40 results on '"Karnam K"'
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2. RP12146, a novel, selective, and potent small molecule inhibitor of PARP 1/2, synergizes with SOC therapy in preclinical models of solid tumors
- Author
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Viswanadha, S., primary, Eleswarapu, S., additional, Karnam, K., additional, and Vakkalanka, S., additional
- Published
- 2022
- Full Text
- View/download PDF
3. Preclinical Profile of RP14042, a novel, selective, and potent small molecule inhibitor of PARP7
- Author
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Viswanadha, S., primary, Eleswarapu, S., additional, Karnam, K., additional, Veeraraghavan, S., additional, Kota, A., additional, and Vakkalanka, S., additional
- Published
- 2022
- Full Text
- View/download PDF
4. SAT-091 HISTONE DEACETYLASE 5 (HDAC5)-BMP-7 AXIS REGULATES EPITHELIAL MESENCHYMAL TRANSITION IN RENAL TUBULAR EPITHELIAL CELLS
- Author
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SHARMA, P., primary, Karnam, K., additional, Sedmaki, K., additional, and Kulkarni, O., additional
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- 2020
- Full Text
- View/download PDF
5. SUN-016 REGULATION OF IL-1β BY HDAC6 AND PKR IN CALCIUM OXALATE CRYSTALS INDUCED ACUTE RENAL INJURY
- Author
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SEDMAKI, K., primary, Karnam, K., additional, Sharma, P., additional, Ghosh, B., additional, and Kulkarni, O., additional
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- 2020
- Full Text
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6. 93 (PB083) - Preclinical Profile of RP14042, a novel, selective, and potent small molecule inhibitor of PARP7
- Author
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Viswanadha, S., Eleswarapu, S., Karnam, K., Veeraraghavan, S., Kota, A., and Vakkalanka, S.
- Published
- 2022
- Full Text
- View/download PDF
7. 92 (PB082) - RP12146, a novel, selective, and potent small molecule inhibitor of PARP 1/2, synergizes with SOC therapy in preclinical models of solid tumors
- Author
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Viswanadha, S., Eleswarapu, S., Karnam, K., and Vakkalanka, S.
- Published
- 2022
- Full Text
- View/download PDF
8. Biochemical analysis of methanolic extract from Evolvulus alsinoides .
- Author
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Nithya K, Siddaraman R, Sheelajoice PP, Rajarathinam M, and Bhopal Chandra V
- Abstract
Evolvulus alsinoides is a medicinal plant in the Convolvulaceae family. Traditionally, it is used for different ailments in India and in several other countries. It has a variety of pharmacological qualities, including those that aid wound healing, hepato-protection, cardio-protection, anti-diabetic action, asthma, and epilepsy, memory and learning, and neuroprotection. The whole plant is utilized in Ayurvedic medicine to treat neurological disorders, including amnesia, and it is called the brain tonic by them. Therefore, the use of GC-MS in phytochemical research and chemotaxonomic investigations of medicinal plants containing physiologically active components is critical. Hence, the various secondary metabolites from the methanolic extract of E. alsinoides were analyzed using GC-MS technique. The methanolic extract of E. alsinoides yielded ten compounds. All ten compounds showed the highest number of hits. Those with the highest concentration were chosen to identify the qualitative compound. All compounds are non-toxic. Molecules with specific properties are capable of modulating a variety of proteins, including some enzymes. Thus, these molecules are potential hit-to-lead molecules in preclinical studies., Competing Interests: Nil., (© 2023 Biomedical Informatics.)
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- 2023
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9. Nootropic activity of methanolic extract from Evolvulus alsinoides Linn. in mice with scopolamine-induced amnesia.
- Author
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Nithya K, Siddaraman R, Sheelajoice PP, Rajarathinam M, and Chandra VB
- Abstract
Plants have been used as therapeutic agents in both un-ionized (Unani, Ayurveda) and unstructured forms since ancient times. Therefore, it is of interest to document the nootropic activity of methanolic extract from Evolvulus alsinoides Linn (Vishnukranthi) in mice with scopolamine-induced amnesia. Healthy male Swiss albino mice ranging between 25 and 30 g were used in the study. Scopolamine induced amnesia, the following two tests are performed, elevated plus maze test, passive avoidance test. The mean time spent in the open arm, closed arm, and central platform for each group of animals. The total transitions were 12.6±0.89 by GS group mice, 3.4±0.55 by GSP group mice, 7±0.71 by GSLD group mice and 10±0.71 by GSHD group mice. A significant difference was seen between GS and GSP group mice means. The mean time in the safe zone and shock zone for each group of animals when comparing to Group 2 Vs Group 3, 4 showed a statistical significance of p < 0.05. The findings of this study suggest that Evolvulus alsinoides may be a promising candidate for the development of new treatments for memory impairment and other cognitive disorders. It should be noted that more data is needed to confirm the safety and efficacy of Evolvulus alsinoides in humans and to investigate its long-term effects., Competing Interests: There are no conflicts of interest., (© 2023 Biomedical Informatics.)
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- 2023
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10. Boosting wheat yield, profitability and NUE with prilled and nano urea in conservation tillage.
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Kumar N, Tripathi SC, Yadav DB, Samota SR, Venkatesh K, Sareen S, and Singh G
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- Urea analysis, Agriculture methods, Crop Production, Edible Grain chemistry, Nitrogen analysis, Fertilizers analysis, Soil chemistry, Triticum, Oryza
- Abstract
Rice-wheat production in the Indo-gangetic plains (IGPs) of India faces major concerns such as depleting resources, rice residue burning, excessive fertilizer use, and decreasing nitrogen use efficiency. These issues threaten sustainable crop production in the future. Therefore, a field study was conducted during the winter seasons of 2020-21 and 2021-22 to evaluate the effect of combined conventional and nano fertilizers on nitrogen application just before or after irrigation to improve wheat productivity, profitability and NUE under conservation tillage. The study evaluated eight treatment combinations of nitrogen application through conventionally applied urea (46% N) and foliar applied nano urea (4% N) under zero tillage with rice residue retention. Results revealed that growth, physiological indices, yield, and quality parameters were enhanced with the application of 150 kg N/ha in three equal splits as basal and just before 1st and 2nd irrigation alone (T2) or along with a spray of nano urea (T5) compared to other treatments. T5 recorded 7.2%, 8.5%, and 7.8% more plant dry matter, number of tillers, and grain yield, respectively, over the conventional practice of applying 150 kg N/ha in three equal splits as basal and 7-10 days after 1st and 2nd irrigation (T3, farmers practice). Although, T2 showed similar results to T5, T5 recorded significantly higher gross ($2542/ha) and net returns ($1279/ha) than the other treatments. However, the benefit-cost ratio of T2 and T5 was same (2.01). A significant and positive correlation coefficient between grain yield and physiological parameters such as CCI and NDVI confirmed that increasing the nitrogen dose enhanced the chlorophyll content, greenness, and plant vigor. Based on the results, it can be concluded that applying 150 kg N/ha in three equal splits as basal and just before 1st and 2nd irrigation under conservation agriculture, along with a single spray of nano urea (4% N) at 60-65 days after sowing, can improve growth, yield attributes, wheat yield, and NUE compared to farmers practice (T3) in India., (© 2023. Springer Nature Limited.)
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- 2023
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11. Pharmacological blockade of HDAC3 accelerates diabetic wound healing by regulating macrophage activation.
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Karnam K, Sedmaki K, Sharma P, Mahale A, Ghosh B, and Kulkarni OP
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- Animals, Mice, Macrophage Activation, Lipopolysaccharides pharmacology, Mice, Inbred C57BL, Wound Healing, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Experimental metabolism
- Abstract
Aims: Here, we report the effect of histone deacetylase 3 (HDAC3) inhibition associated with macrophage activation, IL-1β expression, angiogenesis and wound healing in diabetic mice., Main Methods: To determine the expression of HDAC3 in diabetic mice wounds, hyperglycemia was induced in C57BL/6 mice with streptozotocin followed by induction of 6 mm wounds. To understand the effect of HDAC3 selective inhibitor, BG45, wound tissues were isolated for analysing M1/M2 markers expression, immune cells infiltration, angiogenesis and healing factors expression. CD11b
+ F4/80+ cells were sorted from the wound tissues and analysed for the expression of M1/M2 markers using RT-qPCR and flow cytometer. In cell based assays, HDAC3 expression was measured in macrophages stimulated with high glucose (HG) plus LPS. Macrophages treated with BG45 and HG + LPS were analysed for the expression of pro-IL-1β, mature IL-1β, oxidative stress and pro-inflammatory (M1) and anti-inflammatory (M2) factors., Key Findings: HDAC3 was found to be upregulated in impaired diabetic mice wounds and in macrophages stimulated with HG + LPS. Topical application of BG45 loaded gel accelerated the wound healing in diabetic mice and was evident by improved expression of Collagen-1A, IL-10, TGF-β, and angiogenesis (CD31, VEGF). BG45 treatment decreased the expression of IL-1β, TNF-α, and IL-6 (M1 phenotype), reduced oxidative stress and promoted the expression of Arginase-1 and YM1/2 (M2 phenotype) in macrophages treated with HG + LPS. BG45 also improved the expression of CD11b+ F4/80+ CD206+ cells in wound tissues and reduced expression of inflammatory markers., Significance: HDAC3 is upregulated in diabetic mice wounds and HDAC3 selective inhibitor promotes the wound healing by regulating macrophage activation, angiogenesis and IL-1β., Competing Interests: Declaration of competing interest Authors does not have any conflict of interest with anyone., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2023
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12. Milk from Halari Donkey Breed: Nutritional Analysis, Vitamins, Minerals, and Amino Acids Profiling.
