Uma Maheswari Krishnan

SASTRA University, Thousand Oaks, CA, United States

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Publications (92)304.86 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Precise estimation of Michaelis-Menten constant (K m ) and maximum rate of reaction (V max ) is very significant in studying enzyme inhibition as well as the catalytic efficiency of the immobilized enzyme in electrochemical nanointerface based biosensors. Generally linear regression models such as Lineweaver-Burk plot, Eadie-Hosftee plot, Eadie-Scatchard plot and Hanes-Woolf plot have been used to estimate enzyme kinetic parameters. But, the disadvantage of using linear regression plots is changing error statistics. As an alternative to linear regression models, three nonlinear regression models namely Gauss Newton plot, Chi Square plot and Levenberg-Marquardt fit (LVM) have been used, which fits the data by successive iterations. In this work, a sample data of lactate detect- ing electrochemical biosensor (Au/Nano-ZnO/LDH) has been considered for the precise estimation of K m and V max by employing nonlinear mathematical tools. Finally regression, residual, standard deviation, coefficient of variation, Chi Square, residual sum of squares and percent average relative error analyses are carried out on the adapted nonlinear mathematical models to choose optimized Michaelis-Menten equation.
    Journal of Computational and Theoretical Nanoscience 12/2014; 11(12). · 1.03 Impact Factor
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    ABSTRACT: In view of the difficulties in finding the precise value of Michaelis-Menten constant (K M) and maximum net current (I max) of a biosensor from linear plots, we framed two modified non-linear equations employing Michaelis-Menten equation. In this work, data of lactate detecting sensor were used to exemplify practicability and accuracy of the modified Michaelis-Menten equation. Standard and modified Michaelis-Menten model was normalized using Levenberg-Marquardt algorithm. The validity of the two modified Michaelis-Menten models was statistically analyzed using numerical error analysis, unpaired student t-Test and Akaike's Information Criterion (AIC) method, and the results were satisfactory. This method is quite easy and has assured convergence with no initial guess for K M and I max .
    Journal of Computational and Theoretical Nanoscience 12/2014; 11(12). · 1.03 Impact Factor
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    ABSTRACT: Abstract Context: Metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) are the emerging co-morbidities of skin inflammation. Occurrence of skin inflammation such as psoriasis is substantially higher in NAFLD patients than normal. Currently, there are no animal models to study the interaction between these co-morbidities. Objective: The present study seeks to develop a simple mouse model of NAFLD-enhanced skin inflammation and to study the effect of NAFLD on different parameters of skin inflammation. Materials and method: Metabolic syndrome and NAFLD were induced in C57BL/6 mice by feeding high-fat diet (HFD, 60% kcal) and high fructose liquid (HFL, 40% kcal) in drinking water. Skin inflammation was induced by repeated application of oxazolone (1% sensitization and repeated 0.5% challenge) in both normal and NAFLD mice and various parameters of skin inflammation and NAFLD were measured. Results: HFD and HFL diet induced obesity, hyperglycemia, hyperinsulinemia, and histological features of NAFLD in mice. Oxazolone challenge significantly increased ear thickness, ear weight, MPO activity, NF-κB activity, and histological features of skin inflammation in NAFLD mice as compared with normal mice. Overall, induction of oxazolone-induced skin inflammation was more prominent in NAFLD mice than normal mice. Hence, HFD and HFL diet followed by topical oxazolone application develops metabolic syndrome, NAFLD, and enhanced skin inflammation in mice. Discussion and conclusion: This simple model can be utilized to evaluate a therapeutic strategy for the treatment of metabolic syndrome and NAFLD with skin inflammation and also to understand the nexus between these co-morbidities.
