scholarly journals Interception of Signaling Circuits of Esophageal Adenocarcinoma Cells by Resveratrol Reveals Molecular and Immunomodulatory Signatures

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5811
Author(s):  
Hardika Dhir ◽  
Monica Choudhury ◽  
Ketki Patil ◽  
Candice Cheung ◽  
Adriana Bodlak ◽  
...  

Deregulation of signaling pathways due to mutations sets the cell on a path to neoplasia. Therefore, recent reports of increased mutations observed in esophageal tissue reflects the enhanced risk of tumor formation. In fact, adenocarcinoma of the esophagus has been on the rise lately. Increase in mortality due to a paucity of efficacious drugs for this cancer prompted us to discover molecular signatures to combat this malady. To this end, we chose resveratrol—a polyphenol with anticancer property—and studied its impact on three esophageal adenocarcinoma cell lines (OE33, OE19 and FLO-1) by multilevel profiling. Here, we show the impact of resveratrol on the viability of the three adenocarcinoma esophageal cell systems studied, at the cellular level. Furthermore, an analysis at the molecular level revealed that the action was through the programmed cell death pathway, resulting in an increase in apoptotic and caspase-positive cells. The impact on reactive oxygen species (ROS) and a decrease in Bcl2 levels were also observed. Moreover, proteomic profiling highlighted pivotal differentially regulated signaling molecules. The phenotypic effect observed in resveratrol-treated esophageal cells could be due to the stoichiometry per se of the fold changes observed in entities of key signaling pathways. Notably, the downregulation of Ku80 and other pivotal entities by resveratrol could be harnessed for chemo-radiation therapy to prevent DNA break repair after radiation therapy. Additionally, multilevel profiling has shed light on molecular and immune-modulatory signatures with implications for discovering novel treatments, including chemo-immunotherapy, for esophageal adenocarcinomas which are known to be aggressive cancers.

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 308
Author(s):  
Marion Buffard ◽  
Aurélien Naldi ◽  
Gilles Freiss ◽  
Marcel Deckert ◽  
Ovidiu Radulescu ◽  
...  

Spleen tyrosine kinase (SYK) can behave as an oncogene or a tumor suppressor, depending on the cell and tissue type. As pharmacological SYK inhibitors are currently evaluated in clinical trials, it is important to gain more information on the molecular mechanisms underpinning these opposite roles. To this aim, we reconstructed and compared its signaling networks using phosphoproteomic data from breast cancer and Burkitt lymphoma cell lines where SYK behaves as a tumor suppressor and promoter. Bioinformatic analyses allowed for unveiling the main differences in signaling pathways, network topology and signal propagation from SYK to its potential effectors. In breast cancer cells, the SYK target-enriched signaling pathways included intercellular adhesion and Hippo signaling components that are often linked to tumor suppression. In Burkitt lymphoma cells, the SYK target-enriched signaling pathways included molecules that could play a role in SYK pro-oncogenic function in B-cell lymphomas. Several protein interactions were profoundly rewired in the breast cancer network compared with the Burkitt lymphoma network. These data demonstrate that proteomic profiling combined with mathematical network modeling allows untangling complex pathway interplays and revealing difficult to discern interactions among the SYK pathways that positively and negatively affect tumor formation and progression.


2015 ◽  
Vol 26 (3-4) ◽  
pp. 116-123
Author(s):  
A. P. Korzh ◽  
T. V. Zahovalko

