Looking at NSAIDs from a historical perspective and their current status in drug repurposing for cancer treatment and prevention.

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most frequently prescribed drug classes with wide therapeutic applications over the centuries. Starting from the use of salicylate-containing willow leaves to the recent rise and fall of highly selective cyclooxygenase-2 (COX-2) inhibitors and the latest dual-acting anti-inflammatory molecules, they have displayed a rapid and ongoing evolution. Despite the enormous advances in the last twenty years, investigators are still in search of the design and development of more potent and safer therapy against inflammatory conditions. This challenge has been increasingly attractive as the emergence of inflammation as a common seed and unifying mechanism for most chronic diseases. Indeed, this fact put the NSAIDs in the spotlight for repurposing against inflammation-related disorders. This review attempts to present a historical perspective on the evolution of NSAIDs, regarding their COX-dependent/independent mode of actions, structural and mechanism-based classifications, and adverse effects. Additionally, a systematic review of previous studies was carried out to show the current situation in drug repurposing, particularly in cancers associated with the GI tract such as gastric and colorectal carcinoma. In the case of non-GI-related cancers, preclinical studies elucidating the effects and modes of action were collected and summarized.

Biofortified Whey/Deglycosylated Whey and Chickpea Protein Matrices: Functional Enrichment by Black Mulberry Polyphenols.

Morus nigra L. (black mulberry-BM) is a promising nutraceutical fruit containing biologically active polyphenols like anthocyanins, proanthocyanidins, catechins, and stilbenes, with well-established anti-inflammatory, antidiabetic, anti-obesity, and anticancer biofunctions. However, these health-promoting properties in raw fruit are greatly masked due to the presence of soluble and insoluble carbohydrates in excess amounts restricting daily intake of the required dose to achieve targeted effects. In the current study, different protein sources (defatted whey and chickpea flours) were optimized through different conditions to capture polyphenols from BM juice while diminishing its glucose content. To optimize polyphenol-protein interactions, various pHs (3.7, 4.2, and 4.7), matrix concentrations (20, 50, and 80 g protein/L), and incubation times (5, 20, and 45 min) were tested. In the present work, optimized BM polyphenol enriched whey matrix inhibited pro-inflammatory mediators and promoted Nrf-2 dependent cytoprotective enzyme expressions in lipopolysaccharide (LPS) induced macrophages at low doses. In addition, whey proteins were also subjected to an enzymatic deglycosylation process by using recently identified EndoBI-1 enzyme for the specific cleavage of N-glycan core in all glycan types including high mannoses, hybrids as well as complex glycans found on defatted whey proteins. After this process, the polyphenol sorption capacity of deglycosylated whey proteins was found to be significantly higher (37%) than the capacity of non-treated normal whey protein under optimized conditions. In conclusion, deglycosylation of protein matrices could be a novel strategy for efficient sorption/concentration of polyphenols from fruits and vegetables, however, more detailed studies are needed to understand this effect.

New nimesulide derivatives with amide/sulfonamide moieties: Selective COX-2 inhibition and antitumor effects.

Seventeen new amide/sulfonamide containing nimesulide derivatives were synthesized and characterized by several spectroscopic techniques and primarily investigated for their inhibitory potential on COX enzymes and other pro-inflammatory factors. Experimental analyses showed that among seventeen compounds, N8 and N10 have remarkable potency and selectivity for the COX-2 enzyme over COX-1 at very low doses as compared to nimesulide. Moreover, both N8 and N10 selectively reduced the Lipopolysaccharide (LPS)-stimulated COX-2 mRNA expression level while the COX-1 level remained stable. Both PGE2 release and nitric oxide production in macrophage cells were significantly suppressed by the N8 and N10 treatment groups. In silico ADME/Tox, molecular docking and molecular dynamics (MD) simulations were also conducted. Additionally, all compounds were also screened in a panel of cancer cell lines for their antiproliferative properties by MTT and SRB assays. Compound N17 exhibited a considerable antiproliferative effect on the colon (IC50: 9.24 µM) and breast (IC50: 11.35 µM) cancer cell lines. N17 exposure for 48 h decreased expression of anti-apoptotic protein BCL-2 and increased the expression of apoptogenic BAX. Besides, the BAX/BCL-2 ratio was increased with visible ultrastructural changes and apoptotic bodies under scanning electron microscopy. In order to investigate the structural and dynamical properties of selected hits on the target structures, multiscale molecular modeling studies are also conducted. Our combined in silico and in vitro results suggest that N8 and N10 could be further developed as potential nonsteroidal anti-inflammatory drugs (NSAIDs), while cytotoxic N17 might be studied as a potential lead compound that could be developed as an anticancer agent.

