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Chronic kidney disease (CKD) is one of the leading causes of mortality across the globe. Early diagnosis of the disease is important in order to prevent the adverse outcome related to CKD. Many laboratories adopt creatinine-based e-GFR equations which yields imprecise results leading to misdiagnosis of CKD. Emerging studies indicated cystatin C as a better renal marker than creatinine. The aim of the study is to compare the efficacy of CKD epidemiology collaboration (CKD-EPI) creatinine e-GFR equations with (CKD EPI) cystatin-based e-GFR equations alone and in combination with creatinine for early detection of CKD. A cross-sectional study employing 473 patients was conducted. Three estimating GFR equations were calculated based on creatinine and cystatin C. Pearson Correlation study was done to assess the correlation of creatinine and cystatin C with their respective GFRs. A predictive model was developed, and ROC curve was constructed to compare efficacy, sensitivity and specificity of the creatinine and cystatin C based equations. Cystatin C exhibited better negative correlation with GFR than creatinine in correlation study performed with three commonly employed eGFR equations including CKD EPI Creatine cystatin C combined equation (2021), cys C alone and CKD EPI creatinine (2021) equations respectively[r=(-) 0.801 vs. r=(-)0.786 vs. r=(-)0.773]. Predictive model demonstrated highest efficiency, sensitivity and specificity for creatinine-cystatin C combined equation (88%, 81% and 93%) followed by cystatin C alone equation (73%,63% and 82%) and creatinine-based equation (61%, 56% and 66% respectively). The study showed better performance of cystatin C based equations for early detection of advance stages in chronic kidney disease as compared to creatinine-based e-GFR equation.
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Obg proteins belong to P-loop guanine triphosphatase (GTPase) that are conserved from bacteria to humans. Like other GTPases, Obg cycles between guanine triphosphate (GTP) bound "on" state and guanine diphosphate (GDP)-bound "off" state, thereby controlling various cellular processes. Different members of this group have unique structural characteristics; a conserved glycine-rich N-terminal domain known as obg fold, a central conserved nucleotide binding domain, and a less conserved C-terminal domain of other functions. Obg is a ribosome dependent GTPase helps in ribosome maturation by interacting with several proteins of the 50S subunit of the ribosome. Obg proteins have been widely considered as a regulator of cellular functions, helping in DNA replication, cell division. Apart from that, this protein also takes part in various stress adaptation pathways like a stringent response, sporulation, and general stress response. In this particular review, the structural features of ObgE have been highlighted and how the structure plays important role in interacting with regulators like GTP, ppGpp that are crucial for executing biological function has been orchestrated. In particular, we believe that Obg-like proteins can provide a link between different global pathways that are necessary for fine-tuning cellular processes to maintain the cellular energy status.
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Bacterias , GTP Fosfohidrolasas , Secuencia de Aminoácidos , Proteínas Bacterianas/metabolismo , GTP Fosfohidrolasas/metabolismo , Guanina , Guanosina Trifosfato/metabolismo , HumanosRESUMEN
Mediator 25 (Med25) is a member of the mediator complex that relays signals from transcription factors to the RNA polymerase II machinery. Multiple transcription factors, particularly those involved in lipid metabolism, utilize the mediator complex, but how Med25 is involved in this context is unclear. We previously identified Med25 in a translatome screen of adult cardiomyocytes (CMs) in a novel cell type-specific model of LMNA cardiomyopathy. In this study, we show that Med25 upregulation is coincident with myocardial lipid accumulation. To ascertain the role of Med25 in lipid accumulation, we utilized iPSC-derived and neonatal CMs to recapitulate the in vivo phenotype by depleting lamins A and C (lamin A/C) in vitro. Although lamin A/C depletion elicits lipid accumulation, this effect appears to be mediated by divergent mechanisms dependent on the CM developmental state. To directly investigate Med25 in lipid accumulation, we induced adipogenesis in Med25-silenced 3T3-L1 preadipocytes and detected enhanced lipid accumulation. Assessment of pertinent mediators driving adipogenesis revealed that C/EBPα and PPARγ are super-induced by Med25 silencing. Our results indicate that Med25 limits adipogenic potential by suppressing the levels of master regulators that govern adipogenesis. Furthermore, we caution the use of early-developmental-stage cardiomyocytes to model adult-stage cells, particularly for dissecting metabolic perturbations emanating from LMNA mutations.
