MicroRNAs as Diagnostic, Prognostic, and Therapeutic Biomarkers in Prostate Cancer.

Prostate cancer is the most prevalent nonskin cancer and a major cause of cancer-related deaths worldwide. Prostate-specific antigen (PSA) testing is routinely used for screening and early detection of prostate cancer; however, it does not reduce death from prostate cancer. Moreover, PSA is not specific for prostate cancer and results in high false-positive rates, and it is poorly correlated with cancer stage. Therefore, the need for another diagnostic and prognostic factor in prostate cancer is apparent. MicroRNAs (miRNAs) are small, single-stranded, noncoding RNAs which are involved in modulation of gene expression posttranscriptionally. Multiple lines of evidence indicate that miRNAs play key roles in various physiological events. Deregulation of miRNAs is related to initiation and development of various diseases such as prostate cancer. It has been shown that various miRNAs (miR-34, miR-21, miR-155, miR-221, miR-222, and let-7) exert their effects by targeting a variety of cellular and molecular pathways (c-Myc, EZH2, c-RSC, BCL2L2, E2F6, ZEB, HMGA251, and CCND2) involved in prostate cancer pathogenesis. Hence, it seems that miRNA expression profiles can be seen as potential candidates for prognosis, diagnosis, and treatment of prostate cancer. Here, we summarize various miRNAs as prognostic, diagnostic, and therapeutic biomarkers for prostate cancer therapy.

NLRP3 inflammasome: Its regulation and involvement in atherosclerosis.

Inflammasomes are intracellular complexes involved in the innate immunity that convert proIL-1ß and proIL-18 to mature forms and initiate pyroptosis via cleaving procaspase-1. The most well-known inflammasome is NLRP3. Several studies have indicated a decisive and important role of NLRP3 inflammasome, IL-1ß, IL-18, and pyroptosis in atherosclerosis. Modern hypotheses introduce atherosclerosis as an inflammatory/lipid-based disease and NLRP3 inflammasome has been considered as a link between lipid metabolism and inflammation because crystalline cholesterol and oxidized low-density lipoprotein (oxLDL) (two abundant components in atherosclerotic plaques) activate NLRP3 inflammasome. In addition, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and lysosome rupture, which are implicated in inflammasome activation, have been discussed as important events in atherosclerosis. In spite of these clues, some studies have reported that NLRP3 inflammasome has no significant effect in atherogenesis. Our review reveals that some molecules such as JNK-1 and ASK-1 (upstream regulators of inflammasome activation) can reduce atherosclerosis through inducing apoptosis in macrophages. Notably, NLRP3 inflammasome can also cause apoptosis in macrophages, suggesting that NLRP3 inflammasome may mediate JNK-induced apoptosis, and the apoptotic function of NLRP3 inflammasome may be a reason for the conflicting results reported. The present review shows that the role of NLRP3 in atherogenesis can be significant. Here, the molecular pathways of NLRP3 inflammasome activation and the implications of this activation in atherosclerosis are explained.

GD2-targeted immunotherapy and potential value of circulating microRNAs in neuroblastoma.

Neuroblastoma (NB) with various clinical presentation is a known childhood malignancy. Despite significant progress in treatment of NB afflicted patients, high risk disease is usually associated with poor outcome, resulting in long-term survival of less that 50%. Known as a disease most commonly originated form the nerve roots, the variants involved in NB imitation and progression remain to be elucidated. The outcome of low to intermediate risk disease is favorable whereas the high risk NB disease with dismal prognosis, positing the necessity of novel approaches for early detection and prognostication of advanced disease. Tailored immunotherapy approaches have shown significant improvement in high-risk NB patients. It has found a link between Gangliosides and progression of NB. The vast majority of neuroblastoma tumors express elevated levels of GD2, opening new insight into using anti-GD2 drugs as potential treatments for NBs. Implication of anti-GD2 monoclonal antibodies for treatment of high risk NBs triggers further investigation to unearth novel biomarkers as prognostic and response biomarker to guide additional multimodal tailored treatment approaches. A growing body of evidence supports the usefulness of miRNAs to evaluate high risk NBs response to anti-GD2 drugs and further prevent drug-related toxicities in refractory or recurrent NBs. miRNAs and circulating proteins in body fluids (plasma and serum) present as potential biomarkers in early detection of NBs. Here, we summarize various biomarkers involved in diagnosis, prognosis and response to treatment in patients with NB. We further attempted to overview prognostic biomarkers in response to treatment with anti-GD2 drugs.

Nanoparticles as new tools for inhibition of cancer angiogenesis.

