Current Drug Targets - Volume 19, Issue 15, 2018

Colorectal cancer (CRC) is a heterogeneous disease entity in terms of both molecular carcinogenesis and morphologic carcinogenesis multistep pathways. Considerable heterogeneity exists within CRC due to the varied genetic and epigenetic mechanisms involved in different carcinogenesis pathways. A better understanding of pathophysiology of tumors is necessary to develop modern and successful means of treatment in metastatic CRC. Over the last 5 years, there has been a surge in interest in the molecular classification of colorectal cancer, as its clinical importance both for predicting prognosis and in guiding personalized treatment had been acknowledged. Recently, the Colorectal Cancer Subtyping Consortium identified four consensus molecular subtypes, CMS 1-4 in CRC; however, attempts to stratify CRC using molecular features for prognostic and predictive purposes in clinical conditions had limited success. In this review, we focused on molecularly defined subtypes of CRC including specific mutations and discuss implications for current and future patient management in metastatic CRC to achieve the maximal therapeutic response for each patient, while reducing adverse side effects of therapy.

Background: Diabetes is one of the major concerns worldwide which leads to increased level of blood glucose due to deficiency of insulin and the development of insulin resistance in diabetic individuals. Basically, its impact arises due to rapid urbanization, improper diet intake, and increasingly inactive lifestyle. Diabetic patients develop serious complications with the development of disease at later stages, such as obesity, the risk of stroke and heart failure. Globally, an estimated 422 million adults are living with type 2 diabetes mellitus. Methods: We searched the scientific database using relevant keywords. Among the searched literature, only peer-reviewed papers were collected which addresses our questions. The retrieved quality papers were screened and analyzed critically. The key findings of these studies are included along with the importance. Results: The quality research paper included in the review, particularly the antidiabetic drugs which account for the second largest market by sales in the pharmaceutical industry after cancer. So the research came up with several novel therapeutic targets for the management of type 2 diabetes, to produce newer generation antidiabetic drug by offering a new concept for developing new drug candidates. Conclusion: This review discusses the strategies and future perspectives in the management of type 2 diabetes mellitus particularly antidiabetic agents which are helpful for the betterment of diabetic patients.

Nucleophagy is a selective autophagy, which selectively removes damaged or non-essential nuclear material from a cell by the autophagy pathway. Additionally, nucleophagy is crucial for promoting cell longevity and ensure body proper function. Increasing evidence has shown that nucleophagy may play a major role in such human diseases as degenerative disorders, tumorigenesis, malnutrition and metabolic disorders, parakeratosis and psoriasis. Studies indicated that nucleophagy can improve degenerative disorders by delaying premature cell senescence, prevent malnutrition and metabolic disorder via maintaining nuclear structure and releasing nutrients for energy production, and alleviate parakeratosis and psoriasis. But the activation of nucleophagy appears to be a double-edged sword. Some studies indicated that overexpression of lamin B1 delays cell senescence. During the process of nucleophagy, appropriate nucleophagy can drive RAS-induced cell senescence and DNA damage-induced cell senescence so as to restrain cell proliferation. Besides, appropriate nucleophagy can degrade excessive amount of DNA content in polyploid tumor cells. Hence, selective nucleophagy may effectively protect cells from tumorigenesis and maintain cell and tissue integrity. However, excessive nucleophagy can attack normal cells and lead to an unforeseen cytotoxicity. In this paper, some signal pathways of nucleophagy occurrence were explained and the role of nucleophagy in these human diseases was analyzed. Our review indicates that nucleophagy may be a potential target in human diseases.

