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Manganese is a diet-derived micronutrient that is essential for critical cellular processes like redox homeostasis, protein glycosylation, and lipid and carbohydrate metabolism. Control of Mn availability, especially at the local site of infection, is a key component of the innate immune response. Less has been elucidated about Mn homeostasis at the systemic level. In this work, we demonstrate that systemic Mn homeostasis is dynamic in response to inflammation and infection in mice. This phenomenon is evidenced in male and female mice, mice of two genetic backgrounds (C57BL/6 and BALB/c), in multiple models of acute (dextran sodium sulfate-induced) and chronic (enterotoxigenic Bacteroides fragilis) colitis, and systemic infection with Candida albicans. When mice were fed a standard corn-based chow with excess Mn (100 ppm), liver Mn decreased and biliary Mn increased threefold in response to infection or colitis. Liver iron, copper, and zinc were unchanged. When dietary Mn was restricted to minimally adequate amounts (10 ppm), baseline hepatic Mn levels decreased by approximately 60% in the liver, and upon induction of colitis, liver Mn did not decrease further, however, biliary Mn still increased 20-fold. In response to acute colitis, hepatic Slc39a8 mRNA (gene encoding the Mn importer, Zip8) and Slc30a10 mRNA (gene encoding the Mn exporter, Znt10) are decreased. Zip8 protein is decreased. Inflammation/infection-associated dynamic Mn homeostasis may represent a novel host immune/inflammatory response that reorganizes systemic Mn availability through differential expression of key Mn transporters with down-regulation of Zip8.
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Proteínas de Transporte de Catión , Colitis , Masculino , Femenino , Animales , Ratones , Manganeso/metabolismo , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismo , Ratones Endogámicos C57BL , Inflamación , Homeostasis , Colitis/inducido químicamente , ARN MensajeroRESUMEN
The treatment of defective glycosylation in clinical practice has been limited to patients with rare and severe phenotypes associated with congenital disorders of glycosylation (CDG). Carried by approximately 5% of the human population, the discovery of the highly pleiotropic, missense mutation in a manganese transporter ZIP8 has exposed under-appreciated roles for Mn homeostasis and aberrant Mn-dependent glycosyltransferases activity leading to defective N-glycosylation in complex human diseases. Here, we test the hypothesis that aberrant N-glycosylation contributes to disease pathogenesis of ZIP8 A391T-associated Crohn's disease. Analysis of N-glycan branching in intestinal biopsies demonstrates perturbation in active Crohn's disease and a genotype-dependent effect characterized by increased truncated N-glycans. A mouse model of ZIP8 391-Thr recapitulates the intestinal glycophenotype of patients carrying mutations in ZIP8. Borrowing from therapeutic strategies employed in the treatment of patients with CDGs, oral monosaccharide therapy with N-acetylglucosamine ameliorates the epithelial N-glycan defect, bile acid dyshomeostasis, intestinal permeability, and susceptibility to chemical-induced colitis in a mouse model of ZIP8 391-Thr. Together, these data support ZIP8 391-Thr alters N-glycosylation to contribute to disease pathogenesis, challenging the clinical paradigm that CDGs are limited to patients with rare diseases. Critically, the defect in glycosylation can be targeted with monosaccharide supplementation, providing an opportunity for genotype-driven, personalized medicine.