Angiogenesis is known as one of the hallmarks of cancer. Multiple lines evidence indicated that vascular endothelium growth factor (VEGF) is a key player in the progression of angiogenesis and exerts its functions via interaction with tyrosine kinase receptors (TKRs). These receptors could trigger a variety of cascades that lead to the supply of oxygen and nutrients to tumor cells and survival of these cells. With respect to pivotal role of angiogenesis in the tumor growth and survival, finding new therapeutic approaches via targeting angiogenesis could open a new horizon in cancer therapy. Among various types of therapeutic strategies, nanotechnology has emerged as new approach for the treatment of various cancers. Nanoparticles (NPs) could be used as effective tools for targeting a variety of therapeutic agents. According to in vitro and in vivo studies, NPs are efficient in depriving tumor cells from nutrients and oxygen by inhibiting angiogenesis. However, the utilization of NPs are associated with a variety of limitations. It seems that new approaches such as NPs conjugated with hydrogels could overcome to some limitations. In the present review, we summarize various mechanisms involved in angiogenesis, common anti-angiogenesis strategies, and application of NPs for targeting angiogenesis in various cancers.

MicroRNAs in retinoblastoma: Potential diagnostic and therapeutic biomarkers.

Retinoblastoma (Rb) is known as one of important childhood malignancies which due to inactivation of the RB gene (tumor suppressor gene in various patients). The early detection of Rb could provide better treatment for Rb patients. Imaging techniques (e.g., MRI and CT) are known as one of effective diagnosis approaches for detection of patients with Rb. It has been shown that utilization of imaging techniques is associated with some limitations. Hence, identification of new diagnosis approaches might provide a better treatment for Rb patients. Identification of new biomarkers could contribute to better understanding of pathogenesis events involved in Rb and provide new insights into design better treatment approaches for these patients. Among the various biomarkers, microRNAs (miRNAs) have emerged as attractive tools for Rb detection. miRNAs are one classes of small non-coding RNAs which could anticipate in a variety of biological process via targeting sequence of cellular and molecular pathways. Deregulations of these molecules are associated with cancerous condition. Multiple lines of evidence indicated that deregulation of various miRNAs involved in various stages of Rb. Here, we summarized a variety of tissue-specific and circulating miRNAs involved in Rb pathogenesis which could be used as diagnostic, prognostic, and therapeutic biomarkers in Rb patients.

Angiogenesis biomarkers and their targeting ligands as potential targets for tumor angiogenesis.

Angiogenesis is known as one of the hallmarks in cancer which could play a key role in providing oxygen and nutrients for tumor cells. It has been shown that tumor cannot grow without sufficient development of new blood vessels. Accordingly, targeting angiogenesis, especially endothelial cells, could be considered as a common therapeutic target in tumors and more investigation on already existing biomarkers and potentially new biomarkers of endothelial cells seems to be necessary in cancer therapy. Moreover, the use of effective targeting approaches such as proteins and peptides, aptamers, and small molecules is an important step for targeting biomarkers associated with endothelial cells and angiogenesis in cancer therapy. These agents are FDA approved, or are currently under investigation in pre-clinical and clinical studies. Among various biomarkers for angiogenesis microRNAs are suitable candidates for target therapy. These molecules play key roles in tumor angiogenesis which exert their effect via targeting a variety of cellular and molecular pathways involved in tumor angiogenesis. Here, we summarize a variety of biomarkers which their expressions or their functions could change the function of endothelial cells in tumor microenvironments. Moreover, we highlighted various therapeutic agents which could target these biomarkers.

Therapeutic application of multipotent stem cells.

Cell therapy is an emerging fields in the treatment of various diseases such as cardiovascular, pulmonary, hepatic, and neoplastic diseases. Stem cells are an integral tool for cell therapy. Multipotent stem cells are an important class of stem cells which have the ability to self-renew through dividing and developing into multiple specific cell types in a specific tissue or organ. These cells are capable to activate or inhibit a sequence of cellular and molecular pathways leading to anti-inflammatory and anti-apoptotic effects which might contribute to the treatment of various diseases. It has been showed that multipotent stem cells exert their therapeutic effects via inhibition/activation of a sequence of cellular and molecular pathways. Although the advantages of multipotent stem cells are numerous, further investigation is still necessary to clarify the biology and safety of these cells before they could be considered as a potential treatment for different types of diseases. This review summarizes different features of multipotent stem cells including isolation, differentiation, and therapeutic applications.

MicroRNA: Relevance to stroke diagnosis, prognosis, and therapy.

