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ABSTRACT: Genomic instability contributes to cancer progression and is at least partly due to dysregulated homologous recombination (HR). Here, we show that an elevated level of ABL1 kinase overactivates the HR pathway and causes genomic instability in multiple myeloma (MM) cells. Inhibiting ABL1 with either short hairpin RNA or a pharmacological inhibitor (nilotinib) inhibits HR activity, reduces genomic instability, and slows MM cell growth. Moreover, inhibiting ABL1 reduces the HR activity and genomic instability caused by melphalan, a chemotherapeutic agent used in MM treatment, and increases melphalan's efficacy and cytotoxicity in vivo in a subcutaneous tumor model. In these tumors, nilotinib inhibits endogenous as well as melphalan-induced HR activity. These data demonstrate that inhibiting ABL1 using the clinically approved drug nilotinib reduces MM cell growth, reduces genomic instability in live cell fraction, increases the cytotoxicity of melphalan (and similar chemotherapeutic agents), and can potentially prevent or delay progression in patients with MM.
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Antineoplásicos , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Melfalán/farmacología , Inestabilidad Genómica , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
BACKGROUND & AIMS: The purpose of this study was to identify drivers of genomic evolution in esophageal adenocarcinoma (EAC) and other solid tumors. METHODS: An integrated genomics strategy was used to identify deoxyribonucleases correlating with genomic instability (as assessed from total copy number events in each patient) in 6 cancers. Apurinic/apyrimidinic nuclease 1 (APE1), identified as the top gene in functional screens, was either suppressed in cancer cell lines or overexpressed in normal esophageal cells and the impact on genome stability and growth was monitored in vitro and in vivo. The impact on DNA and chromosomal instability was monitored using multiple approaches, including investigation of micronuclei, acquisition of single nucleotide polymorphisms, whole genome sequencing, and/or multicolor fluorescence in situ hybridization. RESULTS: Expression of 4 deoxyribonucleases correlated with genomic instability in 6 human cancers. Functional screens of these genes identified APE1 as the top candidate for further evaluation. APE1 suppression in EAC, breast, lung, and prostate cancer cell lines caused cell cycle arrest; impaired growth and increased cytotoxicity of cisplatin in all cell lines and types and in a mouse model of EAC; and inhibition of homologous recombination and spontaneous and chemotherapy-induced genomic instability. APE1 overexpression in normal cells caused a massive chromosomal instability, leading to their oncogenic transformation. Evaluation of these cells by means of whole genome sequencing demonstrated the acquisition of changes throughout the genome and identified homologous recombination as the top mutational process. CONCLUSIONS: Elevated APE1 dysregulates homologous recombination and cell cycle, contributing to genomic instability, tumorigenesis, and chemoresistance, and its inhibitors have the potential to target these processes in EAC and possibly other cancers.
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Adenocarcinoma , Resistencia a Antineoplásicos , Masculino , Animales , Ratones , Humanos , Resistencia a Antineoplásicos/genética , Hibridación Fluorescente in Situ , Línea Celular Tumoral , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Carcinogénesis/genética , Transformación Celular Neoplásica/genética , Recombinación Homóloga , Ciclo Celular , Inestabilidad Genómica , Genómica , Inestabilidad Cromosómica/genética , Desoxirribonucleasas/genética , Evolución MolecularRESUMEN
PURPOSE: Thyroid eye disease (TED) associated with diabetes mellitus (DM) presents unique challenges. DM is a risk factor for TED. Standard management of TED with glucocorticoids (GC), orbital radiation, or teprotumumab can cause adverse events in poor glycemic control. The authors reviewed the literature on the relationship between TED and DM and the management of co-existing diseases. METHODS: The authors searched PubMed with keywords "thyroid eye disease," "diabetes mellitus," and similar terms from 2013 to 2022. The authors included relevant studies after screening the abstracts. Additional references to the selected studies were included where applicable. Data were extracted from the final articles according to the preplanned outline of the review. RESULTS: The initial search yielded 279 abstracts. The final review included 93 articles. TED and DM interact at multiple levels-genetic, immunologic, cellular, nutritional, and metabolic. Both DM and thyroid dysfunction exacerbate the morbidity caused by the other. Metabolic factors also affect the inflammatory pathway for TED. Patients with DM develop TED with greater frequency and severity, necessitating interventions for vision salvage. Agents (GC, teprotumumab, or radiation) used for TED are often unsuitable for treatment with DM, especially if there is poor glycemic control or diabetic retinopathy. There were no studies on using steroid-sparing agents in TED with DM. CONCLUSION: TED and DM co-exist because of multiple intersections in the pathophysiology. Challenges in the treatment include increased TED severity and risk of hyperglycemia and retinopathy. Multidisciplinary teams best undertake treatment of TED with DM.
