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1.
China Journal of Chinese Materia Medica ; (24): 6500-6508, 2023.
Article in Chinese | WPRIM | ID: wpr-1008849

ABSTRACT

This study aimed to investigate the effect of Jiaotai Pills on protein expression in the hippocampus of the rat model of chronic unpredictable mild stress(CUMS)-induced depression by quantitative proteomics and explore the anti-depression mechanism of Jiaotai Pills. The SD rats were randomized into control, model, Jiaotai Pills, and fluoxetine groups(n=8). Other groups except the control group were subjected to CUMS modeling for 4 weeks. After 4 weeks of continuous administration, the changes of behavior and pathological morphology of the hippocampal tissue were observed. Proteins were extracted from the hippocampal tissue, and bioinformatics analysis was performed for the differentially expressed proteins(DEPs) identified by quantitative proteomics. Western blot was employed to verify the key DEPs. The results showed that Jiaotai Pills significantly alleviated the depression behaviors and hippocampal histopathological changes in the rat model of CUMS-induced depression. A total of 5 412 proteins were identified in the hippocampus of rats, including 65 DEPs between the control group and the model group and 35 DEPs between the Jiaotai Pills group and the model group. There were 16 DEPs with the same trend in the Jiaotai Pills group and the control group, which were mainly involved in sphingolipid, AMPK, and dopaminergic synapse signaling pathways. The Western blot results of Ppp2r2b, Cers1, and Ndufv3 in the hippocampus were consistent with the results of proteomics. In conclusion, Jiaotai Pills may play an anti-depression role by modulating the levels of Ppp2r2b, Cers1, Ndufv3 and other proteins and regulating sphingolipid, AMPK, and dopaminergic synapse signaling pathways.


Subject(s)
Rats , Animals , Rats, Sprague-Dawley , Depression/drug therapy , AMP-Activated Protein Kinases/metabolism , Proteomics , Hippocampus , Stress, Psychological/metabolism , Sphingolipids/metabolism , Disease Models, Animal , Drugs, Chinese Herbal
2.
China Journal of Chinese Materia Medica ; (24): 2187-2194, 2022.
Article in Chinese | WPRIM | ID: wpr-928159

ABSTRACT

The present study investigated the effect of emodin on the serum metabolite profiles in the chronic constriction injury(CCI) model by non-target metabolomics and explored its analgesic mechanism. Twenty-four Sprague Dawley(SD) rats were randomly divided into a sham group(S), a CCI group(C), and an emodin group(E). The rats in the emodin group were taken emodin via gavage once a day for fifteen days(50 mg·kg~(-1)) on the first day after the CCI surgery. Mechanical withdrawal threshold(MWT) and thermal withdrawal threshold(TWL) in each group were performed before the CCI surgery and 3,7, 11, and 15 days after surgery. After 15 days, blood samples were collected from the abdominal aorta. The differential metabolites were screened out by non-target metabolomics and analyzed with Kyoto Encyclopedia of Genes and Genomes(KEGG) and ingenuity pathway analysis(IPA). From the third day after CCI surgery, the MWT and TWL values were reduced significantly in both CCI group and emodin group, compared with the sham group(P<0.01). At 15 days post-surgery, the MWT and TWL values in emodin group increased significantly compared with the CCI group(P<0.05). As revealed by non-target metabolomics, 72 differential serum metabolites were screened out from the C-S comparison, including 41 up-regulated and 31 down-regulated ones, while 26 differential serum metabolites from E-C comparison, including 10 up-regulated and 16 down-regulated ones. KEGG analysis showed that the differential metabolites in E-C comparison were enriched in the signaling pathways, such as sphingolipid metabolism, arginine biosynthesis, glycerophospholipid metabolism, and tryptophan metabolism. IPA showed that the differential metabolites were mainly involved in the lipid metabolism-molecular transport-small molecule biochemistry network. In conclusion, emodin can exert an analgesic role via regulating sphingolipid metabolism and arginine biosynthesis.


Subject(s)
Animals , Rats , Analgesics/pharmacology , Arginine , Emodin/pharmacology , Neuralgia/metabolism , Rats, Sprague-Dawley , Sphingolipids
3.
Journal of Lipid and Atherosclerosis ; : 23-49, 2020.
Article in English | WPRIM | ID: wpr-786083

ABSTRACT

Cardiomyopathy is the leading cause of mortality worldwide. While the causes of cardiomyopathy continue to be elucidated, current evidence suggests that aberrant bioactive lipid signaling plays a crucial role as a component of cardiac pathophysiology. Sphingolipids have been implicated in the pathophysiology of cardiovascular disease, as they regulate numerous cellular processes that occur in primary and secondary cardiomyopathies. Experimental evidence gathered over the last few decades from both in vitro and in vivo model systems indicates that inhibitors of sphingolipid synthesis attenuate a variety of cardiomyopathic symptoms. In this review, we focus on various cardiomyopathies in which sphingolipids have been implicated and the potential therapeutic benefits that could be gained by targeting sphingolipid metabolism.