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BACKGROUND: A pathogenic mutation in the manganese transporter ZIP8 (A391T; rs13107325) increases the risk of Crohn's disease. ZIP8 regulates manganese homeostasis and given the shared need for metals between the host and resident microbes, there has been significant interest in alterations of the microbiome in carriers of ZIP8 A391T. Prior studies have not examined the ileal microbiome despite associations between ileal disease and ZIP8 A391T. METHODS: Here, we used the Pediatric Risk Stratification Study (RISK) cohort to perform a secondary analysis of 16S ribosomal RNA gene sequencing data obtained from ileal and rectal mucosa to study associations between ZIP8 A391T carrier status and microbiota composition. RESULTS: We found sequence variants mapping to Veillonella were decreased in the ileal mucosa of ZIP8 A391T carriers. Prior human studies have demonstrated the sensitivity of Veillonella to bile acid abundance. We therefore hypothesized that bile acid homeostasis is differentially regulated in carriers of ZIP8 A391T. Using a mouse model of ZIP8 A391T, we demonstrate an increase in total bile acids in the liver and stool and decreased fibroblast growth factor 15 (Fgf15) signaling, consistent with our hypothesis. We confirmed dysregulation of FGF19 in the 1000IBD cohort, finding that plasma FGF19 levels are lower in ZIP8 A391T carriers with ileocolonic Crohn's disease. CONCLUSIONS: In the search for genotype-specific therapeutic paradigms for patients with Crohn's disease, these data suggest targeting the FGF19 pathway in ZIP8 A391T carriers. Aberrant bile acid metabolism may precede development of Crohn's disease and prioritize study of the interactions between manganese homeostasis, bile acid metabolism and signaling, and complicated ileal Crohn's disease.
A pathogenic mutation in the manganese transporter ZIP8 A391T increases the risk of ileal Crohn's disease. Analysis of the ileal microbiome revealed decreased bile acidsensitive microbes. Animal and human studies confirmed aberrant bile acid signaling ZIP8 A391T carriers.
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Ácidos y Sales Biliares , Proteínas de Transporte de Catión , Enfermedad de Crohn , Íleon , Mucosa Intestinal , Mutación , Enfermedad de Crohn/microbiología , Enfermedad de Crohn/genética , Enfermedad de Crohn/metabolismo , Animales , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismo , Humanos , Ratones , Ácidos y Sales Biliares/metabolismo , Íleon/microbiología , Íleon/metabolismo , Íleon/patología , Femenino , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Masculino , Recto/microbiología , Recto/metabolismo , Microbioma Gastrointestinal , Niño , Manganeso/metabolismo , Adolescente , Modelos Animales de EnfermedadRESUMEN
Manganese is a diet-derived micronutrient that is essential for critical cellular processes like redox homeostasis, protein glycosylation, and lipid and carbohydrate metabolism. Control of Mn availability, especially at the local site of infection, is a key component of the innate immune response. Less has been elucidated about Mn homeostasis at the systemic level. In this work, we demonstrate that systemic Mn homeostasis is dynamic in response to illness in mice. This phenomenon is evidenced in male and female mice, mice of two genetic backgrounds (C57/BL6 and BALB/c), in multiple models of acute (dextran-sodium sulfate-induced) and chronic ( enterotoxigenic Bacteriodes fragilis ) colitis, and systemic infection with Candida albicans . When mice were fed a standard corn-based chow with excess Mn (100 ppm), liver Mn decreased and biliary Mn increased 3-fold in response to infection or colitis. Liver iron, copper, and zinc were unchanged. When dietary Mn was restricted to minimally adequate amounts (10ppm), baseline hepatic Mn levels decreased by approximately 60% in the liver, and upon induction of colitis, liver Mn did not decrease further, however biliary Mn still increased 20-fold. In response to acute colitis, hepatic Slc39a8 mRNA (gene encoding the Mn importer, Zip8) and Slc30a10 mRNA (gene encoding the Mn exporter, Znt10) are decreased. Zip8 protein is decreased. Illness- associated dynamic Mn homeostasis may represent a novel host immune/inflammatory response that reorganizes systemic Mn availability through differential expression of key Mn transporters with down-regulation of Zip8.
