ABSTRACT
Contractors' low-carbon construction behaviors (CLCB) are pivotal in advancing decarbonization during the construction phase. However, there exists a notable gap in the comprehensive exploration of the multifaceted factors and mechanisms influencing CLCB. Therefore, this study aims to systematically identify the factors influencing CLCB in China, examine the interrelationships among these factors, and pinpoint the key determinants. Based on topic modeling of Latent Dirichlet Allocation (LDA), influencing factors are identified firstly from the pertinent literature. Subsequently, the causality degree and centrality degree between these factors are assessed by the Decision-Making Trial and Evaluation Laboratory (DEMATEL), followed by the establishment of a hierarchical structure using the Interpretive Structural Modeling (ISM) method, culminating in the identification of pivotal factors. Findings reveal that (1) 21 influential factors influencing CLCB are identified. (2) "Incentive policies for relevant stakeholders" and "Low-carbon regulation and supervision" emerge as key influences. (3) CLCB should be guided by policy and subjective awareness, fortified by market and management support, underpinned by technology, and directly driven by economic considerations. This research furnishes valuable insights for promoting low-carbon development during the construction phase, thereby assisting the construction sector in achieving carbon peak and carbon neutrality.
Subject(s)
Carbon , China , Construction IndustryABSTRACT
IgA nephropathy (IgAN) is the most common type of glomerulonephritis that frequently progresses to kidney failure. However, the molecular pathogenesis underlying IgAN remains largely unknown. Here, we investigated the role of galectin-3 (Gal-3), a galactoside-binding protein in IgAN pathogenesis, and showed that Gal-3 expression by the kidney was significantly enhanced in patients with IgAN. In both TEPC-15 hybridoma-derived IgA-induced, passive, and spontaneous "grouped" ddY IgAN models, Gal-3 expression was clearly increased with disease severity in the glomeruli, peri-glomerular regions, and some kidney tubules. Gal-3 knockout (KO) in the passive IgAN model had significantly improved proteinuria, kidney function and reduced severity of kidney pathology, including neutrophil infiltration and decreased differentiation of Th17 cells from kidney-draining lymph nodes, despite increased percentages of regulatory T cells. Gal-3 KO also inhibited the NLRP3 inflammasome, yet it enhanced autophagy and improved kidney inflammation and fibrosis. Moreover, administration of 6-de-O-sulfated, N-acetylated low-molecular-weight heparin, a competitive Gal-3 binding inhibitor, restored kidney function and improved kidney lesions in passive IgAN mice. Thus, our results suggest that Gal-3 is critically involved in IgAN pathogenesis by activating the NLRP3 inflammasome and promoting Th17 cell differentiation. Hence, targeting Gal-3 action may represent a new therapeutic strategy for treatment of this kidney disease.
ABSTRACT
Although most cell membrane proteins are modified by glycosylation, our understanding of the role and actions of protein glycosylation is still very limited. ß1,3galactosyltransferase (C1GalT1) is a key glycosyltransferase that controls the biosynthesis of the Core 1 structure of O-linked mucin type glycans and is overexpressed by many common types of epithelial cancers. This study reports that suppression of C1GalT1 expression in human colon cancer cells caused substantial changes of protein glycosylation of cell membrane proteins, many of which were ligands of the galactoside-binding galectin-3 and the macrophage galactose-type lectin (MGL). This led to significant reduction of cancer cell proliferation, adhesion, migration and the ability of tumour cells to form colonies. Crucially, C1GalT1 suppression significantly reduced galectin-3-mediated tumour cell-cell interaction and galectin-3-promoted tumour cell activities. In the meantime, C1GalT1 suppression substantially increased MGL-mediated macrophage-tumour cell interaction and macrophage-tumour cell phagocytosis and cytokine secretion. C1GalT1-expressing cancer cells implanted in chick embryos resulted in the formation of significantly bigger tumours than C1GalT1-suppressed cells and the presence of galectin-3 increased tumour growth of C1GalT1-expressing but not C1GalT1-suppressed cells. More MGL-expressing macrophages and dendritic cells were seen to be attracted to the tumour microenvironment in ME C1galt1-/-/Erb mice than in C1galt1f/f /Erb mice. These results indicate that expression of C1GalT1 by tumour cells reciprocally controls tumour cell-cell and tumour-macrophage interactions mediated by galectin-3 and MGL with double impact on cancer development and progression. C1GalT1 overexpression in epithelial cancers therefore may represent a fundamental mechanism in cancer promotion and in reduction of immune response/surveillance in cancer progression.