Subject(s)
Cardiomyopathies , Cardiovascular Diseases , Ceramides , In Vitro Techniques , Metabolism , Mortality , Myocytes, Cardiac , Pathology , Receptors, Lysosphingolipid , Sphingolipids
4.
Endocrinology and Metabolism ; : 403-412, 2018.
Article in English | WPRIM | ID: wpr-716963

ABSTRACT

BACKGROUND: Emerging evidence suggests that sphingolipids may be involved in type 2 diabetes. However, the exact signaling defect through which disordered sphingolipid metabolism induces β-cell dysfunction remains unknown. The current study demonstrated that sphingosine-1-phosphate (S1P), the product of sphingosine kinase (SphK), is an essential factor for maintaining β-cell function and survival via regulation of mitochondrial action, as mediated by prohibitin (PHB). METHODS: We examined β-cell function and viability, as measured by mitochondrial function, in mouse insulinoma 6 (MIN6) cells in response to manipulation of cellular S1P and PHB levels. RESULTS: Lack of S1P induced by sphingosine kinase inhibitor (SphKi) treatment caused β-cell dysfunction and apoptosis, with repression of mitochondrial function shown by decreases in cellular adenosine triphosphate content, the oxygen consumption rate, the expression of oxidative phosphorylation complexes, the mitochondrial membrane potential, and the expression of key regulators of mitochondrial dynamics (mitochondrial dynamin-like GTPase [OPA1] and mitofusin 1 [MFN1]). Supplementation of S1P led to the recovery of mitochondrial function and greatly improved β-cell function and viability. Knockdown of SphK2 using small interfering RNA induced mitochondrial dysfunction, decreased glucose-stimulated insulin secretion (GSIS), and reduced the expression of PHB, an essential regulator of mitochondrial metabolism. PHB deficiency significantly reduced GSIS and induced mitochondrial dysfunction, and co-treatment with S1P did not reverse these trends. CONCLUSION: Altogether, these data suggest that S1P is an essential factor in the maintenance of β-cell function and survival through its regulation of mitochondrial action and PHB expression.


Subject(s)
Animals , Mice , Adenosine Triphosphate , Apoptosis , GTP Phosphohydrolases , Insulin , Insulin-Secreting Cells , Insulinoma , Membrane Potential, Mitochondrial , Metabolism , Mitochondria , Mitochondrial Dynamics , Oxidative Phosphorylation , Oxygen Consumption , Phosphotransferases , Repression, Psychology , RNA, Small Interfering , Sphingolipids , Sphingosine
5.
Chinese Medical Journal ; (24): 1078-1086, 2016.
Article in English | WPRIM | ID: wpr-290122

ABSTRACT

<p><b>BACKGROUND</b>This study was to establish a disease differentiation model for ST-segment elevation myocardial infarction (STEMI) youth patients experiencing ischemia and reperfusion via ultra-performance liquid chromatography and mass spectrometry (UPLC/MS) platform, which searches for closely related characteristic metabolites and metabolic pathways to evaluate their predictive value in the prognosis after discharge.</p><p><b>METHODS</b>Forty-seven consecutive STEMI patients (23 patients under 45 years of age, referred to here as "youth," and 24 "elderly" patients) and 48 healthy control group members (24 youth, 24 elderly) were registered prospectively. The youth patients were required to provide a second blood draw during a follow-up visit one year after morbidity (n = 22, one lost). Characteristic metabolites and relative metabolic pathways were screened via UPLC/MS platform base on the Kyoto encyclopedia of genes and genomes (KEGG) and Human Metabolome Database. Receiver operating characteristic (ROC) curves were drawn to evaluate the predictive value of characteristic metabolites in the prognosis after discharge.</p><p><b>RESULTS</b>We successfully established an orthogonal partial least squares discriminated analysis model (R2X = 71.2%, R2Y = 79.6%, and Q2 = 55.9%) and screened out 24 ions; the sphingolipid metabolism pathway showed the most drastic change. The ROC curve analysis showed that ceramide [Cer(d18:0/16:0), Cer(t18:0/12:0)] and sphinganine in the sphingolipid pathway have high sensitivity and specificity on the prognosis related to major adverse cardiovascular events after youth patients were discharged. The area under curve (AUC) was 0.671, 0.750, and 0.711, respectively. A follow-up validation one year after morbidity showed corresponding AUC of 0.778, 0.833, and 0.806.</p><p><b>CONCLUSIONS</b>By analyzing the plasma metabolism of myocardial infarction patients, we successfully established a model that can distinguish two different factors simultaneously: pathological conditions and age. Sphingolipid metabolism is the top most altered pathway in young STEMI patients and as such may represent a valuable prognostic factor and potential therapeutic target.</p>


Subject(s)
Adolescent , Adult , Aged , Aged, 80 and over , Humans , Area Under Curve , Chromatography, High Pressure Liquid , Methods , Least-Squares Analysis , Mass Spectrometry , Methods , Myocardial Ischemia , Metabolism , Myocardial Reperfusion , ST Elevation Myocardial Infarction , Metabolism , Sphingolipids , Metabolism
6.
Pesqui. vet. bras ; 35(5): 451-455, May 2015. tab, ilus
Article in Portuguese | LILACS | ID: lil-759375

