内毒素是引起多器官功能障碍综合征(multiple organ dysfunction syndrome,MODS)的重要因素,而MODS是感染性休克的主要死亡原因,因此及早干预严重感染患者的内毒素血症状态对于改善患者的预后有积极有效的作用。但是目前对于内毒素的干...内毒素是引起多器官功能障碍综合征(multiple organ dysfunction syndrome,MODS)的重要因素,而MODS是感染性休克的主要死亡原因,因此及早干预严重感染患者的内毒素血症状态对于改善患者的预后有积极有效的作用。但是目前对于内毒素的干预手段有限,其拮抗剂由于价格昂贵及可能诱发严重的过敏反应而使其在临床的应用受到限制。多粘菌素B与脂多糖的脂质A部分具有高度亲和力,能吸附除去介质中的内毒素,并能破坏G^-菌外层或细胞质膜的通透性,具有抗菌和灭活内毒素的作用。多粘菌素B可以吸附固定到α一氯乙酰胺-甲基聚苯乙烯纤维的氨基上,利用此种灌流器的血液灌流可以直接吸附去除血浆中的内毒素,此治疗手段已经在日本较广泛地应用于严重脓毒症及感染性休克患者的治疗。通过对此疗法作用机制进行的研究,从内毒素清除效率、细胞因子的改变、血流动力学改善、器官功能保护等角度证实了这一方法的有效性,在器官、组织、细胞乃至基因层面逐步揭示了固定多粘菌素B纤维(polymyxin B-immobilizedfiber,PMX)治疗内毒素血症的意义。展开更多
Inflammation is an established etiopathogenesis factor of infantile spasms（IS）, a therapy-resistant epileptic syndrome of infancy. We investigated the IS-associated transcriptomic alterations of neurotransmission in...Inflammation is an established etiopathogenesis factor of infantile spasms（IS）, a therapy-resistant epileptic syndrome of infancy. We investigated the IS-associated transcriptomic alterations of neurotransmission in rat hypothalamic arcuate nucleus, how they are corrected by antiinflamatory treatments and whether there are sex differences. IS was triggered by repeated intraperitoneal administration of N-methyl-D-aspartic acid following anti-inflammatory treatment（adreno-cortico-tropic-hormone（ACTH） or PMX53）or normal saline vehicle to prenatally exposed to betamethasone young rats. We found that treatments with both ACTH and PMX53 resulted in substantial recovery of the genomic fabrics of all types of synaptic transmission altered by IS. While ACTH represents the first line of treatment for IS, the even higher efficiency of PMX53（an antagonist of the complement C5 a receptor） in restoring the normal transcriptome was not expected. In addition to the childhood epilepsy, the recovery of the neurotransmission genomic fabrics by PMX53 also gives hope for the autism spectrum disorders that share a high comorbidity with IS. Our results revealed significant sex dichotomy in both IS-associated transcriptomic alterations（males more affected） and in the efficiency of PMX53 anti-inflammatory treatment（better for males）. Our data further suggest that anti-inflammatory treatments correcting alterations in the inflammatory transcriptome may become successful therapies for refractory epilepsies.展开更多
Perpose: In order to establish the pathophysiological features and strategy for stercoral perforation of the colon, we herein analyze a series of stercoral perforation of the colon. Method: Ten patients were diagnosed...Perpose: In order to establish the pathophysiological features and strategy for stercoral perforation of the colon, we herein analyze a series of stercoral perforation of the colon. Method: Ten patients were diagnosed with stercoral perforation. Clinical features, primary diseases, triggers, causative bacteria in ascites, postoperative complications, pathological features, severity of the disease, and effect of direct hemoperfusion with polymyxin B immobilized fiber (PMX-DHP) were investigated. Results: Nine patients had a long history of serious and chronic constipation and 7 patients had hypertension. Causative bacteria in ascites during the operation were most commonly Escherichia coli. There were a lot of severe postoperative complications such as sepsis, disseminated intravascular coagulation, and acute lung injury. With regard to the microscopic findings of the perforation site, the intestinal wall showed severe nonspecific inflammatory changes, including an increase of mono-nuclear cells in the lamina propria. There were 4 hospital deaths, so the mortality rate was 40%. APACHE- II and SOFA score were high postoperation and 24 hours after the operation. PMX-DHP was performed in 8 cases of severe conditions of stercoral perforation of the colon. Because the catecholamine index improved within 24 hours, four of 8 cases were rescued. Conclusion: Most of the patients with stercoral perforation of the colon had severe postoperative complications. The severity of the disease was extremely high, therefore, early diagnosis based on pathophy-siological features and comprehensive therapies including PMX-DHP were necessary for strategy of treating stercoral perforation of the colon.展开更多
