Both glial cells and glia scar greatly affect the development of spinal cord injury and have become hot spots in research on spinal cord injury treatment.The cellular deposition of dense extracellular matrix proteins ...Both glial cells and glia scar greatly affect the development of spinal cord injury and have become hot spots in research on spinal cord injury treatment.The cellular deposition of dense extracellular matrix proteins such as chondroitin sulfate proteoglycans inside and around the glial scar is known to affect axonal growth and be a major obstacle to autogenous repair.These proteins are thus candidate targets for spinal cord injury therapy.Our previous studies demonstrated that 810 nm photo biomodulation inhibited the formation of chondroitin sulfate proteoglycans after spinal cord injury and greatly improved motor function in model animals.However,the specific mechanism and potential targets involved remain to be clarified.In this study,to investigate the therapeutic effect of photo biomodulation,we established a mouse model of spinal cord injury by T9 clamping and irradiated the injury site at a power density of 50 mW/cm~2 for 50 minutes once a day for 7 consecutive days.We found that photobiomodulation greatly restored motor function in mice and down regulated chondroitin sulfate proteoglycan expression in the injured spinal cord.Bioinformatics analysis revealed that photobiomodulation inhibited the expression of proteoglycan-related genes induced by spinal cord injury,and versican,a type of proteoglycan,was one of the most markedly changed molecules.Immunofluorescence staining showed that after spinal cord injury,versican was present in astrocytes in spinal cord tissue.The expression of versican in primary astrocytes cultured in vitro increased after inflammation induction,whereas photobiomodulation inhibited the expression of ve rsican.Furthermore,we found that the increased levels of p-Smad3,p-P38 and p-Erk in inflammatory astrocytes were reduced after photobiomodulation treatment and after delivery of inhibitors including FR 180204,(E)-SIS3,and SB 202190.This suggests that Sma d 3/Sox9 and MAP K/Sox9 pathways may be involved in the effects of photobiomodulation.In summary,our findings show that photobiomodulation modulates the expression of chondroitin sulfate proteoglycans,and versican is one of the key target molecules of photo biomodulation.MAPK/Sox9 and Smad3/Sox9 pathways may play a role in the effects of photo biomodulation on chondroitin sulfate proteoglycan accumulation after spinal cord injury.展开更多
Proteoglycans in the central nervous system play integral roles as ＂traffic signals＂ for the direction of neurite outgrowth. This attribute of proteoglycans is a major factor in regeneration of the injured central n...Proteoglycans in the central nervous system play integral roles as ＂traffic signals＂ for the direction of neurite outgrowth. This attribute of proteoglycans is a major factor in regeneration of the injured central nervous system. In this review, the structures of proteoglycans and the evidence suggesting their involvement in the response following spinal cord injury are presented. The review further describes the methods routinely used to determine the effect proteoglycans have on neurite outgrowth. The effects of proteoglycans on neurite outgrowth are not completely understood as there is disagreement on what component of the molecule is interacting with growing neurites and this ambiguity is chronicled in an historical context. Finally, the most recent findings suggesting possible receptors, interactions, and sulfation patterns that may be important in eliciting the effect of proteoglycans on neurite outgrowth are discussed. A greater understanding of the proteoglycan-neurite interaction is necessary for successfully promoting regeneration in the iniured central nervous system.展开更多
Proteoglycans are a group of molecules that contain at least one glycosaminoglycan chain,such as a heparan,dermatan,chondroitin,or keratan sulfate,covalently attached to the protein core.These molecules arecategorized...Proteoglycans are a group of molecules that contain at least one glycosaminoglycan chain,such as a heparan,dermatan,chondroitin,or keratan sulfate,covalently attached to the protein core.These molecules arecategorized based on their structure,localization,and function,and can be found in the extracellular matrix,on the cell surface,and in the cytoplasm.Cell-surface heparan sulfate proteoglycans,such as syndecans,are the primary type present in healthy liver tissue.However,deterioration of the liver results in overproduction of other proteoglycan types.The purpose of this article is to provide a current summary of the most relevant data implicating proteoglycans in the development and progression of human and experimental liver cancer.A review of our work and other studies in the literature indicate that deterioration of liver function is accompanied by an increase in the amount of chondroitin sulfate proteoglycans.The alteration of proteoglycan composition interferes with the physiologic function of the liver on several levels.This article details and discusses the roles of syndecan-1,glypicans,agrin,perlecan,collagen XVIII/endostatin,endocan,serglycin,decorin,biglycan,asporin,fibromodulin,lumican,and versican in liver function.Specifically,glypicans,agrin,and versican play significant roles in the development of liver cancer.Conversely,the presence of decorin could potentially provide protective effects.展开更多
The current dogma in neural regeneration research implies that chondroitin sulfate proteoglycans（CSPGs） inhibit plasticity and regeneration in the adult central nervous system（CNS）. We argue that the role of the C...The current dogma in neural regeneration research implies that chondroitin sulfate proteoglycans（CSPGs） inhibit plasticity and regeneration in the adult central nervous system（CNS）. We argue that the role of the CSPGs can be reversed from inhibition to activation by developmentally expressed CSPG-binding factors. Heparin-binding growth-associated molecule（HB-GAM; also designated as pleiotrophin） has been studied as a candidate molecule that might modulate the role of CSPG matrices in plasticity and regeneration. Studies in vitro show that in the presence of soluble HB-GAM chondroitin sulfate（CS） chains of CSPGs display an enhancing effect on neurite outgrowth. Based on the in vitro studies, we suggest a model according to which the HB-GAM/CS complex binds to the neuron surface receptor glypican-2, which induces neurite growth. Furthermore, HB-GAM masks the CS binding sites of the neurite outgrowth inhibiting receptor protein tyrosine phosphatase sigma（PTPσ）, which may contribute to the HB-GAM-induced regenerative effect. In vivo studies using two-photon imaging after local HB-GAM injection into prick-injury of the cerebral cortex reveal regeneration of dendrites that has not been previously demonstrated after injuries of the mammalian nervous system. In the spinal cord, two-photon imaging displays HB-GAM-induced axonal regeneration. Studies on the HB-GAM/CS mechanism in vitro and in vivo are expected to pave the way for drug development for injuries of brain and spinal cord.展开更多
As one major component of extracellular matrix （ECM） in the central nervous system, chondroitin sul- fate proteoglycans （CSPGs） have long been known as inhibitors enriched in the glial scar that prevent axon regen...As one major component of extracellular matrix （ECM） in the central nervous system, chondroitin sul- fate proteoglycans （CSPGs） have long been known as inhibitors enriched in the glial scar that prevent axon regeneration after injury. Although many studies have shown that CSPGs inhibited neurite out- growth in vitro using different types of neurons, the mechanism by which CSPGs inhibit axonal growth remains poorly understood. Using cerebellar granule neuron （CGN） culture, in this study, we evaluated the effects of different concentrations of both immobilized and soluble CSPGs on neuronal growth, in- cluding cell adhesion, spreading and neurite growth. Neurite length decreased while CSPGs concentration arised, meanwhile, a decrease in cell density accompanied by an increase in cell aggregates formation was observed. Soluble CSPGs also showed an inhibition on neurite outgrowth, but it required a higher concen- tration to induce cell aggregates formation than coated CSPGs. We also found that growth cone size was significantly reduced on CSPGs and neuronal cell spreading was restrained by CSPGs, attributing to an inhibition on lamellipodial extension. The effect of CSPGs on neuron adhesion was further evidenced by interference reflection microscopy （IRM） which directly demonstrated that both CGNs and cerebral cortical neurons were more loosely adherent to a CSPG substrate. These data demonstrate that CSPGs have an effect on cell adhesion and spreading in addition to neurite outgrowth.展开更多
