CEL
Bile salt-activated lipase precursor (EC 3.1.1.13) (EC 3.1.1.3) (EC 3.1.1.6) (BAL) (Bile salt-stimulated lipase) (BSSL) (Bucelipase) (Carboxyl ester lipase) (Cholesterol esterase) (Pancreatic lysophospholipase) (Sterol esterase) [BAL]
Publications[править]
In desmoplastic melanoma, tumor cells and tumor-associated fibroblasts are the major dominators playing a critical role in the fibrosis morphology as well as the immunosuppressive tumor microenvironment (TME), compromising the efficacy of therapeutic options. To overcome this therapeutic hurdle, we developed an innovative chemo-immunostrategy based on targeted delivery of mitoxantrone (MIT) and celastrol (CEL), two potent medicines screened and selected with the best anticancer and antifibrosis potentials. Importantly, CEL worked in synergy with MIT to induce immunogenic tumor cell death. Here, we show that when effectively co-delivered to the tumor site at their optimal ratio by a TME-responsive nanocarrier, the 5:1 combination of MIT and CEL significantly triggered immunogenic tumor apoptosis and recovered tumor antigen recognition, thus eliciting overall antitumor immunity. Furthermore, the strong synergy benefitted the host in reduced drug exposure and side effects. Collectively, the nanocarrier-mediated chemo-immunotherapy successfully remodeled fibrotic and immunosuppressive TME, arrested cancer progression, and further inhibited tumor metastasis to major organs. The affected tumors remained dormant long after dosing stopped, resulting in a prolonged progression-free survival and sustained immune surveillance of the host bearing desmoplastic melanoma.
MeSH Terms
- Animals
- Antineoplastic Agents
- Cell Death
- Cell Line, Tumor
- Cell Proliferation
- Disease Progression
- Drug Carriers
- Drug Delivery Systems
- Drug Screening Assays, Antitumor
- Immunosenescence
- Immunotherapy
- Melanoma
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mitoxantrone
- NIH 3T3 Cells
- Nanoparticles
- Skin Neoplasms
- Triterpenes
- Tumor Microenvironment
Keywords
- celastrol
- chemo-immunotherapy
- desmoplastic melanoma
- immunogenic cell death
- mitoxantrone
- tumor dormancy
- tumor microenvironment
Advanced Glycation Endproducts (AGEs) accumulate in long-lived tissue proteins like collagen in bone and tendon causing modification of the biomechanical properties. This has been hypothesized to raise the risk of orthopedic injury such as bone fractures and tendon ruptures. We evaluated the relationship between AGE content in the diet and accumulation of AGEs in weight-bearing animal Achilles tendon. Two groups of mice (C57BL/6Ntac) were fed with either high-fat diet low in AGEs high-fat diet (HFD) ([i]n[/i] = 14) or normal diet high in AGEs (ND) ([i]n[/i] = 11). AGE content in ND was six to 50-fold higher than HFD The mice were sacrificed at week 40 and Achilles and tail tendons were carefully excised to compare weight and nonweight-bearing tendons. The amount of the AGEs carboxymethyllysine (CML), methylglyoxal-derived hydroimidazolone (MG-H1) and carboxyethyllysine (CEL) in Achilles and tail tendon was measured using ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) and pentosidine with high-pressure liquid chromatography (HPLC) with fluorescent detection. AGEs in Achilles tendon were higher than in tail tendon for CML ([i]P[/i] < 0.0001), CEL ([i]P[/i] < 0.0001), MG-H1 and pentosidine (for both ND and HFD) ([i]P[/i] < 0.0001). The AGE-rich diet (ND) resulted in an increase in CML ([i]P[/i] < 0.0001), MG-H1 ([i]P[/i] < 0.001) and pentosidine ([i]P[/i] < 0.0001) but not CEL, in Achilles and tail tendon. This is the first study to provide evidence for AGE accumulation in injury-prone, weight-bearing Achilles tendon associated with intake of an AGE-rich diet. This indicates that food-derived AGEs may alter tendon properties and the development of tendon injuries.
