Molecular insight into isoform specific inhibition of PI3K-α and PKC-η with dietary agents through an ensemble pharmacophore and docking studies

Dietary compounds play an important role in the prevention and treatment of many cancers, although their specific molecular mechanism is not yet known. In the present study, thirty dietary agents were analyzed on nine drug targets through in silico studies. However, nine dietary scaffolds, such as silibinin, flavopiridol, oleandrin, ursolic acid, α-boswellic acid, β-boswellic acid, triterpenoid, guggulsterone, and oleanolic acid potentially bound to the cavity of PI3K-α, PKC-η, H-Ras, and Ras with the highest binding energy. Particularly, the compounds silibinin and flavopiridol have been shown to have broad spectrum anticancer activity. Interestingly, flavopiridol was embedded in the pockets of PI3K-α and PKC-η as bound crystal inhibitors in two different conformations and showed significant interactions with ATP binding pocket residues. However, complex-based pharmacophore modeling achieved two vital pharmacophoric features namely, two H-bond acceptors for PI3K-α, while three are hydrophobic, one cat-donor and one H-bond donor and acceptor for PKC-η, respectively. The database screening with the ChemBridge core library explored potential hits on a valid pharmacophore query. Therefore, to optimize perspective lead compounds from the hits, which were subjected to various constraints such as docking, MM/GBVI, Lipinski rule of five, ADMET and toxicity properties. Henceforth, the top ligands were sorted out and examined for vital interactions with key residues, arguably the top three promising lead compounds for PI3K-α, while seven for PKC-η, exhibiting binding energy from − 11.5 to − 8.5 kcal mol−1. Therefore, these scaffolds could be helpful in the development of novel class of effective anticancer agents.

Antiradical Activity of Beetroot (Beta vulgaris L.) Betalains

Flavonoids, phenolic acids, and anthocyanidins are widely studied polyphenolics owing to their antiradical activity. Recently, beetroot dyes have drawn an attention as possible radical scavengers, but scant information can be found on this topic. In this study selected compounds were investigated using computational chemistry methods. Implicit water at physiological pH was chosen as the environment of interest. Betalains’ dissociation process and electronic structure were examined, as well as the reactivity in six pathways against some common radicals, such as hydroxyl, hydroperoxide, superoxide, and nitric oxide. The study showed that all carboxyl groups are dissociated in the given conditions. The dissociation process impacts the electronic structure, which has consequences for the overall activity. Highly stabilized conjugated structures favor the electron–accepting type of scavenging reactions, primarily by a radical adduct formation mechanism. Betanidin and indicaxanthin were found to be the most promising of the compounds studied. Nevertheless, the study established the role of betalains as powerful antiradical dietary agents.

Combinational Therapy Using Chemotherapeutic Agents and Dietary Bioactive Compounds

Diet-derived phytochemicals find prominent use in traditional medicine and have been credited with lowering cancer risk significantly. Dietary agents demonstrate anticancer activity by modulating various molecular targets and cell signaling pathways. Several studies have focused on combinations of dietary bioactive compounds and conventional chemotherapeutic agents to augment their therapeutic response and mitigate the side effects of conventional chemotherapy. The observed synergistic response heralds promise for successful future chemopreventive and chemotherapeutic strategies in cancer management. Animal models and pre-clinical trials of the effective combinations must be undertaken to clearly understand the mechanism of action. This chapter catalogues recent studies that have used dietary bioactive compounds (sulforaphane, EGCG, curcumin, genistein, resveratrol, eugenol) in combination with conventional chemopreventive agents and with other phytochemicals.

Small dense low-density lipoprotein-lowering agents

Metabolic disorders, including obesity, diabetes, and hyperlipidemia, as well as cardiovascular diseases (CVD), particularly atherosclerosis, are still leading causes of death worldwide. Plasma levels of low-density lipoprotein (LDL) are currently being considered as a critical risk factor for the diseases mentioned above, especially atherosclerosis. Because of the heterogeneous nature of LDL, many studies have already been conducted on its subclasses, especially small dense LDL (sdLDL). According to available evidence, sdLDL levels can be considered as an ideal alternative to LDL levels for monitoring CVD and early diagnosis of atherosclerosis. Recently, several researchers have focused on factors that are able to decrease sdLDL levels and improve health quality. Therefore, the purpose of this study is to describe the production process of sdLDL particles and review the effects of pharmaceutical and dietary agents as well as lifestyle on sdLDL plasma levels. In brief, their mechanisms of action are discussed. Apparently, cholesterol and LDL-lowering compounds are also effective in the reduction of sdLDL levels. In addition, improving lipid profile, especially the reduction of triglyceride levels, appropriate regimen, and lifestyle can decrease sdLDL levels. Therefore, all the aforementioned parameters should be taken into consideration simultaneously in sdLDL levels reducing strategies.

