New recyclable and functionalized chitosan-based polyurethane foams for effective and incessant removal of Orange II (OII) and Rhodamine B (RhB) dyes from water.

The development of new efficient materials for the removal of water-soluble toxic organic dyes has been one of the focused research areas in the recent past. There is a strong demand for the new materials as most of the reported techniques/materials suffer from serious limitations. In this regard, a series of flexible chitosan-based task-specific polyurethane foams (PUCS-GP, PUCS-CA-GP, PUCS-TA-GP, and PUCS-GA-GP) associated with naturally available hydroxycarboxylic acids was developed. The basis for the preparation of these task-specific and functionalized PU foams is to possess amine groups for trapping the anionic dyes (example: Orange II denoted as OII) and carboxylic acid groups for attracting the cationic dyes (example: Rhodamine B denoted as RhB) under specified pH conditions. Batch adsorption experiments were conducted to assess and improve various parametric conditions. The experimental results revealed that the adsorption kinetics closely agree with the pseudo-second-order model having a maximum sorption capacity of 38.3 mg/g at pH 3 for OII on PUCS-GP and 48.4 mg/g at pH 6 for RhB on PUCS-CA-GP. Furthermore, the adsorption process was described by isotherms, kinetic equations and thermodynamic parameters (ΔG°, ΔH° and ΔS°). Notably, the regeneration of OII and RhB dyes from the exhausted PUCS-GP and PUCS-CA-GP materials was effectively accomplished. The recovered PUCS-GP shows >90 % OII and PUCS-CA-GP displays >70 % RhB removal efficiency even after twelve adsorption-desorption processes under mild conditions, demonstrating excellent recyclability/durability. The advantages of these functionalized foam materials are facile preparation, high adsorption capacity, good reusability, and very efficient removal of organic dyes from wastewater streams.

Development of methyl 5-((cinnamoyloxy)methyl)picolinate, exploring its bio-target potential aiming at CVD mediated by multiple proteins through surface and physiochemical analysis.

The emphasis on sustainable sources of drug development seems imminent with phytochemicals emerging as promising candidates due to their minimal probability of adverse effects. This study focuses on utilizing simple cinnamic acid and nicotinic acid derivatives as starting materials, employing an efficient synthetic protocol to obtain methyl 5-((cinnamoyloxy)methyl)picolinate targeting CVD mediated by multiple enzymes such as MAPK, PCSK9, MPO, SIRT1 and TNF-α. Comprehensive characterization of synthesized molecule is achieved through 1H, 13C, FT-IR, and HRMS methods. Additionally, the crystal structure was established via SC-XRD. Comparative analysis with the DFT-optimized structure identifies key nucleophilic and electrophilic regions for determining interactions with bio-targets. Notably, Compound 5 adheres to all drug-likeness criteria, further validated through screening similar pharmacophoric drugs from databases. Targeting bio-relevant areas with a specific focus on CVD drug development. The molecular docking studies elucidate ligand-protein interactions for better binding connectivity. This investigation further underscores the importance of sustainable practices, simple chemical synthesis, and computational approaches, contributing to the pursuit of eco-friendly drug development with enhanced safety profiles (MTT assay).

Synthesis, Structural Elucidation, In Silico and In Vitro Studies of New Class of Methylenedioxyphenyl-Based Amide Derivatives as Potential Myeloperoxidase Inhibitors for Cardiovascular Protection.

