphosphate （ATP） and activities of adenosine triphosphatases （ATPase） in jejunum ti...Objective： To observe the effect of moxibustion on intestinal propulsion rate, content of serum D-xylose, content of adenosine triphosphate （ATP） and activities of adenosine triphosphatases （ATPase） in jejunum tissues of spleen-deficiency rats, and to explore the effect of moxibustion on the production of ATP and activities of membrane proteins, for analyzing the mechanism of moxibustion in reinforcing the spleen-stomach. Methods： Forty healthy Sprague Dawley rats were randomly divided into four groups, namely group A （blank control group）, group B （model control group）, group C （moxibustion group） and group D （herbs group）. The animal model of spleen-deficiency was established by intragastric administration with Da Huang （Radix et Rhizoma Rhei） infusion. The rats in group C received moxibustion at Zusanli （ST 36）, Zhongwan （CV 124 Guanyuan （CV 4）, Pishu （BL 20） and Weishu （BL 21）. The rats in group D received intragastric administration with 5i Jun Zi decoction. The intestinal propulsion was measured by toner method, and the content of D-xylose in serum was detected by phloroglucinol method. Colorimetry method was used to detect the content of ATP and activities of Na^＋-K^＋-ATPase and Ca^2＋-Mg^2＋-ATPase in jejunum tissues. Results： Compared with group A, the intestinal propulsion rate, content of D-xylose in serum, content of ATP, activities of Na^＋-K^＋-ATPase and Ca^2＋-Mg^2＋-ATP in jejunum tissues decreased significantly in group B （P〈0.05 or P〈O.O1）. Compared with group B, the intestinal propulsion rate, content of D-xylose in serum, content of ATP, activities of Na^＋-K^＋-ATPase and Ca^2＋-Mg^2＋-ATPase in jejunum tissues increased significantly in group C and D （P〈0.05 or P〈0.01）, while there were no significant differences between group C and group D. Conclusion： Moxibustion can increase the intestinal propulsion rate, content of D-xylose in serum and ATP in jejunum tissues, as well as the activities of Na^-K＋-ATPase and Ca^2＋-Mg^2＋-ATPase of spleen-deficiency rats, which suggests that moxibustion can enhance the motility and absorption functions of small intestine by promoting the production of ATP in intestinal epithelial cells, increasing the content of membrane proteins, and improving transmembrane transport.展开更多
RAB guanosine triphosphatases （GTPases） are key regulators of vesicle trafficking and are essential to the growth and development of all eukaryotic cells. During evolution, the RAB family has expanded in different p...RAB guanosine triphosphatases （GTPases） are key regulators of vesicle trafficking and are essential to the growth and development of all eukaryotic cells. During evolution, the RAB family has expanded in different patterns to facilitate distinct cellular, developmental and physiological adaptations. Yeast has only 11 family members, whereas mammalian RABs have expanded to 18 RAB subfamilies. Plant RABs have diversified primarily by duplicating members within a single subfamily. Plant RABs are divided into eight subfamilies, corresponding to mammalian RAB1, RAB2, RAB5, RAB6, RAB7, RAB8, RAB11 and RAB18. Functional diversification of these is exemplified by the RAB1 ls, orthologs of which are partitioned into unique cell compartments in plants where they function to transport vesicles during localized tip growth. Similarly, the RAB2 family in grasses is likely involved in vesicle secretion associated with wall expansion, as determined by analysis of over-expression mutants. We propose that dicots and monocots have also diverged in their RAB profiles to accommodate unique cellular functions between the two groups. Here we present a bioinformatics analysis comparing the RAB sub-families of rice, maize and Arabidopsis. These results will guide future functional studies to test for the role of diversification of subfamilies unique to monocots compared to dicots.展开更多
