The Marine-Derived Sipholenol A-4-O-3′,4′-Dichlorobenzoate Inhibits Breast Cancer Growth and Motility in Vitro and in Vivo through the Suppression of Brk and FAK Signaling

Sipholenol A is a natural sipholane triterpenoid isolated from the Red Sea sponge, Callyspongia siphonella. Previous studies showed the antimigratory and antiproliferative activities of the semisynthetic sipholenol A esters against breast cancer cell lines. This study investigated the effects of sipholenol A-4-O-3′,4′-dichlorobenzoate (SPA) on the growth, migration and invasion of diverse human breast cancer cells. Results showed that SPA inhibited the growth of the human breast cancer cells, MDA-MB-231, MCF-7, BT-474 and T-47D, in a dose-dependent manner. Immunofluorescent analysis showed that SPA significantly reduced Ki-67-positive cells in MDA-MB-231 cells. Flow cytometry and Western blot analyses revealed that SPA treatment suppressed MDA-MB-231 cell growth by inducing cell cycle arrest at the G1 phase. In addition, SPA suppressed breast cancer cell migration, invasion and decreased Brk and FAK activation in a dose-dependent manner. Molecular docking study suggested a perfect fitting at the FAK’s FERM domain, inhibiting the main autophosphorylation site, Y397, which was further confirmed by Western blot analysis. Most known small molecule FAK inhibitors target the kinase domain, creating several off-target side effects. The in vivo studies showed that SPA treatment suppressed breast tumor growth and Ki-67, CD31, p-Brk and p-FAK expression in orthotopic breast cancer in nude mice. In conclusion, SPA inhibited the growth, invasion and migration of breast cancer cells possibly via deactivating Brk and FAK signaling, suggesting good potential for therapeutic use to control invasive breast cancer.     

Discovery of Novel Antiangiogenic Marine Natural Product Scaffolds

Marine natural products (MNPs) are recognized for their structural complexity, diversity, and novelty. The vast majority of MNPs are pharmacologically relevant through their ability to modulate macromolecular targets underlying human diseases. Angiogenesis is a fundamental process in cancer progression and metastasis. Targeting angiogenesis through selective modulation of linked protein kinases is a valid strategy to discover novel effective tumor growth and metastasis inhibitors. An in-house marine natural products mini-library, which comprises diverse MNP entities, was submitted to the Lilly’s Open Innovation Drug Discovery platform. Accepted structures were subjected to in vitro screening to discover mechanistically novel angiogenesis inhibitors. Active hits were subjected to additional angiogenesis-targeted kinase profiling. Some natural and semisynthetic MNPs, including multiple members of the macrolide latrunculins, the macrocyclic oxaquinolizidine alkaloid araguspongine C, and the sesquiterpene quinone puupehenone, showed promising results in primary and secondary angiogenesis screening modules. These hits inhibited vascular endothelial growth factor (VEGF)-mediated endothelial tube-like formation, with minimal cytotoxicity at relevant doses. Secondary kinase profiling identified six target protein kinases, all involved in angiogenesis signaling pathways. Molecular modeling and docking experiments aided the understanding of molecular binding interactions, identification of pharmacophoric epitopes, and deriving structure-activity relationships of active hits. Marine natural products are prolific resources for the discovery of chemically and mechanistically unique selective antiangiogenic scaffolds.     

Marine natural products as prototype agrochemical agents

In the interest of identifying new leads that could serve as prototype agrochemical agents, 18 structurally diverse marine-derived compounds were examined for insecticidal, herbicidal, and fungicidal activities. Several new classes of compounds have been shown to be insecticidal, herbicidal, and fungicidal, which suggests that marine natural products represent an intriguing source for the discovery of new agrochemical agents.     