Novel methylenedioxyphenyl-based amides, especially N-(4-methoxybenzyl)-6-nitrobenzo-[1,3]-dioxole-5-carboxamide (MDC) and N-(3-acetylphenyl)-6-nitrobenzo-[1,3]-dioxole-5-carboxamide (ADC), potential cardiovascular preventive agents, are successfully synthesized, and their chemical structures are verified by 1H and 13C NMR, Fourier transform infrared (FT-IR), high-resolution mass spectrometry (HRMS), and single-crystal X-ray diffraction (SC-XRD) analyses. Data obtained from SC-XRD reveal that MDC and ADC are both monoclinic molecules with Z = 2 and 4, respectively. From density functional theory (DFT) calculations, 3.54 and 3.96 eV are the energy gaps of the optimized MDC and ADC structures, respectively. MDC and ADC exhibit an electrophilicity index value of more than 1.5 eV, suggesting that they can act as an electrophile, facilitating bond formation with biomolecules. Hirshfeld surface analysis demonstrates that more than 25% of atomic interactions in both MDC and ADC are from H···H interactions. Based on pharmacokinetic predictions, MDC and ADC exhibit drug-like properties, and molecular docking simulations revealed favorable interactions with active site pockets. Both MDC and ADC achieved higher docking scores of -7.74 and -7.79 kcal/mol, respectively, with myeloperoxidase (MPO) protein. From docking results, MPO was found to be most favorable followed by dipeptidyl peptidase-4 (DPP-4) and α-glucosidase (α-GD). Antioxidant, anti-inflammatory, and in vitro enzymatic studies of MDC and ADC indicate that MDC is more selective toward MPO and more potent than ADC. The application of MDC to inhibit myeloperoxidase could be ascertained to reduce the cardiovascular risk factor. This can be supported from the results of computational docking (based on hydrogen bonding and docking score), in vitro antioxidant and anti-inflammatory properties, and MPO enzymatic inhibition (based on the percentage of inhibition and IC50 values).

Designing, Synthesis, and Anti-Breast Cancer Activity of a Series of New Quinazolin-4(1H)-one Derivatives.

The inhibition of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein could be a promising treatment for breast cancer. In this regard, docking studies were accomplished on various functionalized organic molecules. Among them, several derivatives of quinazolin-4(1H)-one exhibited anti-breast cancer activity and satisfied the drug likeliness properties. Further, the in vitro inhibitory studies by a series of 2-(2-phenoxyquinolin-3-yl)-2,3-dihydroquinazolin-4(1H)-one molecules showed strong anti-cancer activity than the currently available drug, wortmannin. The MTT cytotoxicity assay was used to predict the anti-proliferative activity of these drugs against MCF-7 cancer cells by inhibiting the PIK3CA protein. The dose-dependent analysis showed a striking decrease in cancer cell viability at 24 h with inhibitory concentrations (IC50 ) of 3b, 3c, 3d, 3f and 3m are 15±1, 17±1, 8±1, 10±1 and 60±1 (nanomoles), respectively. This is the first report in the literature on the inhibition of PIK3CA protein by quinazolinone derivatives that can be used in the treatment of cancer. Quinazolinone analogs have the potential to be safe and economically feasible scaffolds if they are produced using a chemical technique that is both straightforward and amenable to modification. From the cancer research perspective, this study can eventually offer better care for cancer patients.

In Silico Analysis to Link Insulin Resistance, Obesity and Ageing with Alzheimer's Disease.

The process of ageing accompanies several metabolic diseases. With ageing, fats accumulate to increase the visceral and abdominal adiposity leading to hyperinsulinemia, insulin resistance, obesity and several other diseases. Drosophila melanogaster is often used to study the ageing process and its related disorders. Therefore, in this study, we performed an in silico analysis to relate the process of ageing and insulin resistance. We analysed the data of insulin-resistant Drosophila from the GEO database and compared it with the data from the literature survey. We observed that 98 genes were common in both the models, and they showed gene modulations related to metabolic pathways, fatty acid metabolism, insulin resistance and neural receptor-ligand binding pathways. Analysis of the REACTOME database against human data revealed that the TRKB signalling pathway is commonly affected. The TRKB-mediated BDNF pathway is a major regulator of memory loss. We further analysed the common genes in Alzheimer's disease and compared the fly data with human data to identify the diseases related to these common genes. Then, we performed a literature survey to provide protective mechanisms for the TRKB signalling pathway activation, mediated through polyphenols. We treated the flies with sesamol-conjugated lipoic acid derivative (a phenolic compound) at hormetic doses to evaluate its effect on the memory of flies.