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Adipogénesis , Lamina Tipo A , Animales , Ratones , Células 3T3-L1 , Adipogénesis/genética , Diferenciación Celular , Lamina Tipo A/genética , Lamina Tipo A/metabolismo , Lípidos/farmacología , Complejo Mediador/genética , Complejo Mediador/metabolismo , PPAR gamma/metabolismo , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND/AIMS: Diabetic cardiomyopathy (DCM) is characterized by structural and functional alterations that can lead to heart failure. Several mechanisms are known to be involved in the pathogenesis of DCM, however, the molecular mechanism that links inflammation to DCM is incompletely understood. To learn about this mechanism, we investigated the role of inflammatory serine proteases (ISPs) during the development of DCM. METHODS: Eight weeks old mice with deletion of dipeptidyl peptidase I (DPPI), an enzyme involved in the maturation of major ISPs, and wild type (WT) mice controls were injected with streptozotocin (50 mg/kg for 5 days intraperitoneally) and studied after 4, 8, 16, and 20 week after induction of type 1 diabetes mellitus (T1DM). Induction of diabetes was followed by echocardiographic measurements, glycemic and hemoglobulin A1c profiling, immunoblot, qPCR, enzyme activity assays, and immunohistochemistry (IHC) analysis of DPPI, ISPs, and inflammatory markers. Fibrosis was determined from left ventricular heart by Serius Red staining and qPCR. Apoptosis was determined by TUNEL assay and immunoblot analysis. RESULTS: In the diabetic WT mice, DPPI expression increased along with ISP activation, and DPPI accumulated abundantly in the left ventricle mainly from infiltrating neutrophils. In diabetic DPPI-knockout (DPPI-KO) mice, significantly decreased activation of ISPs, myocyte apoptosis, fibrosis, and cardiac function was improved compared to diabetic WT mice. In addition, DPPI-KO mice showed a decrease in overall inflammatory status mediated by diabetes induction which was manifested by decreased production of pro-inflammatory cytokines like TNF-α, IL-1ß and IL-6. CONCLUSION: This study elucidates a novel role of ISPs in potentiating the immunological responses that lead to the pathogenesis of DCM in T1DM. To the best of our knowledge, this is the first study to report that DPPI expression and activation promotes the inflammation that enhances myocyte apoptosis and contributes to the adverse cardiac remodeling that subsequently leads to DCM.
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Catepsina C/metabolismo , Cardiomiopatías Diabéticas/patología , Serina Proteasas/metabolismo , Animales , Apoptosis , Glucemia/análisis , Catepsina C/genética , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patología , Cardiomiopatías Diabéticas/etiología , Regulación hacia Abajo , Fibrosis , Corazón/fisiología , Ventrículos Cardíacos/metabolismo , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/citología , Neutrófilos/inmunología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
BACKGROUND/AIMS: Systemic hyperlipidemia and intracellular lipid accumulation induced by chronic high fat diet (HFD) leads to enhanced fatty acid oxidation (FAO) and ketogenesis. The present study was aimed to determine whether activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) by surplus free fatty acids (FA) in hyperlipidemic condition, has a positive feedback regulation over FAO and ketogenic enzymes controlling lipotoxicity and cardiac apoptosis. METHODS: 8 weeks old C57BL/6 wild type (WT) or PPAR-γ-/- mice were challenged with 16 weeks 60% HFD to induce obesity mediated type 2 diabetes mellitus (T2DM) and diabetic cardiomyopathy. Treatment course was followed by echocardiographic measurements, glycemic and lipid profiling, immunoblot, qPCR and immunohistochemistry (IHC) analysis of PPAR-γ and following mitochondrial metabolic enzymes 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2), mitochondrial ß- hydroxy butyrate dehydrogenase (BDH1) and pyruvate dehydrogenase kinase isoform 4 (PDK4). In vivo model was translated in vitro, with neonatal rat cardiomyocytes (NRCM) treated with PPAR-γ agonist/antagonist and PPAR-γ overexpression adenovirus in presence of palmitic acid (PA). Apoptosis was determined in vivo from left ventricular heart by TUNEL assay and immunoblot analysis. RESULTS: We found exaggerated circulating ketone bodies production and expressions of the related mitochondrial enzymes HMGCS2, BDH1 and PDK4 in HFD-induced diabetic hearts and in PA-treated NRCM. As a mechanistic approach we found HFD mediated activation of PPAR-γ is associated with the above-mentioned mitochondrial enzymes. HFD-fed PPAR-γ-/-mice display decreased hyperglycemia, hyperlipidemia associated with increased insulin responsiveness as compared to HFD-fed WT mice PPAR-γ-/-HFD mice demonstrated a more robust functional recovery after diabetes induction, as well as significantly reduced myocyte apoptosis and improved cardiac function. CONCLUSIONS: PPAR-γ has been described previously to regulate lipid metabolism and adipogenesis. The present study suggests for the first time that increased PPAR-γ expression by HFD is responsible for cardiac dysfunction via upregulation of mitochondrial enzymes HMGCS2, BDH1 and PDK4. Targeting PPAR-γ and its downstream mitochondrial enzymes will provide novel strategies in preventing metabolic and myocardial dysfunction in diabetes mellitus.