    Pharmaceutical Biology 11/2014; · 1.21 Impact Factor
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    ABSTRACT: Background: RNA interference (RNAi) technology using short interfering RNA (si-RNA) has shown immense potential in the treatment of cancers through silencing of specific genes. Cationic non-viral vectors employed for gene delivery exhibit toxic effects in normal cells limiting their widespread use, therefore, site-specific delivery using benign carriers could address this issue. Objective: Design of a non-toxic carrier that enables site-specific delivery of si-RNA into the cancer cells is of prime importance to realize the promise of gene silencing. Methods: In the present study, non-cationic liposomes encapsulating si-RNA against epithelial cell adhesion molecule (EpCAM) were developed and characterized for encapsulation efficiency, colloidal stability,in vitro andin vivo gene silencing efficacy. Results: PEGylated liposomes containing phosphatidyl choline and phosphatidyl ethanolamine exhibited maximumsi-RNA encapsulation efficiency of 47%, zeta potential of -21 mV, phase transition temperature of 51C and good colloidal stability in phosphate-buffered saline (PBS) containing bovine serum albumin (BSA) and plasma protein (PP) at 37 C. Conjugation of epithelial cell adhesion molecule (EpCAM) antibody to the liposomes resulted in enhanced cell internalization and superior down-regulation of EpCAM gene in MCF-7 cell lines when compared with free si-RNA and the non-targeted liposomes. In vivo evaluation of immunoliposomes for their efficacy in regressing the tumor volume in Balb/c SCID mice showed about 35% reduction of tumor volume in comparison with the positive control when administered with an extremely low dose of 0.15 mg/kg twice a week for 4 weeks. Conclusion: Our results exhibit that the nanocarrier-mediated silencing of EpCAM gene is a promising strategy to treat epithelial cancers.
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    ABSTRACT: Background: RNA interference (RNAi) technology using short interfering RNA (si-RNA) has shown immense potential in the treatment of cancers through silencing of specific genes. Cationic non-viral vectors employed for gene delivery exhibit toxic effects in normal cells limiting their widespread use, therefore, site-specific delivery using benign carriers could address this issue. Objective: Design of a non-toxic carrier that enables site-specific delivery of si-RNA into the cancer cells is of prime importance to realize the promise of gene silencing. Methods: In the present study, non-cationic liposomes encapsulating si-RNA against epithelial cell adhesion molecule (EpCAM) were developed and characterized for encapsulation efficiency, colloidal stability, in vitro and in vivo gene silencing efficacy. Results: PEGylated liposomes containing phosphatidyl choline and phosphatidyl ethanolamine exhibited maximum si-RNA encapsulation efficiency of 47%, zeta potential of -21 mV, phase transition temperature of 51 °C and good colloidal stability in phosphate-buffered saline (PBS) containing bovine serum albumin (BSA) and plasma protein (PP) at 37 °C. Conjugation of epithelial cell adhesion molecule (EpCAM) antibody to the liposomes resulted in enhanced cell internalization and superior down-regulation of EpCAM gene in MCF-7 cell lines when compared with free si-RNA and the non-targeted liposomes. In vivo evaluation of immunoliposomes for their efficacy in regressing the tumor volume in Balb/c SCID mice showed about 35% reduction of tumor volume in comparison with the positive control when administered with an extremely low dose of 0.15 mg/kg twice a week for 4 weeks. Conclusion: Our results exhibit that the nanocarrier-mediated silencing of EpCAM gene is a promising strategy to treat epithelial cancers.
    Drug Delivery. 11/2014;
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    ABSTRACT: Chandraprabha Vati (CPV), a multi-ingredient phyto formulation, is widely used in Ayurveda for the treatment of liver and kidney disorders. In this study, we attempt to elucidate the mode of action of CPV. We specifically focus on the effects of CPV on the transcriptional regulation of Pregnane-X-Receptor (PXR) and its subsequent effects on interleukins, Peroxisome Proliferator-Activated Receptor-γ (PPARγ) and type 4 Glucose Transporter (GLUT4). Our results show that CPV up-regulates PXR moderately in contrast to its individual ingredients such as chebulinic acid or linalool that down regulate PXR. Further, the expression of Cytochrome P450 3A4 (CYP3A4), the gene involved in drug elimination, is only moderately up-regulated by CPV, again in contrast to the effect of some of its ingredients. CPV down regulates the levels of pro-inflammatory cytokines and upregulates the levels of PPARγ, which in turn upregulates GLUT4 expression. These together suggest that the therapeutic properties of CPV can be attributed to its multi-pronged action, viz., prevention of inflammation, moderate expression of PXR that activates several downstream pathways and tight regulation of CYP3A4 thereby slowing down the elimination of the chemical constituents. In addition, these results emphasize on the need for multi-ingredient approach towards designing effective therapeutic formulations.
