Micro RNA facilitated chemoresistance in gastric cancer: a novel biomarkers and potential therapeutics

Introduction: In spite of the substantial advances in clinical practice, Gastric cancer (GC) remains the third leading cause of cancer death worldwide. The incidence of drug resistance remains a hindrance to effective treatment for GC. Although the molecular mechanisms of chemoresistance have broadly studied, the gene regulation and expression mechanisms of miRNA have not entirely understood. Methods: Online databases of PubMed, Scopus, Google Scholar, and Embase databases were searched to retrieve relevant publications. The following keywords were used: MicroRNA, Noncoding RNA, miRNA, Gastric cancer, drug resistance, and chemoresistance. Results: miRNAs play a pivotal role in the initiation, progression of tumor and metastasis, as well as in the development of pathways mediating resistance to chemotherapy in GC. Unluckily, to date, there is no consistent, reliable biomarker available to predict the response of chemotherapy before the start of the treatment. Discussion: In this review, we would like to provide an overview of the miRNAs and miRNA facilitated chemoresistance machinery in GC to develop a personalized treatment to overcome GC drug resistance

New Insights into the Potential Roles of 3-Iodothyronamine (T1AM) and Newly Developed Thyronamine-Like TAAR1 Agonists in Neuroprotection

3-Iodothyronamine (T1AM) is an endogenous high-affinity ligand of the trace amine-associated receptor 1 (TAAR1), detected in mammals in many organs, including the brain. Recent evidence indicates that pharmacological TAAR1 activation may offer a novel therapeutic option for the treatment of a wide range of neuropsychiatric and metabolic disorders. To assess potential neuroprotection by TAAR1 agonists, in the present work, we initially investigated whether T1AM and its corresponding 3-methylbiaryl-methane analog SG-2 can improve learning and memory when systemically administered to mice at submicromolar doses, and whether these effects are modified under conditions of MAO inhibition by clorgyline. Our results revealed that when i.p. injected to mice, both T1AM and SG-2 produced memory-enhancing and hyperalgesic effects, while increasing ERK1/2 phosphorylation and expression of transcription factor c-fos. Notably, both compounds appeared to rely on the action of ubiquitous enzymes MAO to produce the corresponding oxidative metabolites that were then able to activate the histaminergic system. Since autophagy is key for neuronal plasticity, in a second line of experiments we explored whether T1AM and synthetic TAAR1 agonists SG1 and SG2 were able to induce autophagy in human glioblastoma cell lines (U-87MG). After treatment of U-87MG cells with 1 μM T1AM, SG-1, SG-2 transmission electron microscopy (TEM) and immunofluorescence (IF) showed a significant time-dependent increase of autophagy vacuoles and microtubule-associated protein 1 light chain 3 (LC3). Consistently, Western blot analysis revealed a significant increase of the LC3II/LC3I ratio, with T1AM and SG-1 being the most effective agents. A decreased level of the p62 protein was also observed after treatment with T1AM and SG-1, which confirms the efficacy of these compounds as autophagy inducers in U-87MG cells. In the process to dissect which pathway induces ATG, the effects of these compounds were evaluated on the PI3K-AKT-mTOR pathway. We found that 1 μM T1AM, SG-1 and SG-2 decreased pAKT/AKT ratio at 0.5 and 4 h after treatment, suggesting that autophagy is induced by inhibiting mTOR phosphorylation by PI3K-AKT-mTOR pathway. In conclusion, our study shows that T1AM and thyronamine-like derivatives SG-1 and SG-2 might represent valuable tools to therapeutically intervene with neurological disorder

Hit-to-Lead Optimization of Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists with a Diphenylmethane-Scaffold: Design, Synthesis, and Biological Study

The trace amine-associated receptor 1 (TAAR1) is a G-protein-coupled receptors (GPCR) potently activated by a variety of molecules besides trace amines (TAs), including thyroid hormone-derivatives like 3-iodothyronamine (T1AM), catechol-O-methyltransferase products like 3-methoxytyramine, and amphetamine-related compounds. Accordingly, TAAR1 is considered a promising target for medicinal development. To gain more insights into TAAR1 physiological functions and validation of its therapeutic potential we recently developed a new class of thyronamine-like derivatives. Among them compound SG2 showed high affinity and potent agonist activity at mouse TAAR1. In the present work we describe design, the synthesis and SAR study of a new series of compounds (1-16) obtained by introducing specific structural changes at key points of our lead-compound SG2 skeleton. Five of the newly synthesized compounds displayed mTAAR1 agonist activity higher than both SG2 and T1AM. Selected diphenylmethane analogs, namely 1 and 2, showed potent functional activity in in vitro and in vivo models