Dataset on the differentiation of THP-1 monocytes to LPS inducible adherent macrophages and their capacity for NO/iNOS signaling.

When THP-1 cells are differentiated into adherent macro-phage-like cells, they respond to inflammatory stimuli by changing their phenotypes to an activation state and altering the expression of inflammation-related genes. Nitric oxide (NO) is a diatomic molecule implicating in various pathological conditions including tissue damage, ER stress, obesity, and cancer. The sustained inflammatory microenvironment leads to increased NO release through the activation of the inducible nitric oxide synthase (iNOS) gene in macrophages. Here, we provide a dataset on the optimized conditions for the THP-1 differentiation and the induction of NO/iNOS signaling under inflammatory stimulus. The human monocytic cells were differentiated into adherent macrophage-like phenotype by phorbol-12-myristate-13-acetate (PMA) stimulation under optimized conditions. In this study, NO/iNOS signaling capacity and the regulation of other pro-inflammatory genes including TNF-α, IL-1ß, and COX-2 in the LPS-induced THP-1 were examined.

Multitarget Profiling of a Strigolactone Analogue for Early Events of Alzheimer's Disease: In Vitro Therapeutic Activities against Neuroinflammation.

Neuropathological changes in Alzheimer's disease (AD) are directly linked to the early inflammatory microenvironment in the brain. Therefore, disease-modifying agents targeting neuroinflammation may open up new avenues in the treatment of AD. Strigolactones (SLs), subclasses of structurally diverse and biologically active apocarotenoids, have been recently identified as novel phytohormones. In spite of the remarkable anticancer capacity shown by SLs, their effects on the brain remained unexplored. Herein, the SIM-A9 microglial cell line was used as a phenotypic screening tool to search for the representative SL, GR24, demonstrating marked potency in the suppression of lipopolysaccharide (LPS)-induced neuroinflammatory/neurotoxic mediators by regulating NF-κB, Nrf2, and PPARγ signaling. GR24 also in the brain endothelial cell line bEnd.3 mitigated the LPS-increased permeability as evidenced by reduced Evans' blue extravasation through enhancing the expression of tight junction protein, occludin. Collectively, the present work shows the anti-neuroinflammatory and glia/neuroprotective properties of GR24, making SLs promising scaffolds for the development of novel anti-AD candidates.

In vitro and in silico studies of nitrobenzamide derivatives as potential anti-neuroinflammatory agents.

Communicated by Ramaswamy H. Sarma.

Natural Products and Synthetic Analogs as a Source of Antitumor Drugs.

Cancer is a heterogeneous disease and one of the major issues of health concern, especially for the public health system globally. Nature is a source of anticancer drugs with abundant pool of diverse chemicals and pharmacologically active compounds. In recent decade, some natural products and synthetic analogs have been investigated for the cancer treatment. This article presents the utilization of natural products as a source of antitumor drugs.

Symphytum Species: A Comprehensive Review on Chemical Composition, Food Applications and Phytopharmacology.

