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排序方式: 共有311条查询结果,搜索用时 296 毫秒
81.
Ling Guo Junting Ai Zhong Zheng Deborah A. Howatt Alan Daugherty Bin Huang Xiang-An Li 《The Journal of biological chemistry》2013,288(25):17947-17953
HDL has been considered to be a protective factor in sepsis; however, most contributing studies were conducted using the endotoxic animal model, and evidence from clinically relevant septic animal models remains limited and controversial. Furthermore, little is known about the roles of HDL in sepsis other than LPS neutralization. In this study, we employed cecal ligation and puncture (CLP), a clinically relevant septic animal model, and utilized apoA-I knock-out (KO) and transgenic mice to elucidate the roles of HDL in sepsis. ApoA-I-KO mice were more susceptible to CLP-induced septic death as shown by the 47.1% survival of apoA-I-KO mice versus the 76.7% survival of C57BL/6J (B6) mice (p = 0.038). ApoA-I-KO mice had exacerbated inflammatory cytokine production during sepsis compared with B6 mice. Further study indicated that serum from apoA-I-KO mice displayed less capacity for LPS neutralization compared with serum from B6 mice. In addition, apoA-I-KO mice had less LPS clearance, reduced corticosterone generation, and impaired leukocyte recruitment in sepsis. In contrast to apoA-I-KO mice, apoA-I transgenic mice were moderately resistant to CLP-induced septic death compared with B6 mice. In conclusion, our findings reveal multiple protective roles of HDL in CLP-induced sepsis. In addition to its well established role in neutralization of LPS, HDL exerts its protection against sepsis through promoting LPS clearance and modulating corticosterone production and leukocyte recruitment. Our study supports efforts to raise HDL levels as a therapeutic approach for sepsis. 相似文献
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83.
Summary In sepsis tissue O2 uptake may be abnormally limited because of a depressed O2 consumption/O2 transport relationship. This study has been performed to assess patterns of O2 consumption, CO2 production and O2 transport in septic patients undergoing total parenteral nutrition; more in particular, this study has investigated the interdependence between the patterns of blood O2 uptake and simultaneous CO2 release, and the availability of substrates (amino acids, glucose and fat). It has been shown that the O2 consumption/O2 transport relationship is significantly influenced by the exogenous amino acid load, which tends to increase O2 uptake and O2 consumption at any given O2 transport, thus suggesting a favourable effect of amino acid administration on energy metabolism. The data on CO2 production and CO2 release, in addition to reconfirming the results of previous studies, have shown that the changes in O2 uptake and in CO2 production mediated by substrate doses have a quantifiable impact on blood O2-CO2 exchange interactions. 相似文献
84.
Sunyoung Park Sang Doo Kim Ha Young Lee Dobeen Hwang Joon Seong Park Yoe-Sik Bae Junho Chung 《Biochemical and biophysical research communications》2014
Although many peptides have therapeutic effects against diverse disease, their short half-lives in vivo hurdle their application as drug candidates. To extend the short elimination half-lives of therapeutic peptides, we developed a novel delivery platform for therapeutic peptides using an anti-hapten antibody and its corresponding hapten. We selected cotinine because it is non-toxic, has a well-studied metabolism, and is physiologically absent. We conjugated WKYMVm-NH2, an anti-sepsis therapeutic peptide, to cotinine and showed that the conjugated peptide in complex with an anti-cotinine antibody has a significantly improved in vivo half-life while retaining its therapeutic efficacy. We suggest that this novel delivery platform for therapeutic peptides will be very useful to develop effective peptide therapeutics. 相似文献
85.
Amin Afrazi Maria F. Branca Chhinder P. Sodhi Misty Good Yukihiro Yamaguchi Charlotte E. Egan Peng Lu Hongpeng Jia Shahab Shaffiey Joyce Lin Congrong Ma Garrett Vincent Thomas Prindle Jr. Samantha Weyandt Matthew D. Neal John A. Ozolek John Wiersch Markus Tschurtschenthaler Chiyo Shiota George K. Gittes Timothy R. Billiar Kevin Mollen Arthur Kaser Richard Blumberg David J. Hackam 《The Journal of biological chemistry》2014,289(14):9584-9599
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87.
Katarina Maher Barbara Jeri? Kokelj Miha Butinar Georgy Mikhaylov Mateja Man?ek-Keber Veronika Stoka Olga Vasiljeva Boris Turk Sergei A. Grigoryev Nata?a Kopitar-Jerala 《The Journal of biological chemistry》2014,289(46):31736-31750
Stefin B (cystatin B) is an endogenous cysteine cathepsin inhibitor, and the loss-of-function mutations in the stefin B gene were reported in patients with Unverricht-Lundborg disease (EPM1). In this study we demonstrated that stefin B-deficient (StB KO) mice were significantly more sensitive to the lethal LPS-induced sepsis and secreted higher amounts of pro-inflammatory cytokines IL-1β and IL-18 in the serum. We further showed that increased caspase-11 gene expression and better pro-inflammatory caspase-1 and -11 activation determined in StB KO bone marrow-derived macrophages resulted in enhanced IL-1β processing. Pretreatment of macrophages with the cathepsin inhibitor E-64d did not affect secretion of IL-1β, suggesting that the increased cathepsin activity determined in StB KO bone marrow-derived macrophages is not essential for inflammasome activation. Upon LPS stimulation, stefin B was targeted into the mitochondria, and the lack of stefin B resulted in the increased destabilization of mitochondrial membrane potential and mitochondrial superoxide generation. Collectively, our study demonstrates that the LPS-induced sepsis in StB KO mice is dependent on caspase-11 and mitochondrial reactive oxygen species but is not associated with the lysosomal destabilization and increased cathepsin activity in the cytosol. 相似文献
88.