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Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Dieta Alta en Grasa/efectos adversos , Ácidos Grasos/metabolismo , Cuerpos Cetónicos/metabolismo , PPAR gamma/metabolismo , Disfunción Ventricular Izquierda/metabolismo , Animales , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/patología , Cardiomiopatías Diabéticas/sangre , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/patología , Ácidos Grasos/sangre , Hipertrofia Ventricular Izquierda/sangre , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/patología , Cuerpos Cetónicos/sangre , Masculino , Ratones Endogámicos C57BL , Oxidación-Reducción , Disfunción Ventricular Izquierda/sangre , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/patologíaRESUMEN
High fat diet group showed a significant rise in serum and hepatic total cholesterol, triglyceride and atherogenic index which are major biomarkers of dyslipidemia and cardiovascular risk. The liver function markers, lipid peroxidation and proinflammatory cytokine levels were elevated in high fat diet group whereas antioxidant levels significantly reduced. These findings manifest hepatic damage which was further confirmed by histological findings. Quercetin and beta-sitosterol though structurally different yet both ameliorate the sickening changes in different mechanism. The current investigation is perhaps the first report of the mechanistic role of two polyphenols over dyslipidemia and subsequent hepatotoxicity.
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Dislipidemias/tratamiento farmacológico , Lípidos/sangre , Quercetina/administración & dosificación , Sitoesteroles/administración & dosificación , Animales , Antioxidantes/metabolismo , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/patología , Dieta Alta en Grasa , Dislipidemias/patología , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Ratones , Triglicéridos/sangreRESUMEN
Mutations in the LMNA gene encoding lamins A/C cause an array of tissue-selective diseases, with the heart being the most commonly affected organ. Despite progress in understanding the perturbations emanating from LMNA mutations, an integrative understanding of the pathogenesis underlying cardiac dysfunction remains elusive. Using a novel conditional deletion model capable of translatome profiling, we observed that cardiomyocyte-specific Lmna deletion in adult mice led to rapid cardiomyopathy with pathological remodeling. Before cardiac dysfunction, Lmna-deleted cardiomyocytes displayed nuclear abnormalities, Golgi dilation/fragmentation, and CREB3-mediated stress activation. Translatome profiling identified MED25 activation, a transcriptional cofactor that regulates Golgi stress. Autophagy is disrupted in the hearts of these mice, which can be recapitulated by disrupting the Golgi. Systemic administration of modulators of autophagy or ER stress significantly delayed cardiac dysfunction and prolonged survival. These studies support a hypothesis wherein stress responses emanating from the perinuclear space contribute to the LMNA cardiomyopathy development.
