Crohn's disease and ulcerative colitis,the major forms of inflammatory bowel diseases(IBD) in man,are complex diseases in which genetic and environmental factors interact to promote an excessive mucosal immune res...Crohn's disease and ulcerative colitis,the major forms of inflammatory bowel diseases(IBD) in man,are complex diseases in which genetic and environmental factors interact to promote an excessive mucosal immune response directed against normal components of the bacterial microflora.There is also evidence that the pathologic process is due to defects in counterregulatory mechanisms,such as those involving the immunosuppressive cytokine transforming growth factor(TGF)-1.Indeed,studies in human IBD tissues and murine models of colitis have documented a disruption of TGF-1 signalling marked by a block in the phosphorylation of Smad3,a signalling molecule associated with the activated TGF-receptor,due to up-regulation of Smad7,an intracellular inhibitor of Smad3 phosphorylation.Knock-down of Smad7 with a specific antisense oligonucleotide restores TGF-1/Smad3 signalling,thus resulting in a marked suppression of inflammatory cytokine production and attenuation of murine colitis.These findings together with the demonstration that Smad7 antisense oligonucleotide is not toxic when administered in mice have paved the way for the development of a Smad7 antisense oligonucleotidebased pharmaceutical compound that is now ready to enter the clinics.In this article we review the available data supporting the pathogenic role of Smad7 in IBD and discuss whether and how Smad7 antisense therapy could help dampen the ongoing inflammation in IBD.展开更多
Retinal ischemia is a common clinical entity and, due to relatively ineffective treatment, remains a common cause of visual impairment and blindness. Generally, ischemic syndromes are initially characterized by low ho...Retinal ischemia is a common clinical entity and, due to relatively ineffective treatment, remains a common cause of visual impairment and blindness. Generally, ischemic syndromes are initially characterized by low homeostatic responses which, with time, induce injury to the tissue due to cell loss by apoptosis. In this re-spect, retinal ischemia is a primary cause of neuronal death. It can be considered as a sort of fnal common pathway in retinal diseases and results in irreversible morphological and functional changes. This review summarizes the recent knowledge on the effects of ischemia in retinal tissue and points out experimental strategies/models performed to gain better compre-hension of retinal ischemia diseases. In particular, the nature of the mechanisms leading to neuronal damage （i.e., excess of glutamate release, oxidative stress and infammation） will be outlined as well as the potential and most intriguing retinoprotective approaches and the possible therapeutic use of naturally occurring molecules such as neuropeptides. There is a general agreement that a better understanding of the funda-mental pathophysiology of retinal ischemia will lead tobetter management and improved clinical outcome. In this respect, to contrast this pathological state, spe-cifc pharmacological strategies need to be developed aimed at the many putative cascades generated during ischemia.展开更多
Following ischemic stroke, blood-brain barrier （BBB） is disrupted and is further aggravated with the corresponding incidence of hyperlipidemia. BBB breakdown promotes inflammation infiltration into the brain, which ...Following ischemic stroke, blood-brain barrier （BBB） is disrupted and is further aggravated with the corresponding incidence of hyperlipidemia. BBB breakdown promotes inflammation infiltration into the brain, which exacerbates cerebral ischemic injury as a result. Here, we report that 10-O-（N,N-dimethylaminoethyl）-ginkgolide B methanesulfonate （XQ-1H） , a novel analog of ginkgolide B, alleviates BBB breakdown in hyperlipidemic rats and protects endothelial cells against inflammatory response. Middle cerebral artery occlusion （MCAO） modeled is- chemic stroke in rats. Before surgery, these rats were fed a cholesterol-rich diet to induce an experimental hyperlip- idemic condition. Additionally, lipopolysaccharide （LPS） incubation with rat brain microvessel endothelial cells （rBMECs） was applied to mimic hyperlipidemia-induced inflammatory injury of BBB. The results indicated more severe infarct size, increased BBB permeability, excessive secretion of pro-inflammatory cytokines, and exaggerated inflammation infiltration of the brain in hyperlipidemic rats following MCAO when compared to rats fed with normal diet. XQ-1H protected BBB integrity, lessoned brain edema and inflammation penetration, down- regulated MMP- 9 and VCMA-1 expressions, and extenuated ischemic infarction. XQ-1H alleviated LPS-induced inflammatory re- sponse in rBMECs, characterized by promoting cell viability, inhibiting TNF-α, IL-1β, and IL-6 releasing, and downregulating NF-KB inflammatory signal and down- stream proteins, such as VCAM-1 and iNOS. In conclusion, the present study shows that XQ-1H stabilizes BBB function following ischemic stroke in hyperlipidemic rats, and the possible mechanisms may be related to inflammation inhibition.展开更多