Axon growth is a central event in the development and post-injury plasticity of the nervous system. Growing axons encounter a wide variety of environmental instructions. Much like traffic lights in controlling the mig...Axon growth is a central event in the development and post-injury plasticity of the nervous system. Growing axons encounter a wide variety of environmental instructions. Much like traffic lights in controlling the migrating axons, chondroitin sulfate proteoglycans （CSPGs） and heparan sulfate proteoglycans （HSPGs） often lead to ＂stop＂ and ＂go＂ growth responses in the axons, respectively. Recently, the LAR family and NgR family molecules were identified as neuronal receptors for CSPGs and HSPGs. These discoveries provided molecular tools for further study of mechanisms underlying axon growth regulation. More importantly, the identification of these proteoglycan receptors offered potential therapeutic targets for promoting post-injury axon regeneration.展开更多
Proteoglycans and collagen molecules are interacting with each other thereby forming various connective tissues. The sulfation pattern of proteoglycans differs depending on the kind of tissue and/or the degree of matu...Proteoglycans and collagen molecules are interacting with each other thereby forming various connective tissues. The sulfation pattern of proteoglycans differs depending on the kind of tissue and/or the degree of maturation. Tissues from Cnidaria are suitable examples for exploration of the effects in relation to the presence and the absence of sulfate groups, when studying characteristic fragments of the long proteoglycan carbohydrate chains in silico. It has been described that a non-sulfated chondroitin appears as a scaffold in early morphogenesis of all nematocyst types in Hydra. On the other hand, sulfated glucosaminoglycans play an important role in various developmental processes of Cnidaria. In order to understand this biological phenomenon on a sub-molecular level we have analysed the structures of sulfated and non-sulfated proteoglycan carbohydrate chains as well as the structure of diverse collagen molecules with computational methods including quantum chemical calculations. The strong interactions between the sulfate groups of the carbohydrates moieties in proteoglycans and positively charged regions of collagen are essential in stabilizing various Cnidaria tissues but could hinder the nematocyst formation and its proper function. The results of our quantum chemical calculations show that the sulfation pattern has a significant effect on the conformation of chondroitin structures under study.展开更多
Esophageal squamous cell carcinoma(ESCC)is a highly malignant disease that has a poor prognosis.Its high lethality is mainly due to the lack of symptoms at early stages,which culminates in diagnosis at a late stage wh...Esophageal squamous cell carcinoma(ESCC)is a highly malignant disease that has a poor prognosis.Its high lethality is mainly due to the lack of symptoms at early stages,which culminates in diagnosis at a late stage when the tumor has already metastasized.Unfortunately,the common cancer biomarkers have low sensitivity and specificity in esophageal cancer.Therefore,a better understanding of the molecular mechanisms underlying ESCC progression is needed to identify novel diagnostic markers and therapeutic targets for intervention.The invasion of cancer cells into the surrounding tissue is a crucial step for metastasis.During metastasis,tumor cells can interact with extracellular components and secrete proteolytic enzymes to remodel the surrounding tumor microenvironment.Proteoglycans are one of the major components of extracellular matrix.They are involved in multiple processes of cancer cell invasion and metastasis by interacting with soluble bioactive molecules,surrounding matrix,cell surface receptors,and enzymes.Apart from having diverse functions in tumor cells and their surrounding microenvironment,proteoglycans also have diagnostic and prognostic significance in cancer patients.However,the functional significance and underlying mechanisms of proteoglycans in ESCC are not well understood.This review summarizes the proteoglycans that have been studied in ESCC in order to provide a comprehensive view of the role of proteoglycans in the progression of this cancer type.A long term goal would be to exploit these molecules to provide new strategies for therapeutic intervention.展开更多
AIM:To investigate the expression of chondroitin sulphate proteoglycans(CSPGs)in rat liver tissues of hepatocellular carcinoma(HCC).METHODS:Thirty male Sprague Dawley rats were randomly divided into two groups:control...AIM:To investigate the expression of chondroitin sulphate proteoglycans(CSPGs)in rat liver tissues of hepatocellular carcinoma(HCC).METHODS:Thirty male Sprague Dawley rats were randomly divided into two groups:control group(n=10) and HCC model group(n=20).Rats in the HCC model groups were intragastrically administrated with 0.2%(w/v)N-diethylnitrosamine(DEN)every 5 d for 16 wk,whereas 0.9%(w/v)normal saline was administered to rats in the control group.After 16 wk from the initiation of experiment,all rats were killed and livers were collected and fixed in 4%(w/v)paraformaldehyde.All tissues were embedded in paraffin and sectioned.Histological staining(hematoxylin and eosin and Toluidine blue)was performed to demonstrate the onset of HCC and the content of sulphated glycosaminoglycan(sGAG).Immunohistochemical staining was performed to investigate the expression of chondroitin sulphate(CS)/dermatan sulphate(DS)-GAG,heparan sulphate(HS)-GAG,keratan sulphate(KS)-GAG in liver tissues.Furthermore,expression and distribution of CSPG family members,including aggrecan,versican,biglycan and decorin in liver tissues,were also immunohistochemically determined.RESULTS:After 16 wk administration of DEN,malignant nodules were observed on the surface of livers from the HCC model group,and their hepatic lobule structures appeared largely disrupted under microscope.Toluidine blue staining demonstrated that there was an significant increase in sGAG content in HCC tissues when compared with that in the normal liver tissues from the control group[0.37±0.05 integrated optical density per stained area(IOD/area)and 0.21± 0.01 IOD/area,P<0.05].Immunohistochemical studies demonstrated that this increased sGAG in HCC tissues was induced by an elevated expression of CS/DS(0.28±0.02 IOD/area and 0.18±0.02 IOD/area,P< 0.05)and HS(0.30±0.03 IOD/area and 0.17±0.02 IOD/area,P<0.01)but not KS GAGs in HCC tissues.Further studies thereby were performed to investigate the expression and distribution of several CSPG components in HCC tissues,including aggrecan,versican,biglycan and decorin.Interestingly,there was a distinct distribution pattern for these CSPG components between HCC tissues and the normal tissues.Positive staining of aggrecan,biglycan and decorin was localized in hepatic membrane and/or pericellular matrix in normal liver tissues;however,their expression was mainly observed in the cytoplasm,cell membranes in hepatoma cells and/or pericellular matrix within HCC tissues.Semi-quantitative analysis indicated that there was a higher level of expression of aggrecan(0.43± 0.01 and 0.35±0.03,P<0.05),biglycan(0.32±0.01 and 0.25±0.01,P<0.001)and decorin(0.29±0.01 and 0.26±0.01,P<0.05)in HCC tissues compared with that in the normal liver tissues.Very weak versican positive staining was observed in hepatocytes near central vein in normal liver tissues;however there was an intensive versican distribution in fibrosis septa between the hepatoma nodules.Semi-quantitative analysis indicated that the positive rate of versican in hepatoma tissues from the HCC model group was much higher than that in the control group(33.61%and 21.28%,P <0.05).There was no positive staining in lumican and keratocan,two major KSPGs,in either normal or HCC liver tissues.CONCLUSION:CSPGs play important roles in the onset and progression of HCC,and may provide potential therapeutic targets and clinical biomarkers for this prevalent tumor in humans.展开更多