ABSTRACT

A fumonisina B1 (FB1) é um metabólito secundário produzido principalmente por Fusarium verticilioides em diversos tipos de alimentos, principalmente o milho, o qual constitui a base para composição de rações para várias espécies de animais domésticos. A FB1é particularmente tóxica para suínos, cujas manifestações clínicas são evidentes em animais expostos a altas concentrações de FB1 na ração (em geral, acima de 30mg/kg). No entanto, são escassos os estudos sobre os efeitos da FB1em suínos alimentados com rações contendo baixas concentrações de fumonisinas, as quais são mais prováveis de serem encontradas em condições de campo. O objetivo do estudo foi avaliar os efeitos da exposição de leitões a baixos níveis de FB1 na ração, durante 28 dias, sobre o ganho de peso, consumo de ração, peso relativo de órgãos e aspectos histológicos do baço, fígado, pulmões, rins e coração. Vinte e quatro leitões foram distribuídos em 4 grupos experimentais e alimentados com rações contendo 0mg (controle), 3,0mg, 6,0mg ou 9,0mg FB1/kg de ração. As diferentes dietas não afetaram (P>0,05) o ganho de peso e nem o peso relativo dos órgãos analisados. Não foram constatadas lesões macroscópicas ou histopatológicas no baço, fígado, rins e coração. No entanto, foram observadas lesões histopatológicas nos pulmões de todos os suínos alimentados com rações contaminadas com fumonisinas, indicando que nenhum dos níveis de FB1 usados no experimento poderia ser considerado como seguro para suínos. São necessários novos estudos sobre os mecanismos de ação tóxica da FB1 em suínos, sobretudo em condições de exposição prolongada a baixos níveis de contaminação na ração.


Fumonisin B1 (FB1) is a secondary metabolite produced mainly by Fusarium verticilioides in several types of foods, particularly corn, which is the basis for composition of feed for several domestic animals. FB1 is particularly toxic to pigs, being the clinical manifestations evident in animals exposed to high concentrations of FB1 in the diet (generally above 30mg/kg). However, there are few studies on the effects of FB1 on pigs fed rations containing low concentrations of fumonisin, which are most probably found under field conditions. The aim of the study was to evaluate the effects of a 28-day exposure of piglets to low levels of FB1 in the feed on the weight gain, feed consumption, organ weights and histological aspects of the spleen, liver, lungs, kidneys and heart. Twenty-four pigs were assigned into 4 experimental groups and fed diets containing 0mg (control), 3.0mg, 6.0mg or 9.0mg FB1/kg diet. The different diets did not affect (P>0.05) the weight gain or the weight of organs examined. There were no macroscopic or histological lesions in the spleen, liver, kidneys and heart. However, histological lesions were found in the lungs from all animals fed rations containing fumonisin, hence indicating that none of the FB1 levels used in the experiment could be considered as safe for piglets. Further studies on the mechanisms of toxic action of FB1 in pigs are needed, particularly under conditions of prolonged exposure to low contamination levels in the diet.


Subject(s)
Animals , Fumonisins/analysis , Fumonisins/toxicity , Animal Feed/toxicity , Animal Feed , Weight Gain , Zea mays/toxicity , Pulmonary Edema/veterinary , Sphingolipids/biosynthesis , Sphingolipids/adverse effects , Mycotoxicosis/veterinary , Lung/physiopathology
7.
Acta Pharmaceutica Sinica ; (12): 1551-1558, 2015.
Article in Chinese | WPRIM | ID: wpr-320043

ABSTRACT

Sphingolipids, especially ceramide and S1P, are structural components of biological membranes and bioactive molecules which participate in diverse cellular activities such as cell division, differentiation, gene expression and apoptosis. Emerging evidence demonstrates the role of sphingolipids in hepatocellular death, which contributes to the progression of several liver diseases including ischaemia-reperfusion liver injury, steatohepatitis or hepatocarcinogenesis. Furthermore, some data indicate that the accumulation of some sphingolipids contributes to the hepatic dysfunctions. Hence, understanding of sphingolipid may open up a novel therapeutic avenue to liver diseases. This review focuses on the progress in the sphingolipid metabolic pathway with a focus on hepatic diseases and drugs targeting the sphingolipid pathway.


Subject(s)
Humans , Apoptosis , Ceramides , Metabolism , Fatty Liver , Metabolism , Liver Diseases , Metabolism , Lysophospholipids , Metabolism , Reperfusion Injury , Metabolism , Sphingolipids , Metabolism , Sphingosine , Metabolism
8.
Acta Pharmaceutica Sinica ; (12): 830-835, 2015.
Article in Chinese | WPRIM | ID: wpr-257060

ABSTRACT

In order to evaluate the effect and mechanism of the mulberry leaf alkaloid, flavones, and polysaccharide intervention on diabetes, the overall metabolite profiling characteristics for the plasma of diabetic mouse was performed by using an ultra-performance liquid chromatography/electrospray-tandem mass spectrometry (UPLC-ESI-MS). The 8 potential biomarkers were found in diabetic mice plasma based on the data of MS/MS characteristics obtained from the UPLC-OrbitrapMS analysis, which mainly involved in sphingolipids, amino acid metabolic pathway. The principal component analysis showed that the normal group and model group were obviously distinguished and implied that metabolic disturbance was happened in diabetic mice plasma. The extracts of mulberry leaf flavonoids, polysaccharide, alkaloid had exhibited the effects of callback function for diabetic mice through regulating the amino acid metabolism and sphingolipid metabolism.