Stroke is a life-threatening disease that accounts for a considerable burden of mortality in both developing and developed world. Identification of specific biomarkers for stroke and its outcomes can greatly contribute to improved care of patients. MicroRNAs (miRNAs) are known as novel biomarkers that could be used as diagnostic, prognostic, and therapeutic biomarkers. Various studies have shown that miRNAs have key roles in the pathogenesis of stroke, and its complications and outcomes. In addition, there is evidence showing that mesenchaymal stromal cell-derived exosomes containing miRNAs can be used for monitoring and treatment of various diseases such as stroke. Here, we summarized various aspects of miRNA applications in different stages of stroke.

MicroRNA: A novel target of curcumin in cancer therapy.

Curcumin is known as a natural dietary polyphenol which is extracted from Curcuma longa L. It has been shown that curcumin has a variety of pharmacological effects such as antioxidant, anti-cancer, anti-inflammatory, and anti-microbial activities. Anti-cancer effects of curcumin are due to targeting of a wide range of cellular and molecular pathways involved in cancer pathogenesis including NF-kB, MAPK, PTEN, P53, and microRNAs (miRNA) network. Multiple lines of evidence have indicated that curcumin exerts its therapeutic effects via regulating miRNA expression (e.g., miR-1, miR-7, miR-9, miR-34a, miR-181, miR-21, and miR-19) which could lead to the regulation of underlying cellular and molecular pathways involved in cancer pathogenesis. Exosomes are one of the important classes of biological vehicles which could be released from various types of cells such as cancer cells and stem cells and could change the behavior of recipient cells. It has been shown that treatment of cancer cells with different dose of curcumin leads to the release of exosomes containing curcumin. These exosomes could induce anti-cancer properties in recipient cells and reduce tumor growth. Hence, exosomes containing curcumin could be applied as powerful tools for cancer treatment. Here, we highlighted various miRNAs which could be affected by curcumin in various types of cancer. Moreover, we highlight exosomes containing curcumin as suitable therapeutic tools in cancer therapy.

State of the art in microRNA as diagnostic and therapeutic biomarkers in chronic lymphocytic leukemia.

Early diagnostic is one of the most important steps in cancer therapy which helps to design and choose a better therapeutic approach. The finding of biomarkers in various levels including genomics, transcriptomics, and proteomics levels could provide better treatment for various cancers such as chronic lymphocytic leukemia (CLL). The CLL is the one of main lymphoid malignancies which is specified by aggregation of mature B lymphocytes. Among different biomarkers (e.g., CD38, chromosomes abnormalities, ZAP-70, TP53, and microRNA [miRNA]), miRNAs have appeared as new diagnostic and therapeutic biomarkers in patients with the CLL disease. Multiple lines of evidence indicated that deregulation of miRNAs could be associated with pathological events which are present in the CLL. These molecules have an effect on a variety of targets such as Bcl2, c-fos, c-Myc, TP53, TCL1, and STAT3 which play critical roles in the CLL pathogenesis. It has been shown that expression of miRNAs could lead to the activation of B cells and B cell antigen receptor (BCR). Moreover, exosomes containing miRNAs are one of the other molecules which could contribute to BCR stimulation and progression of CLL cells. Hence, miRNAs and exosomes released from CLL cells could be used as potential diagnostic and therapeutic biomarkers for CLL. This critical review focuses on a very important aspect of CLL based on biomarker discovery covers the pros and cons of using miRNAs as important diagnostics and therapeutics biomarkers for this deadly disease.

Plasminogen Activator Inhibitor Type-1 as a Regulator of Fibrosis.

Fibrosis is known as a frequent and irreversible pathological condition which is associated with organ failure. Tissue fibrosis is a central process in a variety of chronic progressive diseases such as diabetes, hypertension, and persistent inflammation. This state could contribute to chronic injury and the initiation of tissue repair. Fibrotic disorders represent abnormal wound healing with defective matrix turnover and clearance that lead to excessive accumulation of extracellular matrix components. A variety of identified growth factors, cytokines, and persistently activated myofibroblasts have critical roles in the pathogenesis of fibrosis. Irrespective of etiology, the transforming growth factor-ß pathway is the major driver of fibrotic response. Plasminogen activator inhibitor-1 (PAI-1) is a crucial downstream target of this pathway. Transforming growth factor-ß positively regulates PAI-1 gene expression via two main pathways including Smad-mediated canonical and non-canonical pathways. Overexpression of PAI-1 reduces extracellular matrix degradation via perturbing the plasminogen activation system. Indeed, elevated PAI-1 levels inhibit proteolytic activity of tissue plasminogen activator and urokinase plasminogen activator which could contribute to a variety of inflammatory elements in the injury site and to excessive matrix deposition. This review summarizes the current knowledge of critical pathways that regulate PAI-1 gene expression and suggests effective approaches for the treatment of fibrotic disease. J. Cell. Biochem. 119: 17-27, 2018. © 2017 Wiley Periodicals, Inc.

