scholarly journals Hormonal Carcinogenesis in Canine Mammary Cancer: Molecular Mechanisms of Estradiol Involved in Malignant Progression

Animals ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 608
Author(s):  
Cristian G. Torres ◽  
María P. Iturriaga ◽  
Pamela Cruz
Keyword(s):  
Intracellular Signaling ◽  
Mammary Cancer ◽  
Molecular Mechanisms ◽  
Malignant Progression ◽  
Post Translational Modification ◽  
Sexual Hormones ◽  
Specific Receptors ◽  
Genomic Effects ◽  
High Concentrations ◽  
Underlying Mechanisms

Mammary cancer is a frequent neoplasia in female dogs, in which most important risk factors are hormonal. Sexual hormones as estradiol play an important role in mammary carcinogenesis, being able to induce carcinogenic initiation, promotion and progression. However, the molecular mechanisms involved are incompletely understood. Estradiol is synthesized mainly in the ovaries, nevertheless, high concentrations of estradiol and some of its hormonal precursors have also been described in malignant mammary tumor tissue. The mechanisms of action of estradiol include the classic genomic effects that modulate gene transcription, and non-genomic effects, which trigger quick effects after estradiol binds to its specific receptors. These responses modulate various intracellular signaling pathways, triggering post-translational modification of several proteins. This review will discuss the well-known underlying mechanisms associated with the action of estradiol in the malignant progression of canine mammary tumors.

scholarly journals Inhibition of Single Routes of Intracellular Signaling is Not Sufficient to Neutralize the Biphasic Disturbance of a Retinal Endothelial Cell Barrier Induced by VEGF-A165

2017 ◽  
Vol 42 (4) ◽  
pp. 1493-1513 ◽  
Author(s):  
Heidrun L. Deissler ◽  
Gerhard K. Lang ◽  
Gabriele E. Lang
Keyword(s):  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Early Response ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Retinal Endothelial Cell ◽  
Specific Receptors ◽  
Barrier Breakdown ◽  
High Concentrations ◽  
Endothelial Growth Factor

Background/Aims: Hallmark of diabetic macular edema is the enhanced permeability of retinal endothelial cells (REC) induced by vascular endothelial growth factor (VEGF-A165), which acts through activating specific receptors. To improve the predictability of inhibitors' potentials to block harmful effects of VEGF-A165, we investigated if its signaling pathways triggered in REC are redundant. Methods: Immortalized bovine REC monolayers were treated with inhibitors specific for various protein kinases in combination with VEGF-A165. Permeability was monitored continuously by measurements of the cell index (CI) to reveal even subtle and transient changes. Expression of tight junction (TJ) proteins was determined as additional indicator of barrier stability. Results: After a sharp but transient CI drop caused by VEGF-A165 early after its addition, further exposure resulted in a continuous CI decline over several days associated with loss of TJ protein claudin-1. Both phases were blocked by inhibition of VEGF receptor 2. Tested inhibitors of intracellular kinases had a limited or no effect, or were efficient only in certain phases of exposure to VEGF-A165, e.g. inhibiting protein kinase C only prevented the early response. High concentrations of some inhibitors even resulted in VEGF-independent barrier destabilization. Conclusions: Specific kinase inhibitors differently affect VEGF-A165-triggered processes in distinct phases of its action. VEGF-A165-initiated signaling is redundant and blocking of key proteins of single pathways is not sufficient to suppress REC barrier breakdown.

The Mechanisms Behind the Biological Activity of Flavonoids

2019 ◽  
Vol 26 (39) ◽  
pp. 6976-6990 ◽  
Author(s):  
Ana María González-Paramás ◽  
Begoña Ayuda-Durán ◽  
Sofía Martínez ◽  
Susana González-Manzano ◽  
Celestino Santos-Buelga
Keyword(s):  
Gene Expression ◽  
Biological Activity ◽  
Phenolic Compounds ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Radical Scavenging ◽  
Model Organism ◽  
Stress Theory ◽  
Radical Scavenging Properties