Subject(s)
Animals , Mice , Alkaloids , Chemistry , Amino Acids , Metabolism , Biomarkers , Blood , Chromatography, High Pressure Liquid , Diabetes Mellitus, Experimental , Drug Therapy , Flavones , Chemistry , Flavonoids , Chemistry , Metabolic Networks and Pathways , Metabolomics , Morus , Chemistry , Plant Leaves , Chemistry , Sphingolipids , Metabolism , Tandem Mass Spectrometry
9.
Rev. chil. urol ; 79(1): 41-44, 2014. tab
Article in Spanish | LILACS | ID: lil-783417

ABSTRACT

El cáncer de vejiga representa un problema de salud pública importante a nivel mundial. En Chile su relevancia es aún mayor en la región de Antofagasta. Este cáncer se caracteriza por una alta tasa de recurrencia, por lo que los pacientes requieren un seguimiento estricto que afecta su calidad de vida e implica elevados costos para los sistemas de salud. Esto explica la necesidad de optimizar los tratamientos actuales (quimioterapia e inmunoterapia con BCG intravesical) para reducir las tasas de recurrencia y progresión. Los esfingolípidos son lípidos bioactivos que a nivel celular cumplen funciones relacionadas con la regulación del crecimiento, proliferación, migración, invasión, resistencia a drogas y apoptosis. La evidencia disponible a la fecha sobre el rol de los esfingolípidos en cáncer de vejiga es escasa, pero sugiere que en este cáncer existe un metabolismo esfingolipídico desplazado hacia la reducción de los niveles intracelulares de ceramida y esfingosina (esfingolípidos pro-apoptóticos) y aumento de esfingosina 1-fosfato (esfingolípido anti-apoptótico). La manipulación del metabolismo esfingolipídico para invertir esta relación se propone en esta revisión como una estrategia que podría ayudar a optimizar el efecto de las terapias disponibles actualmente para reducir las recurrencias y progresiones de los tumores de vejiga no músculo-invasores...


Bladder cancer is an important health problem worldwide. In Chile it has particular relevance in the region of Antofagasta. This cancer is characterized by a high recurrence rate, for which patients need a strict follow up that impairs their quality of life and determines increased costs for health care systems. These facts explain the necessity of optimizing the actual treatments (chemotherapy and BCG immunotherapy) for reducing the rates of recurrence and progression. Sphingolipids are bioactive lipids that at a cellular level have roles related to the regulation of growth, proliferation, migration, invasiveness, drug resistance and apoptosis. To date, the available evidence about the role of sphingolipids in bladder cancer is scarce, but suggests that in this cancer there is a sphingolipid metabolism shifted towards a reduction of the intracellular levels of ceramide and sphingosine (pro-apoptotic sphingolipids) and an increase of sphingosine 1-phosphate (anti-apoptotic sphingolipid). In this review we propose that the manipulation of the sphingolipid metabolism to invert this balance can contribute to optimize the effect of the actual therapies to reduce the rates of recurrence and progression of non-muscle invasive bladder cancers...


Subject(s)
Humans , Sphingolipids/metabolism , Sphingolipids/therapeutic use , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/drug therapy
10.
Biomolecules & Therapeutics ; : 83-92, 2014.
Article in English | WPRIM | ID: wpr-228921

ABSTRACT

Fatty acids (FAs) are highly diverse in terms of carbon (C) chain-length and number of double bonds. FAs with C>20 are called very long-chain fatty acids (VLCFAs). VLCFAs are found not only as constituents of cellular lipids such as sphingolipids and glycerophospholipids but also as precursors of lipid mediators. Our understanding on the function of VLCFAs is growing in parallel with the identification of enzymes involved in VLCFA synthesis or degradation. A variety of inherited diseases, such as ichthyosis, macular degeneration, myopathy, mental retardation, and demyelination, are caused by mutations in the genes encoding VLCFA metabolizing enzymes. In this review, we describe mammalian VLCFAs by highlighting their tissue distribution and metabolic pathways, and we discuss responsible genes and enzymes with reference to their roles in pathophysiology.


Subject(s)
Carbon , Demyelinating Diseases , Fatty Acids , Glycerophospholipids , Ichthyosis , Intellectual Disability , Macular Degeneration , Metabolic Networks and Pathways , Metabolism , Muscular Diseases , Sphingolipids , Tissue Distribution
11.
Annals of Laboratory Medicine ; : 274-278, 2013.
Article in English | WPRIM | ID: wpr-105286

ABSTRACT

Recently, lyso-globotriaosylsphingosine (lyso-Gb3) was found to be elevated in plasma of treatment naive male patients and some female patients with Fabry Disease (FD). This study tested whether lyso-Gb3 could be analyzed in dried blood spots (DBS) from filter cards and whether concentrations are elevated in newborn infants with FD. Lyso-Gb3 concentrations were analyzed in DBS following extraction using a novel HPLC-mass spectrometry (MS)/MS method. Lyso-Gb3 levels in DBS were above the lower limit of quantitation (0.28 ng/mL) in 5/17 newborn FD infants (16 males; range: 1.02-8.81 ng/mL), but in none of the newborn controls, in all 13 patients (4 males) with classic FD (range: 2.06-54.1 ng/mL), in 125/159 Taiwanese individuals with symptomatic or asymptomatic FD who carry the late onset alpha-galactosidase A (GLA) mutation c.936+919G>A (IVS4+919G>A) (3.75+/-0.69 ng/mL; range: 0.418-3.97 ng/mL) and in 20/29 healthy controls (0.77+/-0.24 ng/mL; range: 0.507-1.4 ng/mL). The HPLC-MS/MS method for analysis of lyso-Gb3 is robust and yields reproducible results in DBS in patients with FD. However, concentrations of lyso-Gb3 were below the limit of quantitation in most newborn infants with FD rendering this approach not suitable for newborn screening. In addition, most females with the late onset mutation have undetectable lyso-Gb3 concentrations.


