The senescence-associated secretory phenotype in ovarian cancer dissemination.

Ovarian cancer is a highly aggressive disease with poor survival rates in part due to diagnosis after dissemination throughout the peritoneal cavity. It is well-known that inflammatory signals affect ovarian cancer dissemination. Inflammation is a hallmark of cellular senescence, a stable cell cycle arrest induced by a variety of stimuli including many of the therapies used to treat patients with ovarian cancer. Indeed, recent work has illustrated that ovarian cancer cells in vitro, mouse models, and patient tumors undergo senescence in response to platinum-based or poly(ADP-ribose) polymerase (PARP) inhibitor therapies, standard-of-care therapies for ovarian cancer. This inflammatory response, termed the senescence-associated secretory phenotype (SASP), is highly dynamic and has pleiotropic roles that can be both beneficial and detrimental in cell-intrinsic and cell-extrinsic ways. Recent data on other cancer types suggest that the SASP promotes metastasis. Here, we outline what is known about the SASP in ovarian cancer and discuss both how the SASP may promote ovarian cancer dissemination and strategies to mitigate the effects of the SASP.

Rosemary (Salvia rosmarinus): Health-promoting benefits and food preservative properties.

Natural food preservatives in the form of herb extracts and spices are increasing in popularity due to their potential to replace synthetic compounds traditionally used as food preservatives. Rosemary (Salvia rosmarinus) is an herb that has been traditionally used as an anti-inflammatory and analgesic agent, and currently is being studied for anti-cancer and hepatoprotective properties. Rosemary also has been reported to be an effective food preservative due to its high anti-oxidant and anti-microbial activities. These properties allow rosemary prevent microbial growth while decreasing food spoilage through oxidation. Rosemary contains several classes of compounds, including diterpenes, polyphenols, and flavonoids, which can differ between extracts depending on the extraction method. In particular, the diterpenes carnosol and carnosic acid are two of the most abundant phytochemicals found in rosemary, and these compounds contribute up to 90% of the anti-oxidant potential of the herb. Additionally, several in vivo studies have shown that rosemary administration has a positive impact on gastrointestinal (GI) health through decreased oxidative stress and inflammation in the GI tract. The objective of this review is to highlight the food preservative potential of rosemary and detail several studies that investigate rosemary to improve in vivo GI health.

Pharmacokinetic characterization of carnosol from rosemary (Salvia Rosmarinus) in male C57BL/6 mice and inhibition profile in human cytochrome P450 enzymes.

Rosemary (Salvia Rosmarinus) is a rich source of dietary diterpenes with carnosol as one of the major polyphenols used to standardize rosemary extracts approved as a food preservative, however, at present there is not any information on the murine pharmacokinetic profile of carnosol or its potential for drug interactions. The present study utilizes cell-free, cell-based, and animal-based experiments to define the pharmacokinetic profile of the food based phytochemical carnosol. Mice were administered carnosol (100 mg/kg body weight) by oral gavage and plasma levels were analyzed by LC-MS/MS to establish a detailed pharmacokinetic profile. The maximum plasma concentration exceeded 1 µM after a single administration. The results are significant as they offer insights on the potential for food-drug interactions between carnosol from rosemary and active pharmaceutical ingredients. Carnosol was observed to inhibit selected CYP450 enzymes and modulate metabolic enzymes and transporters in in vitro assays.

Pharmacokinetic Analysis of Carnosic Acid and Carnosol in Standardized Rosemary Extract and the Effect on the Disease Activity Index of DSS-Induced Colitis.

Rosemary extract (RE) is an approved food preservative in the European Union and contains dietary phytochemicals that are beneficial for gastrointestinal health. This study investigated the effects of RE on dextran sodium sulfate (DSS)-induced colitis and also determined the pharmacokinetics of dietary phytochemicals administered to mice via oral gavage. Individual components of rosemary extract were separated and identified by LC-MS/MS. The pharmacokinetics of two major diterpenes from RE, carnosic acid (CA) and carnosol (CL), administered to mice via oral gavage were determined. Then, the effect of RE pre-treatment on the disease activity index (DAI) of DSS-induced colitis in mice was investigated. The study determined that 100 mg/kg RE significantly improved DAI in DSS-induced colitis compared to negative control. Sestrin 2 protein expression, which increased with DSS exposure, was reduced with RE treatment. Intestinal barrier integrity was also shown to improve via fluorescein isothiocyanate (FITC)-dextran administration and Western blot of zonula occludens-1 (ZO-1), a tight junction protein. Rosemary extract was able to improve the DAI of DSS-induced colitis in mice at a daily dose of 100 mg/kg and showed improvement in the intestinal barrier integrity. This study suggests that RE can be an effective preventative agent against IBD.

Covalent Modification of Proteins by Plant-Derived Natural Products: Proteomic Approaches and Biological Impacts.

Plant-derived natural products (NPs) with electrophilic functional groups engage various subsets of the proteome via covalent modification of nucleophilic cysteine residues. This electrophile-nucleophile interaction can change protein conformation, alter protein function, and modulate their biological action. The biological significance of these covalent protein modifications in health and disease is increasingly recognized. One way to understand covalent NP-protein interactions is to utilize traditional proteomics and modern mass spectrometry (MS)-based proteomic strategies. These strategies have proven effective in uncovering specific NP protein targets and are critical first steps that allow for a much deeper understanding of the ability of NPs to modulate cellular processes. Here, plant-derived NPs that covalently modify proteins are reviewed, the biological significance of these covalent modifications, and the different proteomic strategies that have been employed to study these NP-protein interactions.