Recently, the number of published works devoted to the processes of synanthropization of fauna, is growing like an avalanche, which indicates the extreme urgency of this theme. In our view, the process of forming devices to coexist with human and the results of his life reflects the general tandency of the modern nature evolution. Urbanization is characteristic for such a specific group of animals like amphibians, the evidence of which are numerous literature data. Many researchers use this group to assess the bioindicative quality of the environment. For this aim a variety of indicators are used: from the cellular level of life of organization up to the species composition of the group in different territories. At the same time, the interpretation of the results is not always comparable for different areas and often have significantly different interpretations by experts. Urban environment, primarily due to the contamination is extremely aggressive to amphibians. As a consequence, the urban populations of amphibians may be a change in the demographic structure, affecting the reproductive ability of the population, the disappearance of the most sensitive species or individuals, resizing animals, the appearance of abnormalities in the development, etc. At the same time play an important amphibians in the ecosystems of cities, and some species in these conditions even feel relatively comfortable. Therefore, it is interesting to understand the mechanisms of self-sustaining populations of amphibians in urban environments. To assess the impact of natural and anthropogenic factors on the development of amphibian populations were used cognitive modeling using the program Vensim PLE. Cognitive map of the model for urban and suburban habitat conditions were the same. The differences concerned the strength of connections between individual factors (migration, fertility, pollution) and their orientation. In general, factors like pollution, parasites, predators had negative impact on the population, reducing its number. The birth rate, food and migration contributed to raising number of individuals. Some of the factors affected on the strength to of each other as well: the majority of the factors affected the structure of the population, had an influence on the fertility. Thanks to it the model reflects the additive effect of complex of factors on the subsequent status of the population. Proposed and analyzed four scenarios differing strength and duration of exposure. In the first scenario, a one-time contamination occurs and not subsequently repeated. The second and third scenario assumes half board contamination, 1 year (2 scenario) and two years (scenario 3). In the fourth scenario, the pollution affected the population of amphibians constantly. In accordance with the results of simulation, much weaker than the natural populations respond to pollution - have them as an intensive population growth and its disappearance at constant pollution is slow. Changes to other parameters of the model showed that this pollution is the decisive factor -only the constant action leads to a lethal outcome for the populations. All other components of the model have a corrective effect on the population dynamics, without changing its underlying trand. In urban areas due to the heavy impact of pollution maintaining the population is only possible thanks to the migration process – the constant replenishment of diminishing micropopulations of natural reserves. This confirms the assumption that the form of existence metapopulations lake frog in the city. In order to maintain the number of amphibians in urban areas at a high level it is necessary to maintain existing migration routes and the creation of new ones. Insular nature of the placement of suitable habitats in urban areas causes the metapopulation structure of the types of urbanists. Therefore, the process of urbanization is much easier for those species whicht are capable of migration in conditions of city. In the initial stages of settling the city micropopulationis formed by selective mortality of the most susceptible individuals to adverse effects. In future, maintaining the categories of individuals is provided mainly due to migration processes metapopulisation form of the species of existence is supported). It should be noted that the changes in the previous levels are always saved in future. In the case of reorganizations of individuals we of morphology can assume the existence of extremely adverse environmental conditions that threaten the extinction of the micropopulations. 


2020 ◽  
Vol 14 (1) ◽  
pp. 88-100
Author(s):  
Fares E.M. Ali ◽  
Heba M. Saad Eldien ◽  
Nashwa A.M. Mostafa ◽  
Abdulrahman H. Almaeen ◽  
Mohamed R.A. Marzouk ◽  
...  

Objective: The present study was conducted to elucidate the underlying molecular mechanism as well as the potential hepatoprotective effects of royal jelly (RJ) against hepatic ischemia/reperfusion (IR) injury. Methods: Rats were assigned into four groups; sham (received vehicle), IR (30 minutes ischemia and 45 minutes reperfusion), sham pretreated with RJ (200 mg/kg P.O.), and IR pretreated with RJ (200 mg/kg P.O.). The experiment has lasted for 28 days. Results: Hepatic IR significantly induced hepatic dysfunctions, as manifested by elevation of serum transaminases, ALP and LDH levels. Moreover, hepatic IR caused a significant up-regulation of P38-MAPK, NF-κB-p65, TNF-α and MDA levels along with marked down-regulation of Nrf-2, HO-1, COX-4, cytoglobin, IκBa, IL-10, GSH, GST and SOD levels. Additionally, marked histopathological changes were observed after hepatic IR injury. On the contrary, pretreatment with RJ significantly improved hepatic functions along with the alleviation of histopathological changes. Moreover, RJ restored oxidant/antioxidant balance as well as hepatic expressions of Nrf-2, HO-1, COX-4, and cytoglobin. Simultaneously, RJ significantly mitigated the inflammatory response by down-regulation of P38-MAPK, NF-κB-p65, TNF-α expression. Conclusion: The present results revealed that RJ has successfully protected the liver against hepatic IR injury through modulation of cytoglobin, Nrf-2/HO-1/COX-4, and P38-MAPK/NF-κB-p65/TNF-α signaling pathways.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kerrie Ní Dhufaigh ◽  
Eugene Dillon ◽  
Natasha Botwright ◽  
Anita Talbot ◽  
Ian O’Connor ◽  
...  