This paper reports a comparative study of the extraction rate of rat brain proteoglycans (PGs) by three different methods, with chromatography, papain digestion and electrophoretic technique. The results showed: ① T...This paper reports a comparative study of the extraction rate of rat brain proteoglycans (PGs) by three different methods, with chromatography, papain digestion and electrophoretic technique. The results showed: ① The extraction rate of brain PGs by 4mol/L guanidine HCl (GuHCl)was higher than that by phosphate-buffered saline (PBS) In any method, however the protein/PGs ratio in the GuHCl-extract was lower than that in the PBS-extract. ② PBS mainly extracted the soluble chondroitin sulfate proteoglycan (CSPG), whereas the 4mol/L GuHCl could extracted both soluble CSPG and insoluble heparan sulfate proteoglycan (HSPG). ③ After delipidation of brain by organic reagents, the extraction rate of delipidized brain PGs either by the PBS or by the 4mol/L GuHCl decreased obviously. ④ By direct extraction with PBS, GuHCl seguentially, few amount of PGs in the residue from brain was found.展开更多
Osteoarthritis is a degenerative disease that affects articular cartilage,leading to changes on the macro and micro levels of this multi-component tissue.Understanding the processes underlying this pathology plays an ...Osteoarthritis is a degenerative disease that affects articular cartilage,leading to changes on the macro and micro levels of this multi-component tissue.Understanding the processes underlying this pathology plays an important role in planning the following management tactics.Timely detection of the knee joint degradation at the level of tissue changes can prevent its progressive damage due to the early beginning of appropriate treatment.This study aimed to provide an overview of the current level of knowledge about the composition of cartilage and menisci using a wide range of different diagnostic methods.A systematic review of the literature published from 1978 to 2023was conducted.Original studies of the knee joint cartilage(articular and meniscus) research,reporting content composition and mechanical properties,were included.Studies of the non-knee joint cartilage,tissue research other than cartilage and meniscus,or reporting treatment outcomes were excluded(n=111).Thirty-one papers were included in this review,which reported on the composition of animal and human cartilage(articular and meniscus).The most frequently investigated parameters were quantitative proteoglycan determination and hydration level of the cartilage.Cartilage and meniscus degeneration,i.e.,reduced collagen and proteoglycan content,reduced mechanical pro perties,and increased hydration level,was shown in eve ry article about osteoarthritis.Among all diagnostic methods,laboratory methods(biochemical and histological analysis) are the most frequently used,compared to the instrumental ones(spectroscopy,MRI,and CT).At the same time,spectroscopy takes the lead and becomes the most common approach for determining cartilage composition(collagen and proteoglycans content).展开更多
Spinal cord injuries have overwhelming physical and occupational implications for patients.Moreover,the extensive and long-term medical care required for spinal cord injury significantly increases healthcare costs and...Spinal cord injuries have overwhelming physical and occupational implications for patients.Moreover,the extensive and long-term medical care required for spinal cord injury significantly increases healthcare costs and resources,adding a substantial burden to the healthcare system and patients'families.In this context,chondroitinase ABC,a bacterial enzyme isolated from Proteus vulgaris that is modified to facilitate expression and secretion in mammals,has emerged as a promising therapeutic agent.It works by degrading chondroitin sulfate proteoglycans,cleaving the glycosaminoglycanchains of chondroitin sulfate proteoglycans into soluble disaccharides or tetrasaccharides.Chondroitin sulfate proteoglycans are potent axon growth inhibitors and principal constituents of the extracellular matrix surrounding glial and neuronal cells attached to glycosaminoglycan chains.Chondroitinase ABC has been shown to play an effective role in promoting recovery from acute and chronic spinal cord injury by improving axonal regeneration and sprouting,enhancing the plasticity of perineuronal nets,inhibiting neuronal apoptosis,and modulating immune responses in various animal models.In this review,we introduce the classification and pathological mechanisms of spinal cord injury and discuss the pathophysiological role of chondroitin sulfate proteoglycans in spinal cord injury.We also highlight research advancements in spinal cord injury treatment strategies,with a focus on chondroitinase ABC,and illustrate how improvements in chondroitinase ABC stability,enzymatic activity,and delivery methods have enhanced injured spinal cord repair.Furthermore,we emphasize that combination treatment with chondroitinase ABC further enhances therapeutic efficacy.This review aimed to provide a comprehensive understanding of the current trends and future directions of chondroitinase ABC-based spinal cord injury therapies,with an emphasis on how modern technologies are accelerating the optimization of chondroitinase ABC development.展开更多
Purpose:Regular exercise can reduce incidence and progression of breast cancer,but the mechanisms for such effects are not fully understood.The purpose of this study was to examine the mechanisms behind the protective...Purpose:Regular exercise can reduce incidence and progression of breast cancer,but the mechanisms for such effects are not fully understood.The purpose of this study was to examine the mechanisms behind the protective effects of exercise.Methods:We used a variety of rodent and human experimental model systems to determine whether exercise training can reduce tumor burden in breast cancer and to identify mechanism associated with any exercise training effects on tumor burden.Results:We show that voluntary wheel running slows tumor development in the mammary specific polyomavirus middle T antigen overexpression(MMTV-PyMT)mouse model of breast cancer but only when mice are not housed alone.We identify the proteoglycan decorin as a contraction-induced secretory factor that systemically increases in patients with breast cancer immediately following exercise.Moreover,high expression of decorin in tumors is associated with improved prognosis in patients,while treatment of breast cancer cells in vitro with decorin reduces cell proliferation.Notwithstanding,when we overexpressed decorin in murine muscle or injected recombinant decorin systemically into mouse models of breast cancer,elevated plasma decorin concentrations did not result in higher tumor decorin levels and tumor burden was not improved.Conclusion:Exercise training is anti-tumorigenic in a mouse model of luminal breast cancer,but the effect is abrogated by social isolation.The proteoglycan decorin is an exercise-induced secretory protein,and tumor decorin levels are positively associated with improved prognosis in patients.The hypothesis that elevated plasma decorin is a mechanism by which exercise training improves breast cancer progression in humans is not,however,supported by our pre-clinical data since elevated circulating decorin did not increase tumor decorin levels in these models.展开更多
