ABSTRACT
Researchers have endeavored to identify the etiology of inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis. Though the pathogenesis of inflammatory bowel diseases remains unknown, dysregulation of the immune system in the host gastrointestinal tract is believed to be the major causative factor. Omics is a powerful methodological tool that can reveal biochemical information stored in clinical samples. Lipidomics is a subset of omics that explores the lipid classes associated with inflammation. One objective of the present systematic review was to facilitate the identification of biochemical targets for use in future lipidomic studies on inflammatory bowel diseases. The use of high-resolution mass spectrometry to observe alterations in global lipidomics might help elucidate the immunoregulatory mechanisms involved in inflammatory bowel diseases and discover novel biomarkers for them. Assessment of the characteristics of previous clinical trials on inflammatory bowel diseases could help researchers design and establish patient selection and analytical method criteria for future studies on these conditions. In this study, we curated literature exclusively from four databases and extracted lipidomics-related data from literature, considering criteria. This paper suggests that the lipidomics approach toward research in inflammatory bowel diseases can clarify their pathogenesis and identify clinically valuable biomarkers to predict and monitor their progression.
ABSTRACT
Lipids, which along with carbohydrates and proteins are among the most important nutrients for the living organism, have a variety of biological functions that can be applied widely in biomedicine. A fatty acid, the most fundamental biological lipid, may be classified by length of its aliphatic chain, and the short-, medium-, and long-chain fatty acids and each have distinct biological activities with therapeutic relevance. For example, short-chain fatty acids have immune regulatory activities and could be useful against autoimmune disease; medium-chain fatty acids generate ketogenic metabolites and may be used to control seizure; and some metabolites oxidized from long-chain fatty acids could be used to treat metabolic disorders. Glycerolipids play important roles in pathological environments, such as those of cancers or metabolic disorders, and thus are regarded as a potential therapeutic target. Phospholipids represent the main building unit of the plasma membrane of cells, and play key roles in cellular signaling. Due to their physical properties, glycerophospholipids are frequently used as pharmaceutical ingredients, in addition to being potential novel drug targets for treating disease. Sphingolipids, which comprise another component of the plasma membrane, have their own distinct biological functions and have been investigated in nanotechnological applications such as drug delivery systems. Saccharolipids, which are derived from bacteria, have endotoxin effects that stimulate the immune system. Chemically modified saccharolipids might be useful for cancer immunotherapy or as vaccine adjuvants. This review will address the important biological function of several key lipids and offer critical insights into their potential therapeutic applications.
ABSTRACT
Lipids, which along with carbohydrates and proteins are among the most important nutrients for the living organism, have a variety of biological functions that can be applied widely in biomedicine. A fatty acid, the most fundamental biological lipid, may be classified by length of its aliphatic chain, and the short-, medium-, and long-chain fatty acids and each have distinct biological activities with therapeutic relevance. For example, short-chain fatty acids have immune regulatory activities and could be useful against autoimmune disease; medium-chain fatty acids generate ketogenic metabolites and may be used to control seizure; and some metabolites oxidized from long-chain fatty acids could be used to treat metabolic disorders. Glycerolipids play important roles in pathological environments, such as those of cancers or metabolic disorders, and thus are regarded as a potential therapeutic target. Phospholipids represent the main building unit of the plasma membrane of cells, and play key roles in cellular signaling. Due to their physical properties, glycerophospholipids are frequently used as pharmaceutical ingredients, in addition to being potential novel drug targets for treating disease. Sphingolipids, which comprise another component of the plasma membrane, have their own distinct biological functions and have been investigated in nanotechnological applications such as drug delivery systems. Saccharolipids, which are derived from bacteria, have endotoxin effects that stimulate the immune system. Chemically modified saccharolipids might be useful for cancer immunotherapy or as vaccine adjuvants. This review will address the important biological function of several key lipids and offer critical insights into their potential therapeutic applications.