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Garhwal R, Bhardwaj A, Sangwan K, Mehra R, Pal Y, Nayan V, Iquebal MA, Jaiswal S, and Kumar H
- Abstract
This current research set out to characterize Halari donkey milk by investigating its nutritional constituents, including its proximate analysis, water activity, titratable acidity, energy, and microbiological analysis. A comprehensive profiling of vitamins, minerals, and amino acids was also carried out. It was found that the composition of Halari donkey milk was consistent with previously published donkey milk literature and was comparable to that of human milk. Halari donkey milk has low 0.86 ± 0.04% fat content, 2.03 ± 0.03% protein content, 0.51 ± 0.05% ash content, and high 5.75 ± 0.15% lactose content making it sweet and palatable. The energy content of Halari donkey milk was 40.39 ± 0.31 kcal/100 g, and the water activity ranged from 0.973 to 0.975. Titratable acidity was 0.03 ± 0.01%. Halari donkey milk can be considered acceptable and microbiologically safe, having low total plate count and yeast and mould counts. Mineral testing revealed that Halari donkey milk included significant amounts of magnesium, sodium, calcium, potassium, phosphorus, and zinc. The concentration of different vitamins and amino acids such as isoleucine and valine also contribute to the nutritional value of Halari donkey milk.
- Published
- 2023
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13. Selective inhibition of PKR by C16 accelerates diabetic wound healing by inhibiting NALP3 expression in mice.
- Author
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Karnam K, Sedmaki K, Sharma P, Venuganti VVK, and Kulkarni OP
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- Mice, Animals, Lipopolysaccharides pharmacology, Wound Healing physiology, Caspase 1, Protein Kinases, Diabetes Mellitus, Experimental metabolism
- Abstract
Objective and Design: To understand the expression of dsRNA-dependent protein kinase R (PKR) in impaired diabetic wounds, hyperglycemia was induced in C57/BL6 mice with streptozotocin. Murine macrophage cell line, Raw 264.7, stimulated with high glucose and LPS was used to mimic diabetic wound environment in in-vitro., Materials: Macrophages stimulated with HG + LPS, in presence and absence of PKR inhibitor (C16) and wound tissue samples from topically treated mice with C16, were analyzed for the expression of PKR, NALP3, active caspase-1, mature IL-1β and phosphorylation of PKR and eIF2α. Wounds tissues were also analyzed for inflammatory cell infiltration by immunohistochemistry, angiogenesis by CD31 staining, collagen expression by western blotting, expression of CD206+ macrophages by flow cytometry and wound strength by texture analyzer., Results: PKR and NALP3 were found to be upregulated in macrophages stimulated with HG + LPS as well as in impaired diabetic wounds. PKR inhibition using C16 ameliorated expression of NALP3, caspase-1, IL-1β and phosphorylation of PKR and eIF2α, in macrophages and also in diabetic wounds. Treatment with C16 promoted the wound healing in diabetic mice by increasing collagen synthesis, reducing infiltration of F4/80
+ macrophages and MPO+ neutrophil cells, increased angiogenesis, and increased number of M2 macrophages., Conclusion: PKR inhibition using C16 accelerates the wound healing process in diabetic mice by decreasing NALP3-mediated IL-1β maturation., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)- Published
- 2023
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14. HDAC5 RNA interference ameliorates acute renal injury by upregulating KLF2 and inhibiting NALP3 expression in a mouse model of oxalate nephropathy.
- Author
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Sharma P, Karnam K, Mahale A, Sedmaki K, Krishna Venuganti V, and Kulkarni OP
- Subjects
- Animals, Mice, Creatinine, Disease Models, Animal, Histone Deacetylases genetics, Histone Deacetylases metabolism, Inflammasomes metabolism, Interleukin-1beta metabolism, Kruppel-Like Transcription Factors genetics, Kruppel-Like Transcription Factors metabolism, Lipocalin-2 metabolism, NLR Family, Pyrin Domain-Containing 3 Protein genetics, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Oxalates, RNA Interference, RNA, Small Interfering, Transcription Factors genetics, Tumor Necrosis Factor-alpha metabolism, Acute Kidney Injury chemically induced, Acute Kidney Injury genetics, Acute Kidney Injury therapy, Chitosan
- Abstract
Krüppel-like factor 2 (KLF2) and NLR family pyrin domain containing 3 (NALP3) are important regulators of macrophage activation in the context of various pathological conditions. NALP3 also plays an important role in the maturation of IL-1 β which is central to the pathogenesis of acute oxalate nephropathy. The functional role of KLF2 and regulation of both KLF2 and NALP3 in the pathogenesis of acute oxalate nephropathy is comparably less studied. Here, we explored the regulation of KLF2 and NALP3 by Histone deacetylase 5 (HDAC5) in oxalate crystals stimulated macrophages, and in the pathogenesis of acute oxalate nephropathy in mice. We observed upregulated expression of HDAC5 along with IL-1β, Caspase1, and NALP3, while the expression of KLF2 was downregulated in stimulated macrophages and in the renal tissue of mice with acute oxalate nephropathy. We formulated chitosan HDAC5 siRNA nanoparticles to deliver the siRNA in in-vitro and in-vivo settings. siHDAC5 treated cells exhibited decreased expression of IL-1β, and TNF-α in the supernatant, and reduced expression of NALP3, Pro-caspase1, active caspase1, Pro-IL-1β, and IL-1β in cell lysate. Concurrently, the expression of KLF2 was upregulated in HDAC5 depleted cells upon stimulation with crystals. Mice treated with siHDAC5 nanoparticles showed protection against renal impairment with improved renal function (plasma BUN and creatinine levels), reduced inflammation (IL-1β expression), reduced accumulation of neutrophils, reduced tubular injury, reduced acute renal injury markers (KIM-1, NGAL-1), reduced expression of NALP3, Pro-caspase1, active caspase1, Pro-IL-1β, and IL-1β. Whereas, the expression of KLF2 was significantly upregulated by depletion of HDAC5 in mice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Published
- 2022
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15. HDAC6 inhibition attenuates renal injury by reducing IL-1β secretion and RIP kinase mediated necroptosis in acute oxalate nephropathy.
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Sedmaki K, Karnam K, Sharma P, Mahale A, Routholla G, Ghosh B, and Prakash Kulkarni O
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- Animals, Inflammation metabolism, Kidney pathology, Mice, Mice, Inbred C57BL, Oxalic Acid, Tubulin, Acute Kidney Injury chemically induced, Acute Kidney Injury drug therapy, Acute Kidney Injury pathology, Necroptosis
- Abstract
Background: Pathogenesis of acute kidney injury is driven by necro-inflammation, which is comprised of IL-1β mediated inflammation and RIP-1 mediated tubular necroptosis. HDAC6 is reported to regulate both inflammation and cell death. In the present study, we explored the role of HDAC6 in the lysosomal exocytosis of IL-1β and RIP-1 mediated necroptosis in the context of oxalate nephropathy., Methods: Raw 264.7 macrophages and NRK52E stimulated with oxalate crystals and LPS with or without HDAC6 inhibitor for in vitro experiments. Acute oxalate nephropathy was induced in C57BL/6 mice by injecting sodium oxalate (75 mg/kg). For the drug intervention study, Tubastain A (TSA) was given an hour before injection of sodium oxalate. Mice were sacrificed 24 hrs after the oxalate injection, blood and kidney were harvested. Blood samples were analyzed for BUN and IL-1β levels. Renal tissues were analyzed for histology, immunohistochemistry, RNA, and protein expression., Results: HDAC6 and IL-1β upregulated in crystal stimulated macrophages and acute oxalate nephropathy. Pre-treatment of macrophages with TSA reduced IL-1β in supernatant without affecting the expression of pro-IL-1β and mature IL-1β in cell lysate. The effect of TSA on IL-1β secretion was influenced by tubulin acetylation. Renal epithelial cell NRK52E stimulated with crystals showed upregulation of necroptosis pathway markers and concentration-dependent cell death. TSA inhibited RIP-1, RIP3, and MLKL expression along with p-MLKL in stimulated epithelial cells. TSA treatment of oxalate nephropathy mice showed decreased inflammation and tubular cell death by regulating IL-1β and necroptosis and reduced renal injury., Conclusion: This study highlights the role of HDAC6 in regulating the tubulin-mediated secretion of IL-1β and RIP kinase mediated necroptosis in acute oxalate nephropathy., (Copyright © 2022. Published by Elsevier B.V.)
