Yarrow supercritical extract exerts antitumoral properties by targeting lipid metabolism in pancreatic cancer

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Metabolic reprogramming is considered a hallmark of cancer. Currently, the altered lipid metabolism in cancer is a topic of interest due to the prominent role of lipids regulating the progression of various types of tumors. Lipids and lipid-derived molecules have been shown to activate growth regulatory pathways and to promote malignancy in pancreatic cancer. In a previous work, we have described the antitumoral properties of Yarrow (Achillea Millefolium) CO 2 supercritical extract (Yarrow SFE) in pancreatic cancer. Herein, we aim to investigate the underlaying molecular mechanisms by which Yarrow SFE induces cytotoxicity in pancreatic cancer cells. Yarrow SFE downregulates SREBF1 and downstream molecular targets of this transcription factor, such as fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD). Importantly, we demonstrate the in vivo effect of Yarrow SFE diminishing the tumor growth in a xenograft mouse model of pancreatic cancer. Our data suggest that Yarrow SFE can be proposed as a complementary adjuvant or nutritional supplement in pancreatic cancer therapyThis work was supported by Ministerio de Economía y Competitividad del Gobierno de España (MINECO, Plan Nacional I+D+i AGL2013-48943-C2 and AGL2016-76736-C3), Gobierno regional de la Comunidad de Madrid (P2013/ABI-2728, ALIBIRD-CM) and EU Structural Funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscri

Marigold Supercritical Extract as Potential Co-adjuvant in Pancreatic Cancer: The Energetic Catastrophe Induced via BMP8B Ends Up With Autophagy-Induced Cell Death

The recent development of powerful “omics” technologies (genomics, transcriptomics, proteomics, metabolomics, and lipidomics) has opened new avenues in nutritional sciences toward precision nutrition, which is a genotype-directed nutrition that takes into account the differential responses to nutritional interventions based on gene variation (nutrigenetics) and the effect of nutrients on gene expression (nutrigenomics). Current evidence demonstrates that up to one third of the deaths caused by cancer could be prevented by acting on key risk factors, with diet being one of the most important risk factors due to its association with obesity. Additional factors such as composition of gut microbiome, the immune system, and the nutritional status will have an impact on the final outcome. Nutrient components and bioactive compounds from natural sources can have an impact on cancer progression or even the risk of cancer development by regulating gene expression and/or associated risk factors such as obesity and chronic inflammation. Nowadays, among the different methods to produce natural extracts, the green technology of supercritical fluid extraction (SFE) is quite popular, with a special interest on the use of supercritical CO2 for the extraction of compounds with low polarity. The success of nutritional interventions based on the use of nutraceuticals requires several steps: (i) in vitro and preclinical demonstration of their antitumoral effects; (ii) knowledge of their mechanism of action and molecular targets, which will allow for identification of the specific subgroups of patients who will benefit from them; (iii) the study of genetic variants associated with the differential responses; and (iv) innovative approaches of formulations to improve the in vivo bioavailability of the bioactive ingredients. Herein, we investigate the antitumoral properties and mechanism of action of a supercritical CO2 extract from Calendula officinalis, commonly known as marigold (marigold SFE) in the context of pancreatic cancer. Mechanistically, marigold SFE induces the expression of BMP8B, which leads to an energetic catastrophe ending up with autophagy-induced cell death (AICD). As metabolic reprogramming is a well-recognized hallmark of cancer, the direct impact of marigold SFE on pancreatic cancer cell metabolism encourages further research of its potential as a coadjuvant in pancreatic cancer therapy. Finally, we discuss innovative formulation approaches to augment the clinical therapeutic potential of marigold SFE in nutritional interventionsThis work was supported by the Spanish Ministry of Science (Plan Nacional I + D + i AGL2016-76736-C3), Regional Government of Community of Madrid (P2018/BAA-4343- ALIBIRD2020-CM), Ramón Areces Foundation, and EU Structural Fund

CALHM1 and its polymorphism P86L differentially control Ca²⁺ homeostasis, mitogen-activated protein kinase signaling, and cell vulnerability upon exposure to amyloid β