Subject(s)
Colonic Neoplasms , Galectin 3 , Chick Embryo , Humans , Animals , Mice , Galectin 3/genetics , Galactose , Colonic Neoplasms/genetics , Glycosylation , Macrophages , Tumor MicroenvironmentABSTRACT
Galectin-3 is a galactoside-binding protein that is commonly overexpressed in many epithelial cancers. It is increasingly recognized as a multi-functional, multi-mode promoter in cancer development, progression, and metastasis. This study reports that galectin-3 secretion by human colon cancer cells induces cancer cell secretion, in an autocrine/paracrine manner, of a number of proteases including cathepsin-B, MMP-1 and MMP-13. The secretion of these proteases causes disruption of epithelial monolayer integrity, increases its permeability and promotes tumour cell invasion. This effect of galectin-3 is shown to be mediated through induction of cellular PYK2-GSK3α/ß signalling and can be prevented by the presence of galectin-3 binding inhibitors. This study thus reveals an important mechanism in galectin-3-mediated promotion of cancer progression and metastasis. It provides further evidence to the increased realization of galectin-3 as a potential therapeutic target for the treatment of cancer.
Subject(s)
Colonic Neoplasms , Galectin 3 , Humans , Galectin 3/genetics , Galectin 3/metabolism , Peptide Hydrolases , Colonic Neoplasms/metabolism , Epithelium/metabolismABSTRACT
[Background] Metal exposure is suspected to be correlated to kidney function. However, the combined effects of co-exposing to multiple metals, especially both toxic and protective metals, have not been completely evaluated. [Method] A prospective cohort study was conducted with the "135" cohort for the evaluation of how plasma metal levels are correlated to kidney function in a midlife and elderly community in southern China. An amount of 1368 subjects without kidney disease at baseline were enrolled in the final analysis. By using linear regression and logistic regression models, the correlation of individual metal values with renal function parameters was assessed. Measuring of the multiple metal exposure level was performed by principal component analysis (PCA). [Results] Diminished renal function, as evaluated based on fast kidney function decline, or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, was positively associated with the plasma concentrations of chromium and potassium, but it was negatively associated with selenium and iron (p < 0.05). In multiple-metal analyses, linear and logistic regression models showed that the iron and chromium exposure pattern had a protective effect on renal function, whereas the sodium and potassium exposure pattern and the cadmium and lead exposure pattern increased the risk for fast kidney function decline, and eGFR < 60 mL/min/1.73 m2. [Conclusions] Certain metals, including chromium, potassium, selenium, and iron, were correlated with kidney function in a midlife and elderly community in China. In addition, the potential combined influences of co-exposing to multiple metals were observed.
ABSTRACT
Melanoma cell adhesion molecule (MCAM, CD146, MUC18) is a heavily glycosylated transmembrane protein and a marker of melanoma metastasis. It is expressed in advanced primary melanoma and metastasis but rarely in benign naevi or normal melanocytes. More and more evidence has shown that activation of the MCAM on cell surface plays a vital role in melanoma progression and metastasis. However, the natural MCAM binding ligand that initiates MCAM activation in melanoma so far remains elusive. This study revealed that galectin-3, a galactoside-binding protein that is commonly overexpressed in many cancers including melanoma, is naturally associated with MCAM on the surface of both skin and uveal melanoma cells. Binding of galectin-3 to MCAM, via O-linked glycans on the MCAM, induces MCAM dimerization and clustering on cell surface and subsequent activation of downstream AKT signalling. This leads to the increases of a number of important steps in melanoma progression of cell proliferation, adhesion, migration, and invasion. Thus, galectin-3 is a natural binding ligand of MCAM in melanoma, and their interaction activates MCAM and promotes MCAM-mediated melanoma progression. Targeting the galectin-3-MCAM interaction may potentially be a useful therapeutic strategy for melanoma treatment.