- Published
- 2022
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16. A Systematic Review of the Bioactive Components, Nutritional Qualities and Potential Therapeutic Applications of Donkey Milk.
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Garhwal R, Sangwan K, Mehra R, Kumar N, Bhardwaj A, Pal Y, Buttar HS, and Kumar H
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- Allergens, Animals, Antioxidants, Cattle, Equidae, Female, Humans, Milk, Human, Powders, Cattle Diseases, Milk Hypersensitivity veterinary
- Abstract
In addition to providing individualized, specific, and ample nutritional compounds, donkey milk (DM) offers immunological modulation during health and disease. Recently, DM has attracted major interest in preparing infant formulas due to its similarity to human milk in terms of high protein and lactose content and low-fat concentration. The antimicrobial, anti-inflammation, antioxidant, and hypo-allergenicity properties of DM in human infants are well-documented. The purpose of this review is to summarize the knowledge of studies done in characterizing the composition of DM, including bioactive macronutrient levels influenced by the lactation status. The manufacture of DM-based food products and promising therapeutic applications in humans will also be discussed. The beneficial health effects of DM have been extensively studied as a valuable alternative source to breast milk. DM has proven to be a suitable nutrient to relieve milk-related allergies in human infants as opposed to cow's milk. Factors that influence the levels of macronutrients in DM include lactation status, processing, and manufacturing techniques. A wide variety of dairy products have been prepared using DM, such as cheese, ice cream, milk powder, novel functional fermented beverages, and milk powder for infant formulas. The bioactive macromolecules of DM exhibit antibacterial, antiviral, and antifungal effects as well as hypo-allergenicity, anti-inflammation, and antioxidant properties., (Copyright © 2022. Published by Elsevier Inc.)
- Published
- 2022
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17. Physio-molecular traits of contrasting bread wheat genotypes associated with 15 N influx exhibiting homeolog expression bias in nitrate transporter genes under different external nitrate concentrations.
- Author
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Kumar A, Kumar S, Venkatesh K, Singh NK, Mandal PK, and Sinha SK
- Subjects
- Bread, Genotype, Nitrate Transporters, Nitrogen metabolism, Plant Roots genetics, Plant Roots metabolism, Soil, Nitrates metabolism, Triticum genetics, Triticum metabolism
- Abstract
Main Conclusion: The high affinity nitrate transport system is a potential target for improving nitrogen use efficiency of bread wheat growing either under optimal or limiting nitrate concentration. Nitrate uptake is one of the most important traits to take into account to improve nitrogen use efficiency in wheat (Triticum aestivum L.). In this study, we aimed to gain an insight into the regulation of NO
3 - -uptake and translocation systems in two contrasting wheat genotypes [K9107(K9) vs. Choti Lerma (CL)]. Different conditions, such as NO3 - -uptake rates, soil-types, N-free solid external media, and external NO3 - levels at the seedling stage, were considered. We also studied the contribution of homeolog expression of five genes encoding two nitrate transporters in the root tissue, along with their overall transcript expression levels relative to specific external nitrate availability. We observed that K9107 had a higher15 N influx than Choti Lerma under both limiting as well as optimum external N conditions in vermiculite-perlite (i.e., N-free solid) medium, with the improved translocation efficiency in Choti Lerma. However, in different soil types, different levels of15 N-enrichment in both the genotypes were found. Our results also demonstrated that the partitioning of dry matter in root and shoot was different under these growing conditions. Moreover, K9107 showed significantly higher relative expression of TaNRT2.1 at the lowest and TaNPF6.1 and TaNPF6.2 at the highest external nitrate concentrations. We also observed genotype-specific and nitrate starvation-dependent homeolog expression bias in all five nitrate transporter genes. Our data suggest that K9107 had a higher NO3 - influx capacity, involving different nitrate transporters, than Choti Lerma at the seedling stage., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2022
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18. Insights into the Research Trends on Bovine Colostrum: Beneficial Health Perspectives with Special Reference to Manufacturing of Functional Foods and Feed Supplements.
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Mehra R, Garhwal R, Sangwan K, Guiné RPF, Lemos ET, Buttar HS, Visen PKS, Kumar N, Bhardwaj A, and Kumar H
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- Animals, Cattle, Commerce, Dietary Supplements, Female, Gastrointestinal Tract, Pregnancy, Colostrum chemistry, Functional Food
- Abstract
Bovine colostrum (BC) is the initial mammary secretion after parturition, which is nature's bountiful source consisting of nutritional and bioactive components present in a highly concentrated low-volume format. All mammalian newborns require colostrum to enhance physiological processes such as lifelong immunity, gastrointestinal development, and resistance to microbial infections. The genetic, environmental, and processing methods can all have an impact on the biochemical contents of BC and its supplements. BC and its derivatives have been intensively researched for their potential use in functional foods, medicines, and animal feed. Evidence from clinical studies suggests that BC products are well-tolerated, nontoxic, and safe for human ingestion. Functional foods, feed, and pharmaceutical formulations based on bovine colostrum are playing noteworthy roles in the development of innovative products for promoting health and the prevention of chronic illnesses. This systematic review sheds light on recent research on (a) the effects of processing techniques on BC components, (b) emerging techniques used in the isolation and identification of novel components, (c) BC-based functional foods for human consumption and animal feed supplements, and (d) the role of BC in current drug delivery, as well as future recommendations.
- Published
- 2022
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19. Sustainable intensification of maize and wheat cropping system through pulse intercropping.
- Author
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Tripathi SC, Venkatesh K, Meena RP, Chander S, and Singh GP
- Abstract
The intercropping of legumes with cereals help to achieve sustainable intensification by their mutual complementarity at efficiently using radiation, nutrients, etc. Several studies indicated such beneficial effects on the other component crop however, little research has been conducted to quantify their effects on the subsequent crop in a cropping system. In this study, the effect of the legume intercropping on the entire cropping system, particularly the maize + legume-wheat system was studied. Four legumes intercropped to maize followed by wheat crop were studied for intensification measures such as wheat equivalent yield (WEY), land equivalent ratio (LER), sustainable value index (SVI), and economic returns. N saving effect of legumes on the subsequent wheat crop was quantified with two N levels. Maize + cowpea-wheat combination was the most productive and economic intercrop combination (LER = 1.71, SVI = 0.96) with an increase in net economic return (43.63%) with a B:C ratio of 1.94. An additional 25% N (37.5 kg ha
-1 ) was saved in the wheat crop when the legume intercropping was undertaken with maize. The results suggest that intercropping is the key to diversification and reduces the risk of crop failures by enhancing land-use efficiency, soil fertility, and economic returns under weather vagaries. This will be beneficial to small and marginal farmers of many countries., (© 2021. The Author(s).)- Published
- 2021
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20. HDAC6 inhibitor accelerates wound healing by inhibiting tubulin mediated IL-1β secretion in diabetic mice.
