International Journal of Molecular Medicine

Di Liegro, Carlo Maria; Schiera, Gabriella Maria; Di Liegro, Italia Maria

doi: 10.3892/ijmm.2014.1629pmid: 24452120

Post-transcriptional control of mRNA trafficking and metabolism plays a critical role in the actualization and fine tuning of the genetic program of cells, both in development and in differentiated tissues. Cis-acting signals, responsible for post-transcriptional regulation, reside in the RNA message itself, usually in untranslated regions, 5' or 3' to the coding sequence, and are recognized by trans-acting factors: RNA-binding proteins (RBPs) and/or non-coding RNAs (ncRNAs). ncRNAs bind short mRNA sequences usually present in the 3'-untranslated (3'-UTR) region of their target messages. RBPs recognize specific nucleotide sequences and/or secondary/tertiary structures. Most RBPs assemble on mRNA at the moment of transcription and shepherd it to its destination, somehow determining its final fate. Regulation of mRNA localization and metabolism has a particularly important role in the nervous system where local translation of pre-localized mRNAs has been implicated in developing axon and dendrite pathfinding, and in synapse formation. Moreover, activity-dependent mRNA trafficking and local translation may underlie long-lasting changes in synaptic efficacy, responsible for learning and memory. This review focuses on the role of RBPs in neuronal development and plasticity, as well as possible connections between ncRNAs and RBPs.

Wyganowska-Świątkowska, Marzena ; Surdacka, Anna ; Skrzypczak-Jankun, Ewa ; Jankun, Jerzy

doi: 10.3892/ijmm.2014.1653pmid: 24535478

The plasminogen activation system (PAS) plays an essential role in tissue proteolysis in physiological and pathological processes. Periodontitis is a chronic infection associated with increased proteolysis driven by plasminogen activation. In this comprehensive review, we summarise the effects of PAS in wound healing, tissue remodelling, inflammation, bacterial infection, and in the initiation and progression of periodontal disease. Specifically, we discuss the role of plasminogen activators (PAs), including urokinase PA (uPA), tissue-type PA (tPA), PA inhibitor type 1 (PAI-1) and 2 (PAI-2) and activated plasminogen in periodontal tissue, where their concentrations can reach much higher values than those found in other parts of the body. We also discuss whether PA deficiencies can have effects on periodontal tissue. We conclude that in periodontal disease, PAS is unbalanced and equalizing its function can improve the clinical periodontal tissue condition.

Ji, Yi-Fei ; Huang, Hua ; Jiang, Feng ; Ni, Run-Zhou ; Xiao, Ming-Bing

doi: 10.3892/ijmm.2014.1633pmid: 24481067

The occurrence and development of pancreatic cancer is a complex process convoluted by multi-pathogenies, multi-stages and multi-factors. S100 proteins are members of the S100 family that regulate multiple cellular pathways related to pancreatic cancer progression and metastasis. S100 proteins have a broad range of intracellular and extracellular functions, including the regulation of protein phosphorylation and enzyme activity, calcium homeostasis and the regulation of cytoskeletal components and transcriptional factors. S100 proteins interact with receptor for advanced glycation end-products (RAGE), p53 and p21, which play a role in the degradation of the extracellular matrix (ECM) and metastasis, and also interact with cytoskeletal proteins and the plasma membrane in pancreatic cancer progression and metastasis. S100A11 and S100P are significant tumor markers for pancreatic cancer and unfavorable predictors for the prognosis of patients who have undergone surgical resection. Recently, S100A2 has been suggested to be a negative prognostic biomarker in pancreatic cancer, and the expression of S100A6 may be an independent prognostic impact factor. The expression of S100A4 and S100P is associated with drug resistance, differentiation, metastasis and clinical outcome. This review summarizes the role and significance of the S100 family signaling network and related proteins in pancreatic cancer.

Signorelli, Salvatore Santo; Fiore, Valerio Santo; Malaponte, Grazia Santo

doi: 10.3892/ijmm.2014.1657pmid: 24535646

Peripheral arterial disease (PAD) is a manifestation of atherosclerotic vascular disease and is often associated with other comorbidities, such as hypertension, diabetes and dyslipidemia. An increasing body of evidence supports the notion that inflammation plays an important role in the development and progression of PAD. A number of studies have investigated the association of various acute phase proteins, particularly C-reactive protein (CRP), with PAD. Apart from CRP, other circulating biomarkers, such as matrix metalloproteinases (MMPs), selectins and interleukin (IL)-1, IL-2, IL-6, IL-8 and IL-10 have been considered to play a role in the development of PAD. In this review, the role of these circulating biomarkers in PAD is discussed. Current data indicate that the appropriate use of biomarkers in patients with PAD may contribute to an early diagnosis, an enhanced knowledge of the developmental process of the disease, as well as to the subsequent improvement of current therapies and to the development of new ones.