Circadian rhythms are daily oscillations of multiple biological processes. Recently, relationships between circadian rhythms and immune functions have also been described. In a mouse sepsis model, the death rate due t...Circadian rhythms are daily oscillations of multiple biological processes. Recently, relationships between circadian rhythms and immune functions have also been described. In a mouse sepsis model, the death rate due to lipopolysaccharide (LPS)-induced endotoxic shock was found to be dependent on LPS administration as determined by circadian time. In humans, a pronounced inflammatory response to endotoxemia differs depending on whether it is daytime or night-time: Levels of tumor necrosis factor-alpha and interleukin-6 were higher during the night. Therefore, it is reasonable to assume that circadian rhythms influence not only organ dysfunction and the prognosis induced by LPS, but also the therapeutic effect of anti-LPS therapy such as Polymyxin-B direct hemoperfusion. We herein postulate the concept that it is important to discuss septic shock treatment in terms of whether or not the treatment is adjusted for the optimal time window as determined by circadian rhythms.展开更多
AIM: To investigate the effectiveness of direct hemo- perfusion with polymyxin B-immobilized fibers (DHP- PMX therapy) on warm ischemia-reperfusion (I/R) injury of the small intestine. METHODS: The proximal jejunum an...AIM: To investigate the effectiveness of direct hemo- perfusion with polymyxin B-immobilized fibers (DHP- PMX therapy) on warm ischemia-reperfusion (I/R) injury of the small intestine. METHODS: The proximal jejunum and distal ileum of mongrel dogs were resected. Warm ischemia was performed by clamping the superior mesenteric artery (SMA) and vein (SMV) for 2 h. Blood flow to the proximal small intestine was restored 1 h after reperfusion, and the distal small intestine was used as a stoma. The experiment was discontinued 6 h after reperfusion. The dogs were divided into two groups: the DHP-PMX group (n = 6, DHP-PMX was performed for 180 min; from 10 min prior to reperfusion to 170 min after reperfusion) and the control group (n = 5). The rate pressure product (RPP), SMA blood flow, mucosal tissue blood flow, and intramucosal pH (pHi) were compared between the two groups. The serum interleukin (IL)-10 levels measured 170 min after reperfusion were also compared. RESULTS: The RPP at 6 h after reperfusion was significantly higher in the PMX group than in the control group (12 174 ± 1832 mmHg/min vs 8929 ± 1797 mmHg/min, P < 0.05). The recovery rates ofthe SMA blood flow at 1 and 6 h after reperfusion were significantly better in the PMX group than in the control group (61% ± 7% vs 44% ± 4%, P < 0.05, and 59% ± 5% vs 35% ± 5%, P < 0.05, respectively). The recovery rate of the mucosal tissue blood flow and the pHi levels at 6 h after reperfusion were significantly higher in the PMX group (61% ± 8% vs 31% ± 3%, P < 0.05 and 7.91 ± 0.06 vs 7.69 ± 0.08, P < 0.05, respectively). In addition, the serum IL-10 levels just before DHP-PMX removal were significantly higher in the PMX group than in the control group (1 569 ± 253 pg/mL vs 211 ± 40 pg/mL, P < 0.05). CONCLUSION: DHP-PMX therapy reduced warm I/R injury of the small intestine. IL-10 may play a role in inhibiting I/R injury during DHP-PMX therapy.展开更多
Blockade of the interaction of anaphylatoxin C5a with its receptor C5aR1 has been actively studied as a potential treatment for many inflammatory diseases;but current C5a antagonists exhibit inadequate potency and poo...Blockade of the interaction of anaphylatoxin C5a with its receptor C5aR1 has been actively studied as a potential treatment for many inflammatory diseases;but current C5a antagonists exhibit inadequate potency and poor species cross-reactivity, and novel biochemical tools are needed to investigate whether the core region of C5a contains important interaction epitopes that can explain these limitations. Herein, we report the development of chimeric protein C5a probes containing both the complete core region of rat or human C5a, and the small-molecule antagonist PMX53-1. These probes were chemically synthesized through hydrazide-based native chemical ligation of a linear peptide hydrazide with the requisite cyclopeptidic antagonist, both of which were made by solid-phase synthesis. Quasi-racemic X-ray crystallography established that attachment of PMX53-1 did not affect the structure of the core region of C5a. Subsequent C5aR1 activity assays demonstrated the probes can provide valuable insights into the development of C5a antagonists;for example, they exhibited significantly better binding affinity and much improved species cross-reactivity than PMX53-1, supporting the notion that the effect of some epitopes outside the C-terminus of C5a should be taken into consideration when designing better C5a antagonists. Surprisingly, the core region of C5a was found to partially agonize C5aR1, suggesting the presence of more than one agonistic interaction in the binding of C5a to C5aR1. This study exemplifies the value of chemical protein synthesis in developing novel receptor probes for drug discovery research.展开更多