- Author
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Karnam K, Sedmaki K, Sharma P, Routholla G, Goli S, Ghosh B, Venuganti VVK, and Kulkarni OP
- Subjects
- Animals, Blotting, Western, Endotoxemia chemically induced, Glucose metabolism, Histone Deacetylase 6 antagonists & inhibitors, Immunohistochemistry, Interleukin-10 metabolism, Interleukin-1beta metabolism, Lipopolysaccharides pharmacology, Macrophages drug effects, Macrophages metabolism, Male, Mice, Mice, Inbred C57BL, Nocodazole pharmacology, RAW 264.7 Cells, Real-Time Polymerase Chain Reaction, Endotoxemia drug therapy, Endotoxemia metabolism, Enzyme Inhibitors therapeutic use, Histone Deacetylase 6 metabolism, Hydroxamic Acids therapeutic use, Indoles therapeutic use
- Abstract
Delayed wound healing in diabetes is characterized by sustained activation of inflammasome and increased expression of IL-1β in macrophages. Identification and validation of novel pathways to regulate IL-1β expression will provide therapeutic targets for diabetic wounds. Here we report sustained over-expression of histone deacetylase 6 (HDAC6) in wounds of diabetic mice and its role in delayed wound healing. Topical application of HDAC6 inhibitor; Tubastatin A (TSA) gel promoted the wound healing in diabetic mice. TSA hydrogel reduced the infiltration of neutrophils, T-cells and macrophages in the early phase of wound healing. TSA treatment promoted the wound healing by inducing collagen deposition, angiogenesis (CD31) and fibrotic factors (TGF-β1) in the late phase of healing. Protein analysis of the diabetic wounds treated with TSA showed increased acetylated α-tubulin and decreased levels of mature IL-1β with no significant effect on the expression of pro-IL-1β, pro-caspase-1 and active caspase-1. In in vitro assays, macrophages exhibited upregulation of HDAC6, IL-1β and downregulation of IL-10 upon stimulation with high glucose and LPS. TSA inhibited the IL-1β secretion and promoted IL-10 in stimulated macrophages with high glucose and LPS. Further investigations showed that TSA inhibits IL-1β release by inhibiting tubulin dependent lysosomal exocytosis without affecting its transcription and maturation. Nocodazole (known acetylation inhibitor) pre-treatment inhibited TSA effect on IL-1β secretion in high glucose stimulated macrophages. Overall, our findings indicate that sustained HDAC6 expression in diabetic wounds contributes to impaired healing responses and HDAC6 may represent a new therapeutic target for diabetic wounds., Competing Interests: Declaration of competing interest With the submission of this manuscript we would like to undertake that the above mentioned manuscript has not been published elsewhere, accepted for publication elsewhere or under editorial review for publication elsewhere; and that my Institute's BITS-Pilani, Hyderabad campus and co-authors are fully aware of this submission. The authors declare no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2020
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21. Root architecture traits variation and nitrate-influx responses in diverse wheat genotypes under different external nitrogen concentrations.
- Author
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Sinha SK, Kumar A, Tyagi A, Venkatesh K, Paul D, Singh NK, and Mandal PK
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- Genotype, Nitrogen pharmacology, Nitrates metabolism, Nitrates pharmacology, Plant Roots drug effects, Triticum drug effects, Triticum genetics
- Abstract
In order to identify the genetic variations in root system architecture traits and their probable association with high- and low-affinity nitrate transport system, we performed several experiments on a genetically diverse set of wheat genotypes grown under two external nitrogen levels (optimum and limited nitrate conditions) at two growth points of the seedling stage. Further, we also examined the nitrate uptake and its transport under different combinations of nitrate availability in the external media using
15 N-labelled N-source (15 NO3 - ), and gene expression pattern of different high- and low-affinity nitrate transporters. We observed that nitrate starvation invariably increases the total root size in all genotypes. However, the variation of component traits of total root size under nitrate starvation is genotype-specific at both stages. Further, we also observed genotypic variation in both nitrate uptake and translocation depending on the growth stage, external nitrate concentration and growing conditions. The expression of the TaNRT2.1 gene was invariably up-regulated under low external nitrate concentration; however, it gets reduced after a longer period (21 days) of starvation than the early stage (14 days). Among the four NRT1.1 orthologs, TaNPF6.3 and TaNPF6.4 consistently showed higher expression than TaNPF6.1 and TaNPF6.2 at higher nitrate concentration at both the growth stages. TaNPF6.3 and TaNPF6.4 apparently showed a feature of typical low-affinity nitrate transporter gene at higher external nitrate concentration at 14 and 21 days growth stages, respectively. The present study reveals the complex root system of wheat that has genotype-specific N-foraging along with highly coordinated high- and low-affinity nitrate transport systems for nitrate uptake and transport., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)- Published
- 2020
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22. Zygomycosis of the Scalp Caused by Rhizopus oryzae Presenting as Kerion in an Immunocompetent Child.
- Author
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Rao AG, Reddy VS, Aparna K, Haqqani R, Jagadevapuram K, Gupta S, Fathima K, Tejal M, and Muppirala D
- Abstract
Deep mycosis of the scalp caused by Rhizopus oryzae mimicking kerion is rare. Herein, we report a case of such infection in a 5-year-old immunocompetent boy who presented with multiple painful boggy swellings with discharging sinuses on the scalp of 4 months' duration. Purulent discharge from the swelling cultured on Sabouraud's dextrose agar yielded R. oryzae species which was confirmed by molecular analysis by polymerase chain reaction. The child was managed with parenteral liposomal amphotericin-B which helped in clearance of infection., Competing Interests: There are no conflicts of interest.
- Published
- 2019
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23. 4-PBA prevents diabetic muscle atrophy in rats by modulating ER stress response and ubiquitin-proteasome system.
- Author
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Reddy SS, Shruthi K, Joy D, and Reddy GB
- Subjects
- Animals, Apoptosis drug effects, Biomarkers metabolism, Diabetes Mellitus, Experimental chemically induced, Diabetes Mellitus, Experimental pathology, Injections, Intraperitoneal, Male, Muscular Atrophy chemically induced, Muscular Atrophy pathology, Phenylbutyrates administration & dosage, Rats, Rats, Sprague-Dawley, Streptozocin, Diabetes Mellitus, Experimental prevention & control, Endoplasmic Reticulum Stress drug effects, Muscular Atrophy prevention & control, Phenylbutyrates pharmacology, Proteasome Endopeptidase Complex metabolism, Ubiquitin metabolism
- Abstract
Purpose: Skeletal muscle is severely affected in diabetes leading to muscle atrophy. Previously we reported the role of ER stress in muscle atrophy due to hyperglycemia. Hence, in the present study, we investigated the effect of a classical ER stress inhibitor, 4-phenylbutyric acid (PBA), on muscle atrophy in diabetic rats., Methods: Diabetes was induced in male rats by streptozotocin, and PBA was administered (40 mg/kg/day; intraperitoneal) after two months of diabetes for two more months. Gastrocnemius muscle is collected after four months of experimental period. The cross-sectional area of myocytes was measured on Hematoxylin and Eosin stained muscle sections. Protein levels of ER stress markers, ubiquitin-proteasome system (UPS) components, and apoptosis were analysed by immunoblot. Proteasomal activity and apoptotic cells were measured., Results: ER stress markers (GRP78, ATF6, ATF4 and CHOP) that are elevated in diabetes are decreased with PBA treatment. PBA also averted diabetes-induced alterations in UPS (higher levels of E1, atrogin-1, UCHL1 and UCHL5, accumulation of ubiquitinated proteins and increased proteasomal activity). Apoptosis mediators-p53, BAX, and cleaved caspase-3 protein levels, and TUNEL positive cells were decreased in PBA treated diabetic rats. PBA notably improved the muscle-cross sectional area., Conclusions: Results highlighted the therapeutic potential of PBA in diabetes muscle wastage., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2019
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24. Optimization of Agrobacterium-mediated transformation in spring bread wheat using mature and immature embryos.
- Author
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Kumar R, Mamrutha HM, Kaur A, Venkatesh K, Sharma D, and Singh GP
- Subjects
- Agriculture methods, Agrobacterium genetics, Agrobacterium metabolism, Agrobacterium tumefaciens physiology, DNA, Bacterial genetics, DNA, Bacterial metabolism, Genetic Engineering methods, Genetic Markers, Plants, Genetically Modified genetics, Poaceae genetics, Promoter Regions, Genetic genetics, Seeds genetics, Transformation, Genetic physiology, Transgenes, Triticum growth & development, Agrobacterium tumefaciens genetics, Transformation, Genetic genetics, Triticum genetics
- Abstract
Wheat is the most widely grown staple food crop in the world and accounts for dietary needs of more than 35% of the human population. Current status of transgenic wheat development is slow all over the world due to the lack of a suitable transformation system. In the present study, an efficient and reproducible Agrobacterium-mediated transformation system in bread wheat (Triticum aestivum L.) is established. The mature and immature embryos of six recently released high yielding spring bread wheat genotypes were used to standardize various parameters using Agrobacterium tumefaciens strain EHA105 harbouring binary vector pCAMBIA3301 having gus and bar as marker genes. The optimum duration for embryo pre-culture, inoculation time and co-cultivation were 2 days, 30 min and 48 h, respectively. The bacterial inoculum concentration of OD of 1 at 600 nm showed 67.25% transient GUS expression in the histochemical GUS assay. The filter paper based co-cultivation limits the Agrobacterium overgrowth and had 82.3% explants survival rate whereas medium based strategy had 22.7% explants survival only. The medium having picloram 4 mg/l along with antibiotics (cefotaxime 500 mg/l and timentin 300 mg/l) was found best suitable for initial week callus induction. The standardized procedure gave overall 14.9% transformation efficiency in immature embryos and 9.8% in mature embryos and confirmed by gene-specific and promoter-specific PCR and southern analysis. These results indicate that the developed Agrobacterium-mediated transformation system is suitable for diverse wheat genotypes. The major obstacle for the implication of the CRISPR-based genome editing techniques is the non-availability of a suitable transformation system. Thus, the present system can be exploited to deliver the T-DNA into the wheat genome for CRISPR-based target modifications and transgene insertions.