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Cardiomiopatías , Lamina Tipo A , Miocitos Cardíacos , Membrana Nuclear , Animales , Lamina Tipo A/metabolismo , Lamina Tipo A/genética , Ratones , Membrana Nuclear/metabolismo , Cardiomiopatías/metabolismo , Cardiomiopatías/etiología , Cardiomiopatías/patología , Cardiomiopatías/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Autofagia , Estrés Fisiológico , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico , Aparato de Golgi/metabolismo , Ratones NoqueadosRESUMEN
Mutations in the LMNA gene encoding nuclear lamins A/C cause a diverse array of tissue-selective diseases, with the heart being the most commonly affected organ. Despite progress in understanding the molecular perturbations emanating from LMNA mutations, an integrative understanding of the pathogenesis leading to cardiac dysfunction remains elusive. Using a novel cell-type specific Lmna deletion mouse model capable of translatome profiling, we found that cardiomyocyte-specific Lmna deletion in adult mice led to rapid cardiomyopathy with pathological remodeling. Prior to the onset of cardiac dysfunction, lamin A/C-depleted cardiomyocytes displayed nuclear envelope deterioration, golgi dilation/fragmentation, and CREB3-mediated golgi stress activation. Translatome profiling identified upregulation of Med25, a transcriptional co-factor that can selectively dampen UPR axes. Autophagy is disrupted in the hearts of these mice, which can be recapitulated by disrupting the golgi or inducing nuclear damage by increased matrix stiffness. Systemic administration of pharmacological modulators of autophagy or ER stress significantly improved the cardiac function. These studies support a hypothesis wherein stress responses emanating from the perinuclear space contribute to the development of LMNA cardiomyopathy. Teaser: Interplay of stress responses underlying the development of LMNA cardiomyopathy.
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The application of antimicrobial peptides has emerged as an alternative therapeutic tool to encounter against multidrug resistance of different pathogenic organisms. α-Melanocyte stimulating hormone (α-MSH), an endogenous neuropeptide, is found to be efficient in eradicating infection of various kinds of Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA). However, the chemical stability and efficient delivery of these biopharmaceuticals (i.e., α-MSH) to bacterial cells with a significant antibacterial effect remains a key challenge. To address this issue, we have developed a chitosan-cholesterol polymer using a single-step, one-pot, and simple chemical conjugation technique, where α-MSH is loaded with a significantly high amount (37.7%), and the final product is obtained as chitosan-cholesterol α-MSH polymer-drug nanoconjugates. A staphylococcal growth inhibition experiment was performed using chitosan-cholesterol α-MSH and individual controls. α-MSH and chitosan-cholesterol both show bacterial growth inhibition by a magnitude of 50 and 79%, respectively. The killing efficiency of polymer-drug nanoconjugates was very drastic, and almost no bacterial colony was observed (â¼100% inhibition) after overnight incubation. Phenotypic alternation was observed in the presence of α-MSH causing changes in the cell structure and shape, indicating stress on Staphylococcus aureus. As a further consequence, vigorous cell lysis with concomitant release of the cellular material in the nearby medium was observed after treatment of chitosan-cholesterol α-MSH nanoconjugates. This vigorous lysis of the cell structure is associated with extensive aggregation of the bacterial cells evident in scanning electron microscopy (SEM). The dose-response experiment was performed with various concentrations of chitosan-cholesterol α-MSH nanoconjugates to decipher the degree of the bactericidal effect. The concentration of α-MSH as low as 1 pM also shows significant inhibition of bacterial growth (â¼40% growth inhibition) of Staphylococcus aureus. Despite playing an important role in inhibiting bacterial growth, our investigation on hemolytic assay shows that chitosan-cholesterol α-MSH is significantly nontoxic at a wide range of concentrations. In a nutshell, our analysis demonstrated novel antimicrobial activity of nanoparticle-conjugated α-MSH, which could be used as future therapeutics against multidrug-resistant Staphylococcus aureus and other types of bacterial cells.
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Consumption of high-fat diet (HFD) induces nonalcoholic fatty liver disease (NAFLD) and may lead to multiple complications affecting human health. In the present study, effect of Moringa oleifera leaf extract (MoLE) in alleviating HFD induced liver injury in mice has been reported. Liver histology and serum activity of hepatic marker enzymes i.e. aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) have been studied. Lipid peroxidation (LPO), ferric reducing antioxidant power (FRAP) and reduced glutathione (GSH) were also estimated using liver homogenate. Results of the study suggested that MoLE treatment protected HFD-induced liver damage as indicated by histopathology and liver enzyme activity compared to only-HFD fed group (P < 0.05). Interestingly, early signs of HFD-induced fatty liver were also alleviated by MoLE. Moreover, significant increase in endogenous antioxidant parameters and lower lipid peroxidation were found in liver of all MoLE treated groups. Results of the study indicated that MoLE has both preventive as also curative hepatoprotective activity.
