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Adriamycin is a well-known anthracycline chemotherapeutic agent widely used in treating a variety of malignancies. However, Adriamycin's clinical use is limited due to its adverse side-effects, most importantly cardiomyopathy. Adriamycin-induced cardiotoxicity reportedly includes mitochondrial dysfunction. We hypothesize that modulation of KLF4, a key regulator of cardiac mitochondrial homeostasis might play a role in the development of Adriamycin-induced cardiomyopathy. Therefore, in the current work, we evaluated the interaction of Adriamycin with KLF4 and its subsequent downstream targets. Molecular docking revealed that Adriamycin interacts strongly with KLF4 at residues Thr 448, Arg 452, Ser 444 falls within C2H2 motif which is the active site. Quantitative real-time PCR also revealed that KLF4 is downregulated by Adriamycin in cardiomyocytes in vitro. The expression of KLF4 is downregulated in a dose-dependent manner, with a 0.12 ± 0.09-fold (p ≤ 0.05, n = 3) downregulation at a low dosage and 0.21 ± 0.02-fold (p ≤ 0.05, n = 3) downregulation at high dosage. Deficiency of KLF4 leads to an impairment of PPARγ that consequently supresses the proteins/enzymes involved in the fatty acid metabolism. Adriamycin-mediated suppression of KLF4 also affected the expression of PPARα in vitro. PPARα dysfunction is likely to cause defects in ß-oxidation which ultimately results in impaired ATP synthesis. Cardiac cells are thus forced to switch over the substrate from free fatty acid to glucose. Moreover, Adriamycin elevates the expression of PPARß due to downregulation of KLF4 leads to increased myocardial glucose utilization. Thus, a change in substrate preference affects the flexibility of metabolic network culminating in diminished energy production and other regulatory activities, altogether contributing to the development of cardiomyopathy. Thus, we conclude that the effect of Adriamycin on KLF4 disrupts mitochondrial homeostasis and lipid/glucose homeostasis resulting in a reduction of ATP synthesis which ultimately results in dilated cardiomyopathy.
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The global incidence of Alzheimer's disease (AD) is on the rise with the increase in obesity and metabolic disease epidemic. Obesity is co-morbid with the increase in mass of adipose tissue, which secretes numerous molecules that are biologically important. Obesity and its associated conditions are perhaps involved in the causative pathway of AD. Immunologically important cytokines such as IL-1ß, IL-10, and IL-18, which are released by adipose tissue, are also found to be associated with AD. Besides, the expression of IL-6, IFNγ, and TNF alpha are also associated with AD. Ang-I and Ang-II are found to mediate the progression of AD. Complement factors B, C4b, and H are differentially expressed in AD. Overall, several adipocyte-derived cytokines are found to be dysregulated in AD, and their role in AD remains to be studied. The induction of autophagy is a very promising strategy in the treatment of AD. A variety of adipose-derived molecules have been shown to modulate autophagy. However, very little literature is available on the role of adipose-derived molecules in inducing autophagy in microglial cells of AD. Understanding the role of adipose-derived molecules in the development of AD, especially in the induction of autophagy, would open up new avenues in devising strategies for the treatment of AD.
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Adriamycin is an effective anticancer drug used in a wide range of cancers. Anticancer drugs modulate oncogenes and nodal regulatory molecules that affect cell differentiation and organismal development. In this study, we explore the effect of adriamycin on Kruppel-like factor4 (Klf4), an essential pluripotent factor by choosing zebrafish embryos as a model system. Klf4 is involved in the regulation of cellular growth, proliferation, and differentiation. In zebrafish embryogenesis, Klf4 is a major regulator of differentiation of polster in the anterior mesendoderm region of cells into hatching gland cells. The importance of this study is to check the effect of adriamycin on embryonic development. We found, adriamycin dose dependently altered the gene expression level of Klf4 that occurs in parallel to its detrimental effect on hatching. Supportively, cathepsin L and cyclase-associated protein1 are the other two markers of hatching that are altered along with Klf4.
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Vitamin D, a free sunshine vitamin available for mankind from nature, is capable to avert many health-related critical circumstances. Vitamin D is no more regarded as a nutrient involved in bone metabolism alone. The presence of vitamin D receptor in a number of tissues implies that vitamin D has various physiological roles apart from calcium and phosphorus metabolism. Low serum vitamin D has been found to be associated with various types of metabolic illness such as obesity, diabetes mellitus, insulin resistance, cardiovascular diseases including hypertension. Various studies reported that vitamin D insufficiency or deficiency in linked with metabolic syndrome risk. This review focuses on various metabolic diseases and its relationship with serum vitamin D status.