- Published
- 2019
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25. Ubiquitin-proteasome system and ER stress in the brain of diabetic rats.
- Author
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Shruthi K, Reddy SS, Chitra PS, and Reddy GB
- Subjects
- Animals, Apoptosis drug effects, Brain metabolism, Cell Death drug effects, Cerebral Cortex drug effects, Cerebral Cortex metabolism, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Experimental genetics, Endoplasmic Reticulum Stress drug effects, Immunoblotting, Immunohistochemistry, In Situ Nick-End Labeling, Male, Phenylbutyrates pharmacology, Phenylbutyrates therapeutic use, Proteasome Endopeptidase Complex drug effects, Rats, Rats, Sprague-Dawley, Unfolded Protein Response drug effects, Diabetes Mellitus, Experimental metabolism, Endoplasmic Reticulum Stress physiology, Proteasome Endopeptidase Complex metabolism, Ubiquitin metabolism
- Abstract
The ubiquitin-proteasome system (UPS) has been implicated in the pathogenesis of many neurodegenerative diseases. Endoplasmic reticulum (ER) stress is shown to play a pathological role in the development of diabetes and its complications. Hence, the current study is aimed to investigate the role of UPS and ER stress in the cerebral cortex of diabetic rats and examine the therapeutic effect of 4-phenylbutyric acid (4-PBA), an ER stress inhibitor. Male Sprague-Dawley rats were divided into three groups: control, diabetes, and diabetes plus 4-PBA treatment group. Diabetes was induced by single intraperitoneal streptozotocin injection (37 mg/kg body weight [bw]), and 4-PBA was administered (40 mg/kg bw/d, intraperitoneal) for 2 months, starting from 2 months of diabetes induction. At the end of 4 months, cerebral cortex was collected for analysis. Declined proteasome activity and ubiquitin C-terminal hydrolase (UCH)-L1 expression, increased ubiquitinated proteins, and apoptosis were observed in the diabetic rats. The expression of the ubiquitin-activating enzyme E1, UCHL5, and ER stress markers (ATF6, pPERK, and CHOP) was markedly elevated, whereas the expression of ER-associated protein degradation (ERAD) components was downregulated in the diabetic rats. 4-PBA intervention attenuated ER stress, alterations in UPS, and ERAD components in diabetic rats. Importantly, neuronal apoptosis was lowered in 4-PBA-treated diabetic rats. Our observations demonstrate that altered UPS could be one of the underlying mechanisms of neuronal apoptosis in diabetes and chemical chaperones such as 4-PBA could be potential candidates for preventing these alterations under hyperglycemic conditions., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2019
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26. Implication of altered ubiquitin-proteasome system and ER stress in the muscle atrophy of diabetic rats.
- Author
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Reddy SS, Shruthi K, Prabhakar YK, Sailaja G, and Reddy GB
- Subjects
- Animals, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Experimental pathology, Leupeptins pharmacology, Male, Muscle Proteins metabolism, Muscle, Skeletal pathology, Muscular Atrophy chemically induced, Muscular Atrophy drug therapy, Muscular Atrophy pathology, Proteasome Inhibitors pharmacology, Rats, Rats, Sprague-Dawley, Tripartite Motif Proteins metabolism, Ubiquitin Thiolesterase metabolism, Ubiquitin-Protein Ligases metabolism, Ubiquitinated Proteins metabolism, Vesicular Transport Proteins metabolism, Diabetes Mellitus, Experimental metabolism, Endoplasmic Reticulum Stress, Muscle, Skeletal metabolism, Muscular Atrophy metabolism, Proteasome Endopeptidase Complex metabolism, Ubiquitin metabolism
- Abstract
Background: Skeletal muscle is adversely affected in type-1 diabetes, and excessively stimulated ubiquitin-proteasome system (UPS) was found to be a leading cause of muscle wasting or atrophy. The role of endoplasmic reticulum (ER) stress in muscle atrophy of type-1 diabetes is not known. Hence, we investigated the role of UPS and ER stress in the muscle atrophy of chronic diabetes rat model., Methods: Diabetes was induced with streptozotocin (STZ) in male Sprague-Dawley rats and were sacrificed 2- and 4-months thereafter to collect gastrocnemius muscle. In another experiment, 2-months post-STZ-injection diabetic rats were treated with MG132, a proteasome inhibitor, for the next 2-months and gastrocnemius muscle was collected., Results: The muscle fiber cross-sectional area was diminished in diabetic rats. The expression of UPS components: E1, MURF1, TRIM72, UCHL1, UCHL5, ubiquitinated proteins, and proteasome activity were elevated in the diabetic rats indicating activated UPS. Altered expression of ER-associated degradation (ERAD) components and increased ER stress markers were detected in 4-months diabetic rats. Proteasome inhibition by MG132 alleviated alterations in the UPS and ER stress in diabetic rat muscle., Conclusion: Increased UPS activity and ER stress were implicated in the muscle atrophy of diabetic rats and proteasome inhibition exhibited beneficiary outcome., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
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27. Development of an efficient and reproducible regeneration system in wheat ( Triticum aestivum L.).
- Author
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Kumar R, Mamrutha HM, Kaur A, Venkatesh K, Grewal A, Kumar R, and Tiwari V
- Abstract
The availability of reproducible regeneration system through tissue culture is a major bottleneck in wheat improvement program. The present study has considered to develop an efficient callus induction and regeneration system using mature and immature embryos as explants in recently released agronomically superior spring wheat varieties. An efficient sterilization process was standardized using 0.1% HgCl
2 and 70% ethanol for both seeds and embryos. The maximum possible combinations of plant growth regulators (PGRs) were evaluated for their effect on different wheat regeneration processes through tissue culture starting from callus to root induction. Picloram is found as an effective auxin with 87.63-98.67% callus induction efficiency in both explants. Supplementation of CuSO4 along with 2,4-D, zeatin in regeneration medium significantly enhanced the multiple shoot induction. The shoot development was achieved using full strength Murashige and Skoog's (MS) medium and root induction using half MS medium without PGRs. The optimized medium and method has resulted up to 100% regeneration irrespective of the genotype used with high reproducibility. Thus, the standardized regeneration system can be used in the regeneration of healthy plants from embryos rescued from interspecies crosses, transgenic production, induced mutation breeding and recently developed genome editing techniques for the procreation of wheat plants having novel traits.- Published
- 2017
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28. Ubiquitin-proteasome system and ER stress in the retina of diabetic rats.
- Author
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Shruthi K, Reddy SS, and Reddy GB
- Subjects
- Animals, Apoptosis, Autophagy, Diabetes Mellitus, Experimental complications, Diabetes Mellitus, Experimental pathology, Diabetic Retinopathy pathology, Glial Fibrillary Acidic Protein analysis, Glial Fibrillary Acidic Protein metabolism, Hypoxia-Inducible Factor 1, alpha Subunit analysis, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Male, Proteasome Endopeptidase Complex analysis, Rats, Sprague-Dawley, Retina metabolism, Rhodopsin analysis, Rhodopsin metabolism, Ubiquitin analysis, Diabetes Mellitus, Experimental metabolism, Diabetic Retinopathy metabolism, Endoplasmic Reticulum Stress, Proteasome Endopeptidase Complex metabolism, Retina pathology, Ubiquitin metabolism
- Abstract
Purpose: Diabetic retinopathy (DR) is the most frequently occurring complication of diabetes. Alterations in ubiquitin-proteasome system (UPS) have been associated with several degenerative disorders. Hence, in this study, we investigated the status and role of UPS and ER stress in the retina of diabetic rats., Methods: Diabetes was induced in rats by streptozotocin. Retinal markers, ER stress markers, components of UPS, ERAD, and autophagy were analyzed after 2- and 4-months of diabetes. Apoptosis was analyzed by TUNEL Assay., Results: There were increased acellular capillaries and pericyte loss in diabetic rat retina. Decreased protein expression of UPS components - ubiquitin activating enzyme (E1), deubiquitinating enzymes (UCHL1 and UCHL5), SIAH1 (E3 ligase) and free ubiquitin were observed in the diabetic rats. Increased ER stress markers (ATF6, XBP1, and CHOP), decreased expression of HRD1, declined autophagy (LC3B) and increased apoptosis were observed in diabetic rats. Interestingly, treatment of diabetic rats with a chemical chaperone (4-PBA) restored the levels of DUBs and ameliorated ER stress-induced retinal cell death in type 1 diabetic rats., Conclusion: The declined UPS components: E1 and HRD1 in the retina of diabetic rats could elicit ER stress, and the prolonged ER stress may trigger CHOP-mediated neuronal apoptosis., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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29. Evaluation of analgesic and anti-inflammatory activity of a combination of tramadol-ibuprofen in experimental animals.