MeSH Terms
- Achilles Tendon
- Animals
- Chromatography, Liquid
- Diet
- Diet, High-Fat
- Glycation End Products, Advanced
- Tail
- Tandem Mass Spectrometry
Keywords
- AGE‐rich diet
- Achilles tendon
- advanced glycation endproducts
- aging
Advanced glycation end products (AGEs) accumulate in the aging skin. To understand the biological effects of individual AGEs, skin reconstructed with collagen selectively enriched with N(ɛ)-(carboxymethyl)-lysine (CML), N(ɛ)-(carboxyethyl)-lysine (CEL), methylglyoxal hydroimidazolone (MG-H1), or pentosidine was studied. Immunohistochemistry revealed increased expression of α6 integrin at the dermal epidermal junction by CEL and CML (p<0.01). Laminin 5 was diminished by CEL and MG-H1 (p<0.05). Both CML and CEL induced a robust increase (p<0.01) in procollagen I. In the culture medium, IL-6, VEGF, and MMP1 secretion were significantly decreased (p<0.05) by MG-H1. While both CEL and CML decreased MMP3, only CEL decreased IL-6 and TIMP1, while CML stimulated TIMP1 synthesis significantly (p<0.05). mRNA expression studies using qPCR in the epidermis layer showed that CEL increased type 7 collagen (COL7A1), β1, and α6 integrin, while CML increased only COL7A1 (p<0.05). MG-H1-modified collagen had no effect. Importantly, in the dermis layer, MMP3 mRNA expression was increased by both CML and MG-H1. CML also significantly increased the mRNAs of MMP1, TIMP1, keratinocyte growth factor (KGF), IL-6, and monocyte chemoattractant protein 1 (MCP1) (p<0.05). Mixed effects were present in CEL-rich matrix. Minimally glycoxidized pentosidine-rich collagen suppressed most mRNAs of the genes studied (p<0.05) and decreased VEGF and increased MCP1 protein expression. Taken together, this model of the aging skin suggests that a combination of AGEs tends to counterbalance and thus minimizes the detrimental biological effects of individual AGEs.
Keywords
- aging
- extracellular matrix
- glucose
- glycation
- methylglyoxal
- oxoaldehydes
Previous experiments from our laboratory showed that the oral intake of selected guanidino compounds could block the formation of crystallin-bound advanced ascorbylation products. Here we tested whether these were also active when applied as eye drops. Two month old hSVCT2 transgenic mice (n=10) were treated twice daily with one drop of 0.1% L-arginine, γ-guanidinobutyric acid (GBA), penicillamine (PA) or N-acetylcysteine (NAC) in one eye and vehicle only in the other eye. After seven months, lens crystallins were isolated, dialyzed, and proteolytically digested to determine the protein-bound fluorescence at 335/385 and 370/440 nm excitation/emission and the advanced glycation/ascorbylation endproducts carboxymethyl-lysine (CML), carboxyethyl-lysine (CEL), glucosepane, glyoxal, and methylglyoxal hydroimidazolones G-H1 and MG-H1. The topical uptake of L-arginine and NAC was also evaluated in vitro and in vivo in rabbit lens. In hSVCT2 mice, L-arginine decreased 335/385 and 370/440 nm fluorescence by 40% (p<0.001), CML, CEL, and glucosepane crystallin crosslinks by 35% (p<0.05), 30% (p<0.05), and 37% (p<0.05), respectively, without affecting MG-H1 and G-H1. NAC decreased 335/385 nm fluorescence by 50% (p<0.001) but, like PA and GBA, had no effect on other modifications. L-Arginine uptake into rabbit eyes treated topically reached identical lenticular plateau levels (~400 nmol/g wet weight) at 0.5% and 2.0% but levels remained three times higher at 5 h at 2% versus 0.5% concentration, respectively. In vitro studies showed a 100 fold higher L-arginine level than NAC levels, implicating high affinity uptake of the former. L-Arginine when applied both orally and topically is a potent and broad suppressor of advanced ascorbylation in the lens. Its uptake in rabbit lens upon topical application suggests transcorneal uptake into the human lens should be feasible for testing its potential anticataract properties in clinical trials.
