OBJECTIVE To investigated the effects of INI-0602 on nociceptive reflex,depression-associated andanxiety-related behaviors caused by neuropathic pain in sciatic nerve injury rats.METHODS Male rat were subjected to sci...OBJECTIVE To investigated the effects of INI-0602 on nociceptive reflex,depression-associated andanxiety-related behaviors caused by neuropathic pain in sciatic nerve injury rats.METHODS Male rat were subjected to sciatic nerve injury(SNI)or sham surgery.Rat received daily treatment with INI-0602 intrathecally,at a dose of 0.25μg/10μL.The response frequency to mechanical allodynia in animals was measured with von Frey hairs on day 1,3,5,7,14,21.Rats were evaluated in the forced swimming test(FST)test,tail suspension test(TST),sucrose preference test(SPT)for depression-like behavior.We performed open field test(OFT)and elevated plus-maze test(EPM)to evaluate anxiety-associated behaviors.Besides,we investigated the alterations of NMDA receptor and the brain-derived neurotrophic factor(BDNF)and also the expression of connexin43 and connexin32,structure protein of gap junction channel,on the protein level and the number of activated astrocyte showed by immunohistochemical.RESULTS The SNI procedure produced mechanical allodynia and accompanied with depressive-like and anxiety-like behavior.Treatment with INI-0602 produced a significant analgesic effect in SNI rats at day 7(model+NS:11.017±1.506 g;model+INI-0602:31.157±1.532 g,P<0.01),and still obviously on the 21th day(31.067±1.787,P<0.01).INI-0602 could also improve the performance of sciatic nerve injury rats among program behavior tests related to depression and anxiety.In parallel with relief of pain,the alterations of NMDA receptor and the brain-derived neurotrophic factor(BDNF),involved in central sensitization and synaptic plasticity,were investigated.INI-0602 not only could inhibited spared nerve injury induced up-regulated of NR2B and phosphorylation NR2B in early and late neuropathic pain(early phase:Nr2b:2.897±0.228,P<0.01;p-Nr2b:2.984±0.236,P<0.01;late phase:Nr2b:2.594±0.187,P<0.01;p-Nr2b:3.124±0.330,P<0.01),but also could inhibit the increased of BDNF in the early(model+NS:3.637±0.381,model+INI-0602:1.148±0.372,P<0.01)and upregulate the BDNF in late stage(model+NS:0.438±0.103,model+INI-0602:1.222±0.092,P<0.01).Meanwhile,INI-0602 significantly decreased the expression of connexin43 and connexin32,structure protein of gap junction channel,on the protein level and the number of activated astrocyte showed by immunohistochemical.CONCLUSION INI-0602 blocked behavioral changes induced by neuropathic pain,suggesting that it might be a promising pharmacological approach of painemotion diseases.展开更多
A major susceptibility gene for psoriasis is located in the major histocompatibility complex class I region on chromosome 6 very close to the HLA-Cw6 gene. We collected a cohort of 1,019 patients with chronic plaque p...A major susceptibility gene for psoriasis is located in the major histocompatibility complex class I region on chromosome 6 very close to the HLA-Cw6 gene. We collected a cohort of 1,019 patients with chronic plaque psoriasis. The patients were typed for HLA-C and HLA-B. A total of 654 (64.2%) were HLA-Cw*0602 positive but 365 (35.8%) carried other HLA-C alleles. We confirmed that HLA-Cw*0602 positive patients have younger age of onset (17.5 vs 24.3 years, P< 10-10), higher incidence of guttate and the eruptive type of psoriasis (P< 0.0001), more frequent exacerbations with throat infections (P=0.01), higher incidence of the Koebner’s phenomenon (P=0.01), and more extensive disease (P=0.03). A striking new finding was a diverging pattern of disease severity in HLACw*0602 positive and negative patients depending on the age of onset of the disease (P=0.0006). HLA-Cw*0602 positive women also had more frequent remissions during pregnancy (P< 0.0001). All types of nail changes were, however, more common in the Cw*0602 negative patients (P=0.003) and they more often had multiple types of nail lesions (P< 0.0001). The three ancestral haplotypes of Cw*0602 all conferred an increase in odds ratio but showed no difference in any of the clinical features studied. Our findings indicate that the genetic factor on chromosome 6 has a strong influence on the phenotype of the disease, and underline that differences in clinical features of psoriasis may be to a large extent genetically determined.展开更多
The HLA-Cw 0602 has been associated with psoriasis in different ethnic groups. But, it remains unclear whether HLA-C is the PSORS1 gene (the psoriasis gene in the MHC). Thus, several case-control studies have been p...The HLA-Cw 0602 has been associated with psoriasis in different ethnic groups. But, it remains unclear whether HLA-C is the PSORS1 gene (the psoriasis gene in the MHC). Thus, several case-control studies have been performed in order to investigate whether HLA-C itself determines the susceptibility to the disease. We studied 59 Jewish patients with type I psoriasis and 79 matched controls. Polymorphic genes and markers from HLA-B (centromeric to HLA-C) to the corneodesmosin (CDSN) gene (telomeric to HLA-C) were genotyped in order to determine their contribution to the susceptibility to psoriasis. Neither HLA-Cw 0602 nor the allele CDSN TTC were significantly associated with psoriasis with the size of the sample studied. The genes and markers telomeric to HLA-C such as the microsatellite C1-4- 4 (OR = 2.6, 95% CI = 1.4- 4.7, Pc =0.018) the octamer transcription factor (OTF)- 3 gene (OR = 2.6, 95% CI = 1.6- 4.3, Pc = 0.0001) and the α -helix coiled-coil rod homologue (HCR) gene (OR = 2.5, 95% CI = 1.3- 4.5, Pc = 0.004), however, were associated with the disease. These results suggest that a major psoriasis susceptibility gene is likely to be located within a region of 150 kb telomeric to HLA-C and centromeric to the CDSN gene.展开更多