    RSC Advances 11/2014; · 3.71 Impact Factor
  • L.R. Jaidev, Uma Maheswari Krishnan, Swaminathan Sethuraman
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    ABSTRACT: Pancreatic cancer is the fourth leading cancer with 85% mortality rate in USA alone and it is prevalent in many other developed and developing countries. Clinically, gemcitabine is prescribed as the first line chemotherapeutic drug for pancreatic cancer treatment. Gemcitabine-loaded poly(lactide-co-glycolide) (PLGA) nanospheres were synthesized and their physico-chemical properties were evaluated. The FESEM images showed that the gemcitabine loaded and blank nanospheres were 180 nm and 200 nm, respectively. The optimized encapsulation efficiency of gemcitabine was 15%. It was observed that 100% of gemcitabine was released from the PLGA nanospheres for 41 days in phosphate buffered saline (PBS) at pH 7.4. The uptake of nanospheres in MiaPaCa-2 cells was studied using sulforhodamine B loaded PLGA nanospheres and our results showed that the nanospheres were taken up within 3 h. Furthermore, the cytotoxicity of PLGA nanospheres loaded with gemcitabine showed a relative decrease in IC50 in MiaPaCa-2 and ASPC-1 pancreatic cancer cells in comparison to free gemcitabine. The study demonstrates that this system hold promise to improve the therapeutic efficacy of gemcitabine in vitro.
    Materials Science and Engineering: C. 11/2014;
  • Indian Journal of Pharmaceutical Sciences 11/2014; · 0.34 Impact Factor
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    ABSTRACT: Atorvastatin is a 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor used in the treatment of atherosclerosis and dyslipidemia. Studies have evaluated the utility of statins in the treatment of skin inflammation but with varied results. In the present study, we investigated the effect of atorvastatin on TNF-α release and keratinocyte proliferation in vitro and in acute and chronic 12-O-tetradecanoylphorbol-13-acetate (TPA) induced skin inflammation in vivo. Atorvastatin significantly inhibited lipopolysacharide induced TNF-α release in THP-1 cells and keratinocyte proliferation in HaCaT cells. In an acute study, topical atorvastatin showed dose dependent reduction in TPA induced skin inflammation with highest efficacy observed at 500 µg/ear dose. In chronic study, topical atorvastatin significantly reduced TPA induced ear thickness, ear weight, cutaneous cytokines, MPO activity and improved histopathological features comparable to that of dexamethasone. Atorvastatin also inhibited TPA stimulated NF-κB activation in mouse ear. In conclusion, our results suggest that atorvastatin ameliorates TPA induced skin inflammation in mice at least in part, due to inhibition of cytokine release and NF-κB activation and may be beneficial for the treatment skin inflammation like psoriasis.
    Archives of Pharmacal Research 10/2014; · 1.54 Impact Factor
  • Purushothaman Kuppan, Swaminathan Sethuraman, Uma Maheswari Krishnan
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    ABSTRACT: PCL and PCL-gelatin random and aligned nanofibers with diameters in the range of 200-400 nm were developed through electrospinning. Mechanical properties of aligned PCL and PCL-gelatin nanofibers were compared, and it was found that aligned PCL nanofibers showed significantly higher tensile strength and Young's modulus than the PCL-gelatin nanofiber system (p<0.05). The in vitro degradation of aligned nanofibers showed that PCL-gelatin nanofibers degrade faster than aligned PCL nanofibers. Further, human smooth muscle cells (hSMCs) were cultured on the random and aligned PCL-gelatin nanofibers and evaluated for adhesion, orientation, morphology, viability, proliferation and gene expression. Our results demonstrate that PCL-gelatin promotes higher cell adhesion and proliferation than the PCL nanofibers after 3, 7 and 10 days of culture. Aligned topography favored orientation of the cells along their directions and cell stretching was better in aligned nanofibers than the random nanofibers. The up-regulation of α-actin, myosin heavy chain, collagen type I and elastin genes demonstrate good cell-matrix interactions in both random and aligned scaffolds. Therefore, the present study concludes that aligned PCL-gelatin nanofibers could serve as potential scaffolding for culture of smooth muscle cells and may promote functional regeneration of tubular organs.