MeSH Terms
- Acetylcysteine
- Administration, Topical
- Aging
- Animals
- Arginine
- Ascorbic Acid
- Biological Transport, Active
- Cataract
- Crystallins
- Gene Knock-In Techniques
- Glycation End Products, Advanced
- Guanidines
- Humans
- Lens, Crystalline
- Mass Spectrometry
- Mice
- Mice, Transgenic
- Ophthalmic Solutions
- Penicillamine
- Rabbits
- Sodium-Coupled Vitamin C Transporters
- Spectrometry, Fluorescence
A trial was conducted to study the effects of type and particle size of dietary fiber on growth performance and digestive traits of broilers from 1 to 21 d of age. There was a negative control diet with 1.54% crude fiber, a positive control diet that included 3% cellulose (CEL), and 4 additional diets arranged factorially that included 3% oat hulls (OH) or sugar beet pulp (SBP) ground through a 0.5- or a 2.0-mm screen. For the entire experimental period, fiber inclusion improved BW gain (P≤0.01) and feed conversion ratio (P≤0.001), but particle size of the fiber source did not affect performance. The relative weight of the gizzard was higher (P≤0.001) with OH and SBP than with CEL or the control diet. Also, gizzard weight decreased (P≤0.001) with a reduction in particle size of the fiber source. Fiber inclusion increased HCl concentration and reduced gizzard pH (P≤0.01), and the effects were more noticeable with OH and SBP than with CEL. Fiber inclusion increased total tract apparent retention of nitrogen (P≤0.001) and soluble ash (P≤0.001) as well as the AMEn of the diet (P≤0.001). All of these effects were in general more pronounced with OH than with CEL, with SBP being intermediate. A reduction in particle size of the OH and SBP improved total tract apparent retention of DM (P≤0.001), nitrogen (P≤0.05), and soluble ash (P≤0.01) as well as the AMEn of the diet (P≤0.05). It is concluded that additional OH and SBP improves gizzard weight and growth performance in young chicks fed low-fiber diets and that the effects are more pronounced with OH than with CEL. Particle size of OH and SBP does not affect broiler performance, but coarse grinding increases gizzard development and reduces nutrient digestibility in young birds.
MeSH Terms
- Aging
- Animal Feed
- Animal Nutritional Physiological Phenomena
- Animals
- Chickens
- Diet
- Dietary Fiber
- Digestion
- Female
- Hydrogen-Ion Concentration
CEL-MODY is a monogenic form of diabetes and exocrine pancreatic insufficiency due to mutations in the carboxyl-ester lipase (CEL) gene. We aimed to investigate endocrine and exocrine pancreatic function in CEL knockout mice (CELKO). A knockout mouse model with global targeted deletion of CEL was investigated physiologically and histopathologically, and compared to littermate control CEL / mice at 7 and 12 months on normal chow and high-fat diets (HFD), i.e. 42 and 60% fat by calories. CELKO / and -/- mice showed normal growth and development and normal glucose metabolism on a chow diet. Female CEL-/- mice on 60% HFD, on the other hand, had increased random blood glucose compared to littermate controls (p = 0.02), and this was accompanied by a reduction in glucose tolerance that did not reach statistical significance. In these mice there was also islet hyperplasia, however, α- and β-islet cells appeared morphologically normal and pancreatic exocrine function was also normal. Although we observed mild glucose intolerance in female mice with whole-body knockout of CEL, the full phenotype of human CEL-MODY was not reproduced, suggesting that the pathogenic mechanisms involved are more complex than a simple loss of CEL function. and IAP.