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Mutations in either of the polycystic kidney disease genes, PKD1 or PKD2, engender the growth of cysts, altering renal function. Cystic growth is supported by major changes in cellular metabolism, some of which involve the mitochondrion, a major storage site for Ca2+ and a key organelle in cellular Ca2+ signaling. The goal here was to understand the role of components of the mitochondrial Ca2+ uptake complex in PC1-mutant cells in autosomal dominant polycystic kidney disease (ADPKD). We found that the mitochondrial Ca2+ uniporter (MCU) and voltage-dependent anion channels 1& 3 (VDAC) were down-regulated in different mouse and cell models of ADPKD along with the Ca2+-dependent enzyme, pyruvate dehydrogenase phosphatase (PDHX). The release of Ca2+ from the endoplasmic reticulum, and Ca2+ uptake by the mitochondria were upregulated in PC1(polycystin)-null cells. We also observed an enhanced staining with MitoTracker Red CMXRos in PC1-null cultured cells than in PC1-containing cells and a substantially higher increase in response to ER Ca2+ release. Increased colocalization of the Ca2+ sensitive dye, rhodamine2, with MitoTracker Green suggested an increase Ca2+ entry into the mitochondria in PC1 null cells subsequent to Ca2+ release from the ER or from Ca2+ entry from the extracellular solution. These data clearly demonstrate abnormal release of Ca2+ by the ER and corresponding alterations in Ca2+ uptake by the mitochondria in PC1-null cells. Importantly, inhibiting mitochondrial Ca2+ uptake with the specific inhibitor Ru360 inhibited cyst growth and altered both apoptosis and cell proliferation. We further show that the decrease in mitochondrial proteins and abnormally high Ca2+ signaling can be reversed by application of the cystic fibrosis (CFTR) corrector, VX-809. We conclude that enhanced Ca2+ signaling and alterations in proteins association with the mitochondrial Ca2+ uptake complex are associated with malfunction of PC1. Finally, our results identify novel therapeutic targets for treating ADPKD.
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Quistes , Riñón Poliquístico Autosómico Dominante , Animales , Calcio/metabolismo , Ratones , Mitocondrias/metabolismo , Riñón Poliquístico Autosómico Dominante/genética , Canales Catiónicos TRPPRESUMEN
Repeat dosing poses a major hurdle for the development of an adeno-associated virus (AAV)-based gene therapy for cystic fibrosis, in part because of the potential for development of an immune reaction to the AAV1 capsid proteins. Here, to dampen the immune response to AAV1, we treated Rhesus monkeys with methylprednisolone before and after the instillation of two doses of AAV1Δ27-264-CFTR into their airways at 0 and 30 days, followed by a single dose of AAV1-GFP on day 60. Animals were euthanized on day 90, except for one monkey that was sacrificed at 1 year. No adverse events occurred, indicating that the two AAV1 vectors are safe. rAAV1-CFTR and AAV1-GFP vector genomes and mRNA transcripts were detectable in all lung sections and in the liver and pancreas at day 90 and after 1 year at levels comparable with animals necropsied at 90 days. The numbers of vector genomes for cystic fibrosis transmembrane regulator (CFTR) and green fluorescent protein (GFP) detected here were higher than those found in the monkeys infected without methylprednisolone treatment that we tested previously.1 Also, lung surface and keratin 5-positive basal cells showed higher CFTR and GFP staining than did the cells from the uninfected monkey control. Positive immunostaining, also detected in the liver and pancreas, remained stable for at least a year. All animals seroconverted for anticapsid antibodies by 90 days post-treatment. The neutralizing antibody titer declined in the animal necropsied at 1 year. Conclusion: AAV1 safely and effectively transduces monkey airway and basal cells. Both the presence of vector genomes and transduction from AAV1-CFTR and AAV1-GFP virus seen in the monkeys 4 months to 1 year after the first instillation suggest that repeat dosing with AAV1-based vectors is achievable, particularly after methylprednisolone treatment.