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Diabetes Mellitus , Oftalmopatía de Graves , Enfermedades de la Retina , Humanos , Glucocorticoides/efectos adversos , Oftalmopatía de Graves/complicaciones , Factores de RiesgoRESUMEN
Autophagy is a quality-control mechanism that helps to maintain cellular homeostasis by removing damaged proteins and organelles through lysosomal degradation. During autophagy, signaling events lead to the formation of a cup-shaped structure called the phagophore that matures into the autophagosome. Recruitment of the autophagy-associated Atg12-5-16L1 complex to Wipi2-positive phagophores is crucial for producing microtubule-associated protein 1 light chain 3-II (LC3-II), which is required for autophagosome formation. Here, we explored the role of the autophagy receptor optineurin (Optn) in autophagosome formation. Fibroblasts from Optn knock-out mouse showed reduced LC3-II formation and a lower number of autophagosomes and autolysosomes during both basal and starvation-induced autophagy. However, the number of Wipi2-positive phagophores was not decreased in Optn-deficient cells. We also found that the number of Atg12/16L1-positive puncta and recruitment of the Atg12-5-16L1 complex to Wipi2-positive puncta are reduced in Optn-deficient cells. Of note, Optn was recruited to Atg12-5-16L1-positive puncta, and interacted with Atg5 and also with Atg12-5 conjugate. A disease-associated Optn mutant, E478G, defective in ubiquitin binding, was also defective in autophagosome formation and recruitment to the Atg12-5-16L1-positive puncta. Moreover, we noted that Optn phosphorylation at Ser-177 was required for autophagosome formation but not for Optn recruitment to the phagophore. These results suggest that Optn potentiates LC3-II production and maturation of the phagophore into the autophagosome, by facilitating the recruitment of the Atg12-5-16L1 complex to Wipi2-positive phagophores.
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Proteínas Relacionadas con la Autofagia/metabolismo , Proteínas Portadoras/metabolismo , Proteínas del Ojo/metabolismo , Proteínas de la Membrana/metabolismo , Factor de Transcripción TFIIIA/metabolismo , Animales , Autofagosomas/metabolismo , Autofagia/fisiología , Proteínas de Ciclo Celular , Femenino , Células HEK293 , Humanos , Masculino , Proteínas de Transporte de Membrana , Ratones , Ratones Noqueados , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas de Unión a Fosfato , Unión ProteicaRESUMEN
Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.
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Axones/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Genoma/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Animales , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Ratones , Mutación , Proteínas/genética , Transducción de SeñalRESUMEN
OBJECTIVES: To examine the potential of ferulic acid and 4-vinylguaiacol for inhibiting epidermal growth factor receptor (EGFR) in human breast cancer cells in vitro. RESULTS: Ferulic acid and 4-vinylguaiacol limit the EGF (epidermal growth factor)-induced breast cancer proliferation and new DNA synthesis. Western blot analysis revealed both ferulic acid and 4-vinylguaiacol exhibit sustained inhibition of EGFR activation through down-regulation of Tyr 1068 autophosphorylation. Molecular docking analysis shows ferulic acid forming hydrogen bond interaction with Lys 745 and Met 793 whereas, 4-vinylguaiacol forms two hydrogen bonds with Phe 856 and exhibits stronger hydrophobic interactions with multiple amino acid residues at the EGFR kinase domain. CONCLUSIONS: Ferulic acid and 4-vinylguaiacol could serve as a potential structure for the development of new small molecule therapeutics against EGFR.
