The positive effect of levodopa in the treatment of Parkinson’s disease,although it is limited in time and has severe side effects,has encouraged the scientific community to look for new drugs that can stop the neuro...The positive effect of levodopa in the treatment of Parkinson’s disease,although it is limited in time and has severe side effects,has encouraged the scientific community to look for new drugs that can stop the neurodegenerative process or even regenerate the neuromelanin-containing dopaminergic nigrostriatal neurons.Successful preclinical studies with coenzyme Q10,mitoquinone,isradipine,nilotinib,TCH346,neurturin,zonisamide,deferiprone,prasinezumab,and cinpanemab prompted clinical trials.However,these failed and after more than 50 years levodopa continues to be the key drug in the treatment of the disease,despite its severe side effects after 4–6 years of chronic treatment.The lack of translated successful results obtained in preclinical investigations based on the use of neurotoxins that do not exist in the human body as new drugs for Parkinson’s disease treatment is a big problem.In our opinion,the cause of these failures lies in the experimental animal models involving neurotoxins that do not exist in the human body,such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine,that induce a very fast,massive and expansive neurodegenerative process,which contrasts with the extremely slow one of neuromelanin-containing dopaminergic neurons.The exceedingly slow progress of the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson’s patients is due to(i)a degenerative model in which the neurotoxic effect of an endogenous neurotoxin affects a single neuron,(ii)a neurotoxic event that is not expansive and(iii)the fact that the neurotoxin that triggers the neurodegenerative process is produced inside the neuromelanin-containing dopaminergic neurons.The endogenous neurotoxin that fits this degenerative model involving one single neuron at a time is aminochrome,since it(i)is generated within neuromelanin-containing dopaminergic neurons,(ii)does not cause an expansive neurotoxic effect and(iii)triggers all the mechanisms involved in the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson’s disease.In conclusion,based on the hypothesis that the neurodegenerative process of idiopathic Parkinson’s disease corresponds to a single-neuron neurodegeneration model,we must search for molecules that increase the expression of the neuroprotective enzymes DT-diaphorase and glutathione transferase M2-2.It has been observed that the activation of the Kelch-like ECH-associated protein 1/nuclear factor(erythroid-derived 2)-like 2 pathway is associated with the transcriptional activation of the DT-diaphorase and glutathione transferase genes.展开更多
Grass pea(Lathyrus sativus L.) is a crop that is considered one of the more resilient to climate change. With protein-rich seeds and leaves, it has strong potential as human food as well as animal feed and fodder. How...Grass pea(Lathyrus sativus L.) is a crop that is considered one of the more resilient to climate change. With protein-rich seeds and leaves, it has strong potential as human food as well as animal feed and fodder. However, genetic improvement in this crop remains stagnant owing to the poor characterization of its genetic resources. In this study, we characterized 118 accessions of grass pea with 18 EST-SSR markers. A total of 118 accessions, 101 of L. sativus(100 cultivated accessions from Bangladesh and one wild accession) and 17 wild accessions of other Lathyrus species, were used. A total of 67 alleles were detected, with an average of 3.72 alleles per locus and average polymorphism information content of 0.52. A dissimilarity matrix was formed and hierarchical cluster analysis performed using the UPGMA method grouped genotypes into four main clusters. Cluster analysis based on the genetic dissimilarity revealed a clear grouping of the 100 cultivated and 18 wild accessions into four main groups. Group I consisted of 20 accessions with high β-N-oxalyl-L-α,β-diaminopropionic acid(β-ODAP) concentration. Of these 20 accessions, 17 were wild accessions. Only one wild accession(L. cicera) was clustered in group II, which contained 35 accessions. Most of the group II accessions contained low β-ODAP. Group III was represented by 34 accessions, many of them with high β-ODAP. Group IV consisted of 29 accessions, a few of which had very high β-ODAP concentrations. Analysis of molecular variance of the microsatellite data showed significantly higher values of molecular variance between(83%) than within(17%) populations. These characterized accessions will be useful in grass pea breeding programs.展开更多