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Diabetic cardiomyopathy is one of the life threatening complications of diabetes.A number of animal models are being used for studying diabetic cardiomyopathy.In laboratory animal models,induction of cardiomyopathy happens in two stages:first being the induction of diabetic condition and the second being the induction of cardiomyopathy by prolonging diabetic condition.It takes a longer time to develop diabetes with the limited success rate for development of cardiomyopathy.Adriamycin is an effective anticancer drug limited by its major side-effect cardiomyopathy.A number of features of Adriamycin treatment mimics diabetes.We postulate that Adriamycin-induced cardiomyopathy might be used as a model system to study diabetic cardiomyopathy in rodents since a number of features of both the cardiomyopathies overlap.Left ventricular hypertrophy,systolic and diastolic dysfunction,myofibrillar loss,and fibrosis are hallmarks of both of the cardiomyopathies.At the molecular level,calcium signaling,endoplasmic redculum stress,advance glycation endproduct activation,mitochondfial dysfunction,inflammation,lipotoxicity and oxidative stress are similar in both the cardiomyopathies.The signature profile of both the cardiomyopathies shares commonalities.In conclusion,we suggest that Adriamycin induced cardiomyopathic animal model can be used for studying diabetic cardiomyopathy and would save time for researchers working on cardiomyopathy developed in rodent using the traditional method.
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In this study, we investigated the anti-obesity effects of soybean paste-Cheonggukjang, fermented with poly gamma glutamic acid producing Bacillus licheniformis-67 in diet induced obese C57BL/6J mice. Forty male C57BL/6J mice aged 4 weeks were divided into four dietary groups; normal diet control, high fat diet control, high fat diet containing 30% of unfermented soybean and high fat diet containing 30% Cheonggukjang fermented with Bacillus licheniformis-67. After 13 weeks of dietary intervention the mice were sacrificed; serum and tissue samples were examined. Serum and hepatic lipid profile, blood glucose, insulin, leptin level were lower (<0.05) along with the body weight and epididymal fat pad weight in the 30% Cheonggukjang supplemented group compared with the high fat diet control group. The expression level of lipid anabolic gene was significantly decreased; whereas the expression level of lipid catabolic genes were significantly increased in the 30% Cheonggukjang supplemented group compared to the high fat diet control group. Collectively, these results suggested that intake of Cheonggukjang fermented with Bacillus licheniformis-67 significantly prevents obesity related parameters.
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Dietary fiber and proteins are individually known to decrease feeding, but could result greater weight management benefit when both are combined. We hypothesized that supplementing the diet with fermented barley, being rich in both dietary fiber and proteins, could lower energy intake by modulating the mRNA expression level of hypothalamic genes associated with the regulation of feeding behavior and satiety; thereby decreasing body weight gain. To test our hypothesis, four groups of Sprague Dawley rats were arranged in a 2 × 2 factorial design (n = 6), low-fat diet with either guar gum (LFD-G) or fermented barley (LFD-FB) and high-fat diet with either guar gum (HFD-G) or fermented barley (HFD-FB). Using oral gavage, fermented barley was given at a dosage of 1500 mg/kg body weight and guar gum was supplemented in an equivalent quantity to that of the fiber in the fermented barley. After 19 weeks, the fermented barley-supplemented groups showed a significant reduction in energy intake, triglyceride, body weight gain, and serum leptin, compared to the guar gum-supplemented groups in both the low- and high-fat diet groups. Likewise, the anorexigenic gene proopiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) mRNA level were significantly higher in the fermented barley-supplemented groups compared to the guar gum-supplemented groups in rats fed on both high- and low-fat diets. In conclusion, fermented barley supplementation upregulated hypothalamic POMC/CART, decreased energy intake in both low- and high-fat diet groups, and prevented excessive weight gain in rats.
