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Supplementary Fig. S1 from Identification of a small molecule class to enhance cell-cell adhesion and attenuate prostate tumor growth and metastasis

Epidemiological and clinical studies compellingly showed the ability of Mediterranean diet rich in extra-virgin olive oil (EVOO) to reduce multiple diseases such as cancer, cardiovascular diseases, and aging cognitive functions decline. The S-(−)-Oleocanthal (OC) is a minor phenolic secoiridoid exclusively found in extra-virgin olive oil (EVOO). OC recently gained notable research attention due to its excellent in vitro and in vivo biological effects against multiple cancers, inflammations, and Alzheimer’s disease. However, OC safety has not been comprehensively studied yet. This study reports for the first time the detailed safety of oral single OC dose in Swiss albino mice, applying the OECD 420 procedure. Male and female Swiss albino mice (n = 10) were orally treated with a single OC dose of either 10, 250, or 500 mg/kg bodyweight or equivalent volumes of distilled water. Mice fed a regular diet, and carefully observed for 14 days. Further, mice were then sacrificed, blood samples, and organs were collected and subjected to hematological, biochemical, and histological examinations. OC 10 mg/kg oral dose appears to be without adverse effects. Further, 250 mg/kg OC, p.o., is suggested as a possible upper dose for preclinical studies in the future.

Veratrum alkaloids are a group of steroidal alkaloids with penta-, hexa-, or heptacyclic C-nor-D-homosteroidal or regular hexacycliccholestane skeleton. Activation of the Hedgehog (Hh) pathway aberrantly associated with numerous malignancies. Cyclopamine blocked Hh pathway by directly binding Smo and slows down the growth of these tumors in various animal models. To less extent, jervine and the veratrane Veratrum alkaloid veratramine were also reported as possible Hh signaling inhibitors. This encouraged the study of our small library of natural, biocatalytic, and semisynthetic jervane and veratrane alkaloids’ ability to inhibit the growth, proliferation, and migration of the prostate metastatic cancer cell line PC-3 to establish a preliminary structure–activity relationship. Alkaloids possessing C-3-keto functionality with ∆4,5 or ∆1,2 and ∆4,5 exhibited significant enhancement of antiproliferative and antimigratory activities. A common feature pharmacophore model of active Veratrum alkaloids was built and validated using receiver-operating characteristic curve analyses.

Prostrate cancer constitutes the second leading cause of cancer deaths in men in United States. In the process of discovery of new antiproliferative and anti-metastatic agents against prostate cancer, marine-derived phenylmethylene hydantoin (PMH) derivatives were identified with activity level range between 50 and 200 μM. 3D-QSAR CoMFA model was used in virtual screening of commercially available derivatives of PMH. PMH derivatives with manifold increase in anti-migratory and anti-invasive activities were discovered using wound-healing and Cultrex invasion assays. Benzene ring replacement with other heterocyclic rings did not significantly improve the methylene hydantoins activities. Multivariate analysis performed on the whole series of methylene hydantoins, which further supported the findings of CoMFA model. Predictive QSAR model with conventional r 2 and cross-validated coefficient ( q 2 ) values up to 0.982 and 0.803 were established. The molecular volume (MV) and the log P were identified as critical parameters for methylene hydatoins migration inhibitory activity. PMH is a novel anti-metastatic lead class with potential therapeutic activity against prostate cancer.

Nanostructured lipid carriers (NLCs), made from mixtures of solid and liquid lipids, were postulated to have superior properties over solid lipid nanoparticles (SLNs). Nonetheless, the architecture of their inner cores remains elusive. The objective of this study was to elucidate the mode by which tocotrienol-rich fraction (TRF) is entrapped within NLCs and the impact of TRF interaction with solid lipids on the long-term stability of the nanoparticles. The mode of TRF localization was postulated from TEM image analysis and (1)H NMR signals' amplitude. The size, polydispersity, and fusion enthalpy were found to decrease with an increase in TRF loading, which implied a distortion in the crystallinity of the nanoparticles and the preferential entrapment of TRF within the cores of the NLCs. Nonetheless, (1)H NMR spectra of TRF-NLCs broadened as TRF load decreased from 100 to 10%, which was attributed to partial TRF mobility on the surface of the nanoparticles. This was confirmed by TEM images of NLCs at 50% TRF loads. These data led to the conclusion that NLCs have limited capacity to accommodate TRF with the excess being expelled to the surface of the nanoparticles. Such arrangement may have implication on future utility of the NLCs as drug delivery vehicles.