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Dieta Alta en Grasa/efectos adversos , Hepatopatías/prevención & control , Moringa oleifera/química , Extractos Vegetales/farmacología , Hojas de la Planta/química , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Animales , Antioxidantes/metabolismo , Aspartato Aminotransferasas/sangre , Relación Dosis-Respuesta a Droga , Depuradores de Radicales Libres/aislamiento & purificación , Depuradores de Radicales Libres/farmacología , Glutatión/metabolismo , Humanos , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hepatopatías/sangre , Hepatopatías/etiología , Masculino , Ratones , Fitoterapia/métodos , Extractos Vegetales/aislamiento & purificaciónRESUMEN
OBJECTIVE: Measurement of total vitamin B12 (vit B12) concentration raised concerns over early detection of vit B12 deficiency due to its clinical unreliability. In this present article we aimed to assess the efficacy of holo-transcobolamin (active vit B12) for true evaluation of vit B12 deficiency. METHODS: This retrospective study included 100 participants referred for vit B12 assay. Serum total vit B12, active vit B12 and homocysteine were estimated. RESULTS: Our study showed 59% of the total participants with vit B12 deficiency (185 ± 64.62 pg/ml) and 18% with hyper-cobalaminemia (1666.9 ± 367.13 pg/ml) based on their total vit B12 concentrations. A comparative study on total vit B12 and active vit B12 was done which reflected a striking disparity in results. Active vit B12 reported 28.8% patients with vit B12 deficiency (19.8 ± 17.48 pg/ml) and only 16.6% patients with hyper-cobalaminemia (224.14 ± 10 pg/ml). Active vit B12 appeared to be more sensitive (82.35% vs 65%) and specific (46.6% vs. 43.8%) diagnostic marker compared to total vit B12. Pearson Correlation study indicated a strong positive correlation (r = 0.695 at p < 0.01) hence justified use of the two methods. CONCLUSION: We claim that active vit B12 is a much more reliable biomarker than total vit B12 for early diagnosis of vit B12 deficiency.
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Transcobalaminas , Deficiencia de Vitamina B 12 , Humanos , Estudios Retrospectivos , Reproducibilidad de los Resultados , Deficiencia de Vitamina B 12/diagnóstico , Vitamina B 12 , Biomarcadores , HomocisteínaRESUMEN
The molecular pathways activated in response to acute cathepsin G (CG) exposure, as well as the mechanisms involved in activation of signaling pathways that culminate in myocyte detachment and apoptosis remain unclear. This study aimed to determine the changes in gene expression patterns associated with time dependent CG exposure to neonatal rat cardiomyocytes (NRCMs). Microarray analysis revealed a total of 451, 572 and 1127 differentially expressed genes after CG exposure at 1, 4 and 8â¯h respectively. A total of 54 overlapped genes at each time point were mapped by Ingenuity Pathway Analysis (IPA). The top up-regulated genes included Hamp, SMAD6, NR4A1, FOSL2, ID3 and SLAMF7, and down-regulated genes included CYR61, GDF6, Olr640, Vom2r36, DUSP6 and MMP20. Our data suggest that there are multiple deregulated pathways associated with cardiomyocyte death after CG exposure, including JAK/Stat signaling, IL-9 signaling and Nur77 signaling. In addition, we also generated the molecular network of expressed gene and found most of the molecules were connected to ERK1/2, caspase, BCR (complex) and Cyclins. Our study reveals the ability to assess time-dependent changes in gene expression patterns in NRCMs associated with CG exposure. The global gene expression profiles may provide insight into the cellular mechanism that regulates CG dependent myocyte apoptosis. In future, the pathways important in CG response, as well as the genes found to be differentially expressed might represent the therapeutic targets for myocyte survival in heart failure.
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Catepsina G/farmacología , Redes Reguladoras de Genes/efectos de los fármacos , Miocitos Cardíacos/citología , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Animales , Animales Recién Nacidos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Ratas , Programas Informáticos , Factores de TiempoRESUMEN
Diabetes increases the risk of Cardio-vascular disease (CVD). CVD is more prevalent in type 2 diabetes (T2D) than type 1 diabetes (T1D), but the mortality risk is higher in T1D than in T2D. The pathophysiology of CVD in T1D is poorly defined. To learn more about biological pathways that are potentially involved in T1D with cardiac dysfunction, we sought to identify differentially expressed genes in the T1D heart. Our study used T1D mice with severe hyperglycemia along with significant deficits in echocardiographic measurements. Microarray analysis of heart tissue RNA revealed that the T1D mice differentially expressed 10 genes compared to control. Using Ingenuity Pathway Analysis (IPA), we showed that these genes were significantly involved in ketogenesis, cardiovascular disease, apoptosis and other toxicology functions. Of these 10 genes, the 3-Hydroxy-3-Methylglutaryl-CoA Synthase 2 (HMGCS2) was the highest upregulated gene in T1D heart. IPA analysis showed that HMGCS2 was center to many biological networks and pathways. Our data also suggested that apart from heart, the expression of HMGCS2 was also different in kidney and spleen between control and STZ treated mice. In conclusion, The HMGCS2 molecule may potentially be involved in T1D induced cardiac dysfunction.