MeSH Terms
- Animals
- Blood Glucose
- Disease Models, Animal
- Female
- Glucagon-Secreting Cells
- Glucose Tolerance Test
- Insulin-Secreting Cells
- Intestinal Absorption
- Islets of Langerhans
- Lipase
- Longevity
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Pancreas, Exocrine
- Weight Gain
The Virchow-Robin spaces (VRS), perivascular compartments surrounding small blood vessels as they penetrate the brain parenchyma, are increasingly recognized for their role in leucocyte trafficking as well as for their potential to modulate immune responses. In the present study, we investigated VRS numbers and volumes in different brain regions in 45 multiple sclerosis patients and 30 healthy controls of similar age and gender distribution, applying three different MRI sequence modalities (T(2)-weighted, T(1)-weighted and FLAIR). VRS were detected in comparable numbers in both multiple sclerosis patients and healthy individuals, indicating that perivascular compartments present on MRI are not a unique feature of multiple sclerosis. However, multiple sclerosis patients had significantly larger VRS volumes than healthy controls (P = 0.004). This finding was not explained by a significantly lower brain parenchymal fraction (BPF), resulting from a higher degree of atrophy, in the patient cohort. In a multiple linear regression analysis, age had a significant influence on VRS volumes in the control group but not in multiple sclerosis patients (P = 0.023 and P = 0.263, respectively). A subsequent prospective longitudinal substudy with monthly follow-up MRI over a period of up to 12 months in 18 patients revealed a significant increase in VRS volumes and counts accompanying the occurrence of contrast-enhancing lesions (CEL). At time points when blood-brain barrier (BBB) breakdown was indicated by the appearance of CEL, total VRS volumes and counts were significantly higher compared with preceding time points without CEL (P = 0.011 and P = 0.041, respectively), whereas a decrease thereafter was not statistically significant. Thus, our data points to an association of VRS with CEL as a sign for inflammation rather than with factors such as age, observed in healthy controls, and therefore suggests a role of VRS in inflammatory processes of the brain.
MeSH Terms
- Acute Disease
- Adult
- Aging
- Basal Ganglia
- Blood-Brain Barrier
- Brain
- Extracellular Space
- Female
- Humans
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Multiple Sclerosis, Relapsing-Remitting
- Prospective Studies
The epsilon-amino group of lysyl residues oxidatively deaminates in the presence of alpha-dicarbonyl sugars and redox-active metals forming alpha-aminoadipic acid-delta-semialdehyde (allysine; Suyama's hypothesis), which can further oxidize into 2-aminoadipic acid. Here we show that 2-aminoadipic acid is significantly (P < 0.05) correlated with 6-hydroxynorleucine, carboxyethyllysine (CEL), and carboxymethyllysine (CML) in human skin collagen. Since CEL and CML can originate from carbohydrate and lipid by oxidative decomposition and alpha-dicarbonyl formation, these results provide support for Suyama's hypothesis. Allysine, in turn, is readily converted by oxidation into 2-aminoadipic acid, which accumulates to high levels in skin (i.e., > 2 nmol/mg collagen).