Although atherosclerosis is a multifactorial process,proteoglycans mediated lipoprotein(LDL)retention at the subendothelial space is a necessary and sufficient event in provoking lesion initiation.Proteoglycans(PGs)ar...Although atherosclerosis is a multifactorial process,proteoglycans mediated lipoprotein(LDL)retention at the subendothelial space is a necessary and sufficient event in provoking lesion initiation.Proteoglycans(PGs)are usually composed of one core protein backbone with one or more glycosaminoglycan chains(GAGs)covalently linked,mainly include perlecan,biglycan,versican,and decorin.The interaction between LDL and proteoglycans is apparently mediated by the basic amino acids in apoB-100,the moiety of LDL,electrostatic interacting with the negatively charged GAGs(sulfate or carbohydrate groups)of proteoglycans or though some bridge molecules like sphingomyelinase(SMase)or lipoprotein lipase(LpL).In the later section,we collate the promising therapeutic approaches that have been proposed up to now,targeting LDL-PGs interaction.It should be concluded that previous studies on interaction between LDL and PGs mainly focused on perlecan,biglycan,decorin,and versican that all located in the extracellular matrix(ECM),future studies should pay more attention to the endothelial surface glycocalyx and its interaction with LDLs,seeking promising therapeutic targets more specifically.展开更多
Articular cartilage is an avascular and non-nervous tissue. The transport of metabolites to and from the chondrocytes has to take place through the matrix and hence depends on its composition and structure. A major pa...Articular cartilage is an avascular and non-nervous tissue. The transport of metabolites to and from the chondrocytes has to take place through the matrix and hence depends on its composition and structure. A major parameter controlling the properties of cartilage is the proteoglycan (PG) content of the matrix, whose small展开更多
Aim:Heterogeneity of glioblastoma(GB)cells significantly contributes to tumor resistance against temozolomide(TMZ)and the development of disease relapse.Multiple molecular mechanisms are involved in this process,yet t...Aim:Heterogeneity of glioblastoma(GB)cells significantly contributes to tumor resistance against temozolomide(TMZ)and the development of disease relapse.Multiple molecular mechanisms are involved in this process,yet the contribution of proteoglycans(PGs)remains unknown.This study aimed to investigate the potential involvement of PGs(both at core proteins and polysaccharide chains)in the heterogeneity and TMZ resistance of GB cells.Methods:Seven human GB cell lines were characterized for TMZ sensitivity,cell phenotypic traits,gene expression for glucocorticoid receptor(GR,NR3C1),PG core proteins-and heparan sulfate(HS)biosynthesis-related genes and content of their chondroitin sulfate(CS)and HS chains.Results:Although the studied cell lines have similar proliferation rates,they significantly differ in their migration activity,clonogenicity,and TMZ resistance(IC508.51-369.59µM in the line of U343,LN215,HS683,U87,LN71,LN405,LN18),creating a specific phenotype for each cell line.Some PGs(NG2/CSPG4,CSPG5,and versican)contributed to the molecular heterogeneity of these cells being cell line-specifically expressed in all cell lines,which also differed in terms of the CS/HS content.Transcriptional activity of the HS metabolic system was low in these GB cell lines,expressing mainly EXT1/2 and NDST1/2,while expression levels of sulfotransferases and SULF2 were cell line-specific.TMZ resistance of these cells was correlated with the expression of stem-cell marker CD44(+3.5-fold,r=0.73)and GR(-3-fold,r=-0.81).TMZ treatment of the resistant(LN405)and sensitive(LN215)cells resulted in complex changes in cell migration as well as NG2/CSPG4 expression and CS/HS content.Conclusion:Differential expression of PGs and CS/HS content contribute to the heterogeneity of GB cells,and CD44 and NR3C1 might be informative biomarkers for TMZ resistance.展开更多
A long-standing goal of spinal cord injury research is to develop effective repair strategies,which can restore motor and sensory functions to near-normal levels.Recent advances in clinical management of spinal cord i...A long-standing goal of spinal cord injury research is to develop effective repair strategies,which can restore motor and sensory functions to near-normal levels.Recent advances in clinical management of spinal cord injury have significantly improved the prognosis,survival rate and quality of life in patients with spinal cord injury.In addition,a significant progress in basic science research has unraveled the underlying cellular and molecular events of spinal cord injury.Such efforts enabled the development of pharmacologic agents,biomaterials and stem-cell based therapy.Despite these efforts,there is still no standard care to regenerate axons or restore function of silent axons in the injured spinal cord.These challenges led to an increased focus on another therapeutic approach,namely neuromodulation.In multiple animal models of spinal cord injury,epidural electrical stimulation of the spinal cord has demonstrated a recovery of motor function.Emerging evidence regarding the efficacy of epidural electrical stimulation has further expanded the potential of epidural electrical stimulation for treating patients with spinal cord injury.However,most clinical studies were conducted on a very small number of patients with a wide range of spinal cord injury.Thus,subsequent studies are essential to evaluate the therapeutic potential of epidural electrical stimulation for spinal cord injury and to optimize stimulation parameters.Here,we discuss cellular and molecular events that continue to damage the injured spinal cord and impede neurological recovery following spinal cord injury.We also discuss and summarize the animal and human studies that evaluated epidural electrical stimulation in spinal cord injury.展开更多
As chondroitinase ABC can improve the hostile microenvironment and cell transplantation is proven to be effective after spinal cord injury, we hypothesized that their combination would be a more effective treatment op...As chondroitinase ABC can improve the hostile microenvironment and cell transplantation is proven to be effective after spinal cord injury, we hypothesized that their combination would be a more effective treatment option. At 5 days after T8 spinal cord crush injury, rats were injected with bone marrow mesenchymal stem cell suspension or chondroitinase ABC 1 mm from the edge of spinal cord damage zone. Chondroitinase ABC was first injected, and bone marrow mesenchymal stem cell suspension was injected on the next day in the combination group. At 14 days, the mean Basso, Beattie and Bresnahan score of the rats in the combination group was higher than other groups. Hematoxylin-eosin staining showed that the necrotic area was significantly reduced in the combination group compared with other groups. Glial fibrillary acidic protein-chondroitin sulfate proteoglycan double staining showed that the damage zone of astrocytic scars was significantly reduced without the cavity in the combination group. Glial fibrillary acidic protein/growth associated protein-43 double immunostaining revealed that positive fibers traversed the damage zone in the combination group. These results suggest that the combination of chondroitinase ABC and bone marrow mesenchymal stem cell transplantation contributes to the repair of spinal cord injury.展开更多
INTRODUCTIONDevelopment of drug-resistance to chemotherapyand subsequent metastasis of tumor are primarilyresponsible for treatment failure and the death fromcancer. There have been many previous studies onthe relatio...INTRODUCTIONDevelopment of drug-resistance to chemotherapyand subsequent metastasis of tumor are primarilyresponsible for treatment failure and the death fromcancer. There have been many previous studies onthe relationship between expression of multidrugresistance (MDR) phenotype P-glycoprotein (P-gp)and the malignant properties of tumors, but theresults are often conflicting[1-8]. The difference intumor types or MDR phenotype induced by specificagents might account for this discrepancy. Taxotere(TXT), a member of the family of taxanes, hasantitumor activity through its effect of promotingthe polymerization of tubulin[9,10].展开更多
