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1.
Int J Obes (Lond) ; 48(4): 584-593, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38219005

RESUMEN

OBJECTIVES: We aimed to discover CpG sites with differential DNA methylation in peripheral blood leukocytes associated with body mass index (BMI) in pregnancy and gestational weight gain (GWG) in women of European and South Asian ancestry. Furthermore, we aimed to investigate how the identified sites were associated with methylation quantitative trait loci, gene ontology, and cardiometabolic parameters. METHODS: In the Epigenetics in pregnancy (EPIPREG) sample we quantified maternal DNA methylation in peripheral blood leukocytes in gestational week 28 with Illumina's MethylationEPIC BeadChip. In women with European (n = 303) and South Asian (n = 164) ancestry, we performed an epigenome-wide association study of BMI in gestational week 28 and GWG between gestational weeks 15 and 28 using a meta-analysis approach. Replication was performed in the Norwegian Mother, Father, and Child Cohort Study, the Study of Assisted Reproductive Technologies (MoBa-START) (n = 877, mainly European/Norwegian). RESULTS: We identified one CpG site significantly associated with GWG (p 5.8 × 10-8) and five CpG sites associated with BMI at gestational week 28 (p from 4.0 × 10-8 to 2.1 × 10-10). Of these, we were able to replicate three in MoBa-START; cg02786370, cg19758958 and cg10472537. Two sites are located in genes previously associated with blood pressure and BMI. DNA methylation at the three replicated CpG sites were associated with levels of blood pressure, lipids and glucose in EPIPREG (p from 1.2 × 10-8 to 0.04). CONCLUSIONS: We identified five CpG sites associated with BMI at gestational week 28, and one with GWG. Three of the sites were replicated in an independent cohort. Several genetic variants were associated with DNA methylation at cg02786379 and cg16733643 suggesting a genetic component influencing differential methylation. The identified CpG sites were associated with cardiometabolic traits. GOV REGISTRATION NO: Not applicable.


Asunto(s)
Enfermedades Cardiovasculares , Ganancia de Peso Gestacional , Femenino , Humanos , Embarazo , Índice de Masa Corporal , Enfermedades Cardiovasculares/genética , Estudios de Cohortes , Metilación de ADN/genética , Epigénesis Genética/genética , Epigenoma , Pueblo Europeo , Estudio de Asociación del Genoma Completo , Ganancia de Peso Gestacional/genética , Leucocitos , Personas del Sur de Asia , Metaanálisis como Asunto
2.
Mol Cell Endocrinol ; 521: 111107, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33309639

RESUMEN

Here we show that scratch family transcriptional repressor 1 (SCRT1), a zinc finger transcriptional regulator, is a novel regulator of beta cell function. SCRT1 was found to be expressed in beta cells in rodent and human islets. In human islets, expression of SCRT1 correlated with insulin secretion capacity and the expression of the insulin (INS) gene. Furthermore, SCRT1 mRNA expression was lower in beta cells from T2D patients. siRNA-mediated Scrt1 silencing in INS-1832/13 cells, mouse- and human islets resulted in impaired glucose-stimulated insulin secretion and decreased expression of the insulin gene. This is most likely due to binding of SCRT1 to E-boxes of the Ins1 gene as shown with ChIP. Scrt1 silencing also reduced the expression of several key beta cell transcription factors. Moreover, Scrt1 mRNA expression was reduced by glucose and SCRT1 protein was found to translocate between the nucleus and the cytosol in a glucose-dependent fashion in INS-1832/13 cells as well as in a rodent model of T2D. SCRT1 was also regulated by a GSK3ß-dependent SCRT1-serine phosphorylation. Taken together, SCRT1 is a novel beta cell transcription factor that regulates insulin secretion and is affected in T2D.


Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Regulación de la Expresión Génica/genética , Glucosa/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Factores de Transcripción/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular , Núcleo Celular/genética , Núcleo Celular/metabolismo , Inmunoprecipitación de Cromatina , Citoplasma/genética , Citoplasma/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Silenciador del Gen , Humanos , Inmunohistoquímica , Insulina/genética , Secreción de Insulina/efectos de los fármacos , Células Secretoras de Insulina/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , ARN Interferente Pequeño , RNA-Seq , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de la Célula Individual , Factores de Transcripción/genética
3.
Mol Cell Endocrinol ; 511: 110835, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32371087