Mediterranean diet (MD) is considered one of the most health promoting diets adopted initially by the Mediterranean population. Recent studies showed a link between MD and lowering the incidence of mild cognitive impairment and Alzheimer's disease (AD). Clinical and preclinical studies have suggested several health promoting effects for the dietary consumption of extra-virgin olive oil (EVOO), a major component of MD, that could protect and decrease the risk of developing AD. Moreover, recent studies have linked this protective effect to oleocanthal, a phenolic secoiridoid component of EVOO. Here we provide evidence to support the role of EVOO and oleocanthal in enhancing the clearance of amyloid-beta (As), a major pathological hallmark in AD, and reducing the overall inflammatory burden on the brain. In our study, both EVOO and oleocanthal treatment significantly decreased As load in the hippocampal parenchyma and microvessels. Furthermore, our mechanistic studies demonstrated an effect on increasing the expression of important amyloid clearance proteins at the blood-brain barrier (BBB) including P-glycoprotein (P-gp) and low density lipoprotein receptor-related protein 1 (LRP1), and to activate the ApoE-dependent amyloid clearance pathway in the mice brains. Additionally, oleocanthal was able to reduce astrocytes activation and IL-1s levels. The reduction in As levels and microvessels deposition could be explained, at least in part, to the enhanced As clearance across the BBB and by ApoE-dependent pathway. In addition, oleocanthal demonstrated an anti-inflammatory effect by reducing astrocytes activation and IL-1s brain levels, which emphasize the importance of considering EVOO and oleocanthal as a potential therapeutic interventions in AD.

Objective: Obesity and its complications including metabolic syndrome (MetS) have been increased in children and adolescents recently. Leptin is known to play an important role in the pathogenesis of obesity. The objective of this study was to evaluate the relationship between Leptin, Ghrelin and Insulin resistance in the development of metabolic syndrome in obese persons. Methods: this study was carried out on fifty obese persons. All patients have BMI ≥ 30 Kg/m2. Twenty of them have metabolic syndrome. Body Mass Index (BMI), Waist Circumference (WC), and blood pressure were measured. Fasting Plasma Glucose (FBG), two hours Post Prandial Blood Glucose (PPBG), Glycated hamoglobin A1C (HbA1c), triglyceride (TG), Total Cholesterol (TC), high and low density lipoprotein cholesterol (HDL-C and LDL-C), serum Leptin, Ghrelin and Insulin were done. HOMA-IR and HOMA- β were calculated. Results: SBP, DBP, FBS, PPBG, HbA1c, HOMA-IR and HOMA-β were significantly increased in obese and MetS groups compared to control group. There was a significant increase in insulin and Leptin, serum TG, TC and LDL-C with a significant decrease in HDL cholesterol and Ghrelin in obese and MetS groups. A significant negative correlation between plasma Ghrelin and BMI, WC, SBP, DBP, and FBS, PPBG, serum TG, TC, LDL-C, HbA1c, and HOMA-B was observed while leptin showed a significant positive correlation with them and a negative correlation with HOMA-IR. Plasma Ghrelin was positively correlated with HDL-C while Leptin was positively correlated with it in obese and MetS groups. There was a significant negative correlation between plasma Ghrelin, Insulin and leptin with significant positive correlation between plasma insulin and leptin in obese and MS groups. Conclusion: There are hormonal changes associated with clusters of metabolic abnormalities and elevation of blood pressure that may have a role in the development of MetS in obese persons and are major CHD risk factors. Insulin has stimulatory trophic effect on leptin secretion, but the effect of leptin on insulin is controversial as leptin may modulate insulin action and participates in the development of insulin resistance. As regard Ghrelin secretion, there are many suppressive factors: insulin, Leptin and glucose. Our study produces a preliminary result, thus further studies with large number of patients are required.

The marine-derived macrolide latrunculins A and B, from the Red Sea sponge Negombata magnifica, are known to reversibly bind actin monomers, forming 1:1 complex with G-actin, disrupting its polymerization. Latrunculins have remarkable physiological properties and widely used as biochemical markers. Nevertheless, no QSAR studies have been developed for any kind of actin disruptors. In the present study, Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) implemented in the SYBYL software packages were used to develop predictive 3D-QSAR models. Two alignment strategies were used to fit analyzed molecules to a suitable conformational template. By means of the SYBYL multifit alignment function, the best CoMFA and CoMSIA results presented cross-validated correlation coefficient values (q(2)) of 0.621 and 0.659, and non-cross-validated values (r(2)) of 0.938 and 0.965, respectively. Comparable to multifit-derived models, CoMFA and CoMSIA 3D-QSAR models were also derived using a molecular alignment obtained by docking latrunculin derivatives into the ATP active site of actin. In addition to q(2), the predictive ability was validated using external test set of five compounds. The results of this study suggest that the established model has a strong predictive ability and can be prospectively used in the molecular design and action mechanism analysis of this kind of cytotoxic compounds.

The microfilament cytoskeleton protein actin plays an important role in cell biology and affects cytokinesis, morphogenesis, and cell migration. These functions usually fail and become abnormal in cancer cells. The marine-derived macrolides latrunculins A and B, from the Red Sea sponge Negombata magnifica, are known to reversibly bind actin monomers, forming 1:1 stoichiometric complexes with G-actin, disrupting its polymerization. To identify novel therapeutic agents for effective treatment of metastatic breast cancer, several semisynthetic derivatives of latrunculin A with diverse steric, electrostatic, and hydrogen bond donor and acceptor properties were rationally prepared. Analogues were designed to modulate the binding affinity toward G-actin. Examples of these reactions are esterification, acetylation, and N-alkylation. Semisynthetic latrunculins were then tested for their ability to inhibit pyrene-conjugated actin polymerization, and subsequently assayed for their antiproliferative and anti-invasive properties against MCF7 and MDA-MB-231 cells using MTT and invasion assays, respectively.