IM To study the distribution of arylsulfatase, βgalactosidase and lysozyme in gastric cancer cells, and its relationship to differentiation and invasion of gastric cancer cells.METHODS Histochemical, immunohistoc...IM To study the distribution of arylsulfatase, βgalactosidase and lysozyme in gastric cancer cells, and its relationship to differentiation and invasion of gastric cancer cells.METHODS Histochemical, immunohistochemical and ruthenium red (RR) electrocytochemical technique for three types of hydrolases and proteoglycans in pericancerous matrix in 33 cases of gastric cancer were observed under light and electron microscopy.RESULTS The expression intensities of arylsulfatase, βglactosidase and lysozyme in mucinous cell carcinomas were more intensive than those in welldifferentiated and poorlydifferentiated adenocarcinomas (P<005-001). The fibrous tissues smooth muscle and proteoglycans close to the cancer cells were degraded. They were found in the region far from the cancer cells. Expression of three enzymes mentioned above was low in adenocarcinoma cells, and fibrous tissues and RR granules were present and intact near the welldifferentiated and poorly differentiated adenocarcinoma cells.CONCLUSION Mucinous cell carcinoma may release various hydrolases into extracellular matrix, inducing degradation of pericancerous matrix and facilitating cancer cell invasion and metastasis..展开更多
基金supported by the National Natural Science Foundation of China,Nos.81070996(to ZW),81572151(to XH)Shaanxi Provincial Key R&D Program,Nos.2020ZDLSF02-05(to ZW),2021ZDLSF02-10(to XH)+1 种基金Everest Project of Military Medicine of Air Force Medical University,No.2018RCFC02(to XH)Boosting Project of the First Affiliated Hospital of Air Force Medical University,No.XJZT19Z22(to ZW)。
文摘Both glial cells and glia scar greatly affect the development of spinal cord injury and have become hot spots in research on spinal cord injury treatment.The cellular deposition of dense extracellular matrix proteins such as chondroitin sulfate proteoglycans inside and around the glial scar is known to affect axonal growth and be a major obstacle to autogenous repair.These proteins are thus candidate targets for spinal cord injury therapy.Our previous studies demonstrated that 810 nm photo biomodulation inhibited the formation of chondroitin sulfate proteoglycans after spinal cord injury and greatly improved motor function in model animals.However,the specific mechanism and potential targets involved remain to be clarified.In this study,to investigate the therapeutic effect of photo biomodulation,we established a mouse model of spinal cord injury by T9 clamping and irradiated the injury site at a power density of 50 mW/cm~2 for 50 minutes once a day for 7 consecutive days.We found that photobiomodulation greatly restored motor function in mice and down regulated chondroitin sulfate proteoglycan expression in the injured spinal cord.Bioinformatics analysis revealed that photobiomodulation inhibited the expression of proteoglycan-related genes induced by spinal cord injury,and versican,a type of proteoglycan,was one of the most markedly changed molecules.Immunofluorescence staining showed that after spinal cord injury,versican was present in astrocytes in spinal cord tissue.The expression of versican in primary astrocytes cultured in vitro increased after inflammation induction,whereas photobiomodulation inhibited the expression of ve rsican.Furthermore,we found that the increased levels of p-Smad3,p-P38 and p-Erk in inflammatory astrocytes were reduced after photobiomodulation treatment and after delivery of inhibitors including FR 180204,(E)-SIS3,and SB 202190.This suggests that Sma d 3/Sox9 and MAP K/Sox9 pathways may be involved in the effects of photobiomodulation.In summary,our findings show that photobiomodulation modulates the expression of chondroitin sulfate proteoglycans,and versican is one of the key target molecules of photo biomodulation.MAPK/Sox9 and Smad3/Sox9 pathways may play a role in the effects of photo biomodulation on chondroitin sulfate proteoglycan accumulation after spinal cord injury.
基金supported by the NIH(NS53470)the Kentucky Spinal Cord and Head Injury Research Trust(#10-11A)the Department of Defense,CDMRP(SC090248/W81XWH-10-1-0778)
文摘Proteoglycans in the central nervous system play integral roles as ＂traffic signals＂ for the direction of neurite outgrowth. This attribute of proteoglycans is a major factor in regeneration of the injured central nervous system. In this review, the structures of proteoglycans and the evidence suggesting their involvement in the response following spinal cord injury are presented. The review further describes the methods routinely used to determine the effect proteoglycans have on neurite outgrowth. The effects of proteoglycans on neurite outgrowth are not completely understood as there is disagreement on what component of the molecule is interacting with growing neurites and this ambiguity is chronicled in an historical context. Finally, the most recent findings suggesting possible receptors, interactions, and sulfation patterns that may be important in eliciting the effect of proteoglycans on neurite outgrowth are discussed. A greater understanding of the proteoglycan-neurite interaction is necessary for successfully promoting regeneration in the iniured central nervous system.
基金Supported by Hungarian Research Fund(OTKA)(No.100904 to Kovalszky Iand No.105763 to Baghy K)
文摘Proteoglycans are a group of molecules that contain at least one glycosaminoglycan chain,such as a heparan,dermatan,chondroitin,or keratan sulfate,covalently attached to the protein core.These molecules arecategorized based on their structure,localization,and function,and can be found in the extracellular matrix,on the cell surface,and in the cytoplasm.Cell-surface heparan sulfate proteoglycans,such as syndecans,are the primary type present in healthy liver tissue.However,deterioration of the liver results in overproduction of other proteoglycan types.The purpose of this article is to provide a current summary of the most relevant data implicating proteoglycans in the development and progression of human and experimental liver cancer.A review of our work and other studies in the literature indicate that deterioration of liver function is accompanied by an increase in the amount of chondroitin sulfate proteoglycans.The alteration of proteoglycan composition interferes with the physiologic function of the liver on several levels.This article details and discusses the roles of syndecan-1,glypicans,agrin,perlecan,collagen XVIII/endostatin,endocan,serglycin,decorin,biglycan,asporin,fibromodulin,lumican,and versican in liver function.Specifically,glypicans,agrin,and versican play significant roles in the development of liver cancer.Conversely,the presence of decorin could potentially provide protective effects.
基金supported by the Finnish Funding Agency for Innovation Tekes,Academy of FinlandSigrid Jusélius Foundation
文摘The current dogma in neural regeneration research implies that chondroitin sulfate proteoglycans（CSPGs） inhibit plasticity and regeneration in the adult central nervous system（CNS）. We argue that the role of the CSPGs can be reversed from inhibition to activation by developmentally expressed CSPG-binding factors. Heparin-binding growth-associated molecule（HB-GAM; also designated as pleiotrophin） has been studied as a candidate molecule that might modulate the role of CSPG matrices in plasticity and regeneration. Studies in vitro show that in the presence of soluble HB-GAM chondroitin sulfate（CS） chains of CSPGs display an enhancing effect on neurite outgrowth. Based on the in vitro studies, we suggest a model according to which the HB-GAM/CS complex binds to the neuron surface receptor glypican-2, which induces neurite growth. Furthermore, HB-GAM masks the CS binding sites of the neurite outgrowth inhibiting receptor protein tyrosine phosphatase sigma（PTPσ）, which may contribute to the HB-GAM-induced regenerative effect. In vivo studies using two-photon imaging after local HB-GAM injection into prick-injury of the cerebral cortex reveal regeneration of dendrites that has not been previously demonstrated after injuries of the mammalian nervous system. In the spinal cord, two-photon imaging displays HB-GAM-induced axonal regeneration. Studies on the HB-GAM/CS mechanism in vitro and in vivo are expected to pave the way for drug development for injuries of brain and spinal cord.
