Current Pharmaceutical Design - Volume 23, Issue 39, 2017

MicroRNAs are small non-coding RNAs with regulatory biological activity, by modulating target genes on epigenetic, transcriptional, post-transciptional and translational levels. Hundreds of reports indicated that miRNAs play important roles in non-small cell lung cancer (NSCLC). Actually, microRNAs are both regulation targets and regulators targeting effector genes. This article reviewed multifaceted role of microRNAs associated to NSCLC, not only targeting to but also targeted by tumor related genes, to help us understand microRNAs related complex regulation networks. Aberrant expressed micoRNAs and their targets were summarized; the statistical results showed that several microRNAs may play key roles by targeting multiple tumor associated targets. On the other hand, Oncogenes and tumor repressors represented by PTEN were also shown to be the most popular targets of microRNAs. Additionally, ZEB1/2 may be a featured pathway in NSCLC, with significant frequency modulated by microRNAs.

Lung cancer is considered the leading cause of cancer death in the word. Among all lung cancer cases, non-small cell lung cancer (NSCLC) accounts for 85%. Currently, chemotherapy is still the major therapeutic method of lung cancer. However, chemoresistance is a serious obstacle in treating NSCLC. Up to now, many reports have suggested that microRNAs(miRNAs) could contribute to lung cancer cell chemosensitivity. MicroRNAs, a class of endogenous non-coding small RNAs, regulate gene expression by binding to their complementary target messenger RNAs, leading to mRNA degradation or translational suppression. Numerous studies indicate that changes of specific miRNA expression may contribute to chemoresistance or chemosensitivity. Consequently, targeting specific miRNAs could become an effective approach to predict the therapeutic effect of different anticancer agents, achieve more effective personalised treatments and enhance chemosensitivity. This review summarizes the several major drug resistance mechanisms and focuses on the roles of miRNAs in regulating chemoresistance in NSCLC.

Background: miRNA, a small non-coding RNA molecule containing about 22 nucleotides, functions in RNA silencing and post-transcriptional regulation of gene expression. With these qualities, miRNAs modulate multiple signaling pathways involved in cancer development, such as cellular proliferation, apoptosis, and migration. Methods: The goal of this review is to discuss possible miRNAs-based therapeutic strategies, through defining performance of miRNAs in carcinogenesis, in particular in lung cancer. Results: miRNA, a non-coding RNA, is divided into two main types: tumor suppressor miRNAs and oncogenic miRNAs. In addition, special processed miRNAs can be an assistant therapeutic tool. Conclusion: In order to develope antitumor therapy, miRNAs-based therapeutic strategies are worth of deeper studies. In this process, the stability, effectiveness, and side effects should be considered.

MicroRNAs (miRNAs) are small noncoding RNAs, which downregulate gene expression by repressing or degrading mRNA targets. Lung cancer (LC), together with liver and colorectal cancers are the three leading causes of cancer death worldwide, and 80% of LCs belong to non-small cell lung cancers (NSCLCs). Despite a great advancement in developing distinct and delicate tools for early diagnosis and targeted therapies over the last decade, only about 15% of the NSCLC patients eventually survived. MiRNAs are frequently dysregulated in carcinoma, including LC. Numerous lines of evidence have demonstrated various roles played by miRNAs in the development and progression of LC. In this review, we propose to summarize the current understanding of miRNAs in LC, with a particular focus on translational application of miRNAs as novel diagnostic and prognostic biomarkers and tools for treatment.

Lung cancer is one of the most common malignant tumors in the world. Although advanced therapies have been applied for the treatment of lung cancer, the prolongation of overall survival is limited due to treatment resistance. MicroRNAs (miRNAs) are a class of small non-coding, endogenous RNA molecules (about 19-23 nucleotides in length), which could regulate numerous human genes and play key roles in a variety of diseases. MiRNAs are dysregulated in lung cancer and participate in tumor initiation, development and drug resistance. Recent studies showed a new therapeutic strategy for cancer therapy based on miRNAs. In this review, we briefly summarize one classic pathway of miRNAs in lung cancer, and discuss a new miRNA-based therapeutic strategy to manage lung cancer.

Polymeric drug delivery systems in the form of nanocarriers are the most interesting vehicles in anticancer therapy. Among different types of biocompatible polymers, carbohydrate-based polymers or polysaccharides are the most common natural polymers with complex structures consisting of long chains of monosaccharide or disaccharide units bound by glycosidic linkages. Their appealing properties such as availability, biocompatibility, biodegradability, low toxicity, high chemical reactivity, facile chemical modification and low cost led to their extensive applications in biomedical and pharmaceutical fields including development of nano-vehicles for delivery of anti-cancer therapeutic agents. Generally, reducing systemic toxicity, increasing short half-lives and tumor localization of agents are the top priorities for a successful cancer therapy. Polysaccharide-based or - coated nanosystems with respect to their advantageous features as well as accumulation in tumor tissue due to enhanced permeation and retention (EPR) effect can provide promising carrier systems for the delivery of noblest impressive agents. Most challenging factor in cancer therapy was the toxicity of anti-cancer therapeutic agents for normal cells and therefore, targeted delivery of these drugs to the site of action can be considered as an interesting therapeutic strategy. In this regard, several polysaccharides exhibited selective affinity for specific cell types, and so they can act as a targeting agent in drug delivery systems. Accordingly, different aspects of polysaccharide applications in cancer treatment or diagnosis were reviewed in this paper. In this regard, after a brief introduction of polysaccharide structure and its importance, the pharmaceutical usage of carbohydrate-based polymers was considered according to the identity of accompanying active pharmaceutical agents. It was also presented that the carbohydrate based polymers have been extensively considered as promising materials in the design of efficient nanocarriers for anti-cancer biopharmaceuticals including peptide and proteins or nucleic acid-based therapeutics. Then, the importance of various polysaccharide co-polymers in the drug delivery approaches was illustrated.