- Author
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Suthakaran C, Kayalvizhi MK, Nithya K, and Raja TA
- Subjects
- Animals, Drug Therapy, Combination, Female, Inflammation drug therapy, Male, Mice, Pain drug therapy, Pain Measurement, Rats, Rats, Wistar, Analgesia methods, Anti-Inflammatory Agents administration & dosage, Ibuprofen administration & dosage, Tramadol administration & dosage
- Abstract
Background: Pain is the major concern of patients attending dental clinics, and satisfactory pain relief has always been difficult to achieve. Since the pathophysiology of pain is a complex, central and peripheral nervous system process, combined analgesic regimens with different mechanisms of action as a multimodal approach are becoming popular among the clinicians and dentists., Objectives: The aim of the present study was to evaluate the analgesic and anti-inflammatory activity of ibuprofen and tramadol when used alone or in combination in animal models of pain and inflammation., Animals and Methods: The animals were divided into six groups with six animals in each group. Analgesic activity was assessed by hot plate method in rats and by acetic acid-induced writhing test in mice. Paw edema model in rats after induction with 0.1 mL of 1% carrageenan was used to assess the anti-inflammatory activity., Statistical Analysis: Analysis of variance followed by Tukey's honestly significant difference post hoc test was used for statistical analysis., Results and Conclusion: Combined use of tramadol and ibuprofen provided enhanced analgesic and anti-inflammatory effects in animal models of pain and inflammation.
- Published
- 2017
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30. Correlation of Bone Mineral Parameters with Anthropometric Measurements and the Effect of Glucocorticoids on Bone Mineral Parameters in Congenital Adrenal Hyperplasia: Authors' Reply.
- Author
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Ganesh R, Suresh N, Janakiraman L, and Ravikumar K
- Subjects
- Absorptiometry, Photon, Bone Density drug effects, Humans, Minerals, Adrenal Hyperplasia, Congenital, Glucocorticoids
- Published
- 2016
- Full Text
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31. Amelioration of neuronal cell death in a spontaneous obese rat model by dietary restriction through modulation of ubiquitin proteasome system.
- Author
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Shruthi K, Reddy SS, Reddy PY, Shivalingam P, Harishankar N, and Reddy GB
- Subjects
- Animals, Apoptosis, Autophagy, Biomarkers metabolism, Cerebral Cortex enzymology, Cerebral Cortex metabolism, Cerebral Cortex pathology, Endoplasmic Reticulum Stress, Gene Expression Regulation, Developmental, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Neurodegenerative Diseases etiology, Neurons enzymology, Neurons pathology, Obesity metabolism, Obesity pathology, Obesity physiopathology, Rats, Mutant Strains, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Ubiquitination, alpha-Synuclein genetics, alpha-Synuclein metabolism, bcl-2-Associated X Protein genetics, bcl-2-Associated X Protein metabolism, Aging, Caloric Restriction, Neurodegenerative Diseases prevention & control, Neurons metabolism, Neuroprotection, Obesity diet therapy, Proteasome Endopeptidase Complex metabolism
- Abstract
Dietary restriction (DR) has been shown to increase longevity, delay onset of aging, reduce DNA damage and oxidative stress and prevent age-related decline of neuronal activity. We previously reported the role of altered ubiquitin proteasome system (UPS) in the neuronal cell death in a spontaneous obese rat model (WNIN/Ob rat). In this study, we investigated the effect of DR on obesity-induced neuronal cell death in a rat model. Two groups of 40-day-old WNIN/Ob rats were either fed ad libitum (Ob) or pair-fed with lean. The lean phenotype of WNIN/Ob rats served as ad libitum control. These animals were maintained for 6.5months on their respective diet regime. At the end of the study, cerebral cortex was collected and markers of UPS, endoplasmic reticulum (ER) stress and autophagy were analyzed by quantitative real-time polymerase chain reaction, immunoblotting and immunohistochemistry. Chymotrypsin-like activity of proteasome was assayed by the fluorimetric method. Apoptotic cells were analyzed by TUNEL assay. DR improved metabolic abnormalities in obese rats. Alterations in UPS (up-regulation of UCHL1, down-regulation of UCHL5, declined proteasomal activity), increased ER stress, declined autophagy and increased expression of α-synuclein, p53 and BAX were observed in obese rats and DR alleviated these changes in obese rats. Further, DR decreased TUNEL-positive cells. In conclusion, DR in obese rats could not only restore the metabolic abnormalities but also preserved neuronal health in the cerebral cortex by preventing alterations in the UPS., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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32. CYP21A2 gene mutation in South Indian children with congenital adrenal hyperplasia.
- Author
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Ganesh R, Suresh N, Janakiraman L, and Ravikumar K
- Subjects
- DNA Mutational Analysis, Female, Humans, India, Infant, Infant, Newborn, Male, Adrenal Hyperplasia, Congenital genetics, Mutation genetics, Steroid 21-Hydroxylase genetics
- Published
- 2015
33. Altered ubiquitin-proteasome system leads to neuronal cell death in a spontaneous obese rat model.
- Author
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Reddy SS, Shruthi K, Reddy VS, Raghu G, Suryanarayana P, Giridharan NV, and Reddy GB
- Subjects
- Animals, Cerebral Cortex pathology, Dietary Fats adverse effects, Dietary Fats pharmacology, Disease Models, Animal, Neurons metabolism, Neurons pathology, Obesity chemically induced, Obesity pathology, Rats, Tumor Suppressor Protein p53 metabolism, Ubiquitin Thiolesterase metabolism, Apoptosis, Cerebral Cortex metabolism, Endoplasmic Reticulum Stress, Nerve Tissue Proteins metabolism, Obesity metabolism, Proteasome Endopeptidase Complex metabolism, Ubiquitin metabolism
- Abstract
Background: Obesity is associated with various progressive age-related diseases, including neurological disorders. However, underlying molecular basis for increased risk of neurodegeneration in obesity is unknown. A suitable animal model would immensely help in understanding the obesity-linked neurological problems., Methods: A spontaneously developed obese rat (WNIN/Ob) which is highly vulnerable for a variety of degenerative diseases was isolated from the existing WNIN stock rats. Ultrastructure of neurons in the cerebral cortex of 12-month old obese rats was evaluated by transmission electron microscopy. qRT-PCR and immunoblotting of ubiquitin C-terminal hydrolases (UCHs), ubiquitin, proteasomal sub-units, markers of ER stress and apoptosis were performed in the cerebral cortex. Proteasome activity was assayed by fluorometric method. Immunohistochemistry was performed for mediators of apoptosis, which was further confirmed by TUNEL assay. These investigations were also carried in high-fat diet-induced obese rat model., Results: Neurons in the cerebral cortex of 12-month obese rats showed swollen mitochondria, disrupted ER and degenerating axons, nucleus and finally neurons. Results showed altered UPS, existence of ER stress, up-regulation of apoptotic markers and apoptosis in the cerebral cortex of obese rats. It appears that UCHL-1 mediated apoptosis through stabilizing p53 might play a role in neuronal cell death in obese rat. Similar changes were observed in the brain of diet-induced obese WNIN rats., Conclusion: Altered UPS could be one of the underlying mechanisms for the neuronal cell death in obese conditions., General Significance: This is the first report to highlight the role of altered UPS in neurodegeneration due to obesity., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
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34. Vitamins C and E for asthma and exercise-induced bronchoconstriction.