A rapid and simple method is presented for determining β-N-oxalyl-α. β- diaminopropionic acid (β -ODAP) and its much less toxic α -isomer (α -ODAP) in Lathyrus sativus. Seed and foliage extracts of Lathyrus sat...A rapid and simple method is presented for determining β-N-oxalyl-α. β- diaminopropionic acid (β -ODAP) and its much less toxic α -isomer (α -ODAP) in Lathyrus sativus. Seed and foliage extracts of Lathyrus sativus were treated with 1-fluoro-2,4-dinitrobenzene (FDNB) and a reversed-phase high-performance liquid chromatographic method for the separation of the derivatives in the pmol range is reported.展开更多
A method has been presented for the simultaneous analysis of neurotoxin β-N-oxalyl-α, β-diaminopropionic acid (β-ODAP) and its non- or low-toxic isomer α-ODAP as well as other amino acids in Lathyrus sativus extr...A method has been presented for the simultaneous analysis of neurotoxin β-N-oxalyl-α, β-diaminopropionic acid (β-ODAP) and its non- or low-toxic isomer α-ODAP as well as other amino acids in Lathyrus sativus extracts after derivatization with para-nitrobenzyloxycarbonyl chloride (PNZ-Cl) by reversed-phase (C18 column) high performance liquid chromatography (RP-HPLC). Detection limits of isomers were 0.08 μg/mL for both β-, α-ODAP, for homoarginine 0.09 μg/ mL at a signal-to-noise ratio of 3:1.展开更多
A loop modeling method, adaptive simulated annealing, for ab initio prediction of protein loop structures, as an optimization problem of searching the global minimum of a given energy function, is proposed. An interfa...A loop modeling method, adaptive simulated annealing, for ab initio prediction of protein loop structures, as an optimization problem of searching the global minimum of a given energy function, is proposed. An interface-friendly toolbox—LoopModeller in Windows and Linux systems, VC++ and OpenGL environments is developed for analysis and visualization. Simulation results of three short-chain neurotoxins modeled by LoopModeller show that the method proposed is fast and efficient.展开更多
Objective: To describe the latest progress in the use of botulinum neurotoxin for post-stroke limb spasm. Methods: This paper looks up the relevant research literatures in recent years in PubMed, Web of Science, Sprin...Objective: To describe the latest progress in the use of botulinum neurotoxin for post-stroke limb spasm. Methods: This paper looks up the relevant research literatures in recent years in PubMed, Web of Science, Springer, Ovid, CNKI, WanFang databases and summarizes them. Results: The latest progress in the use of botulinum neurotoxin for post-stroke limb spasm was studied from the following aspects: the action mechanism of botulinum neurotoxin;efficacy evaluation;injection dose;target muscle selection;guiding technology;combination therapy. Conclusion: Botulinum neurotoxin is the first-line treatment for post-stroke limb spasm. We need to make continuous improvement and progress from the treatment period, injection dose, target muscle selection, guiding technology and efficacy evaluation to improve the quality of life of the majority of post-stroke survivors in China.展开更多
Neurodegeneration is attributable to metabolic disturbances in the various cell types responsible for this condition, in respect of glucose utilisation and dysfunctional mitochondrial oxidative mechanisms. The propert...Neurodegeneration is attributable to metabolic disturbances in the various cell types responsible for this condition, in respect of glucose utilisation and dysfunctional mitochondrial oxidative mechanisms. The properties of neurotoxins and antagonists that limit their action are well documented in disease models, whereas effective therapy is very limited. Cell apoptosis, a general marker of neurodegeneration, is also of therapeutic interest in the treatment of cancer. cGMP nucleotide influences apoptosis and has a role in maintaining equilibrium within cell redox parameters. The chemical structure of cGMP provides a comparative template for demonstrating relative molecular similarity within the structures of natural and synthetic compounds influencing tumour cell apoptosis. The present study uses computational software to investigate molecular similarity within the structures of cGMP and compounds that modulate cell apoptosis in experimental models of diabetic peripheral neuropathy (DPN), Parkinson’s and multiple sclerosis. Differential molecular similarity demonstrated in neurotoxin and antagonist structures implicate metabolite impairment of cGMP signaling function as a common mechanism in the initial phases of these neurodegenerative conditions.展开更多
