Extraction of dermatan sulfate using ionic liquid-assisted enzymatic digestion: An efficient approach.

Dermatan sulfate is one of the major glycosaminoglycan (GAG) present in the animal hides, which is a waste/byproduct from meat industry. Efficient utilization of these meat industry wastes is garnering attention because these wastes render a possibility for their conversion into useful products. With the increased concerns over health, various initiatives have been developed to permit more efficient utilization of these by-products and thereby directly impacting environmental sustainability. Herein, we demonstrate for the first time an efficient and environmentally safe ionic liquid-assisted enzymatic process for the extraction of dermatan sulfate from buffalo hides. Dermatan sulfate has been extracted, separated, and purified from the GAG mixture using IL-assisted enzymatic digestions and chromatographic separations. NMR, FT-IR, and ESI-MS measurements showed typical characteristic peaks for dermatan sulfate. The advantages of this eco-friendly process adopted include i) use of fewer chemicals, ii) elimination of harsh chemicals, iii) elimination of various steps and sub-steps, iv) reduction in process time (12 h), and v) increase in extraction yield by 75% when compared to conventional enzymatic process (57%). Thus, the use of ionic liquids alongside enzymes will serve as an efficient methodology for the futuristic development of these derived GAGs for their potential applications.

Partial Activation of PPAR-γ by Synthesized Quercetin Derivatives Modulates TGF-ß1-Induced EMT in Lung Cancer Cells.

Non-small cell lung cancer (NSCLC) has a very low survival rate due to poor response to chemotherapy and late detection. Epithelial to mesenchymal transition (EMT) is regarded as a major contributor to drive metastasis during NSCLC progression. Towards this, transforming growth factor-beta 1 (TGF-ß1) is the key driver that endows cancer cells with increased aggressiveness. Recently, this group synthesized a series of Schiff base quercetin derivatives (QDs) and ascertained their effectiveness on EMT markers of A549 cell line. This study evidenced that the EMT process is counteracted via the partial activation of a nuclear hormone receptor, Peroxisome proliferator-activated receptor (PPAR)-γ through QDs. Here, that work is extended to investigate the interplay between PPAR-γ partial activation and TGF-ß1-induced EMT in human lung cancer A549 cells. The results reveal that TGF-ß1 plays a critical role in suppressing PPAR-γ, which is markedly reversed and increased by partial agonists: QUE2FH and QUESH at both protein and transcriptional levels. The partial agonists not only stimulate PPAR-γ in a balanced manner but also prevent the loss of E-cadherin and acquisition of TGF-ß1-induced mesenchymal markers (Snail, Slug, Vimentin, and Zeb-1). Subsequently, the effects are accompanied by attenuation of TGF-ß1-induced migratory ability of A549 cells.

Design, Synthesis, and Biological Evaluation of Novel Quercetin Derivatives as PPAR-γ Partial Agonists by Modulating Epithelial-Mesenchymal Transition in Lung Cancer Metastasis.

Epithelial-to-mesenchymal transition (EMT) is responsible for driving metastasis of multiple cancer types including lung cancer. Peroxisome proliferator-activated receptor (PPAR)-γ, a ligand-activated transcription factor, controls expression of variety of genes involved in EMT. Although several synthetic compounds act as potent full agonists for PPAR-γ, their long term application is restricted due to serious adverse effects. Therefore, partial agonists involving reduced and balanced PPAR-γ activity are more effective and valued. A previous study discerned the efficacy of quercetin and its derivatives to attain favorable stabilization with PPAR-γ. Here this work is extended by synthesizing five novel quercetin derivatives (QDs) namely thiosemicarbazone (QUETSC)) and hydrazones (quercetin isonicotinic acid hydrazone (QUEINH), quercetin nicotinic acid hydrazone (QUENH), quercetin 2-furoic hydrazone (QUE2FH), and quercetin salicyl hydrazone (QUESH)) and their effects are analyzed in modulating EMT in lung cancer cell lines via PPAR-γ partial activation. QDs-treated A549 cells diminish cell proliferation strongly at nanomolar concentration compared to NCI-H460 cells. Of the five screened derivatives, QUETSC, QUE2FH, and QUESH exhibit the property of partial activation as compared to the overexpressive level of rosiglitazone. Consistently, these QDs also suppress EMT process by markedly downregulating the levels of mesenchymal markers (Snail, Slug, and zinc finger E-box binding homeobox 1) and concomitant upregulation of epithelial marker (E-cadherin).