Objective: To study the mechanism of acupuncture in treating simple obesity. Methods: Central nerve push-pull perfusion and biochemical technique were used to observe the effect of acupuncture on the obese parameters,...Objective: To study the mechanism of acupuncture in treating simple obesity. Methods: Central nerve push-pull perfusion and biochemical technique were used to observe the effect of acupuncture on the obese parameters, changes of monoamine transmitters and activity of ATPase in the lateral hypothalamic area (LHA) of obese rats. Results: Noradrenaline (NA) level in LHA of obese rats was higher but serotonin (5-HT) level and ATPase activity were lower than those in normal rats. After acupuncture treatment, in the same time of reducing body weight, NA level in LHA of rats was reduced, and 5-HT level and ATPase activity in it were increased.(P<0.05 and P<0.01). Conclusion:The effective regulation on LHA of obese rats is possibly one of the key factors in anti-obesity effect of acupuncture.展开更多
DDX21 belongs to the DEAD-box(DDX)family of helicases but deviates from the characteristic sequence Asp–Glu–Ala–Asp(DEAD)to Asp–Glu–Val–Asp.In addition to the typical helicase activity associated with the DEAD-b...DDX21 belongs to the DEAD-box(DDX)family of helicases but deviates from the characteristic sequence Asp–Glu–Ala–Asp(DEAD)to Asp–Glu–Val–Asp.In addition to the typical helicase activity associated with the DEAD-box family,DDX21 also possesses foldase and adenosine triphosphatase activities.It plays crucial roles in various molecular processes,including the regulation of transcription,ribosomal RNA processing,modification,and unwinding of RNA spatial structures.DDX21 is subject to intricate regulation by multiple upstream factors,including expression control and posttranslational modification.In numerous cancer types,abnormal expression of DDX21 has been observed to influence cancer cell behaviors,such as the cell cycle,proliferation,invasion,migration,and apoptosis.In addition,DDX21 modulates innate immunity following viral infection and plays a dual role in the viral infection process.This review comprehensively explores the protein structure,molecular regulatory mechanisms,and pathophysiological functions of DDX21.Consequently,this study not only offers potential avenues for future research but also sparks novel ideas for targeted treatments for both cancer and viral infections.展开更多
文摘Genetic disruption of the RAS binding domain(RBD)of Phosphoinositide 3-kinase alpha(PI3Kα)impairs the growth of tumors driven by the small guanosine triphosphatase RAS in mice and does not impact PI3Kα's role in insulin mediated control of glucose homeostasis.Selectively blocking the RAS-PI3Kαinteraction may represent a strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3Kαlipid kinase activity.We developed compounds that bind covalently to cysteine 242 in the RBD of PI3K p110αand block RAS activation of PI3Kαactivity.In mice,inhibitors slow the growth of RAS mutant tumors and Human Epidermal Growth Factor Receptor 2(HER2)overexpressing tumors,particularly when combined with other inhibitors of the RAS/Mitogen-activated protein kinase pathway,without causing hyperglycemia.Oncogenic mutations in the small guanosine triphosphatase RAS occur in 20%of human cancers,with RAS proteins activating both the mitogen-activated protein kinase(MAPK)and Phosphoinositide 3-kinase(PI3K)pathways(1-3).As each of these pathways has oncogenic potential,simultaneous activation,as occurs in mutant RAS driven cancers,generates aggressive disease.In RAS-driven cell and animal models,inhibition of both the MAPK and PI3K pathways is more efficacious than targeting the individual pathways(4);however,dose-limiting toxicities in humans prevent clinical success of this strategy.