- Author
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Wilkinson M, Hart A, Milan SJ, and Sugumar K
- Subjects
- Adult, Asthma etiology, Asthma, Exercise-Induced drug therapy, Child, Chronic Disease, Humans, Randomized Controlled Trials as Topic, Antioxidants therapeutic use, Ascorbic Acid therapeutic use, Asthma drug therapy, Bronchoconstriction drug effects, Exercise, Vitamins therapeutic use
- Abstract
Background: The association between dietary antioxidants and asthma or exercise-induced bronchoconstriction (EIB) is not fully understood. Vitamin C and vitamin E are natural antioxidants that are predominantly present in fruits and vegetables; inadequate vitamin E intake is associated with airway inflammation. It has been postulated that the combination may be more beneficial than either single antioxidant for people with asthma and exercise-induced bronchoconstriction., Objectives: To assess the effects of supplementation of vitamins C and E versus placebo (or no vitamin C and E supplementation) on exacerbations and health-related quality of life (HRQL) in adults and children with chronic asthma. To also examine the potential effects of vitamins C and E on exercise-induced bronchoconstriction in people with asthma and in people without a diagnosis of asthma who experience symptoms only on exercise., Search Methods: Trials were identified from the Cochrane Airways Review Group Specialised Register and from trial registry websites. Searches were conducted in September 2013., Selection Criteria: We included randomised controlled trials of adults and children with a diagnosis of asthma. We separately considered trials in which participants had received a diagnosis of exercise-induced bronchoconstriction (or exercise-induced asthma). Trials comparing vitamin C and E supplementation versus placebo were included. We included trials in which asthma management for treatment and control groups included similar background therapy. Short-term use of vitamins C and E at the time of exacerbation or for cold symptoms in people with asthma is outside the scope of this review., Data Collection and Analysis: Two review authors independently screened the titles and abstracts of potential studies and subsequently screened full-text study reports for inclusion. We used standard methods as expected by The Cochrane Collaboration., Main Results: It was not possible to aggregate the five included studies (214 participants). Four studies (206 participants) addressed the question of whether differences in outcomes were seen when vitamin C and E supplementation versus placebo was provided for participants with asthma, and only one of those studies (160 children) included a paediatric population; the remaining three studies included a combined total of just 46 adults. An additional study considered the question of whether differences in outcomes were noted when vitamin C and E supplementation was compared with placebo for exercise-induced asthma; this trial included only eight participants. The randomisation process of the trials were unclear leading us to downgrade the quality of the evidence. Four of the studies were double blind while the other study was single blind.None of these studies provided data on our two prespecified primary outcome measures: exacerbations and HRQL. Lung function data obtained from the studies were inconclusive. The only studies that provided any suggestion of an effect, and only with some outcomes, were the paediatric study, especially for children with moderate to severe asthma, and the small study on exercise-induced asthma. Even so, this evidence was judged to be at moderate/low quality. Only one study contributed data on asthma symptoms and adverse events, reporting no evidence of an effect of the intervention for symptoms and that one participant in the treatment group dropped out due to cystitis., Authors' Conclusions: It is not possible to draw firm conclusions from this review with respect to the comparison of vitamin C and E supplementation versus placebo in the management of asthma or exercise-induced bronchoconstriction. We found only one study relevant to exercise-induced bronchoconstriction; most included participants came from studies designed to assess the effect of vitamin supplementation on the impact of atmospheric pollutants (such as ozone). Evidence is lacking on the comparison of vitamin C and E supplementation versus placebo for asthma with respect to outcomes such as HRQL and exacerbations, which were not addressed by any of the included studies.When compared with lung function tests alone, HRQL scores and exacerbation frequency are better indicators of the severity of asthma, its impact on daily activities and its response to treatment in a patient population. These end points are well recognised in good quality studies of asthma management. However, clinical studies of vitamins C and E in the management of asthma using these important end points of exacerbations and effects on quality of life are not available, and evidence is insufficient to support robust conclusions on the role of vitamin C and E supplementation in asthma and exercise-induced breathlessness.
- Published
- 2014
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35. Inhaled hyperosmolar agents for bronchiectasis.
- Author
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Hart A, Sugumar K, Milan SJ, Fowler SJ, and Crossingham I
- Subjects
- Anti-Bacterial Agents therapeutic use, Cross-Over Studies, Health Status, Humans, Mucociliary Clearance, Osmolar Concentration, Powders, Randomized Controlled Trials as Topic, Bronchiectasis drug therapy, Hypertonic Solutions administration & dosage, Mannitol administration & dosage
- Abstract
Background: Mucus retention in the lungs is a prominent feature of bronchiectasis. The stagnant mucus becomes chronically colonised with bacteria, which elicit a host neutrophilic response. This fails to eliminate the bacteria, and the large concentration of host-derived protease may contribute to the airway damage. The sensation of retained mucus is itself a cause of suffering, and the failure to maintain airway sterility probably contributes to the frequent respiratory infections experienced by many patients.Hypertonic saline inhalation is known to accelerate tracheobronchial clearance in many conditions, probably by inducing a liquid flux into the airway surface, which alters mucus rheology in a way favourable to mucociliary clearance. Inhaled dry powder mannitol has a similar effect. Such agents are an attractive approach to the problem of mucostasis, and deserve further clinical evaluation., Objectives: To determine whether inhaled hyperosmolar substances are effective in the treatment of bronchiectasis., Search Methods: We searched the Cochrane Airways Group Specialised Register, trials registries, and the reference lists of included studies and review articles. Searches are current up to April 2014., Selection Criteria: Any randomised controlled trial (RCT) using hyperosmolar inhalation in patients with bronchiectasis not caused by cystic fibrosis., Data Collection and Analysis: Two review authors assessed studies for suitability. We used standard methods recommended by The Cochrane Collaboration., Main Results: Eleven studies met the inclusion criteria of the review (1021 participants).Five studies on 833 participants compared inhaled mannitol with placebo but poor outcome reporting meant we could pool very little data and most outcomes were reported by only one study. One 12-month trial on 461 participants provided results for exacerbations and demonstrated an advantage for mannitol in terms of time to first exacerbation (median time to exacerbation 165 versus 124 days for mannitol and placebo respectively (hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.63 to 0.96, P = 0.022) and number of days on antibiotics for bronchiectasis exacerbations was significantly better with mannitol (risk ratio (RR) 0.76, 95%CI 0.58 to 1.00, P = 0.0496). However, exacerbation rate per year was not significantly different between mannitol and placebo (RR 0.92 95% CI 0.78 to 1.08). The quality of this evidence was rated as moderate. There was also an indication, from only three trials, again based on moderate quality evidence, that mannitol improves health-related quality of life (mean difference (MD) -2.05; 95% CI -3.69 to -0.40). An analysis of adverse events data, also based on moderate quality evidence, revealed no difference between mannitol and placebo (OR 0.96; 95% CI 0.61 to 1.51). Two additional small trials on 25 participants compared mannitol versus no treatment and the data from these studies were inconclusive.Four studies (combined N = 113) compared hypertonic saline versus isotonic saline. On most outcomes there were conflicting results and the opportunities for the statistical aggregation of data from studies was very limited. It is not possible to draw robust conclusions for this comparison and judgments should be reserved until further data are available., Authors' Conclusions: There is an indication from a single, large, unpublished study that inhaled mannitol increases time to first exacerbation in patients with bronchiectasis. In patients with near normal lung function, spirometry does not change dramatically with mannitol and adverse events are not more frequent than placebo. Further investigation is required in a patient population with impaired lung function.It is not possible to draw firm conclusions regarding the effect of nebulised hypertonic saline due to significant differences in the methodology, patient groups, and findings amongst the limited data available. The data suggest that it is unlikely to have benefit over isotonic saline in patients with milder disease, and hence future studies should test its use in those with more severe disease.
- Published
- 2014
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36. Mucolytics for bronchiectasis.