Background: The recent regulatory approvals of immune checkpoint protein inhibitors, such as ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab ushered a new era in cancer therapy. These inhibitors do not attack tumor cells directly but instead mobilize the immune system to re-recognize and eradicate tumors, which endows them with unique advantages including durable clinical responses and substantial clinical benefits. PD-1/PD-L1 inhibitors, a pillar of immune checkpoint protein inhibitors, have demonstrated unprecedented clinical efficacy in more than 20 cancer types. Besides monoclonal antibodies, diverse PD- 1/PD-L1 inhibiting candidates, such as peptides, small molecules have formed a powerful collection of weapons to fight cancer. Methods: The goal of this review is to summarize and discuss the current PD-1/PD-L1 inhibitors including candidates under clinical development, their molecular interactions with PD-1 or PD-L1, the disclosed structureactivity relationships of peptides and small molecules as inhibitors. Results: Current PD-1/PD-L1 inhibitors under clinical development are exclusively dominated by antibodies. The molecular interactions of therapeutic antibodies with PD-1 or PD-L1 have been gradually elucidated for the design of novel inhibitors. Various peptides and traditional small molecules have been investigated in preclinical model to discover novel PD-1/PD-L1 inhibitors. Conclusion: Peptides and small molecules may play an important role in immuno-oncology because they may bind to multiple immune checkpoint proteins via rational design, opening opportunity for a new generation of novel PD-1/PD-L1 inhibitors.

Early life stress is considered a risk factor for the development of many diseases in both adolescence and adulthood. It has been reported that chronic stress (for instance, due to maternal separation during breast feeding), causes damage to the central nervous system at the level of neurons and glial cells, which are reflected in behavioral disturbances and susceptibility to the development of primarily emotional psychopathology. The aim of this review is to identify the overall state of the scientific literature that relates the information about the consequences of early life stress, contextualizing the mechanisms that may be altered, the behavioral consequences that have been studied and the possible dimorphic effects and its causes. At the end a short overview of pharmacological treatments that have been proposed to reduce the behavioral and neuroendocrine consequences caused by early life stress is presented. This review pretends to integrate general but relevant information based primarily on studies in animal models, which allow the experimental approach and the study of the mechanisms involved. A series of questions remains for reflection and surely will be answered in the near future.

Obesity is damaging the lives of more than 300 million people worldwide and maintaining a healthy weight using popular weight loss tactics remains a very difficult undertaking. Managing the obesity problem seems within reach, as better understanding develops, of the function of our genome in drug/nutrient responses. Strategies indicated by this understanding of nutriepigenomics and neurogenetics in the treatment and prevention of metabolic syndrome and obesity include moderation of mRNA expression by DNA methylation, and inhibition of histone deacetylation. Based on an individual's genetic makeup, deficient metabolic pathways can be targeted epigenetically by, for example, the provision of dietary supplementation that includes phytochemicals, vitamins, and importantly functional amino acids. Also, the chromatin structure of imprinted genes that control nutrients during fetal development can be modified. Pathways affecting dopamine signaling, molecular transport and nervous system development are implicated in these strategies. Obesity is a subtype of Reward Deficiency Syndrome (RDS) and these new strategies in the treatment and prevention of obesity target improved dopamine function. It is not merely a matter of gastrointestinal signaling linked to hypothalamic peptides, but alternatively, finding novel ways to improve ventral tegmental area (VTA) dopaminergic function and homeostasis.

In this work, we explored the protective effect of DT-018, a danshensu and tetramethylpyrazine conjugate, on mitochondrial injury induced by tert-butylhydroperoxide (t-BHP) and its possible mechanisms of action. DT-018 effectively quenched intracellular and mitochondrial reactive oxygen species (ROS), preserved the mitochondrial function, restored the intracellular level of ATP and augmented mitochondrial membrane potential (Δψm) while suppressed mitochondrial swelling in isolated myocardial mitochondria. DT-018 increased the expression of MEF2D and PGC-1α as well as Nrf2 and Tfam in H9c2 cells. Transfection of MEF2D-siRNA and PGC-1α-siRNA down-regulated the protein expression of PGC-1α and partially abolished the cardioprotection of DT-018 in t-BHP injured cells. For the in vivo studies, administration of DT-018 significantly alleviated infarct area induced by ischemia and reperfusion injury. These observations demonstrated that the cardioprotective effect of DT-018 is mediated, at least in part, by preservation of mitochondrial integrity through up-regulation of MEF2D/PGC-1α pathway.