Sesamol: a powerful functional food ingredient from sesame oil for cardioprotection.

Phytophenols are important bioactive food based chemical entities, largely present in several natural sources. Among them, sesamol is one of the key natural phenols found in sesame seeds, Piper cubeba etc. Several studies have reported that sesame oil is a potent cardioprotective functional food. Papers on the utility of sesamol in sesame oil (the chemical name of sesamol is methylenedioxyphenol, MDP) have appeared in the literature, though there is no single concise review on the usefulness of sesamol in sesame oil in CVD in the literature. Cardiovascular disease (CVD) is the most challenging health problem encountered by the global population. There has been increasing interest in the growth of effective cardiovascular therapeutics, specifically of natural origin. Among various natural sources of chemicals, phytochemicals are micronutrients and bio-compatible scaffolds having an extraordinary efficacy at multiple disease targets with minimal or no adverse effect. This review offers a perspective on the existing literature on functional ingredients in sesame oil with particular focus on sesamol and its derivatives having nutritional and cardioprotective properties. This is demonstrated to have shown a specifically modulating oxidative enzyme myeloperoxidase (MPO) and other proteins which are detrimental to human well-being. The molecular mechanism of cardioprotection by this food ingredient is primarily attributed to the methylenedioxy group present in the sesamol component.

Methoxyphenol derivatives as reversible inhibitors of myeloperoxidase as potential antiatherosclerotic agents.

Aim: To evaluate new chemical entities, based on ferulic acid scaffolds, as reversible myeloperoxidase inhibitors (MPOI). Methodology & results:In silico docking studies are performed with MPO protein as a target for several ferulic acid analogs followed by multiple in vitro assays to validate this approach. Two lead compounds 2a and 3 are identified with optimum docking and IC50 values: -7.95 kcal/mol, 0.9 µM and -8.35 kcal/mol, 8.5 µM, respectively. These MPOIs are able to inhibit oxidation of high-density lipoprotein and further promoted functionality of high-density lipoprotein. Conclusion: Lead analogs are potent MPOIs that exert specific effects on MPO-mediated oxidation as well as inflammatory pathways. It also acts as promoters of cholesterol efflux that sheds light on pharmacological approach in atherosclerosis treatment.

Lipoicmethylenedioxyphenol Reduces Experimental Atherosclerosis through Activation of Nrf2 Signaling.

OBJECTIVE: Oxidative stress is implicated in the pathogenesis of atherosclerosis, and Nrf2 is the transcriptional factor central in cellular antioxidant responses. In the present study, we investigate the effect of a dihydrolipoic acid derivative lipoicmethylenedioxyphenol (LMDP) on the progression of atherosclerosis and test whether its effect on atherosclerosis is mediated by Nrf2. METHODS AND RESULTS: Both magnetic resonance imaging (MRI) scanning and en face analysis reveal that 14 weeks of treatment with LMDP markedly reduced atherosclerotic burden in a rabbit balloon vascular injury model. Myograph analyses show decreased aortic contractile response to phenylephrine and increased aortic response to acetylcholine and insulin in LMDP-treated animals, suggesting that LMDP inhibits atherosclerosis through improving vascular function. A role of Nrf2 signaling in mediating the amelioration of vascular function by LMDP was supported by increased Nrf2 translocation into nuclear and increased expression of Nrf2 target genes. Furthermore, chemotaxis analysis with Boydem chamber shows that leukocytes isolated from LMDP-treated rabbits had reduced chemotaxis, and knock-down of Nrf2 significantly reduced the effect of LMDP on the chemotaxis of mouse macrophages. CONCLUSION: Our results support that LMDP has an anti-atherosclerotic effect likely through activation of Nrf2 signaling and subsequent inhibition of macrophage chemotaxis.

Incidence and carrier frequency of Sandhoff disease in Saskatchewan determined using a novel substrate with detection by tandem mass spectrometry and molecular genetic analysis.