ABSTRACT
Cell membranes have recently emerged as a new source of materials for molecular delivery systems. Cell membranes have been extruded or sonicated to make nanoscale vesicles. Unlike synthetic lipid or polymeric nanoparticles, cell membrane-derived vesicles have a unique multicomponent feature, comprising lipids, proteins, and carbohydrates. Because cell membrane-derived vesicles contain the intrinsic functionalities and signaling networks of their parent cells, they can overcome various obstacles encountered
ABSTRACT
Conjugation of antibodies to nanoparticles allows specific cancer targeting, but conventional conjugation methods generate heterogeneous conjugations that cannot guarantee the optimal orientation and functionality of the conjugated antibody. Here, a molecular engineering technique was used for site-specific conjugation of antibodies to nanoparticles. We designed an anti-claudin 3 (CLDN3) antibody containing a single cysteine residue, h4G3cys, then linked it to the maleimide group of lipid polydopamine hybrid nanoparticles (LPNs). Because of their negatively charged lipid coating, LPNs showed high colloidal stability and provided a functional surface for site-specific conjugation of h4G3cys. The activity of h4G3cys was tested by measuring the binding of h4G3cys-conjugated LPNs (C-LPNs) to CLDN3-positive tumor cells and assessing its subsequent photothermal effects. C-LPNsspecifically recognized CLDN3-overexpressing T47D breast cancer cells but not CLDN3-negative Hs578T breast cancer cells. High binding of C-LPNs to CLDN3-overexpressing T47D cells resulted in significantly higher temperature generation upon NIR irradiation and potent anticancer photothermal efficacy. Consistent with this, intravenous injection of C-LPNsin a T47D xenograft mouse model followed by NIR irradiation caused remarkable tumor ablation compared with other treatments through high temperature increases. Our results establish an accurate antibody-linking method and demonstrate the possibility of developing therapeutics using antibody-guided nanoparticles.
ABSTRACT
The safety of nanomaterials, a crucial consideration for clinical translation, is enhanced by using building blocks that are biologically nontoxic. Here, we used poly(-glutamic acid) (-PGA) and dopamine as building blocks of polymeric nanomaterials for carrying hydrophobic anticancer drugs. The introduction of phenylalanine onto -PGA enabled the resulting amphiphilic derivative of -PGA acid to self-assemble in the presence of the anticancer drug paclitaxel (PTX) to form PTX-encapsulated micelles. The surfaces of PTX-loaded micelles were then coated with polymerized dopamine (PDA). The PDA-coated, amphiphilic -PGA-based micelles (AM) carrying PTX (PDA/AM/P) exerted near-infrared-responsive photothermal effects. Near-infrared irradiation of cancer cells treated with PDA/AM/P nanoparticles produced a greater anticancer effect than that observed in other treatment groups, indicating a synergistic effect. Intravenous administration of PDA/AM/P completely ablated tumors and prevented their recurrence. Notably, the safety profile of PDA/AM/P nanoparticles allowed PTX to be delivered at a 3.6-fold higher dose than was possible with PTX solubilized in surfactant, and circumvented the side effects of the surfactant. These results support the multifunctional potential of PDA/AM for the delivery of various hydrophobic drugs and imaging dyes for safe translation of nanomaterials into the clinic.
ABSTRACT
Helicobacter pylori-infected gastric mucosa is characterized by infiltration of various inflammatory cells such as neutrophils and eosinophils. Although several mechanisms for neutrophil infiltration are well known, there has been little known the role of eotaxin, which is a potent chemoattractant for eosinophils, on the inflammatory process of H. pylori infection. The present study was to investigate the mechanisms of eotaxin expression in gastric epithelial cells stimulated with H. pylori vacuolating cytotoxin (VacA). Stimulation with VacA purified from VacA+ H. pylori slightly increased eotaxin expression in MKN-45 gastric epithelial cells. In contrast, the combined stimulation with VacA and IL-4 synergistically increased the eotaxin expression as determined by quantitative RT-PCR and ELISA. In MKN-45 cells transfected with an eotaxin promoter-luciferase reporter plasmid, costimulation with VacA and IL-4 induced more luciferase activity than either VacA or IL-4 alone did. However, such up-regulation was significantly decreased in the cells transfected with luciferase reporter plasmid bearing an eotaxin promoter which has a mutation at STAT6 binding site. These results suggest that the up-regulation of eotaxin in VacA-stimulated gastric epithelial cells may be synergistically facilitated by IL-4 via a STAT6-dependent mechanism.