基金Supported by National Natural Science Foundation of China:Study on the Mechanism of Microenvironment in Cerebral Palsy Induced by Scalp Acupuncture based on Metabonomics Technique(No.81560795)Study on the Effect of Electroacupuncture Stimulation of Head Motor area on PI3K/AKT Signaling Pathway on Neural Behavior in Neonatal Cerebral Palsy Rats(No.81303035)。
文摘OBJECTIVE:To compare and observe the effects of three kinds of cephalic acupuncture therapies commonly used in the clinic on promoting nerve function rehabilitation in the brain microenvironment of rats with cerebral palsy.METHODS:A negative control group,positive control group,and three cephalic acupuncture groups based on the administration of three cephalic acupuncture therapies were established.Ten experimental rats were selected from each group at 1,2,and 3 weeks after modeling.Neuromotor function after treatment was rated according to the Basso,Beattie,and Bresnahan method.White matter fiber bundles were evaluated by head diffusion tensor imaging.The expression levels of neuron-specific enolase,microtubule-associated protein 2,and myelin basic protein in the brain tissue extract were detected by Western blot analysis and the activities of ATPases were determined using a fixed phosphorus method.RESULTS:The pathological changes in brain tissue were restored and motor function scores were increased in the mice in each cephalic acupuncture group,and the expression of neuronal growth-related proteins in the brain tissue extract was significantly increased.Additionally,the activities of ATPases in the lesion area were significant enhanced(P<0.05).Diffusion tensor imaging revealed that the white matter fiber bundles of mice in each cephalic acupuncture group gradually increased and recovered.The nervous system structure was significantly improved.CONCLUSIONS:All three acupuncture methods promoted the rehabilitation of nerve function damaged by cerebral palsy.These effects are likely related to the improved expression of nerve growth-related proteins,enhancement of ATPase activities,and regulation of the brain microenvironment.
基金Supported by The Shandong Provincial Natural Science Foundation,No.ZR2021MH059。
文摘BACKGROUND Hereditary spastic paraplegia(HSP)is a group of neurogenetic diseases of the corticospinal tract,accompanied by distinct spasticity and weakness of the lower extremities.Mutations in the spastic paraplegia type 4(SPG4)gene,encoding the spastin protein,are the major cause of the disease.This study reported a Chinese family with HSP caused by a novel mutation of the SPG4 gene.CASE SUMMARY A 44-year-old male was admitted to our hospital for long-term right lower limb weakness,leg stiffness,and unstable walking.His symptoms gradually worsened,while no obvious muscle atrophy in the lower limbs was found.Neurological examinations revealed that the muscle strength of the lower limbs was normal,and knee reflex hyperreflexia and bilateral positive Babinski signs were detected.Members of his family also had the same symptoms.Using mutation analysis,a novel heterozygous duplication mutation,c.1053dupA,p.(Gln352Thrfs*15),was identified in the SPG4 gene in this family.CONCLUSION A Chinese family with HSP had a novel mutation of the SPG4 gene,which is autosomal dominant and inherited as pure HSP.The age of onset,sex distribution,and clinical manifestations of all existing living patients in this family were analyzed.The findings may extend the current knowledge on the existing mutations in the SPG4 gene.
基金Supported by The National Natural Science Foundation of China,No.30470846
文摘AIM: To study the mechanism underlying carbon tetrachloride (CCl4)-induced alterations of protein synthesis in liver. METHODS: Male Sprague-Dawley rats were given CCl4 (1 mL/100 g body weight) and 3H-leucine incorporation. Malondialdehyde (MDA) level in the liver, in vitro response of hepatocyte nuclei nucleotide triphosphatase (NTPase) to free radicals, and nuclear export of total mRNA with 3'-poly A+ were measured respectively. Survival response of HepG2 cells to CCl4 treatment was assessed by methyl thiazolyl tetrazolium. Km and Vmax values of nuclear envelope NTPase activity in liver of rats treated with CCl4 were assayed by a double-reciprocal plot. RESULTS: The protein synthesis was inhibited while the MDA level was signif icantly increased in liver of rats treated with CCl4. In addition, CCl4 decreased the NTPase binding capacity of nuclear envelope (Km value) in cultured HepG2 cells. Moreover, in vitro ferrous radicals from Fenton's system suppressed the NTPase activity of liver nuclear envelope in a dose-dependent manner. Down-regulation of the nuclear envelope NTPase activity indicated a lower energy provision for nucleocytoplasmic transport of mRNA molecules, an evidence in CCl4-treated HepG2 cells correspondingly supported by the nuclear sequestration of poly (A)+ mRNA molecules in morphological hybridization research. CONCLUSION: Inhibition of mRNA transport, suggestive of decreased NTPase activity of the nuclear envelope, may be involved in carbon tetrachloride-inhibited protein synthesis in liver.