Sandhoff disease is a rare progressive neurodegenerative genetic disorder with a high incidence among certain isolated communities and ethnic groups around the world. Previous reports have shown a high occurrence of Sandhoff disease in northern Saskatchewan. Newborn screening cards from northern Saskatchewan were retrospectively screened in order to investigate the incidence and determine the carrier frequency of Sandhoff disease in these communities. PCR-based screening was conducted for the c.115delG (p.(Val39fs)) variant in the HEXB gene that was previously found in 4 Sandhoff disease patients from this area. The carrier frequency for this allele was estimated to be ~1:27. MS/MS-based screening of hexosaminidase activity along with genetic sequencing allowed for the identification of additional variants based on low total hexosaminidase activity and high % hexosaminidase A activity relative to c.115delG carriers. In total 4 pathogenic variants were discovered in the population (c.115delG, c.619A>G, c.1601G>T, and c.1652G>A) of which two are previously unreported (c.1601G>T and c.1652G>A). The combined carrier frequency of these alleles in the study area was estimated at ~1:15. Based on the number of cases of Sandhoff disease from this area we estimate the incidence to be ~1:390 corresponding to a child being born with the disease every 1-2 years on average. The results from our study were then compared with variants in the HEXB gene from the genomes available from the 1000 Genomes project. A total of 19 HEXB variants were found in the 1092 genomes of which 5 are suspected of having a deleterious effect on hexosaminidase activity. The estimated carrier frequency of Sandhoff disease in Saskatchewan at 1:15 is more than 3 times higher than the carrier frequency in the global sample provided by the 1000 Genomes project at 1:57.

Effects of a novel pharmacologic inhibitor of myeloperoxidase in a mouse atherosclerosis model.

Inflammation and oxidative stress play fundamental roles in the pathogenesis of atherosclerosis. Myeloperoxidase has been extensively implicated as a key mediator of inflammatory and redox-dependent processes in atherosclerosis. However, the effect of synthetic myeloperoxidase inhibitors on atherosclerosis has been insufficiently studied. In this study, ApoE(-/-) mice were randomized to low- and high-dose INV-315 groups for 16 weeks on high-fat diet. INV-315 resulted in reduced plaque burden and improved endothelial function in response to acetylcholine. These effects occurred without adverse events or changes in body weight or blood pressure. INV-315 treatment resulted in a decrease in iNOS gene expression, superoxide production and nitrotyrosine content in the aorta. Circulating IL-6 and inflammatory CD11b(+)/Ly6G(low)/7/4(hi) monocytes were significantly decreased in response to INV-315 treatment. Acute pretreatment with INV-315 blocked TNFα-mediated leukocyte adhesion in cremasteric venules and inhibited myeloperoxidase activity. Cholesterol efflux was significantly increased by high-dose INV-315 via ex-vivo reverse cholesterol transport assays. Our results suggest that myeloperoxidase inhibition may exert anti-atherosclerotic effects via inhibition of oxidative stress and enhancement of cholesterol efflux. These findings demonstrate a role for pharmacologic modulation of myeloperoxidase in atherosclerosis.

Modified methylenedioxyphenol analogs lower LDL cholesterol through induction of LDL receptor expression.

Although statin therapy is a cornerstone of current low density lipoprotein (LDL)-lowering strategies, there is a need for additional therapies to incrementally lower plasma LDL cholesterol. In this study, we investigated the effect of several methylenedioxyphenol derivatives in regulating LDL cholesterol through induction of LDL receptor (LDLR). INV-403, a modified methylenedioxyphenol derivative, increased LDLR mRNA and protein expression in HepG2 cells in a dose- and time-dependent fashion. These effects were apparent even under conditions of HMG-CoA reductase inhibition. Electrophoresis migration shift assays demonstrated that INV-403 activates SREBP2 but not SREBP1c, with immunoblot analysis showing an increased expression of the mature form of SREBP2. Knockdown of SREBP2 reduced the effect of INV-403 on LDLR expression. The activation of SREBP2 by INV-403 is partly mediated by Akt/GSK3ß pathways through inhibition of phosphorylation-dependent degradation by ubiquitin-proteosome pathway. Treatment of C57Bl/6j mice with INV-403 for two weeks increased hepatic SREBP2 levels (mature form) and upregulated LDLR with concomitant lowering of plasma LDL levels. Transient expression of a LDLR promoter-reporter construct, a SRE-mutant LDLR promoter construct, and a SRE-only construct in HepG2 cells revealed an effect predominantly through a SRE-dependent mechanism. INV-403 lowered plasma LDL cholesterol levels through LDLR upregulation. These results indicate a role for small molecule approaches other than statins for lowering LDL cholesterol.