Heinzelmann-Schwarz, Viola A.; Nixdorf, Sheri A.; Valadan, Mehrnaz A.; Diczbalis, Monica A.; Olivier, Jake A.; Otton, Geoff A.; Fedier, André A.; Hacker, Neville F.; Scurry, James P.

doi: 10.3892/ijmm.2014.1659pmid: 24535703

Kirsch, Sebastian ; Schrezenmeier, Eva ; Klare, Sabrina ; Zaade, Daniela ; Seidel, Kerstin ; Schmitz, Jennifer ; Bernhard, Sarah ; Lauer, Dilyara ; Slack, Mark ; Goldin-Lang, Petra ; Unger, Thomas ; Zollmann, Frank S.; Funke-Kaiser, Heiko S.

Cao, Yanping ; Hao, Yongmei ; Li, Hang ; Liu, Qingjuan ; Gao, Feng ; Liu, Wei ; Duan, Huijun

doi: 10.3892/ijmm.2014.1642pmid: 24503896

Podocytes are terminally differentiated epithelial cells lacking the ability to proliferate. The loss of podocytes is a hallmark of progressive kidney diseases, including diabetic nephropathy (DN). Endoplasmic reticulum stress (ERS)-induced apoptosis is involved in a number of pathological conditions, including DN. The aim of the present study was to investigate whether a high glucose environment induces the apoptosis of podocytes through ERS. Differentiated mouse podocytes were divided into three groups: the normal glucose group (NG, 1 g/l D-glucose), the high glucose group (HG, 4.5 g/l D-glucose) and the mannitol group (M, 1 g/l D-glucose plus 24.4 mM mannitol). The cells were harvested following stimulation with the indicated treatments for 12, 24, 48 and 72 h. Podocyte apoptosis was determined using TUNEL assay and flow cytometry (propidium iodide staining). Glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP/GADD153) and caspase-12 expression was analyzed by RT-PCR, western blot analysis and immunocytochemistry. The apoptotic rate increased significantly in the HG group compared with the NG and M groups at 48 and 72 h (all P<0.01). GRP78 expression, an indicator of ERS, was increased from 12 h, indicating that ERS was activated. Subsequently, two ER-associated death (ERAD) pathways, the CHOP/GADD153- and caspase‑12-dependent pathways, were detected. CHOP/GADD153 expression reached its peak at 48 h, and caspase-12 expression gradually increased with time. Spearman's correlation analysis revealed that caspase-12 and CHOP/GADD153 positively correlated with the apoptotic rate (r=0.915, P<0.01 and r=0.639, P<0.01). Our results demonstrated that hyperglycemia (high glucose) induced apoptosis partly through ERS in the differentiated mouse podocytes, which possibly contributes to the pathogenesis of DN.

Zhang, Jian-Zheng ; Liu, Zhi ; Liu, Jia ; Ren, Ji-Xin ; Sun, Tian-Sheng

doi: 10.3892/ijmm.2014.1650pmid: 24535292

Mitochondrial DNA (mtDNA) contains unmethylated CpG motifs that exhibit immune stimulatory capacities. The aim of this study was to investigate whether mtDNA activates the Toll-like receptor 9 (TLR9)/nuclear factor-κB (NF-κB) pathway, thereby contributing to post-traumatic systemic inflammatory response syndrome (SIRS) and lung injury in rats. The effects of mtDNA on macrophage culture were examined in order to elucidate the putative cellular mechanisms. Rats and macrophage cultures were treated with phosphate-buffered saline, nuclear DNA, or mtDNA for 2, 4, 8 and 24 h. Histological analysis of lung tissue was undertaken following hematoxylin and eosin staining, and cytokine levels were assessed by ELISA. NF-κB and IκB-α phosphorylation levels, as well as TLR9 protein expression were determined by western blot analysis; NF-κB, IκB-α and TLR9 mRNA levels were analyzed by RT-PCR. A greater degree of inflammation and lung injury was observed in response to mtDNA. In addition, mtDNA increased serum tumor necrosis factor-α, interleukin (IL)-6 and IL-10 levels in vivo and increased their secretion by cultured macrophages (p<0.05). In lung tissue, mtDNA increased NF-κB, IκB-α and TLR9 mRNA levels (p<0.05); it also increased phosphorylated NF-κB p65 and TLR9 protein levels in the macrophage cultures. Thus, mtDNA may be part of the danger-associated molecular patterns, contributing to the initiation of sterile SIRS through the activation of the TLR9/NF-κB pathway and the induction of pro-inflammatory cytokine production.