Stem Cell Therapy: A New Therapeutic Option for Cardiovascular Diseases.

Cardiovascular diseases are known as one of major causes of morbidity and mortality worldwide. Despite the many advancement in therapies are associated with cardiovascular diseases, it seems that finding of new therapeutic option is necessary. Cell therapy is one of attractive therapeutic platforms for treatment of a variety of diseases such as cardiovascular diseases. Among of various types of cell therapy, stem cell therapy has been emerged as an effective therapeutic approach in this area. Stem cells divided into multipotent stem cells and pluripotent stem cells. A large number studies indicated that utilization of each of them are associated with a variety of advantages and disadvantages. Multiple lines evidence indicated that stem cell therapy could be used as suitable therapeutic approach for treatment of cardiovascular diseases. Many clinical trials have been performed for assessing efficiency of stem cell therapies in human. However, stem cell therapy are associated with some challenges, but, it seems resolving of them could contribute to using of them as effective therapeutic approach for patients who suffering from cardiovascular diseases. In the current review, we summarized current therapeutic strategies based on stem cells for cardiovascular diseases. J. Cell. Biochem. 119: 95-104, 2018. © 2017 Wiley Periodicals, Inc.

Biosensors for the Detection of Environmental and Urban Pollutions.

Release of harmful pollutants such as heavy metals, pesticides, and pharmaceuticals to the environment is a global concern. Rapid and reproducible detection of these pollutants is thus necessary. Biosensors are the sensitive and high specific tools for detection of environmental pollutants. Broad range various types of biosensors have been fabricated for this purpose. This review focuses on the feature and application of biosensors developed for environmental and urban pollutants detection. J. Cell. Biochem. 119: 207-212, 2018. © 2017 Wiley Periodicals, Inc.

Association between oral lichen planus and Epstein-Barr virus in Iranian patients.

BACKGROUND: Oral lichen planus (OLP) is a common mucocutaneous disease with malignant transformation potential. Several etiologies such as humoral, autoimmunity, and viral infections might play a role, but still there is no definite etiology for this disease. The aim of this study was to investigate the presence of Epstein-Barr virus (EBV) genome in Iranian patients with OLP as compared to people with normal mucosa. MATERIALS AND METHODS: The study was carried out on a case group including 38 tissue specimens of patients with histopathological confirmation of OLP and a control group including 38 samples of healthy mucosa. All samples were examined by nested polymerase chain reaction (PCR) method to determine the DNA of EBV. RESULTS: Twenty-two (57.9%) female samples and 16 (42.1%) male samples with OLP were randomly selected as the case group, and 20 (52.6%) female samples and 18 (47.4%) male samples with healthy mucosa as the control group. There was a statistically significant difference in the percentage of EBV positivity between the case (15.8%) and the control groups (P < 0.05); in the case group, three female samples (13.6%) and three male samples (18.8%) were infected with EBV; the difference between the genders was not statistically significant (P = 0.50). CONCLUSION: Results emphasized that EBV genome was significantly higher among Iranian patients with OLP so antiviral therapy might be helpful.

Implantation Window and Angiogenesis.

In recent decades, infertility is one of the health problems worldwide. One of the most crucial events in reproductive period is implantation window (IW). In the time after IW period, the embryo cannot connect to the endometrium; therefore the most critical issue for successful implantation is timely entrance of embryo to the uterine cavity during the IW. Implantation failure is responsible for many cases of infertility and is the most important limiting factor for achieving a successful outcome using the assisted reproductive techniques (ART). The aim of this study was to investigate the receptivity of the endometrium and factors affecting it with emphasizing on the role of angiogenesis. Interaction between the embryo and the endometrium is affected by molecular interactions among cytokines, growth factors, hormones, and cell adhesion molecules, causing endometrial receptivity. Also, angiogenesis is a process that has an important role in human implantation. Estrogen and progesterone hormones are two important regulation keys in angiogenesis and implantation process. It is expected that effective and stimulating drugs of angiogenesis can improve the characteristics of endometrial receptivity and prevent implantation failure in ART. It is hoped that with recent advances in the field of molecular medicine, improvement of angiogenesis in human endometrium and prevention of the implantation failure be achieved. Here, we summarized various factors could affect on endometrial receptivity and the role of them on angiogenesis. J. Cell. Biochem. 118: 4141-4151, 2017. © 2017 Wiley Periodicals, Inc.

Molecular Imaging and Oral Cancer Diagnosis and Therapy.