Subject(s)
Galectin 3 , Melanoma , Humans , CD146 Antigen/metabolism , Galectin 3/genetics , Ligands , Proto-Oncogene Proteins c-akt , Melanoma/pathology , GalactosidesABSTRACT
Matrix metalloproteinase-13 (MMP-13) is a member of the Matrix metalloproteinases (MMPs) family of endopeptidases. MMP-13 is produced in low amounts and is well-regulated during normal physiological conditions. Its expression and secretion are, however, increased in various cancers, where it plays multiple roles in tumour progression and metastasis. As an interstitial collagenase, MMP-13 can proteolytically cleave not only collagens I, II and III, but also a range of extracellular matrix proteins (ECMs). Its action causes ECM remodelling and often leads to the release of various sequestered growth and angiogenetic factors that promote tumour cell growth, invasion and angiogenesis. This review summarizes our current understanding of the regulation of MMP-13 expression and secretion and discusses the actions of MMP-13 in cancer progression and metastasis.
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Background: The incidence of childhood obesity has increased rapidly, and its relationship with adult diseases is constantly being revealed. Maternal factors have been shown to play an important role in the growth and development of newborns. In this article, we explored the relationship between the gestational weight gain (GWG) rate and overweight/obesity in offspring at 3 years of age. Methods: A total of 5146 pregnant women and their children registered between January 2010 and December 2018 were studied by a retrospective cohort study. The Group-based Trajectory Model was used to distinguish the GWG rate patterns. Overweight/obesity was diagnosed by the weight-for-height Z-score at 3 years of age. Logistic regression was used to analyze the association between GWG rate patterns and outcomes. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated to analyze the association between GWG rate patterns and overweight/obesity in offspring at 3 years of age. Results: Three GWG rate growth patterns were identified in this study. The incidence of offspring overweight/obesity in the low-stable, high-stable, and low-sharp patterns was 8.33%, 3.68%, and 6.03% respectively. After adjusting covariates, compared with the low-stable pattern, the high-stable pattern increased the risk for offspring to be overweight/obesity at 3 years of age, with OR of 2.26 (95% CI, 1.31-3.90). However, the low-sharp pattern was not associated with overweight/obesity in offspring at 3 years of age. Conclusions: The high-stable increasing pattern of the GWG rate is a risk factor for overweight/obesity in offspring at 3 years of age.
Subject(s)
Gestational Weight Gain , Pediatric Obesity , Child , Infant, Newborn , Pregnancy , Female , Humans , Retrospective Studies , Pediatric Obesity/epidemiology , FamilyABSTRACT
Galectin-2 is a prototype member of the galactoside-binding galectin family. It is predominately expressed in the gastrointestinal tract but is also detected in several other tissues such as the placenta and in the cardiovascular system. Galectin-2 expression and secretion by epithelial cells has been reported to contribute to the strength of the mucus layer, protect the integrity of epithelia. A number of studies have also suggested the involvement of galectin-2 in tissue inflammation, immune response and cell apoptosis. Alteration of galectin-2 expression occurs in inflammatory bowel disease, coronary artery diseases, rheumatoid arthritis, cancer, and pregnancy disorders and has been shown to be involved in disease pathogenesis. This review discusses our current understanding of the role and actions of galectin-2 in regulation of these pathophysiological conditions.
