Search

Toward the development of selective cyclooxygenase-2 inhibitors, a series of pyrrolidine derivatives is described. All the compounds containing sulfonamide, ester, nitrile, acid, amide and urea functionalities were computationally screened, and binding affinity scores for all synthesized compounds with cyclooxygenase-1 and cyclooxygenase -2 were compared. The computational observations showed three top-ranked compounds (8b, 8d and 10a) having selectively more affinity for cyclooxygenase -2. These were selected for pharmacological evaluation using carrageenan-induced rat paw edema model. Compound 8b showed maximum activity (54.83%) which was closer to standard drug indometacin (57.48%). The safety parameter of the potent compound (8b) was assessed using aspirin induced gastric ulceration animal model.

Under normal conditions, astrocytes perform a number of important physiological functions centered around neuronal support and synapse maintenance. In neurodegenerative diseases including Alzheimer’s, Parkinson’s and prion diseases, astrocytes acquire reactive phenotypes, which are sustained throughout the disease progression. It is not known whether in the reactive states associated with prion diseases, astrocytes lose their ability to perform physiological functions and whether the reactive states are neurotoxic or, on the contrary, neuroprotective. The current work addresses these questions by testing the effects of reactive astrocytes isolated from prion-infected C57BL/6J mice on primary neuronal cultures. We found that astrocytes isolated at the clinical stage of the disease exhibited reactive, pro-inflammatory phenotype, which also showed downregulation of genes involved in neurogenic and synaptogenic functions. In astrocyte-neuron co-cultures, astrocytes from prion-infected animals impaired neuronal growth, dendritic spine development and synapse maturation. Toward examining the role of factors secreted by reactive astrocytes, astrocyte-conditioned media was found to have detrimental effects on neuronal viability and synaptogenic functions via impairing synapse integrity, and by reducing spine size and density. Reactive microglia isolated from prion-infected animals were found to induce phenotypic changes in primary astrocytes reminiscent to those observed in prion-infected mice. In particular, astrocytes cultured with reactive microglia-conditioned media displayed hypertrophic morphology and a downregulation of genes involved in neurogenic and synaptogenic functions. In summary, the current study provided experimental support toward the non-cell autonomous mechanisms behind neurotoxicity in prion diseases and demonstrated that the astrocyte reactive phenotype associated with prion diseases is synaptotoxic.

To confront a disease like Alzheimer's disease having complex pathogenesis, development of multitarget-directed ligands has emerged as a promising drug discovery approach. In our endeavor towards the development of multitarget-directed ligands for Alzheimer's disease, a series of indoloquinoxaline derivatives were designed and synthesized. In vitro cholinesterase inhibition studies revealed that all the synthesized compounds exhibited moderate to good cholinesterase inhibitory activity. 6-(6-(Piperidin-1-yl)hexyl)-6

Phagocytosis is one of the most important physiological functions of the glia directed at maintaining a healthy, homeostatic environment in the brain. Under a homeostatic environment, the phagocytic activities of astrocytes and microglia are tightly coordinated in time and space. In neurodegenerative diseases, both microglia and astrocytes contribute to neuroinflammation and disease pathogenesis, however, whether their phagocytic activities are up- or downregulated in reactive states is not known. To address this question, this current study isolated microglia and astrocytes from C57BL/6J mice infected with prions and tested their phagocytic activities in live-cell imaging assays that used synaptosomes and myelin debris as substrates. The phagocytic uptake by the reactive microglia was found to be significantly upregulated, whereas that of the reactive astrocytes was strongly downregulated. The up- and downregulation of phagocytosis by the two cell types were observed irrespective of whether disease-associated synaptosomes, normal synaptosomes, or myelin debris were used in the assays, indicating that dysregulations are dictated by cell reactive states, not substrates. Analysis of gene expression confirmed dysregulation of phagocytic functions in both cell types. Immunostaining of animal brains infected with prions revealed that at the terminal stage of disease, neuronal cell bodies were subject to engulfment by reactive microglia. This study suggests that imbalance in the phagocytic activities of the reactive microglia and astrocytes, which are dysregulated in opposite directions, is likely to lead to excessive microglia-mediated neuronal death on the one hand, and the inability of astrocytes to clear cell debris on the other hand, contributing to the neurotoxic effects of glia as a whole.