MeSH Terms
- 2-Aminoadipic Acid
- Adolescent
- Adult
- Aging
- Child
- Child, Preschool
- Collagen
- Diabetes Mellitus
- Diabetic Nephropathies
- Humans
- Infant
- Infant, Newborn
- Lysine
- Middle Aged
- Oxidation-Reduction
- Skin
- Skin Aging
The present investigation studies the effect of aging, short-term and long-term caloric restriction on four different markers of oxidative, glycoxidative or lipoxidative damage to heart mitochondrial proteins: protein carbonyls (measured by ELISA); Nepsilon-(carboxyethyl)lysine (CEL), Nepsilon-(carboxymethyl)lysine (CML), and Nepsilon-(malondialdehyde)lysine (MDA-lys) measured by gas chromatography/mass spectrometry. Aging increased the steady state level of CML in rat heart mitochondria without changing the levels of the other three markers of protein damage. Short-term caloric restriction (six weeks) did not change any of the parameters measured. However, long-term (one year) caloric restriction decreased CEL and MDA-lys in heart mitochondria and did not change protein carbonyls and CML levels. The decrease in MDA-lys was not due to changes in the sensitivity of mitochondrial lipids to peroxidation since the measurements of the fatty acid composition showed that the total number of fatty acid double bonds was not changed by caloric restriction. The decrease in CEL and MDA-lys in caloric restriction agrees with the previously and consistently described finding that caloric restriction agrees with the previously and consistently described finding that caloric restriction lowers the rate of generation of reactive oxygen species (ROS) in rodent heart mitochondria, although in the case of CEL a caloric restriction-induced lowering of glycaemia can also be involved. The CEL and MDA-lys results support the notion that caloric restriction decreases oxidative stress-derived damage to heart mitochondrial proteins.
MeSH Terms
- Aging
- Animals
- Enzyme-Linked Immunosorbent Assay
- Fatty Acids
- Food Deprivation
- Gas Chromatography-Mass Spectrometry
- Lysine
- Male
- Malondialdehyde
- Mitochondria
- Models, Statistical
- Myocardium
- Oxidative Stress
- Phospholipids
- Rats
- Rats, Wistar
- Reactive Oxygen Species
- Time Factors
We used immunohistochemical methods and four monoclonal antibodies for specific molecular structures of advanced glycation end products (AGE)-6D12, KNH-30, 1F6, and 2A2-to examine localization of AGE in fetal, young, and adult rats, and rats with streptozotocin-induced diabetes. 6D12 recognized N(epsilon)-(carboxymethyl)lysine (CML); KNH-30, N(epsilon)-(carboxyethyl)lysine (CEL); and 1F6, fluorolink. The epitope of 2A2 is as yet unknown. Immunoreactivities for these monoclonal antibodies were found in various organs and tissues in postnatal and adult rats, and accumulation increased with aging. In the fetuses, AGE structures were detected at 10 fetal days, and their accumulation increased during ontogeny. Reversed-phase high-performance liquid chromatography revealed CML in fetuses at 13 fetal days and in lungs of 28-week-old rats. In various organs and tissues of fetal, young, and adult rats, CML, CEL, 2A2-positive AGE, and fluorolink accumulated, in that order, which suggests that the accumulation of CML, a nonfluorescent/noncross-linked AGE, occurs earlier than accumulation of fluorolink, a fluorescent/cross-linked AGE. In diabetic rats, hepatocytes, splenic macrophages, renal glomerular endothelial and mesangial cells, testicular Leydig cells, and erythrocytes showed excessive accumulation of AGE, leading to the pathologic changes characteristic of diabetes mellitus. For the induction of these changes, persistent hyperglycemia and hyperketonemia might be important for acceleration of intracellular AGE accumulation in diabetic rats. Thus, AGE accumulation in tissues and cells occurs not only during aging and in diabetes mellitus but also from an early stage of ontogeny.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Chromatography, High Pressure Liquid
- Diabetes Mellitus, Experimental
- Fetus
- Glycation End Products, Advanced
- Immunohistochemistry
- Male
- Rats
- Rats, Wistar
- Reference Values
- Tissue Distribution
In the mollusc Lymnaea stagnalis, neuroendocrine caudodorsal cells (CDCs) were studied physiologically and morphologically from egg layers (EL) (aged 154-400), and animals 4 weeks (CEL-4) (342-455 days), and 8 weeks (CEL-8) (477-660 days) after production of their last egg mass. After recording chemical transmission, electrical coupling and stimulation induced afterdischarges (ADs), CDCs then were filled with Lucifer Yellow. Based on the axonal branching revealed by Lucifer Yellow, CDCs were classified as extensively, moderately, or minimally branched. In EL-CDCs, induction of AD activity, which normally (9) precedes egg-laying, only was initiated in the resting state. CEL-4 CDCs exhibited ADs whereas CEL-8 CDCs did not. CEL-8 CDCs exhibited significantly reduced chemical and electrical transmission, and CEL-4 CDCs did not differ from resting state EL-CDCs. CDC branching was significantly reduced with both increasing age and declining egg-laying. Minimally branched CDCs most frequently failed to exhibit an AD and exhibited reduced electrical coupling. We conclude that both physiology and morphology of CDCs are related to age and reproductive state.