Inhibition of CDK2/CyclinE1 by xanthones from the mangosteen (Garcinia mangostana): a structure-activity relationship study.

Uncontrolled regulation of cyclin dependent kinases (CDKs) has negative implications in many cancers and malignancies and has recently led to the approval of select CDK inhibitors. Herein we present data reporting that xanthones, a class of compounds isolated from the purple mangosteen (Garcinia mangostana) fruit, can inhibit CDK2/CyclinE1. We evaluated nine different xanthones, including α-mangostin, ß-mangostin, γ-mangostin, gartanin, 8-desoxygartanin, garcinone C, garcinone D, 9-hydroxycalabaxanthone, and 3-isomangostin for toxicity in 22Rν1 (prostate cancer cells) and MDA-MB-231 (breast cancer cells). All compounds dose-dependently inhibited the viability of both cell lines. A cell free biochemical assay was performed to determine if selected phytochemicals inhibited CDK2/CyclinE1. γ-Mangostin and α-mangostin were the strongest inhibitors, respectively. The results suggest that the position of key functional groups including hydroxyl and isoprenyl groups contribute to the CDK2 inhibitory effect. Taken together, the evidence suggests that xanthones can directly target CDK2 providing a possible explanation for their therapeutic potential.

Structure activity relationship of xanthones for inhibition of Cyclin Dependent Kinase 4 from mangosteen (Garcinia mangostana L.).

The mangosteen fruit is a popular Southeast Asian fruit consumed for centuries. There have been a variety of xanthones isolated from the fruit, bark, roots and leaves with each having unique chemical and physical properties. Previously, the most abundant xanthone α-mangostin has been shown to inhibit CDK4. Herein we describe the role of selected xanthones from the mangosteen inhibiting CDK4. The evidence we provide here is that key functional groups are required to inhibit the CDK4 protein to prevent the phosphorylation of downstream targets critical to inhibiting uncontrolled cell cycle progression. To define the properties of xanthones for inhibiting CDK4 we utilized a cell free biochemical assay to identify inhibitors of CDK4. The following xanthones were used for the analysis: α-mangostin, ß-mangostin, γ-mangostin, gartanin, 8-desoxygartanin, garcinone C and garcinone D, 9-hydroxycalabaxanthone, and 3-isomangostin These results further substantiate the unique pharmacological properties of individual xanthones and how a mixture of xanthones may be responsible for a multi-targeted effect in cell based pharmacology systems.

Oregano (Origanum vulgare) extract for food preservation and improvement in gastrointestinal health.

The Mediterranean diet has long been known to provide a variety of health benefits such as cardiovascular protection, cancer prevention, and lowering gastrointestinal inflammation. Oregano (Origanum vulgare) is an herb prominent in the Mediterranean diet, and has been shown to possess several bioactive properties including anti-oxidant, anti-microbial, anti-inflammatory, and analgesic properties. The anti-oxidant and anti-microbial properties of oregano also make it a strong candidate as a natural food preservative. Because of the recent public concern with synthetic food preservatives, natural alternatives are increasingly being evaluated for effective food preservation. Oregano extract (OE) and essential oil (OEO) are two such agents that have shown promise as natural food preservatives. Additionally, oregano is being evaluated for its positive effect on gastrointestinal health, suggesting an additional benefit of food preservation with oregano. This review will describe in vitro studies related to the anti-microbial and anti-oxidant properties of oregano along with food preservation studies with oregano in various model food matrices. The major phytochemical content reported for OE and OEO will also be outlined to highlight the importance of characterizing the extract that is used, since the extraction process can have a significant effect on the phytochemicals therein. Finally, in vivo studies that investigate the gastrointestinal health benefits of oregano, specifically against inflammation, will be addressed to show the impact of oregano on gastrointestinal health.

Carnosol, a dietary diterpene from rosemary (Rosmarinus officinalis) activates Nrf2 leading to sestrin 2 induction in colon cells.

BACKGROUND: Rosemary is abundant with phytochemicals and has recently been approved as an antioxidant food preservative in the European Union. The safety of rosemary is well established, however, the benefits on gastrointestinal health are less known. Our overall hypothesis is that the phytochemicals in rosemary including carnosol have the potential to promote gastrointestinal health by activation of the antioxidant sestrin-2 when consumed in our diet. METHODS: Colon cells HCT116 and SW480 were treated with carnosol and evaluated by MTT, immunofluorescence, ELISA, and Western blot analysis to understand the modulation of the PERK/Nrf2/Sestrin-2 pathway. RESULTS: Carnosol was found to modulate PERK and increase the concentration of nuclear Nrf2. Furthermore, a downstream marker of Nrf2 expression, Sestrin-2 was shown to be upregulated. CONCLUSION: Based on these observations carnosol modulates the PERK and Nrf2 pathways along with increased expression of sestrin-2, a known stress inducible antioxidant.

Scale, mergers and efficiency: the case of Dutch housing corporations.

The efficiency of social housing providers is a contentious issue. In the Netherlands, there is a widespread belief that housing corporations have substantial potential for efficiency improvements. A related question is whether scale influences efficiency, since recent decades have shown a trend of mergers among corporations. This paper offers a framework to assess the effects of scale and mergers on the efficiency of Dutch housing corporations by using both a data envelopment analysis and a stochastic frontier analysis, using panel data for 2001-2012. The results indicate that most housing corporations operate under diseconomies of scale, implying that merging would be undesirable in most cases. However, merging may have beneficial effects on pure technical efficiency as it forces organizations to reconsider existing practices. A data envelopment analysis indeed confirms this hypothesis, but these results cannot be replicated by a stochastic frontier analysis, meaning that the evidence for this effect is not robust.