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Enfermedades Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Hidroximetilglutaril-CoA Sintasa/metabolismo , Cuerpos Cetónicos/biosíntesis , Animales , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/fisiopatología , Biología Computacional/métodos , Diabetes Mellitus Tipo 1/genética , Ecocardiografía , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Hemodinámica , Humanos , Hidroximetilglutaril-CoA Sintasa/genética , Masculino , Ratones , Anotación de Secuencia Molecular , TranscriptomaRESUMEN
Radioprotective action of gossypetin (GTIN) against gamma (γ)-radiation-induced oxidative stress in liver was explored in the present article. Our main aim was to evaluate the protective efficacy of GTIN against radiation-induced alteration of liver in murine system. To evaluate the effect of GTIN, it was orally administered to mice at a dose of 30 mg/kg body weight for three consecutive days prior to γ-radiation at a dose of 5 Gy. Radioprotective efficacy of GTIN were evaluated at physiological, cellular, and molecular level using biochemical analysis, comet assay, flow cytometry, histopathology, immunofluorescence, and immunoblotting techniques. Ionizing radiation was responsible for augmentation of hepatic oxidative stress in terms of lipid peroxidation and depletion of endogenous antioxidant enzymes. Immunoblotting and immunofluorescence studies showed that irradiation enhanced the nuclear translocation of nuclear factor kappa B (NF-κB) level, which leads to hepatic inflammation. To investigate further, we found that radiation induced the activation of stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK)-mediated apoptotic pathway and deactivation of the NF-E2-related factor 2 (Nrf2)-mediated redox signaling pathway, whereas GTIN pretreatment ameliorated these radiation-mediated effects. This is the novel report where GTIN rationally validated the molecular mechanism in terms of the modulation of cellular signaling system' instead of ' This is the novel report where GTIN is rationally validated in molecular terms to establish it as promising radioprotective agents. This might be fruitful especially for nuclear workers and defense personnel assuming the possibility of radiation exposure.
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Antioxidantes/uso terapéutico , Flavonoides/uso terapéutico , Depuradores de Radicales Libres/uso terapéutico , Rayos gamma/efectos adversos , Hígado/efectos de los fármacos , Protectores contra Radiación/uso terapéutico , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Animales , Antioxidantes/química , Antioxidantes/farmacología , Aspartato Aminotransferasas/sangre , Disponibilidad Biológica , Catalasa/metabolismo , Roturas del ADN de Doble Cadena , Evaluación Preclínica de Medicamentos , Flavonoides/química , Flavonoides/farmacología , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Glutatión/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/efectos de la radiación , Interleucina-6/sangre , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/efectos de la radiación , Hígado/efectos de la radiación , Hígado/ultraestructura , Masculino , Ratones , Estructura Molecular , Factor 2 Relacionado con NF-E2/metabolismo , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Protectores contra Radiación/química , Protectores contra Radiación/farmacología , Transducción de Señal/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/sangreRESUMEN
The present study demonstrates for the first time the protective role of two common flavonoids, quercetin and its glycone rutin, against high cholesterol diet (2%) induced hepatotoxicity and inflammation. Swiss albino mice were given either a standard laboratory diet (control), high cholesterol diet (HCD) or high cholesterol diet along with quercetin or rutin (100 mg kg(-1) body weight) in their respective groups. The HCD mice exhibited a gain in body weight, significant rise in serum and hepatic level of total cholesterol, triglyceride, liver function enzymes, lipid peroxidation, and pro-inflammatory cytokines (P < 0.05). Histopathological studies showed hepatic fat accumulation and tissue disintegration. There was significant depletion of major hepatic antioxidants (P < 0.05). Immunoblot studies revealed a high expression of redox sensitive transcription factors NF-κB and TNF-α. A subsequent rise in the mRNA expression of inflammatory markers like C reactive protein and inducible nitric oxide synthase 2 were also found from the RT-PCR study. Simultaneous treatment with quercetin or rutin along with HCD significantly prevented the gains in body weight, lipid level, liver function enzymes, lipid peroxidation level and expression of inflammatory markers. The restoration of hepatic antioxidant homeostasis and hepatic morphology has also been observed. Hence, the present study illustrates the hypolipidemic, hepatoprotective and anti-inflammatory effects of two similar flavonoids.