MeSH Terms
- Aging
- Animals
- Electrophysiology
- Evoked Potentials
- Neurons
- Neurosecretory Systems
- Reproduction
Methylglyoxal is formed in vivo by spontaneous decomposition of triose phosphate intermediates in aerobic glycolysis. It may also be formed during oxidative degradation of both carbohydrates (pentoses and ascorbate) and lipids (arachidonate). In addition to reaction with arginine residues to form imidazolone adducts, methylglyoxal reacts with lysine residues in protein to form N(epsilon)-(carboxyethyl)lysine (CEL) and the imidazolium crosslink, methylglyoxal-lysine dimer (MOLD). Like the glycoxidation products, N(epsilon)-(carboxymethyl)lysine (CML) and glyoxal-lysine dimer (GOLD) which are formed on reaction of glyoxal with protein, CEL and MOLD increase in lens proteins and skin collagen with age. CML and CEL also increase in skin collagen in diabetes, while all four compounds increase in plasma proteins in uremia. Overall, CML, CEL, GOLD and MOLD are quantitatively the major biomarkers of the Maillard reaction in tissue proteins. GOLD and MOLD, in particular, are present at 10-50 fold higher concentrations than the fluorescent crosslink, pentosidine. Together, these dicarbonyl-derived advanced glycation endproducts (AGEs) represent the major chemical modifications that accumulate in tissue proteins with age and in chronic diseases such as diabetes and atherosclerosis.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Animals
- Aorta
- Arginine
- Child
- Collagen
- Crystallins
- Diabetes Mellitus, Type 1
- Dogs
- Glycation End Products, Advanced
- Humans
- Lens, Crystalline
- Lysine
- Maillard Reaction
- Middle Aged
- Proteins
- Pyruvaldehyde
- Rats
- Skin
- Uremia
Advanced glycation end-products and glycoxidation products, such as Nepsilon-(carboxymethyl)lysine (CML) and pentosidine, accumulate in long-lived tissue proteins with age and are implicated in the aging of tissue proteins and in the development of pathology in diabetes, atherosclerosis and other diseases. In this paper we describe a new advanced glycation end-product, Nepsilon-(carboxyethyl)lysine (CEL), which is formed during the reaction of methylglyoxal with lysine residues in model compounds and in the proteins RNase and collagen. CEL was also detected in human lens proteins at a concentration similar to that of CML, and increased with age in parallel with the concentration of CML. Although CEL was formed in highest yields during the reaction of methylglyoxal and triose phosphates with lysine and protein, it was also formed in reactions of pentoses, ascorbate and other sugars with lysine and RNase. We propose that levels of CML and CEL and their ratio to one another in tissue proteins and in urine will provide an index of glyoxal and methylglyoxal concentrations in tissues, alterations in glutathione homoeostasis and dicarbonyl metabolism in disease, and sources of advanced glycation end-products in tissue proteins in aging and disease.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Carbohydrate Metabolism
- Child
- Collagen
- Crystallins
- Humans
- Lens, Crystalline
- Lysine
- Middle Aged
- Oxidative Stress
- Pyruvaldehyde
- Ribonucleases
- Skin