RESUMEN

It is not known how ghrelin affects insulin secretion in human islets from patients with type 2 diabetes (T2D) or whether islet ghrelin expression or circulating ghrelin levels are altered in T2D. Here we sought out to identify the effect of ghrelin on insulin secretion in human islets and the impact of T2D on circulating ghrelin levels and on islet ghrelin cells. The effect of ghrelin on insulin secretion was assessed in human T2D and non-T2D islets. Ghrelin expression was assessed with RNA-sequencing (n = 191) and immunohistochemistry (n = 21). Plasma ghrelin was measured with ELISA in 40 T2D and 40 non-T2D subjects. Ghrelin exerted a glucose-dependent insulin-suppressing effect in islets from both T2D and non-T2D donors. Compared with non-T2D donors, T2D donors had reduced ghrelin mRNA expression and 75% less islet ghrelin cells, and ghrelin mRNA expression correlated negatively with HbA1c. T2D subjects had 25% lower fasting plasma ghrelin levels than matched controls. Thus, ghrelin has direct insulin-suppressing effects in human islets and T2D patients have lower fasting ghrelin levels, likely as a result of reduced number of islet ghrelin cells. These findings support inhibition of ghrelin signaling as a potential therapeutic avenue for stimulation of insulin secretion in T2D patients.


Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Ghrelina/sangre , Ghrelina/farmacología , Secreción de Insulina , Islotes Pancreáticos/patología , Recuento de Células , Ayuno/sangre , Glucosa/metabolismo , Humanos , Secreción de Insulina/efectos de los fármacos , Islotes Pancreáticos/efectos de los fármacos , Fenotipo , RNA-Seq , Donantes de Tejidos
4.
J Intern Med ; 286(2): 192-206, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30919529

RESUMEN

OBJECTIVE: Gestational diabetes mellitus (GDM) is a transient form of diabetes characterized by impaired insulin secretion and action during pregnancy. Population-based differences in prevalence exist which could be explained by phenotypic and genetic differences. The aim of this study was to examine these differences in pregnant women from Punjab, India and Scandinavia. METHODS: Eighty-five GDM/T2D loci in European and/or Indian populations from previous studies were assessed for association with GDM based on Swedish GDM criteria in 4018 Punjabi Indian and 507 Swedish pregnant women. Selected loci were replicated in Scandinavian cohorts, Radiel (N = 398, Finnish) and STORK/STORK-G (N = 780, Norwegian). RESULTS: Punjabi Indian women had higher GDM prevalence, lower insulin secretion and better insulin sensitivity than Swedish women. There were significant frequency differences of GDM/T2D risk alleles between both populations. rs7178572 at HMG20A, previously associated with GDM in South Indian and European women, was replicated in North Indian women. The T2D risk SNP rs11605924 in the CRY2 gene was associated with increased GDM risk in Scandinavian but decreased GDM risk in Punjabi Indian women. No other overlap was seen between GDM loci in both populations. CONCLUSIONS: Gestational diabetes mellitus is more common in Indian than Swedish women, which partially can be attributed to differences in insulin secretion and action. There was marked heterogeneity in the GDM phenotypes between the populations which could only partially be explained by genetic differences.


Asunto(s)
Criptocromos/genética , Diabetes Gestacional/epidemiología , Diabetes Gestacional/genética , Proteínas del Grupo de Alta Movilidad/genética , Adulto , Alelos , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , India/epidemiología , Resistencia a la Insulina , Fenotipo , Polimorfismo de Nucleótido Simple , Embarazo , Prevalencia , Países Escandinavos y Nórdicos/epidemiología
5.
J Intern Med ; 285(1): 40-48, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30403316

RESUMEN

The Precision Medicine Initiative defines precision medicine as 'an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment and lifestyle for each person'. This approach will facilitate more accurate treatment and prevention strategies in contrast to a one-size-fits-all approach, in which disease treatment and prevention strategies are developed for generalized usage. Diabetes is clearly more heterogeneous than the conventional subclassification into type 1 and type 2 diabetes. Monogenic forms of diabetes like MODY and neonatal diabetes have paved the way for precision medicine in diabetes, as carriers of unique mutations require unique treatment. Diagnosis of diabetes in the past has been dependent upon measuring one metabolite, glucose. By instead including six variables in a clustering analysis, we could break down diabetes into five distinct subgroups, with better prediction of disease progression and outcome. The severe insulin-resistant diabetes (SIRD) cluster showed the highest risk of kidney disease and highest prevalence of nonalcoholic fatty liver disease, whereas patients in the insulin-deficient cluster 2 (SIDD) had the highest risk of retinopathy. In the future, this will certainly be improved and expanded by including genetic, epigenetic and other biomarker to allow better prediction of outcome and choice of more precise treatment.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/terapia , Medicina de Precisión , Biomarcadores , Progresión de la Enfermedad , Humanos , Estilo de Vida
6.
Food Chem ; 248: 210-216, 2018 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-29329846