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Regulador de Conductancia de Transmembrana de Fibrosis Quística , Fibrosis Quística , Animales , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Dependovirus/metabolismo , Vectores Genéticos/genética , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Macaca mulatta/genética , Macaca mulatta/metabolismo , Metilprednisolona/farmacología , Metilprednisolona/uso terapéutico , EsteroidesRESUMEN
BACKGROUND & AIMS: Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in PKHD1, encoding fibrocystin/polyductin (FPC). Severe disease occurs in perinates. Those who survive the neonatal period face a myriad of comorbidities, including systemic and portal hypertension, liver fibrosis, and hepatosplenomegaly. The goal here was to uncover therapeutic strategies for ARPKD. METHODS: We used wild-type and an FPC-mutant cholangiocyte cell line in 3-dimenional cysts and in confluent monolayers to evaluate protein expression using western blotting and protein trafficking using confocal microscopy. RESULTS: We found that the protein level of the cystic fibrosis transmembrane conductance regulator (CFTR) was downregulated. The levels of heat shock proteins (HSPs) were altered in the FPC-mutant cholangiocytes, with HSP27 being downregulated and HSP90 and HSP70 upregulated. FPC-mutant cholangiocytes formed cysts, but normal cells did not. Cyst growth could be reduced by increasing HSP27 protein levels, by HSP90 and HSP70 inhibitor treatments, by silencing HSP90 through messenger RNA inhibition, or by the novel approach of treating the cysts with the CFTR corrector VX-809. In wild-type cholangiocytes, CFTR is present in both apical and basolateral membranes. FPC malfunction resulted in altered colocalization of CFTR with both apical and basolateral membranes. Whereas, treatment with VX-809, increasing HSP27 or inhibiting HSP70 or HSP90 restored CFTR localization toward normal values. CONCLUSIONS: FPC malfunction induces the formation of cysts, which are fueled by alterations in HSPs and in CFTR protein levels and miss-localization. We suggest that CFTR correctors, already in clinical use to treat cystic fibrosis, could also be used as a treatment for ARPKD.
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Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Predisposición Genética a la Enfermedad , Riñón Poliquístico Autosómico Recesivo/genética , Riñón Poliquístico Autosómico Recesivo/metabolismo , Receptores de Superficie Celular/genética , Animales , Línea Celular , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Modelos Animales de Enfermedad , Degradación Asociada con el Retículo Endoplásmico , Regulación de la Expresión Génica , Silenciador del Gen , Terapia Genética/métodos , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Ratones , Ratones Noqueados , Mutación , Fenotipo , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Riñón Poliquístico Autosómico Recesivo/terapia , Transporte de Proteínas , Receptores de Superficie Celular/metabolismo , Eliminación de SecuenciaRESUMEN
Chalcone, a privileged structure, is considered as an effective template in the field of medicinal chemistry for potent drug discovery. In the present study, a privileged template chalcone was designed, synthesized, and characterized by various spectroscopic techniques (NMR, high-resolution mass spectrometry, Fourier transform infrared (FT-IR) spectroscopy, UV spectroscopy, and single-crystal X-ray diffraction). The mechanism of binding of chalcone with bovine serum albumin (BSA) was determined by multispectroscopic techniques and computational methods. Steady-state fluorescence spectroscopy suggests that the intrinsic fluorescence of BSA was quenched upon the addition of chalcone by the combined dynamic and static quenching mechanism. Time-resolved spectroscopy confirms complex formation. FT-IR and circular dichroism spectroscopy suggested the presence of chalcone in the BSA molecule microenvironment and also the possibility of rearrangement of the native structure of BSA. Moreover, molecular docking studies confirm the moderate binding of chalcone with BSA and the molecular dynamics simulation analysis shows the stability of the BSA-drug complex system with minimal deformability fluctuations and potential interaction by the covariance matrix. Moreover, pharmacodynamics and pharmacological analysis show good results through Lipinski rules, with no toxicity profile and high gastrointestinal absorptions by boiled egg permeation assays. This study elucidates the mechanistic profile of the privileged chalcone scaffold to be used in therapeutic applications.
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Lysozyme is a well-characterized protein in terms of its structure, dynamics, and functions. It has thus emerged as a potential target to understand protein-drug interactions. The aim of our study is to gain a biophysical outlook on the interaction of lysozyme (Lyz), a well-known model protein, with Noscapine, a potent tubulin-binding anticancer drug. Noscapine (Nos) is effective against a wide range of cancer and shows low toxicity and few side effects. We report the underlying mechanism of complex formation between Nos and Lyz using spectroscopic and advanced computational avenues. The spectroscopic techniques, that is, absorption and steady-state and time-resolved fluorescence, proved that Lyz-Nos forms a complex, and the quenching mechanism was of the static type. The binding constant was in the order of 103 indicative of moderate binding, while the stoichiometry of the protein-drug complex was 1:1 at 298 K. The secondary structural analysis using CD and UV thermal denaturation further confirmed the conformational changes in the protein upon binding with Nos. Molecular dynamics simulation studies confirmed the stable binding with minimum deviations in RMSD. The above conclusions are significant to the development of the pharmacokinetics and pharmacodynamic properties of Nos, and its successful interaction with a versatile protein like Lyz will help in overcoming its previous limitations.