We explore the hypothesis that a potential explanation for the initiation of motor neuron disease is an unappreciated vulnerability in central nervous system defense,the direct delivery of neurotoxins into motor neuro...We explore the hypothesis that a potential explanation for the initiation of motor neuron disease is an unappreciated vulnerability in central nervous system defense,the direct delivery of neurotoxins into motor neurons via peripheral nerve retrograde transport.This further suggests a mechanism for focal initiation of neuro-degenerative diseases in general,with subsequent spread by network degeneration as suggested by the Frost-Diamond hypothesis.We propose this vulnerability may be a byproduct of vertebrate evolution in a benign aquatic environment,where external surfaces were not exposed to concentrated neurotoxins.展开更多
文摘The positive effect of levodopa in the treatment of Parkinson’s disease,although it is limited in time and has severe side effects,has encouraged the scientific community to look for new drugs that can stop the neurodegenerative process or even regenerate the neuromelanin-containing dopaminergic nigrostriatal neurons.Successful preclinical studies with coenzyme Q10,mitoquinone,isradipine,nilotinib,TCH346,neurturin,zonisamide,deferiprone,prasinezumab,and cinpanemab prompted clinical trials.However,these failed and after more than 50 years levodopa continues to be the key drug in the treatment of the disease,despite its severe side effects after 4–6 years of chronic treatment.The lack of translated successful results obtained in preclinical investigations based on the use of neurotoxins that do not exist in the human body as new drugs for Parkinson’s disease treatment is a big problem.In our opinion,the cause of these failures lies in the experimental animal models involving neurotoxins that do not exist in the human body,such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine,that induce a very fast,massive and expansive neurodegenerative process,which contrasts with the extremely slow one of neuromelanin-containing dopaminergic neurons.The exceedingly slow progress of the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson’s patients is due to(i)a degenerative model in which the neurotoxic effect of an endogenous neurotoxin affects a single neuron,(ii)a neurotoxic event that is not expansive and(iii)the fact that the neurotoxin that triggers the neurodegenerative process is produced inside the neuromelanin-containing dopaminergic neurons.The endogenous neurotoxin that fits this degenerative model involving one single neuron at a time is aminochrome,since it(i)is generated within neuromelanin-containing dopaminergic neurons,(ii)does not cause an expansive neurotoxic effect and(iii)triggers all the mechanisms involved in the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson’s disease.In conclusion,based on the hypothesis that the neurodegenerative process of idiopathic Parkinson’s disease corresponds to a single-neuron neurodegeneration model,we must search for molecules that increase the expression of the neuroprotective enzymes DT-diaphorase and glutathione transferase M2-2.It has been observed that the activation of the Kelch-like ECH-associated protein 1/nuclear factor(erythroid-derived 2)-like 2 pathway is associated with the transcriptional activation of the DT-diaphorase and glutathione transferase genes.
基金supported partially by Bioversity VavilovFrankel Fellowship to Priyanka Gupta(Grant no.CONT/12/217/RF)supported by Grains Research and Development Corporation(GRDC),Australia
文摘Grass pea(Lathyrus sativus L.) is a crop that is considered one of the more resilient to climate change. With protein-rich seeds and leaves, it has strong potential as human food as well as animal feed and fodder. However, genetic improvement in this crop remains stagnant owing to the poor characterization of its genetic resources. In this study, we characterized 118 accessions of grass pea with 18 EST-SSR markers. A total of 118 accessions, 101 of L. sativus(100 cultivated accessions from Bangladesh and one wild accession) and 17 wild accessions of other Lathyrus species, were used. A total of 67 alleles were detected, with an average of 3.72 alleles per locus and average polymorphism information content of 0.52. A dissimilarity matrix was formed and hierarchical cluster analysis performed using the UPGMA method grouped genotypes into four main clusters. Cluster analysis based on the genetic dissimilarity revealed a clear grouping of the 100 cultivated and 18 wild accessions into four main groups. Group I consisted of 20 accessions with high β-N-oxalyl-L-α,β-diaminopropionic acid(β-ODAP) concentration. Of these 20 accessions, 17 were wild accessions. Only one wild accession(L. cicera) was clustered in group II, which contained 35 accessions. Most of the group II accessions contained low β-ODAP. Group III was represented by 34 accessions, many of them with high β-ODAP. Group IV consisted of 29 accessions, a few of which had very high β-ODAP concentrations. Analysis of molecular variance of the microsatellite data showed significantly higher values of molecular variance between(83%) than within(17%) populations. These characterized accessions will be useful in grass pea breeding programs.
