Protein degradation through the ubiquitin-proteasome system is the major pathway of non-lysosomal proteolysis of intracellular proteins. It plays important roles in a variety of fundamental cellular processes such as ...Protein degradation through the ubiquitin-proteasome system is the major pathway of non-lysosomal proteolysis of intracellular proteins. It plays important roles in a variety of fundamental cellular processes such as regulation of cell cycle progression, division, development and differentiation, apoptosis, cell trafficking, and modulation of the immune and inflammatory responses. The central element of this system is the covalent linkage of ubiquitin to targeted proteins, which are then recognized by the 26S proteasome, an adenosine triphosphate-dependent, multi-catalytic protease. Damaged, oxidized, or misfolded proteins as well as regulatory proteins that control many critical cellular functions are among the targets of this degradation process. Aberration of this system leads to the dysregulation of cellular homeostasis and the development of multiple diseases. In this review, we described the basic biochemistry and molecular biology of the ubiquitin-proteasome system, and its complex role in the development of inflammatory and autoimmune diseases. In addition, therapies and potential therapeutic targets related to the ubiquitin-proteasome system are discussed as well.展开更多
Wnts are a large family of growth factors that mediate essential biological processes like embryogenesis, morpho- genesis and organogenesis. These proteins also play a role in oncogenesis, and they regulate apoptosis ...Wnts are a large family of growth factors that mediate essential biological processes like embryogenesis, morpho- genesis and organogenesis. These proteins also play a role in oncogenesis, and they regulate apoptosis in many tissues. Wnts bind to a membrane receptor complex comprised of a frizzled （FZD） G-protein-coupled receptor and a low-density lipoprotein （LDL） receptor-related protein （LRP）. The formation of this ligand-receptor complex initiates a number of signaling cascades that include the canonical/beta-catenin pathway as well as several noncanonical pathways. In recent years, canonical Wnt signaling has been reported to play a significant role in the control of bone formation. Clinical studies have found that mutations in LRP-5 are associated with reduced bone mineral density （BMD） and fractures. Investigations of knockout and transgenic mouse models of Wnt pathway components have shown that canonical Wnt signaling modulates most aspects ofosteoblast physiology including proliferation, differentiation, function and apoptosis. Transgenic mice expressing a gain of function mutant of LRP-5 in bone, or mice lacking the Wnt antagonist secreted frizzled-related protein-l, exhibit elevated BMD and suppressed osteoblast apoptosis. In addition, preclinical studies with pharmacologic compounds such as those that inhibit glycogen synthase kinase-3β support the importance of the canonical Wnt pathway in modulation of bone formation and osteoblast apoptosis.展开更多
As part of our efforts to identify novel contraceptive targets in the epididymis we performed transcriptional profiling on each of the 10 and 19 segments of the mouse and rat epididymidis, respectively, using Affymetr...As part of our efforts to identify novel contraceptive targets in the epididymis we performed transcriptional profiling on each of the 10 and 19 segments of the mouse and rat epididymidis, respectively, using Affymetrix whole genome microarrays. A total of 17 096 and 16 360 probe sets representing transcripts were identified as being expressed in the segmented mouse and rat epididymal transcriptomes, respectively. Comparison of the expressed murine transcripts against a mouse transcriptional profiling database derived from 22 other mouse tissues identified 77 transcripts that were expressed uniquely in the epididymis. The expression of these genes was further evaluated by reverse transcription polymerase chain reaction （RT-PCR） analysis of RNA from 21 mouse tissues. RT-PCR