Current Signal Transduction Therapy - Volume 12, Issue 1, 2017

Background: Invasive tumor growth and metastasis require the formation of a chaotic network of blood vessels that nourish cancer cells and provide them with a direct access to peripheral circulation, which is essential for them to diffuse throughout the organism. Tumor vascularization is sustained by multiple mechanisms, including sprouting angiogenesis and vasculogenesis, which consists in the recruitment of endothelial progenitor cells (EPCs) from either the bone marrow or the arterial wall. Tumor endothelium presents significant morphologic, genetic and functional differences as compared to normal cells. Methods: Recent work has shown that the Ca2+ signaling machinery is heavily remodeled in both tumor endothelial cells (TECs) and tumor-associated EPCs (T-EPCs). The rearrangement of the Ca2+ toolkit in TECs and T-EPCs leads to a dramatic improvement of their pro-angiogenic activity and increases cancer resistance to chemotherapeutics and anti-angiogenic treatments. Herein, the major changes involved in this process are analyzed. Results: The major changes observed include the reduction in the endogenous Ca2+ reservoir, the upregulation of store-operated Ca2+ entry or TRPC5 and the alteration in TRPV4 levels. Additionally, a growing number of studies revealed that other transporters involved in Ca2+ homeostasis are aberrantly expressed in TECs, including Na+/H+ exchanger, chloride intracellular channels, and nicotinic acetylcholine receptors. This emerging field of investigation is, therefore, coming of age because of its tremendous therapeutic potential. Conclusions: Understanding the impact of Ca2+ dysregulation in tumor vascularization is mandatory to circumvent patient refractoriness to current anti-cancer regimens.

Toll-like receptor 4 (TLR4) belongs to a large family of pattern recognition receptors that play a key role in innate immunity and inflammatory response. Increasing evidence has shown that TLR4 signaling pathway plays an essential role in mediating the immune response and central nervous system (CNS) repair and development. Brain inflammation and innate immunity has been implicated as a secondary injury mechanism following stroke, exacerbating neural damage to impede recovery. After stroke, a series of signaling pathways are triggered by dying cells or other factors in both the local innate immune cells in brain and other immune cells from bloodstream, contributing to the brain inflammatory response. In this review, we discuss the TLR4 signaling in association with recent findings concerning the involvement of TLR4 signaling pathway in stroke-induced inflammation and brain injury, and then study the key mechanisms associated with TLR4 signaling pathway in the above processes, suggesting the potential for therapeutic intervention by targeting TLR4 signaling pathway.

Background: Aryl hydrocarbon receptor (AhR) is an exogenous ligand-activating or constitutively active transcription factor. AhR regulates cellular differentiation, cell migration and other molecular and cellular processes. In general, AhR is biologically a very complex molecule in terms of its structure and functions in stemness, differentiation and clinical diseases. Here we review the debated issue of AhR in stem cell and cancer stem cell signaling. Methods: We searched literatures in PubMed and Google Scholar for related articles to review the AhR function and signal transduction in stem cells and cancer stem cells. Experimental data and results were analyzed. Results: It has been shown that AhR is an oncogenic protein but recent studies suggest that AhR can also inhibit cancer signaling through cancer stem cell pathways which are mostly common in OCT4. AhR either activates or inhibits tumorigenesis possibly through regulation of stemness or differentiation. Furthermore, how AhR can switch this function is largely unknown. Conclusion: AhR may inhibit or promote stem cell/cancer stem cell signaling through molecular switches of ageing, tissue specific signaling, ligand, and systems interaction networks. Targeting these signaling would provide a new avenue for efficient therapy in precision medicine.

Background: Skin photodamage exhibits poorly clinical efficacy and so far has rarely satisfactory treatments. Ultraviolet (UV)-induced overproduction of reactive oxygen species (ROS), NF-E2-related factor 2 (Nrf2) inactivation and Nrf2/antioxidant response elements (ARE) signaling pathway blockage play important roles in skin photodamage pathogenesis. Skin-derived precursor cells (SKPs), a population of dermal stem cells, are predominant over wound repair and skin regeneration. Objective: To hypothesize that SKPs are useful in skin photodamage by Nrf2 activation. Methods: Published papers on skin photodamage and SKPs were collected and reviewed. Besides, the findings from our preliminary experiment were reported in this article. Results: It has been confirmed that stem cells could participate in tissue repair via activating Nrf2 and Nrf2/ARE signal transduction pathway. Furthermore, our previous and current outcomes revealed that SKPs could ameliorate UVB-induced apoptosis or damage and significantly up-regulate Nrf2 expression after UV irradiation. Conclusion: Together the above data, we speculate that SKPs may be good candidates for control of skin photodamage through activating Nrf2 and its signaling pathway. These would provide a new approach for resisting skin photodamage.