Oral cancer is known as one of relatively common type of cancer worldwide. Despite the easy access of the oral cavity to examination, oral tumors are diagnosed in more advanced stages of the disease. Imaging techniques have been recently emerged as non-invasive approaches to detect molecular and cellular changes in living cells and organisms. These techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) could help physicians to screen patients with oral tumors particularly oral squamous cell carcinoma (OSCC) in early stage of the disease. In this review, we discuss that early detection and diagnosis of oral tumors through using more robust and precise imaging techniques and a variety of cellular/molecular biomarkers not only could lead to more effective and less aggressive form of treatment for the disease but also could improve survival rates and lower treatment costs. J. Cell. Biochem. 118: 3055-3060, 2017. © 2017 Wiley Periodicals, Inc.

MicroRNAs-Based Imaging Techniques in Cancer Diagnosis and Therapy.

Cancer is one of the most serious global health concerns in different populations. Several studies indicated that there are many potentially promising cellular and molecular targets for cancer therapy within cancer cells and their microenvironment. Among different cellular and molecular targets involved in cancer pathogenesis, microRNAs (miRNAs) are well known as key targets for cancer therapy. miRNAs are one of main classes of non-coding RNAs. These molecules play important roles in different critical processes of cancer pathogenesis. Hence, this makes miRNAs as a suitable tool for cancer diagnosis and therapy. There are different approaches for monitoring miRNAs in cancer patients. Some conventional approaches including next-generation sequencing, real-time polymerase chain reaction (PCR), northern blotting, and microarrays could be used for assessment of miRNAs expression. Some studies revealed that the utilization of these approaches associated with various limitations. Recently, it has been revealed that molecular imaging techniques are powerful tools for monitoring of different cellular and molecular targets involved in various diseases such as cancer. These techniques help investigators to investigate and monitor miRNAs functions through assessing different targets by fluorescent proteins, bioluminescent enzymes, molecular beacons, as well as various nanoparticles. Therefore, utilization of molecular imaging techniques could assist investigators to better monitor and more effectively treat patients during different phases of malignancy. Here, we give a review on the current state of miRNAs-based imaging techniques in cancer diagnosis and therapy. J. Cell. Biochem. 118: 4121-4128, 2017. © 2017 Wiley Periodicals, Inc.

Retraction notice to "The therapeutic potential of human adipose-derived mesenchymal stem cells producing CXCL10 in a mouse melanoma lung metastasis model" [Cancer Lett. 419 (2018) 30-39].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor. After publication, the Editors were contacted by a concerned reader regarding alleged image duplication. These allegations are in regard to Fig. 3a being duplicated from a previously published paper in the journal Stem Cells (Stem Cells. 2008 Sep;26 (9):2332-8. doi: 10.1634/stemcells.2008-0084) and Fig. 8a being duplicated from a previously published paper in the journal Molecular Cancer (Mol Cancer 13, 255 (2014). https://doi.org/10.1186/1476-4598-13-255). After a thorough investigation by the editorial team, the Editors determined that there are multiple identical details between Fig. 5A (Cancer Letters) and Fig. 3A (Stem Cells) and the authors did not produce satisfactory evidence that the published images in Cancer Letters were original. Due to this, the Editor does not have confidence in the results and conclusions presented and has made the decision to retract.

The therapeutic potential of human adipose-derived mesenchymal stem cells producing CXCL10 in a mouse melanoma lung metastasis model.

Interferon γ-induced protein 10 kDa (IP-10) is a potent chemoattractant and has been suggested to enhance antitumor activity and mediate tumor regression through multiple mechanisms of action. Multiple lines of evidence have indicated that genetically-modified adult stem cells represent a potential source for cell-based cancer therapy. In the current study, we assessed therapeutic potential of human adipose derived mesenchymal stem cells (hADSC) genetically-modified to express IP-10 for the treatment of lung metastasis in an immunocompetent mouse model of metastatic melanoma. A Piggybac vector encoding IP-10 was employed to transfect hADSC ex vivo. Expression and bioactivity of the transgenic protein from hADSCs expressing IP-10 were confirmed prior to in vivo studies. Our results indicated that hADSCs expressing IP-10 could inhibit the growth of B16F10 melanoma cells and significantly prolonged survival. Immunohistochemistry analysis, TUNEL assay and western blot analysis indicated that hADSCs expressing IP-10 inhibited tumor cell growth, hindered tumor infiltration of Tregs, restricted angiogenesis and significantly prolonged survival. In conclusion, our results demonstrated that targeting metastatic tumor sites by hADSC expressing IP-10 could reduce melanoma tumor growth and lung metastasis.