The mutated form of the Ca2+ channel CALHM1 (Ca2+ homeostasis modulator 1), P86L-CALHM1, has been correlated with early onset of Alzheimer’s disease (AD). P86L-CALHM1 increases production of amyloid beta (Ab) upon extracellular Ca2+ removal and its subsequent addback. The aim of this study was to investigate the effect of the overexpression of CALHM1 and P86L-CALHM, upon Ab treatment, on the following: (i) the intracellular Ca2+ signal pathway; (ii) cell survival proteins ERK1/2 and Ca2+/cAMP response element binding (CREB); and (iii) cell vulnerability after treatment with Ab. Using aequorins to measure the effect of nuclear Ca2+ concentrations ([Ca2+]n) and cytosolic Ca2+ concentrations ([Ca2+]c) on Ca2+ entry conditions, we observed that baseline [Ca2+]n was higher in CALHM1 and P86L-CALHM1 cells than in control cells. Moreover, exposure to Ab affected [Ca2+]c levels in HeLa cells overexpressing CALHM1 and P86L-CALHM1 compared with control cells. Treatment with Ab elicited a significant decrease in the cell survival proteins p-ERK and p-CREB, an increase in the activity of caspases 3 and 7, and more frequent cell death by inducing early apoptosis in P86L-CALHM1- overexpressing cells than in CALHM1 or control cells. These results suggest that in the presence of Ab, P86L-CALHM1 shifts the balance between neurodegeneration and neuronal survival toward the stimulation of pro-cytotoxic pathways, thus potentially contributing to its deleterious effects in AD.This work was partly supported by the following grants: Ministerio de Economía y Competitividad, FPU Program, Refs. AP2009/0343 (AJMO) and AP2010/1219 (IB). ARN: FIS PI10/01426. MGL: Ministerio de Economía y Competitividad, Ref. SAF2012-23332. MFCA: Consolidación de grupos de investigación UAM-CAM 1004040047. We also thank Fundación Teófilo Hernando, Madrid, Spain, for their continued suppor

Marigold supercritical extracts as a potencial anticancer agent

Resumen del trabajo presentado a las III Jornadas Científicas CIAL Fórum, celebradas del 22 al 23 de noviembre de 2018 en el Instituto de Investigación en Ciencias de la Alimentación (CIAL).Calendula officinalis, commonly known as marigold, has been used in traditional medicine for its anti-inflammatory and antiseptic virtues, and against gastric spasms. Here, we had obtained marigold extracts through supercritical CO2 extraction (SFE) and through ultrasonic assisted extraction (UAE), and we had characterized their bioactivity in the framework of cancer. We have found that marigold UAE extracts have a higher content of phenolic and flavonoid than marigold SFE extract, as well as a higher antioxidant activity. On the contrary, marigold SFE extract has a stronger cytotoxic and antiproliferative activity against pancreatic tumor-derived cells, being independent to its antioxidant effect. These results suggest that marigold SFE could be considered for further studies as a potential nutritional supplement which could improve current cancer therapies.This work has been supported by the Spanish MINECO (AGL2016-76736-C3-3-R MINECO/FEDER), Regional government Comunidad de Madrid (P2013/ABI-2728, ALIBIRD-CM) and EU Structural Funds.Peer reviewe

Improving in vivo efficacy of bioactive molecules: An overview of potentially antitumor phytochemicals and currently available lipid-based delivery systems

Cancer is among the leading causes of morbidity and mortality worldwide. Many of the chemotherapeutic agents used in cancer treatment exhibit cell toxicity and display teratogenic effect on nontumor cells. Therefore, the search for alternative compounds which are effective against tumor cells but reduce toxicity against nontumor ones is of great importance in the progress or development of cancer treatments. In this sense, scientific knowledge about relevant aspects of nutrition intimately involved in the development and progression of cancer progresses rapidly. Phytochemicals, considered as bioactive ingredients present in plant products, have shown promising effects as potential therapeutic/preventive agents on cancer in several in vitro and in vivo assays. However, despite their bioactive properties, phytochemicals are still not commonly used in clinical practice due to several reasons, mainly attributed to their poor bioavailability. In this sense, new formulation strategies are proposed as carriers to improve their bioefficacy, highlighting the use of lipid-based delivery systems. Here, we review the potential antitumoral activity of the bioactive compounds derived from plants and the current studies carried out in animal and human models. Furthermore, their association with lipids as a formulation strategy to enhance their efficacy in vivo is also reported. The development of high effective bioactive supplements for cancer treatment based on the improvement of their bioavailability goes through this association.This work has been supported by Ministerio de Economía y Competitividad del Gobierno de España (MINECO, Plan Nacional I+D+i AGL2013-48943-C2-2-R), Gobierno Regional de la Comunidad de Madrid (P2013/ABI-2728, ALIBIRD-CM), and EU Structural Funds. Marta Corzo Martínez also thanks Ministerio de Economía y Competitividad (Spain) for her Juan de la Cierva contract.Peer reviewe

Yarrow supercritical extract ameliorates the metabolic stress in a model of obesity induced by high-fat diet