The multifaceted nature of Alzheimer's disease (AD) demands treatment with multitarget-directed ligands (MTDLs) to confront the key pathological aberrations. A novel series of triazinoindole derivatives were designed and synthesized. In vitro studies revealed that all the compounds showed moderate to good anticholinesterase activity; the most active compound

The major risk associated with low platelet count in pregnancy is the increased risk of bleeding during the childbirth or post that. There is an increased blood supply to the uterus during pregnancy and the surgical procedure requires cutting of major blood vessels. Women with thrombocytopenia are at increased risk of losing excessive blood. The risk is more in case of caesarean delivery as compared to vaginal delivery. Hence based on above findings the present study was planned for Assessment of the Platelet Count in the Pregnant Women in IGIMS, Patna, Bihar. The present study was planned in Department of Pathology, Indira Gandhi Institute of Medical Science, Patna, Bihar, India. The present study was planned from duration of January 2019 to June 2019. In the present study 200 pregnant females samples received for the platelet estimation were enrolled in the present study. Clinically platelet indices can be a useful screening test for early identification of preeclampsia and eclampsia. Also platelet indices can assess the prognosis of this disease in pregnant women and can be used as an effective prognostic marker because it correlates with severity of the disease. Platelet count is a simple, low cost, and rapid routine screening test. Hence the data generated from the present study concludes that platelet count can be used as a simple and cost effective tool to monitor the progression of preeclampsia, thereby preventing complications to develop during the gestational period. Keywords: Platelet Count, Pregnant Women, IGIMS, Patna, Bihar, etc.

Direct air capture (DAC) removes CO2 from the atmosphere and can therefore address sizable nonpoint sources emissions of CO2 such as those from transportation. We propose a five-step temperature vacuum swing adsorption process for direct air capture using solid adsorbents coated as films on monolithic contactors using steam as the stripping agent during desorption. We perform a modeling study and economic assessment for DAC using two metal organic frameworks, MIL-101(Cr)-PEI-800 and mmen-Mg2(dobpdc), for which we have experimentally demonstrated film growth on monolith structures. The results indicate minimum energy requirements, and cost estimates are 0.145 MJ/mol-CO2 and $75–140/t-CO2 for MIL-101(Cr)-PEI-800, and 0.113 MJ/mol-CO2 and $60–190/t-CO2 for mmen-Mg2(dobpdc), respectively. The overall DAC cost is sensitive to adsorbent purchase cost and lifetime as well as cycle parameters such as adsorption and desorption times. We conclude that mmen-Mg2(dobpdc) has better performance compared to MIL-101(Cr)-...

Optimization using data from complex simulations has become an attractive decision-making option, due to ability to embed high-fidelity, non-linear understanding of processes within the search for optimal values. Due to lack of tractable algebraic equations, the link between simulations and optimization is oftentimes a surrogate metamodel. However, several forms of uncertainty exist within the cycle that links simulation data, to metamodels, to optimization. Uncertainty may originate from parameters of the simulation, or the form and fitted parameters of the metamodel. This paper reviews different literatures that are relevant to surrogate-based optimization and proposes different strategies for handling uncertainty, by combining machine learning with stochastic programming, robust optimization, and discrepancy modeling. We show that incorporating uncertainty management within simulation-based optimization leads to more robust solutions, which protect the decision-maker from infeasible solutions. We present the results of our proposed approaches through a case study for direct-air capture through temperature swing adsorption.

Recent advances in adsorptive gas separations have focused on the development of porous materials with high operating capacity and selectivity, useful parameters that provide early guidance during the development of new materials. Although this material-focused work is necessary to advance the state of the art in adsorption science and engineering, a substantial problem remains: how to integrate these materials into a fixed bed to efficiently utilize the separation. Structured sorbent contactors can help manage kinetic and engineering factors associated with the separation, including pressure drop, sorption enthalpy effects, and external heat integration (for temperature swing adsorption, or TSA). In this review, we discuss monoliths and fiber sorbents as the two main classes of structured sorbent contactors; recent developments in their manufacture; advantages and disadvantages of each structure relative to each other and to pellet packed beds; recent developments in system modeling; and finally, critical needs in this area of research.