Symphytum species belongs to the Boraginaceae family and have been used for centuries for bone breakages, sprains and rheumatism, liver problems, gastritis, ulcers, skin problems, joint pain and contusions, wounds, gout, hematomas and thrombophlebitis. Considering the innumerable potentialities of the Symphytum species and their widespread use in the world, it is extremely important to provide data compiling the available literature to identify the areas of intense research and the main gaps in order to design future studies. The present review aims at summarizing the main data on the therapeutic indications of the Symphytum species based on the current evidence, also emphasizing data on both the efficacy and adverse effects. The present review was carried out by consulting PubMed (Medline), Web of Science, Embase, Scopus, Cochrane Database, Science Direct and Google Scholar (as a search engine) databases to retrieve the most updated articles on this topic. All articles were carefully analyzed by the authors to assess their strengths and weaknesses, and to select the most useful ones for the purpose of review, prioritizing articles published from 1956 to 2018. The pharmacological effects of the Symphytum species are attributed to several chemical compounds, among them allantoin, phenolic compounds, glycopeptides, polysaccharides and some toxic pyrrolizidine alkaloids. Not less important to highlight are the risks associated with its use. In fact, there is increasing consumption of over-the-counter drugs, which when associated with conventional drugs can cause serious and even fatal adverse events. Although clinical trials sustain the folk topical application of Symphytum species in musculoskeletal and blunt injuries, with minor adverse effects, its antimicrobial potency was still poorly investigated. Further studies are needed to assess the antimicrobial spectrum of Symphytum species and to characterize the active molecules both in vitro and in vivo.

Piper Species: A Comprehensive Review on Their Phytochemistry, Biological Activities and Applications.

Piper species are aromatic plants used as spices in the kitchen, but their secondary metabolites have also shown biological effects on human health. These plants are rich in essential oils, which can be found in their fruits, seeds, leaves, branches, roots and stems. Some Piper species have simple chemical profiles, while others, such as Piper nigrum, Piper betle, and Piper auritum, contain very diverse suites of secondary metabolites. In traditional medicine, Piper species have been used worldwide to treat several diseases such as urological problems, skin, liver and stomach ailments, for wound healing, and as antipyretic and anti-inflammatory agents. In addition, Piper species could be used as natural antioxidants and antimicrobial agents in food preservation. The phytochemicals and essential oils of Piper species have shown strong antioxidant activity, in comparison with synthetic antioxidants, and demonstrated antibacterial and antifungal activities against human pathogens. Moreover, Piper species possess therapeutic and preventive potential against several chronic disorders. Among the functional properties of Piper plants/extracts/active components the antiproliferative, anti-inflammatory, and neuropharmacological activities of the extracts and extract-derived bioactive constituents are thought to be key effects for the protection against chronic conditions, based on preclinical in vitro and in vivo studies, besides clinical studies. Habitats and cultivation of Piper species are also covered in this review. In this current work, available literature of chemical constituents of the essential oils Piper plants, their use in traditional medicine, their applications as a food preservative, their antiparasitic activities and other important biological activities are reviewed.

GR24, a synthetic analog of Strigolactones, alleviates inflammation and promotes Nrf2 cytoprotective response: In vitro and in silico evidences.

Naturally occurring phytohormones have shown distinguished potential in chemoprevention and treatment of chronic inflammatory diseases in mammalian cells. Strigolactones (SLs) are a class of carotenoid-derived lactones regulating many aspects of plant development and recently recognized as phytohormones with promising anticancer activity. In this study, GR24, a synthetic analog and representative of SLs, induced the expression of phase II detoxifying enzymes such as HO-1 and NQO1 in hepatic and macrophage cell lines under normal and inflammatory conditions, respectively. This effect has been found to be mediated by Nrf2 activation. In silico molecular docking against 16-mer peptide binding site on Keap1 suggested that GR24 may exert its biological activity by interfering with Keap1 and Nrf2 binding. GR24 also displayed remarkably potent inhibitory activity against the production of nitric oxide (NO) and molecular docking analysis on iNOS supported experimental data. Furthermore, GR24 dose dependently suppressed the LPS-induced iNOS expression at both mRNA and protein level. It also significantly decreased IL-1ß release, mRNA expression of IL-1ß and COX-2, as well as nuclear accumulation of NFÒ¡B at the low micro molar range in LPS-stimulated murine macrophages. GR24 promoted AKT activation in insulin resistant skeletal muscle cells and downregulated the expression of enzymes, PEPCK and G6Pase control the rate limiting steps of gluconeogenesis in hepatic cells. The results of molecular docking and ADMET analyses indicated that GR24 might be classified as druggable molecule in drug design. Taken together, all results suggest that SLs can be promising multi-potent botanical leads for the mitigation of inflammatory-mediated chronic disorders.