RESUMEN

An enzymatic process was developed for the preparation of a nutritionally enriched 1,3-diacylglycerol(DAG)-rich oil from a blend of refined sunflower and rice bran oils. The process involves hydrolysis of vegetable oil blend using Candida cylindracea followed by esterification with glycerol using Lipozyme RM1M. The resultant DAG-rich oil contains 84% of DAG (66% of 1,3-DAG, 18% of 1,2-DAG) and 16% of triacylglycerol (TAG) along with micro nutrients like γ-oryzanol, tocotrienols, tocopherols and phytosterols. Nutritional studies of the DAG-rich oil were conducted in Wistar rats and compared with sunflower oil (SFO). The calorific value of the DAG-rich oil was estimated to be 6.45 Kcals/g as against 9.25 Kcals/g for SFO. The serum and liver cholesterol and TAG levels in rats fed with 1,3-DAG-rich oil were found to be significantly reduced as compared to rats fed diet containing SFO. We conclude that 1,3-DAG-rich oil is a low calorie fat and exhibits hypolipidemic effects.


Asunto(s)
Diglicéridos/química , Hipolipemiantes/química , Hipolipemiantes/farmacología , Aceite de Salvado de Arroz/química , Aceite de Girasol/química , Animales , Restricción Calórica , Candida , Colesterol/sangre , Colesterol/metabolismo , Esterificación , Lipasa/química , Lipasa/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Fitosteroles/análisis , Ratas , Ratas Wistar , Tocoferoles/análisis , Triglicéridos/análisis , Triglicéridos/metabolismo
7.
Diabet Med ; 34(10): 1477-1482, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28731584

RESUMEN

AIM: The relative roles(s) of impaired insulin secretion vs. insulin resistance in the development of gestational diabetes mellitus depend upon multiple risk factors and diagnostic criteria. Here, we explored their relative contribution to gestational diabetes as defined by the WHO 1999 (GDM1999) and adapted WHO 2013 (GDM2013) criteria, excluding the 1-h glucose value, in a high-risk Indian population from Punjab. METHODS: Insulin secretion (HOMA2-B) and insulin action (HOMA2-IR) were assessed in 4665 Indian women with or without gestational diabetes defined by the GDM1999 or adapted GDM2013 criteria. RESULTS: Gestational diabetes defined using both criteria was associated with decreased insulin secretion compared with pregnant women with normal glucose tolerance. Women with gestational diabetes defined by the adapted GDM2013, but not GDM1999 criteria, were more insulin resistant than pregnant women with normal glucose tolerance, and furthermore displayed lower insulin secretion than GDM1999 women. Urban habitat, illiteracy, high age and low BMI were independently associated with reduced insulin secretion, whereas Sikh religion, increasing age and BMI, as well as a family history of diabetes were independently associated with increased insulin resistance. CONCLUSIONS: Gestational diabetes risk factors influence insulin secretion and action in North Indian women in a differential manner. Gestational diabetes classified using the adapted GDM2013 compared with GDM1999 criteria is associated with more severe impairments of insulin secretion and action.


Asunto(s)
Insulina/metabolismo , Insulina/fisiología , Embarazo/metabolismo , Adulto , Pueblo Asiatico , Diabetes Gestacional/epidemiología , Diabetes Gestacional/metabolismo , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , India/epidemiología , Resistencia a la Insulina , Secreción de Insulina , Factores de Riesgo , Adulto Joven
8.
Bioorg Med Chem Lett ; 27(15): 3370-3373, 2017 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-28615134

RESUMEN

In the present study, the synthesis of 1, 3, 4-thiadiazole-based thioglycosides were accomplished in good yields with employing a convergent synthetic route. The starting material 5-amino-1, 3, 4-thiadiazole-2-thiol and followed by a series of 5-fatty-acylamido-1, 3, 4-thiadiazole-2-thiols (4a-4j) were synthesized with different fatty acid chlorides. The glycosylation of compounds 4a-4j were achieved with trichloroacetimidate methodology. Antimicrobial and cytotoxicity activities of title compounds were evaluated. Among the entire compounds lauric acid and myristic acid derivatives showed good and moderate antimicrobial activity. In case of cytotoxicity results of compounds 8a-8j and 9a-9j, the acetate protected short chain (C6:0, C8:0, C10:0) compounds and the free hydroxyl long chain saturated (C16:0, C18:0) and unsaturated (C18:1, C22:1) compounds exhibited good activity against different cancer cell lines. Further, the free hydroxyl compounds 9a, 9c-9j did not show any toxicity towards normal CHO-K1 cell line whereas acylated compounds 8a-8j exhibited toxicity.


