In conclusion, high leptin levels and alteration in acute phase proteins in obese patients may exaggerate the inflammation status. As inflammation has the potential to increase the susceptibility of the patients to metastasis development, it is necessary to decline its rate.

Background: Circular RNAs (circRNAs), as covalently closed single-stranded noncoding RNA molecules, have been recently identified to involve in several biological processes, principally through targeting microRNAs. Among various neurodegenerative diseases (NDs), accumulating evidence has proposed key roles for circRNAs in the pathogenesis of Alzheimer’s disease (AD); although the exact relationship between these RNA molecules and AD progression is not clear, they have been believed to mostly act as miRNA sponges or gene transcription modulators through correlating with multiple proteins, involved in the accumulation of Amyloid β (Aβ) peptides, as well as tau protein, as AD’s pathological hallmark. More interestingly, circRNAs have also been reported to play diagnostic and therapeutic roles during AD progression. Objective: Literature review indicated that circRNAs could essentially contribute to the onset and development of AD. Thus, in the current review, the circRNAs’ biogenesis and functions are addressed at first, and then the interplay between particular circRNAs and AD is comprehensively discussed. Eventually, the diagnostic and therapeutic significance of these noncoding RNAs is highlighted in brief. Results: A large number of circRNAs are expressed in the brain. Thereby, these RNA molecules are noticed as potential regulators of neural functions in healthy circumstances, as well as neurological disorders. Moreover, circRNAs have also been reported to have potential diagnostic and therapeutic capacities in relation to AD, the most prevalent ND. Conclusion: CircRNAs have been shown to act as sponges for miRNAs, thereby regulating the function of related miRNAs, including oxidative stress, reduction of neuroinflammation, and the formation and metabolism of Aβ, all of which developed in AD. CircRNAs have also been proposed as biomarkers that have potential diagnostic capacities in AD. Despite these characteristics, the use of circRNAs as therapeutic targets and promising diagnostic biomarkers will require further investigation and characterization of the function of these RNA molecules in AD.

Vascular endothelial growth factor receptor 3 (VEGFR3) is expressed in cancer cell lines and exerts a critical role in cancer progression. However, the signaling pathways of VEGFR3 in ovarian cancer cell proliferation remain unclear. This study aimed to demonstrate the signaling pathways of VEGFR3 through the upregulated expression of miR-1236 in ovarian cancer cells. We found that the messenger RNA and protein of VEGFR3 were expressed in the ovarian cancer cell lines, but downregulated after microRNA-1236 (miR-1236) transfection. The inhibition of VEGFR3, using miR-1236, significantly reduced cell proliferation, clonogenic survival, migration, and invasion ability in SKOV3 and OVCAR3 cells (p < 0.01). The flow cytometry results indicated that the rate of apoptotic cells in SKOV3 (38.65%) and OVCAR3 (41.95%) cells increased following VEGFR3 inhibition. Moreover, VEGFR3 stimulation (using a specific ligand, VEGF-CS) significantly increased extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (AKT) phosphorylation (p < 0.01), whereas VEGFR3 suppression reduced p-ERK1/2 (67.94% in SKOV3 and 93.52% in OVCAR3) and p-AKT (59.56% in SKOV3 and 78.73% in OVCAR3) compared to the VEGF-CS treated group. This finding demonstrated that miR-1236 may act as an endogenous regulator of ERK1/2 and AKT signaling by blocking the upstream regulator of VEGFR3. Overall, we demonstrated the important role of the miR-1236/VEGFR3 axis in ovarian cancer cell proliferation by regulating the ERK1/2 and AKT signaling that might be an effective strategy against ovarian cancer.

Background: Tyrosine kinase inhibitors (TKIs) can be used to inhibit cancer cell proliferation by targeting the vascular endothelial growth factor receptor (VEGFR) family. SAR131675 is a highly selective receptor tyrosine kinase inhibitor to VEGFR3 that reveals the inhibitory effect on proliferation in human lymphatic endothelial cells. However, the molecular mechanisms underlying this process are generally unclear. Objective: This study was performed to investigate the possible involvement of the Bcl-2/Bax/Cyto c apoptosis pathway in human umbilical vein endothelial cells (HUVECs). In addition, the role of reactive oxygen species (ROS) and mitochondrial membrane potential was evaluated. Methods: The effect of SAR131675 on HUVEC cell viability was evaluated by MTT assay. The activity of SAR131675 in inducing apoptosis was carried out through the detection of Annexin V-FITC/PI signal by flow cytometry. To determine the mechanisms underlying SAR131675 induced apoptosis, the mitochondrial membrane potential, ROS generation, the activity of caspase-3, and expression of apoptosis-related proteins such as Bcl-2, Bax, and cytochrome c were evaluated in HUVECs. Results: SAR131675 significantly inhibited cell viability and induced apoptosis in HUVECs in a dose-dependent manner. Moreover, SAR131675 induced mitochondrial dysfunction, ROS generation, Bcl-2 down-regulation, Bax up-regulation, cytochrome c release, and caspase-3 activation, which displays features of the mitochondria-dependent apoptosis signaling pathway. Conclusion: Our present data demonstrated that SAR131675-induced cytotoxicity in HUVECs is associated with the mitochondria apoptotic pathway. These results suggest that further studies are required to fully elucidate the role of TKIs in these cellular processes.

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Background Tumor lymphangiogenesis is a critical component in the progression of cancers and specific microRNAs have been reported to be implicated in this process. Recent studies revealed the involvement of miR‐1236 in lymphangiogenic signaling by targeting vascular endothelial growth factor receptor 3 (VEGFR3). However, the prognostic importance of miR‐1236 and its clinical relevance for lymphangiogenesis in ovarian cancer (OC) remains unclear. Methods The study included 52 ovarian tumors and 28 normal ovarian tissues. Quantitative real‐time PCR was utilized to analyze the VEGFR3, VEGF‐C, LYVE‐1 and PROX1 mRNA expression as well as miR‐1236. VEGFR3 protein expression was measured by immunohistochemistry staining. Immunohistochemistry for the podoplanin marker (D2‐40) was performed to measure lymphatic vessel density (LVD). In addition, diagnostic evaluation based on the receiver‐operating characteristic (ROC) curve was performed. The influence of miR‐1236 on overall survival was evaluated by Kaplan–Meier method. Results Here, we show that miR‐1236 expression was significantly decreased in ovarian tumors compared with control tissues (p < 0.001) and correlated with advanced clinical stage, lymph node metastasis, distant metastasis and patient survival (All P < 0.05). Moreover, in ovarian tumors, LVD as well as the gene expression of VEGFR3, VEGF‐C and LYVE‐1, but not PROX1, were found to be remarkably higher compared with control tissues. We also detected a more robust positive staining for VEGFR3 in OC tissues than in control tissues. Furthermore, our results demonstrated an inverse association of miR‐1236 expression with LVD, VEGFR3, LYVE‐1 and PROX1 expression in OC tissues. The ROC curve analysis indicated that miR‐1236 expression has the potential to be used as a diagnostic and prognostic biomarker in OC. Survival analysis further verified a lowered overall survival rate in patients with low miR‐1236 expression than in those with high expression. Conclusions Our results provide evidence for the translational involvement of miR‐1236 in the lymphangiogenesis of OC by regulating lymphangiogenesis‐related factors and support the clinical importance of miR‐1236 as a new diagnostic and prognostic biomarker for OC.

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