文摘内毒素是引起多器官功能障碍综合征(multiple organ dysfunction syndrome,MODS)的重要因素,而MODS是感染性休克的主要死亡原因,因此及早干预严重感染患者的内毒素血症状态对于改善患者的预后有积极有效的作用。但是目前对于内毒素的干预手段有限,其拮抗剂由于价格昂贵及可能诱发严重的过敏反应而使其在临床的应用受到限制。多粘菌素B与脂多糖的脂质A部分具有高度亲和力,能吸附除去介质中的内毒素,并能破坏G^-菌外层或细胞质膜的通透性,具有抗菌和灭活内毒素的作用。多粘菌素B可以吸附固定到α一氯乙酰胺-甲基聚苯乙烯纤维的氨基上,利用此种灌流器的血液灌流可以直接吸附去除血浆中的内毒素,此治疗手段已经在日本较广泛地应用于严重脓毒症及感染性休克患者的治疗。通过对此疗法作用机制进行的研究,从内毒素清除效率、细胞因子的改变、血流动力学改善、器官功能保护等角度证实了这一方法的有效性,在器官、组织、细胞乃至基因层面逐步揭示了固定多粘菌素B纤维(polymyxin B-immobilizedfiber,PMX)治疗内毒素血症的意义。
基金supported by Citizens United for Research in Epilepsy (CURE) Infantile Spasms Research Initiative(to LV and DAI)NIH grant NS-072966(to LV)
文摘Inflammation is an established etiopathogenesis factor of infantile spasms（IS）, a therapy-resistant epileptic syndrome of infancy. We investigated the IS-associated transcriptomic alterations of neurotransmission in rat hypothalamic arcuate nucleus, how they are corrected by antiinflamatory treatments and whether there are sex differences. IS was triggered by repeated intraperitoneal administration of N-methyl-D-aspartic acid following anti-inflammatory treatment（adreno-cortico-tropic-hormone（ACTH） or PMX53）or normal saline vehicle to prenatally exposed to betamethasone young rats. We found that treatments with both ACTH and PMX53 resulted in substantial recovery of the genomic fabrics of all types of synaptic transmission altered by IS. While ACTH represents the first line of treatment for IS, the even higher efficiency of PMX53（an antagonist of the complement C5 a receptor） in restoring the normal transcriptome was not expected. In addition to the childhood epilepsy, the recovery of the neurotransmission genomic fabrics by PMX53 also gives hope for the autism spectrum disorders that share a high comorbidity with IS. Our results revealed significant sex dichotomy in both IS-associated transcriptomic alterations（males more affected） and in the efficiency of PMX53 anti-inflammatory treatment（better for males）. Our data further suggest that anti-inflammatory treatments correcting alterations in the inflammatory transcriptome may become successful therapies for refractory epilepsies.
文摘Perpose: In order to establish the pathophysiological features and strategy for stercoral perforation of the colon, we herein analyze a series of stercoral perforation of the colon. Method: Ten patients were diagnosed with stercoral perforation. Clinical features, primary diseases, triggers, causative bacteria in ascites, postoperative complications, pathological features, severity of the disease, and effect of direct hemoperfusion with polymyxin B immobilized fiber (PMX-DHP) were investigated. Results: Nine patients had a long history of serious and chronic constipation and 7 patients had hypertension. Causative bacteria in ascites during the operation were most commonly Escherichia coli. There were a lot of severe postoperative complications such as sepsis, disseminated intravascular coagulation, and acute lung injury. With regard to the microscopic findings of the perforation site, the intestinal wall showed severe nonspecific inflammatory changes, including an increase of mono-nuclear cells in the lamina propria. There were 4 hospital deaths, so the mortality rate was 40%. APACHE- II and SOFA score were high postoperation and 24 hours after the operation. PMX-DHP was performed in 8 cases of severe conditions of stercoral perforation of the colon. Because the catecholamine index improved within 24 hours, four of 8 cases were rescued. Conclusion: Most of the patients with stercoral perforation of the colon had severe postoperative complications. The severity of the disease was extremely high, therefore, early diagnosis based on pathophy-siological features and comprehensive therapies including PMX-DHP were necessary for strategy of treating stercoral perforation of the colon.