基金Tshe prOject!(39770469) supported by the National Natural Science Foundation of China.
文摘A rapid and simple method is presented for determining β-N-oxalyl-α. β- diaminopropionic acid (β -ODAP) and its much less toxic α -isomer (α -ODAP) in Lathyrus sativus. Seed and foliage extracts of Lathyrus sativus were treated with 1-fluoro-2,4-dinitrobenzene (FDNB) and a reversed-phase high-performance liquid chromatographic method for the separation of the derivatives in the pmol range is reported.
基金This work was supported by NKBRSF Project(G200001 8603)the National Natural Science Foundation of China(No.30270965).
文摘A method has been presented for the simultaneous analysis of neurotoxin β-N-oxalyl-α, β-diaminopropionic acid (β-ODAP) and its non- or low-toxic isomer α-ODAP as well as other amino acids in Lathyrus sativus extracts after derivatization with para-nitrobenzyloxycarbonyl chloride (PNZ-Cl) by reversed-phase (C18 column) high performance liquid chromatography (RP-HPLC). Detection limits of isomers were 0.08 μg/mL for both β-, α-ODAP, for homoarginine 0.09 μg/ mL at a signal-to-noise ratio of 3:1.
文摘A loop modeling method, adaptive simulated annealing, for ab initio prediction of protein loop structures, as an optimization problem of searching the global minimum of a given energy function, is proposed. An interface-friendly toolbox—LoopModeller in Windows and Linux systems, VC++ and OpenGL environments is developed for analysis and visualization. Simulation results of three short-chain neurotoxins modeled by LoopModeller show that the method proposed is fast and efficient.
文摘Objective: To describe the latest progress in the use of botulinum neurotoxin for post-stroke limb spasm. Methods: This paper looks up the relevant research literatures in recent years in PubMed, Web of Science, Springer, Ovid, CNKI, WanFang databases and summarizes them. Results: The latest progress in the use of botulinum neurotoxin for post-stroke limb spasm was studied from the following aspects: the action mechanism of botulinum neurotoxin;efficacy evaluation;injection dose;target muscle selection;guiding technology;combination therapy. Conclusion: Botulinum neurotoxin is the first-line treatment for post-stroke limb spasm. We need to make continuous improvement and progress from the treatment period, injection dose, target muscle selection, guiding technology and efficacy evaluation to improve the quality of life of the majority of post-stroke survivors in China.
文摘Neurodegeneration is attributable to metabolic disturbances in the various cell types responsible for this condition, in respect of glucose utilisation and dysfunctional mitochondrial oxidative mechanisms. The properties of neurotoxins and antagonists that limit their action are well documented in disease models, whereas effective therapy is very limited. Cell apoptosis, a general marker of neurodegeneration, is also of therapeutic interest in the treatment of cancer. cGMP nucleotide influences apoptosis and has a role in maintaining equilibrium within cell redox parameters. The chemical structure of cGMP provides a comparative template for demonstrating relative molecular similarity within the structures of natural and synthetic compounds influencing tumour cell apoptosis. The present study uses computational software to investigate molecular similarity within the structures of cGMP and compounds that modulate cell apoptosis in experimental models of diabetic peripheral neuropathy (DPN), Parkinson’s and multiple sclerosis. Differential molecular similarity demonstrated in neurotoxin and antagonist structures implicate metabolite impairment of cGMP signaling function as a common mechanism in the initial phases of these neurodegenerative conditions.
基金supported by grants from the New Jersey Commission on Spinal Cord Research (05-304711-015)
文摘We explore the hypothesis that a potential explanation for the initiation of motor neuron disease is an unappreciated vulnerability in central nervous system defense,the direct delivery of neurotoxins into motor neurons via peripheral nerve retrograde transport.This further suggests a mechanism for focal initiation of neuro-degenerative diseases in general,with subsequent spread by network degeneration as suggested by the Frost-Diamond hypothesis.We propose this vulnerability may be a byproduct of vertebrate evolution in a benign aquatic environment,where external surfaces were not exposed to concentrated neurotoxins.