CO2 capture from enclosed environments such as commercial buildings can result in reduced ventilation, thereby leading to decreased energy loads on the HVAC systems. We propose a model which regulates the air quality inside the room by adsorption of CO2 on monoliths coated with zeolite 13X, and water adsorption on packed beds with silica gel. We perform a modeling study and energy assessment by simulating a multi-component, multi-bed system which controls carbon dioxide level inside the room on a 24 hr basis. The results obtained indicate a 75% reduction in energy load with the CO2 capture system as compared to the conventional ventilation system. We have identified areas of uncertainty in the model and compared non-intrusive polynomial chaos method with Monte Carlo simulations to quantify the model uncertainties. The results show improvement in computational efficiency with non-intrusive methods as compared to Monte Carlo simulations. We conclude that the CO2 capture system can lead to improvement in building energy performance and application of polynomial chaos methods can result in reduction of computational time.

This article describes discovery of a novel and new class of cholinesterase inhibitors as potential therapeutics for Alzheimer's disease. A series of novel isoalloxazine derivatives were synthesized and biologically evaluated for their potential inhibitory outcome for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These compounds exhibited high activity against both the enzymes AChE as well as BuChE. Of the synthesized compounds, the most potent isoalloxazine derivatives (7m and 7q) showed IC50 values of 4.72 μM and 5.22 μM respectively against AChE; and, 6.98 μM and 5.29 μM respectively against BuChE. These two compounds were further evaluated for their anti-aggregatory activity for β-amyloid (Aβ) in presence and absence of AChE by performing Thioflavin-T (ThT) assay and Congo red (CR) binding assay. In order to evaluate cytotoxic profile of these two potential compounds, cell viability assay of SH-SY5Y human neuroblastoma cells was performed. Further, to understand the binding behavior of these two compounds with AChE and BuChE enzymes, docking studies have been reported.

The benzazepine ring system has offered interesting CNS-active medicinal agents. Taking this privileged structure as the basic scaffold, $$\hbox {C}_{1}$$ and/or $$\hbox {N}_{3}$$ -alkylated benzazepin-2-one derivatives and their reduced analogs have been prepared as potential $$\hbox {5-HT}_{\mathrm{2C}}$$ receptor agonists. The selective alkylation at the $$\hbox {C}_{1}$$ and/or $$\hbox {N}_{3}$$ positions of this seven-membered lactam ring is here reported for the first time under different reaction conditions. The synthesized compounds were evaluated for their biological profile as potential $$\hbox {5-HT}_{\mathrm{2C}}$$ agonists using a classic pharmacological approach. Three derivatives (15, 17, and 20) have shown promising $$\hbox {5-HT}_{\mathrm{2C}}$$ agonistic activity which can be further optimized as anti-obesity agents for the treatment of male sexual dysfunction. Further, a homology model for $$\hbox {5-HT}_{\mathrm{2C}}$$ receptor was generated using MODELLER, and ligand–receptor interactions for these potential molecules were studied.

ABC India Ltd. (ABCIL), started in 1963 was a pioneer in the field of logistics since its inception. The company was specialized in surface transportation, international freight forwarding and integrated logistics services. ABCIL got their business plunged off as they were not able to generate new business and was even facing challenges in maintaining its market share. It was feeling the heat of intense competition from both large Full Truckload FTL competitors who constantly negotiated bargains with their larger customers to wean away those accounts, and from smaller fleet owners whose lower-cost structures and scant regard for regulations allowed them to undercut prices to smaller and mid-tier customers. In order to maintain its position and market share, the company has to come up with viable and long sustaining solution.

The Cyert and March (1963:123) aspirations model has spawned research into organizational aspirations and their influence on firm behavior. In the absence of actual aspirations measures, researcher...