基金supported by the National Natural Science Foundation of China,No.81601066the Natural Science Foundation of Guangdong Province of China,No.2017A030313103 and 2016A030313096+2 种基金a grant from the Program of Introducing Talents of Discipline to Universities,No.B14036the Fundamental Research Funds for the Central Universities,No.21616340the Division of Intramural Research of the National Heart,Lung,and Blood Institute of National Institutes of Health
文摘As one major component of extracellular matrix （ECM） in the central nervous system, chondroitin sul- fate proteoglycans （CSPGs） have long been known as inhibitors enriched in the glial scar that prevent axon regeneration after injury. Although many studies have shown that CSPGs inhibited neurite out- growth in vitro using different types of neurons, the mechanism by which CSPGs inhibit axonal growth remains poorly understood. Using cerebellar granule neuron （CGN） culture, in this study, we evaluated the effects of different concentrations of both immobilized and soluble CSPGs on neuronal growth, in- cluding cell adhesion, spreading and neurite growth. Neurite length decreased while CSPGs concentration arised, meanwhile, a decrease in cell density accompanied by an increase in cell aggregates formation was observed. Soluble CSPGs also showed an inhibition on neurite outgrowth, but it required a higher concen- tration to induce cell aggregates formation than coated CSPGs. We also found that growth cone size was significantly reduced on CSPGs and neuronal cell spreading was restrained by CSPGs, attributing to an inhibition on lamellipodial extension. The effect of CSPGs on neuron adhesion was further evidenced by interference reflection microscopy （IRM） which directly demonstrated that both CGNs and cerebral cortical neurons were more loosely adherent to a CSPG substrate. These data demonstrate that CSPGs have an effect on cell adhesion and spreading in addition to neurite outgrowth.
文摘Axon growth is a central event in the development and post-injury plasticity of the nervous system. Growing axons encounter a wide variety of environmental instructions. Much like traffic lights in controlling the migrating axons, chondroitin sulfate proteoglycans （CSPGs） and heparan sulfate proteoglycans （HSPGs） often lead to ＂stop＂ and ＂go＂ growth responses in the axons, respectively. Recently, the LAR family and NgR family molecules were identified as neuronal receptors for CSPGs and HSPGs. These discoveries provided molecular tools for further study of mechanisms underlying axon growth regulation. More importantly, the identification of these proteoglycan receptors offered potential therapeutic targets for promoting post-injury axon regeneration.
基金Elements of the project are financed by the European Commission’s Framework Program 7(BIO-NMR-00007)-Bio-NMR grant:Jellyfish protein NMR(BIO-NMR-00007)-IEP.
文摘Proteoglycans and collagen molecules are interacting with each other thereby forming various connective tissues. The sulfation pattern of proteoglycans differs depending on the kind of tissue and/or the degree of maturation. Tissues from Cnidaria are suitable examples for exploration of the effects in relation to the presence and the absence of sulfate groups, when studying characteristic fragments of the long proteoglycan carbohydrate chains in silico. It has been described that a non-sulfated chondroitin appears as a scaffold in early morphogenesis of all nematocyst types in Hydra. On the other hand, sulfated glucosaminoglycans play an important role in various developmental processes of Cnidaria. In order to understand this biological phenomenon on a sub-molecular level we have analysed the structures of sulfated and non-sulfated proteoglycan carbohydrate chains as well as the structure of diverse collagen molecules with computational methods including quantum chemical calculations. The strong interactions between the sulfate groups of the carbohydrates moieties in proteoglycans and positively charged regions of collagen are essential in stabilizing various Cnidaria tissues but could hinder the nematocyst formation and its proper function. The results of our quantum chemical calculations show that the sulfation pattern has a significant effect on the conformation of chondroitin structures under study.
基金Supported by Research Grants Council of the Hong Kong SAR,China,No.17111016 and No.17100819.
文摘Esophageal squamous cell carcinoma(ESCC)is a highly malignant disease that has a poor prognosis.Its high lethality is mainly due to the lack of symptoms at early stages,which culminates in diagnosis at a late stage when the tumor has already metastasized.Unfortunately,the common cancer biomarkers have low sensitivity and specificity in esophageal cancer.Therefore,a better understanding of the molecular mechanisms underlying ESCC progression is needed to identify novel diagnostic markers and therapeutic targets for intervention.The invasion of cancer cells into the surrounding tissue is a crucial step for metastasis.During metastasis,tumor cells can interact with extracellular components and secrete proteolytic enzymes to remodel the surrounding tumor microenvironment.Proteoglycans are one of the major components of extracellular matrix.They are involved in multiple processes of cancer cell invasion and metastasis by interacting with soluble bioactive molecules,surrounding matrix,cell surface receptors,and enzymes.Apart from having diverse functions in tumor cells and their surrounding microenvironment,proteoglycans also have diagnostic and prognostic significance in cancer patients.However,the functional significance and underlying mechanisms of proteoglycans in ESCC are not well understood.This review summarizes the proteoglycans that have been studied in ESCC in order to provide a comprehensive view of the role of proteoglycans in the progression of this cancer type.A long term goal would be to exploit these molecules to provide new strategies for therapeutic intervention.
基金Supported by The National Natural Science Foundation of China,No.30471982(to Dang SS and Cheng YA)Arthritis Research UK,No.18331(to Hughes CE and Caterson B)
文摘AIM:To investigate the expression of chondroitin sulphate proteoglycans(CSPGs)in rat liver tissues of hepatocellular carcinoma(HCC).METHODS:Thirty male Sprague Dawley rats were randomly divided into two groups:control group(n=10) and HCC model group(n=20).Rats in the HCC model groups were intragastrically administrated with 0.2%(w/v)N-diethylnitrosamine(DEN)every 5 d for 16 wk,whereas 0.9%(w/v)normal saline was administered to rats in the control group.After 16 wk from the initiation of experiment,all rats were killed and livers were collected and fixed in 4%(w/v)paraformaldehyde.All tissues were embedded in paraffin and sectioned.Histological staining(hematoxylin and eosin and Toluidine blue)was performed to demonstrate the onset of HCC and the content of sulphated glycosaminoglycan(sGAG).Immunohistochemical staining was performed to investigate the expression of chondroitin sulphate(CS)/dermatan sulphate(DS)-GAG,heparan sulphate(HS)-GAG,keratan sulphate(KS)-GAG in liver tissues.Furthermore,expression and distribution of CSPG family members,including aggrecan,versican,biglycan and decorin in liver tissues,were also immunohistochemically determined.RESULTS:After 16 wk administration of DEN,malignant nodules were observed on the surface of livers from the HCC model group,and their hepatic lobule structures appeared largely disrupted under microscope.Toluidine blue staining demonstrated that there was an significant increase in sGAG content in HCC tissues when compared with that in the normal liver tissues from the control group[0.37±0.05 integrated optical density per stained area(IOD/area)and 0.21± 0.01 IOD/area,P<0.05].Immunohistochemical studies demonstrated that this increased sGAG in HCC tissues was induced by an elevated expression of CS/DS(0.28±0.02 IOD/area and 0.18±0.02 IOD/area,P< 0.05)and HS(0.30±0.03 IOD/area and 0.17±0.02 IOD/area,P<0.01)but not KS GAGs in HCC tissues.Further studies thereby were performed to investigate the expression and distribution of several CSPG components in HCC tissues,including aggrecan,versican,biglycan and decorin.Interestingly,there was a distinct distribution pattern for these CSPG components between HCC tissues and the normal tissues.Positive staining of aggrecan,biglycan and decorin was localized in hepatic membrane and/or pericellular matrix in normal liver tissues;however,their expression was mainly observed in the cytoplasm,cell membranes in hepatoma cells and/or pericellular matrix within HCC tissues.Semi-quantitative analysis indicated that there was a higher level of expression of aggrecan(0.43± 0.01 and 0.35±0.03,P<0.05),biglycan(0.32±0.01 and 0.25±0.01,P<0.001)and decorin(0.29±0.01 and 0.26±0.01,P<0.05)in HCC tissues compared with that in the normal liver tissues.Very weak versican positive staining was observed in hepatocytes near central vein in normal liver tissues;however there was an intensive versican distribution in fibrosis septa between the hepatoma nodules.Semi-quantitative analysis indicated that the positive rate of versican in hepatoma tissues from the HCC model group was much higher than that in the control group(33.61%and 21.28%,P <0.05).There was no positive staining in lumican and keratocan,two major KSPGs,in either normal or HCC liver tissues.CONCLUSION:CSPGs play important roles in the onset and progression of HCC,and may provide potential therapeutic targets and clinical biomarkers for this prevalent tumor in humans.