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Antibiotic resistance is not only a global public health threat but also a huge economic burden to our society that urgently needs to be addressed by improved antibiotics and continuing development of novel molecules to treat resistant bacterial infections. Nowadays combination therapies offer a competent approach to counteract antibiotic resistance in bacteria. Better knowledge of mechanisms of antibiotic resistance has lead to the finding of new alternatives to antibiotic therapy. Hence, in this article, we report a novel series of indoline derivatives and their computational study as potent antimicrobials. The present study investigates the indoline based derived library interaction with DNA gyrase B enzyme to be used as a potential antimicrobial drug. Computational approaches were employed to carry out the molecular interactions and pharmacological studies. In this study, we have compared indoline with its derivatives and have found that compound 13 (1m) resulted in the strong binding with the highest score (-9.02 kcal/mol) in the designed library where indoline showed (-6.43 kcal/mol). Furthermore, molecular dynamics simulation run also confirmed the strongest interaction of a compound and target protein with less RMSD and RMSF deviation of the complex. Notably, the compound was also found to possess the good pharmacological properties and pharmacokinetic properties.
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Antibacterianos/síntesis química , Antibacterianos/farmacología , Diseño de Fármacos , Indoles/química , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/farmacología , Antibacterianos/química , Proteínas Bacterianas , ADN-Topoisomerasas/genética , ADN-Topoisomerasas/metabolismo , Sistemas de Liberación de Medicamentos , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Conformación Proteica , Inhibidores de Topoisomerasa II/químicaRESUMEN
The prevalence of obesity is increasing at an alarming rate worldwide with about 30% of the world population classified as obese. Obese body structure results when energy intake exceeds energy expenditure in an individual. Increase in the consumption of high-energy eatables, in the context of portion and energy provided, has resulted in obese populations which is becoming the leading cause of metabolic disorders related to morbidity. The obesity-related comorbidity is an enormous liability on health services and will affect measures taken in tackling the increasing obesity rate. Prevention of an obese phenotype is the most suitable long-term strategy. Another approach towards the treatment of obesity is weight management through phytotherapeutics. In this study, we explored the anti-obesity effects of Cinnamon (Cinnamomum zeylanicum) in adult male zebrafish. Through BMI measurements, blood glucose level analyses, serum triglyceride analyses, Oil Red O staining as well as quantitative Real Time-PCR, the ability of cinnamon to reduce metabolic disorders associated with obesity is investigated for the first time in a zebrafish model. Our studies indicate that cinnamon ameliorates the genotypic and phonotypic characteristics associated with obesity through lowering of BMI, blood glucose, triglyceride levels, lipid levels in the liver and through gene modulation.
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Adiposidad/efectos de los fármacos , Glucemia/metabolismo , Cinnamomum zeylanicum/química , Dieta/efectos adversos , Regulación de la Expresión Génica/efectos de los fármacos , Obesidad/metabolismo , Obesidad/patología , Animales , Índice de Masa Corporal , Tamaño Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Hígado/efectos de los fármacos , Hígado/patología , Obesidad/etiología , Obesidad/genética , Triglicéridos/sangre , Pez CebraRESUMEN
It would be of great significance to introduce a new biocompatible Layered Double Hydroxide (LDH) for the efficient remediation of wastewater. Herein, we designed a facile, biocompatible and environmental friendly layered double hydroxide (LDH) of NiFeTi for the very first time by the hydrothermal route. The materialization of NiFeTi LDH was confirmed by FTIR, XRD and Raman studies. BET results revealed the high surface area (106 m2/g) and the morphological studies (FESEM and TEM) portrayed the sheets-like structure of NiFeTi nanoparticles. The material so obtained was employed as an efficient adsorbent for the removal of organic dyes from synthetic waste water. The dye removal study showed >96% efficiency for the removal of methyl orange, congo red, methyl blue and orange G, which revealed the superiority of material for decontamination of waste water. The maximum removal (90%) of dyes was attained within 2 min of initiation of the adsorption process which supported the ultrafast removal efficiency. This ultrafast removal efficiency was attributed to high surface area and large concentration of -OH and CO32- groups present in NiFeTi LDH. In addition, the reusability was also performed up to three cycles with 96, 90 and 88% efficiency for methyl orange. Furthermore, the biocompatibility test on MHS cell lines were also carried which revealed the non-toxic nature of NiFeTi LDH at lower concentration (100% cell viability at 15.6 µg/ml). Overall, we offer a facile surfactant free method for the synthesis of NiFeTi LDH which is efficient for decontamination of anionic dyes from water and also non-toxic.