基金supported by the China "973" Basic Research Program (2013CB911101)China NSFC grants (81130083 and 81271817)
文摘The 5′-cap structures of eukaryotic m RNAs are important for RNA stability, pre-m RNA splicing,m RNA export, and protein translation. Many viruses have evolved mechanisms for generating their own cap structures with methylation at the N7 position of the capped guanine and the ribose 2′-Oposition of the first nucleotide, which help viral RNAs escape recognition by the host innate immune system. The RNA genomes of coronavirus were identified to have 5′-caps in the early1980 s. However, for decades the RNA capping mechanisms of coronaviruses remained unknown.Since 2003, the outbreak of severe acute respiratory syndrome coronavirus has drawn increased attention and stimulated numerous studies on the molecular virology of coronaviruses. Here, we review the current understanding of the mechanisms adopted by coronaviruses to produce the 5′-cap structure and methylation modification of viral genomic RNAs.
基金supported in part by research grants from the Astellas Foundation for Research on Metabolic Disorders,the Japan Foundation for Applied Enzymology,the Uehara Memorial Foundation,Mochida Memorial Foundation for Medical and Pharmaceutical Research,YOKOYAMA Foundation for Clinical Pharmacology(YRY1308)Japan Intractable Diseases Research Foundation,Japan Research Foundation for Clinical Pharmacology,ONO Medical Research Foundation,Takeda Science Foundation,Japan National Society for the Prevention of Blindness,a Grant-in-Aid for Young Scientists(24791850,to IHO+2 种基金15K20255,to HM)the Ministry of Education,Culture,Sports,Science,and Technology of Japan(to IHO)the Ministry of Health,Labour and Welfare of Japan(to IHO)
文摘Retinal ischemia causes several vision-threatening diseases, including diabetic retinopathy, retinal artery occlusion, and retinal vein occlusion. Intracellular adenosine triphosphate（ATP） depletion and subsequent induced endoplasmic reticulum（ER） stress are proposed to be the underlying mechanisms of ischemic retinal cell death. Recently, we found that a naphthalene derivative can inhibit ATPase activity of valosin-containing protein, universally expressed within various types of cells, including retinal neural cells, with strong cytoprotective activity. Based on the chemical structure, we developed novel valosin-containing protein modulators, Kyoto University Substances（KUSs）, that not only inhibit intracellular ATP depletion, but also ameliorate ER stress. Suppressing ER stress by KUSs is associated with neural cell survival in animal models of several neurodegenerative diseases, such as glaucoma and retinal degeneration. Given that a major pathology of ischemic retinal diseases, other than intracellular ATP depletion, is ER stress-induced cell death, KUSs may provide a novel strategy for cell protection in ischemic conditions. Hence, we investigated the efficacy of KUS121 in a rat model of retinal ischemic injury. Intravitreal injections of KUS121, which is clinically preferable route of drug administration in retinal diseases, significantly suppressed inner retinal thinning and retinal cell death, and maintained visual functions. Valosin-containing protein modulation by KUS is a promising novel therapeutic strategy for ischemic retinal diseases.
文摘AIM: To investigate if the presence of relevant genetic polymorphisms has effect on the effectual clearance of bacteria by monocytes and granulocytes in patients with Crohn’s disease (CD).
文摘Hepatitis C virus(HCV)infection is a global health problem that affects more than 170 million people worldwide.It is a major cause of cirrhosis and hepatocellular carcinoma,making the virus the most common cause of liver failure and transplantation.The standardof-care treatment for chronic hepatitis C(CHC)has been changed during the last decade and direct acting antiviral drugs have already been used.Besides,understanding of the pathogenesis of CHC has evolved rapidly during the last years and now several host factors are known to affect the natural history and response to treatment.Recent genome-wide association studies have shown the important role of interleukin-28B and inosine triphosphatase in HCV infection.The present review article attempts to summarize the current knowledge on the role of host factors towards individualization of HCV treatment.