Antioxidant Effects of Vitamins C and E on the Low-Density Lipoprotein Oxidation Mediated by Myeloperoxidase

Background: Oxidative modification of low-density lipoprotein (LDL) appears to be an early step in the pathogenesis of atherosclerosis. Meanwhile, myeloperoxidase (MPO)-catalyzed reaction is one of the potent pathways for LDL oxidation in vivo. The aim of this study was to evaluate in vitro antioxidant effects of vitamins C and E on LDL oxidation mediated by MPO. Methods: MPO was isolated from fresh plasma by sequential centrifugation using density ultracentrifugation. It was incubated with LDL and the LDL oxidation level was determined spectrophotometrically by measuring conjugated diene absorbance at 234 nm. Furthermore, vitamin C (50-200 mM) and vitamin E (10-40 mM) were added and the LDL oxidation level was determined. Results: The purity index of MPO and its enzymatic activity were 0.69 and 1127 U/mg protein, respectively. It was demonstrated that vitamin C in vitro inhibited LDL oxidation mediated by MPO; however, vitamin E was unable to act in the same way. The protection by vitamin C was concentration dependent and maximum protective effect of vitamin C was observed at 150 mM, where about 64% of the LDL oxidation was inhibited. Vitamin C increased lag time of LDL oxidation mediated by MPO up to 2.4 times. Conclusion: It can be concluded from our results that vitamin C is able to improve LDL resistance to oxidative modification in vitro. In addition, vitamin C might be effective in LDL oxidation mediated by MPO in vivo, resulting in reduction of atherosclerosis process rate. Key Words: Antioxidant, Myeloperoxidase (MPO), Low-density lipoprotein (LDL), Vitamin E     

Role of sponge gourd in apical leaf curl disease of potato in Northern India

Potato (Solanum tuberosum) is one of the important vegetable crops in the world and its production is seriously affected by apical leaf curl disease in northern India. This paper reveals the role of cucurbits in maintaining Tomato leaf curl New Delhi virus (ToLCNDV) and Potato apical leaf curl (PALCD) disease in that region. The affected plants showed severe leaf curling and stunted growth. The begomovirus causing leaf curling and mosaic disease in cucurbits could be easily transmitted by the whitefly to potato crops and develop apical leaf curl disease in northern India. The movement of the virus by whiteflies from cucurbits to potato and tomato is possible because of overlapping of planting and harvesting dates of these crops. The causal virus was identified as a begomovirus on the basis of whitefly transmission, PCR, dot blot hybridization, cloning and sequencing of the coat protein gene. The comparison of full length coat protein gene sequence homology revealed that 90% identity with the coat protein gene of ToLCNDV- [Luffa] isolate and the phylogenetic tree derived from these sequences with other selected begomoviruses formed a close cluster with ToLCNDV isolates. The findings proved that the virus causing disease in cucurbits could easily move to tomato and potato and cause leaf curl disease naturally. This is the first observation on the role of sponge gourd for maintenance of ToLCNDV and serving as a host for PALCD in northern India. The findings indicate that the causal organism is a strain of ToLCNDV.     

Current Status on Marine Products with Reversal Effect on Cancer Multidrug Resistance

The resistance of tumor cells to a broad range of anticancer agents continues to be a problem for the success of cancer chemotherapy. Multidrug resistance (MDR) is due in part to three drug transporter proteins: ABCB1/P-glycoprotein (P-gp), ABCC1/multidrug resistance protein 1 (MRP1) and ABCG2/breast cancer resistance protein (BCRP). These transporters are part of the ATP-binding cassette (ABC) superfamily, whose members function as ATP-dependent drug-efflux pumps. Their activity can be blocked by various drugs such as verapamil (calcium channel blocker) and cyclosporin A (immunosuppressive agent), etc. These compounds are called MDR modulators or reversals. This review highlights several marine natural products with reversal effect on multidrug resistance in cancer, including agosterol A, ecteinascidin 743, sipholane triterpenoids, bryostatin 1, and welwitindolinones.     