    Journal of Biomedical Materials Research Part A 10/2014; · 2.83 Impact Factor
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    ABSTRACT: Flavonoid glycosides are a group of polyphenols with different glycoside substituents that possess diverse pharmacological activities albeit with lesser potency than their aglycone counterparts. Complexation with transition metal ions may alter their pharmacological activity, but this facet has remained unexplored thus far. Therefore, the present study aims to synthesize copper and iron complexes of naringin and investigate their nature of membrane interactions employing erythrocyte membrane models. An attempt to correlate their interaction and localization in the membrane with their cytotoxic effects was also made. Hypotonic hemolysis experiments carried out in the presence of naringin or its complexes with copper or iron reveals their different extent of penetration in to the membrane. Naringin and naringin-iron were found to preferentially interact with the membrane surface when compared with naringin-copper. The transformation of erythrocyte membrane from the normal discoidal shape to an echinocyte form induced by the addition of naringin, naringin-copper and naringin-iron complex suggests their interaction with the outer leaflet of erythrocyte membrane. Naringin-copper exhibited the maximum tendency to alter the morphology of erythrocyte membranes. The copper and iron complexes of naringin exhibit superior cytotoxicity against MCF-7 cancer cells that can be a manifestation of their degree of perturbation of the membrane architecture as well as different levels of activation of various molecular targets.
    RSC Advances 09/2014; · 3.71 Impact Factor
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    ABSTRACT: Axially aligned nanofibrous matrices were evaluated as small diameter cardiovascular grafts. Grafts were prepared using the poly(L-lactic acid) (PLA) and poly(ε-caprolactone) (PCL) physical blends in the ratios of 75:25 and 25:75 with the dimension of (40 × 0.2 × 4) millimeter by electrospinning using dynamic collector (1500 RPM). Hydrophobicity and tensile stress were significantly higher in PLA-PCL (75:25), whereas tensile strain and fiber density were significantly higher in PLA-PCL (25:75). Properties such as anastomatic strength porosity, average pore size, degradation with retained fiber orientation, and thromboresistivity were comparable between blends. Human umbilical vascular endothelial cells (HUVEC) adhesion on the scaffolds was observed within 24 h. Cell viability and proliferation were rationally influenced by the aligned nanofibers. Gene expression reveals the grafts thromboresistivity, elasticity, and aided neovascularization. Thus, these scaffolds could be an ideal candidate for small diameter blood vessel engineering.
    Journal of Biomaterials Science Polymer Edition 08/2014; · 1.70 Impact Factor
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    ABSTRACT: Human Immunodeficiency Virus (HIV) infection remains a significant cause of mortality globally. Though antiretroviral therapy has significantly reduced AIDS-related morbidity and mortality, there are several drawbacks in the current therapy, including toxicity, drug-drug interactions, development of drug resistance, necessity for long-term drug therapy, poor bio-availability and lack of access to tissues and reservoirs. To circumvent these problems, recent anti-HIV therapeutic research has focused on improving drug delivery systems through drug delivery targeted specifically to host cells infected with HIV or could potentially get infected with HIV. In this regard, several surface molecules of both viral and host cell origin have been described in recent years, that would enable targeted drug delivery in HIV infection. In the present review, we provide a comprehensive overview of the need for novel drug delivery systems, the successes and challenges in the identification of novel viral and host-cell molecules for the targeted drug delivery of anti-HIV drugs. Such targeted anti-retroviral drug delivery approaches could pave the way for effective treatment and eradication of HIV from the body.