基金The project supported by National Natural Science Foundation of China(81473234,U1303221)
文摘OBJECTIVE To investigated the effects of INI-0602 on nociceptive reflex,depression-associated andanxiety-related behaviors caused by neuropathic pain in sciatic nerve injury rats.METHODS Male rat were subjected to sciatic nerve injury(SNI)or sham surgery.Rat received daily treatment with INI-0602 intrathecally,at a dose of 0.25μg/10μL.The response frequency to mechanical allodynia in animals was measured with von Frey hairs on day 1,3,5,7,14,21.Rats were evaluated in the forced swimming test(FST)test,tail suspension test(TST),sucrose preference test(SPT)for depression-like behavior.We performed open field test(OFT)and elevated plus-maze test(EPM)to evaluate anxiety-associated behaviors.Besides,we investigated the alterations of NMDA receptor and the brain-derived neurotrophic factor(BDNF)and also the expression of connexin43 and connexin32,structure protein of gap junction channel,on the protein level and the number of activated astrocyte showed by immunohistochemical.RESULTS The SNI procedure produced mechanical allodynia and accompanied with depressive-like and anxiety-like behavior.Treatment with INI-0602 produced a significant analgesic effect in SNI rats at day 7(model+NS:11.017±1.506 g;model+INI-0602:31.157±1.532 g,P<0.01),and still obviously on the 21th day(31.067±1.787,P<0.01).INI-0602 could also improve the performance of sciatic nerve injury rats among program behavior tests related to depression and anxiety.In parallel with relief of pain,the alterations of NMDA receptor and the brain-derived neurotrophic factor(BDNF),involved in central sensitization and synaptic plasticity,were investigated.INI-0602 not only could inhibited spared nerve injury induced up-regulated of NR2B and phosphorylation NR2B in early and late neuropathic pain(early phase:Nr2b:2.897±0.228,P<0.01;p-Nr2b:2.984±0.236,P<0.01;late phase:Nr2b:2.594±0.187,P<0.01;p-Nr2b:3.124±0.330,P<0.01),but also could inhibit the increased of BDNF in the early(model+NS:3.637±0.381,model+INI-0602:1.148±0.372,P<0.01)and upregulate the BDNF in late stage(model+NS:0.438±0.103,model+INI-0602:1.222±0.092,P<0.01).Meanwhile,INI-0602 significantly decreased the expression of connexin43 and connexin32,structure protein of gap junction channel,on the protein level and the number of activated astrocyte showed by immunohistochemical.CONCLUSION INI-0602 blocked behavioral changes induced by neuropathic pain,suggesting that it might be a promising pharmacological approach of painemotion diseases.
文摘A major susceptibility gene for psoriasis is located in the major histocompatibility complex class I region on chromosome 6 very close to the HLA-Cw6 gene. We collected a cohort of 1,019 patients with chronic plaque psoriasis. The patients were typed for HLA-C and HLA-B. A total of 654 (64.2%) were HLA-Cw*0602 positive but 365 (35.8%) carried other HLA-C alleles. We confirmed that HLA-Cw*0602 positive patients have younger age of onset (17.5 vs 24.3 years, P< 10-10), higher incidence of guttate and the eruptive type of psoriasis (P< 0.0001), more frequent exacerbations with throat infections (P=0.01), higher incidence of the Koebner’s phenomenon (P=0.01), and more extensive disease (P=0.03). A striking new finding was a diverging pattern of disease severity in HLACw*0602 positive and negative patients depending on the age of onset of the disease (P=0.0006). HLA-Cw*0602 positive women also had more frequent remissions during pregnancy (P< 0.0001). All types of nail changes were, however, more common in the Cw*0602 negative patients (P=0.003) and they more often had multiple types of nail lesions (P< 0.0001). The three ancestral haplotypes of Cw*0602 all conferred an increase in odds ratio but showed no difference in any of the clinical features studied. Our findings indicate that the genetic factor on chromosome 6 has a strong influence on the phenotype of the disease, and underline that differences in clinical features of psoriasis may be to a large extent genetically determined.
文摘The HLA-Cw 0602 has been associated with psoriasis in different ethnic groups. But, it remains unclear whether HLA-C is the PSORS1 gene (the psoriasis gene in the MHC). Thus, several case-control studies have been performed in order to investigate whether HLA-C itself determines the susceptibility to the disease. We studied 59 Jewish patients with type I psoriasis and 79 matched controls. Polymorphic genes and markers from HLA-B (centromeric to HLA-C) to the corneodesmosin (CDSN) gene (telomeric to HLA-C) were genotyped in order to determine their contribution to the susceptibility to psoriasis. Neither HLA-Cw 0602 nor the allele CDSN TTC were significantly associated with psoriasis with the size of the sample studied. The genes and markers telomeric to HLA-C such as the microsatellite C1-4- 4 (OR = 2.6, 95% CI = 1.4- 4.7, Pc =0.018) the octamer transcription factor (OTF)- 3 gene (OR = 2.6, 95% CI = 1.6- 4.3, Pc = 0.0001) and the α -helix coiled-coil rod homologue (HCR) gene (OR = 2.5, 95% CI = 1.3- 4.5, Pc = 0.004), however, were associated with the disease. These results suggest that a major psoriasis susceptibility gene is likely to be located within a region of 150 kb telomeric to HLA-C and centromeric to the CDSN gene.