Asunto(s)
Antibacterianos/farmacología , Antineoplásicos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Tioglicósidos/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Células CHO , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cricetulus , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Tioglicósidos/síntesis química , Tioglicósidos/química
9.
Colloids Surf B Biointerfaces ; 152: 133-142, 2017 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-28103530

RESUMEN

Development of safe non-viral carrier systems for efficient intra-cellular delivery of drugs and genes hold promise in the area of translational research. Liposome based delivery systems have emerged as one of the attractive strategies for efficient delivery of drugs and nucleic acids. To this end, number of investigations was carried on liposomal formulations using lipids for achieving higher efficiency in transfection with lower cytotoxicities. In our efforts to develop safer and efficient liposomal delivery systems, we synthesized a novel anti-oxidant lipid, α-lipoyl, oleyl-sn-phosphatidylcholine (LOPC) and used as a helper lipid in combination with a cationic amphiphile, Di-Stearyl Dihydroxy Ethyl Ammonium Chloride (DSDEAC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) at varying concentrations of LOPC. DNA binding properties of the liposomal formulations (DS, DS LA1, DS LA2 and DS LA3) revealed that increasing the percentage of single aliphatic chain lipid LOPC, did not affect the DNA binding properties. But, transfection profiles of these liposomal formulations in 3 different cell lines (HeLa, HEK 293 and MCF7) showed difference in their efficacies. Results showed that optimal percentage of LOPC i.e. 25% in DSDEAC and DOPC at 1:1 molar ratio (DS LA1) enhanced transfection as compared to DSDEAC:DOPC alone. The endosomal escape studies with NBD labelled lysotracker and Rhodamine labelled liposomal formulations revealed that DS LA1 and DS LA2 facilitated the release of genetic cargo with a better efficiency than their counter parts. Reactive Oxygen Species (ROS), a key modulator of necroptosis were lowered with the treatment of DS LA1 than other liposomal formulations. Here in, we present a novel liposomal formulation using DSDEAC and DOPC at 1:1 molar ratio doped with 25-50% (mole ratio) LOPC as an efficient delivery system for enhanced transfection with quenching of ROS levels compared to formulations without LOPC.


Asunto(s)
Antioxidantes/química , Liposomas/química , Fosfatidilcolinas/química , Ácido Tióctico/química , Células HEK293 , Células HeLa , Humanos , Células MCF-7 , Especies Reactivas de Oxígeno/metabolismo , Transfección
10.
Food Chem ; 221: 664-672, 2017 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-27979256

RESUMEN

Novel phenoylated phosphatidylcholines were synthesized from 1,2-dipalmitoyl phosphatidylcholine/egg 1,2-diacyl phosphatidylcholine and phenolic acids such as ferulic, sinapic, vanillic and syringic acids. The structures of phenoylated phosphatidylcholines were confirmed by spectral analysis. 2-acyl-1-lyso phosphatidylcholine was synthesized from phosphatidylcholine via regioselective enzymatic hydrolysis and was reacted with hydroxyl protected phenolic acids to produce corresponding phenoylated phosphatidylcholines in 48-56% yields. Deprotection of protected phenoylated phosphatidylcholines resulted in phenoylated phosphatidylcholines in 87-94% yields. The prepared compounds were evaluated for their preliminary in vitro antimicrobial and antioxidant activities. Among the active derivatives, compound 1-(4-hydroxy-3,5-dimethoxy) cinnamoyl-2-acyl-sn-glycero-3-phosphocholine exhibited excellent antioxidant activity with EC50 value of 16.43µg/mL. Compounds 1-(4-hydroxy-3-methoxy) cinnamoyl-2-acyl-sn-glycero-3-phosphocholine and 1-(4-hydroxy-3,5-dimethoxy) cinnamoyl-2-palmitoyl-sn-glycero-3-phosphocholine exhibited good antioxidant activity with EC50 values of 36.05 and 33.35µg/mL respectively. Compound 1-(4-hydroxy-3-methoxy) cinnamoyl-2-palmitoyl-sn-glycero-3-phosphocholine exhibited good antibacterial activity against Klebsiella planticola with MIC of 15.6µg/mL and compound 1-(4-hydroxy-3-methoxy) benzoyl-2-acyl-sn-glycero-3-phosphocholine exhibited good antifungal activity against Candida albicans with MIC of 15.6µg/mL.