基金Supported by The Research Program of Intractable Disease provided by the Ministry of Health,Labor and Welfare of Japana Grant-in-Aid for Clinical Research from the National Hospital Organization of Japan
文摘AIM:To analyzed the association between inosine triphosphatase(ITPA)(rs1127354) genotypes and sustained virological response(SVR) rates in peginterferon(Peg-IFN)α + ribavirin(RBV) treatment.METHODS:Patients who underwent Peg-IFNα + RBV combination therapy were enrolled(n = 120) and they had no history of other IFN-based treatments.Variation in hemoglobin levels during therapy,cumulative reduction of RBV dose,frequency of treatment withdrawal,and SVR rates were investigated in each ITPA genotype.RESULTS:In patients with ITPA CC genotype,hemoglobin decline was significantly greater and the percentage of patients in whom total RBV dose was < 60% of standard and/or treatment was withdrawn was significantly higher compared with CA/AA genotype.However,SVR rates were equivalent between CC and CA/AA genotypes,and within a subset of patients with Interleukin 28B(IL28B)(rs8099917) TT genotype,SVR rates tended to be higher in patients with ITPA CC genotype,although the difference was not significant.CONCLUSION:ITPA CC genotype was a disadvantageous factor for Peg-IFNα + RBV treatment in relation to completion rates and RBV dose.However,CC genotype was not inferior to CA/AA genotype for SVR rates.When full-length treatment is accomplished,it is plausible that more SVR is achieved in patients with ITPA CC variant,especially in a background of IL28B TT genotype.
文摘Aim: To study the effect of mercuric chloride on the membrane-bound enzymes. Methods: The effect of mercuric chloride at two different doses, 1 mg/kg (low dose) and 2 mg/kg (high dose), orally for 30 days, was observed on the membrane-bound enzymes in the testis of adult albino rats. Results: Mercuric chloride significantly decreased the body weight and testis weight in the high dose group (P<0.05), but not in the low dose group. The activities of 5' nucleotidase and adenosine triphosphatases were markedly decreased (P<0.01) in the testis of both groups. Alkaline phosphatase and γ-glutamyl transferase activities were significantly increased (P<0.01) in both groups. However, the effect was more pronounced in the high than in the low dose groups. Conclusion: The dose dependent effect of mercuric chloride on these enzymes may affect the membrane characteristics and thereby the fertility of the animal. (Asian J Androl 2002 Dec; 4:309-311)
文摘Objectives.To observe if lysophosphatidic acid(LPA)can influence nuclear nucleoside triphos-phatase(NTPase)activity of isolated hepatocyte from rat,and to investigate the possible mechanisms by which LPA affects the NTPase.Method.Isolated and cultured hepatocytes from rat liver were exposed to LPA(1×10 -9 ,1×10 -8 and5×10 -8 mol/L)with or without inhibitors of protein kinase C(PKC)and mitogen activating protein kinase kinase(MAPKK),and the NTPase activity on nuclear envelope was assayed using ATP and GTP as substrate,respectively.Results.Nuclear NTPase activity of rat hepatocytes was potently stimulated by incubation of hepato-cytes with LPA in concentration?and time ?dependent manners.In hepatocytes incubated with LPA,nu-clear NTPase activity was significantly higher than that of the control(P<0.01).In hepatocytes preincu-bated with PKC inhibitor H-7or MAPKK inhibitor PD98059,LPA-stimulated activation of nuclear NT-Pase was obviously attenuated.In addition,direct incubation of isolated hepatic nuclei with LPA had no effect on nuclear NTPase activity.Conclusion.LPA is involved in modulating nuclear NTPase activity in hepatocytes.The stimulating effect of LPA on the nuclear NTPase is mediated at least partly by PKC and MAPK-dependent pathway.
文摘The present study was carried out to investigate the effect of lead acetate on the ultrastructure of albino rat hepatocytes with special reference to its effect on the mitochondrial and lysosomal activity. Lead acetate was given orally to albino rats at a dose of 1% lead acetate / 100 g body weight, three times / week for one month （Gila）, two months （Glib）, three months （GIIc）. Liver total protein, body / liver weight ratio and cytochrome P-450 value were calculated. Three parts of the liver samples were incubated in media containing adenosine triphosphate, p-nitrophenyl phosphate and 2% glutlraldehyde and prepared for electron microscopy to visualize adenosine triphosphatase, acid phosphatase and the fine structures ofhepatocytes respectively. The main changes of the fine structures was found in the nucleus, as irregularity of the nuclear membrane, clumped heterochromatin and sun radiation of lead inclusion bodies. The cytoplasm was characterized by shortened, dilated rough endoplasmic reticulum, destroyed and hazy mitochondria with increased number of lysosomes with storage secretion. Ultrastructure findings showed hepatocytes damage due to increased hydrolysis enzymes and decreased cytotoxic enzymes （cytochrome P-450） as well as oxidative enzymes that proved the toxic effect of lead according to the duration of exposure.
