Current Pharmaceutical Design - Volume 24, Issue 39, 2018

Noncoding RNAs play important regulatory roles in diverse biological processes and their misregulation might lead to different diseases, including cancer. Previous studies have reported the evolving role of miRNAs as new potential biomarkers in cancer diagnosis, prognosis, as well as predictive biomarkers of chemotherapy response or therapeutic targets. In this review, we outline the involvement of noncoding RNA in pancreatic cancer, providing an overview of known miRNAs in its diagnosis, prognosis and chemoresistance. In addition, we discuss the influence of non-coding RNAs in the metastatic behavior of pancreatic cancer, as well as the role of diet in epigenetic regulation of non-coding RNAs in cancer, which can, in turn, lead the development of new prevention’s techniques or novel targets for cancer therapy.

Colorectal cancer (CRC) is the leading cause of cancer death worldwide and its incidence is increasing. In most patients with CRC, the PI3K/AKT signaling axis is over-activated. Regulatory oncogenic or tumor suppressor microRNAs (miRNAs) for PI3K/AKT signaling regulate cell proliferation, migration, invasion, angiogenesis, as well as resistance to chemo-/radio-therapy in colorectal cancer tumor tissues. Thus, regulatory miRNAs of PI3K/AKT/mTOR signaling represent novel biomarkers for new patient diagnosis and obtaining clinically invaluable information from post-treatment CRC patients for improving therapeutic strategies. This review summarizes the current knowledge of miRNAs’ regulatory roles of PI3K/AKT signaling in CRC pathogenesis.

Colorectal cancer (CRC) is one of the most common cancers globally and is associated with a high mortality rate. The transforming growth factor beta (TGF-β) signaling pathway plays an important role in normal intestinal tissue function, but has also been implicated in the development of CRC. MicroRNAs (miRNAs) have also recently emerged as important regulators of cancer development and progression. They act by targeting multiple signaling pathways including the TGF-β signaling pathway. There is growing evidence demonstrating that miRNAs target various components of the TGF-β signaling pathway, including TGF-β1, TGF-β2, regulatory SMADs (SMAD1, 2, 3, 5 and 9), co-mediator SMAD4, inhibitory SMADs (SMAD6 and 7) and the TGF-β receptors, and thereby alter the proliferation and migration of CRC cells. In this review, we summarize the data concerning the interaction between TGF-β signaling pathway and miRNAs with the aim to better understanding the CRC molecular mechanisms and hence better management of this disease.

The c-mesenchymal-epithelial transition factor (c-MET) is involved in the tumorigenesis of various cancers. HGF/Met inhibitors are now attracting considerable interest due to their anti-tumor activity in multiple malignancies such as pancreatic cancer. It is likely that within the next few years, HGF/Met inhibitors will become a crucial component for cancer management. In this review, we summarize the role of HGF/Met pathway in the pathogenesis of pancreatic cancer, with particular emphasize on HGF/Met inhibitors in the clinical setting, including Cabozantinib (XL184, BMS-907351), Crizotinib (PF-02341066), MK-2461, Merestinib (LY2801653), Tivantinib (ARQ197), SU11274, Onartuzumab (MetMab), Emibetuzumab (LY2875358), Ficlatuzumab (AV- 299), Rilotumumab (AMG 102), and NK4 in pancreatic cancer.

Background: Colorectal cancer (CRC) is one of the most common causes of cancer-associated mortality in the world. Anti-tumor effect of curcumin has been shown in different cancers; however, the therapeutic potential of novel phytosomal curcumin, as well as the underlying molecular mechanism in CRC, has not yet been explored. Methods: The anti-proliferative, anti-migratory and apoptotic activity of phytosomal curcumin in CT26 cells was assessed by MTT assay, wound healing assay and Flow cytometry, respectively. Phytosomal curcumin was also tested for its in-vivo activity in a xenograft mouse model of CRC. In addition, oxidant/antioxidant activity was examined by DCFH-DA assay in vitro, measurement of malondialdehyde (MDA), Thiol and superoxidedismutase (SOD) and catalase (CAT) activity and also evaluation of expression levels of Nrf2 and GCLM by qRT-PCR in tumor tissues. In addition, the effect of phytosomal curcumin on angiogenesis was assessed by the measurement of VEGF-A and VEGFR-1 and VEGF signaling regulatory microRNAs (miRNAs) in tumor tissue. Results: Phytosomal curcumin exerts anti-proliferative, anti-migratory and apoptotic activity in-vitro. It also decreases tumor growth and augmented 5-fluorouracil (5-FU) anti-tumor effect in-vivo. In addition, our data showed that induction of oxidative stress and inhibition of angiogenesis through modulation of VEGF signaling regulatory miRNAs might be underlying mechanisms by which phytosomal curcumin exerted its antitumor effect. Conclusion: Our data confirmed this notion that phytosomal curcumin administrates anticancer effects and can be used as a complementary treatment in clinical settings.