Asunto(s)
Antiinfecciosos/uso terapéutico , Antioxidantes/uso terapéutico , Hidroxibenzoatos/química , Hidroxibenzoatos/síntesis química , Fosfatidilcolinas/química , Fosfatidilcolinas/síntesis química
11.
J Oleo Sci ; 65(12): 1023-1031, 2016 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-27829607

RESUMEN

A series of novel fatty substituted 4-methyl-2H-chromen-2-one (coumarins) were synthesized by employing cross metathesis, a key step in the synthesis. The antioxidant activities of the title compounds were compared with the commercial antioxidants, namely butylated hydroxy toluene (BHT) and α-tocopherol, glycosidic and other substituted 4-methyl-2H-chromen-2-ones. Among the different 4-methyl-2H-chromen-2-ones, the glycosidic substituted 4-methyl-2H-chromen-2-ones was excellent, while those with aliphatic fatty acid chain and hydroxyl substitutents were good. Among the substituted 4-methyl-2H-chromen-2-ones, glycosidic, hydroxyl and cyano containing 4-methyl-2H-chromen-2-ones exhibited good, while fatty substituted exhibited moderate anticancer activities against the four different cancer cell lines tested, namely DU145 (Prostate carcinoma cancer cell), HepG2 (Hepato cellular carcinoma cancer cell), SKOV3 (Ovarian cancer cell) and MDA-MB 231 (Human breast cancer cell). The study reveals that these substituted coumarins can be potential candidates in a number of food and pharmaceutical formulations.


Asunto(s)
Antineoplásicos/farmacología , Antioxidantes/farmacología , Cumarinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antioxidantes/síntesis química , Antioxidantes/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cumarinas/síntesis química , Cumarinas/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Relación Estructura-Actividad
12.
Bioorg Med Chem Lett ; 26(21): 5198-5202, 2016 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-27707604

RESUMEN

A series of novel ricinoleic acid based lipoamino acid derivatives were synthesized from (Z)-methyl-12-aminooctadec-9-enoate and different l-amino acids (glycine, alanine, phenyl alanine, valine, leucine, isoleucine, proline and tryptophan). The structures of all the prepared compounds were characterized by 1H NMR, 13C NMR and mass spectral studies. The title compounds were evaluated for their antimicrobial and anti-biofilm activities. Among all the derivatives, compound 7a (Z)-methyl-12-(2-aminoacetamido)octadec-9-enoate exhibited promising antibacterial activity (MIC, 3.9-7.8µg/mL) and compounds 7b (Z)-methyl 12-(2-aminopropanamido)octadec-9-enoate and 7g (Z)-methyl-12-(pyrrolidine-2-carboxamido)octadec-9-enoate exhibited moderate activity (MIC, 7.8-31.2µg/mL) selectively against four different Gram-positive bacterial strains such as Staphylococcus aureus MTCC 96, Bacillus subtilis MTCC 121, S. aureus MLS-16 MTCC 2940, Micrococcus luteus MTCC 2470. These compounds also exhibited excellent antifungal activity against studied fungal strains. Further, the compounds 7a, 7b and 7g were also screened for anti-biofilm activity. Among these lipoamino acid derivatives, compound 7a exhibited good anti-biofilm activity (IC50, 1.9-4.1µg/mL) against four Gram-positive bacterial strains.