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Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Ácidos Cumáricos/farmacología , Receptores ErbB/antagonistas & inhibidores , Guayacol/análogos & derivados , Línea Celular Tumoral , Ácidos Cumáricos/química , Ácidos Cumáricos/metabolismo , Receptores ErbB/química , Receptores ErbB/efectos de los fármacos , Receptores ErbB/metabolismo , Femenino , Guayacol/química , Guayacol/metabolismo , Guayacol/farmacología , Humanos , Simulación del Acoplamiento MolecularRESUMEN
BACKGROUND: Cardiovascular disease (CVD) is a common cause of morbidity and mortality in end-stage renal disease (ESRD) patients on hemodialysis (HD) among whom it is 5-20 times higher than in the general population. Some of the nontraditional risk factors such as oxidative stress and inflammation are related to the progress of CVD in HD patients. Several, but not all studies, reported that inflammatory and oxidative stress markers are increased during a single session of HD, mimicking changes that occur during acute immune activation. This study was taken up to evaluate the changes in the inflammatory and oxidative stress markers during a single HD session in patients with chronic kidney disease. METHODS: Twenty-five ESRD patients on maintenance HD and 25 controls were included in the study. Blood samples were obtained from the patients before starting of hemodialysis (pre-HD) and after completion of hemodialysis (post-HD). The changes in serum Pentraxin-3, hs-CRP, malondialdehyde (MDA) and ferric reducing ability of plasma (FRAP) levels were measured in pre- and post-HD ESRD patients and compared with healthy control group. RESULTS: This study found increased levels of Pentraxin-3, hs-CRP, MDA, and decreased level of FRAP in HD patients compared to controls. CONCLUSIONS: Hemodialysis procedure contributes to inflammation and oxidative stress.
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Inflamación/sangre , Fallo Renal Crónico/terapia , Estrés Oxidativo , Diálisis Renal/efectos adversos , Adulto , Anciano , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Enfermedades Cardiovasculares/etiología , Estudios de Casos y Controles , Femenino , Humanos , India , Fallo Renal Crónico/complicaciones , Masculino , Malondialdehído/sangre , Persona de Mediana Edad , Factores de Riesgo , Componente Amiloide P Sérico/análisisRESUMEN
BACKGROUND AND AIMS: Magnesium sulfate and midazolam have been used as adjuvants to local anesthetics via intrathecal and epidural routes to augment the quality of block and prolong postoperative analgesia. This study compares addition of intrathecal magnesium sulfate versus intrathecal midazolam to epidurally administered isobaric ropivacaine as a part of combined spinal epidural technique in pre-eclamptic parturients undergoing elective cesarean section. MATERIAL AND METHODS: After institutional ethics committee approval and written informed consent, 50 pre-eclamptic parturients were randomly allocated to one of the two groups of 25 each to either receive intrathecal magnesium sulfate (50 mg) or intrathecal midazolam (1 mg) in combination with epidural ropivacaine (0.75%; 14-16 ml). The onset and duration of sensory and motor blockade, duration of postoperative analgesia, postoperative visual analogue scores for pain, and perioperative side effects were noted. Data were analyzed statistically using Graphpad.com software. RESULTS: Onset times to sensory and motor blockade were faster in midazolam than in magnesium group (P < 0.01). Duration of sensory and motor blockade, and time to first request of analgesia were significantly longer in the magnesium group compared to the midazolam group (P < 0.01). The fetal outcomes according to APGAR scores were comparable in both the groups, the median APGAR score at 1 minute was 8 and at 5 minutes was 10 in both the groups. CONCLUSION: Intrathecal magnesium with epidural ropivacaine significantly prolonged postoperative analgesia compared to intrathecal midazolam without any complications. Perioperative hemodynamics were comparable in both groups.
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An altered metabolism supports growth of tumor. AKT, a major signal integrator plays a key role in cell metabolism. We have shown that nutritional deprivation activates AKT as observed by increased phosphorylation of both Thr308 and Ser473. Pharmacological inhibition or silencing of AKT by siRNA affects cell viability during starvation. The tumor suppressor, p53 is also observed to be elevated during nutritional deprivation due to AKT. Silencing of AKT and p53 enhanced autophagy as evidenced by increased acidic vesicular organelles and LC3B II levels, suggesting AKT-p53 to play a significant role in cell survival through regulating autophagy during nutritional deprivation.