Background Oxitard, a polyherbal formulation comprising the extracts of Withania somnifera , Mangifera indica , Glycyrrhiza glabra , Daucus carota , Vitis vinifera , powders of Syzygium aromaticum , Yashada bhasma and Emblica officinalis ; and oils of Triticum sativum . Objective Current study deals with the assessment of Oxitard (a marketed polyherbal formulation) for its adaptogenic potential in chronic unpredictable stress (CUS) and chronic stress (CS) induced dysfunctional homeostasis in rodents. Materials & methods Animals were immobilized for 2 h every day for ten days to induce CS. In order to induce CUS, animals were employed in a battery of stressors of variable value and duration for ten days. Following administration of Oxitard, stress was induced in the animals. Stress-induced efficient changes were evaluated by assessing organ (adrenal gland) weights, ulcer index, hematological parameters and biochemical levels of reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS) and catalase (CAT). Results CS and CUS significantly modified the oxidative stress parameters (increased MDA and decreased GSH). Furthermore, CS and CUS lead to weight reduction, adrenal hypertrophy and gastric ulceration. Pre-treatment with Oxitard (200 and 400 mg/kg, p.o.) significantly modified CS and CUS induced hematological changes, oxidative stress parameters and pathological effects. Conclusion In conclusion, Oxitard-intervened antioxidant actions are accountable for its adaptogenic effects in stress-induced dysfunctional homeostasis.

In an effort to develop potent antithrombotic agents, a series of novel 2-aminobenzamide derivatives were synthesized and screened for their in vivo antithrombotic activity. Among the 23 compounds tested, compound (8g) showed the most promising antithrombotic activity, which was comparable with clinically used aspirin or warfarin, but at variance with these standard drugs, 8g did not exhibit the increased bleeding time, suggesting its potential as a novel antithrombotic agent.

Purpose To evaluate whether 23-gauge (23 G) pars plana vitrectomy is associated with earlier visual recovery compared with standard 20-gauge (20 G) pars plana vitrectomy. Methods Retrospective chart review of patients who underwent pars plana vitrectomy for various indications was performed. Thirty consecutive eyes in each group of 23-G and 20-G pars plana vitrectomy were analyzed. The mean decimal acuity of each patient was recorded at baseline, Day 1, and Weeks 1 and 6. The visual acuity on postoperative Day 1 and Week 1 was calculated as a proportion of the visual acuity at Week 6. The primary outcome measure was the rate of gain in visual acuity. The secondary outcome measures were intraocular pressure and surgical time. Results The baseline visual acuity between the two groups was similar. The mean visual acuity on Day 1 (0.05 ± 0.09 20 G versus 0.16 ± 0.18 23 G; Snellen equivalent 20/400 versus 20/125; P = 0.004) and Week 1 (0.12 ± 0.20 20 G versus 0.30 ± 0.27 23 G; Snellen equivalent 20/160 versus 20/63; P = 0.002) was significantly better in the 23-G pars plana vitrectomy group. There was no significant difference in best-corrected Snellen visual acuity at Week 6 between the 2 groups. Eighty-three percent of the mean final visual acuity was attained by Week 1 in the 23-G group compared with only 43% in the 20-G group. Conclusion Twenty-three gauge pars plana vitrectomy is associated with faster visual recovery compared with 20-G pars plana vitrectomy.

Previous reports suggest that Alzheimer's disease is protected by cholinesterase inhibitors. We synthesized some isoalloxazine derivatives and evaluated them using in vitro cholinesterase inhibition assay. Two of the compounds (7m and 7q) were figured out as potent cholinesterase inhibitors. They further showed anti-Aβ aggregatory activity in the in vitro assay. The current study deals with the evaluation of neuroprotective potentials of the potent compounds (7m and 7q) using different in vitro and in vivo experiments. The compounds were first assessed for their tendency to cross blood-brain barrier using in vitro permeation assay. They were evaluated using scopolamine-induced amnesic mice model. Additionally, ROS scavenging and anti-apoptotic properties of 7m and 7q were established against Aβ1-42-induced toxicity in rat hippocampal neuronal cells. 7m and 7q were also evaluated using Aβ1-42-induced Alzheimer's rat model. Lastly, their involvement in Wnt/β-catenin pathway was also demonstrated. The results indicated good CNS penetration for 7m and 7q. The neuroprotective effects of 7m and 7q were evidenced by improved cognitive ability in both scopolamine and Aβ1-42-induced Alzheimer's-like condition in rodents. The in vivo results also confirmed their anti-cholinesterase and anti-oxidant potential. Immunoblot results showed that treatment with 7m and 7q decreased Aβ1-42, p-tau, cleaved caspase-3, and cleaved PARP levels in Aβ1-42-induced Alzheimer's rat brain. Additionally, immunoblot results demonstrated that 7m and 7q activated the Wnt/β-catenin pathway as evidenced by increased p-GSK-3, β-catenin, and neuroD1 levels in Aβ1-42-induced Alzheimer's rat brain. These findings have shown that isoalloxazine derivatives (7m and 7q) could be the potential leads for developing effective drugs for the treatment of AD.