Subject(s)
Arthritis, Rheumatoid , Neoplasms , Pregnancy , Female , Humans , Galectin 2/genetics , Galectins , Neoplasms/metabolism , Placenta/metabolismABSTRACT
The findings regarding the associations between red meat, fish and poultry consumption, and the metabolic syndrome (Mets) have been inconclusive, and evidence from Chinese populations is scarce. A cross-sectional study was performed to investigate the associations between red meat, fish and poultry consumption, and the prevalence of the Mets and its components among the residents of Suzhou Industrial Park, Suzhou, China. A total of 4424 participants were eligible for the analysis. A logistic regression model was used to estimate the OR and 95 % CI for the prevalence of the Mets and its components according to red meat, fish and poultry consumption. In addition, the data of our cross-sectional study were meta-analysed under a random effects model along with those of published observational studies to generate the summary relative risks (RR) of the associations between the highest v. lowest categories of red meat, fish and poultry consumption and the Mets and its components. In the cross-sectional study, the multivariable-adjusted OR for the highest v. lowest quartiles of consumption was 1·23 (95 % CI 1·02, 1·48) for red meat, 0·83 (95 % CI 0·72, 0·97) for fish and 0·93 (95 % CI 0·74, 1·18) for poultry. In the meta-analysis, the pooled RR for the highest v. lowest categories of consumption was 1·20 (95 % CI 1·06, 1·35) for red meat, 0·88 (95 % CI 0·81, 0·96) for fish and 0·97 (95 % CI 0·85, 1·10) for poultry. The findings of both cross-sectional studies and meta-analyses indicated that the association between fish consumption and the Mets may be partly driven by the inverse association of fish consumption with elevated TAG and reduced HDL-cholesterol and, to a lesser extent, fasting plasma glucose. No clear pattern of associations was observed between red meat or poultry consumption and the components of the Mets. The current findings add weight to the evidence that the Mets may be positively associated with red meat consumption, inversely associated with fish consumption and neutrally associated with poultry consumption.
Subject(s)
Metabolic Syndrome , Red Meat , Animals , Cross-Sectional Studies , Fishes , Humans , Meat , Metabolic Syndrome/epidemiology , Metabolic Syndrome/etiology , Observational Studies as Topic , Poultry , Risk FactorsABSTRACT
C1GalT1 (T-synthase) is one of the key glycosyltransferases in the biosynthesis of O-linked mucin-type glycans of glycoproteins. It controls the formation of Core-1 disaccharide Galß1,3GalNAcα- (Thomsen-Friedenreich oncofetal antigen, T or TF antigen) and Core-1-associated carbohydrate structures. Recent studies have shown that C1GalT1 is overexpressed in many cancers of epithelial origin including colon, breast, gastric, head and neck, pancreatic, esophageal, prostate, and hepatocellular cancer. Overexpression of C1GalT1 is often seen to also be associated with poorer prognosis and poorer patient survival. Change of C1GalT1 expression causes glycosylation changes of many cell membrane glycoproteins including mucin proteins, growth factor receptors, adhesion molecules, and death receptors. This leads to alteration of the interactions of these cell surface molecules with their binding ligands, resulting in changes of cancer cell activity and behaviors. This review summarizes our current understanding of the expression of C1GalT1 in various cancers and discusses the impact of C1GalT change on cancer cell activities in cancer development and progression.
