Current Molecular Medicine - Volume 15, Issue 8, 2015

Besides being involved in the gradual formation of blood vessels during embryonic development, vascular remodeling also contributes to the progression of various cardiovascular diseases, such as; myocardial infarction, heart failure, atherosclerosis, pulmonary artery hypertension, restenosis, aneurysm, etc. The integrated mechanisms; proliferation of medial smooth muscle cell, dysregulation of intimal endothelial cell, activation of adventitial fibroblast, inflammation of macrophage, and the participation of extracellular matrix proteins are important factors in vascular remodeling. In the recent studies, microRNAs (miRs) have been shown to be expressed in all of these cell-types and play important roles in the mechanisms of vascular remodeling. Therefore, some miRs may be involved in prevention and others in the aggravation of the vascular lesions. miRs are small, endogenous, conserved, single-stranded, non-coding RNAs; which degrade target RNAs or inhibit translation post-transcriptionally. In this paper, we reviewed the function and mechanisms of miRs, which are highly expressed in various cells types, especially endothelial and smooth muscle cells, which are closely involved in the process of vascular remodeling. We also assess the functions of these miRs in the hope that they may provide new possibilities of diagnosis and treatment choices for the related diseases.

Endometriosis is one of the most common gynecological inflammatory diseases, occurring in adolescents and women in the reproductive age group and leading to infertility. The precise etiopathogenesis of endometriosis is unknown, but several theories concerning the phenomena involved in its development have been proposed. Beside classic retrograde menstruation, these include lymphatic and vascular metastases, iatrogenic direct implantation, coelomic metaplasia, embryonic remnants and mesenchymal cell differentiation or induction; the persistence of a form of embryonic endometriosis may also be involved, as well as the theory of the possible role of endometrial stem/progenitor cells. This paper deals with other risk factors which may be potentially involved in the etiopathogenesis of endometriosis, including the immune, inflammatory, endocrine, genetic, anatomical and environmental factors. At present, endometriosis can only be diagnosed with surgery, where laparoscopy is considered a gold standard. Therefore, there is an urgent need for a test allowing to detect non-invasive molecular biomarkers to identify the symptoms of endometriosis early on in disease development. A thorough understanding of the etiopathogenesis of endometriosis is essential toward the development of novel diagnostic assays and effective treatments of the disease.

Integrins are a large family of transmembrane heterodimeric proteins that constitute the main receptors for extracellular matrix components. Integrins were initially thought to be primarily involved in the maintenance of cell adhesion and tissue integrity. However, it is now appreciated that integrins play important roles in many other biological processes such as cell survival, proliferation, differentiation, migration, cell shape and polarity. Lung cells express numerous combinations and permutations of integrin heterodimers. The complexity and diversity of different integrin heterodimers being implicated in different lung diseases present a major challenge for drug development. Here we provide a comprehensive overview of the current knowledge of integrins from studies in cell culture to integrin knockout mouse models and provide an update of results from clinical trials for which integrins are therapeutic targets with a focus on respiratory diseases (asthma, emphysema, pneumonia, lung cancer, pulmonary fibrosis and sarcoidosis).

Eukaryotic cells respond to various types of stresses caused by changes in the extracellular environment. Intracellular factors, such as the accumulation of misfolded proteins in the endoplasmic reticulum (ER), also cause stress and activate the unfolded protein response (UPR), which induces the expression of chaperones and proteins involved in the recovery process. However, if the stress is excessive or sustained, and ER function cannot be restored, the UPR triggers apoptosis, thereby removing the affected cell. It is now apparent that ER stress is also a potent trigger for autophagy, a self-degradative process that has an adaptive function. This review surveys the intersection of ER stress and autophagy and highlights the potential therapeutic implications thereof.

Lysosomal storage diseases (LSDs) is a group consisting of over 50 disorders caused mostly by dysfunctions of lysosomal proteins and resultant accumulation of particular compounds inside cells and extracellular volumes in affected organisms. Genetic diseases are among the most difficult targets for medical treatment. Nevertheless, understanding of molecular bases of LSDs made it possible to develop novel procedures of treatment, employing molecular medicine. Although various therapeutic approaches have been proposed, and some of them were introduced into clinical practice, none of them was found to be effective in correcting all symptoms in treated patients. Central nervous system and skeleton appear to be the most difficult targets to be improved. Therefore, a proposal appeared that perhaps no single therapeutic procedure may be fully effective in treatment of LSD patients, and only combination of two or more approaches could be a successful therapy. In this review, we present and discuss current stage of various combination therapies for LSDs, based on already available published data.