文摘Circadian rhythms are daily oscillations of multiple biological processes. Recently, relationships between circadian rhythms and immune functions have also been described. In a mouse sepsis model, the death rate due to lipopolysaccharide (LPS)-induced endotoxic shock was found to be dependent on LPS administration as determined by circadian time. In humans, a pronounced inflammatory response to endotoxemia differs depending on whether it is daytime or night-time: Levels of tumor necrosis factor-alpha and interleukin-6 were higher during the night. Therefore, it is reasonable to assume that circadian rhythms influence not only organ dysfunction and the prognosis induced by LPS, but also the therapeutic effect of anti-LPS therapy such as Polymyxin-B direct hemoperfusion. We herein postulate the concept that it is important to discuss septic shock treatment in terms of whether or not the treatment is adjusted for the optimal time window as determined by circadian rhythms.
文摘AIM: To investigate the effectiveness of direct hemo- perfusion with polymyxin B-immobilized fibers (DHP- PMX therapy) on warm ischemia-reperfusion (I/R) injury of the small intestine. METHODS: The proximal jejunum and distal ileum of mongrel dogs were resected. Warm ischemia was performed by clamping the superior mesenteric artery (SMA) and vein (SMV) for 2 h. Blood flow to the proximal small intestine was restored 1 h after reperfusion, and the distal small intestine was used as a stoma. The experiment was discontinued 6 h after reperfusion. The dogs were divided into two groups: the DHP-PMX group (n = 6, DHP-PMX was performed for 180 min; from 10 min prior to reperfusion to 170 min after reperfusion) and the control group (n = 5). The rate pressure product (RPP), SMA blood flow, mucosal tissue blood flow, and intramucosal pH (pHi) were compared between the two groups. The serum interleukin (IL)-10 levels measured 170 min after reperfusion were also compared. RESULTS: The RPP at 6 h after reperfusion was significantly higher in the PMX group than in the control group (12 174 ± 1832 mmHg/min vs 8929 ± 1797 mmHg/min, P < 0.05). The recovery rates ofthe SMA blood flow at 1 and 6 h after reperfusion were significantly better in the PMX group than in the control group (61% ± 7% vs 44% ± 4%, P < 0.05, and 59% ± 5% vs 35% ± 5%, P < 0.05, respectively). The recovery rate of the mucosal tissue blood flow and the pHi levels at 6 h after reperfusion were significantly higher in the PMX group (61% ± 8% vs 31% ± 3%, P < 0.05 and 7.91 ± 0.06 vs 7.69 ± 0.08, P < 0.05, respectively). In addition, the serum IL-10 levels just before DHP-PMX removal were significantly higher in the PMX group than in the control group (1 569 ± 253 pg/mL vs 211 ± 40 pg/mL, P < 0.05). CONCLUSION: DHP-PMX therapy reduced warm I/R injury of the small intestine. IL-10 may play a role in inhibiting I/R injury during DHP-PMX therapy.
基金supported by the National Key R&D Program of China (2017YFA0505200)the National Natural Science Foundation of China (21532004, 91753205, 81621002, 21621003)
文摘Blockade of the interaction of anaphylatoxin C5a with its receptor C5aR1 has been actively studied as a potential treatment for many inflammatory diseases;but current C5a antagonists exhibit inadequate potency and poor species cross-reactivity, and novel biochemical tools are needed to investigate whether the core region of C5a contains important interaction epitopes that can explain these limitations. Herein, we report the development of chimeric protein C5a probes containing both the complete core region of rat or human C5a, and the small-molecule antagonist PMX53-1. These probes were chemically synthesized through hydrazide-based native chemical ligation of a linear peptide hydrazide with the requisite cyclopeptidic antagonist, both of which were made by solid-phase synthesis. Quasi-racemic X-ray crystallography established that attachment of PMX53-1 did not affect the structure of the core region of C5a. Subsequent C5aR1 activity assays demonstrated the probes can provide valuable insights into the development of C5a antagonists;for example, they exhibited significantly better binding affinity and much improved species cross-reactivity than PMX53-1, supporting the notion that the effect of some epitopes outside the C-terminus of C5a should be taken into consideration when designing better C5a antagonists. Surprisingly, the core region of C5a was found to partially agonize C5aR1, suggesting the presence of more than one agonistic interaction in the binding of C5a to C5aR1. This study exemplifies the value of chemical protein synthesis in developing novel receptor probes for drug discovery research.