Subject(s)
Adolescent , Adult , Child , Female , Humans , Infant, Newborn , Male , Young Adult , Blood Chemical Analysis/methods , Chromatography, High Pressure Liquid , Dried Blood Spot Testing , Fabry Disease/blood , Glycolipids/blood , Sphingolipids/blood , Tandem Mass Spectrometry
12.
Biomolecules & Therapeutics ; : 251-257, 2013.
Article in English | WPRIM | ID: wpr-59936

ABSTRACT

Inflammatory skin diseases such as atopic dermatitis (AD) and rosacea were complicated by barrier abrogation and deficiency in innate immunity. The first defender of epidermal innate immune response is the antimicrobial peptides (AMPs) that exhibit a broad-spectrum antimicrobial activity against multiple pathogens, including Gram-positive and Gram-negative bacteria, viruses, and fungi. The deficiency of these AMPs in the skin of AD fails to protect our body against virulent pathogen infections. In contrast to AD where there is a suppression of AMPs, rosacea is characterized by overexpression of cathelicidin antimicrobial peptide (CAMP), the products of which result in chronic epidermal inflammation. In this regard, AMP generation that is controlled by a key ceramide metabolite S1P-dependent mechanism could be considered as alternate therapeutic approaches to treat these skin disorders, i.e., Increased S1P levels strongly stimulated the CAMP expression which elevated the antimicrobial activity against multiple pathogens resulting the improved AD patient skin.


Subject(s)
Humans , Dermatitis, Atopic , Endoplasmic Reticulum Stress , Fungi , Gram-Negative Bacteria , Immunity, Innate , Inflammation , Peptides , Rosacea , Skin , Skin Diseases , Sphingolipids
13.
Annals of Dermatology ; : 321-326, 2013.
Article in English | WPRIM | ID: wpr-131878

ABSTRACT

BACKGROUND: Ceramides are the main lipid component of the stratum corneum and are a structurally heterogeneous and complex group of sphingolipids of which sphingoid bases are the basic structural constituents. Altered levels of sphingoid bases have been reported in skin conditions that involve dryness and barrier disruption, including atopic dermatitis. OBJECTIVE: The purpose of this study was to investigate the altered levels of sphingoid bases in psoriatic epidermis and their relationship with the clinical severity of the psoriasis. METHODS: Samples from the lesional and non-lesional epidermis were obtained from eight psoriasis patients. Levels of sphingosine and sphinganine were analyzed by high-performance liquid chromatography. The expression of ceramide synthase and ceramidase proteins, which are related to sphingosine and sphinganine metabolism, were measured using Western blot analysis. RESULTS: Levels of sphingosine and sphinganine in the lesional epidermis were significantly higher than those in the non-lesional epidermis. Although there was no altered ceramide synthase and ceramidase, there was a highly significant positive correlation between the % change of ceramidase, the degradative enzyme of ceramide into sphingosine, and the Psoriasis Area Severity Index (PASI) score. CONCLUSION: The levels of sphingosine and sphinganine were significantly increased in psoriatic epidermis and the % change of ceramidase was positively correlated with the clinical severity of psoriasis.


Subject(s)
Humans , Blotting, Western , Ceramidases , Ceramides , Chromatography, Liquid , Epidermis , Oxidoreductases , Proteins , Psoriasis , Skin , Sphingolipids , Sphingosine
14.
Annals of Dermatology ; : 321-326, 2013.
Article in English | WPRIM | ID: wpr-131875

ABSTRACT

BACKGROUND: Ceramides are the main lipid component of the stratum corneum and are a structurally heterogeneous and complex group of sphingolipids of which sphingoid bases are the basic structural constituents. Altered levels of sphingoid bases have been reported in skin conditions that involve dryness and barrier disruption, including atopic dermatitis. OBJECTIVE: The purpose of this study was to investigate the altered levels of sphingoid bases in psoriatic epidermis and their relationship with the clinical severity of the psoriasis. METHODS: Samples from the lesional and non-lesional epidermis were obtained from eight psoriasis patients. Levels of sphingosine and sphinganine were analyzed by high-performance liquid chromatography. The expression of ceramide synthase and ceramidase proteins, which are related to sphingosine and sphinganine metabolism, were measured using Western blot analysis. RESULTS: Levels of sphingosine and sphinganine in the lesional epidermis were significantly higher than those in the non-lesional epidermis. Although there was no altered ceramide synthase and ceramidase, there was a highly significant positive correlation between the % change of ceramidase, the degradative enzyme of ceramide into sphingosine, and the Psoriasis Area Severity Index (PASI) score. CONCLUSION: The levels of sphingosine and sphinganine were significantly increased in psoriatic epidermis and the % change of ceramidase was positively correlated with the clinical severity of psoriasis.