Asunto(s)
Aminoácidos/química , Antibacterianos/farmacología , Ácidos Ricinoleicos/síntesis química , Ácidos Ricinoleicos/farmacología , Bacillus subtilis/efectos de los fármacos , Biopelículas/efectos de los fármacos , Espectroscopía de Resonancia Magnética con Carbono-13 , Espectrometría de Masas , Pruebas de Sensibilidad Microbiana , Micrococcus luteus/efectos de los fármacos , Espectroscopía de Protones por Resonancia Magnética , Ácidos Ricinoleicos/química , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad
13.
Eur J Med Chem ; 120: 86-96, 2016 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-27187861

RESUMEN

A highly concise and expedient total synthesis of bioactive clavaminols (1-4) has been executed using commercially available achiral compound decanol. The synthetic strategy relied on trans-Wittig olefination, Sharpless asymmetric epoxidation, regioselective azidolysis and in situ detosylation followed by reduction as key reactions with good overall yield. Based on biological evaluation studies of all the synthesized compounds, it was observed that the clavaminol A (1) exhibited good cytotoxicity against DU145 and SKOV3 cell lines with IC50 value of 10.8 and 12.5 µM, respectively. Clavaminol A (1) and deacetyl clavaminol H (3) displayed selective promising inhibition towards Gram-positive pathogenic bacterial strains and showed good antifungal activity against the tested Candida strains. In addition, compounds 1 and 3 have demonstrated significant bactericidal activity. Compound 3 was found to be equipotent to the standard drug Miconazole displaying MFC value of 15.6 µg/mL against Candida albicans MTCC 854, C. albicans MTCC 1637, C. albicans MTCC 3958 and Candida glabrata MTCC 3019. Compounds 1 and 3 were also able to inhibit the biofilm formation of Micrococcus luteus MTCC 2470 and Staphylococcus aureus MLS16 MTCC 2940. Clavaminol A (1) increased the levels of reactive oxygen species (ROS) accumulation in M. luteus MTCC 2470.


Asunto(s)
Antibacterianos/química , Antifúngicos/química , Biopelículas/efectos de los fármacos , Ceramidas/farmacología , Antibacterianos/farmacología , Antifúngicos/farmacología , Candida/efectos de los fármacos , Candida/fisiología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Ceramidas/síntesis química , Bacterias Grampositivas/efectos de los fármacos , Humanos , Especies Reactivas de Oxígeno/análisis
14.
Eur J Med Chem ; 118: 98-106, 2016 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-27128176

RESUMEN

A conceptual synthetic approach of short-chain C12-sphinganine 1 and a small library of its 1,2,3-triazole analogs 2(a-f) has been accomplished using the commercially available and inexpensive 10-undecenoic acid as a starting material. Miyashita's C-2 selective endo mode azidolysis and Huisgen click reaction was employed for the synthesis of the designed analogs. Based on biological evaluation studies of all the synthesized compounds, it was observed that, (2S,3R)-2-(4-(3-hydroxyphenyl)-1H-1,2,3-triazol-1-yl)dodecan-1,3-diol (2b) exhibited promising antimicrobial and antifungal activities. Furthermore, compound 2b was able to inhibit the biofilm formation of Candida albicans MTCC 227, Micrococcus luteus MTCC 2470 and Staphylococcus aureus MTCC 96 with IC50 values of 1.9, 2.1 and 2.9 µg/mL, respectively. Compound 2b increased the levels of reactive oxygen species (ROS) in C. albicans MTCC 227.


Asunto(s)
Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Biopelículas/efectos de los fármacos , Diseño de Fármacos , Esfingosina/análogos & derivados , Triazoles/síntesis química , Triazoles/farmacología , Antiinfecciosos/química , Candida albicans/citología , Candida albicans/efectos de los fármacos , Candida albicans/metabolismo , Candida albicans/fisiología , Técnicas de Química Sintética , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Pruebas de Sensibilidad Microbiana , Micrococcus luteus/efectos de los fármacos , Micrococcus luteus/fisiología , Especies Reactivas de Oxígeno/metabolismo , Esfingosina/química , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/fisiología , Triazoles/química
15.
Sci Rep ; 6: 21624, 2016 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-26902658

RESUMEN

The role of the unique proline-glutamic acid (PE)/proline-proline-glutamic acid (PPE) family of proteins in the pathophysiology and virulence of Mycobacterium tuberculosis is not clearly understood. One of the PE family proteins, PE11 (LipX or Rv1169c), specific to pathogenic mycobacteria is found to be over-expressed during infection of macrophages and in active TB patients. In this study, we report that M. smegmatis expressing PE11 (Msmeg-PE11) exhibited altered colony morphology and cell wall lipid composition leading to a marked increase in resistance against various environmental stressors and antibiotics. The cell envelope of Msmeg-PE11 also had greater amount of glycolipids and polar lipids. Msmeg-PE11 was found to have better survival rate in infected macrophages. Mice infected with Msmeg-PE11 had higher bacterial load, showed exacerbated organ pathology and mortality. The liver and lung of Msmeg-PE11-infected mice also had higher levels of IL-10, IL-4 and TNF-α cytokines, indicating a potential role of this protein in mycobacterial virulence.