Parvalbumins (PVALBs) are particularly abundant in the fast-contracting muscles and correlate positively with muscle relaxation speed in amphibians and fishes. MiRNAs play important roles in diverse biologic processes via binding to the 3’ untranslated region (3’UTR) of the target mRNAs. In the study, four PVALB isoforms, named as PVALB1, 2, 3, and 4, were identified in the mandarin fish (Siniperca chuatsi) fast muscle and PVALB4 exhibited the highest expression level among them. By bioinformatics analysis, a putative miR-181a binding site in PVALB4 was detected and the direct interaction between miR-181a and PVALB4 was confirmed with the luciferase reporter assay. Further, when miR-181a was inhibited, it substantially increased PVALB4 mRNA expression level and the muscle relaxation rate in vivo. Taken together, the obtained results suggest that miRNA-181a/PVALB4 is an evolutionarily conserved miRNAtarget pair and their interaction is correlated with muscle relaxation rate in the mandarin fish. Therefore, the study revealed a novel molecular mechanism in the regulation of skeletal muscle relaxation in fish.

Osteoporosis has become a world-wide health problem. As a promising intervention, mechanical strain is considered to be an important factor in bone remodeling. However, the underlying mechanisms are still not clarified clearly. In the present study, we aim to investigate the possible mechanism by which mechanical stimulation induces osteogenic differentiation of bone mesenchymal stem cells (BMSCs) from ovariectomized rats (OVX BMSCs). The results demonstrated that intermittent mechanical strain (IMS) promoted osteogenic differentiation of OVX BMSCs by activating Runt-related transcription factor 2 (Runx2). When the extracellular regulated kinase1/2-mitogen activated protein kinases (ERK1/2-MAPK) signaling pathway was blocked, the osteogenenic effects of IMS were diminished; while blocking of the p38-MAPK signaling pathway had little effect on subsequent osteogenic events. In addition, the phosphorylation level of JNK was not affected by IMS. Our results indicated that strain-induced osteogenic differentiation of OVX BMSCs may take effect via ERK1/2-MAPK not p38 or c-Jun N-terminal (JNK)-MAPK signaling pathway. These findings may have implications for physical treatment of osteoporosis in vitro.

Diabetic retinopathy (DR) is a leading cause of blindness in adults at working age. Human diabetic retinopathy is characterized by the basement membrane thick, pericytes loss, microaneurysms formation, retina neovascularization and vitreous hemorrhage. To investigate whether UPP activated ROS/PARP and NF-ΚB inflammatory factor pathways in Diabetic Retinopathy, human retinal endothelial cells (HRECs) and rats with streptozotocin-induced diabetes were used to determine the effect of UPP on ROS generation, cell apoptosis, mitochondrial membrane potential (ΔΨm) and inflammatory factor protein expression, through flow cytometry assay, immunohistochemistry, Real-time PCR, Western blot analysis and ELISA. The levels of ROS and apoptosis and the expressions of UPP (Ub and E3) and inflammatory factor protein were increased in high glucose-induced HRECs and retina of diabetic rats, while ΔΨm was decreased. The UPP inhibitor and UbshRNA could attenuate these effects through inhibiting the pathway of ROS/PARP and the expression of NF-ΚB inflammatory factors, and the increased UPP was a result of high glucose-induced increase of ROS generation and NF-ΚBp65 expression, accompanied with the decrease of ΔΨm. Clinical study showed the overexpression of UPP and detachment of epiretinal membranes in proliferative DR (PDR) patients. It has been indicated that the pathogenic effect of UPP on DR was involved in the increase of ROS generation and NF-ΚB expression, which associated with the ROS/PARP and NF-ΚB inflammatory factor pathways. Our study supports a new insight for further application of UPP inhibitor in DR treatment.