Subject(s)
Binding Sites , Enzyme-Linked Immunosorbent Assay , Eosinophils , Epithelial Cells , Gastric Mucosa , Helicobacter pylori , Helicobacter , Interleukin-4 , Luciferases , Neutrophil Infiltration , Neutrophils , Plasmids , Up-RegulationABSTRACT
Helicobacter pylori-infected gastric mucosa is characterized by infiltration of various inflammatory cells such as neutrophils and eosinophils. Although several mechanisms for neutrophil infiltration are well known, there has been little known the role of eotaxin, which is a potent chemoattractant for eosinophils, on the inflammatory process of H. pylori infection. The present study was to investigate the mechanisms of eotaxin expression in gastric epithelial cells stimulated with H. pylori vacuolating cytotoxin (VacA). Stimulation with VacA purified from VacA+ H. pylori slightly increased eotaxin expression in MKN-45 gastric epithelial cells. In contrast, the combined stimulation with VacA and IL-4 synergistically increased the eotaxin expression as determined by quantitative RT-PCR and ELISA. In MKN-45 cells transfected with an eotaxin promoter-luciferase reporter plasmid, costimulation with VacA and IL-4 induced more luciferase activity than either VacA or IL-4 alone did. However, such up-regulation was significantly decreased in the cells transfected with luciferase reporter plasmid bearing an eotaxin promoter which has a mutation at STAT6 binding site. These results suggest that the up-regulation of eotaxin in VacA-stimulated gastric epithelial cells may be synergistically facilitated by IL-4 via a STAT6-dependent mechanism.
Subject(s)
Binding Sites , Enzyme-Linked Immunosorbent Assay , Eosinophils , Epithelial Cells , Gastric Mucosa , Helicobacter pylori , Helicobacter , Interleukin-4 , Luciferases , Neutrophil Infiltration , Neutrophils , Plasmids , Up-RegulationABSTRACT
A 20 kDa heat-labile toxin (BFT) produced by enterotoxigenic Bacteroides fragilis (B. fragilis) is associated with diarrhea and mucosal inflammation. Although intestinal epithelial cells are known to activate mitogen-activated protein kinase (MAPK) in response to bacterial infection, there has been little understanding on the association between MAPK activation and BFT-induced enteritis. This study was performed to investigate the role of MAPK in enteritis induced by BFT. In human colon epithelial cells, BFT increased IL-8 secretion in a dose-dependent manner. BFT activated the three main MAPK cascades, including extracellular signal-regulated kinase (ERK), p38, and c-Jun NH2-terminal kinase (JNK). BFT stimulation also activated AP-1 activation signals. Overexpression of dominant-negative plasmid of the c-Jun decreased the activated AP-1 signals and the up-regulated IL-8 expression induced by BFT stimulation. In addition, SB203580 and ERK inhibitor U0126 significantly reduced IL-8 secretion in colon epithelial cells stimulated with BFT. Furthermore, SB203580 significantly prevented BFT-induced severity of enteritis and fluid secretion in mouse ileum. These results suggest that MAPK activation may be required for IL-8 transcription in intestinal epithelial cells exposed to BFT and that the activated MAPK can mediate intestinal inflammation and mucosal damage induced by BFT.