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Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Autofagia/fisiología , Línea Celular Tumoral , Femenino , Glucosa/metabolismo , Glutamina/metabolismo , Humanos , Células MCF-7 , Estabilidad Proteica , Proteínas Proto-Oncogénicas c-akt/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Metabolic syndrome-induced cardiac hypertrophy is a global concern leading to an increase in the morbidity and mortality of patients, with the signalling mechanism associated with them still unclear. The present study attempts to understand the metabolic syndrome-associated cardiac hypertrophy through an in vitro model using external stimuli well known for inducing metabolic disorders, i.e. dexamethasone (DEX), a synthetic glucocorticoid. DEX (0.1 and 1 µM) promoted cardiac hypertrophy in H9C2 cells at 4 days of treatment as evidenced through increased cell size and protein content. A significant induction in foetal gene reprogramming was observed, confirming the establishment of hypertrophy. Moreover, the hypertrophic response at 4 days was perceived to be physiological at 0.1 µM and pathological at 1 µM based on α-MHC and IGF1R expression, but complete inhibition in the PKB/AKT expression confirmed it to be pathological hypertrophy at both the concentrations (0.1 and 1 µM). The present study reports for the first time the mechanistic insights into DEX-mediated hypertrophy. It is hypothesized to be orchestrated through the activation of AT1R that is involved in the alteration of the cardiac isoform of SERCA2 expression perturbing the calcium homeostasis. This leads to the activation of calcineurin B, independent of NFAT involvement, which in coordination with ROS induces the activation of JNK of the MAPK signalling.
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Calcineurina/metabolismo , Dexametasona/farmacología , Miocitos Cardíacos/efectos de los fármacos , Factores de Transcripción NFATC/metabolismo , Línea Celular , Humanos , Cadenas Ligeras de Miosina/metabolismoRESUMEN
AIM/HYPOTHESIS: Type 2 diabetes is a complex disease characterised by hyperglycaemia, hyperinsulinaemia, dyslipidaemia and insulin resistance accompanied by inflammation. Previously, we showed that mice lacking the Wdr13 gene had increased islet mass due to enhanced beta cell proliferation. We hypothesised that introgression of a Wdr13-null mutation, a beta cell-proliferative phenotype, into Lepr(db/db) mice, a beta cell-destructive phenotype, might rescue the diabetic phenotype of the latter. METHODS: Wdr13-deficient mice were crossed with Lepr(db/db) mice to generate mice with the double mutation. We measured various serum metabolic variables of Wdr13(+/0)Lepr(db/db) and Wdr13(-/0) Lepr(db/db) mice. Further, we analysed the histopathology and gene expression of peroxisome proliferator-activated receptor (PPAR)γ and, activator protein (AP)1 targets in various metabolic tissues. RESULTS: Lepr(db/db) mice with the Wdr13 deletion had a massively increased islet mass, hyperinsulinaemia and adipocyte hypertrophy. The increase in beta cell mass in Wdr13(-/0)Lepr(db/db) mice was due to an increase in beta cell proliferation. Hypertrophy of adipocytes may be the result of increase in transcription of Pparg and its target genes, leading in turn to increased expression of several lipogenic genes. We also observed a significant decrease in the expression of AP1 and nuclear factor κ light chain enhancer of activated B cells (NFκB) target genes involved in inflammation. CONCLUSIONS/INTERPRETATION: This study provides evidence that loss of WD repeat domain 13 (WDR13) protein in the Lepr (db/db) mouse model of diabetes is beneficial. Based on these findings, we suggest that WDR13 may be a potential drug target for ameliorating hyperglycaemia and inflammation in diabetic conditions.