AbstractThe causative agent of amoebic gill disease, Neoparamoeba perurans is reported to lose virulence during prolonged in vitro maintenance. In this study, the impact of prolonged culture on N. perurans virulence and its proteome was investigated. Two isolates, attenuated and virulent, had their virulence assessed in an experimental trial using Atlantic salmon smolts and their bacterial community composition was evaluated by 16S rRNA Illumina MiSeq sequencing. Soluble proteins were isolated from three isolates: a newly acquired, virulent and attenuated N. perurans culture. Proteins were analysed using two-dimensional electrophoresis coupled with liquid chromatography tandem mass spectrometry (LC–MS/MS). The challenge trial using naïve smolts confirmed a loss in virulence in the attenuated N. perurans culture. A greater diversity of bacterial communities was found in the microbiome of the virulent isolate in contrast to a reduction in microbial community richness in the attenuated microbiome. A collated proteome database of N. perurans, Amoebozoa and four bacterial genera resulted in 24 proteins differentially expressed between the three cultures. The present LC–MS/MS results indicate protein synthesis, oxidative stress and immunomodulation are upregulated in a newly acquired N. perurans culture and future studies may exploit these protein identifications for therapeutic purposes in infected farmed fish.


Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 940
Author(s):  
Chi-Yu Lai ◽  
Kun-Yun Yeh ◽  
Chiu-Ya Lin ◽  
Yang-Wen Hsieh ◽  
Hsin-Hung Lai ◽  
...  

MicroRNA-21 (miR-21) is one of the most frequently upregulated miRNAs in liver diseases such as nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). However, mechanistic pathways that connect NAFLD and HCC remain elusive. We developed a doxycycline (Dox)-inducible transgenic zebrafish model (LmiR21) which exhibited an upregulation of miR-21 in the liver, which in turn induced the full spectrum of NAFLD, including steatosis, inflammation, fibrosis, and HCC, in the LmiR21 fish. Diethylnitrosamine (DEN) treatment led to accelerated liver tumor formation and exacerbated their aggressiveness. Moreover, prolonged miR-21 expression for up to ten months induced nonalcoholic steatohepatitis (NASH)-related HCC (NAHCC). Immunoblotting and immunostaining confirmed the presence of miR-21 regulatory proteins (i.e., PTEN, SMAD7, p-AKT, p-SMAD3, and p-STAT3) in human nonviral HCC tissues and LmiR21 models. Thus, we demonstrated that miR-21 can induce NAHCC via at least three mechanisms: First, the occurrence of hepatic steatosis increases with the decrease of ptenb, pparaa, and activation of the PI3K/AKT pathway; second, miR-21 induces hepatic inflammation (or NASH) through an increase in inflammatory gene expression via STAT3 signaling pathways, and induces liver fibrosis through hepatic stellate cell (HSC) activation and collagen deposition via TGF-β/Smad3/Smad7 signaling pathways; finally, oncogenic activation of Smad3/Stat3 signaling pathways induces HCC. Our LmiR21 models showed similar molecular pathology to the human cancer samples in terms of initiation of lipid metabolism disorder, inflammation, fibrosis and activation of the PI3K/AKT, TGF-β/SMADs and STAT3 (PTS) oncogenic signaling pathways. Our findings indicate that miR-21 plays critical roles in the mechanistic perspectives of NAHCC development via the PTS signaling networks.


2021 ◽  
pp. 019459982110104
Author(s):  
Carly E. A. Barbon ◽  
Douglas B. Chepeha ◽  
Andrew J. Hope ◽  
Melanie Peladeau-Pigeon ◽  
Ashley A. Waito ◽  
...  