Background: Electrocardiogram (ECG) signals provide confirmation about the cardiac rhythmic deviations and its function. But throughout the acquisition of Electrocardiogram signal from the human body, it becomes distorted with artifacts like 50 Hz power line interference, wandering of base line, respiratory signals and muscle artifacts. In spite of the noises in ECG, 50 Hz power line interference will relentlessly disturb the nature of the ECG signal. In 1990, Huang presented the algorithm called Empirical Mode Decomposition (EMD). It is an adaptive recursive decomposing algorithm that disintegrates the signal into different levels called Intrinsic Mode Functions (IMF). EMD has the limitations like sensitivity to noise and sampling. This problem is only partially addressed by other techniques like synchrosqueezing and empirical wavelets. Variational mode decomposition (VMD) is a non-recursive method in which the modes are extracted concomitantly. This technique is more robust to sampling and noise. Methods: In this paper novel VMD based subtraction techniques are developed and its denoising performances are analysed. This proposed that method outperforms other denoising methods like notch filtering and wavelet transform. Thus the characteristic features of ECG signal are undisturbed by preserving its originality. Results: The comparative performance of various methods in terms of the performance parameters like MSE, SNR, PRD and PSNR is carried out. The SNR level is stable in all noise levels. The SNR is varying from 19dB to25dB using hard and soft thresholding techniques. But it is almost double when our proposed approach is applied. The SNR value of direct method is ranging from 38dB to 43dB with a minimum MSE of 0.004 at 5% noise level. The noise band of 48 Hz to 51Hz is separated from the VMF level so that the desired ECG signal component is undestroyed. Thus compared to direct subtraction indirect subtraction technique performs well. The SNR value ranging from a range of 54dBto 55dB is obtained using an indirect method. Highest SNR value of 55.98 dB is obtained at 5% noise level and a very low MSE value is also obtained. Conclusion: This paper provides a novel method in the area of denoising Biosignals. Two techniques are proposed for denoising such as direct subtraction and indirect subtraction techniques. A comparative study is performed to study the performance of the proposed method. The parameters used for comparison are MSE, SNR, PRD and PSNR. Indirect subtraction technique outperforms the direct subtraction method. An improved SNR value and minimized MSE indicates the performance of denoising method. Thus VMD based subtraction techniques give better denoised signals even though the decomposition process takes time.

Objective: Lung cancer is one of the main causes of cancer-related mortality. The identification of early diagnostic biomarkers improved outcomes for lung cancer patients. This study investigated the correlation of preoperative plasma fibrinogen level with distant metastasis and prognosis in lung cancer patients. Methods: A total of 139 lung cancer patients who underwent curative surgery between January 2009 and November 2010 were enrolled in this study. In addition to clinical and pathological prognostic factors, we evaluated the prognostic value of plasma fibrinogen on distant metastasis and relapse. Univariate analysis was performed using the Kaplan-Meier survival analysis and multivariate analysis was performed using the Cox regression model in order to measure 5-year distant metastasisfree survival (DMFS), locoregional relapse-free survival (LRFS), relapse-free survival (RFS), and overall survival (OS). Results: Median plasma fibrinogen level was 3.59 g/L (range: 1.92-8.73 g/L). A total of 86 patients (61.9%) had normal plasma fibrinogen levels (<4 g/L) and 53 patients (38.1%) had hyperfibrinogenemia (<4g/L). Pearson's chi-square test showed that plasma fibrinogen level was significantly associated with age (P=0.047), tumor stage (P<0.001), and lymph node status (P=0.037) whereas there was no significant association between plasma fibrinogen level and gender, smoking, alcohol, tumor size, and tumor differentiation. Median follow-up time was 37 months. The 5-year DMFS, LRMFS, RFS, and OS rates were 26.40, 18.90, 7.50, and 28.30% with hyperfibrinogenemia respectively. Multivariate analysis showed that lymph node status (P=0.001, HR=0.397 with 95% CI=0.233-0.677) and plasma fibrinogen level (P=0.002, HR=0.410 with 95% CI=0.234-0.718) were significantly related to LRFS. RFS was significantly related to plasma fibrinogen level (P=0.036, HR=0.596 with 95% CI=0.368- 0.966) and lymph node status (P<0.001, HR=0.405 with 95% CI=0.260-0.631). DMFS was also significantly related to lymph node stage (P=0.006, HR=0.501 with 95% CI=0.307-0.817) and plasma fibrinogen level (P=0.001, HR=0.399 with 95% CI=0.236-0.674). Conclusion: Preoperative increased plasma fibrinogen level was a predictor of distant metastasis and was independently associated with the prognosis of lung cancer patients.

Background: The vessel stenosis and re-stenosis processes are mainly related to cellular and molecular events. The vascular smooth muscle cell (VSMC) activation is the basic element in these lesions. Based on monocyte and macrophage inflammatory responses and also VSMC motility, a complex protein network is dynamically proposed between these cells. The aim of this study was to highlight the protein communications involved in VSMC proliferation and migration signaling pathways. Methods: A bibliographic search was performed on finding total macrophage, monocyte and VSMC proteomes (n=1262). The proteomes were compartmented on cellular components (Gene Ontology). The primary protein-protein interaction (PPIs) networks were constructed after merging the VSMC proteome with extracellular monocyte and macrophage proteins. The network clusters were determined using STRING server and were evaluated for contributing in KEGG signaling pathways. Results: The associations between extracellular monocyte (n=71) and macrophage (n=43) proteins and VSMC signaling pathways were evaluated on four PPI networks. Several clusters were observed on each network. The genes were merged in similar clusters and were the subjects for contributing in KEGG signaling pathways. Conclusion: The cytokine-cytokine receptor interaction, focal adhesion and regulation of actin cytoskeleton pathways were suggested to be involved in VSMC proliferation and migration by extracellular monocyte and macrophage proteins.