The Regulation of Endoplasmic Reticulum Stress in Cancer: Special Focuses on Luteolin Patents

Cancer is a major health problem across the globe, and is expeditiously growing at a faster rate worldwide. The endoplasmic reticulum (ER) is a membranous cell organelle having inextricable links in cellular homeostasis. Altering ER homeostasis initiates various signaling events known as the unfolded protein response (UPR). The basic purpose of the UPR is to reinstate the homeostasis; however, a continuous UPR can stimulate pathways of cell death, such as apoptosis. As a result, there is great perturbation to target particular signaling pathways of ER stress. Flavonoids have gained significant interest as a potential anticancer agent because of their considerable role in causing cytotoxicity of the cancerous cells. Luteolin, a flavonoid isolated from natural products, is a promising phytochemical used in the treatment of cancer. The current study is designed to review the different endoplasmic reticulum stress pathways involved in the cancer, mechanistic insights of luteolin as an anticancer agent in modulating ER stress, and the available luteolin patent formulations were also highlighted. The patents were selected on the basis of pre-clinical and/or clinical trials, and established antitumor effects using patent databases of FPO IP and Espacenet. The patented formulation of luteolin studied so far has shown promising anticancer potential against different cancer cell lines. However, further research is still required to determine the molecular targets of such bioactive molecules so that they can be used as anticancer drugs.     

Secondary Metabolite Profiling,Anti-Inflammatory and Hepatoprotective Activity of Neptunia triquetra (Vahl) Benth

The present study aimed to analyze the phytoconstituents of Neptunia triquetra (Vahl) Benth. Anti-inflammatory and hepatoprotective activities of ethanol (EE), chloroform (CE) and dichloromethane (DCME) of stem extracts were evaluated using in vivo experimental models. The extracts were analyzed for phytoconstituents using GC-HRMS. Anti-inflammatory activity of CE, EE and DCME was accessed using carrageenan-induced paw oedema, cotton pellet-induced granuloma and the carrageenan-induced air-pouch model in Wistar albino rats. The hepatotoxicity-induced animal models were investigated for the biochemical markers in serum (AST, ALT, ALP, GGT, total lipids and total protein) and liver (total protein, total lipids, GSH and wet liver weight). In the in vivo study, animals were divided into different groups (six in each group) for accessing the anti-inflammatory and hepatoprotective activity, respectively. GC-HRMS analysis revealed the presence of 102 compounds, among which 24 were active secondary metabolites. In vivo anti-inflammatory activity of stem extracts was found in the order: indomethacin > chloroform extract (CE) > dichloromethane extract (DCME) > ethanolic extract (EE), and hepatoprotective activity of stem extracts in the order: CE > silymarin > EE > DCME. The results indicate that N. triquetra stem has a higher hepatoprotective effect than silymarin, however the anti-inflammatory response was in accordance with or lower than indomethacin.     

Deep Learning and Structure-Based Virtual Screening for Drug Discovery against NEK7: A Novel Target for the Treatment of Cancer

NIMA-related kinase7 (NEK7) plays a multifunctional role in cell division and NLRP3 inflammasone activation. A typical expression or any mutation in the genetic makeup of NEK7 leads to the development of cancer malignancies and fatal inflammatory disease, i.e., breast cancer, non-small cell lung cancer, gout, rheumatoid arthritis, and liver cirrhosis. Therefore, NEK7 is a promising target for drug development against various cancer malignancies. The combination of drug repurposing and structure-based virtual screening of large libraries of compounds has dramatically improved the development of anticancer drugs. The current study focused on the virtual screening of 1200 benzene sulphonamide derivatives retrieved from the PubChem database by selecting and docking validation of the crystal structure of NEK7 protein (PDB ID: 2WQN). The compounds library was subjected to virtual screening using Auto Dock Vina. The binding energies of screened compounds were compared to standard Dabrafenib. In particular, compound 762 exhibited excellent binding energy of −42.67 kJ/mol, better than Dabrafenib (−33.89 kJ/mol). Selected drug candidates showed a reactive profile that was comparable to standard Dabrafenib. To characterize the stability of protein–ligand complexes, molecular dynamic simulations were performed, providing insight into the molecular interactions. The NEK7–Dabrafenib complex showed stability throughout the simulated trajectory. In addition, binding affinities, pIC50, and ADMET profiles of drug candidates were predicted using deep learning models. Deep learning models predicted the binding affinity of compound 762 best among all derivatives, which supports the findings of virtual screening. These findings suggest that top hits can serve as potential inhibitors of NEK7. Moreover, it is recommended to explore the inhibitory potential of identified hits compounds through in-vitro and in-vivo approaches.     

Gamma irradiation induced enhancement of phenylalanine ammonia-lyase (PAL) and antioxidant activity in peach (Prunus persica Bausch,Cv. Elberta)

Effect of medium dose gamma irradiation on PAL and antioxidant activity of peach fruit was investigated. Peach fruit after harvest at commercial maturity was irradiated in the dose range 1.0–2.0 kGy, stored under refrigerated conditions (3±1 °C, RH 80%) and evaluated at intervals of 7 days. The antioxidant activity as determined by DPPH and FRAP methods revealed significant (p≤0.05) increase particularly in the dose range 1.6–2.0 kGy. During storage, maximum increase in both PAL and antioxidant activity was observed after 21 days. Positive correlation (r=0.75) existed between antioxidant activity and total phenols. EC₅₀ values as obtained from DPPH and FRAP experiments were significantly (p≤0.05) lower in irradiated fruits compared to control.     