Differences in Carbohydrate Composition and Digestion In Vitro of Selected Barley Cultivars as Influenced by Pearling and Cooking

Among common cereals, barley is a low glycemic index food. In an attempt to better understand this character, the nutritional properties of glycemic carbohydrates and dietary fiber concentrations of nine cultivars were evaluated. The cultivars were selected based on botanical variations and commercial value to investigate the impact of pearling and cooking on nutritional properties. Each cultivar was pearled into four fractions ranging from hull removal only to hull, bran, germ, and crease removal. The study showed that botanical class and degree of pearling significantly affect the carbohydrate composition and digestion indices of barley. Waxy starch cultivars had less total starch and more rapidly digestible starch (RDS), rapidly available glucose (RAG), and β‐glucan than the other nonwaxy cultivars. Regardless of the barley type, the less pearled kernels had significantly lower total starch and higher total low molecular weight sugars, insoluble, and total fiber. However, β‐glucan content was fairly comparable in the whole grain and pearled fractions. Cooking had a significant effect on nutritional properties of Celebrity and AC Klinck cultivars. The only consistent significant difference between raw and cooked barley was resistant starch (RS), which increased after cooking regardless of cultivar or fraction. The study showed that barley cultivar and carbohydrate composition significantly affected starch digestion with some cultivar fractions holding a promise for the development of low glycemic index foods.     

Feeding increasing levels of corn gluten meal induces suboptimal muscle pigmentation of rainbow trout (Oncorhynchus mykiss)

A 24‐week growth trial was conducted to evaluate the effects of feeding levels of corn gluten meal (CGM) on growth performance and pigment deposition in the muscle of rainbow trout (Oncorhynchus mykiss). Three isonitrogenous and isoenergetic (digestible energy basis) experimental diets were formulated to contain increasing levels of CGM (0%, 9% and 18%) and 50 mg kg^?1 of astaxanthin. Each diet was fed in triplicate to groups of 75 fish (initial average body weight = 549 g fish^?1) reared at 8.5°C. The inclusion of CGM did not significantly (P > 0.05) affect final body weight, thermal growth efficiency (TGC) or feed efficiency. Carotenoid concentration determined by liquid chromatography showed a significant (P < 0.05) linear reduction in the concentration of one astaxanthin isomer, all‐trans astaxanthin and all‐trans lutein in the muscle of fish in response to increasing levels of CGM. Tristimulus colour analysis of the muscle showed a significant (P < 0.05) linear reduction in a* (redness) and C*ab (chroma). Salmofan^? score showed a significant (P < 0.05) linear and quadratic reduction in response to increasing levels of CGM. In conclusion, the inclusion of CGM up to 18% does not significantly impact growth performance of rainbow trout. However, the concentration of all‐trans astaxanthin as well as the expression of important colour attributes of the muscle can be negatively affected at levels exceeding 9% of CGM in the diet. More research on this topic is needed to discern the mechanism(s) behind the negative effects of dietary CGM and/or its intrinsic yellow pigments on muscle pigmentation of rainbow trout.     

Effect of dietary phosphorus supplementation on utilization of algae in the grow‐out diet of Nile tilapia Oreochromis niloticus

This research involved testing the replacement of corn gluten protein concentrate in the diet of 1.5 g Nile tilapia with biofuel algae‐based or algae supplemented with phosphorus diets. Experimental diets were formulated to replace 50% of the gluten meal protein in the control diet with biofuel algae protein (Alga50) or Spirulina (Spirulina50) protein. In addition, dicalcium phosphate (P) was added to the Alga50 at a concentration of 3.8% or 7.74% to mitigate aluminium (Al) toxicity and designated as Alga50 + P, and Alga50 + PP respectively. After 9 weeks of the feeding experiment, fish fed diets supplemented with P, Alga50 + P and Alga50 + PP differed significantly (P < 0.05) with respect to the feed conversion and protein deposition from the control. The mineral composition of the fish body showed a decrease in levels of Al and iron (Fe) due to the P supplements. The mineral composition of the faeces indicated that Al and Fe were excreted in the faeces and were not accumulated in the fish body. The effect of dicalcium P supplementation on the neutralization of Al in the diet resulted in improved fish growth and histological integrity of the gastrointestinal tract.