A modified sesamol derivative inhibits progression of atherosclerosis.

OBJECTIVE: Sesamol, a phenolic component of lignans, has been previously shown to reduce lipopolysaccharide-induced oxidative stress and upregulate phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase pathways. In the present study, we synthesized a modified form of sesamol (INV-403) to enhance its properties and assessed its effects on atherosclerosis. METHODS AND RESULTS: Watanabe heritable hyperlipidemic rabbits were fed with high-cholesterol chow for 6 weeks and then randomized to receive high-cholesterol diet either alone or combined with INV-403 (20 mg/kg per day) for 12 weeks. Serial MRI analysis demonstrated that INV-403 rapidly reduced atherosclerotic plaques (within 6 weeks), with confirmatory morphological analysis at 12 weeks posttreatment revealing reduced atherosclerosis paralleled by reduction in lipid and inflammatory cell content. Consistent with its effect on atherosclerosis, INV-403 improved vascular function (decreased constriction to angiotensin II and increased relaxation to acetylcholine), reduced systemic and plaque oxidative stress, and inhibited nuclear factor-κB activation via effects on nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) phosphorylation with coordinate reduction in key endothelial adhesion molecules. In vitro experiments in cultured endothelial cells revealed effects of INV-403 in reducing IκBα phosphorylation via inhibition of IκB kinase 2 (IKK2). CONCLUSIONS: INV-403 is a novel modified lignan derivative that potently inhibits atherosclerosis progression via its effects on IKK2 and nuclear factor-κB signaling.

Lipoic acid effects on established atherosclerosis.

AIMS: Alpha-lipoic acid (LA) is a commonly used dietary supplement that exerts anti-oxidant and anti-inflammatory effects in vivo and in vitro. We investigated the mechanisms by which LA may confer protection in models of established atherosclerosis. MAIN METHODS: Watanabe heritable hyperlipidemic (WHHL) rabbits were fed with high cholesterol chow for 6 weeks and then randomized to receive either high cholesterol diet alone or combined with LA (20mg/kg/day) for 12 weeks. Vascular function was analyzed by myography. The effects of LA on T cell migration to chemokine gradients was assessed by Boyden chamber. NF-kappaB activation was determined by measuring translocation and electrophoresis migration shift assay (EMSA). KEY FINDINGS: LA decreased body weight by 15+/-5% without alterations in lipid parameters. Magnetic Resonance Imaging (MRI) analysis demonstrated that LA reduced atherosclerotic plaques in the abdominal aorta, with morphological analysis revealing reduced lipid and inflammatory cell content. Consistent with its effect on atherosclerosis, LA improved vascular reactivity (decreased constriction to angiotensin II and increased relaxation to acetylcholine and insulin), inhibited NF-kappaB activation, and decreased oxidative stress and expression of key adhesion molecules in the vasculature. LA reduced T cell content in atherosclerotic plaque in conjunction with decreasing ICAM and CD62L (l-selectin) expression. These effects were confirmed by demonstration of a direct effect of LA in reducing T cell migration in response to CCL5 and SDF-1 and decreasing T cell adhesion to the endothelium by intra-vital microscopy. SIGNIFICANCE: The present findings offer a mechanistic insight into the therapeutic effects of LA on atherosclerosis.