文摘Background Organophosphate poisoning is an important health problem in developing countries which causes death mainly by inducing acute lung injury. In this study, we examined the effects of penehyclidine hydrochloride （PHC）, a selective M-receptor inhibitor, on dichlorvos-induced acute lung injury in swine. Methods Twenty-two female swines were randomly divided into control （n=5）, dichlorvos （n=6）, atropine （n=6）, and PHC （n=5） groups. Hemodynamic data, extravascular lung water index （EVLWI）, and pulmonary vascular permeability index （PVPI） were monitored; blood gas analysis and acetylcholinesterase （AchE） levels were measured. PaO2/FiO2, cardiac index （CI）, and pulmonary vascular resistance indices （PVRI） were calculated. At termination of the study, pulmonary tissue was collected for ATPase activity determination and wet to dry weight ratio （W/D） testing 6 hours post-poisoning. TUNEL assay, and Bax, Bcl-2, and caspase-3 expression were applied to pulmonary tissue, and histopathology was observed. Results After poisoning, PHC markedly decreased PVRI, increased CI more effectively than atropine. Anticholinergic treatment reduced W/D, apoptosis index （AI）, and mitigated injury to the structure of lung; however, PHC reduced AI and caspase-3 expression and improved Bcl-2/Bax more effectively than atropine. Atropine and PHC improved ATPase activities; a significant difference between groups was observed in Ca2＋-ATPase activity, but not Na＋-K＋-ATPase activity. Conclusions The PHC group showed mild impairment in pathology, less apoptotic cells, and little impact on cardiac function compared with the atropine group in dichlorvos-induced acute lung injury.
基金supported by the Priority Academic Program Development of Jiangsu Higher Education Institutionsthe Open Project Program of Traditional Chinese Medicine Department of Nanjing University of Chinese Medicine(No.YS2012ZYX414)+1 种基金Subject of Hunan Education Department(No.11C0965)Hunan University Innovation Fund Project Open Platform(No.12K088)
文摘Objective： To observe the effect of moxibustion on intestinal propulsion rate, content of serum D-xylose, content of adenosine triphosphate （ATP） and activities of adenosine triphosphatases （ATPase） in jejunum tissues of spleen-deficiency rats, and to explore the effect of moxibustion on the production of ATP and activities of membrane proteins, for analyzing the mechanism of moxibustion in reinforcing the spleen-stomach. Methods： Forty healthy Sprague Dawley rats were randomly divided into four groups, namely group A （blank control group）, group B （model control group）, group C （moxibustion group） and group D （herbs group）. The animal model of spleen-deficiency was established by intragastric administration with Da Huang （Radix et Rhizoma Rhei） infusion. The rats in group C received moxibustion at Zusanli （ST 36）, Zhongwan （CV 124 Guanyuan （CV 4）, Pishu （BL 20） and Weishu （BL 21）. The rats in group D received intragastric administration with 5i Jun Zi decoction. The intestinal propulsion was measured by toner method, and the content of D-xylose in serum was detected by phloroglucinol method. Colorimetry method was used to detect the content of ATP and activities of Na^＋-K^＋-ATPase and Ca^2＋-Mg^2＋-ATPase in jejunum tissues. Results： Compared with group A, the intestinal propulsion rate, content of D-xylose in serum, content of ATP, activities of Na^＋-K^＋-ATPase and Ca^2＋-Mg^2＋-ATP in jejunum tissues decreased significantly in group B （P〈0.05 or P〈O.O1）. Compared with group B, the intestinal propulsion rate, content of D-xylose in serum, content of ATP, activities of Na^＋-K^＋-ATPase and Ca^2＋-Mg^2＋-ATPase in jejunum tissues increased significantly in group C and D （P〈0.05 or P〈0.01）, while there were no significant differences between group C and group D. Conclusion： Moxibustion can increase the intestinal propulsion rate, content of D-xylose in serum and ATP in jejunum tissues, as well as the activities of Na^-K＋-ATPase and Ca^2＋-Mg^2＋-ATPase of spleen-deficiency rats, which suggests that moxibustion can enhance the motility and absorption functions of small intestine by promoting the production of ATP in intestinal epithelial cells, increasing the content of membrane proteins, and improving transmembrane transport.
