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Targeting Autophagy in Breast Cancer Cocco, Stefania; Leone, Alessandra; Piezzo, Michela ...
International journal of molecular sciences,
10/2020, Letnik:
21, Številka:
21
Journal Article
Recenzirano
Odprti dostop
Breast cancer is a heterogeneous disease consisting of different biological subtypes, with differences in terms of incidence, response to diverse treatments, risk of disease progression, and sites of ...metastases. In the last years, several molecular targets have emerged and new drugs, targeting PI3K/Akt/mTOR and cyclinD/CDK/pRb pathways and tumor microenvironment have been integrated into clinical practice. However, it is clear now that breast cancer is able to develop resistance to these drugs and the identification of the underlying molecular mechanisms is paramount to drive further drug development. Autophagy is a highly conserved homeostatic process that can be activated in response to antineoplastic agents as a cytoprotective mechanism. Inhibition of autophagy could enhance tumor cell death by diverse anti-cancer therapies, representing an attractive approach to control mechanisms of drug resistance. In this manuscript, we present a review of autophagy focusing on its interplay with targeted drugs used for breast cancer treatment.
Consumers highly appreciate table grapes for their pleasant sensory attributes and as good sources of nutritional and functional compounds. This explains the rising market and global interest in this ...product. Along with other fruits and vegetables, table grapes are considerably perishable post-harvest due to the growth of undesired microorganisms. Among the microbial spoilers, Botrytis cinerea represents a model organism because of its degrading potential and the huge economic losses caused by its infection. The present review provides an overview of the recent primary physical, chemical, and biological control treatments adopted against the development of B. cinerea in table grapes to extend shelf life. These treatments preserve product quality and safety. This article also focuses on the compliance of different approaches with organic and sustainable production processes. Tailored approaches include those that rely on controlled atmosphere and the application of edible coating and packaging, as well as microbial-based activities. These strategies, applied alone or in combination, are among the most promising solutions in order to prolong table grape quality during cold storage. In general, the innovative design of applications dealing with hurdle technologies holds great promise for future improvements.
From a ‘farm to fork’ perspective, there are several phases in the production chain of fruits and vegetables in which undesired microbial contaminations can attack foodstuff. In managing these ...diseases, harvest is a crucial point for shifting the intervention criteria. While in preharvest, pest management consists of tailored agricultural practices, in postharvest, the contaminations are treated using specific (bio)technological approaches (physical, chemical, biological). Some issues connect the ‘pre’ and ‘post’, aligning some problems and possible solution. The colonisation of undesired microorganisms in preharvest can affect the postharvest quality, influencing crop production, yield and storage. Postharvest practices can ‘amplify’ the contamination, favouring microbial spread and provoking injures of the product, which can sustain microbial growth. In this context, microbial biocontrol is a biological strategy receiving increasing interest as sustainable innovation. Microbial-based biotools can find application both to control plant diseases and to reduce contaminations on the product, and therefore, can be considered biocontrol solutions in preharvest or in postharvest. Numerous microbial antagonists (fungi, yeasts and bacteria) can be used in the field and during storage, as reported by laboratory and industrial-scale studies. This review aims to examine the main microbial-based tools potentially representing sustainable bioprotective biotechnologies, focusing on the biotools that overtake the boundaries between pre- and postharvest applications protecting quality against microbial decay.
Abstract This work implemented a non-invasive volatile organic compounds (VOCs) monitoring approach to study how food components are metabolised by the gut microbiota in-vitro. The fermentability of ...a model food matrix rich in dietary fibre (oat bran), and a pure prebiotic (inulin), added to a minimal gut medium was compared by looking at global changes in the volatilome. The substrates were incubated with a stabilised human faecal inoculum over a 24-h period, and VOCs were monitored without interfering with biological processes. The fermentation was performed in nitrogen-filled vials, with controlled temperature, and tracked by automated headspace-solid-phase microextraction coupled with gas chromatography–mass spectrometry. To understand the molecular patterns over time, we applied a multivariate longitudinal statistical framework: repeated measurements—ANOVA simultaneous component analysis. The methodology was able to discriminate the studied groups by looking at VOCs temporal profiles. The volatilome showed a time-dependency that was more distinct after 12 h. Short to medium-chain fatty acids showed increased peak intensities, mainly for oat bran and for inulin, but with different kinetics. At the same time, alcohols, aldehydes, and esters showed distinct trends with discriminatory power. The proposed approach can be applied to study the intertwined pathways of gut microbiota food components interaction in-vitro.