The benzazepine ring system has offered interesting CNS-active medicinal agents. Taking this privileged structure as the basic scaffold, [Formula: see text] and/or [Formula: see text]-alkylated benzazepin-2-one derivatives and their reduced analogs have been prepared as potential [Formula: see text] receptor agonists. The selective alkylation at the [Formula: see text] and/or [Formula: see text] positions of this seven-membered lactam ring is here reported for the first time under different reaction conditions. The synthesized compounds were evaluated for their biological profile as potential [Formula: see text] agonists using a classic pharmacological approach. Three derivatives (15, 17, and 20) have shown promising [Formula: see text] agonistic activity which can be further optimized as anti-obesity agents for the treatment of male sexual dysfunction. Further, a homology model for [Formula: see text] receptor was generated using MODELLER, and ligand-receptor interactions for these potential molecules were studied.

It has been reported in the literature that cholinesterase inhibitors provide protection in Alzheimer’s disease (AD). Recent reports have implicated triazine derivatives as cholinesterase inhibitors. These findings led us to investigate anti-cholinestrase property of some novel triazine derivatives synthesized in this laboratory. In vitro cholinesterase inhibition assay was performed using Ellman method. The potent compounds screened out from in vitro assay were further evaluated using scopolamine-induced amnesic mice model. Further, in vitro reactive oxygen species (ROS) scavenging and anti-apoptotic property of the potent compounds were demonstrated against Aβ1–42-induced neurotoxicity in rat hippocampal cells. Their neuroprotective role was assessed using Aβ1–42-induced Alzheimer’s-like phenotype in rats. Further, the role of compounds on the activation of the Wnt/β-catenin pathway was studied. The results showed that the chosen compounds are having protective effect in Alzheimer’s-like condition; the ex vivo results advocated their anti-cholinestrase and anti-oxidant activities. Treatment with TRZ-15 and TRZ-20 showed neuroprotective ability of the compounds as evidenced from the improved cognitive ability in the animals, and decrease in Aβ1–42 burden and cytochrome c and cleaved caspase-3 levels in the brain. This study also demonstrates positive involvement of the novel triazine derivatives in the Wnt/β-catenin pathway. Immunoblot and immunofluorescence data suggested that ratio of pGSK3/GSK3 and β-catenin got dramatically improved after treatment with TRZ-15 and TRZ-20. TRZ-15 and TRZ-20 showed neuroprotection in scopolamine-induced amnesic mice and Aβ1–42-induced Alzheimer’s rat model and also activate the Wnt/β-catenin signaling pathway. These findings conclude that TRZ-15 and TRZ-20 could be a therapeutic approach to treat AD.

The authors retract the article entitled “Novel 2-Aminobenzamides as Potential Orally Active Antithrombotic Agents” published in ACS Medicinal Chemistry Letters, 2013, 4, 32–36 (DOI: 10.1021/ml300217f) due to the confirmed scientific misconduct of Mr. Amit Verma. Based on the results of investigation of a committee established by The Head, Pharmacy Department, Faculty of Technology and Engineering, The M. S. University of Baroda, Vadodara, the authors conclude that some of the biological experiments represented in the Letter are not reproducible due to manipulation and/or misrepresentation by Mr. Amit Verma. Therefore, all authors agreed on retraction of this paper.