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Heme is central to functions of many biologically important enzymes (hemoproteins). It is an assembly of four porphyrin rings joined through methylene bridges with a central Fe (II). Heme is present in all cells, and its synthesis and degradation balance its amount in the cell. The deregulations of heme networks and incorporation in hemoproteins lead to pathogenic state. This article addresses the detailed structure, biosynthesis, degradation, and transportation associated afflictions to heme. The article is followed by its roles in various diseased conditions where it is produced mainly as the cause of increased hemolysis. It manifests the symptoms in diseases as it is a pro-oxidant, pro-inflammatory and pro-hemolytic agent. We have also discussed the genetic defects that tampered with the biosynthesis, degradation, and transportation of heme. In addition, a brief about the largest hemoprotein group of enzymes- Cytochrome P450 (CYP450) has been discussed with its roles in drug metabolism.
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Sistema Enzimático del Citocromo P-450/metabolismo , Interacciones Farmacológicas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Hemo/química , Animales , Hemo/metabolismo , Hemo/toxicidad , HumanosRESUMEN
In present investigation, an attempt was undertaken to modify the C-9 position of noscapine (Nos), an opium alkaloid to yield 9 -hydroxy methyl and 9 -carbaldehyde oxime analogues for augmenting anticancer potential. The synthesis of 9-hydroxy methyl analogue of Nos was carried out by Blanc reaction and 9-carbaldehyde oxime was engineered by oxime formation method and characterized using FT-IR, 1H NMR, 13C NMR, mass spectroscopy, and so on techniques. In silico docking techniques informed that 9-hydroxy methyl and 9-carbaldehyde oxime analogues of Nos had higher binding energy score as compared to Nos. The IC50 of Nos was estimated to be 46.8 µM signficantly (P < 0.05) higher than 8.2 µM of 9-carbaldehyde oxime and 4.6 µM of 9-hydroxy methyl analogue of Nos in U87, human glioblastoma cells. Moreover, there was significant (P < 0.05) difference between the IC50 of 9-carbaldehyde oxime and 9-hydroxy methyl analogue of Nos. Consistent to in vitro cytotoxicity data, 9-hydroxy methyl analogue of Nos induced significantly (P < 0.05) higher degree of apoptosis of 84.6% in U87 cells as compared to 78.5% and 64.3% demonstrated by 9-carbaldehyde oxime and Nos, respectively. Thus the higher therapeutic efficacy of 9-hydroxy methyl analogue of Nos may be credited to higher solubility and inhibitory constant (K).
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Antineoplásicos/farmacología , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Noscapina/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Humanos , Espectroscopía de Resonancia Magnética , Noscapina/análogos & derivados , Oximas/metabolismo , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Serotonin is one of the important neurotransmitters of our body. It's abnormal concentration is associated with multiple disorders and diseases. Sensitive and precise electrochemical determination of serotonin is not possible with bare working electrodes due to various reasons viz. electro-chemical fouling, presence of other biological molecules having similar oxidation potential, and lower concentration of serotonin in biological samples. Surface modification of working electrode is required for fast, precise, selective, and sensitive detection of serotonin. We have extensively reviewed the research approaches where serotonin has been sensitively detected using surface modified electrodes in the presence of other interfering agents. This review aims at presenting the electrochemical detection of serotonin using various surface modified electrodes such as glassy carbon, graphite, carbon fiber, diamond, screen printed, ITO, and metal electrodes modified with conducting polymers and polyelectrolytes, carbon nanomaterials, metal or metal oxide nanoparticles, biological compounds, and other conducting materials. The analytical figures of merits of various research approaches for detection of serotonin have been compared in the article. The properties of material used for surface modification, chemical interactions at the interfaces, and electrocatalytic effects of modified surfaces on sensing of serotonin have been thoroughly discussed in this review.