ABSTRACT
BACKGROUND: Coronavirus disease 2019 (COVID-19) is a huge challenge worldwide. Although previous studies have suggested that type I interferon (IFN-I) could inhibit the virus replication, the expression characteristics of IFN-I signaling-related miRNAs (ISR-miRNAs) during acute severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and its relationship with receptor-binding domain (RBD) IgG antibody response at the recovery phase remain unclear. METHODS: Expression profiles of 12 plasma ISR-miRNAs in COVID-19 patients and healthy controls were analyzed using RT-qPCR. The level of RBD-IgG antibody was determined using the competitive ELISA. Spearman correlation was done to measure the associations of plasma ISR-miRNAs with clinical characteristics during acute SARS-CoV-2 infection and RBD-IgG antibody response at the recovery phase. RESULTS: Compared with the healthy controls, COVID-19 patients exhibited higher levels of miR-29b-3p (Z = 3.15, P = 0.002) and miR-1246 (Z = 4.98, P < 0.001). However, the expression of miR-186-5p and miR-15a-5p were significantly decreased. As the results shown, miR-30b-5p was negatively correlated with CD4 + T cell counts (r = - 0.41, P = 0.027) and marginally positively correlated with fasting plasma glucose in COVID-19 patients (r = 0.37, P = 0.052). The competitive ELISA analysis showed the plasma level of miR-497-5p at the acute phase was positively correlated with RBD-IgG antibody response (r = 0.48, P = 0.038). CONCLUSIONS: Our present results suggested that the expression level of ISR-miRNAs was not only associated with acute SARS-CoV-2 infection but also with RBD-IgG antibody response at the recovery phase of COVID-19. Future studies should be performed to explore the biological significance of ISR-miRNAs in SARS-CoV-2 infection.
Subject(s)
Antibodies, Viral/immunology , COVID-19/diagnosis , Immunoglobulin G/immunology , Interferon Type I/genetics , MicroRNAs , Virus Replication/genetics , COVID-19/blood , COVID-19 Nucleic Acid Testing , Case-Control Studies , Enzyme-Linked Immunosorbent Assay/methods , Female , Humans , Immunoglobulin G/blood , Interferon Type I/blood , Male , MicroRNAs/blood , MicroRNAs/genetics , MicroRNAs/metabolism , Middle Aged , SARS-CoV-2ABSTRACT
BACKGROUND: High blood pressure during pregnancy has been suggested to be associated with adverse birth outcomes (ABO), but it is unclear how different blood pressure changes and the extent of the effect. Therefore, we aimed to investigate the association between blood pressure trajectories (systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), pulse pressure (PP)) of pregnant women and ABO in a real-world study. MATERIAL AND METHODS: Leveraging 28,679 pregnant women and their fetuses from a register-based cohort from January 1, 2010, to December 31, 2019. Blood pressure trajectories were estimated by package "traj" in R software using real-world blood pressure data of routine antenatal care examinations. Logistic regression models were applied to examine the association between trajectories of different blood pressure components (SBP, DBP, MAP, and PP) during pregnancy and the risk of ABO. RESULTS: Trajectories of all blood pressure components were identically labeled as low-stable, moderate-increasing, moderate-decreasing and high-stable. After adjusting for confounding factors, compared with pregnant women with the low-stable pattern, pregnant women with a high-stable or moderate-increasing pattern had a significantly increased risk of developing adverse birth outcomes. Pregnant women with a moderate-decreasing pattern had no significant increased risk of ABO but had a lower risk of adverse birth outcomes than those with a moderate-increasing pattern. The trajectories crossed at 17-20 weeks of gestation for all blood pressure components. CONCLUSION: Our study results indicated that reduction and maintenance of blood pressure to a low level of less than 110 mmHg for SBP and 65 mmHg for DBP after 20 weeks of gestation would benefit prevention of adverse birth outcomes, regardless of the level of blood pressure at early pregnancy.
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Peanut agglutinin (PNA) is a carbohydrate-binding protein in peanuts that accounts for ~0.15% peanut weight. PNA is highly resistant to cooking and digestion and is rapidly detectable in the blood after peanut consumption. Our previous studies have shown that circulating PNA mimics the actions of endogenous galactoside-binding protein galectin-3 by interaction with tumour cell-associated MUC1 and promotes circulating tumour cell metastatic spreading. The present study shows that circulating PNA interacts with micro- as well as macro-vascular endothelial cells and induces endothelial secretion of cytokines MCP-1 (CCL2) and IL-6 in vitro and in vivo. The increased secretion of these cytokines autocrinely/paracrinely enhances the expression of endothelial cell surface adhesion molecules including integrins, VCAM and selectin, leading to increased tumour cell-endothelial adhesion and endothelial tubule formation. Binding of PNA to endothelial surface MCAM (CD146), via N-linked glycans, and subsequent activation of PI3K-AKT-PREAS40 signalling is here shown responsible for PNA-induced secretion of MCP-1 and IL-6 by vascular endothelium. Thus, in addition to its influence on promoting tumour cell spreading by interaction with tumour cell-associated MUC1, circulating PNA might also influence metastasis by enhancing the secretion of metastasis-promoting MCP-1 and IL-6 from the vascular endothelium.