Asunto(s)
Proteínas Bacterianas/genética , Pared Celular/metabolismo , Infecciones por Mycobacterium no Tuberculosas/patología , Mycobacterium tuberculosis/patogenicidad , Transgenes , Factores de Virulencia/genética , Animales , Proteínas Bacterianas/inmunología , Pared Celular/química , Expresión Génica , Interleucina-10/biosíntesis , Interleucina-10/inmunología , Interleucina-4/biosíntesis , Interleucina-4/inmunología , Hígado/microbiología , Hígado/patología , Pulmón/microbiología , Pulmón/patología , Macrófagos/microbiología , Masculino , Ratones , Ratones Endogámicos BALB C , Infecciones por Mycobacterium no Tuberculosas/genética , Infecciones por Mycobacterium no Tuberculosas/microbiología , Infecciones por Mycobacterium no Tuberculosas/mortalidad , Mycobacterium smegmatis/genética , Mycobacterium smegmatis/metabolismo , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Organismos Modificados Genéticamente , Análisis de Supervivencia , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/inmunología , Virulencia , Factores de Virulencia/inmunología
16.
Eur J Med Chem ; 109: 134-45, 2016 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-26774921

RESUMEN

In the present study, Lactobacillus plantarum glycolipid (GL1) molecule in ß-configuration and its fatty acid analogues were synthesized using trichloroacetimidate methodology. The ß-configuration of the GL1 molecule was unambiguously assigned by NMR studies using 2D-ROESY (NOE) and J-coupling analysis. Dihydrosterculic acid was synthesized using Furukawa's reagent and the selective esterification of dihydrosterculic acid at C-3 position of glycerol was achieved with EDC-HCl at 0 °C. In vitro cytotoxicity of the GL1 molecule and its fatty acid analogues was evaluated against DU145, A549, SKOV3 and MCF7 cell lines. Among all the synthesized molecules, the GL1 molecule and compound 7d showed moderate activity, while the compound 7b showed promising activity against all the tested cell lines with IC50 values of 20.1, 18.2, 19.1 and 17.6 µM, respectively. In addition, all tested compounds showed poor cytotoxicity against normal HUVEC cells. The MCF7 cells when treated with compound 7b showed lower bromodeoxyuridine incorporation levels as compared to untreated cells, suggesting that the compound 7b was highly effective and inhibited the cell proliferation. In addition, the compounds showed significant increase in caspases 3 and 9 levels by inducing apoptosis in MCF 7 cells.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Ácidos Grasos/química , Ácidos Grasos/farmacología , Glucolípidos/química , Glucolípidos/farmacología , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Mama/efectos de los fármacos , Mama/metabolismo , Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Caspasas/metabolismo , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Activación Enzimática/efectos de los fármacos , Ácidos Grasos/síntesis química , Femenino , Glucolípidos/síntesis química , Humanos , Lactobacillus plantarum/química , Células MCF-7
17.
Bioorg Med Chem Lett ; 26(1): 209-12, 2016 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-26586599

RESUMEN

Seven novel lipoamino acid conjugates were synthesized from methyl oleate and amino acids. Methyl oleate was grafted to different amino acids using thioglycolic acid as a spacer group. Seven derivatives (3a-g) were prepared and characterized by spectral data (NMR, IR and MS spectral studies). All the derivatives were studied for their antimicrobial, anti-biofilm and anticancer activities. Among all the derivatives, it was found that compound 3b was the most potent antibacterial compound which showed good activity against four Gram positive bacterial strains and also exhibited excellent antifungal activity against a fungal strain. In the anti-biofilm assay, compound 3b showed promising activity with IC50 value of 2.8µM against Bacillus subtilis MTCC 121. All the compounds showed anticancer activities with 3c showing promising anticancer activity (IC50=15.3-22.4µM) against the four cell lines tested.