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Ingestión de Energía , Hordeum/metabolismo , Hipotálamo/metabolismo , Obesidad/dietoterapia , Obesidad/genética , Animales , Peso Corporal , Fibras de la Dieta/metabolismo , Suplementos Dietéticos/análisis , Fermentación , Hordeum/microbiología , Humanos , Leptina/sangre , Masculino , Proteínas del Tejido Nervioso/genética , Obesidad/metabolismo , Obesidad/fisiopatología , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Ratas , Ratas Sprague-Dawley , Aumento de PesoRESUMEN
BACKGROUND: Foods that are rich in fat and or sodium chloride promote obesity and associated diseases, whereas intake of dietary fiber averts obesity development. Salicornia herbacea (SH) is a rich source of dietary fiber and high in sodium chloride; therefore, we investigated whether replacing common salt with SH in a high-fat diet could prevent obesity development. RESULTS: Mice were divided into five groups: group ND was fed a normal diet, group HD was fed a high-fat diet, group HD-NaCl was fed a high fat diet with sodium chloride 10 g kg(-1) , group HD-CL was fed a high-fat diet with cellulose 30 g kg(-1) and group HD-SH was fed a high-fat diet with SH powder 50 g kg(-1) . The amount of sodium chloride and cellulose added in the respective diet was equivalent to their amount in SH. Data from our study showed that, SH supplementation significantly decreased body weight gain, liver weight, hepatic triglyceride, serum leptin and insulin, along with the mRNA level of key lipid anabolic genes such as SREBP-1c, PPARγ and FAS compared to the HD group. CONCLUSION: The results of this study demonstrated that SH is a potential natural anti-obesity agent that can be used in place of sodium chloride.
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Chenopodiaceae/química , Dieta Alta en Grasa , Fibras de la Dieta/uso terapéutico , Hígado/efectos de los fármacos , Obesidad/tratamiento farmacológico , Fitoterapia , Aumento de Peso/efectos de los fármacos , Animales , Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/uso terapéutico , Grasas de la Dieta/administración & dosificación , Fibras de la Dieta/farmacología , Suplementos Dietéticos , Insulina/sangre , Leptina/sangre , Metabolismo de los Lípidos/genética , Hígado/metabolismo , Masculino , Ratones Endogámicos ICR , Ratones Obesos , Obesidad/genética , Obesidad/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , ARN Mensajero/metabolismo , Cloruro de Sodio Dietético/administración & dosificación , Triglicéridos/sangreRESUMEN
The current investigation was aimed to determine the hepatocurative role of silver nanoparticles (AgNPs) synthesized rapidly using Andrographis paniculata. The nanoparticles fabricated at varying temperatures were characterized by UV-visible spectroscopy (UV-vis), transmission electron microscopy (TEM), fourier transform infra-red spectroscopy (FTIR), energy dispersive X-ray (EDX) and inductively coupled plasma optical emission spectroscopy (ICP-OES) alongside zeta potential measurement. UV-vis spectroscopic readings indicated a prominent peak at 423 nm. TEM analysis indicated that the biosynthesized nanospheres were in the size range of 13-27 nm. EDX spectrum indicated strong signal for AgNPs with 90.1% purity. The total concentration of AgNps was 216.7 mg/L after synthesis as by ICP-OES. Zeta potential was -34.3 mV indicating stable AgNPs. In vitro radical scavenging assay proved strong antioxidant effect of the AgNPs compared to 5% aqueous leaf extract. CCl(4) was used to induce hepatic injury in mice model. The biosynthesized AgNPs at three different doses (25, 50, 100mg/kg BW of the animal) were used for treatment. Silymarin was used as a standard. Low dose (25mg/kg BW) was effective in revival of all biological parameters to near normal in all intoxicated groups indicating the curing effects on CCl(4) induced liver injury.