The endocannabinoid system (ECS) exerts immunosuppressive effects, which are mostly mediated by cannabinoid receptor 2 (CBR2), whose expression on leukocytes is higher than CBR1, mainly localized in ...the brain. Targeted CBR2 activation could limit inflammation, avoiding CBR1-related psychoactive effects. Herein, we evaluated in vitro the biological activity of a novel, selective and high-affinity CBR2 agonist, called JT11, studying its potential CBR2-mediated anti-inflammatory effect. Trypan Blue and MTT assays were used to test the cytotoxic and anti-proliferative effect of JT11 in Jurkat cells. Its pro-apoptotic activity was investigated analyzing both cell cycle and poly PARP cleavage. Finally, we evaluated its impact on LPS-induced ERK1/2 and NF-kB-p65 activation, TNF-α, IL-1β, IL-6 and IL-8 release in peripheral blood mononuclear cells (PBMCs) from healthy donors. Selective CB2R antagonist SR144528 and CBR2 knockdown were used to further verify the selectivity of JT11. We confirmed selective CBR2 activation by JT11. JT11 regulated cell viability and proliferation through a CBR2-dependent mechanism in Jurkat cells, exhibiting a mild pro-apoptotic activity. Finally, it reduced LPS-induced ERK1/2 and NF-kB-p65 phosphorylation and pro-inflammatory cytokines release in human PBMCs, proving to possess in vitro anti-inflammatory properties. JT11 as CBR2 ligands could enhance ECS immunoregulatory activity and our results support the view that therapeutic strategies targeting CBR2 signaling could be promising for the treatment of chronic inflammatory diseases.
A geochemical study on fluids from selected spontaneous seepages and drilled wells was carried out together with geologic investigation and deep cross-sections reconstruction to examine the petroleum ...system in the western Northern Apennines foothills. The hydrocarbons occurring in the Miocene foredeep units that form the reservoirs are commonly interpreted as generated in a source/reservoir system. However, the low Total Organic Carbon, its elevated dilution in the sediment pile and the limited amount of successions that entered in the oil window indicate a low potential for the hydrocarbons generation. The structures deformation in the Northern Apennines foothills is mainly late Miocene to Pliocene in age and involves successions that are progressively younger towards southeast. The earlier structure forms the Salsomaggiore anticline in the western sector. The comparison of the fluids from the wells and the mud volcanoes shows high geochemical and thermal history similarities. Saline waters originate from the connate pore water entrapped in the Miocene reservoir rocks during their deposition. The gaseous hydrocarbons are a mixture of secondary biogenic methane and primary and secondary thermogenic gases. The associated oils show both early and late maturities. These evidences account for different generation and migration steps, depending on burial conditions and deformation time. The various reservoirs appear confined by the thrust detachment at different depths and by the occurrence of reactivated lateral ramps. These results suggest the occurrence of a common source rock deeper than the Tertiary reservoir units, which progressively entered in the oil window. This source rock could have wide lateral extension, at least comparable with the width of the studied area, and represent a prime exploration target to evaluate the undiscovered oil and gas resources.
•Fluids geochemistry from seeps and drilled wells in Northern Apennines foothills.•Structural and stratigraphic reconstruction of the petroleum system.•Various petroleum generation and migration phases during the foothills deformation.•High similarity of fluids geochemical and thermal histories along the studied area.•Wide lateral extension of a possible deep pre-Miocene source rock.
Prion protein (PrPC) localizes stably in lipid rafts microdomains and is able to recruit downstream signal transduction pathways by the interaction with promiscuous partners. Other proteins have the ...ability to occasionally be recruited to these specialized membrane areas, within multimolecular complexes. Among these, we highlight the presence of the low‐density lipoprotein receptor‐related protein 1 (LRP1), which was found localized transiently in lipid rafts, suggesting a different function of this receptor that through lipid raft becomes able to activate a signal transduction pathway triggered by specific ligands, including Tissue plasminogen activator (tPA). Since it has been reported that PrPC participates in the tPA‐mediated plasminogen activation, in this study, we describe the role of lipid rafts in the recruitment and activation of downstream signal transduction pathways mediated by the interaction among tPA, PrPC and LRP1 in human neuroblastoma SK‐N‐BE2 cell line. Co‐immunoprecipitation analysis reveals a consistent association between PrPC and GM1, as well as between LRP1 and GM1, indicating the existence of a glycosphingolipid‐enriched multimolecular complex. In our cell model, knocking‐down PrPC by siRNA impairs ERK phosphorylation induced by tPA. Moreover the alteration of the lipidic milieu of lipid rafts, perturbing the physical/functional interaction between PrPC and LRP1, inhibits this response. We show that LRP1 and PrPC, following tPA stimulation, may function as a system associated with lipid rafts, involved in receptor‐mediated neuritogenic pathway. We suggest this as a multimolecular signaling complex, whose activity depends strictly on the integrity of lipid raft and is involved in the neuritogenic signaling.
Prion protein (PrPC) localizes stably in lipid rafts microdomains and is able to recruit downstream signal transduction pathways by the interaction with promiscuous partners. It is known that tissue plasminogen activator (tPA) functions by binding a prion–plasminogen complex and forming activated plasmin and that tPA acts as a ligand for LRP1 (lipoprotein receptor‐related protein 1), leading to receptor recruitment in lipid rafts and inducing neurodifferentiation signaling.In this research we show that:
Knocking‐down PrP or LRP1 by siRNA impairs ERK phosphorylation induced by tPA.
Perturbation of lipid raft inhibits the binding of tPA to LRP1/PrP complex .
Inhibition of the interaction among PrP and LRP1 alters signaling mediated by tPA.
Thus we can say that PrP, LRP1 and tPA work in a single complex whose activity depends on lipid raft.
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