Asunto(s)
Aminoácidos/química , Aminoácidos/farmacología , Antibacterianos/farmacología , Antifúngicos/farmacología , Antineoplásicos/farmacología , Ácidos Oléicos/química , Ácidos Oléicos/farmacología , Aminoácidos/síntesis química , Antibacterianos/síntesis química , Antibacterianos/química , Antifúngicos/síntesis química , Antifúngicos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Biopelículas/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Hongos/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Células Hep G2 , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Ácidos Oléicos/síntesis química , Relación Estructura-Actividad , Tioglicolatos/química
18.
Bioorg Med Chem Lett ; 26(2): 613-617, 2016 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-26646219

RESUMEN

A series of novel ethyl 1-ethyl-6-fluoro-7-(fatty amido)-1,4-dihydro-4-oxoquinoline-3-carboxylate derivatives were prepared through multistep synthesis. The key step in the synthesis was to obtain the C-7 fatty amide derivative. The azide was selectively formed at C-7 position using sodium azide at 60°C. Subsequently, the azide was reduced under mild conditions using zinc and ammonium chloride to form the corresponding amine. The synthesized derivatives were further subjected to biological evaluation studies like cytotoxicity against a panel of cancer cell lines such as DU145, A549, SKOV3, MCF7 and normal lung cells, IMR-90 as well as with antimicrobial and antioxidant activities. It was observed that the carboxylated quinolone derivatives with hexanoic (8a), octanoic (8b), lauric (8d) and myristic (8e) moieties exhibited promising cytotoxicity against all the tested cancer cell lines. The results also suggested that hexanoic acid-based fatty amide carboxylated quinolone derivative (8a) exhibited promising activity against both bacterial and fungal strains and significant antibacterial activity was observed against Staphylococcus aureus MTCC 96 (MIC value of 3.9µg/mL). The compound 8a also showed excellent anti-biofilm activity against Staphylococcus aureus MTCC 96 and Bacillus subtilis MTCC 121 with MIC values of 2.1 and 4.6µg/mL, respectively.


Asunto(s)
4-Quinolonas/química , Antiinfecciosos/química , Antineoplásicos/química , Antioxidantes/química , 4-Quinolonas/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Antiinfecciosos/farmacología , Antineoplásicos/farmacología , Antioxidantes/farmacología , Bacterias/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Línea Celular Tumoral , Hongos/efectos de los fármacos , Halogenación , Humanos , Micosis/tratamiento farmacológico , Neoplasias/tratamiento farmacológico
19.
J Food Sci Technol ; 52(8): 4905-14, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26243910

RESUMEN

Lipase catalyzed interesterification of rice bran oil (RBO) with hydrogenated cottonseed oil (HCSO) was carried out for producing a low trans free fat. The interesterification reaction was performed by varying parameters such as weight proportions of RBO and HCSO, reaction temperatures, time period and lipase concentration. Both non specific and specific lipases namely Novozym 435 and Lipozyme TL IM were employed for this study. Based on the data generated, the optimum reaction conditions were found to be: weight proportion of RBO and HCSO, 80:20; lipase concentration, 5 % (w/w) of substrates; reaction temperature, 60 °C; reaction time, 4 h for Lipozyme TL IM and 5 h for Novozym 435. The degree of interesterification, calculated based on the results of solid fat characteristics was used for comparing the catalytic activity of Novozym 435 and Lipozyme TL IM. It was observed that the degree of interesterification (DI) reached a near 100 % at the 4th hour for reaction employing Lipozyme TL IM with a rate constant of 0.191 h(-1) while Novozym 435 catalyzed reaction reached a near 100 % degree of interesterification at the 5th hour with a rate constant of 0.187 h(-1), suggesting that Lipozyme TL IM has a faster catalytic activity.

20.
Bioresour Technol ; 188: 99-102, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25777067

RESUMEN

Solid acid catalysts can hydrolyze cellulose with lower reaction times and are easy to recover and reuse. A glycerol based carbon acid catalyst developed at CSIR-IICT performed well in acid catalysis reactions and hence this study was undertaken to evaluate the catalyst for hydrolysis of biomass (alkali pretreated or native rice straw). The catalyst could release 262 mg/g total reducing sugars (TRS) in 4h at 140 °C from alkali pretreated rice straw, and more importantly it released 147 mg/g TRS from native biomass. Reusability of the catalyst was also demonstrated. Catalytic hydrolysate was used as sugar source for fermentation to produce ethanol. Results indicate the solid acid catalyst as an interesting option for biomass hydrolysis.


Asunto(s)
Biomasa , Biotecnología/métodos , Carbono/química , Etanol/química , Carbohidratos/química , Catálisis , Fermentación , Glicerol/química , Hidrólisis , Oryza , Saccharomyces cerevisiae/enzimología , Temperatura
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