基金Supported by the National Natural Science Foundation of China(30260062)to Jiaming Zhangthe US Department of Energy,Division of Energy Biosciences(PR 03-00ER15098.00)+1 种基金US Department of Agriculture-NRI(2001-35304-09899)National Science Foundation-Plant Genome Research Program DBI#0501862 to Anne Sylvester.
文摘RAB guanosine triphosphatases （GTPases） are key regulators of vesicle trafficking and are essential to the growth and development of all eukaryotic cells. During evolution, the RAB family has expanded in different patterns to facilitate distinct cellular, developmental and physiological adaptations. Yeast has only 11 family members, whereas mammalian RABs have expanded to 18 RAB subfamilies. Plant RABs have diversified primarily by duplicating members within a single subfamily. Plant RABs are divided into eight subfamilies, corresponding to mammalian RAB1, RAB2, RAB5, RAB6, RAB7, RAB8, RAB11 and RAB18. Functional diversification of these is exemplified by the RAB1 ls, orthologs of which are partitioned into unique cell compartments in plants where they function to transport vesicles during localized tip growth. Similarly, the RAB2 family in grasses is likely involved in vesicle secretion associated with wall expansion, as determined by analysis of over-expression mutants. We propose that dicots and monocots have also diverged in their RAB profiles to accommodate unique cellular functions between the two groups. Here we present a bioinformatics analysis comparing the RAB sub-families of rice, maize and Arabidopsis. These results will guide future functional studies to test for the role of diversification of subfamilies unique to monocots compared to dicots.
文摘Objective: To study the mechanism of acupuncture in treating simple obesity. Methods: Central nerve push-pull perfusion and biochemical technique were used to observe the effect of acupuncture on the obese parameters, changes of monoamine transmitters and activity of ATPase in the lateral hypothalamic area (LHA) of obese rats. Results: Noradrenaline (NA) level in LHA of obese rats was higher but serotonin (5-HT) level and ATPase activity were lower than those in normal rats. After acupuncture treatment, in the same time of reducing body weight, NA level in LHA of rats was reduced, and 5-HT level and ATPase activity in it were increased.(P<0.05 and P<0.01). Conclusion:The effective regulation on LHA of obese rats is possibly one of the key factors in anti-obesity effect of acupuncture.
基金supported by the Qiantang Scholars Fund at Hangzhou City University(no.210000-581835).
文摘DDX21 belongs to the DEAD-box(DDX)family of helicases but deviates from the characteristic sequence Asp–Glu–Ala–Asp(DEAD)to Asp–Glu–Val–Asp.In addition to the typical helicase activity associated with the DEAD-box family,DDX21 also possesses foldase and adenosine triphosphatase activities.It plays crucial roles in various molecular processes,including the regulation of transcription,ribosomal RNA processing,modification,and unwinding of RNA spatial structures.DDX21 is subject to intricate regulation by multiple upstream factors,including expression control and posttranslational modification.In numerous cancer types,abnormal expression of DDX21 has been observed to influence cancer cell behaviors,such as the cell cycle,proliferation,invasion,migration,and apoptosis.In addition,DDX21 modulates innate immunity following viral infection and plays a dual role in the viral infection process.This review comprehensively explores the protein structure,molecular regulatory mechanisms,and pathophysiological functions of DDX21.Consequently,this study not only offers potential avenues for future research but also sparks novel ideas for targeted treatments for both cancer and viral infections.