: Flavonoids are phenolic compounds widely distributed in the human diet. Their intake has been associated with a decreased risk of different diseases such as cancer, immune dysfunction or coronary heart disease. However, the knowledge about the mechanisms behind their in vivo activity is limited and still under discussion. For years, their bioactivity was associated with the direct antioxidant and radical scavenging properties of phenolic compounds, but nowadays this assumption is unlikely to explain their putative health effects, or at least to be the only explanation for them. New hypotheses about possible mechanisms have been postulated, including the influence of the interaction of polyphenols and gut microbiota and also the possibility that flavonoids or their metabolites could modify gene expression or act as potential modulators of intracellular signaling cascades. This paper reviews all these topics, from the classical view as antioxidants in the context of the Oxidative Stress theory to the most recent tendencies related with the modulation of redox signaling pathways, modification of gene expression or interactions with the intestinal microbiota. The use of C. elegans as a model organism for the study of the molecular mechanisms involved in biological activity of flavonoids is also discussed.

The Effects of Butyric Acid on the Differentiation, Proliferation, Apoptosis, and Autophagy of IPEC-J2 Cells

2020 ◽  
Vol 20 (4) ◽  
pp. 307-317
Author(s):  
Yuan Yang ◽  
Jin Huang ◽  
Jianzhong Li ◽  
Huansheng Yang ◽  
Yulong Yin
Keyword(s):  
Cell Viability ◽  
P38 Mapk ◽  
Butyric Acid ◽  
Cell Apoptosis ◽  
Mapk Pathway ◽  
Mrna Level ◽  
Dependent Manner ◽  
M Phase ◽  
High Concentrations ◽  
Underlying Mechanisms

Background: Butyric acid (BT), a short-chain fatty acid, is the preferred colonocyte energy source. The effects of BT on the differentiation, proliferation, and apoptosis of small intestinal epithelial cells of piglets and its underlying mechanisms have not been fully elucidated. Methods: In this study, it was found that 0.2-0.4 mM BT promoted the differentiation of procine jejunal epithelial (IPEC-J2) cells. BT at 0.5 mM or higher concentrations significantly impaired cell viability in a dose- and time-dependent manner. In addition, BT at high concentrations inhibited the IPEC-J2 cell proliferation and induced cell cycle arrest in the G2/M phase. Results: Our results demonstrated that BT triggered IPEC-J2 cell apoptosis via the caspase8-caspase3 pathway accompanied by excess reactive oxygen species (ROS) and TNF-α production. BT at high concentrations inhibited cell autophagy associated with increased lysosome formation. It was found that BT-reduced IPEC-J2 cell viability could be attenuated by p38 MAPK inhibitor SB202190. Moreover, SB202190 attenuated BT-increased p38 MAPK target DDIT3 mRNA level and V-ATPase mRNA level that were responsible for normal acidic lysosomes. Conclusion: In conclusion, 1) at 0.2-0.4 mM, BT promotes the differentiation of IPEC-J2 cells; 2) BT at 0.5 mM or higher concentrations induces cell apoptosis via the p38 MAPK pathway; 3) BT inhibits cells autophagy and promotes lysosome formation at high concentrations.

Exploring PLAC1 Structure and Underlying Mechanisms to Design a Derivative Vaccine Against Breast Cancer Progression; In-Silico Study

2020 ◽  
Vol 17 (5) ◽  
pp. 379-391
Author(s):  
Farzaneh Afzali ◽  
Parisa Ghahremanifard ◽  
Mohammad Mehdi Ranjbar ◽  
Mahdieh Salimi
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
In Silico ◽  
Tertiary Structure ◽  
Specific Antigen ◽  
Docking Simulation ◽  
Post Translational Modification ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Underlying Mechanisms