    Journal of Controlled Release 08/2014; · 7.63 Impact Factor
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    ABSTRACT: Biodegradable polymers have been extensively used as scaffolds to regenerate lost tissues. The geometry of the three-dimensional (3D) scaffolds has an influence on the cellular behaviour. In this study, we have developed 3D-scaffolds of axially aligned nanofibres of poly(lactic acid) (PLA), poly(caprolactone) (PCL) and PLA:CL (50:50) with diameters in the range 100-400 nm, internal diameter 4 mm, length 4 cm and wall thickness 0.2 mm, by using a dynamic collector. PCL and PLA:CL nanofibres were significantly less hydrophobic than PLA nanofibres. The porosity of PCL (16.23 ± 9.88%) and PLA:CL nanofibres (14.77 ± 3.41%) were comparable, while PLA (6.57 ± 1.54%) nanofibres had lower porosity. The tensile strength and Young's modulus of PLA was significantly lower than PCL and PLA:CL nanofibres and the suture retention strengths of all three scaffolds were comparable. After 4 weeks, the molecular weight of PLA nanofibres was reduced by 53% compared to 44% and 41% for PCL and the PLA:CL nanofibres, respectively. However, the PLA:CL nanofibres maintained their structural integrity even after 28 days. Platelet adhesion studies showed that PCL nanofibres had least tendency to be thrombogenic, while PLA:CL blend nanofibres were highly thrombogenic. Further, in vitro responses such as cell adhesion, proliferation and gene expression of human umbilical vascular endothelial cells (HUVECs) were evaluated. After 6 days of culture, the surfaces of all the three scaffolds were completely covered with cells. Our results demonstrate that expression levels of elastin, angiopoietin, laminin-4α and -5α were upregulated in PCL and PLA:CL nanofibres without the addition of any exogenous factors. Copyright © 2012 John Wiley & Sons, Ltd.
    Journal of Tissue Engineering and Regenerative Medicine 08/2014; 8(8):640-651. · 4.43 Impact Factor
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    ABSTRACT: Protein folding is a spontaneous self-assembly process, which occurs in the biological system. Understanding this complex process not only helps in deciphering the mechanism involved in protein misfolding diseases but also helps in modeling in vitro and in vivo systems for testing the therapeutic strategies developed for the disease. Among the protein misfolding diseases, much emphasis has been given to Alzheimer's disease because of its prevalence among elderly individuals and propensity to cause external damage to neurons, an effective cure for which is yet to be designed. Though amyloid fibrils are the major cause of neurotoxicity in Alzheimer's disease, their mechanism of self-assembly during pathological conditions is still under active investigation. This review aims to understand the basic mechanism of amyloid fibril formation and how it can be characterized in different stages by various techniques. With this information, it is possible to design both in vitro and in vivo systems, which not only serves as model systems for understanding the mechanism of amyloid fibril formation but also helps to test new therapeutic strategies against the disease. This review also highlights the pros and cons of currently available in vitro and in vivo systems, which can aid the readers to select a suitable system for their further studies.
    Current Alzheimer Research 07/2014; 11(6):588-607. · 3.68 Impact Factor
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    ABSTRACT: Multifunctional nanoparticles are next generation materials that can be simultaneously used for imaging, diagnosis, and delivery of drugs. However, materials intended for cancer diagnosis need to be investigated for its cell uptake, toxicity, and effectiveness. In the current work, we have synthesized fluorescent iron oxide nanoparticles and evaluated its efficacy against retinoblastoma cell imaging. The iron oxide nanoparticles were synthesized and stabilized using oleic acid. Sulforhodamine B was adsorbed onto albumin over the oleic acid-capped iron oxide nanoparticles. Our results demonstrated good cell uptake in a time-dependent manner and nanoparticles were found to localize in the cytosol. Further, the nanoparticles exhibited excellent negative contrast in magnetic resonance imaging (MRI) experiments and with no cytoxicity (5-100 μg/mL iron oxide nanoparticles) to both normal as well as cancer cells demonstrating its biocompatibility. Thus, this novel material integrates the ability to image tissues with high sensitivity by MRI and specifically visualize Y79 retinoblastoma cells by fluorescence imaging with no toxicity.