Wang, Sha ; Liu, Shuangzhen ; Mao, Junfeng ; Wen, Dan

doi: 10.3892/ijmm.2014.1651pmid: 24535401

Zonula occludens-1 (ZO-1) and occludin are important tight junction (TJ)-associated proteins, which are expressed in the retinal pigment epithelium (RPE)-choroid complex. Retinoic acid (RA) is a regulator of eye growth and may play an important role in forming functional TJs. The aim of this study was to detect the changes that occur in the expression of ZO-1 and occludin in the RPE-choroid complex of guinea pigs with lens-induced myopia (LIM), and to investigate the effect of RA on TJ-associated proteins in vivo. We developed an animal model of myopia by placing a -6.00 D negative lens on the right eyes of 3-week‑old guinea pigs. The refractive error and axial length of the eye were measured on days 0, 3, 7 and 14. High-performance liquid chromatography (HPLC) was performed to detect the changes in endogenous RA in the RPE-choroid complex. The expression of ZO-1 and occludin was observed by immunofluorescence and assayed by western blot analysis. Additionally, 2 µl LE540 (2.5 µg/µl), an antagonist of RA receptors (RARs), was injected into the vitreous chamber of the eyes of guinea pigs with LIM and 2 µl phosphate-buffered saline (PBS) (2.5 µg/µl) were injected as a negative control. We observed no obvious change in RA, ZO-1 and occludin expression in the normal control group within 14 days. In the LIM and LIM plus PBS groups, the level of RA and the expression of ZO-1 and occludin in the RPE-choroid complex significantly increased within 14 days along with the development of myopia. However, the level of RA was inhibited and the expression of TJ-associated proteins decreased in the eyes of guinea pigs with LIM following the injection of LE540. Thus, we consider that the expression of ZO-1 and occludin is increased in the RPE-choroid complex during the development of myopia. This change in expression may be regulated by RA, a factor known to be involved in the regulation of eye growth.

Ackermann, Maximilian ; Pabst, Andreas M.; Houdek, Jan P.; Ziebart, Thomas P.; Konerding, Moritz A.

doi: 10.3892/ijmm.2014.1630pmid: 24452195

In the present study, we investigated whether proangiogenic growth factors and endothelial progenitor cells (EPCs) induce favourable effects on cutaneous incisional wound healing in diabetic mice. The proangiogenic effects of human EPCs were initially analyzed using a HUVEC in vitro angiogenesis assay and an in vivo Matrigel assay in nude mice (n=12). For the diabetic wound model, 48 Balb/c mice with streptozotocin (STZ)-induced diabetes were divided randomly into 4 groups (12 mice in each group). Subsequently, 3, 5 and 7 days before a 15‑mm full-thickness incisional skin wound was set, group 1 was pre-treated subcutaneously with a mixture of vascular endothelial growth factor (VEGF)/basic fibroblast growth factor (bFGF)/platelet-derived growth factor (PDGF) (3.5 µg of each), group 2 with 3.5 µg PDGF and group 3 with an aliquot of two million EPCs, whereas the control animals (group 4) were pre-treated with 0.2 ml saline solution. The wounds were assessed daily and the repaired tissues were harvested 7 days after complete wound closure. The angiogenesis assay demonstrated significantly increased sprout densities, areas and lengths in the EPC-treated group (all p<0.01). In the Matrigel assay, significantly increased microvessel densities, areas and sizes (all p<0.001) were also detected in the EPC-treated group. In the STZ-induced model of diabetes, the animals pre-treated with a combination of proangiogenic factors and EPCs showed in general, a more rapid wound closure. Vessel densities were >2-fold higher in the mice treated with a combination of proangiogenic factors and EPCs (p<0.05) and tensile strengths were higher in the groups treated with proangiogenic growth factors compared to the controls (p<0.05). These results suggest a beneficial effect of pre-treatment with proangiogenic growth factors and EPCs in incisional wound healing.