Subject(s)
Humans , Blotting, Western , Ceramidases , Ceramides , Chromatography, Liquid , Epidermis , Oxidoreductases , Proteins , Psoriasis , Skin , Sphingolipids , Sphingosine
15.
Acta Pharmaceutica Sinica ; (12): 1301-1306, 2013.
Article in Chinese | WPRIM | ID: wpr-259478

ABSTRACT

The metabolic effect of Fo-Shou-San on blood deficiency mice was studied by using metabolomic method. UPLC-QTOF/MS was used to analyze the plasma metabolome in blood deficiency mice. MS data were processed by MarkerLynx software. With multivariate statistical analysis of plasma metabolite profiles, a clear separation among control, blood deficiency model, and Fo-Shou-San groups was achieved. Potential biomarkers were selected according to the parameters of variable importance in the projection (VIP) and identified according to MS information and database retrieval. The metabolic network of blood deficiency was predicted via MetPA database. Twenty-two potential biomarkers were identified and used to explain the thiamine metabolism, arachidonic acid metabolism, sphingolipid metabolism, glyoxylate and dicarboxylate metabolism, histidine metabolism, nicotinate and nicotinamide metabolism, cysteine and methionine metabolism, tryptophan metabolism, starch and sucrose metabolism, tyrosine metabolism and citrate cycle (TCA cycle). Those metabolic pathways were disturbed in blood deficiency mice, but which could be regulated nearly to normal state after Fo-Shou-San administration. In this study, the metabolomics of blood deficiency mice and the action mechanism of nourishing blood effect of Fo-Shou-San were evaluated. The physiological and metabolic state of the organism could be represented comprehensively by using metabolomics. And metabolomics can be used to evaluate the pharmacodynamics and related mechanisms of Chinese medicine and formulae.


Subject(s)
Animals , Female , Mice , Arachidonic Acid , Metabolism , Biomarkers , Blood , Blood Coagulation Disorders , Blood , Metabolism , Chromatography, High Pressure Liquid , Drugs, Chinese Herbal , Pharmacology , Metabolic Networks and Pathways , Metabolome , Metabolomics , Mice, Inbred ICR , Plasma , Metabolism , Random Allocation , Spectrometry, Mass, Electrospray Ionization , Sphingolipids , Metabolism , Thiamine , Metabolism
16.
International Journal of Oral Science ; (4): 130-140, 2013.
Article in English | WPRIM | ID: wpr-358181

ABSTRACT

Oral mucosal and salivary lipids exhibit potent antimicrobial activity for a variety of Gram-positive and Gram-negative bacteria; however, little is known about their spectrum of antimicrobial activity or mechanisms of action against oral bacteria. In this study, we examine the activity of two fatty acids and three sphingoid bases against Porphyromonas gingivalis, an important colonizer of the oral cavity implicated in periodontitis. Minimal inhibitory concentrations, minimal bactericidal concentrations, and kill kinetics revealed variable, but potent, activity of oral mucosal and salivary lipids against P. gingivalis, indicating that lipid structure may be an important determinant in lipid mechanisms of activity against bacteria, although specific components of bacterial membranes are also likely important. Electron micrographs showed ultrastructural damage induced by sapienic acid and phytosphingosine and confirmed disruption of the bacterial plasma membrane. This information, coupled with the association of treatment lipids with P. gingivalis lipids revealed via thin layer chromatography, suggests that the plasma membrane is a likely target of lipid antibacterial activity. Utilizing a combination of two-dimensional in-gel electrophoresis and Western blot followed by mass spectroscopy and N-terminus degradation sequencing we also show that treatment with sapienic acid induces upregulation of a set of proteins comprising a unique P. gingivalis stress response, including proteins important in fatty acid biosynthesis, metabolism and energy production, protein processing, cell adhesion and virulence. Prophylactic or therapeutic lipid treatments may be beneficial for intervention of infection by supplementing the natural immune function of endogenous lipids on mucosal surfaces.


Subject(s)
Humans , Anti-Bacterial Agents , Pharmacology , Bacterial Proteins , Colony Count, Microbial , Fatty Acids , Pharmacology , Lipids , Pharmacology , Microscopy, Electron , Mouth Mucosa , Chemistry , Allergy and Immunology , Microbiology , Porphyromonas gingivalis , Chemistry , Saliva , Chemistry , Microbiology , Sphingolipids , Pharmacology , Virulence
17.
Invest. clín ; 53(1): 84-110, mar. 2012. ilus
Article in Spanish | LILACS | ID: lil-664568

ABSTRACT

El Ca2+ es un segundo mensajero que regula funciones directamente relacionadas con el cáncer como la proliferación, diferenciación y la apoptosis. La concentración intracelular de Ca2+ ([Ca2+]i) está altamente regulada por diversos mecanismos entre los que destacan canales iónicos, la Ca2+-ATPasa del retículo endoplasmático (SERCA) y de la membrana plasmática (PMCA), y el transporte de Ca2+ mitocondrial. En el cáncer, la célula tumoral prolifera sin control tras su incapacidad de reconocer señales apoptóticas. La apoptosis es mediada a través de cambios en la actividad de ciertas proteínas como las caspasas y miembros de la familia Bcl-2. Adicionalmente, el “estrés del retículo”, promovido por la acumulación y agregación de proteínas mal plegadas en el interior del retículo endoplasmático (RE), puede desencadenar la apoptosis. El “estrés del retículo” es inducido por una variedad de agentes, entre los que destaca la tapsigargina, inhibidor específico de la SERCA, la cual promueve un notable aumento en la [Ca2+]i, induciendo además apoptosis. En consecuencia, actualmente se están ensayando exitosamente derivados de la tapsigargina como agentes antineoplásicos. El Ca2+ es transferido a la mitocondria desencadenando señales apoptóticas. Por otra parte, los esfingolípidos, como la ceramida y la esfingosina, y sus derivados fosforilados, la ceramida-1-fosfato y la esfingosina-1-fosfato, los cuales regulan la [Ca2+]i, también están estrechamente vinculados con la señalización intracelular en procesos relacionados con el cáncer. Esta revisión discute nuevas evidencias sobre el efecto de estos esfingolípidos en la homeostasis de Ca+2 intracelular y su conexión con la apoptosis y el cáncer.