Gastric cancer (GC) has a high mortality rate with a poor 5-year survival. Helicobacter pylori (H. pylori) is present as part of the normal flora of stomach. It is found in the gastric mucosa of more than half of the world population. This bacterium is involved in developing H. pylori-induced GC due to the regulation of different micro ribonucleic acid (miRNA or miR). miRNAs are small noncoding RNAs and are recognized as prognostic biomarkers for GC that may control gene expression. miRNAs may function as tumor suppressors, or oncogenes. In this review, we evaluated studies that investigated the ectopic expression of miRNAs in the prognosis of H. pylori positive and negative GC.

The Phosphatidylinositol 3-kinase/AKT/Mammalian Target of Rapamycin (PI3K/AKT/mTOR) pathway has a critical regulatory role in cell biology including translation, transcription, and autophagy. Dysregulation of this pathway is involved in the pathogenesis, development, and prognosis of esophageal cancer that has been assessed in the recent years and its potential as a target in therapy. This report summarizes the current knowledge about PI3K/AKT/mTOR pathway and its cross-talk with a focus on the value of targeting this pathway as a potential therapeutic target in the treatment of esophageal cancer.

Colorectal cancer (CRC) is one of the most common causes of cancer-related death in the world. There is a document that angiotensin (AT) which is found to be involved in the progression of CRC. Furthermore, Angiotensin receptor inhibitors (ARIs) and angiotensin-converting enzyme Inhibitors (ACE-Is) demonstrate activity in CRC by their inhibition of both Insulin-like growth factor 1 (IGF-1) and Vascular endothelial growth factor (VEGF), and therefore present a potentially novel therapeutic strategy in colorectal cancer, which have summarized in the current review. Preclinical studies have illustrated the direct effect of major active mediator angiotensin II (ATII) on the promotion of angiogenesis through VEGF and other proliferative mediators. Suppression of the angiotensin II type I receptor (AT1R) via ACE-Is has shown a reduction in the development of solid tumor and metastasis, particularly CRC incidence, polyp formation, and distant metastasis. MicroRNAs (miRs) are a family of small nucleotides without coding that plays an important role after transcribing hundreds to thousands of non-coding and coding gene. Against this background, the application of anti-hypertensive medications such as losartan might have a therapeutic impact, although further preclinical and clinical studies might provide novel insight into the potentially beneficial effect of ACE-Is in the treatment of colorectal cancer patients.

MicroRNAs (miRNAs) are non-coding RNAs with 19 to 24 nucleotides which are evolutionally conserved. MicroRNAs play a regulatory role in many cellular functions such as immune mechanisms, apoptosis, and tumorigenesis. The main function of miRNAs is the post-transcriptional regulation of gene expression via mRNA degradation or inhibition of translation. In fact, many of them act as an oncogene or tumor suppressor. These molecular structures participate in many physiological and pathological processes of the cell. The virus can also produce them for developing its pathogenic processes. It was initially thought that viruses without nuclear replication cycle such as Poxviridae and RNA viruses can not code miRNA, but recently, it has been proven that RNA viruses can also produce miRNA. The aim of this articles is to describe viral miRNAs biogenesis and their effects on cellular and viral genes.

Angiogenesis refers to the formation of recent blood vessels, which is one of the characteristics of cancer progression and it has been deliberated as a putative target to the treatment of many kinds of cancers. The VEGF signaling substrate is very important for angiogenesis and is commonly high-regulated in tumors. As a result, this molecule has attracted the attention of most of the researchers to develop antiangiogenic therapies. We have presented that VEGF blockage in neoadjuvant setting via bevacizumab, aflibercept and sunitinib not only has revealed some promising benefits but also has shown a large negative outcome in the adjuvant trials. However, at an advanced stage of tumors, suppression of VEGF alone is inadequate to stop advancement, encouraging drug resistance, and probably enhancing metastasis and invasion in the tumor microenvironment, thereby suggesting the therapeutic potential of targeting angiogenic pathways in gastrointestinal cancers.