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Adipocitos/metabolismo , Hiperglucemia/metabolismo , Inflamación/metabolismo , Proteínas Nucleares/metabolismo , PPAR gamma/metabolismo , Receptores de Leptina/metabolismo , Animales , Proteínas de Ciclo Celular , Proliferación Celular , Modelos Animales de Enfermedad , Eliminación de Gen , Expresión Génica , Células Secretoras de Insulina , Ratones , Ratones Transgénicos , Proteínas Nucleares/genética , Fenotipo , Receptores de Leptina/genéticaRESUMEN
Neural tube defects (NTDs) are common birth defects of complex etiology. Family and population-based studies have confirmed a genetic component to NTDs. However, despite more than three decades of research, the genes involved in human NTDs remain largely unknown. We tested the hypothesis that rare copy number variants (CNVs), especially de novo germline CNVs, are a significant risk factor for NTDs. We used array-based comparative genomic hybridization (aCGH) to identify rare CNVs in 128 Caucasian and 61 Hispanic patients with non-syndromic lumbar-sacral myelomeningocele. We also performed aCGH analysis on the parents of affected individuals with rare CNVs where parental DNA was available (42 sets). Among the eight de novo CNVs that we identified, three generated copy number changes of entire genes. One large heterozygous deletion removed 27 genes, including PAX3, a known spina bifida-associated gene. A second CNV altered genes (PGPD8, ZC3H6) for which little is known regarding function or expression. A third heterozygous deletion removed GPC5 and part of GPC6, genes encoding glypicans. Glypicans are proteoglycans that modulate the activity of morphogens such as Sonic Hedgehog (SHH) and bone morphogenetic proteins (BMPs), both of which have been implicated in NTDs. Additionally, glypicans function in the planar cell polarity (PCP) pathway, and several PCP genes have been associated with NTDs. Here, we show that GPC5 orthologs are expressed in the neural tube, and that inhibiting their expression in frog and fish embryos results in NTDs. These results implicate GPC5 as a gene required for normal neural tube development.
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Polaridad Celular , Variaciones en el Número de Copia de ADN , Glipicanos/genética , Disrafia Espinal/genética , Animales , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Hispánicos o Latinos/genética , Humanos , Masculino , Tubo Neural/embriología , Tubo Neural/metabolismo , Disrafia Espinal/embriología , Disrafia Espinal/fisiopatología , Población Blanca/genética , Pez CebraRESUMEN
MOTIVATION: Copy number variations (CNVs) are a major source of genomic variability and are especially significant in cancer. Until recently microarray technologies have been used to characterize CNVs in genomes. However, advances in next-generation sequencing technology offer significant opportunities to deduce copy number directly from genome sequencing data. Unfortunately cancer genomes differ from normal genomes in several aspects that make them far less amenable to copy number detection. For example, cancer genomes are often aneuploid and an admixture of diploid/non-tumor cell fractions. Also patient-derived xenograft models can be laden with mouse contamination that strongly affects accurate assignment of copy number. Hence, there is a need to develop analytical tools that can take into account cancer-specific parameters for detecting CNVs directly from genome sequencing data. RESULTS: We have developed WaveCNV, a software package to identify copy number alterations by detecting breakpoints of CNVs using translation-invariant discrete wavelet transforms and assign digitized copy numbers to each event using next-generation sequencing data. We also assign alleles specifying the chromosomal ratio following duplication/loss. We verified copy number calls using both microarray (correlation coefficient 0.97) and quantitative polymerase chain reaction (correlation coefficient 0.94) and found them to be highly concordant. We demonstrate its utility in pancreatic primary and xenograft sequencing data. AVAILABILITY AND IMPLEMENTATION: Source code and executables are available at https://github.com/WaveCNV. The segmentation algorithm is implemented in MATLAB, and copy number assignment is implemented Perl. CONTACT: lakshmi.muthuswamy@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Variaciones en el Número de Copia de ADN , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias/genética , Algoritmos , Alelos , Aneuploidia , Animales , Humanos , Ratones , Análisis de Secuencia de ADN , Programas Informáticos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Polyphosphate (polyP), a polymer of orthophosphate moieties released from the dense granules of activated platelets, is a procoagulant agent. Inositol pyrophosphates, another group of phosphate-rich molecules, consist of mono- and diphosphates substituted on an inositol ring. Diphosphoinositol pentakisphosphate (IP7), the most abundant inositol pyrophosphate, is synthesized on phosphorylation of inositol hexakisphosphate (IP6) by IP6 kinases, of which there are 3 mammalian isoforms (IP6K1/2/3) and a single yeast isoform. Yeast lacking IP6 kinase are devoid of polyP, suggesting a role for IP6 kinase in maintaining polyP levels. We theorized that the molecular link between IP6 kinase and polyP is conserved in mammals and investigated whether polyP-dependent platelet function is altered in IP6K1 knockout (Ip6k1(-/-)) mice. We observe a significant reduction in platelet polyP levels in Ip6k1(-/-) mice, along with slower platelet aggregation and lengthened plasma clotting time. Incorporation of polyP into fibrin clots was reduced in Ip6k1(-/-) mice, thereby altering clot ultrastructure, which was rescued on the addition of exogenous polyP. In vivo assays revealed longer tail bleeding time and resistance to thromboembolism in Ip6k1(-/-) mice. Taken together, our data suggest a novel role for IP6K1 in regulation of mammalian hemostasis via its control of platelet polyP levels.