Ca2+ is a second messenger which regulates many functions directly related with cancer such as proliferation, differentiation and apoptosis. The intracellular Ca2+ concentration ([Ca2+]i) is finely regulated by several mechanisms, among them ionic channels, the endoplasmic reticulum Ca2+-ATPase (SERCA), the plasma membrane calcium pump (PMCA) and the mitochondrial Ca2+ transport. In cancer, the tumour cell proliferates without control since the capacity to recognize apoptotic signals has been lost. The apoptosis is regulated by changes in several proteins, as caspases and the Bcl-2 family members, among others. Additionally, the “reticulum stress”, promoted by the accumulation and aggregation of unfolded proteins in the interior of the endoplasmic reticulum (ER), ussually leads to apoptosis. The “reticulum stress” can be induced by several agents, remarkably with thapsigargin, a selective inhibitor of the SERCA, which in turn induces a large increment in [Ca2+]I, leading to apoptosis. As a consequence, currently, derivatives of thapsigargin are successfully been assayed as anti-neoplastic agents. Ca2+ is then transferred to the mitochondria, where it is known to constitute a main apoptotic signal. On the other hand, several sphingolipids, such as ceramide and sphingosine, and their phosphorylated derivatives ceramide-1-phosphate and sphingosine-1-phosphate, directly involved in the [Ca2+]I regulation, are also recognized as signal messengers related with cancer processes. In this review we discuss new evidences on the effect of several sphingolipids in the intracellular Ca2+ homeostasis and its relationship with apoptosis and cancer.


Subject(s)
Humans , Apoptosis/physiology , Calcium Signaling , Neoplasms/physiopathology , Sphingolipids/physiology , Apoptosis Regulatory Proteins/physiology , Apoptosis/drug effects , Calcium Channels/physiology , Calcium Signaling/physiology , Ceramides/physiology , Endoplasmic Reticulum Stress , Ion Transport , Mitochondria/physiology , Neoplasm Proteins/physiology , Phosphorylation , Signal Transduction/physiology , Sphingosine/physiology
18.
Braz. j. pharm. sci ; 48(3): 353-367, July-Sept. 2012. ilus, graf, tab
Article in English | LILACS | ID: lil-653449

ABSTRACT

P-glycoprotein (P-gp), a transmembrane permeability glycoprotein, is a member of ATP binding cassette (ABC) super family that functions specifically as a carrier mediated primary active efflux transporter. It is widely distributed throughout the body and has a diverse range of substrates. Several vital therapeutic agents are substrates to P-gp and their bioavailability is lowered or a resistance is induced because of the protein efflux. Hence P-gp inhibitors were explored for overcoming multidrug resistance and poor bioavailability problems of the therapeutic P-gp substrates. The sensitivity of drug moieties to P-gp and vice versa can be established by various experimental models in silico, in vitro and in vivo. Ever since the discovery of P-gp, the research plethora identified several chemical structures as P-gp inhibitors. The aim of this review was to emphasize on the discovery and development of newer, inert, non-toxic, and more efficient, specifically targeting P-gp inhibitors, like those among the natural herb extracts, pharmaceutical excipients and formulations, and other rational drug moieties. The applications of cellular and molecular biology knowledge, in silico designed structural databases, molecular modeling studies and quantitative structure-activity relationship (QSAR) analyses in the development of novel rational P-gp inhibitors have also been mentioned.


Glicoproteína-p (P-gp), uma glicoproteína de transmembrana permeável, é um membro da superfamília (ABC) de cassete de gene de ligação de ATP que funciona especificamente como um carreador mediado pelo transportador de efluxo ativo primário. É amplamente distribuído por todo o corpo e apresenta uma gama diversificada de substratos. Diversos agentes terapêuticos vitais são substratos para P-gp e sua biodisponibilidade é reduzida ou a resistência é induzida devido ao efluxo de proteínas. Portanto, os inibidores da P-gp foram explorados para a superação da resistência a múltiplas drogas e problemas de biodisponibilidade deficiente dos substratos terapêuticos da P-gp. A sensibilidade das moléculas da droga à P-gp e vice-versa, pode ser estabelecida por vários modelos experimentais in silico, in vitro e in vivo. Desde a descoberta da P-gp, diversas pesquisas identificaram várias estruturas químicas como inibidores da P-gp. O objetivo deste presente estudo foi o de enfatizar a descoberta e desenvolvimento de inibidores mais novos, inertes, atóxicos e mais eficazes, visando especificamente os da P-gp, como aqueles entre os extratos vegetais, excipientes e formulações farmacêuticas, e outras moléculas racionais de droga. As aplicações do conhecimento de biologia celular e molecular, bancos de dados estruturais in silico, estudos de modelagem molecular e análises da relação quantitativa estrutura-atividade (QSAR) no desenvolvimento de novos inibidores racionais da P-gp também foram mencionados.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/analysis , ATP Binding Cassette Transporter, Subfamily B, Member 1/adverse effects , Sphingolipids/analysis , Drug Resistance, Multiple
19.
Caracas; s.n; oct. 2011. 185 p. ^c30 cmilus. (LFT-4872011615789).
Thesis in Spanish | LILACS, LIVECS | ID: biblio-1152068