Subject(s)
Arachis , Cytokines/metabolism , Neoplasm Metastasis/pathology , Peanut Agglutinin/blood , Animals , Cell Adhesion Molecules/metabolism , Cells, Cultured , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Female , Humans , Inflammation Mediators/metabolism , Mice , Mice, Inbred BALB C , Mucin-1/metabolism , Peanut Agglutinin/pharmacology , Signal TransductionABSTRACT
Dietary factors play a crucial role in the management of type 2 diabetes mellitus (T2DM) by reducing cardiovascular disease (CVD) risk. Therefore, we aimed to examine the associations between habitual green tea consumption and risk factors of CVD among T2DM patients. A total of 1013 patients with T2DM were included in a community-based cross-sectional study. Data on dietary habits, including tea consumption, were collected using a food frequency questionnaire. A multivariable logistic regression model was used to analyze the associations. In men, as compared with nongreen tea drinkers, odds ratios (ORs) (95% confidence interval [CI]) of nonalcoholic fatty liver disease (NAFLD) were 2.06 (95% CI, 1.20-3.55) for those with green tea consumption of once per day and 2.45 (95% CI, 1.31-4.58) for more than or equal to twice per day (P-trend = .004); ORs (95% CI) of general obesity were 2.19 (95% CI, 1.02-4.68) and 2.70 (95% CI, 1.18-6.21), respectively (P-trend = .021); whereas no such association was found in women. Sensitivity analysis according to self-awareness of their T2DM status revealed that the positive association between green tea consumption and general obesity was not reliable. Higher intake of green tea was still positively associated with NAFLD, but it only persisted in participants aged ≥52 years or the lower dietary quality subgroup in further analyses. Our findings suggest that tea consumption was associated with an increased risk of NAFLD among male T2DM patients aged 52 years or older, and those with lower dietary quality, which needs to be confirmed in future prospective studies.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Non-alcoholic Fatty Liver Disease , Tea/chemistry , Cardiovascular Diseases/epidemiology , China/epidemiology , Cross-Sectional Studies , Diabetes Mellitus, Type 2/epidemiology , Female , Heart Disease Risk Factors , Humans , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/epidemiology , Prospective StudiesABSTRACT
Tumor-associated macrophages (TAMs) have been shown to be associated with poor prognosis of cancer and are predominately localized in the hypoxia regions of tumor. We demonstrated in this study that hypoxia increases the synthesis and secretion of galectin-3 by TAMs. The increased expression of galectin-3 in TAMs was seen to be associated with nucleation of transcription factor NF-κB through generation and activation of ROS and promoted tumor growth and metastasis in vitro and in mice through multiple molecular mechanisms. It was found that the TAMs-mediated promotion of tumor growth and metastasis in hypoxia was inhibited by administration of macrophage-depletion agent clodronate liposomal (CL) or galectin-3 inhibitor modified citric pectin (MCP) in orthotopic syngeneic mammary adenocarcinoma model and metastasis model. Co-administration of anti-angiogenesis agent sorafenib or bevacizumab with CL and MCP showed to cause stronger inhibition of tumor growth and metastasis than administration of each agent alone. These results indicate that hypoxia-induced galectin-3 expression and secretion from TAMs promotes tumor growth and metastasis. Targeting the actions of galectin-3 in hypoxia may be a potential therapeutic strategy for cancer treatment.