Small noncoding microRNAs (miRNAs) are known as noninvasive biomarkers for early detection in various cancers. In fact, miRNAs have key roles in carcinogenicity process such as proliferation, apoptosis and metastasis. After cardiovascular disease, cancer is the second cause of death in the world with an estimated 9.6 million deaths in 2018. So, early diagnosis of cancer is critical for successful treatment. To date, several selective and sensitive laboratory-based methods have been applied for the detection of circulating miRNA, but a simple, short assay time and low-cost method such as a biosensor method as an alternative approach to monitor cancer biomarker is required. In this review, we have highlighted recent advances in biosensors for circulating miRNA detection.

Atherosclerosis provokes a continuous worsening of affected vessels causing a blood flow diminution with several complications and with clinical manifestations that generally appear in advanced phases of the illness. Hence, the conventional therapies are not enough because the atherosclerotic injuries are often irrevocable. For this reason, emerges the necessity to implement smart ways of drug supply and develop new therapeutic targets that decrease the advance atherosclerotic lesion. It results due to particular interest to use new tools for prevention, diagnosis, and treatment of this cardiovascular disease, thus concentrating our attention to accomplish better management on the immune system. Finally, this mini-review highlights the most recent knowledge about nanotechnology as a robust, novel and promissory therapeutic option applied to atherosclerotic pathology, nevertheless, we also alert for possible issues associated with their use.

Background: Polycystic ovary syndrome (PCOS) is a frequent female reproductive endocrine disease. It has been associated with a number of severe reproductive and metabolic abnormalities. However, there are still open questions especially regarding the best long-term management. Methods: We summarized the literature focused on the symptoms and negative long-term consequences of untreated PCOS and the existing options for the treatment. We reviewed the Pubmed and China National Knowledge Infrastructure databases and the relevant literature for the last 20 years. Included in this review also are new results of own (published) research and own experience from treating daily more than 100 PCOS patients. Results: Obesity is one of the most common findings. It can cause abnormal ovulations which can lead to infertility. Important long-term consequences can be adverse pregnancy outcomes. There is an agreement that the risk of endometrial cancer can be increased. Insulin resistance, important within the pathophysiology of PCOS, predisposes patients to metabolic dysfunction and increased risk of type 2 diabetes mellitus. Lifestyle modifications including dietary changes, exercise and weight loss are first-line interventions for many patients. Well known drug treatments such as metformin, oral contraceptives, etc. should be selected according to the individual situation and patients' needs. Regarding newer methods in the long-term management of PCOS, we found that orlistat may help to achieve weight loss and to improve lipid and glucose metabolism. Conclusion: In addition to pharmacological interventions, long-term standardized individualized management of PCOS patients is needed to achieve fertility and to reduce the risk of metabolic related diseases.

Parkinson's disease is the second most common neurodegenerative disorder in adults over the age of 65. The characteristic symptoms of Parkinson's disease, such as resting tremor, muscular rigidity, bradykinesia, postural instability and gait imbalance, are thought to be a result of the progressive degeneration of the dopaminergic neurons of the substantia nigra compacta, resulting in insufficient dopamine integrated signalling on GABAergic medium spiny neurons in the striatum. Despite tremendous research, the molecular mechanisms underlying the pathogenesis of neurodegeneration in Parkinson's disease have remained largely unknown. Although a variety of possible pathogenic mechanisms have been proposed over the years, including excessive release of oxygen free radicals, impairment of mitochondrial function, loss of trophic support, abnormal kinase activity, disruption of calcium homeostasis, dysfunction of protein degradation and neuroinflammation, the pathogenesis is still largely uncertain, and there is currently no effective cure for Parkinson's disease. To develop potential therapies for Parkinson's disease, inflammatory processes, mitochondrial dynamics, oxidative stress, production of reactive aldehydes, excitotoxicity and synucleinopathies are to be targeted. In this respect, vasoactive intestinal peptide has beneficial effects that provide an advantage for the treatment of Parkinson's disease. Vasoactive intestinal peptide is a major neuropeptide-neurotransmitter having antioxidant, anti-inflammatory, neurotropic, neuromodulator, and anti-apoptotic properties. In addition to its direct neuroprotective actions regulating the activity of astrocytes, microglia and brain mast cells, it also plays important roles for neuronal adaptation, maintenance and survival.