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Técnicas Biosensibles/instrumentación , Técnicas Electroquímicas/instrumentación , Serotonina/análisis , Animales , Técnicas Biosensibles/métodos , Carbono/química , Técnicas Electroquímicas/métodos , Electrodos , Diseño de Equipo , Humanos , Metales/química , Óxidos/química , Serotonina/sangre , Serotonina/orina , Propiedades de SuperficieRESUMEN
Fluoroquinolone (FQ) antibiotics are an important class of synthetic antibacterial agents. These are the most extensively used drugs for treating bacterial infections in the field of both human and veterinary medicine. Herein, the antibacterial and pharmacological properties of four fluoroquinolones: lomefloxacin, norfloxacin, ciprofloxacin, and ofloxacin have been studied. The objective of this study was to analyze the antibacterial characteristics of the different fluoroquinolones. Also, the pharmacological properties of the compounds including the Lipinski rule of five, absorption, distribution, metabolism, and excretion, LD50, drug likeliness, and toxicity were evaluated. We found that among all four FQ molecules, ofloxacin showed the highest antibacterial activity through in silico assays with a strong interaction (â38.52 kJ/mol) with the antibacterial target protein (topoisomerase-II DNA gyrase enzyme). The pharmacological and pharmacokinetic analysis also showed that the compounds ciprofloxacin, ofloxacin, lomefloxacin and norfloxacin have good pharmacological properties. Notably, ofloxacin was found to possess an IGC50 (concentration needed to inhibit 50% growth) value of 0.286 µg/L against the Tetrahymena pyriformis protozoa. It also tested negative for the Ames toxicity test, showing its non-carcinogenic character.
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Even after huge strides in medicine, cancer continues to be a formidable disease, which is slated to become the leading cause of death worldwide. The present study investigates the 1,3-benzodioxole and its propargyl ether derivatives as a novel histone deacetylase enzyme inhibitor in order to cure cancer, as aberrant expression of histone deacetylases (HDACs) is associated with carcinogenesis. Bioinformatics approaches were employed to carry out preclinical and pharmacological evaluations of designed benzodioxole derivatives. Furthermore, their interaction with HDAC-1 enzyme was studied through computational methods for their specific inhibitory effects and evaluated for their LD50 (oral rat acute toxicity) value. In addition to this work, three-dimensional (3D) structure of HDAC-1 enzyme was extracted and evaluated using various parameters including Ramachandran plot and molecular docking stimulation. In our study, we found that compound 7 and compound 9 have higher binding score than approved drugs (SAHA, TSA and VPA). Importantly, these compounds were found to possess good pharmacological and pharmacokinetic properties and can be considered as potent novel compound to combat the HDAC-1 enzyme to cure cancer. Compounds were also analyzed and validated with parameters like absorption, metabolism, excretion, toxicity and synthetic accessibility during the preclinical evaluation. This study paves way to search for novel and potent small chemical compounds for inhibiting HDAC-1 enzyme and in particular to combat the cancer progression by interrupting the cell cycle.