analysis confirmed epididymis-specific expression of Defensin Beta 13 and identified two additional genes with expression restricted only to the epididymis and testis. Comparison of the 16 360 expressed transcripts in the rat epididymis with data of 21 other tissues from a rat transcriptional profiling database identified 110 transcripts specific for the epididymis. Sixty-two of these transcripts were further investigated by qPCR analysis. Only Defensin 22 （E3 epididymal protein） was shown to be completely specific for the epididymis. In addition, 14 transcripts showed more than 100-fold selective expression in the epididymis. The products of these genes might play important roles in epididymal and/or sperm function and further investigation and validation as contraceptive targets are warranted. The results of the studies described in this report are available at the Mammalian Reproductive Genetics （MRG） Database （http：//mrg. genetics.washington.edu/）. （Asian J Androl 2007July; 9： 522-527）展开更多
Cysteine-rich secretory protein-1 （CRISP-1） is a glycoprotein secreted by the epididymal epithelium. It is a member of a large family of proteins characterized by two conserved domains and a set of 16 conserved cyst...Cysteine-rich secretory protein-1 （CRISP-1） is a glycoprotein secreted by the epididymal epithelium. It is a member of a large family of proteins characterized by two conserved domains and a set of 16 conserved cysteine residues. In mammals, CRISP-1 inhibits sperm-egg fusion and can suppress sperm capacitation. The molecular mechanism of action of the mammalian CRISP proteins remains unknown, but certain non-mammalian CRISP proteins can block ion channels. In the rat, CRISP-1 comprises two forms referred to as Proteins D and E. Recent work in our laboratory demonstrates that the D form of CRISP-1 associates transiently with the sperm surface, whereas the E form binds tightly. When the spermatozoa are washed, the E form of CRISP-1 persists on the sperm surface after all D form has dissociated. Cross-linking studies demonstrate different protein-protein interaction patterns for D and E, although no binding partners for either protein have yet been identified. Mass spectrometric analyses revealed a potential post-translational modification on the E form that is not present on the D form. This is the only discernable difference between Proteins D and E, and presumably is responsible for the difference in behavior of these two forms of rat CRISP- 1. These studies demonstrate that the more abundant D form interacts with spermatozoa transiently, possibly with a specific receptor on the sperm surface, consistent with a capacitation-suppressing function during sperm transit and storage in the epididymis, and also confirm a tightly bound population of the E form that could act in the female reproductive tract. （Asian J Androl 2007 July; 9： 508-514）展开更多
首份卒中治疗专业学术圆桌会议（Stroke Yherapy Academic Industry Roundtable，STAIR）推荐于1999年出版，旨在提高潜在的急性卒中治疗方法的临床前研究质量。虽然这些推荐意见被认为是合理的，但并未得到严格的遵循和验证。为了更好...首份卒中治疗专业学术圆桌会议（Stroke Yherapy Academic Industry Roundtable，STAIR）推荐于1999年出版，旨在提高潜在的急性卒中治疗方法的临床前研究质量。虽然这些推荐意见被认为是合理的，但并未得到严格的遵循和验证。为了更好地向临床转化，有关候选急性卒中疗法的临床前试验的质量和广度已取得实质性进展。更新后的STAIR临床前推荐进一步强调了最初提出的建议，即通过适当的生理学监测在多种动物物种中采用组织学和功能结局来确定可重复的剂量反应和时间窗。更新后的STAIR推荐意见包括：高质量科学研究的基本原则应消除随机和评价偏倚，预先确定纳入和排除标准，计算合适的效能和样本量，并公开潜在的利益冲突。应在年轻的健康雄性动物中进行初步评价之后，在雌性、高龄动物和伴有合并症（如高血压、糖尿病和高胆固醇血症）的动物中做进一步研究。此外还要在动物实验中应用临床相关生物学标志物。尽管只有通过临床试验产生基于此的有效疗法之后才能证实该推荐意见的有效性，但遵循这些推荐有望提高成功的机会。展开更多
The epididymis is divided into caput, corpus and cauda regions, organized into intraregional segments separated by connective tissue septa （CTS）. In the adult rat and mouse these segments are highly differentiated. ...The epididymis is divided into caput, corpus and cauda regions, organized into intraregional segments separated by connective tissue septa （CTS）. In the adult rat and mouse these segments are highly differentiated. Regulation of these segments is by endocrine, lumicrine and paracrine factors, the relative importance of which remains under investigation. Here, the ability of the CTS to limit signaling in the