Background: Low back pain is a common problem, mainly caused by intervertebral disc degeneration (IDD). An important pathophysiological characteristic of IDD is the loss of homeostatic balance of the extracellular matrix metabolism. Interleukin-1β (IL-1β) is one of the inflammatory mediators stimulating the degradation of extracellular matrix in the nucleus pulposus (NP) and contributing to IDD pathogenesis. Icariin, which is isolated from Epimedium brevicornum, acts as an anti-inflammatory drug. Objective: This study aimed to explore the pharmacological effects of icariin in IDD by simulating NP inflammation in vitro. Method: Human NP cells were isolated and cultured in vitro. NP cells were pretreated with icariin (0.1, 1 and 10 μM) and stimulated by IL-1β (10 ng/ml). The concentration of Prostaglandin E2 was determined by enzymelinked immunosorbent assay. Nitric oxide was determined by Griess reagent assay. The expression of cyclooxygenase- 2 (COX-2), inducible nitric oxide synthase (iNOS), degrading enzymes, collagen II, aggrecan, mitogenactivated protein kinase (MAPK), and nuclear factor-kappa B (NF-ΚB)-related signaling molecules was assessed via western blotting. Results: IL-1β induced pronounced expression of COX-2 and iNOS, and stimulated production of prostaglandin E2 and nitric oxide. Icariin exhibited significant anti-inflammatory effect, inhibiting IL-1β-induced production of degrading enzymes, as well as extracellular matrix reduction. Finally, icariin suppressed IL-1β-induced activation of MAPK- and NF-ΚB-related signaling pathways. Conclusion: The present findings suggest that icariin may have a protective effect on NP cells. The antiinflammatory effect may contribute to the therapeutic action of icariin in IDD.

Background: Repeated administrations of insulin injection on daily basis evoke pain and numerous complications with adverse effects on the diabetic patients' life quality. Moreover, wearing insulin pump is also associated with several problems of diabetic ketoacidosis, catheter site infection, contact dermatitis and high cost. Method: We have developed an in situ gel system, consisting of insulin-loaded liposomes dispersed within a thermoreversible gel (Pluronic® F127 gel), which increases the duration of insulin action for the treatment of diabetes. Vesicular phospholipid gel technique was used to encapsulate the insulin into liposomes. Results: The resulting liposomal gel formulation had a longer drug-release period in vitro than a free insulin solution or liposomes and Pluronic® F127 gel individually. Furthermore, the addition of liposomes to the Pluronic® F127 gel improved the stability of the encapsulated insulin at a physiological temperature. In vivo study was performed to investigate the bioactivity and absorption of insulin released from the liposomal gel and other formulations. The liposomal gel released insulin into the bloodstream continuously for up to 7 days and significantly enhanced drug bioavailability compared to insulin released from liposomes or Pluronic® F127 gel individually. Blood glucose levels were reduced for up to 4 days. Histology data demonstrated excellent biocompatibility of the Pluronic® F127 gel-based delivery systems, with no observable inflammatory response in rat subcutaneous tissues. Conclusion: Obtained results show that the insulin-loaded liposomes dispersed within Pluronic® F127 gel can be used as a long-acting drug delivery system, and replacement for conventional insulin therapy.

Background: All stages of chronic kidney disease (CKD) are associated with increased risks of atherosclerosis and cardiovascular morbidity and mortality. According to studies, levels of copeptin, growth differentiation factor-15 (GDF-15) and heart fatty-acid binding protein (h-FABP) are increased in dialysis patients. Materials: This study included 50 patients (19 women, 31 men) chronically undergoing haemodialysis. The concentration of markers such as: copeptin, GDF-15, h-FABP, troponin and serum creatine kinase MB (CKMB) was measured with the use of ELISA tests. Serum concentration of 10 high-density lipoprotein (HDL) subfractions and 7 low-density lipoprotein (LDL) subfractions was analysed with the use of Lipoprint™ system (Quantimetrix Corp.). Results: In this study, we observed higher copeptin level, lower percentage share of cholesterol HDL4 subfraction and higher percentage share of small HDL particles subfraction in HD patients with diabetes mellitus than in those without diabetes. We also found significantly lower percentage share of cholesterol HDL5 subfraction in patients with GDF-15 > 3rd quartile (Q3) compared with those with GFD-15 ≤ Q3. Finally, it was observed that the percentage share of cholesterol HDL5 subfraction was significantly lower in patients with h-FABP > Q3, and the share of intermediate HDL subfractions was significantly lower in haemodialysis (HD) patients with h-FABP > 75 percentile. Conclusion: The fact that increased level of one biomarker correlated with higher values of other markers may suggest that their concentration depends on the severity of disease. The obtained results also suggest that the measurement of copeptin may support the diagnosis of cardiovascular problems in dialysis patients.