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Alquinos/química , Dioxoles/química , Ensayos de Selección de Medicamentos Antitumorales/métodos , Éteres/química , Histona Desacetilasa 1/metabolismo , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/metabolismo , Simulación del Acoplamiento Molecular , Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Biología Computacional/métodos , Bases de Datos de Proteínas , Diseño de Fármacos , Histona Desacetilasa 1/química , Humanos , Modelos Moleculares , Unión Proteica , Relación Estructura-ActividadRESUMEN
Autoimmunity arises when highly active immune responses are developed against the tissues or substances of one's own body. It is one of the most prevalent disorders among the old-age population with prospects increasing with age. The major cause of autoimmunity and associated diseases is the dysregulation of host immune surveillance. Impaired repairment of immune system and apoptosis regulation can be seen as major landmarks in autoimmune disorders such as the mutation of p53 gene which results in rheumatoid arthritis, bowel disease which consequently lead to tissue destruction, inflammation and dysfunctioning of body organs. Cytokines mediated apoptosis and proliferation of cells plays a regulatory role in cell cycle and further in cancer development. Anti-TNF therapy, Treg therapy and stem cell therapy have been used for autoimmune diseases, however, with the increase in the use of immunomodulatory therapies and their development for autoimmune diseases and cancer, the understanding of human immune system tends to become an increasing requirement. Hence, the findings associated with the relationship between autoimmune diseases and cancer may prove to be beneficial for the improvement in the health of suffering patients. Here in, we are eliciting the underlying mechanisms which result in autoimmune disorders causing the onset of cancer, exploration of interactome to find the pathways which are mutual to both, and recognition of hotspots which might play important role in autoimmunity mediated therapeutics with different therapies such as anti-TNF therapy, Treg therapy and stem cell therapy.
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Autoinmunidad , Vigilancia Inmunológica , Inmunoterapia/métodos , Mutación , Neoplasias , Proteína p53 Supresora de Tumor , Animales , Citocinas/genética , Citocinas/inmunología , Humanos , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapia , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/inmunologíaRESUMEN
Bromo-Noscapine (BrNs) is a tubulin-binding cytotoxic agent with significant activity against breast and lung cancer. The mechanistic interaction insight into the binding of bovine serum albumin (BSA) with BrNs can provide critical information about the pharmacodynamics and pharmacokinetics properties. Here, various spectroscopic techniques and computational methods were employed to understand the dynamics of BrNs and BSA interaction. The intrinsic fluorescence of BSA was quenched by BrNs through a static quenching procedure. The stoichiometry of BrNs-BSA complex was 1:1 and binding constant of the complex was in the order of 103 M-1 at 298 K. Based on thermodynamic analysis, it was deduced that binding process of the BrNs with BSA was spontaneous and exothermic, and the major forces between BrNs and BSA were van der waals forces and hydrogen bonding. Moreover, results of FT-IR, CD, UV spectra concluded significant conformational change in BSA on binding with BrNs. The in vitro findings were further confirmed by in silico assays. Molecular docking showed strong interactions with score of -8.08 kcal/mol. Molecular dynamics simulation analysis also suggested the stable binding with lower deviation in RMSD and RMSF values through persistent long simulation run. This study suggests optimal efficiency of diffusion of the BrNs into the bloodstream for the treatment of cancer.
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Simulación del Acoplamiento Molecular , Noscapina/química , Albúmina Sérica Bovina/química , Termodinámica , Animales , Sitios de Unión , Bovinos , Dicroismo Circular , Biología Computacional , Enlace de Hidrógeno , Estructura Molecular , Noscapina/metabolismo , Unión Proteica , Albúmina Sérica Bovina/metabolismo , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Development of nanoparticles (NPs) as a part of cancer therapeutics has given rise to a new field of research - cancer nanomedicine. In comparison to traditional anti-cancer drugs, NPs provide a targeted approach which prevents undesirable effects. In this communication, we have reviewed the role of gold and silver NPs (AgNPs) in the cancer nanomedicine. The preparation of gold NPs (AuNPs) and AgNPs can be grouped into three categories - physical, chemical and biological. Among the three approaches, the biological approach is growing and receiving more attention due to its safe and effective production. In this review, we have discussed important methods for synthesis of gold and AgNPs followed by techniques employed in characterization of their physicochemical properties, such as UV-visible spectroscopy, electron microscopy (TEM and SEM) and size and surface analysis (DLS). The mechanism of formation of these NPs in an aqueous medium through various stages - reduction, nucleation and growth has also been reviewed briefly. Finally, we conclude our review with the application of these NPs as anti-cancer agents and numerous mechanisms by which they render cancer cell toxicity.