文摘This paper reports a comparative study of the extraction rate of rat brain proteoglycans (PGs) by three different methods, with chromatography, papain digestion and electrophoretic technique. The results showed: ① The extraction rate of brain PGs by 4mol/L guanidine HCl (GuHCl)was higher than that by phosphate-buffered saline (PBS) In any method, however the protein/PGs ratio in the GuHCl-extract was lower than that in the PBS-extract. ② PBS mainly extracted the soluble chondroitin sulfate proteoglycan (CSPG), whereas the 4mol/L GuHCl could extracted both soluble CSPG and insoluble heparan sulfate proteoglycan (HSPG). ③ After delipidation of brain by organic reagents, the extraction rate of delipidized brain PGs either by the PBS or by the 4mol/L GuHCl decreased obviously. ④ By direct extraction with PBS, GuHCl seguentially, few amount of PGs in the residue from brain was found.
基金supported by the Russian Science Foundation(grant no.21–79-10325)the academic leadership program Priority 2030 proposed by Federal State Autonomous Educational Institution of Higher Education I.M.Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation(Sechenov University)
文摘Osteoarthritis is a degenerative disease that affects articular cartilage,leading to changes on the macro and micro levels of this multi-component tissue.Understanding the processes underlying this pathology plays an important role in planning the following management tactics.Timely detection of the knee joint degradation at the level of tissue changes can prevent its progressive damage due to the early beginning of appropriate treatment.This study aimed to provide an overview of the current level of knowledge about the composition of cartilage and menisci using a wide range of different diagnostic methods.A systematic review of the literature published from 1978 to 2023was conducted.Original studies of the knee joint cartilage(articular and meniscus) research,reporting content composition and mechanical properties,were included.Studies of the non-knee joint cartilage,tissue research other than cartilage and meniscus,or reporting treatment outcomes were excluded(n=111).Thirty-one papers were included in this review,which reported on the composition of animal and human cartilage(articular and meniscus).The most frequently investigated parameters were quantitative proteoglycan determination and hydration level of the cartilage.Cartilage and meniscus degeneration,i.e.,reduced collagen and proteoglycan content,reduced mechanical pro perties,and increased hydration level,was shown in eve ry article about osteoarthritis.Among all diagnostic methods,laboratory methods(biochemical and histological analysis) are the most frequently used,compared to the instrumental ones(spectroscopy,MRI,and CT).At the same time,spectroscopy takes the lead and becomes the most common approach for determining cartilage composition(collagen and proteoglycans content).
基金supported by the National Natural Science Foundation of China,No.82002645China Postdoctoral Science Foundation,No.2022M722321Jiangsu Funding Program for Excellent Postdoctoral Talent,No.2022ZB552(all to YH)。
文摘Spinal cord injuries have overwhelming physical and occupational implications for patients.Moreover,the extensive and long-term medical care required for spinal cord injury significantly increases healthcare costs and resources,adding a substantial burden to the healthcare system and patients'families.In this context,chondroitinase ABC,a bacterial enzyme isolated from Proteus vulgaris that is modified to facilitate expression and secretion in mammals,has emerged as a promising therapeutic agent.It works by degrading chondroitin sulfate proteoglycans,cleaving the glycosaminoglycanchains of chondroitin sulfate proteoglycans into soluble disaccharides or tetrasaccharides.Chondroitin sulfate proteoglycans are potent axon growth inhibitors and principal constituents of the extracellular matrix surrounding glial and neuronal cells attached to glycosaminoglycan chains.Chondroitinase ABC has been shown to play an effective role in promoting recovery from acute and chronic spinal cord injury by improving axonal regeneration and sprouting,enhancing the plasticity of perineuronal nets,inhibiting neuronal apoptosis,and modulating immune responses in various animal models.In this review,we introduce the classification and pathological mechanisms of spinal cord injury and discuss the pathophysiological role of chondroitin sulfate proteoglycans in spinal cord injury.We also highlight research advancements in spinal cord injury treatment strategies,with a focus on chondroitinase ABC,and illustrate how improvements in chondroitinase ABC stability,enzymatic activity,and delivery methods have enhanced injured spinal cord repair.Furthermore,we emphasize that combination treatment with chondroitinase ABC further enhances therapeutic efficacy.This review aimed to provide a comprehensive understanding of the current trends and future directions of chondroitinase ABC-based spinal cord injury therapies,with an emphasis on how modern technologies are accelerating the optimization of chondroitinase ABC development.
基金supported by an NHMRC Investigator Grant (APP1194141)supported by project grants from the NHMRC (APP1042465, APP1041760, and APP1156511)。
文摘Purpose:Regular exercise can reduce incidence and progression of breast cancer,but the mechanisms for such effects are not fully understood.The purpose of this study was to examine the mechanisms behind the protective effects of exercise.Methods:We used a variety of rodent and human experimental model systems to determine whether exercise training can reduce tumor burden in breast cancer and to identify mechanism associated with any exercise training effects on tumor burden.Results:We show that voluntary wheel running slows tumor development in the mammary specific polyomavirus middle T antigen overexpression(MMTV-PyMT)mouse model of breast cancer but only when mice are not housed alone.We identify the proteoglycan decorin as a contraction-induced secretory factor that systemically increases in patients with breast cancer immediately following exercise.Moreover,high expression of decorin in tumors is associated with improved prognosis in patients,while treatment of breast cancer cells in vitro with decorin reduces cell proliferation.Notwithstanding,when we overexpressed decorin in murine muscle or injected recombinant decorin systemically into mouse models of breast cancer,elevated plasma decorin concentrations did not result in higher tumor decorin levels and tumor burden was not improved.Conclusion:Exercise training is anti-tumorigenic in a mouse model of luminal breast cancer,but the effect is abrogated by social isolation.The proteoglycan decorin is an exercise-induced secretory protein,and tumor decorin levels are positively associated with improved prognosis in patients.The hypothesis that elevated plasma decorin is a mechanism by which exercise training improves breast cancer progression in humans is not,however,supported by our pre-clinical data since elevated circulating decorin did not increase tumor decorin levels in these models.
基金supported by Grants-in-Aid from the National Natural Science Foundation of China(No.31870940,11772036,11572028,11421202)National Key Research and Development Program in China(No.2017YFB0702501)the Fundamental Research Funds for the Central Universities.