ABSTRACT

Los esfingolípidos, como la ceramida (Cer), la ceramida-1-fosfato (C-1-P), la esfingosina (Sph) y la esfingosina-1-fosfato (S-1P) estan relacionados con la señalización intracelular en procesos como crecimiento celular, movilización intracelular de Ca+2 y apoptósis. En este trabajo se evaluó el efecto de estos esfingolípidos en la homeostasis de Ca+2 intracelular y en la apoptósis en células de cáncer de mama MCF-7. Se utilizaron fluoróforos específicos para el Ca+2 y microscopía confocal. Se demostró que en estas células, la Sph (20 uM), la Cer (10uM), la S-P (2uM) y la C--P (uM) aumentaron la concentración intracelular ce Ca+2, induciendo su liberación desde el retículo endoplasmático (RE). Además, se observo que la esfingosina abrioun canal de Ca2+ en la membrana plasmática. También se demostró que la Cer inhibe parcialmente la actividad de la Ca2+-ATPasa del RE (SERCA), de forma dosis dependiente, mientras que la ceramina, su análogo no hidrolisable la inhibe totalmente. La Sph también inhibe completamente la actividad de la SERCA, a la misma concentración que induce la liberación del Ca+2 del RE. Asimismo, se evaluó el efecto de estos esfingolípidos sobre la inducción de la apotósis en células MCF-7 evidenciando que el tratamiento con la Cer, la ceramida, la Sph inducen toxicidad. También se observo que mientras la ceramida activo la caspasa 7 y la caspasa 8, el esfingolipido natural, la Cer no tuvo ningún efecto. Por su parte, la Sph activa la caspasa 8 sin modificar la activdad de la caspasa 7. Tanto la Cer, como la ceramida y la Sph, disminuyeron la expresión de la proteína Bcl-2 amti-apoptótica, y también indujeron la fragmentación de ADN, visualizada mediante la técnica de TUNEL, demostrando que estos esfingolípidos inducen apoptósis en MCF-7. La agelasina B, toxina purificada a partir de la esponja marina Agelas clathrodes tiene un efecto citotóxico un orden de magnitud mayor en MCF-7, en comparación con fibroplastos humanos. La agelasina B induce la liberación del Ca+2 almacenado en el RE en celulas MCF-7, ademas de inhibir la actividad de la SERCA en un 100%. También se demostró que esta toxina induce apoptosis, ya que disminuye el potencial de membrana mitocondrial, activa la caspasa 8, disminuye la expresion de la proteina Bcl-2 e induce fragmentación del ADN de las células MCF-7. Este mecanismo es similar al efecto de la tapsigargina.


Subject(s)
Humans , Animals , Sphingolipids/pharmacology , Breast Neoplasms/metabolism , Signal Transduction/drug effects , Calcium/metabolism , Apoptosis/drug effects , Agelas/chemistry , Purines/therapeutic use , Purines/pharmacology , Sphingolipids/toxicity , Sphingolipids/therapeutic use , Breast Neoplasms/pathology , Breast Neoplasms/drug therapy , Ceramides/toxicity , Calcium-Transporting ATPases/adverse effects , In Situ Nick-End Labeling/methods , Receptors, Calcium-Sensing/therapeutic use , MCF-7 Cells , Naphthalenes/therapeutic use , Naphthalenes/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology
20.
Diabetes & Metabolism Journal ; : 309-316, 2011.
Article in English | WPRIM | ID: wpr-210391

ABSTRACT

Glycosphingolipids (GSLs) are present in all mammalian cell plasma membranes and intracellular membrane structures. They are especially concentrated in plasma membrane lipid domains that are specialized for cell signaling. Plasma membranes have typical structures called rafts and caveola domain structures, with large amounts of sphingolipids, cholesterol, and sphingomyelin. GSLs are usually observed in many organs ubiquitously. However, GSLs, including over 400 derivatives, participate in diverse cellular functions. Several studies indicate that GSLs might have an effect on signal transduction related to insulin receptors and epidermal growth factor receptors. GSLs may modulate immune responses by transmitting signals from the exterior to the interior of the cell. Guillain-Barre syndrome is one of the autoimmune disorders characterized by symmetrical weakness in the muscles of the legs. The targets of the immune response are thought to be gangliosides, which are one group of GSLs. Other GSLs may serve as second messengers in several signaling pathways that are important to cell survival or programmed cell death. In the search for clear evidence that GSLs may play critical roles in various biological functions, many researchers have made genetically engineered mice. Before the era of gene manipulation, spontaneous animal models or chemical-induced disease models were used.


Subject(s)
Animals , Mice , Caveolae , Cell Death , Cell Membrane , Cell Survival , Cholesterol , Diabetes Mellitus , Gangliosides , Glycosphingolipids , Guillain-Barre Syndrome , Intracellular Membranes , Leg , Models, Animal , Muscles , ErbB Receptors , Receptor, Insulin , Second Messenger Systems , Signal Transduction , Sphingolipids
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