interstitial compartment is reviewed as is the effect of 15 days of unilateral efferent duct ligation （EDL） on ipsilateral segmental transcriptional profiles. Inter-segmental microperifusions of epidermal growth factor （EGF）, vascular endothelial growth factor （VEGFA） and fibroblast growth factor 2 （FGF2） increased phosphorylation of mitogen activated protein kinase （MAPK） in segments 1 and 2 of the rat epididymis and the effects of all factors were limited by the CTS separating the segments. Microan＇ay analysis of segmental gene expression determined the effect of 15 days of unilateral EDL on the transcriptome-wide gene expression of rat segments 1-4. Over 11 000 genes were expressed in each of the four segments and over 2 000 transcripts in segment 1 responded to deprivation of testicular lumicrine factors. Segments 1 and 2 of control tissues were the most transcriptionally different and EDL had its greatest effects there. In the absence of lumicrine factors, all four segments regressed to a transcriptionally undifferentiated state, consistent with the less differentiated histology. Deprivation of lumicrine factors could stimulate an individual gene＇s expression in some segments yet suppress it in others. Such results reveal a higher complexity of the regulation of rat epididymal segments than that is generally appreciated. （Asian J Androl 2007 July; 9： 565-573）展开更多
The evidence in this paper indicates that the alarming increase of common allergies can be reduced by the intake of particular “probiotics” or “paraprobiotics” along with food. This appears to build a consensus in...The evidence in this paper indicates that the alarming increase of common allergies can be reduced by the intake of particular “probiotics” or “paraprobiotics” along with food. This appears to build a consensus in the pharmaceutical and food communities about the role of probiotics in the prevention and treatments of common allergies. Food allergy is one of the common allergies, defined as an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food. Improving the digestion of foods and maintaining a healthy gastrointestinal (GI) tract is certainly critical to controlling food allergens. Therefore, the association between a leaky gut or an impaired intestinal permeability and food-allergenic reactions is explained. Gluten has been found to be somehow a justification for protein allergy, and should, therefore, be avoided by people with celiac disease. In several, in vitro models, surface layer (S- layer) proteins of selective paraprobiotics have shown potential in alleviating food allergies and intestinal disorders. Notably, lactobacilli paraprobiotics have proven to be the immediate immunomodulators against common allergies and other diseases, including viral (flu, hepatitis C), bacterial (bronchitis), asthma, chronic fatigue, fibromyalgia, gastrointestinal distress, and autism disorders in humans.展开更多
文摘Protein degradation through the ubiquitin-proteasome system is the major pathway of non-lysosomal proteolysis of intracellular proteins. It plays important roles in a variety of fundamental cellular processes such as regulation of cell cycle progression, division, development and differentiation, apoptosis, cell trafficking, and modulation of the immune and inflammatory responses. The central element of this system is the covalent linkage of ubiquitin to targeted proteins, which are then recognized by the 26S proteasome, an adenosine triphosphate-dependent, multi-catalytic protease. Damaged, oxidized, or misfolded proteins as well as regulatory proteins that control many critical cellular functions are among the targets of this degradation process. Aberration of this system leads to the dysregulation of cellular homeostasis and the development of multiple diseases. In this review, we described the basic biochemistry and molecular biology of the ubiquitin-proteasome system, and its complex role in the development of inflammatory and autoimmune diseases. In addition, therapies and potential therapeutic targets related to the ubiquitin-proteasome system are discussed as well.