Effect of Feijoa Sellowiana Acetonic Extract on Proliferation Inhibition and Apoptosis Induction in Human Gastric Cancer Cells

Gastric cancer (GC) still represents a relevant health problem in the world for both incidence and mortality rates. Many studies underlined that natural products consumption could reduce GC risk, indicating flavonoids as responsible for the beneficial eects through the modulation of several biological processes, such as the inhibition of cancer antioxidant defense and induction of apoptosis. Since Feijoa sellowiana fruit is known to contain high amounts of flavonoids, among which is flavone, we evaluated the antiproliferative and proapoptotic eects of F. sellowiana acetonic extract on GC cell lines through MTS and Annexin-V FITC assays. Among three GC cell lines tested, SNU-1 results being sensitive to both the F. sellowiana acetonic extract and synthetic flavone, which was used as the reference treatment. Moreover, we evaluated their antioxidant eects, assessing the activity of the antioxidant enzymes supeoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) in polymorphonuclear cells. We found a significant increase of their activity after exposure to both F. sellowiana acetonic extract and flavone, supporting the idea that a diet that includes flavone-rich fruits could be of benefit for health. In addition to this antioxidant eect on normal cells, this study indicates, for the first time, an anticancer eect of F. sellowiana acetonic extract in GC cells

Role of IL-6/STAT3 Axis in Resistance to Cisplatin in Gastric Cancers

Gastric cancer, the second most common cause of death worldwide, is characterized by poor prognosis and low responsiveness to chemotherapy. Indeed, multidrug resistance, based mainly on cellular and molecular factors, remains one of the most limiting factors of the current approach to gastric cancer (GC) therapy. We employed a comprehensive gene expression analysis through data mining of publicly available databases to assess the role of the signal transducer and activator of transcription 3 (STAT3) in gastric cancer drug efficiency. It has been proposed that gastric cancer cells are less sensitive to these drugs because they develop resistance to these agents through activating alternative signalling pathways responsible for overcoming pharmacological inhibition. Our study evaluated the hypothesis that activating STAT3 signalling in response to cisplatin reduces the reaction to the drug. Consistent with this hypothesis, inhibition of interleukin 6 (IL-6)/STAT3 in combination therapy with cisplatin prevented both STAT3 activation and more lethality than induction by a single agent. The data suggest that the IL-6/STAT3 axis block associated with cisplatin treatment may represent a strategy to overcome resistance

Gastric Cancer Stem Cells: A Glimpse on Metabolic Reprogramming

Gastric cancer (GC) is one of the most widespread causes of cancer-related death worldwide. Recently, emerging implied that gastric cancer stem cells (GCSCs) play an important role in the initiation and progression of GC. This subpopulation comprises cells with several features, such as self-renewal capability, high proliferating rate, and ability to modify their metabolic program, which allow them to resist current anticancer therapies. Metabolic pathway intermediates play a pivotal role in regulating cell differentiation both in tumorigenesis and during normal development. Thus, the dysregulation of both anabolic and catabolic pathways constitutes a significant opportunity to target GCSCs in order to eradicate the tumor progression. In this review, we discuss the current knowledge about metabolic phenotype that supports GCSC proliferation and we overview the compounds that selectively target metabolic intermediates of CSCs that can be used as a strategy in cancer therapy

Role of IL-6/STAT3 Axis in Resistance to Cisplatin in Gastric Cancers

Gastric cancer, the second most common cause of death worldwide, is characterized by poor prognosis and low responsiveness to chemotherapy. Indeed, multidrug resistance, based mainly on cellular and molecular factors, remains one of the most limiting factors of the current approach to gastric cancer (GC) therapy. We employed a comprehensive gene expression analysis through data mining of publicly available databases to assess the role of the signal transducer and activator of transcription 3 (STAT3) in gastric cancer drug efficiency. It has been proposed that gastric cancer cells are less sensitive to these drugs because they develop resistance to these agents through activating alternative signalling pathways responsible for overcoming pharmacological inhibition. Our study evaluated the hypothesis that activating STAT3 signalling in response to cisplatin reduces the reaction to the drug. Consistent with this hypothesis, inhibition of interleukin 6 (IL-6)/STAT3 in combination therapy with cisplatin prevented both STAT3 activation and more lethality than induction by a single agent. The data suggest that the IL-6/STAT3 axis block associated with cisplatin treatment may represent a strategy to overcome resistance