Phytochemical studies and cytotoxicity evaluations of Colchicum tunicatum Feinbr and Colchicum hierosolymitanum Feinbr (Colchicaceae): two native Jordanian meadow saffrons

As a part of our continuing investigation of Jordanian Colchicum species, the biologically active components of Colchicum hierosolymitanum Feinbr and Colchicum tunicatum Feinbr (Colchicaceae) were pursued. The brine shrimp lethality test (BSLT) was used to direct the fractionation and isolation of active components. Five and four known colchicinoids were isolated and characterized from C. tunicatum and C. hierosolymitanum, respectively. The known colchicinoids, reported for the first time from these two species are: (-)-colchicine (I), 3-demethyl-(-)-colchicine (II), (-)-cornigerine (III), beta-lumicolchicine (IV), and (-)-androbiphenyline (V) from C. tunicatum, and (-)-colchicine (I), 2-demethyl-(-)-colchicine (VI), (-)-cornigerine (III), and beta-lumicolchicine (IV) from C. hierosolymitanum. The chemical structures of the isolated compounds have been elucidated using a series of spectroscopic and spectrometric techniques principally; 1D-NMR (1H and 13C) and low resolution EI-MS and APCIMS. All pure compounds were evaluated for cytotoxicity against three human cancer cell lines; MCF-7 human breast carcinoma, NCI-H460 human large cell lung carcinoma, and SF-268 human astrocytoma. (-)-Colchicine (I) and (-)-cornigerine (III) were found to be the most bioactive of the identified compounds with EC50 values in the range of 0.016-0.097 microM.     

Etching and kinetics of dissolution of Mo1−x WxSe2 single crystals

The dislocation etchant has been established for single crystals of Mo_1−xW_xSe₂ system. Effect of concentration of an etchant on the etch rate has been discussed. The morphology of etch pits is also described. The etch activation energies for all the compositions of these crystals for a particular concentration (7 N) of an etchant has been found out. The etch activation energies for a particular composition (x = 0.4) of crystals with different concentrations of an etchant have been investigated and the results have been discussed.     

Green synthesis and dye-sensitized solar cell application of rutile and anatase TiO2 nanorods

Journal of Solid State Electrochemistry - Nanorods (NRs) of TiO2 have biogenically been prepared, i.e., from the extract of Phellinus linteus mushroom. The presence of mixed anatase and...     

Morphological,cytological and phytochemical studies in naturally occurring diploid and tetraploid populations of Physochlaina praealta from high altitudes of Trans-Himalaya

Physochlaina praealta samples were studied macromorphologically and cytomorphologically along with their detailed phytochemical investigation. The concentration of phytoconstituents showed a strong positive correlation with the ploidy level and altitudinal gradients. The total phenol content was detected maximum in the methanolic extract of leaves and stem of higher altitudinal plants in both cytotypes (2x, 4x). The maximum content of flavonoids was detected in the methanolic extract of root and leaves. Root organ from higher elevation possessed the highest DPPH radical scavenging activity, with the maximum percentage of inhibition being obtained in methanolic extracts. The plants of both cytotypes from higher elevations accumulate an abundant quantity of secondary metabolites. The two cytotypes differ from each other with respect to various morphometric characters thereby depicting the drastic affect of polyploidy.

     

Polymerization of Acrylonitrile Initiated by the Thiourea-Mn3+ Redox System

Kinetics of vinyl polymerization initiated by the redox system thiourea-Mn³⁺ were investigated in the temperature range 30–40°C in sulfuric acid, and the rates of polymerization R_p and disappearance of Mn³⁺ have been measured. The effect of certain water-miscible organic solvents and anionic surfactant on the rates of polymerization was investigated. A mechanism involving the formation of a complex between Mn³⁺ and thiourea whose decomposition yields the initiating free radical with the polymerization terminated by mutual intraction of growing radicals is suggested.     

The total synthesis and anti-fertility activity of 6-silasteroids

4,4-Dimethyl-6-methoxy-4-sila-1-tetralone (2) was prepared by a modified literature procedure and converted to 3-methoxy-6,6-dimethyl-6-silaestra-1,3,5(10),8,14-pentaen-17β-yl acetate (5c). Catalytic hydrogenation of 5c gave 3-methoxy-6,6-dimethyl-6-silaestra-1,3,5(10),8-tetraen-17β-yl acetate (6b), and its 14-iso- and Δ^{1,3,5(10),8(14)} isomers, the proportions varying with the catalyst and solvent. Reduction of 6b with lithium-liquid ammonia, and O-demethylation, gave 6,6-dimethyl-6-silaestradiol (8b). Reduction of the 3-methyl ether of 8b with lithium-liquid ammonia-t-butanol and hydrolysis afforded 3-keto-6,6-dimethyl-6-silaestr-1(10)-en-17β-ol (15), which was catalytically reduced to its 1,10α-dihydro derivative 17. The 5,6 SiC bond of 8b, 15 and their derivatives was cleaved by boron tribromide, aq. ethanolic hydrogen fluoride, and other reagents, providing a series of 5,6-seco-6,6-dimethyl-6-silasteroids. X-ray crystallographic analysis of 17 and the 17α-ethynyl derivative of 15 confirmed the stereochemical assignments. None of the compounds which were subjected to uterotropic, anti-uterotropic, or post-coital assays, showed significant activity. A partially completed synthesis of 6-silaestradiol (21a) is described.