Eric P. Schmidt Guoyun Li Lingyun Li Li Fu Yimu Yang Katherine H. Overdier Ivor S. Douglas Robert J. Linhardt 《The Journal of biological chemistry》2014,289(12):8194-8202
Systemic inflammatory illnesses (such as sepsis) are marked by degradation of the endothelial glycocalyx, a layer of glycosaminoglycans (including heparan sulfate, chondroitin sulfate, and hyaluronic acid) lining the vascular lumen. We hypothesized that different pathophysiologic insults would produce characteristic patterns of released glycocalyx fragments. We collected plasma from healthy donors as well as from subjects with respiratory failure due to altered mental status (intoxication, ischemic brain injury), indirect lung injury (non-pulmonary sepsis, pancreatitis), or direct lung injury (aspiration, pneumonia). Mass spectrometry was employed to determine the quantity and sulfation patterns of circulating glycosaminoglycans. We found that circulating heparan sulfate fragments were significantly (23-fold) elevated in patients with indirect lung injury, while circulating hyaluronic acid concentrations were elevated (32-fold) in patients with direct lung injury. N-Sulfation and tri-sulfation of heparan disaccharides were significantly increased in patients with indirect lung injury. Chondroitin disaccharide sulfation was suppressed in all groups with respiratory failure. Plasma heparan sulfate concentrations directly correlated with intensive care unit length of stay. Serial plasma measurements performed in select patients revealed that circulating highly sulfated heparan fragments persisted for greater than 3 days after the onset of respiratory failure. Our findings demonstrate that circulating glycosaminoglycans are elevated in patterns characteristic of the etiology of respiratory failure and may serve as diagnostic and/or prognostic biomarkers of critical illness. 相似文献
89.
Ling Guo Zhong Zheng Junting Ai Bin Huang Xiang-An Li 《The Journal of biological chemistry》2014,289(21):14666-14673
Recent studies revealed that scavenger receptor BI (SR-BI or Scarb1) plays a critical protective role in sepsis. However, the mechanisms underlying this protection remain largely unknown. In this study, using Scarb1I179N mice, a mouse model specifically deficient in hepatic SR-BI, we report that hepatic SR-BI protects against cecal ligation and puncture (CLP)-induced sepsis as shown by 75% fatality in Scarb1I179N mice, but only 21% fatality in C57BL/6J control mice. The increase in fatality in Scarb1I179N mice was associated with an exacerbated inflammatory cytokine production. Further study demonstrated that hepatic SR-BI exerts its protection against sepsis through its role in promoting LPS clearance without affecting the inflammatory response in macrophages, the glucocorticoid production in adrenal glands, the leukocyte recruitment to peritoneum or the bacterial clearance in liver. Our findings reveal hepatic SR-BI as a critical protective factor in sepsis and point out that promoting hepatic SR-BI-mediated LPS clearance may provide a therapeutic approach for sepsis. 相似文献
90.
Jenny Campos-Salinas Antonio Cavazzuti Francisco O'Valle Irene Forte-Lago Marta Caro Stephen M. Beverley Mario Delgado Elena Gonzalez-Rey 《The Journal of biological chemistry》2014,289(21):14583-14599
Vasoactive intestinal peptide (VIP) is an anti-inflammatory neuropeptide recently identified as a potential antimicrobial peptide. To overcome the metabolic limitations of VIP, we modified the native peptide sequence and generated two stable synthetic analogues (VIP51 and VIP51(6–30)) with better antimicrobial profiles. Herein we investigate the effects of both VIP analogues on cell viability, membrane integrity, and ultrastructure of various bacterial strains and Leishmania species. We found that the two VIP derivatives kill various non-pathogenic and pathogenic Gram-positive and Gram-negative bacteria as well as the parasite Leishmania major through a mechanism that depends on the interaction with certain components of the microbial surface, the formation of pores, and the disruption of the surface membrane. The cytotoxicity of the VIP derivatives is specific for pathogens, because they do not affect the viability of mammalian cells. Docking simulations indicate that the chemical changes made in the analogues are critical to increase their antimicrobial activities. Consequently, we found that the native VIP is less potent as an antibacterial and fails as a leishmanicidal. Noteworthy from a therapeutic point of view is that treatment with both derivatives increases the survival and reduces bacterial load and inflammation in mice with polymicrobial sepsis. Moreover, treatment with VIP51(6–30) is very effective at reducing lesion size and parasite burden in a model of cutaneous leishmaniasis. These results indicate that the VIP analogues emerge as attractive alternatives for treating drug-resistant infectious diseases and provide key insights into a rational design of novel agents against these pathogens. 相似文献