Background: The tolerogenic homeostasis in Breast Cancer (BC) can be surpassed by rationally designed immune-encouraging constructs against tumor-specific antigens through immunoinformatics approach. Objective: Availability of high throughput data providing the underlying concept of diseases and awarded computational simulations, lead to screening the potential medications and strategies in less time and cost. Despite the extensive effects of Placenta Specific 1 (PLAC1) in BC progression, immune tolerance, invasion, cell cycle regulation, and being a tumor-specific antigen the fundamental mechanisms and regulatory factors were not fully explored. It is also worth to design an immune response inducing construct to surpass the hurdles of traditional anti-cancer treatments. Methods and Result: The study was initiated by predicting and modelling the PLAC1 secondary and tertiary structures and then engineering the fusion pattern of PLAC1 derived immunodominant predicted CD8+ and B-cell epitopes to form a multi-epitope immunogenic construct. The construct was analyzed considering the physiochemical characterization, safety, antigenicity, post-translational modification, solubility, and intrinsically disordered regions. After modelling its tertiary structure, proteinprotein docking simulation was carried out to ensure the attachment of construct with Toll-Like Receptor 4 (TLR4) as an immune receptor. To guarantee the highest expression of the designed construct in E. coli k12 as an expressional host, the codon optimization and in-silico cloning were performed. The PLAC1 related miRNAs in BC were excavated and validated through TCGA BC miRNA-sequencing and databases; the common pathways then were introduced as other probable mechanisms of PLAC1 activity. Conclusion: Regarding the obtained in-silico results, the designed anti-PLAC1 multi-epitope construct can probably trigger humoral and cellular immune responses and inflammatory cascades, therefore may have the potential of halting BC progression and invasion engaging predicted pathways.

Novel Findings of Anti-cancer Property of Propofol

2018 ◽  
Vol 18 (2) ◽  
pp. 156-165 ◽  
Author(s):  
Jiaqiang Wang ◽  
Chien-shan Cheng ◽  
Yan Lu ◽  
Xiaowei Ding ◽  
Minmin Zhu ◽  
...  
Keyword(s):  
General Anesthesia ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Intravenous Anesthetic ◽  
The Past ◽  
Anti Cancer ◽  
Underlying Mechanisms ◽  
Recent Attention

Background: Propofol, a widely used intravenous anesthetic agent, is traditionally applied for sedation and general anesthesia. Explanation: Recent attention has been drawn to explore the effect and mechanisms of propofol against cancer progression in vitro and in vivo. Specifically, the proliferation-inhibiting and apoptosis-inducing properties of propofol in cancer have been studied. However, the underlying mechanisms remain unclear. Conclusion: This review focused on the findings within the past ten years and aimed to provide a general overview of propofol's malignance-modulating properties and the potential molecular mechanisms.

scholarly journals Potential Phosphorylation of Viral Nonstructural Protein 1 in Dengue Virus Infection

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1393
Author(s):  
Thanyaporn Dechtawewat ◽  
Sittiruk Roytrakul ◽  
Yodying Yingchutrakul ◽  
Sawanya Charoenlappanit ◽  
Bunpote Siridechadilok ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Nonstructural Protein ◽  
Antiviral Drug ◽  
Denv Infection ◽  
Site Directed Mutagenesis ◽  
Phosphorylation Sites ◽  
Post Translational Modification ◽  
Multifunctional Protein ◽  
Nonstructural Protein 1 ◽  
Underlying Mechanisms

Dengue virus (DENV) infection causes a spectrum of dengue diseases that have unclear underlying mechanisms. Nonstructural protein 1 (NS1) is a multifunctional protein of DENV that is involved in DENV infection and dengue pathogenesis. This study investigated the potential post-translational modification of DENV NS1 by phosphorylation following DENV infection. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), 24 potential phosphorylation sites were identified in both cell-associated and extracellular NS1 proteins from three different cell lines infected with DENV. Cell-free kinase assays also demonstrated kinase activity in purified preparations of DENV NS1 proteins. Further studies were conducted to determine the roles of specific phosphorylation sites on NS1 proteins by site-directed mutagenesis with alanine substitution. The T27A and Y32A mutations had a deleterious effect on DENV infectivity. The T29A, T230A, and S233A mutations significantly decreased the production of infectious DENV but did not affect relative levels of intracellular DENV NS1 expression or NS1 secretion. Only the T230A mutation led to a significant reduction of detectable DENV NS1 dimers in virus-infected cells; however, none of the mutations interfered with DENV NS1 oligomeric formation. These findings highlight the importance of DENV NS1 phosphorylation that may pave the way for future target-specific antiviral drug design.