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Antioxidantes/farmacología , Colesterol en la Dieta/administración & dosificación , Dieta Alta en Grasa , Hígado/efectos de los fármacos , Quercetina/farmacología , Rutina/farmacología , Animales , Apolipoproteína B-100/genética , Apolipoproteína B-100/metabolismo , Peso Corporal , Proteína C-Reactiva/genética , Proteína C-Reactiva/metabolismo , Colesterol/sangre , LDL-Colesterol/sangre , Expresión Génica , Inflamación/tratamiento farmacológico , Interleucina-6/genética , Interleucina-6/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , FN-kappa B/genética , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fitoquímicos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Triglicéridos/sangre , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Consumption of a high-fat diet (HFD) promotes reactive oxygen species (ROS) which ultimately trigger inflammation. The aim of this study was to investigate the role of Moringa oleifera leaf extract (MoLE) and its active component quercetin in preventing NF-κB-mediated inflammation raised by short-term HFD. Quercetin was found to be one of the major flavonoid components from HPLC of MoLE. Swiss mice were fed for 15 days on HFD, both with or without MoLE/quercetin. The antioxidant profile was estimated from liver homogenate. NF-κB and some relevant inflammatory markers were evaluated by immunoblotting, RT-PCR and ELISA. Significantly (P < 0.05) lower antioxidant profile and higher lipid peroxidation was found in HFD group compared to control (P < 0.05). Increased nuclear import of NF-κB and elevated expressions of pro-inflammatory markers were further manifestations in the HFD group. All these changes were reversed in the MoLE/quercetin-treated groups with significant improvement of antioxidant activity compared to the HFD group. MoLE was found to be rich in polyphenols and both MoLE and quercetin showed potent free radical and hydroxyl radical quenching activity. Thus, the present study concluded that short-term treatment with MoLE and its constituent quercetin prevent HFD-mediated inflammation in mice.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Inflamación/tratamiento farmacológico , Moringa oleifera/química , Extractos Vegetales/administración & dosificación , Quercetina/administración & dosificación , Animales , Humanos , Inflamación/etiología , Inflamación/genética , Inflamación/inmunología , Hígado/inmunología , Masculino , Ratones , FN-kappa B/genética , FN-kappa B/inmunologíaRESUMEN
AIMS: The present study evaluated a comparative and combined hepatoprotective effect of atorvastatin (AS) and ferulic acid (F) against high fat diet (HFD) induced oxidative stress in terms of hyperlipidemia, anti-oxidative status, lipid peroxidation and inflammation. MAIN METHODS: Male Swiss albino mice were given a diet containing high fat (H) (23.9% wt/wt), supplemented with AS (10mg/kg) or F (100mg/kg) and both (10 and 100mg/kg) for 8weeks. The control mice (C) were fed with normal diet. KEY FINDINGS: The H mice exhibited increased body weight; hyperlipidemia; serum level of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6); hepatic lipid profile; lipid accumulation; reactive oxygen species (ROS) of hepatocytes, lipid peroxidation and liver antioxidant capacity was decreased. Immunofluorescent and Western blot assay revealed activation of nuclear factor kappa B (NF-κB) signaling pathway. The addition of F or AS and both in the diet significantly counteracted HFD induced body weight gain; hyperlipidemia; TNF-α, IL-6; hepatic lipid profile; fatty infiltration; NF-κB signaling pathway; ROS; lipid peroxidation and moreover elevated levels of hepatic antioxidant enzymes activity were observed. SIGNIFICANCE: Simultaneous treatment with AS, F and their combination protected against HFD induced weight gain and oxidative stress. The protection may be attributed to the hypolipidemic and free radical scavenging activity of AS or F and their combination. This study illustrates that AS and F have relatively similar hypolipidemic, antioxidative, anti-inflammatory actions and the AS+F combination along with HFD has shown outstanding effects as compared to other treated groups.