Subject(s)
Animals , Humans , Mice , Bacterial Infections , Bacteroides fragilis , Bacteroides , Colon , Diarrhea , Enteritis , Enterotoxins , Epithelial Cells , Ileum , Inflammation , Interleukin-8 , Phosphotransferases , Plasmids , Protein Kinases , Transcription Factor AP-1ABSTRACT
A ~20 kDa heat-labile toxin (BFT) produced by enterotoxigenic B. fragilis induces chemokine responses that are associated with mucosal inflammation. In the present study, we assessed whether the activation of mitogen-activated protein kinase (MAPK) affects the levels of IL-8 and MCP-1 produced by BFT stimulation in human epithelial HT-29 cells. Human intestinal epithelial HT-29 cell lines were incubated with purified BFT. MAPK and AP-1 in HT-29 cells were measured by Western blot and luciferase assay, respectively. The expression of chemokines such as IL-8 and MCP-1 were determined by quantitative RT-PCR, ELISA, and luciferase assay. BFT stimulation activated MAPK such as ERK1/2 and p38 in HT-29 cells. Treatment with MAPK inhibitors attenuated BFT-induced expression of IL-8 and MCP-1. Transfection with mutant genes for Ras or c-Jun did not only suppressed AP-1 reporter genes, but also inhibited BFT-induced expression of IL-8 and MCP-1 reporter genes. These results suggest that Ras and MAPK cascade may act as the upstream signaling for the activation of AP-1, which induce chemokine expression in BFT-stimulated intestinal epithelial cells.
Subject(s)
Humans , Bacteroides fragilis , Bacteroides , Blotting, Western , Chemokines , Enterotoxins , Enzyme-Linked Immunosorbent Assay , Epithelial Cells , Genes, Reporter , HT29 Cells , Inflammation , Interleukin-8 , Luciferases , Phosphotransferases , Protein Kinases , Transcription Factor AP-1 , TransfectionABSTRACT
PURPOSE: The biallelic expression of insulin-like growth factor-II (IGF2) and H19 has been reported to be associated with the progression of several tumors. Here, the promoter usage and expression levels of IGF2 and H19 are reported to be altered in cervical and endometrial cancers showing loss of imprinting (LOI). MATERIALS AND METHODS: The imprinting status of IGF2 and H19 was examined in 32 cervical carcinomas, their matched normal tissues, 13 endometrial cancer and 33 normal endometrial tissues. RESULTS: The LOI of IGF2 was observed in 7 of 18 (39%) and 1 of 13 (8.3%) informative cervical carcinomas and informative endometrial cancers, respectively. The LOI of the H19 gene was detected in 5 of 14 (36%) and in all 11 (100%) informative cervical carcinoma cases and informative endometrial cancer cases, respectively. The use of promoter P1 was observed in the LOI tumors of IGF2, but not in the tumors showing maintenance of IGF2 imprinting (MOI), or in cervical and endometrial cancers. Unlike MOI tumors, some LOI tumors revealed a lack of IGF2 transcription from the promoter P3. The LOI tumors of IGF2 showed increased expression of the IGF2 level, but a down-regulation of the H19, relative to normal tissues, whereas the MOI tumors revealed no significant alterations. CONCLUSION: These results suggest that the promoter P1 could be involved in the biallelic expression of IGF2, and that the altered expression of the IGF2 and H19 levels might be associated with the progression of cervical and endometrial cancers that exhibit biallelic IGF2 expression.
Subject(s)
Female , Down-Regulation , Endometrial Neoplasms , Uterine Cervical NeoplasmsABSTRACT
OBJECTIVE: We investigated the expression of chemokine receptors in human ovarian cancer to understand the role of chemokines in ovarian cancer development and metastasis. METHODS: Twenty-two cases of epithelial ovarian cancer were studied for expression of 13 chemokine receptors such as CXCR1-CXCR5 and CCR1-CCR8 by using semi- quantitative RT-PCR and immunohistochemistry. Moreover, we studied the relationship between the chemokine receptors expression and lymph nodes metastasis of ovarian cancers. RESULTS: As compared with normal ovarian tissues, ovarian cancer tissues showed higher mean expression levels of CCR1,3,4,5,7,8 and CXCR1,3,4. Of chemokine receptors, CCR7 revealed the significantly higher levels of expression in ovarian cancer tissues relative to normal tissues. In the cases of retroperitoneal lymph nodes metastasis, increased expression of CCR2,4 and CXCR 1,3,4 was observed although there was no statistical significance. CONCLUSION: These results suggest that there is a complex chemokine/chemokine receptor network in pathogenesis and the way of lymph node metastasis of ovarian cancer rather than a specific chemokine or chemokine receptor.