Studio dei processi di emocoagulazione mediante Quartz Crystal Microbalance

Lo studio ed il controllo dei processi di fibrinolisi e coagulazione del sangue rivestono un vasto interesse medico e clinico in particolar modo per quei pazienti con patologie cardiovascolari, portatori di protesi cardiache ed in tutti quei trattamenti nei quali il sangue entra a contatto con superfici artificiali. L'impiego di anticoagulanti, tipicamente utilizzati in questi casi per prevenire o minimizzare gli indesiderati ma inevitabili effetti di clothing richiede il frequente controllo di alcuni parametri ematici (ad es. tempo di coagulazione) pena l'instaurarsi di una serie di patologie che possono gravemente compromettere la salute del paziente. Il tempo di coagulazione del sangue viene tipicamente valutato dalla misura della variazione della sua viscosità su processi di coagulazione indotti mediante attivatori interfasali o enzimi. Quantunque esistano ben note procedure cliniche strumentali ad hoc, recentemente si sta affacciando l'approccio alternativo basato sui biosensori [1-3], nell'intento di produrre dispositivi avanzati in grado di fornire con tempestività e precisioni parametri ematoclinici anche in regime di self-analysis. Il presente lavoro di ricerca è proprio rivolto allo sviluppo ed utilizzo di un originale sensore basato su microbilancia a cristallo di quarzo, in grado di seguire le cinetiche di emocoagulazione mediante la deposizione del campione stesso sulla superficie del cristallo e la contestuale acquisizione dei relativi spettri di ammittanza. Il sistema messo a punto è in grado di seguire il processo di coagulazione di campioni di sangue del volume di pochi microlitri sia indotto da superficie sia tramite trombina. In plasma umano, la fase di coagulazione è evidenziata da una decisa diminuzione dei picchi di ammittanza con parallela diminuzione della frequenza di risonanza e del fattore Q del sistema cristallo di quarzo - campione di sangue, con cinetiche analoghe a quelle osservate con procedure strumentali standard. Contrariamente a quest'ultime, viceversa, il sensore sviluppato nel presente lavoro di ricerca offre anche la possibilità di evidenziare l'ulteriore processo conseguente la produzione di fibrina ossia la formazione del vero e proprio coagulo, e di fornire utili indicazione sul grado di rigidità dello stesso. Quest'ultimo aspetto appare poco esplorato nella relativa letteratura scientifica e quindi rappresenta un aspetto fortemente originale della presente ricerca. [1] Hansson, K.M. Vikinge, T.P. Ronby, M. Tengvall, P. Lundstrom, L. Johansen, K. Lindahl, T.L., Biosens. Bioelectron., 14, 671 (1999). [2] Puckett, L.G. Barrett, G. Kouzoudis, D. Grimes, C. Bachas, L.G., Biosens. Bioelectron., 18, 675 (2003). [3] Andersson, M. Andersson, J. Sellborn, A. Berglin, M. Nilsson, B. Elwing, H., Biosens. Bioelectron., 21, 79 (2005)

Biomonitoring of Soil Quality By Soil FAUNA

The awareness of the problems related to soil pollution, in heavily populated areas, has led to a growing interest in the soil fauna study; the biological quality of the soil through the soil fauna is, to date, one of the most approved methodologies. Analyses were carried out as part of the environmental monitoring inside the farm “Il Querceto” (Italy), characterized by both forest and agricultural areas. The aim was to verify the evolution of some biological characteristics of the farm’s soil concerned by the burial of an underground pipeline. The monitoring of soils was performed by using the index of Biological Quality of Soil (QBS-ar); proposed by Prof. Vittorio Parisi (University of Parma); it is based on analysis of all groups of microarthropod in the soil (insects, arachnids, myriapods, crustaceans). The changes in the populations of some microarthropod groups (Acari Oribatei, Diptera, Pauropodi, Collembola, isopods, annelids, Coleoptera, Hymenoptera) in relation to different conditions of each soil have been analyzed. A different score, corresponding to stated numerical values, defined Ecomorphological index (EMI), has been attributed to each biological form. Each microarthropod group in the soil sample receives an EMI score from 1 to 20, according to its adaptation to the soil environment. The QBS index is the sum of EMI scores; the underlying concept is that soil quality is positively correlated with the number of microarthropod groups that are well adapted to soil habitats. Thus, the QBS index is a measure of how well the soil fauna adapt to the particular soil conditions. This study has been performed in 4 steps: Sampling; Extraction of soil fauna; Analysis of soil fauna; Calculation of QBS-ar-class quality. In this specific case the QBS-ar allowed to discriminate the impact of oil pipeline in both the forest and agricultural areas