文摘Wnts are a large family of growth factors that mediate essential biological processes like embryogenesis, morpho- genesis and organogenesis. These proteins also play a role in oncogenesis, and they regulate apoptosis in many tissues. Wnts bind to a membrane receptor complex comprised of a frizzled （FZD） G-protein-coupled receptor and a low-density lipoprotein （LDL） receptor-related protein （LRP）. The formation of this ligand-receptor complex initiates a number of signaling cascades that include the canonical/beta-catenin pathway as well as several noncanonical pathways. In recent years, canonical Wnt signaling has been reported to play a significant role in the control of bone formation. Clinical studies have found that mutations in LRP-5 are associated with reduced bone mineral density （BMD） and fractures. Investigations of knockout and transgenic mouse models of Wnt pathway components have shown that canonical Wnt signaling modulates most aspects ofosteoblast physiology including proliferation, differentiation, function and apoptosis. Transgenic mice expressing a gain of function mutant of LRP-5 in bone, or mice lacking the Wnt antagonist secreted frizzled-related protein-l, exhibit elevated BMD and suppressed osteoblast apoptosis. In addition, preclinical studies with pharmacologic compounds such as those that inhibit glycogen synthase kinase-3β support the importance of the canonical Wnt pathway in modulation of bone formation and osteoblast apoptosis.
文摘As part of our efforts to identify novel contraceptive targets in the epididymis we performed transcriptional profiling on each of the 10 and 19 segments of the mouse and rat epididymidis, respectively, using Affymetrix whole genome microarrays. A total of 17 096 and 16 360 probe sets representing transcripts were identified as being expressed in the segmented mouse and rat epididymal transcriptomes, respectively. Comparison of the expressed murine transcripts against a mouse transcriptional profiling database derived from 22 other mouse tissues identified 77 transcripts that were expressed uniquely in the epididymis. The expression of these genes was further evaluated by reverse transcription polymerase chain reaction （RT-PCR） analysis of RNA from 21 mouse tissues. RT-PCR analysis confirmed epididymis-specific expression of Defensin Beta 13 and identified two additional genes with expression restricted only to the epididymis and testis. Comparison of the 16 360 expressed transcripts in the rat epididymis with data of 21 other tissues from a rat transcriptional profiling database identified 110 transcripts specific for the epididymis. Sixty-two of these transcripts were further investigated by qPCR analysis. Only Defensin 22 （E3 epididymal protein） was shown to be completely specific for the epididymis. In addition, 14 transcripts showed more than 100-fold selective expression in the epididymis. The products of these genes might play important roles in epididymal and/or sperm function and further investigation and validation as contraceptive targets are warranted. The results of the studies described in this report are available at the Mammalian Reproductive Genetics （MRG） Database （http：//mrg. genetics.washington.edu/）. （Asian J Androl 2007July; 9： 522-527）
文摘Cysteine-rich secretory protein-1 （CRISP-1） is a glycoprotein secreted by the epididymal epithelium. It is a member of a large family of proteins characterized by two conserved domains and a set of 16 conserved cysteine residues. In mammals, CRISP-1 inhibits sperm-egg fusion and can suppress sperm capacitation. The molecular mechanism of action of the mammalian CRISP proteins remains unknown, but certain non-mammalian CRISP proteins can block ion channels. In the rat, CRISP-1 comprises two forms referred to as Proteins D and E. Recent work in our laboratory demonstrates that the D form of CRISP-1 associates transiently with the sperm surface, whereas the E form binds tightly. When the spermatozoa are washed, the E form of CRISP-1 persists on the sperm surface after all D form has dissociated. Cross-linking studies demonstrate different protein-protein interaction patterns for D and E, although no binding partners for either protein have yet been identified. Mass spectrometric