Exploring binding mode assessment of novel kaempferol, resveratrol, and quercetin derivatives with PPAR-α as potent drug candidates against cancer.

Peroxisome proliferator-activated receptors (PPAR)-α, a ligand-activated transcription factor stands out to be a valuable protein target against cancer. Given that ligand binding is the crucial process for the activation of PPAR-α, fibrate class of synthetic compounds serves as potent agonist for the receptor. However, their serious side effects limit the long-term application in cancer. This emphasizes the dire need to identify new candidates that would exert desired activation by abrogating the adverse effects caused by synthetic agonists. Natural dietary products serve as an important source of drug discovery. Hence, the present study encompasses the investigation of the role of natural plant phenolic compounds: kaempferol, resveratrol, and quercetin and their 8708 derivatives by the means of computational pipeline comprising molecular docking and molecular dynamic (MD) simulation techniques. Docking calculations shortlisted potential candidates, namely 6-cinnamylchrysin (6-CC), resveratrol potassium-4-sulfate (RPS) and 6-[2-(3,4-Dihydroxyphenyl)-5-hydroxy-4-oxochromen-7-yl]oxyhexyl nitrate (DHOON), and derivatives of kaempferol, resveratrol, and quercetin, respectively. 6-CC, RPS, and DHOON manifested better affinities of - 32.83 kcal/mol (Ala333, Lys358, His440), - 27.22 kcal/mol (Tyr314, Met355), and - 30.18 kcal/mol (Ser280, Tyr314, Ala333), respectively, and were found to act as good stimulants for PPAR-α. Among these three compounds, 6-CC caused relatively least deviations and fluctuations analyzed through MD simulation which judiciously held responsible to attain most favorable interaction with PPAR-α. Followed by the binding free energy (ΔG) calculations using MM-GBSA confirmed the key role of 6-CC toward PPAR-α. The compound 6-CC also achieved high drug-likeness and pharmacokinetic properties. Thus, these findings stipulate new drug leads for PPAR-α receptor which abets a way to develop new anti-cancer drugs.

PPAR-γ Partial Agonists in Disease-Fate Decision with Special Reference to Cancer.

Peroxisome proliferator-activated receptor-γ (PPAR-γ) has emerged as one of the most extensively studied transcription factors since its discovery in 1990, highlighting its importance in the etiology and treatment of numerous diseases involving various types of cancer, type 2 diabetes mellitus, autoimmune, dermatological and cardiovascular disorders. Ligands are regarded as the key determinant for the tissue-specific activation of PPAR-γ. However, the mechanism governing this process is merely a contradictory debate which is yet to be systematically researched. Either these receptors get weakly activated by endogenous or natural ligands or leads to a direct over-activation process by synthetic ligands, serving as complete full agonists. Therefore, fine-tuning on the action of PPAR-γ and more subtle modulation can be a rewarding approach which might open new avenues for the treatment of several diseases. In the recent era, researchers have sought to develop safer partial PPAR-γ agonists in order to dodge the toxicity induced by full agonists, akin to a balanced activation. With a particular reference to cancer, this review concentrates on the therapeutic role of partial agonists, especially in cancer treatment. Additionally, a timely examination of their efficacy on various other disease-fate decisions has been also discussed.

Comparative docking analysis of tyrosine kinase inhibitors with HER2 and HER4 receptors.