scholarly journals A novel homeostatic loop of sorcin drives paclitaxel-resistance and malignant progression via Smad4/ZEB1/miR-142-5p in human ovarian cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Jinguo Zhang ◽  
Wencai Guan ◽  
Xiaolin Xu ◽  
Fanchen Wang ◽  
Xin Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Calcium Binding ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Progression ◽  
Bioinformatics Analyses ◽  
Aberrant Expression ◽  
Mesenchymal Transition ◽  
E Box

AbstractThe primary chemotherapy of ovarian cancer (OC) often acquires chemoresistance. Sorcin (SRI), a soluble resistance-related calcium-binding protein, has been reported to be an oncogenic protein in cancer. However, the molecular mechanisms of SRI regulation and the role and aberrant expression of SRI in chemoresistant OC remain unclear. Here, we identified SRI as a key driver of paclitaxel (PTX)-resistance and explored its regulatory mechanism. Using transcriptome profiles, qRT-PCR, proteomics, Western blot, immunohistochemistry, and bioinformatics analyses, we found that SRI was overexpressed in PTX-resistant OC cells and the overexpression of SRI was related to the poor prognosis of patients. SRI was a key molecule required for growth, migration, and PTX-resistance in vitro and in vivo and was involved in epithelial–mesenchymal transition (EMT) and stemness. Mechanistic studies showed that miR-142-5p directly bound to the 3ʹ-UTR of SRI to suppress its expression, whereas a transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) inhibited the transcription of miR-142-5p by directly binding to the E-box fragment in the miR-142 promoter region. Furthermore, ZEB1 was negatively regulated by SRI which physically interacted with Smad4 to block its translocation from the cytosol to the nucleus. Taken together, our findings unveil a novel homeostatic loop of SRI that drives the PTX-resistance and malignant progression via Smad4/ZEB1/miR-142-5p in human OC. Targeting this SRI/Smad4/ZEB1/miR-142-5p loop may reverse the PTX-resistance.

scholarly journals Transcriptome and proteome analysis suggest enhanced photosynthesis in tetraploid Liriodendron sino-americanum

2021 ◽  
Author(s):  
Tingting Chen ◽  
Yu Sheng ◽  
Zhaodong Hao ◽  
Xiaofei Long ◽  
Fangfang Fu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Proteome Analysis ◽  
Tree Height ◽  
Photosynthetic Electron Transport ◽  
Industrial Applications ◽  
Chlorophyll Protein Complexes ◽  
Chlorophyll Protein ◽  
Photosynthesis Genes ◽  
Underlying Mechanisms

Abstract Polyploidy generally provides an advantage in phenotypic variation and growth vigor. However, the underlying mechanisms remain poorly understood. The tetraploid L. sino-americanum exhibits altered morphology compared to its diploid counterpart, including larger, thicker and deeper green leaves, bigger stomata, thicker stems and increased tree height. Such characteristics can be useful in ornamental and industrial applications. To elucidate the molecular mechanisms behind this variation, we performed a comparative transcriptome and proteome analysis. Our transcriptome data indicated that some photosynthesis genes and pathways were differentially altered and enriched in tetraploid L. sino-americanum, mainly related to F-type ATPase, the cytochrome b6/f complex, photosynthetic electron transport, the light harvesting chlorophyll protein complexes, photosystem I and II. Most of the differentially expressed proteins we could identify are also involved in photosynthesis. Our physiological results showed that tetraploids have an enhanced photosynthetic capacity, concomitant with great levels of sugar and starch in leaves. This suggests that tetraploid L. sino-americanum might experience comprehensive transcriptome reprogramming of genes related to photosynthesis. This study has especially emphasized molecular changes involved in photosynthesis that accompany polyploidy, and provides a possible explanation for the altered phenotype of polyploidy plants in comparison to their diploid form.

scholarly journals HSP90-dependent PUS7 overexpression facilitates the metastasis of colorectal cancer cells by regulating LASP1 abundance