Sustained proteinuria is an independent risk factor leading to kidney fibrosis and end-stage renal fail-ure.Over-reabsorption of filtered proteins,notably albu-min,has been proved to trigger interstitial inflammation ...Sustained proteinuria is an independent risk factor leading to kidney fibrosis and end-stage renal fail-ure.Over-reabsorption of filtered proteins,notably albu-min,has been proved to trigger interstitial inflammation and fibrosis in proteinuric renal disease.Cubilin,an endo-cytic receptor expressed on the renal tubular brush bor-der,is responsible for albumin reabsorption in physiologic condition.However,little is known about whether it is required for activation of tubular cells induced by albu-min overload.In this work,we investigated the change of cubilin expression and its potential role in albumin-induced up-regulation of chemokines synthesis in vivo and in vitro.Twenty-six patients with nephrotic syndrome were enrolled in this study.Proximal tubule uptake of albumin,expression of apical membrane cubilin and infiltrating cells in kidney interstitium were determined by immunocytochemistry.In vitro,the transcription of cubilin in HK2 cells after exposure to albumin was ana-lyzed by real-time PCR.Endocytosis of albumin in HK2 cells was examined by fluorescent microscope.The influ-ence of inhibition of cubilin on albumin-induced expres-sions of monocyte chemoattractant protein 1(MCP-1)and regulated upon activation normal T-cell expressed and secreted(RANTES)was investigated by Western blot.The intensity of luminal cubilin and tubular accu-mulation of albumin were significantly increased in nephrotic kidneys.The expression of MCP-1 and RANTES was up-regulated,and there were spatial rela-tionships in localization between these chemokines and cubilin as well as intracellular albumin in kidney tissues.Infiltration of CD-3 and ED-1-positive cells was predom-inant in tubulointerstitial areas displaying signs of increases of cubilin expression and albumin accumula-tion.In vitro,the transcription of cubilin mRNA in HK2 cells was enhanced after 24 h exposure to albumin in a dose-dependent manner.Inhibition of endocytosis of albumin by antisense cubilin nucleotide markedly reduced expression of MCP-1 and RANTES.Cubilin was required for handling a greater amount of protein in nephrotic status and albumin-induced production of MCP-1 and RANTES by renal tubular cells,which further initiated tubulointerstitial inflammation in proteinuric disease.展开更多
基金Supported by The Fondazione "Umberto di Mario" Onlus, Romethe Broad Medical Research Foundation,No.IBD0301RGiuliani SpA,Milan,Italy
文摘Crohn's disease and ulcerative colitis,the major forms of inflammatory bowel diseases(IBD) in man,are complex diseases in which genetic and environmental factors interact to promote an excessive mucosal immune response directed against normal components of the bacterial microflora.There is also evidence that the pathologic process is due to defects in counterregulatory mechanisms,such as those involving the immunosuppressive cytokine transforming growth factor(TGF)-1.Indeed,studies in human IBD tissues and murine models of colitis have documented a disruption of TGF-1 signalling marked by a block in the phosphorylation of Smad3,a signalling molecule associated with the activated TGF-receptor,due to up-regulation of Smad7,an intracellular inhibitor of Smad3 phosphorylation.Knock-down of Smad7 with a specific antisense oligonucleotide restores TGF-1/Smad3 signalling,thus resulting in a marked suppression of inflammatory cytokine production and attenuation of murine colitis.These findings together with the demonstration that Smad7 antisense oligonucleotide is not toxic when administered in mice have paved the way for the development of a Smad7 antisense oligonucleotidebased pharmaceutical compound that is now ready to enter the clinics.In this article we review the available data supporting the pathogenic role of Smad7 in IBD and discuss whether and how Smad7 antisense therapy could help dampen the ongoing inflammation in IBD.