Subject(s)
Adenocarcinoma/drug therapy , Bevacizumab/pharmacology , Breast Neoplasms/drug therapy , Galectin 3/antagonists & inhibitors , Gene Expression Regulation, Neoplastic , Hypoxia/drug therapy , Mammary Neoplasms, Experimental/drug therapy , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Animals , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Clodronic Acid/pharmacology , Coculture Techniques , Disease Progression , Female , Galectin 3/genetics , Galectin 3/metabolism , Humans , Hypoxia/genetics , Hypoxia/metabolism , Hypoxia/pathology , Lymphatic Metastasis , Macrophages/drug effects , Macrophages/metabolism , Macrophages/pathology , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , NF-kappa B/genetics , NF-kappa B/metabolism , Neovascularization, Pathologic , Pectins/pharmacology , Signal Transduction , Sorafenib/pharmacologyABSTRACT
Angiogenesis and vasculogenic mimicry (VM) are the main causes of tumor metastasis and recurrence. In this study, we investigated the antiangiogenesis and anti-VM formation of a novel microtubule depolymerizing agent, DHPAC, as well as combretastatin A4 (CA4, a combretastatin derivate) in non-small-cell lung cancer (NSCLC), subsequently elucidating the underlying mechanisms. In human umbilical vein endothelial cells (HUVECs), DHPAC could enter cells and inhibit proliferation, migration, and angiogenesis in the presence and absence of conditioned medium from H1299 cells. Interestingly, the inhibition was enhanced under the stimulation of the conditioned medium. Under hypoxia or normoxia, DHPAC suppressed signal transducer and activator of transcription 3 phosphorylation and reduced vascular endothelial growth factor (VEGF) expression and secretion from HUVECs, thus impeding the activation of the downstream signal transduction pathway of VEGF/VEGFR2. However, JNK inhibitors reversed the inhibitory effect of DHPAC on the angiogenesis, suggesting that DHPAC regulated angiogenesis through activating JNK. In H1299 cells, DHPAC could inhibit proliferation, migration, invasion, and the formation of VM. In addition, DHPAC inhibited the phosphorylation of FAK and AKT and decreased the expressions of VEGF, matrix metalloproteinase 2 (MMP2), MMP9 and Laminin 5, suggesting that DHPAC inhibited VM formation via the FAK/AKT signaling pathway. In addition, CA4 showed a similar effect as DHPAC against angiogenesis and VM formation. These new findings support the use of microtubule destabilizing agents as a promising strategy for cancer therapy.
ABSTRACT
The inflammatory bowel diseases (IBD), which include mainly Crohn's disease (CD) and ulcerative colitis (UC), are common chronic inflammatory conditions of the digestive system. The diagnosis of IBD relies on the use of a combination of factors including symptoms, endoscopy and levels of serum proteins such as C-reactive protein (CRP) or faecal calprotectin. Currently there is no single reliable biomarker to determine IBD. Galectins are a family of galactoside-binding proteins that are commonly altered in the circulation of disease conditions such as cancer and inflammation. This study investigated serum galectin levels as possible biomarkers in determining IBD and IBD disease activity. Levels of galectins-1, -2, -3, -4, -7 and -8 were analysed in 208 samples from ambulant IBD patients (97 CD, 71 UC) patients and 40 from healthy people. Disease activity was assessed using Harvey-Bradshaw Index for CD and simple clinical colitis activity index for UC. The relationship of each galectin in determining IBD and IBD disease activity were analysed and compared with current IBD biomarker CRP. It was found that serum level of galectin-1 and -3, but not galectins-2, -4, -7 and -8, were significantly higher in IBD patients than in healthy people. At cut-off of 4.1ng/ml, galectin-1 differentiated IBD from healthy controls with 71% sensitivity and 87% specificity. At cut-off of 38.5ng/ml, galectin-3 separated IBD from healthy controls with 53% sensitivity and 87% specificity. None of the galectins however were able to distinguish active disease from remission in UC or CD. Thus, levels of galectins-1 and -3 are significantly elevated in both UC and CD patients compared to healthy people. Although the increased galectin levels are not able to separate active and inactive UC and CD, they may have the potential to be developed as useful biomarkers for IBD diagnosis either alone or in combination with other biomarkers.