- Author
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Wilkinson M, Sugumar K, Milan SJ, Hart A, Crockett A, and Crossingham I
- Subjects
- Anti-Bacterial Agents therapeutic use, Bromhexine therapeutic use, Deoxyribonucleases therapeutic use, Drug Therapy, Combination, Humans, Randomized Controlled Trials as Topic, Recombinant Proteins therapeutic use, Thioglycolates therapeutic use, Thiophenes therapeutic use, Bronchiectasis therapy, Expectorants therapeutic use
- Abstract
Background: Bronchiectasis is predominantly an acquired disease process that represents the end stage of a variety of unrelated pulmonary insults. It is defined as persistent irreversible dilatation and distortion of medium-sized bronchi. It has been suggested that with widespread use of high-resolution computed tomography, more bronchiectasis diagnoses are being made. Patients diagnosed with bronchiectasis frequently have difficulty expectorating sputum. Sputum therefore is retained in the lungs and may become infected, leading to further lung damage. Mucolytic agents target hypersecretion or changed physiochemical properties of sputum to make it easier to clear. One drug, recombinant human DNase, breaks down the DNA that is released at the site of infection by neutrophils.Mucus clearance along with antimicrobial therapy remains an integral part of bronchiectasis management. Chest physiotherapy along with mucolytic agents is commonly used in practice without clear supportive evidence., Objectives: To determine whether ingested or inhaled mucolytics are effective in the treatment of patients with bronchiectasis., Search Methods: We searched the Cochrane Airways Group Specialised Register and reference lists of relevant articles. We contacted experts in the field and drug companies. Searches were current as of June 2013., Selection Criteria: Randomised trials of mucolytic treatment in people with bronchiectasis but not cystic fibrosis., Data Collection and Analysis: Data extraction was performed independently by two review authors. Study authors were contacted for confirmation., Main Results: Four trials (with a combined total of 528 adult participants) were included, but almost none of the data from these studies could be aggregated in a meta-analysis.One trial (with 88 participants) compared bromhexine versus placebo. Compared with placebo, high doses of bromhexine with antibiotics eased difficulty in expectoration (mean difference (MD) -0.53, 95% confidence interval (CI) -0.81 to -0.25 at 16 days); the quality of the evidence was rated as low. A reduction in sputum production was noted with bromhexine (MD -21.5%, 95% CI -38.9 to -4.1 at day 16); again the quality of the evidence was rated as low. No significant differences between bromhexine and placebo were observed with respect to reported adverse events (odds ratio (OR) 2.93; 95% CI 0.12 to 73.97), and again the quality of the evidence was rated as low.In a single small, blinded but not placebo-controlled trial of older (> 55 years) participants with stable bronchiectasis and mucus hypersecretion, erdosteine combined with physiotherapy over a 15-day period improved spirometry and sputum purulence more effectively compared with physiotherapy alone. The spirometric improvement was small (MD 200 mL in forced expiratory volume in one second (FEV1) and 300 mL in forced vital capacity (FVC)) and was apparent only at day 15, not at earlier time points.The remaining two studies (with a combined total of 410 participants) compared recombinant human DNase (RhDNase) versus placebo. These two studies were very different (one was a two-week study of 61 participants, and the other ran for 24 weeks and included 349 participants), and the opportunity for combining data from the two studies was very limited. Compared with placebo, recombinant human DNase showed no difference in FEV1 or FVC in the smaller study but showed a significant negative effect on FEV1 in the larger and longer study. For reported adverse events, no significant differences between recombinant human DNase and placebo were noted. In all of the above comparisons of recombinant human DNase versus placebo, the quality of the evidence was judged to be low., Authors' Conclusions: Given the harmful effects of recombinant human DNase in one trial and no evidence of benefit, this drug should be avoided in non-cystic fibrosis bronchiectasis, except in the context of clinical trials. Evidence is insufficient to permit evaluation of the routine use of other mucolytics for bronchiectasis. High doses of bromhexine coupled with antibiotics may help with sputum production and clearance, but long-term data and robust clinical outcomes are lacking. Similarly, erdosteine may be a useful adjunct to physiotherapy in stable patients with mucus hypersecretion, but robust longer-term trials are required.Generally, clinical trials in children on the use of various mucolytic agents are lacking. As the number of agents available on the market, such as RhDNase, acetylcysteine and bromhexine, is increasing, improvement of the evidence base is needed.
- Published
- 2014
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37. An unusual cause of acute confusional state.
- Author
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Sreenivasa HK and Sugumar K
- Subjects
- Child, Preschool, Female, Humans, Poisoning complications, Poisoning diagnosis, Amphetamine poisoning, Confusion etiology
- Published
- 2012
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38. Synthesis of new Cu(II)-chelating ligand amphiphiles and their esterolytic properties in cationic micelles.
- Author
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Bhattacharya S, Snehalatha K, and Kumar VP
- Abstract
Four new tetradentate 2,6-disubstituted pyridine and tridentate 2-substituted pyridine ligands were synthesized. Two of these compounds possessed a metal ion binding subunit in the form of a 2,6-disubstituted-4-N,N'-dimethylamine pyridine moiety. Cu(2+)-complexes of these ligands incorporated in cetyltrimethylammonium bromide (CTABr) micelles speeded the cleavage of p-nitrophenyldiphenyl phosphate and p-nitrophenyl hexanoate at pH 7.6. On the basis of a kinetic version of Job plot analysis, a 1:1 ligand/Cu(2+) stoichiometry was found to be the most active species. In CTABr micelles, the pK(a) values for the Cu(2+)-coordinated hydroxyl or pendant -CH(2)OH in these ligands were between 7.8 and 7.9. The metallomicellar systems displayed catalytic (turnover) behavior in the presence of excess substrates.
- Published
- 2003
- Full Text
- View/download PDF
39. Synthesis of Some Copper(II)-Chelating (Dialkylamino)pyridine Amphiphiles and Evaluation of Their Esterolytic Capacities in Cationic Micellar Media.
- Author
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Bhattacharya S, Snehalatha K, and George SK
- Abstract
Three new (dialkylamino)pyridine (DAAP)-based ligand amphiphiles 3-5 have been synthesized. All of the compounds possess a metal ion binding subunit in the form of a 2,6-disubstituted DAAP moiety. In addition, at least one ortho-CH(2)OH substituent is present in all the ligands. Complex formation by these ligands with various metal ions were examined under micellar conditions, but only complexes with Cu(II) ions showed kinetically potent esterolytic capacities under micellar conditions. Complexes with Cu(II) were prepared in host comicellar cetyltrimethylammonium bromide (CTABr) media at pH 7.6. Individual complexes were characterized by UV-visible absorption spectroscopy and electron paramagnetic resonance spectroscopy. These metallomicelles speed the cleavage of the substrates p-nitrophenyl hexanoate or p-nitrophenyl diphenyl phosphate. To ascertain the nature of the active esterolytic species, the stoichiometries of the respective Cu(II) complexes were determined from the kinetic version of Job's plot. In all the instances, 2:1 complex ligand/Cu(II) ion are the most kinetically competent species. The apparent pK(a) values of the Cu(II)-coordinated hydroxyl groups of the ligands 3, 4, and 5, in the comicellar aggregate, are 7.8, 8.0, and 8.0, respectively, as estimated from the rate constant vs pH profiles of the ester cleavage reactions. The nucleophilic metallomicellar reagents and the second-order "catalytic" rate constants toward esterolysis of the substrate p-nitrophenyl hexanoate (at 25 degrees C, pH 7.6) are 37.5 for 3, 11.4 for 4, and 13.8 for 5. All catalytic systems comprising the coaggregates of 3, 4, or 5 and CTABr demonstrate turnover behavior in the presence of excess substrate.
- Published
- 1998
- Full Text
- View/download PDF
40. Evidence for the Formation of Acylated or Phosphorylated Monoperoxyphthalates in the Catalytic Esterolytic Reactions in Cationic Surfactant Aggregates.
- Author
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Bhattacharya S and Snehalatha K
- Abstract
Monoperoxyphthalate (MPP) was solubilized in three different aqueous cationic surfactant aggregates composed of (i) a micellar cetyltrimethylammonium chloride (CTACl) solution; (ii) an oil-in-water (O/W) microemulsion (ME) stabilized by CTACl, and a cosurfactant, tert-butyl alcohol, and (iii) a vesicular medium composed of dispersions of dihexadecyldimethylammonium chloride (DHDAC). At pH approximately 8.5 and 25 degrees C, each of these formulations was used to cleave p-nitrophenyl diphenyl phosphate (PNPDPP). The aggregate and the maximum pseudo-first-order rate constants ([MPP] = 4 x 10(-)(5) M, and [PNPDPP] = 1 x 10(-)(5) M) for the PNPDPP cleavages are the following: buffer alone, 0.00034 s(-)(1); micelle: 0.024 s(-)(1); ME: 0.0048 s(-)(1); and vesicle: 0.025 s(-)(1). Importantly all the catalytic formulations showed "turnover" behavior in the presence of excess substrates. By the combined use of (1)H- and (31)P-NMR spectrometry and synthesis, it was possible to provide evidence for the formation of acylated or phosphorylated monoperoxypthalates in the catalytic hydrolyses in cationic surfactant aggregates.
- Published
- 1997
- Full Text
- View/download PDF
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