基金Supported by Italian Ministry of Education,University and Research(PRIN2005,grant No.2005052312)and University of Tuscia
文摘Retinal ischemia is a common clinical entity and, due to relatively ineffective treatment, remains a common cause of visual impairment and blindness. Generally, ischemic syndromes are initially characterized by low homeostatic responses which, with time, induce injury to the tissue due to cell loss by apoptosis. In this re-spect, retinal ischemia is a primary cause of neuronal death. It can be considered as a sort of fnal common pathway in retinal diseases and results in irreversible morphological and functional changes. This review summarizes the recent knowledge on the effects of ischemia in retinal tissue and points out experimental strategies/models performed to gain better compre-hension of retinal ischemia diseases. In particular, the nature of the mechanisms leading to neuronal damage （i.e., excess of glutamate release, oxidative stress and infammation） will be outlined as well as the potential and most intriguing retinoprotective approaches and the possible therapeutic use of naturally occurring molecules such as neuropeptides. There is a general agreement that a better understanding of the funda-mental pathophysiology of retinal ischemia will lead tobetter management and improved clinical outcome. In this respect, to contrast this pathological state, spe-cifc pharmacological strategies need to be developed aimed at the many putative cascades generated during ischemia.
文摘Following ischemic stroke, blood-brain barrier （BBB） is disrupted and is further aggravated with the corresponding incidence of hyperlipidemia. BBB breakdown promotes inflammation infiltration into the brain, which exacerbates cerebral ischemic injury as a result. Here, we report that 10-O-（N,N-dimethylaminoethyl）-ginkgolide B methanesulfonate （XQ-1H） , a novel analog of ginkgolide B, alleviates BBB breakdown in hyperlipidemic rats and protects endothelial cells against inflammatory response. Middle cerebral artery occlusion （MCAO） modeled is- chemic stroke in rats. Before surgery, these rats were fed a cholesterol-rich diet to induce an experimental hyperlip- idemic condition. Additionally, lipopolysaccharide （LPS） incubation with rat brain microvessel endothelial cells （rBMECs） was applied to mimic hyperlipidemia-induced inflammatory injury of BBB. The results indicated more severe infarct size, increased BBB permeability, excessive secretion of pro-inflammatory cytokines, and exaggerated inflammation infiltration of the brain in hyperlipidemic rats following MCAO when compared to rats fed with normal diet. XQ-1H protected BBB integrity, lessoned brain edema and inflammation penetration, down- regulated MMP- 9 and VCMA-1 expressions, and extenuated ischemic infarction. XQ-1H alleviated LPS-induced inflammatory re- sponse in rBMECs, characterized by promoting cell viability, inhibiting TNF-α, IL-1β, and IL-6 releasing, and downregulating NF-KB inflammatory signal and down- stream proteins, such as VCAM-1 and iNOS. In conclusion, the present study shows that XQ-1H stabilizes BBB function following ischemic stroke in hyperlipidemic rats, and the possible mechanisms may be related to inflammation inhibition.
文摘Sustained proteinuria is an independent risk factor leading to kidney fibrosis and end-stage renal fail-ure.Over-reabsorption of filtered proteins,notably albu-min,has been proved to trigger interstitial inflammation and fibrosis in proteinuric renal disease.Cubilin,an endo-cytic receptor expressed on the renal tubular brush bor-der,is responsible for albumin reabsorption in physiologic condition.However,little is known about whether it is required for activation of tubular cells induced by albu-min overload.In this work,we investigated the change of cubilin expression and its potential role in albumin-induced up-regulation of chemokines synthesis in vivo and in vitro.Twenty-six patients with nephrotic syndrome were enrolled in this study.Proximal tubule uptake of albumin,expression of apical membrane cubilin and infiltrating cells in kidney interstitium were determined by immunocytochemistry.In vitro,the transcription of cubilin in HK2 cells after exposure to albumin was ana-lyzed by real-time PCR.Endocytosis of albumin in HK2 cells was examined by fluorescent microscope.The influ-ence of inhibition of cubilin on albumin-induced expres-sions of monocyte chemoattractant protein 1(MCP-1)and regulated upon activation normal T-cell expressed and secreted(RANTES)was investigated by Western blot.The intensity of luminal cubilin and tubular accu-mulation of albumin were significantly increased in nephrotic kidneys.The expression of MCP-1 and RANTES was up-regulated,and there were spatial rela-tionships in localization between these chemokines and cubilin as well as intracellular albumin in kidney tissues.Infiltration of CD-3 and ED-1-positive cells was predom-inant in tubulointerstitial areas displaying signs of increases of cubilin expression and albumin accumula-tion.In vitro,the transcription of cubilin mRNA in HK2 cells was enhanced after 24 h exposure to albumin in a dose-dependent manner.Inhibition of endocytosis of albumin by antisense cubilin nucleotide markedly reduced expression of MCP-1 and RANTES.Cubilin was required for handling a greater amount of protein in nephrotic status and albumin-induced production of MCP-1 and RANTES by renal tubular cells,which further initiated tubulointerstitial inflammation in proteinuric disease.