文摘Although atherosclerosis is a multifactorial process,proteoglycans mediated lipoprotein(LDL)retention at the subendothelial space is a necessary and sufficient event in provoking lesion initiation.Proteoglycans(PGs)are usually composed of one core protein backbone with one or more glycosaminoglycan chains(GAGs)covalently linked,mainly include perlecan,biglycan,versican,and decorin.The interaction between LDL and proteoglycans is apparently mediated by the basic amino acids in apoB-100,the moiety of LDL,electrostatic interacting with the negatively charged GAGs(sulfate or carbohydrate groups)of proteoglycans or though some bridge molecules like sphingomyelinase(SMase)or lipoprotein lipase(LpL).In the later section,we collate the promising therapeutic approaches that have been proposed up to now,targeting LDL-PGs interaction.It should be concluded that previous studies on interaction between LDL and PGs mainly focused on perlecan,biglycan,decorin,and versican that all located in the extracellular matrix(ECM),future studies should pay more attention to the endothelial surface glycocalyx and its interaction with LDLs,seeking promising therapeutic targets more specifically.
文摘Articular cartilage is an avascular and non-nervous tissue. The transport of metabolites to and from the chondrocytes has to take place through the matrix and hence depends on its composition and structure. A major parameter controlling the properties of cartilage is the proteoglycan (PG) content of the matrix, whose small
基金This work was supported by the Russian Science Foundation(Grant No.21-15-00285)in part of GR and HS biosynthesiswithin the state assignment of Ministry of Science and Higher Education of the Russian Federation(theme No.122032200240-8)in part of GB cells characterization and PGs expression.
文摘Aim:Heterogeneity of glioblastoma(GB)cells significantly contributes to tumor resistance against temozolomide(TMZ)and the development of disease relapse.Multiple molecular mechanisms are involved in this process,yet the contribution of proteoglycans(PGs)remains unknown.This study aimed to investigate the potential involvement of PGs(both at core proteins and polysaccharide chains)in the heterogeneity and TMZ resistance of GB cells.Methods:Seven human GB cell lines were characterized for TMZ sensitivity,cell phenotypic traits,gene expression for glucocorticoid receptor(GR,NR3C1),PG core proteins-and heparan sulfate(HS)biosynthesis-related genes and content of their chondroitin sulfate(CS)and HS chains.Results:Although the studied cell lines have similar proliferation rates,they significantly differ in their migration activity,clonogenicity,and TMZ resistance(IC508.51-369.59µM in the line of U343,LN215,HS683,U87,LN71,LN405,LN18),creating a specific phenotype for each cell line.Some PGs(NG2/CSPG4,CSPG5,and versican)contributed to the molecular heterogeneity of these cells being cell line-specifically expressed in all cell lines,which also differed in terms of the CS/HS content.Transcriptional activity of the HS metabolic system was low in these GB cell lines,expressing mainly EXT1/2 and NDST1/2,while expression levels of sulfotransferases and SULF2 were cell line-specific.TMZ resistance of these cells was correlated with the expression of stem-cell marker CD44(+3.5-fold,r=0.73)and GR(-3-fold,r=-0.81).TMZ treatment of the resistant(LN405)and sensitive(LN215)cells resulted in complex changes in cell migration as well as NG2/CSPG4 expression and CS/HS content.Conclusion:Differential expression of PGs and CS/HS content contribute to the heterogeneity of GB cells,and CD44 and NR3C1 might be informative biomarkers for TMZ resistance.
基金This work was supported by the Medical Scientist Training Program T32GM007250Predoctoral Training in Molecular Therapeutics Program T32GM008803(to EHC).
文摘A long-standing goal of spinal cord injury research is to develop effective repair strategies,which can restore motor and sensory functions to near-normal levels.Recent advances in clinical management of spinal cord injury have significantly improved the prognosis,survival rate and quality of life in patients with spinal cord injury.In addition,a significant progress in basic science research has unraveled the underlying cellular and molecular events of spinal cord injury.Such efforts enabled the development of pharmacologic agents,biomaterials and stem-cell based therapy.Despite these efforts,there is still no standard care to regenerate axons or restore function of silent axons in the injured spinal cord.These challenges led to an increased focus on another therapeutic approach,namely neuromodulation.In multiple animal models of spinal cord injury,epidural electrical stimulation of the spinal cord has demonstrated a recovery of motor function.Emerging evidence regarding the efficacy of epidural electrical stimulation has further expanded the potential of epidural electrical stimulation for treating patients with spinal cord injury.However,most clinical studies were conducted on a very small number of patients with a wide range of spinal cord injury.Thus,subsequent studies are essential to evaluate the therapeutic potential of epidural electrical stimulation for spinal cord injury and to optimize stimulation parameters.Here,we discuss cellular and molecular events that continue to damage the injured spinal cord and impede neurological recovery following spinal cord injury.We also discuss and summarize the animal and human studies that evaluated epidural electrical stimulation in spinal cord injury.
文摘As chondroitinase ABC can improve the hostile microenvironment and cell transplantation is proven to be effective after spinal cord injury, we hypothesized that their combination would be a more effective treatment option. At 5 days after T8 spinal cord crush injury, rats were injected with bone marrow mesenchymal stem cell suspension or chondroitinase ABC 1 mm from the edge of spinal cord damage zone. Chondroitinase ABC was first injected, and bone marrow mesenchymal stem cell suspension was injected on the next day in the combination group. At 14 days, the mean Basso, Beattie and Bresnahan score of the rats in the combination group was higher than other groups. Hematoxylin-eosin staining showed that the necrotic area was significantly reduced in the combination group compared with other groups. Glial fibrillary acidic protein-chondroitin sulfate proteoglycan double staining showed that the damage zone of astrocytic scars was significantly reduced without the cavity in the combination group. Glial fibrillary acidic protein/growth associated protein-43 double immunostaining revealed that positive fibers traversed the damage zone in the combination group. These results suggest that the combination of chondroitinase ABC and bone marrow mesenchymal stem cell transplantation contributes to the repair of spinal cord injury.
基金Supported in part by phone-Poulenc Rorer Pharmaceuticals INC
文摘INTRODUCTIONDevelopment of drug-resistance to chemotherapyand subsequent metastasis of tumor are primarilyresponsible for treatment failure and the death fromcancer. There have been many previous studies onthe relationship between expression of multidrugresistance (MDR) phenotype P-glycoprotein (P-gp)and the malignant properties of tumors, but theresults are often conflicting[1-8]. The difference intumor types or MDR phenotype induced by specificagents might account for this discrepancy. Taxotere(TXT), a member of the family of taxanes, hasantitumor activity through its effect of promotingthe polymerization of tubulin[9,10].
文摘IM To study the distribution of arylsulfatase, βgalactosidase and lysozyme in gastric cancer cells, and its relationship to differentiation and invasion of gastric cancer cells.METHODS Histochemical, immunohistochemical and ruthenium red (RR) electrocytochemical technique for three types of hydrolases and proteoglycans in pericancerous matrix in 33 cases of gastric cancer were observed under light and electron microscopy.RESULTS The expression intensities of arylsulfatase, βglactosidase and lysozyme in mucinous cell carcinomas were more intensive than those in welldifferentiated and poorlydifferentiated adenocarcinomas (P<005-001). The fibrous tissues smooth muscle and proteoglycans close to the cancer cells were degraded. They were found in the region far from the cancer cells. Expression of three enzymes mentioned above was low in adenocarcinoma cells, and fibrous tissues and RR granules were present and intact near the welldifferentiated and poorly differentiated adenocarcinoma cells.CONCLUSION Mucinous cell carcinoma may release various hydrolases into extracellular matrix, inducing degradation of pericancerous matrix and facilitating cancer cell invasion and metastasis..