Spectrophotometric Analysis of Dental Enamel Staining to Antiseptic and Dietary Agents: In Vitro Study

Background/Objectives. Use of antiseptics as an adjunct to a traditional mechanical tooth brushing method has limited their application for long duration because of their side effects such as staining and calculus formation. The objective of this in vitro study is to analyse the staining effects of antiseptic mouthwashes on dental enamel and compare it with those containing nanoparticles, dietary agents, and distilled water (control). Material and Methods. 105 intact premolars extracted for orthodontic reasons and without any caries or anatomical defects were selected for analysis. The samples were randomly divided into 7 different groups of fifteen teeth each for different solutions. A spectrophotometer was used to assess the colorimeter analysis of buccal dental enamel surface at R1 (baseline examination), R2 (24 hours after immersion in different solutions), and R3 (after brushing). Statistical analysis was done using the Kolmogorov–Smirnov test and Levene’s test (p<0.05), respectively. One-way ANOVA was used to compare the difference in color (∆E) between the readings, R1, R2, and R3. Results. The mouthwash containing titanium dioxide (TiO2) nanoparticles produced the greater enamel discoloration compared to that of chlorhexidine. Brushing had little effect on removal of stains induced by all mouthwashes except for dietary solutions (lemon with sodium bicarbonate and olive with laurel) and distilled water (control). Conclusion. The results from this study show that mouthwashes containing TiO2 nanoparticles and other antiseptic mouthwashes cause change in color of the teeth and lead to poor esthetic appearance when compared to dietary and control solutions. Thus, future in vivo studies have to be conducted to confirm these findings as in vitro studies may not provide a reliable simulation of the clinical situations.

Development of Functional Screens for Dietary Angiogenesis Inhibitors

Objectives We sought to develop a workflow to evaluate the anti-angiogenic potential of dietary agents in a stringent, systemic manner: 1) in vitro inhibition of angiogenesis, 2) in vivo testing of normal angiogenesis inhibition, and 3) in vivo testing of tumor prevention. Methods We used a tiered workflow for assessment of anti-angiogenic potential of dietary compounds, beginning with cell culture methods, moving to high-throughput D. rerio angiogenesis modeling and finally mouse models of angiogenesis and tumor development to identify potent dietary agents which block tumor angiogenesis. Results We identified quercetin dihydrate as an orally available inhibitor of angiogenesis and our lead candidate for further evaluation for chemoprevention of angiogenesis. Quercetin blocked in vitro sprouting angiogenesis, and displayed a dose-dependent reduction in sprouting angiogenesis in the tail regeneration model in zebrafish. Finally, quercetin implanted at reported physiologic levels blocked blood vessel growth in mouse models of angiogenesis. Conclusions We describe a workflow for systematic evaluation of dietary compounds in increasing complexity models for stringent, systematic evaluation of angiogenesis inhibition. These multi-model approaches allow for filtering of pan-assay interference compounds (PAINS) prior to in vivo screening. This workflow identified quercetin as a potent inhibitor of angiogenesis which warrants further study for chemoprevention through diet. Funding Sources National Cancer Institute Division of Cancer Prevention, National Cancer Institute Center for Cancer Research.

Impact of Natural Dietary Agents on Multiple Myeloma Prevention and Treatment: Molecular Insights and Potential for Clinical Translation

: Chemoprevention is based on the use of non-toxic, pharmacologically active agents to prevent tumor progression. In this regard, natural dietary agents have been described by the most recent literature as promising tools for controlling onset and progression of malignancies. Extensive research has been so far performed to shed light on the effects of natural products on tumor growth and survival, disclosing the most relevant signal transduction pathways targeted by such compounds. Overall, anti-inflammatory, anti-oxidant and cytotoxic effects of dietary agents on tumor cells are supported either by results from epidemiological or animal studies and even by clinical trials. : Multiple myeloma is a hematologic malignancy characterized by abnormal proliferation of bone marrow plasma cells and subsequent hypercalcemia, renal dysfunction, anemia, or bone disease, which remains incurable despite novel emerging therapeutic strategies. Notably, increasing evidence supports the capability of dietary natural compounds to antagonize multiple myeloma growth in preclinical models of the disease, underscoring their potential as candidate anti-cancer agents. : In this review, we aim at summarizing findings on the anti-tumor activity of dietary natural products, focusing on their molecular mechanisms, which include inhibition of oncogenic signal transduction pathways and/or epigenetic modulating effects, along with their potential clinical applications against multiple myeloma and its related bone disease.