    Journal of Biomaterials Science Polymer Edition 06/2014; · 1.70 Impact Factor
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    ABSTRACT: Amyloid beta peptide accumulation in the brain poses a serious threat during Alzheimer’s disease. Various strategies to remove or disrupt these plaques with nanoparticles is an emerging area for the treatment for neurodegenerative diseases. The present work attempts to develop a novel strategy to remove the plaques using magnetic field by employing magnetic nanoparticles conjugated with a plaque–targeting ligand. Thioflavin–S (TF–S) was covalently linked to magnetic iron oxide incorporated mesoporous silica, SBA–15 and the material was characterized using microscopic and spectroscopic techniques. This magnetic conjugate (IO–SBA–TF–S) was found to display the ability to remove in vitro, KLVFF peptide, a recognition motif in β–Amyloid that has been implicated in plaque formation. This system represents a potential smart system that could herald in the next generation therapeutic strategy for Alzheimer’s disease and related disorders.
    Microporous and Mesoporous Materials 06/2014; · 3.37 Impact Factor
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    ABSTRACT: Sulphur, one of the key ingredients in Ayurvedic formulations has been used as a single drug or in combination with metals to treat various diseases. Classical Ayurvedic texts describe purification techniques for sulphur as well for metals used in combination with sulphur. Butter is used to melt sulphur and the molten sulphur is quenched in milk to bring about an allotropic transformation. Elemental analysis revealed increase in calcium, potassium, phosphorus and sodium content in sulphur which gets incorporated from milk. A substantial increase in carbon, hydrogen and nitrogen content in the sulphur samples indicated incorporation of carbohydrate, protein and lactose content from milk. This was corroborated with decrease in protein and lactose content in the milk after quenching. The process of quenching with water did not result in an allotropic transformation, confirming that milk is responsible for this chemical change. The allotropic modification is necessary to facilitate further reactions of sulphur through mechanochemistry.
    Asian Journal of Chemistry. 06/2014; 26(12):3697-3699.
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    ABSTRACT: Objective: Therapeutic formulation to reduce amyloid beta (Aβ) insult in neuronal cells remains an important focus in the treatment of Alzheimer's disease. To combat the multifactorial threats that arise during amyloid plaque formation, multi-dimensional approach is required. Methods: Peptide sequence KLVFF derived from the core recognition motif of Aβ1 - 42 can bind to the plaques and help to reduce further accumulation. In our previous work, we have reported various self-assembling structures of KLVFF along with its surface tension lowering ability to overcome the cytotoxicity caused by Aβ1 - 42. In the present work, we have developed a novel combination of peptide-curcumin-loaded liposomal formulation and characterized for its morphology, protein adsorption and colloidal stability. The therapeutic efficacy of the formulation was tested using a cholinergic neuronal cell line pre-treated with Aβ1 - 42. Results: The physiochemical characterization and in vitro efficacy of peptide-curcumin-loaded liposomal formulation were found to outperform well in bringing down the amyloid toxicity. Conclusion: This cumulative evidence indicates that the nanocarrier-based alternative treatment stratagem is an effective way to treat Alzheimer's disease.
    Expert Opinion on Drug Delivery 05/2014; · 4.87 Impact Factor
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    ABSTRACT: Flavonoid-metal ion complexes are a new class of molecules that have generated considerable interest due to their superior anti-oxidant and pharmacological activities. The metal ion present in these complexes can participate in redox reactions by toggling between different oxidation states. This property can be invaluable for sensing applications. But, the use of flavonoid-metal ion complexes as sensors remains an unexplored facet. The present work attempts to develop a non-enzymatic superoxide sensor using naringin-copper complex. Detection of superoxide has been mainly based on enzymes and cytochromes. However, these sensors are limited by their poor structural stability and high cost. The naringin-copper based non-enzymatic sensor exhibits good sensitivity in a range of 0.2-4.2µM with a response time of <1s. The performance of the sensor is not affected by pH and common interferents.
    Biosensors & Bioelectronics 03/2014; 59C:134-139. · 6.45 Impact Factor