Tyrosine kinase receptors promote the growth and differentiation of normal breast and malignant human breast cancer cells, known as ERBB receptors. Various ERBB receptors are EGFR/ErbB1 and ErbB2/neu, which get over expressed in different solid tumors that activate upon binding of ligand to the extra cellular domain of these receptors. Of note, the epidermal growth factor receptor (EGFR) is a prime contributor to cancer through the involvement of four receptor tyrosine kinases (RTKs), namely, HER1, HER2, HER3, and HER4. Among them, HER2 and HER4 are majorly associated with breast cancer. Non-peptide quinazoline compounds homologous of the adenosine triphosphate (ATP) are competitively inhibited to RTKs to prevent cancer growth and metastasis. Various small drug molecule that targets the RTKs having the same scaffold, includes Lapatinib, Tivozanib, Erlotinib, Gefitinib, Crizotinib, and Ceritinib. The present study aims to investigate the comparative potential of structurally similar TKIs against HER2 and HER4 receptor receptors-silico molecular docking using FlexX software (LeadIT 2.3.2). Each docked complex's interaction profile was performed using BIOVIA Discovery Studio Visualizer 4.0. Molecular docking analysis was performed in order to get deeper insights into the interaction and binding pattern of the ligands with HER2 and HER4 receptors. The docking results revealed the Lapatinib compound acquired the relatively highest binding score of -32.36 kcal/mol and -35.76 kcal/mol with HER2 and HER4 proteins, respectively, concerning other compounds. Lapatinib is identified as a potential inhibitor for both the RTKs. Our study thus suggests the probable direction that could be further explored in inhibiting EGFR protein harboring breast cancer.

Probing intermolecular interactions and binding stability of kaempferol, quercetin and resveratrol derivatives with PPAR-γ: docking, molecular dynamics and MM/GBSA approach to reveal potent PPAR- γ agonist against cancer.

Peroxisome Proliferator-Activated Receptors-γ (PPAR-γ), a ligand-activated transcription factor, suggested having anti-inflammatory effects by activating the target genes when bound to the ligand. Herein, we examined a conformational analysis of 8708 derivatives of Kaempferol, Quercetin, and Resveratrol, the prime activators of PPAR-γ molecular target by employing molecular docking and dynamic simulation pipeline to screen out potential agonists. The structure-based docking procedure performed by FlexX tool shortlisted high binding affinities of these derivatives of Kaempferol, Quercetin and Resveratrol with the protein receptor with a score of -38.94 kcal/mol (4'-Carboxy-5, 7-Dihydroxyflavone-CDHF), -41.63 kcal/mol (Demethyltorosaflavone D- DMTF) and -31.52 kcal/mol (Resveratrol-O-disulphate- RD) respectively, signifying the selected derivatives forms interactions like H-bond, Aromatic H-Bond, Pi-Pi stacking and salt bridges with PPAR-γ. The PPAR-γ-derivative complex was stabilized by intermolecular hydrogen bonds and stacking interactions. A greater interaction was significantly observed between the binding affinities of derivatives compared to the standards. Based on the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) carried by the means of high-speed molecular dynamics (MD) and simulation of best-docked poses, the ligand, DMTF attained the most favored interaction with PPAR-γ. Thus, it appeared to have high chemical scaffold diversity and may confer high drug-likeness. The binding free energy (ΔG) led us to manifest Quercetin derivative to have a key role for PPAR-γ receptor. The result obtained clearly indicates the exploitation of the promising new drug leads that may further influence in synthesizing and analyzing the development as anti-cancer agonists.Communicated by Ramaswamy H. Sarma.

Exploring conformational changes of PPAR-Ɣ complexed with novel kaempferol, quercetin, and resveratrol derivatives to understand binding mode assessment: a small-molecule checkmate to cancer therapy.

Peroxisome proliferator-activated receptors-γ (PPAR-γ), a ligand-activated transcription factor, activated by several ligands like fatty acids (linoleic acid being the most common) or their metabolites, can function as potential therapeutic target for various cancers. Although various synthetic ligands, thiazolidinediones (TZDs), serves as full agonist for PPAR-γ, application of these molecules has been discontinued due to adverse toxicity profile. Hence, with a dire need to identify novel PPAR-γ-agonists, the present in silico study aimed to determine the effectiveness of potent flavonoids, kaempferol (CID: 5280863), quercetin (CID: 5280343), and stilbenoid resveratrol (CID: 445154) and their 806 derivatives towards PPAR-γ that could combat the deleterious effect of TZDs. The molecular docking experiment performed by FlexX elucidated the efficacy of derivatives; Kem204, Qur8, and Res183 of kaempferol, quercetin, and resveratrol respectively to be more effective against PPAR-γ as compared with other derivatives. The physicochemical and pharmacokinetic parameters of Kem204, Qur8, and Res183 follow the drug-likeness and thus comprise a pharmacologically active model to be considered for advancing further potential hits. Further molecular dynamics (MD) simulation study revealed the Qur8 compound to have favorable dynamic interactions within the PPAR-γ which certainly paves away in developing futuristic potential anticancer drugs. Graphical abstract.