Subject(s)
Humans , Chemokines , Immunohistochemistry , Lymph Nodes , Neoplasm Metastasis , Ovarian Neoplasms , Receptors, ChemokineABSTRACT
A ~20 kDa heat-labile toxin (BFT) produced by enterotoxigenic B. fragilis induces chemokine responses that may be associated with mucosal inflammation. To determine whether epithelial cells can contribute to BFT-induced inflammation, we assessed the expression of cyclooxygenase (COX)-2 in BFT-stimulated human intestinal epithelial cells. Human intestinal epithelial cell lines, HT-29 and Caco-2, were incubated with purified BFT. COX-2 mRNA and protein expression were measured by quantitative RT-PCR and Western blot analysis, respectively. BFT increased expression of COX-2, not that of COX-1, in human intestinal epithelial cell lines. Up-regulated COX-2 expression was paralleled by increased prostaglandin E2 (PGE2) production measured by the radioimmunoassay. PGE2 was predominantly secreted from the basolateral surface of BFT-treated epithelial cells, whereas lactate dehydrogenase was released predominantly from the apical surface. Moreover, the COX-2 expression and PGE2 production were significantly suppressed when NF-kappaB activity was inhibited. The basolateral secretion of PGE2 by up-regulated COX-2 in the BFT-stimulated colon epithelial cells seems to contribute to the inflammatory response in the underlying intestinal mucosa.
Subject(s)
Humans , Bacteroides fragilis , Bacteroides , Blotting, Western , Colon , Cyclooxygenase 2 , Dinoprostone , Enterotoxins , Epithelial Cells , Inflammation , Intestinal Mucosa , L-Lactate Dehydrogenase , NF-kappa B , Prostaglandin-Endoperoxide Synthases , Radioimmunoassay , RNA, MessengerABSTRACT
Telomeres are the ends of the linear chromosomes of eukaryotes and consist of tandem GT-rich repeats in telomere sequence i.e. 500-3000 repeats of 5'-TTAGGG-3' in human somatic cells, which are shortened gradually with age. The G-rich overhang of telomere sequence can adopt different intramolecular fold-backs and tetra-stranded DNA structures, in vitro, which inhibit telomerase activity. In this report, DNA binding agents to telomere sequence were studied novel therapeutic possibility to destabilize telomeric DNA sequences. Oligonucleotides containing the guanine repeats in human telomere sequence were synthesized and used for screening potential antitumor drugs. Telomeric DNA sequence was characterized using spectral measurements and CD spectroscopy. CD spectrum indicated that the double-stranded telomeric DNA is in a right-handed conformation. Polyacrylamide gel electrophoresis was performed for binding behaviors of antitumor compounds with telomeric DNA sequence. Drugs interacted with DNA sequence caused changes in the electrophoretic mobility and band intensity of the gels. Depending on the binding mode of the anticancer drugs, telomeric DNA sequence was differently recognized and the efficiency of cleavage of DNA varies in the bleomycin-treated samples under different conditions. DNA cleavage occurred at about 1% by the increments of 1 mM bleomycin-Fe(III). These results imply that the stability of human telomere sequence is important in conjunction with the cancer treatment and aging process.
Subject(s)
Humans , Antineoplastic Agents/metabolism , Bleomycin/metabolism , Circular Dichroism , Comparative Study , DNA/chemistry , DNA Damage , Dactinomycin/metabolism , Doxorubicin/analogs & derivatives , Nogalamycin/metabolism , Nucleic Acid Conformation , Repetitive Sequences, Nucleic Acid , Telomere/drug effectsABSTRACT
No abstract available.
Subject(s)
Humans , Bacteroides fragilis , Bacteroides , Enterotoxins , Epithelial Cells , Signal TransductionABSTRACT
No abstract available.
Subject(s)
Humans , Bacteroides fragilis , Bacteroides , Enterotoxins , Epithelial Cells , Gene Expression , Intestinal MucosaABSTRACT
No abstract available.
Subject(s)
Female , Humans , Endometriosis , Exons , Polycystic Ovary SyndromeABSTRACT
No Abstract Available.
Subject(s)
Humans , Bacteroides fragilis , Bacteroides , Chemokines, CXC , Enterotoxins , Epithelial Cells , NF-kappa BABSTRACT
No Abstract Available.