analyses revealed a potential post-translational modification on the E form that is not present on the D form. This is the only discernable difference between Proteins D and E, and presumably is responsible for the difference in behavior of these two forms of rat CRISP- 1. These studies demonstrate that the more abundant D form interacts with spermatozoa transiently, possibly with a specific receptor on the sperm surface, consistent with a capacitation-suppressing function during sperm transit and storage in the epididymis, and also confirm a tightly bound population of the E form that could act in the female reproductive tract. （Asian J Androl 2007 July; 9： 508-514）
文摘首份卒中治疗专业学术圆桌会议（Stroke Yherapy Academic Industry Roundtable，STAIR）推荐于1999年出版，旨在提高潜在的急性卒中治疗方法的临床前研究质量。虽然这些推荐意见被认为是合理的，但并未得到严格的遵循和验证。为了更好地向临床转化，有关候选急性卒中疗法的临床前试验的质量和广度已取得实质性进展。更新后的STAIR临床前推荐进一步强调了最初提出的建议，即通过适当的生理学监测在多种动物物种中采用组织学和功能结局来确定可重复的剂量反应和时间窗。更新后的STAIR推荐意见包括：高质量科学研究的基本原则应消除随机和评价偏倚，预先确定纳入和排除标准，计算合适的效能和样本量，并公开潜在的利益冲突。应在年轻的健康雄性动物中进行初步评价之后，在雌性、高龄动物和伴有合并症（如高血压、糖尿病和高胆固醇血症）的动物中做进一步研究。此外还要在动物实验中应用临床相关生物学标志物。尽管只有通过临床试验产生基于此的有效疗法之后才能证实该推荐意见的有效性，但遵循这些推荐有望提高成功的机会。
文摘The epididymis is divided into caput, corpus and cauda regions, organized into intraregional segments separated by connective tissue septa （CTS）. In the adult rat and mouse these segments are highly differentiated. Regulation of these segments is by endocrine, lumicrine and paracrine factors, the relative importance of which remains under investigation. Here, the ability of the CTS to limit signaling in the interstitial compartment is reviewed as is the effect of 15 days of unilateral efferent duct ligation （EDL） on ipsilateral segmental transcriptional profiles. Inter-segmental microperifusions of epidermal growth factor （EGF）, vascular endothelial growth factor （VEGFA） and fibroblast growth factor 2 （FGF2） increased phosphorylation of mitogen activated protein kinase （MAPK） in segments 1 and 2 of the rat epididymis and the effects of all factors were limited by the CTS separating the segments. Microan＇ay analysis of segmental gene expression determined the effect of 15 days of unilateral EDL on the transcriptome-wide gene expression of rat segments 1-4. Over 11 000 genes were expressed in each of the four segments and over 2 000 transcripts in segment 1 responded to deprivation of testicular lumicrine factors. Segments 1 and 2 of control tissues were the most transcriptionally different and EDL had its greatest effects there. In the absence of lumicrine factors, all four segments regressed to a transcriptionally undifferentiated state, consistent with the less differentiated histology. Deprivation of lumicrine factors could stimulate an individual gene＇s expression in some segments yet suppress it in others. Such results reveal a higher complexity of the regulation of rat epididymal segments than that is generally appreciated. （Asian J Androl 2007 July; 9： 565-573）
文摘The evidence in this paper indicates that the alarming increase of common allergies can be reduced by the intake of particular “probiotics” or “paraprobiotics” along with food. This appears to build a consensus in the pharmaceutical and food communities about the role of probiotics in the prevention and treatments of common allergies. Food allergy is one of the common allergies, defined as an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food. Improving the digestion of foods and maintaining a healthy gastrointestinal (GI) tract is certainly critical to controlling food allergens. Therefore, the association between a leaky gut or an impaired intestinal permeability and food-allergenic reactions is explained. Gluten has been found to be somehow a justification for protein allergy, and should, therefore, be avoided by people with celiac disease. In several, in vitro models, surface layer (S- layer) proteins of selective paraprobiotics have shown potential in alleviating food allergies and intestinal disorders. Notably, lactobacilli paraprobiotics have proven to be the immediate immunomodulators against common allergies and other diseases, including viral (flu, hepatitis C), bacterial (bronchitis), asthma, chronic fatigue, fibromyalgia, gastrointestinal distress, and autism disorders in humans.