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Plaquetas/metabolismo , Fosfotransferasas (Aceptor del Grupo Fosfato)/fisiología , Polifosfatos/metabolismo , Animales , Tiempo de Sangría , Coagulación Sanguínea , Hemostasis , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Selectina-P/metabolismo , Ácido Fítico/metabolismo , Embolia Pulmonar/metabolismo , Trombina/metabolismo , Tromboembolia/sangreRESUMEN
Trichosporon species are basidiomycetous yeast-like anamorphic organisms (Basidiomycota, Hymenomycetes, Tremelloidae, Trichosporonales) that are widely distributed in nature. Trichosporon species colonize the skin and gastrointestinal tract of humans. We present a report of disseminated Trichosporon in a renal allograft recipient. Our patient satisfied the definitions of both "proven invasive trichosporonosis" and "probable pulmonary infection." Only 2 reports of disseminated Trichosporon infection in renal transplant recipients, to our knowledge, have been published.
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Huésped Inmunocomprometido , Trasplante de Riñón , Complicaciones Posoperatorias/diagnóstico , Tricosporonosis/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/inmunología , Tricosporonosis/inmunologíaRESUMEN
Genomic copy number variation underlies genetic disorders such as autism, schizophrenia, and congenital heart disease. Copy number variations are commonly detected by array based comparative genomic hybridization of sample to reference DNAs, but probe and operational variables combine to create correlated system noise that degrades detection of genetic events. To correct for this we have explored hybridizations in which no genetic signal is expected, namely "self-self" hybridizations (SSH) comparing DNAs from the same genome. We show that SSH trap a variety of correlated system noise present also in sample-reference (test) data. Through singular value decomposition of SSH, we are able to determine the principal components (PCs) of this noise. The PCs themselves offer deep insights into the sources of noise, and facilitate detection of artifacts. We present evidence that linear and piecewise linear correction of test data with the PCs does not introduce detectable spurious signal, yet improves signal-to-noise metrics, reduces false positives, and facilitates copy number determination.
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Variaciones en el Número de Copia de ADN/genética , Bases de Datos Genéticas , Hibridación Genética , Sondas de ADN/metabolismo , Genoma Humano/genética , Humanos , Masculino , Análisis de Componente Principal , Estándares de ReferenciaRESUMEN
This study was undertaken to evaluate cardio protective effect of rutin against sodium fluoride (NaF)-induced oxidative stress-mediated cardiotoxicity and blood toxicity. Cardiac injury was induced by daily administration of NaF 600 ppm in distilled water for four weeks. The animals exposed to NaF exhibited a significant increase in levels of cardiac serum markers, lipid peroxidative markers, serum total cholesterol, LDL, triglycerides and decrease in HDL levels. Decrease in hematological parameters, namely hemoglobin, red blood cells, mean corpuscular volume, mean corpuscular hemoglobin (MCH), MCH count and increase in white blood cells and erythrocyte sedimentation levels were also observed. Marked histopathological lesions and increased DNA fragmentation in cardiac tissues were observed. Activity of antioxidants-catalase, superoxide dismutase and reduced glutathione contents were decreased (p < 0.01), whereas lipid peroxidation product (malondialdehyde) was increased. A significant decrease in body and heart weight was also observed. Treatment with rutin effectively ameliorated the alterations in the studied parameters of rat through its antioxidant nature. There was also significant improvement in hematological parameters. Thus, results of this study clearly demonstrated that treatment with rutin against NaF intoxication has a significant role in protecting F-induced cardiotoxicity, blood toxicity and dyslipidemia in rats.