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Andrographis/química , Nanopartículas del Metal/química , Plata/química , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Masculino , Nanopartículas del Metal/uso terapéutico , Nanopartículas del Metal/ultraestructura , Ratones , Microscopía Electrónica de Transmisión , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Phenolic compounds and flavonoids ameliorate bodyweight, blood glucose, and serum lipid profile. Since seabuckthorn (Hippophae rhamnoides L.) is known as a rich source of isoflavones and flavonoids, we hypothesized that ethanolic extract of seabuckthorn leaves (SL) may have anti-obesity and hypoglycemic effects. To investigate the effect of ethanolic extract of SL, 32 C57BL/6J mice were randomly divided into 4 dietary groups, containing 8 mice in each group: normal diet group; high-fat diet (HD) control group; high-fat diet with SL extract, 500 mg/kg body weight (BW) (SL1) group; and high-fat diet with SL extract, 1000 mg/kg BW (SL2) group. After 13 weeks, it was observed that oral administration of SL extract significantly reduced the energy intake; BW gain; epididymal fat pad weight; hepatic triglyceride, hepatic, and serum total cholesterol levels; and serum leptin levels in the SL groups compared to the HD group. However, differences in serum triglyceride and insulin levels in the SL groups were not significant in comparison to the HD group. The hepatic mRNA expression of peroxisome proliferator-activated receptor (PPAR) α and carnitine palmitoyltransferase 1 along with PPAR-γ were significantly increased in SL groups, whereas the level of acetyl-CoA carboxylase was significantly reduced in SL groups compared to HD group. Our results indicated that SL is effective in preventing BW gain and fat accumulation in the liver; it also reduced adipose tissue mass, hepatic lipid profile, and serum leptin level in the mouse. Together, these observations suggest that SL is a potential agent to study in the management of obesity and related disorders.
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Adipogénesis/efectos de los fármacos , Tejido Adiposo/efectos de los fármacos , Hippophae/química , Lipogénesis/efectos de los fármacos , Hígado/efectos de los fármacos , Obesidad/prevención & control , Fitoterapia , Acetil-CoA Carboxilasa/metabolismo , Adipogénesis/genética , Tejido Adiposo/metabolismo , Administración Oral , Animales , Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/uso terapéutico , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Colesterol/metabolismo , Dieta Alta en Grasa/efectos adversos , Regulación hacia Abajo , Ingestión de Energía/efectos de los fármacos , Flavonoides/farmacología , Flavonoides/uso terapéutico , Insulina/sangre , Leptina/sangre , Lipogénesis/genética , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR gamma/genética , PPAR gamma/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , ARN Mensajero/metabolismo , Distribución Aleatoria , Triglicéridos/metabolismo , Aumento de Peso/efectos de los fármacosRESUMEN
Dextran is a versatile biomacromolecule for preparing electrospun nanofibrous membranes by blending with either water-soluble bioactive agents or hydrophobic biodegradable polymers for biomedical applications. In this study, an antibacterial electrospun scaffold was prepared by electrospinning of a solution composed of dextran, polyurethane (PU) and ciprofloxacin HCl (CipHCl) drug. The obtained nanofiber mats have good morphology. The mats were characterized by various analytical techniques. The interaction parameters between fibroblasts and the PU-dextran and PU-dextran-drug scaffolds such as viability, proliferation, and attachment were investigated. The results indicated that the cells interacted favorably with the scaffolds especially the drug-containing one. Moreover, the composite mat showed good bactericidal activity against both of Gram-positive and Gram-negative bacteria. Overall, our results conclude that the introduced scaffold might be an ideal biomaterial for wound dressing applications.
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Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Vendajes , Ciprofloxacina/química , Dextranos/química , Polímeros/farmacología , Poliuretanos/química , Células 3T3-L1 , Animales , Antibacterianos/química , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Proliferación Celular/efectos de los fármacos , Electroquímica , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Ratones , Polímeros/química , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Adriamycin is an anthracycline antibiotic used as anticancer drug since past few decades. Though effective against cancer, it is cardiotoxic, nephrotoxic, hepatotoxic and also toxic for reproductive system. Although a number of potential toxic mechanisms have been identified following exposure to adriamycin, the major pathogenic mechanism appears to be the generation of toxic reactive oxygen species (ROS). Animals treated with adriamycin have shown a decrease in total sperm count. This implies that adriamycin impairs the process of spermatogenesis. Epididymal white adipose tissue (EWAT) is necessary for normal spermatogenesis, and decrease in the EWAT causes disturbance in spermatogenesis. Factor X is an unknown molecule synthesized by EWAT that plays crucial role in spermatogenesis. Adriamycin inhibits Kruppel-like factor 4 (KLF-4) and thus downregulates the adipogenesis process needed to maintain the EWAT mass. Apart form adipocytes, KLF-4 and peroxisome proliferator-activated receptor gamma (PPAR-γ) are also found in spermatogonium and testis, implying its vital role in spermatogenesis. Adriamycin treatment inhibits KLF-4 and thus PPAR-γ in EWAT and spermatogonium. Reduction of EWAT might cause a decrease in Factor X level. Declining of Factor X level, KLF-4 and PPAR-γ together will lead to disturbance in spermatogenesis process.