This article belongs to the Special Issue Dietary Patterns, Dietary Indices for Colorectal Cancer, Mortality and the Related Disease.Nowadays, obesity and its associated metabolic disorders, including diabetes, metabolic syndrome, cardiovascular disease, or cancer, continue to be a health epidemic in westernized societies, and there is an increased necessity to explore anti-obesity therapies including pharmaceutical and nutraceutical compounds. Considerable attention has been placed on the identification of bioactive compounds from natural sources to manage the metabolic stress associated with obesity. In a previous work, we have demonstrated that a CO2 supercritical fluid extract from yarrow (Yarrow SFE), downregulates the expression of the lipogenic master regulator SREBF1 and its downstream molecular targets FASN and SCD in a tumoral context. Since obesity and diabetes are strongly considered high-risk factors for cancer development, herein, we aimed to investigate the potential therapeutic role of Yarrow SFE in the metabolic stress induced after a high-fat diet in mice. For this purpose, 32 C57BL/6 mice were distributed in four groups according to their diets: standard diet (SD); SD supplemented with Yarrow SFE (SD + Yarrow); high-fat diet (HFD); and HFD supplemented with Yarrow SFE (HFD + Yarrow). Fasting glycemia, insulin levels, homeostasis model assessment for insulin resistance (HOMA-IR), lipid profile, gene expression, and lipid content of liver and adipose tissues were analyzed after three months of treatment. Results indicate improved fasting glucose levels in plasma, enhanced insulin sensitivity, and diminished hypercholesterolemia in the HFD + Yarrow group compared to the HFD group. Mechanistically, Yarrow SFE protects liver from steatosis after the HFD challenge by augmenting the adipose tissue buffering capacity of the circulating plasma glucose.This work was supported by the Spanish Ministry of Science (Plan Nacional I + D + i AGL2016-76736-C3), Regional Government of Community of Madrid (P2013/ABI-2728, ALIBIRD-CM; P2018/BAA-4343-ALIBIRD2020-CM), the Ramón Areces Foundation, and the EU Structural Funds.Peer reviewe

Biological activities of Asteraceae (Achillea millefolium and Calendula officinalis) and Lamiaceae (Melissa officinalis and Origanum majorana) plant extracts

Asteraceae (Achillea millefolium and Calendula officinalis) and Lamiaceae (Melissa officinalis and Origanum majorana) extracts were obtained by applying two sequential extraction processes: supercritical fluid extraction with carbon dioxide, followed by ultrasonic assisted extraction using green solvents (ethanol and ethanol:water 50:50). The extracts were analyzed in terms of the total content of phenolic compounds and the content of flavonoids; the volatile oil composition of supercritical extracts was analyzed by gas chromatography and the antioxidant capacity and cell toxicity was determined. Lamiaceae plant extracts presented higher content of phenolics (and flavonoids) than Asteraceae extracts. Regardless of the species studied, the supercritical extracts presented the lowest antioxidant activity and the ethanol:water extracts offered the largest, following the order Origanum majorana > Melissa officinalis ≈ Achillea millefolium > Calendula officinalis. However, concerning the effect on cell toxicity, Asteraceae (especially Achillea millefolium) supercritical extracts were significantly more efficient despite being the less active as an antioxidant agent. These results indicate that the effect on cell viability is not related to the antioxidant activity of the extracts.The authors gratefully acknowledge the financial support from Ministerio de Economía y Competitividad of Spain (project AGL2013-48943-C2) and the Comunidad Autónoma de Madrid (ALIBIRD, project number S2013/ABI-2728).Peer reviewe

Identification of antitumoral agents against human pancreatic cancer cells from Asteraceae and Lamiaceae plant extracts

Abstract Background Pancreatic cancer is one of the most aggressive and mortal cancers. Although several drugs have been proposed for its treatment, it remains resistant and new alternatives are needed. In this context, plants and their derivatives constitute a relevant source of bioactive components which might efficiently inhibit tumor cell progression. Methods In this study, we have analyzed the potential anti-carcinogenic effect of different Asteraceae (Achillea millefolium and Calendula officinalis) and Lamiaceae (Melissa officinalis and Origanum majorana) plant extracts obtained by different green technologies (Supercritical CO2 Extraction –SFE- and Ultrasonic Assisted Extraction –UAE-) to identify efficient plant extracts against human pancreatic cancer cells that could constitute the basis of novel treatment approaches. Results Asteraceae extracts showed better results as antitumoral agents than Lamiaceae by inducing cytotoxicity and inhibiting cell transformation, and SFE extracts were most efficient than UAE extracts. In addition, SFE derived plant extracts from Achillea millefolium and Calendula officinalis displayed synergism with the chemotherapeutic 5-Fluororacil. Conclusion These results show how Yarrow and Marigold SFE-derived extracts can inhibit pancreatic cancer cell growth, and could be proposed for a comprehensive study to determine the molecular mechanisms involved in their bioactivity with the final aim to propose them as potential adjuvants in pancreatic cancer therapy