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Antioxidantes/farmacología , Dislipidemias/prevención & control , Cardiopatías/prevención & control , Lípidos/sangre , Miocitos Cardíacos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Rutina/farmacología , Fluoruro de Sodio , Animales , Apoptosis/efectos de los fármacos , Biomarcadores/sangre , Citoprotección , Fragmentación del ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Dislipidemias/sangre , Dislipidemias/inducido químicamente , Femenino , Cardiopatías/sangre , Cardiopatías/inducido químicamente , Cardiopatías/patología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas WistarRESUMEN
Macrocycles are key structural elements in numerous bioactive small molecules and are attractive targets in the diversity-oriented synthesis of natural product-based libraries. However, efficient and systematic access to diverse collections of macrocycles has proven difficult using classical macrocyclization reactions. To address this problem, we have developed a concise, modular approach to the diversity-oriented synthesis of macrolactones and macrolactams involving oxidative cleavage of a bridging double bond in polycyclic enol ethers and enamines. These substrates are assembled in only four or five synthetic steps and undergo ring expansion to afford highly functionalized macrocycles bearing handles for further diversification. In contrast to macrocyclization reactions of corresponding seco acids, the ring expansion reactions are efficient and insensitive to ring size and stereochemistry, overcoming key limitations of conventional approaches to systematic macrocycle synthesis. Cheminformatic analysis indicates that these macrocycles access regions of chemical space that overlap with natural products, distinct from currently targeted synthetic drugs.
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Lactamas Macrocíclicas/síntesis química , Lactonas/síntesis química , Compuestos Macrocíclicos/síntesis química , Ciclización , Estructura Molecular , Oxidantes/química , Análisis de Componente PrincipalRESUMEN
Emerging data indicate that gut-derived endotoxin (metabolic endotoxemia) may contribute to low-grade systemic inflammation in insulin-resistant states. Specific gut bacteria seem to serve as lipopolysaccharide (LPS) sources and several reports claim a role for increased intestinal permeability in the genesis of metabolic disorders. Therefore, we investigated the serum levels of LPS and zonulin (ZO-1, a marker of gut permeability) along with systemic levels of tumor necrosis factor-α (TNF-α) and Interleukin-6 (IL-6) in patients with type 2 diabetes mellitus (T2DM) compared to control subjects. Study subjects were recruited from the Chennai Urban Rural Epidemiology Study [CURES], Chennai, India. Study group (n = 45 each) comprised of a) subjects with normal glucose tolerance (NGT) and (b) patients with T2DM. LPS, ZO-1, TNF-α, and IL-6 levels were measured by ELISA. Serum levels of LPS [p < 0.05], LPS activity [p < 0.001], ZO-1 [p < 0.001], TNFα [p < 0.001], and IL-6 [p < 0.001] were significantly increased in patients with T2DM compared to control subjects. Pearson correlation analysis revealed that LPS activity was significantly and positively correlated with ZO-1, fasting plasma glucose, 2 h post glucose, HbA1c, serum triglycerides, TNF-α, IL-6, and negatively correlated with HDL cholesterol. Regression analysis showed that increased LPS levels were significantly associated with type 2 diabetes [odds ratio (OR) 13.43, 95 % CI 1.998-18.9; p = 0.003]. In Asian Indians who are considered highly insulin resistant, the circulatory LPS levels, LPS activity, and ZO-1 were significantly increased in patients with type 2 diabetes and showed positive correlation with inflammatory markers and poor glycemic/lipid control.
Asunto(s)
Biomarcadores/sangre , Diabetes Mellitus Tipo 2/sangre , Inflamación/sangre , Lipopolisacáridos/sangre , Proteína de la Zonula Occludens-1/sangre , Glucemia , HDL-Colesterol/sangre , Endotoxemia/sangre , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Resistencia a la Insulina , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Triglicéridos/sangre , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Hyperinsulinemia is being implicated in the development of insulin resistance but remains poorly understood. The present study focuses on p53-mediated impaired insulin signaling by hyperinsulinemia in 3T3-L1 adipocytes. Hyperinsulinemia impairs insulin-stimulated glucose uptake and its cellular signaling in a dose- and time-dependent manner. An increased level of reactive oxygen species (ROS) and stress response signals were observed, and quenching of the ROS by an antioxidant N-acetylcysteine (NAC) did not revert impaired insulin sensitivity. The tumor suppressor p53 has emerged as a crucial factor in the metabolic adaptation of cancer cells under nutritional starvation and is being studied in the development of insulin resistance in adipocytes at physiological level. Interestingly, we observed hyperinsulinemia-enhanced p53 level in a time-dependent manner without exhibiting cytotoxicity. Transient knockdown of p53 partially improved insulin sensitivity revealing a novel link between p53 and insulin signaling in adipocytes. The findings suggest that hyperinsulinemia-induced p53 impairs insulin sensitivity in 3T3-L1 adipocytes.