Subject(s)
Colitis, Ulcerative/blood , Crohn Disease/blood , Galectin 1/blood , Galectin 3/blood , Adult , Biomarkers/blood , Blood Proteins , C-Reactive Protein/metabolism , Colitis, Ulcerative/pathology , Crohn Disease/pathology , Female , Galectins/blood , Gastrointestinal Tract/metabolism , Gastrointestinal Tract/pathology , Humans , Inflammatory Bowel Diseases/blood , Inflammatory Bowel Diseases/pathology , Male , Middle AgedABSTRACT
The association between milk consumption and the metabolic syndrome remains inconclusive, and data from Chinese populations are scarce. We conducted a cross-sectional study to investigate the association between milk consumption and the metabolic syndrome and its components among the residents of Suzhou Industrial Park, Suzhou, China. A total of 5149 participants were included in the final analysis. A logistic regression model was applied to estimate the OR and 95 % CI for the prevalence of the metabolic syndrome and its components according to milk consumption. In addition, the results of our study were further meta-analysed with other published observational studies to quantify the association between the highest v. lowest categories of milk consumption and the metabolic syndrome and its components. There was no significant difference in the odds of having the metabolic syndrome between milk consumers and non-milk consumers (OR 0·86, 95 % CI 0·73, 1·01). However, milk consumers had lower odds of having elevated waist circumference (OR 0·78, 95 % CI 0·67, 0·92), elevated TAG (OR 0·83, 95 % CI 0·70, 0·99) and elevated blood pressure (OR 0·85, 95 % CI 0·73, 0·99). When the results were pooled together with other published studies, higher milk consumption was inversely associated with the risk of the metabolic syndrome (relative risk 0·80, 95 % CI 0·72, 0·88) and its components (except elevated fasting blood glucose); however, these results should be treated with caution as high heterogeneity was observed. In summary, the currently available evidence from observational studies suggests that higher milk consumption may be inversely associated with the metabolic syndrome.
Subject(s)
Diet/adverse effects , Metabolic Syndrome/epidemiology , Metabolic Syndrome/etiology , Milk , Adult , Animals , China/epidemiology , Cross-Sectional Studies , Female , Humans , Male , Middle AgedABSTRACT
The ß-galactoside-binding protein, galectin-3, is extensively involved in cancer development, progression and metastasis through multiple mechanisms. Inhibition of the galectin-3-mediated actions is increasingly considered as a promising therapeutic approach for cancer treatment. Our early studies have identified several novel galectin-3 binding inhibitors from chemical modification of the anticoagulant drug heparin. These heparin-derived galectin-3 binding inhibitors, which show no anticoagulant activity and bind to the galectin-3 canonical carbohydrate-binding site, induce galectin-3 conformational changes and inhibit galectin-3-mediated cancer cell adhesion, invasion and angiogenesis in vitro and reduce metastasis in mice. In this study, we determined the binding affinities of these heparin-derived ligands to galectin-3 using an isothermal titration calorimetry (ITC) ligand displacement approach. Such ITC experiments showed that the 2-de-O-sulphated, N-acetylated (compound E) and 6-de-O-sulphated, N-acetylated (F) heparin-derived ligands and their ultra-low molecular weight sub-fractions (E3 and F3) bind to galectin-3 with KD ranging from 0.96 to 1.32 mM.Differential scanning fluorimetry analysis revealed that, in contrast to the disaccharide ligand, N-acetyl-lactosamine, which binds to the fully folded form of galectin-3 and promotes galectin-3 thermal stability, the heparin-derived ligands preferentially bind to the unfolded state of galectin-3 and cause destabilization of the galectin-3 protein structure. These results provide molecular insights into the interaction of galectin-3 with the heparin-derived ligands and explain the previously demonstrated in vitro and in vivo effects of these binding inhibitors on galectin-3-mediated cancer cell behaviours.