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Dan Song ◽  
Ming Guo ◽  
Shuai Xu ◽  
Xiaotian Song ◽  
Bin Bai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Intellectual Development ◽  
Molecular Mechanisms ◽  
Hsp90 Inhibitor ◽  
Pseudouridine Synthase ◽  
Novel Approach ◽  
Cell Metastasis ◽  
Underlying Mechanisms

Abstract Background Pseudouridine synthase (PUS) 7 is a member of the PUS family that catalyses pseudouridine formation. It has been shown to be involved in intellectual development and haematological malignancies. Nevertheless, the role and the underlying molecular mechanisms of PUS7 in solid tumours, such as colorectal cancer (CRC), remain unexplored. This study elucidated, for the first time, the role of PUS7 in CRC cell metastasis and the underlying mechanisms. Methods We conducted immunohistochemistry, qPCR, and western blotting to quantify the expression of PUS7 in CRC tissues as well as cell lines. Besides, diverse in vivo and in vitro functional tests were employed to establish the function of PUS7 in CRC. RNA-seq and proteome profiling analysis were also applied to identify the targets of PUS7. PUS7-interacting proteins were further uncovered using immunoprecipitation and mass spectrometry. Results Overexpression of PUS7 was observed in CRC tissues and was linked to advanced clinical stages and shorter overall survival. PUS7 silencing effectively repressed CRC cell metastasis, while its upregulation promoted metastasis, independently of the PUS7 catalytic activity. LASP1 was identified as a downstream effector of PUS7. Forced LASP1 expression abolished the metastasis suppression triggered by PUS7 silencing. Furthermore, HSP90 was identified as a client protein of PUS7, associated with the increased PUS7 abundance in CRC. NMS-E973, a specific HSP90 inhibitor, also showed higher anti-metastatic activity when combined with PUS7 repression. Importantly, in line with these results, in human CRC tissues, the expression of PUS7 was positively linked to the expression of HSP90 and LASP1, and patients co-expressing HSP90/PUS7/LASP1 showed a worse prognosis. Conclusions The HSP90-dependent PUS7 upregulation promotes CRC cell metastasis via the regulation of LASP1. Thus, targeting the HSP90/PUS7/LASP1 axis may be a novel approach for the treatment of CRC.

scholarly journals Vitamin E beyond Its Antioxidant Label

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 634
Author(s):  
Anca Ungurianu ◽  
Anca Zanfirescu ◽  
Georgiana Nițulescu ◽  
Denisa Margină
Keyword(s):  
Vitamin E ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Protective Effects ◽  
Cellular Effects ◽  
Inflammatory Status ◽  
Anti Cancer ◽  
Key Factor ◽  
Exciting Potential ◽  
Underlying Mechanisms

Vitamin E, comprising tocopherols and tocotrienols, is mainly known as an antioxidant. The aim of this review is to summarize the molecular mechanisms and signaling pathways linked to inflammation and malignancy modulated by its vitamers. Preclinical reports highlighted a myriad of cellular effects like modulating the synthesis of pro-inflammatory molecules and oxidative stress response, inhibiting the NF-κB pathway, regulating cell cycle, and apoptosis. Furthermore, animal-based models have shown that these molecules affect the activity of various enzymes and signaling pathways, such as MAPK, PI3K/Akt/mTOR, JAK/STAT, and NF-κB, acting as the underlying mechanisms of their reported anti-inflammatory, neuroprotective, and anti-cancer effects. In clinical settings, not all of these were proven, with reports varying considerably. Nonetheless, vitamin E was shown to improve redox and inflammatory status in healthy, diabetic, and metabolic syndrome subjects. The anti-cancer effects were inconsistent, with both pro- and anti-malignant being reported. Regarding its neuroprotective properties, several studies have shown protective effects suggesting vitamin E as a potential prevention and therapeutic (as adjuvant) tool. However, source and dosage greatly influence the observed effects, with bioavailability seemingly a key factor in obtaining the preferred outcome. We conclude that this group of molecules presents exciting potential for the prevention and treatment of diseases with an inflammatory, redox, or malignant component.

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