The current standard for the treatment of oropharynx cancers is radiation therapy. However, patients are frequently left with dysphagia characterized by penetration-aspiration (impaired safety) and residue (impaired efficiency). Although thickened liquids are commonly used to manage dysphagia, we lack evidence to guide the modification of liquids for clinical benefit in the head and neck cancer population. The objective of this study was to assess the impact of slightly and mildly thick liquids on penetration-aspiration and residue in 12 patients with oropharyngeal cancer who displayed penetration-aspiration on thin liquid within 3 to 6 months after completion of radiotherapy. Significantly fewer instances of penetration-aspiration were seen with slightly and mildly thick liquids as compared with thin ( P < .05). No differences were found across stimuli in the frequency of residue. Patients with oropharyngeal cancers who present with post–radiation therapy dysphagia involving penetration-aspiration on thin liquids may benefit from slightly and mildly thick liquids without risk of worse residue.


2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Fereshteh Shahrabi Farahani ◽  
Keiu Paapsi ◽  
Kaire Innos

Abstract Background Radiation therapy is an important part of multimodal breast cancer treatment. The aim was to examine the impact of sociodemographic factors on radiation therapy use in breast cancer (BC) patients in Estonia, linking cancer registry data to administrative databases. Methods Estonian Cancer Registry provided data on women diagnosed with BC in Estonia in 2007–2018, including TNM stage at diagnosis. Use of radiation therapy within 12 months of diagnosis was determined from Estonian Health Insurance Funds claims, and sociodemographic characteristics from population registry. Receipt of radiation therapy was evaluated over time and by clinical and sociodemographic factors. Poisson regression with robust variance was used to calculate univariate and multivariate prevalence rate ratios (PRR) with 95 % confidence intervals (CI) for receipt of radiation therapy among stage I–III BC patients age < 70 years who underwent primary surgery. Results Overall, of 8637 women included in the study, 4310 (50 %) received radiation therapy within 12 months of diagnosis. This proportion increased from 39 to 58 % from 2007 to 2009 to 2016–2018 (p < 0.001). Multivariate regression analysis showed that compared to women with stage I BC, those with more advanced stage were less likely to receive radiation therapy. Receipt of radiation therapy increased significantly over time and was nearly 40 % higher in 2016–2018 than in 2007–2009. Use of radiation therapy was significantly lower for women with the lowest level of education compared to those with a university degree (PRR 0.88, 95 % CI 0.80–0.97), and for divorced/widowed women (PRR 0.95, 95 % CI 0.91–0.99) and single women (PRR 0.92, 95 % CI 0.86–0.99), compared to married women. Age at diagnosis, nationality and place of residence were not associated with receipt of radiation therapy. Conclusions The study showed considerable increase in the use of radiation therapy in Estonia over the study period, which is in line with increases in available equipment. The lack of geographic variations suggests equal access to therapy for patients living in remote regions. However, educational level and marital status were significantly associated with receipt of radiation therapy, highlighting the importance of psychosocial support in ensuring equal access to care.


2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Camille Ternet ◽  
Christina Kiel

AbstractThe intestinal epithelium acts as a physical barrier that separates the intestinal microbiota from the host and is critical for preserving intestinal homeostasis. The barrier is formed by tightly linked intestinal epithelial cells (IECs) (i.e. enterocytes, goblet cells, neuroendocrine cells, tuft cells, Paneth cells, and M cells), which constantly self-renew and shed. IECs also communicate with microbiota, coordinate innate and adaptive effector cell functions. In this review, we summarize the signaling pathways contributing to intestinal cell fates and homeostasis functions. We focus especially on intestinal stem cell proliferation, cell junction formation, remodelling, hypoxia, the impact of intestinal microbiota, the immune system, inflammation, and metabolism. Recognizing the critical role of KRAS mutants in colorectal cancer, we highlight the connections of KRAS signaling pathways in coordinating these functions. Furthermore, we review the impact of KRAS colorectal cancer mutants on pathway rewiring associated with disruption and dysfunction of the normal intestinal homeostasis. Given that KRAS is still considered undruggable and the development of treatments that directly target KRAS are unlikely, we discuss the suitability of targeting pathways downstream of KRAS as well as alterations of cell extrinsic/microenvironmental factors as possible targets for modulating signaling pathways in colorectal cancer.


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