Background: Irritable bowel syndrome (IBS) is a chronic, recurrent bowel disorder with an unknown etiology, which is most likely multifactorial. Increased mucosal permeability, visceral hypersensitivity and activation status of intestinal mucosal immune cells cause changes in gastrointestinal (GI) motility, secretion and sensation observed in the course of IBS. Permanent, cumbersome symptoms, such as diarrhea, constipation and abdominal pain greatly lower the quality of life of IBS patients. On this basis, according to the Rome IV criteria, different forms of IBS can be distinguished. Objective: This article focuses on the role of serotonin system in the pathophysiology of IBS as a potential therapeutic target. We shortly describe several molecules, associated with serotonin receptors, mainly 5-HT3 receptor antagonists and 5-HT4 receptor agonists, that are used in the treatment of motility disorders and visceral pain in IBS patients. We summarize the findings obtained in the clinical trials and elaborate on the safety of the serotonin ligands. Although the majority of serotonin receptor ligands relieve global symptoms, there are also some adverse effects, which can be dangerous for patients. Results and Conclusion: We postulate that currently, among all serotonin-targeting compounds, ramosetron is the best treatment option for IBS-D patients, due to its exceptional efficacy in both genders as well as good tolerability. Whereas, tegaserod is highly recommended for IBS-C sufferers. Nevertheless, numerous studies on the new serotonin receptor ligands are conducted to ensure the delivery of novel compounds with improved efficacy and safety profiles.

Diabetes mellitus, a metabolic disorder of glucose metabolism, is mainly associated with insulin resistance to the body cells, or impaired production of insulin by the pancreatic β-cells. Insulin is mainly required to regulate glucose metabolism in type 1 diabetes mellitus patients; however, many patients with type 2 diabetes mellitus also require insulin, especially when their condition cannot be controlled solely by oral hypoglycemic agents. Hence, major research is ongoing attempting to improve the delivery of insulin in order to make it more convenient to patients who experience side effects from the conventional treatment procedure or non-adherence to insulin regimen due to multiple comorbid conditions. Conventionally, insulin is administered via subcutaneous route which is also one of the sole reasons of patient's non-compliance due to the invasiveness of this method. Several attempts have been done to improve patient compliance, reduce side effects, improve delivery adherence, and to enhance the pharmaceutical performance of the insulin therapy. Despite facing substantial challenges in developing efficient delivery systems for insulin, vast research studies have been carried out for the development of smart delivery systems to deliver insulin via ocular, buccal, pulmonary, oral, transdermal, as well as rectal routes. Therefore, the present review was aimed to overview the challenges encountered with the current insulin delivery systems and to summarize recent advancements in technology of various novel insulin delivery systems being discovered and introduced in the current market.

Background: Several gene deviations can be responsible for triggering oncogenic processes. However, mutations in tumour suppressor genes are usually more associated to malignant diseases, with p53 being one of the most affected and studied element. p53 is implicated in a number of known cellular functions, including DNA damage repair, cell cycle arrest in G1/S and G2/M and apoptosis, being an interesting target for cancer treatment. Objective: Considering these facts, the development of gene therapy approaches focused on p53 expression and regulation seems to be a promising strategy for cancer therapy. Results: Several studies have shown that transfection of cancer cells with wild-type p53 expressing plasmids could directly drive cells into apoptosis and/or growth arrest, suggesting that a gene therapy approach for cancer treatment can be based on the re-establishment of the normal p53 expression levels and function. Up until now, several clinical research studies using viral and non-viral vectors delivering p53 genes, isolated or combined with other therapeutic agents, have been accomplished and there are already in the market, therapies based on the use of this gene. Conclusion: This review summarizes the different methods used to deliver and/or target the p53 as well as the main results of therapeutic effect obtained with the different strategies applied. Finally, the ongoing approaches are described, also focusing on the combinatorial therapeutics to show increased therapeutic potential of combining gene therapy vectors with chemo or radiotherapy.

Background: Peroxisomal proliferator receptor gamma (PPARγ) is a class of nuclear hormone receptor family involved in insulin sensitization. In addition, PPARγ has a key role in the protection against oxidative stress and inflammation through regulation of NFkappaB levels and crosstalk with the Nrf2 pathway. Also, its role in the modulation of immune response is substantial. Objective: Radiation-induced oxidative stress is the sole determinant of damage to hematopoietic, gastrointestinal system and immune system suppression. Uncontrolled exposure to normal cells during radiotherapy raises the demand for novel and efficient radioprotectors. In this review, we will present an overview of the involvement of PPARγ in radiation-induced damage and inflammation with major emphasis on whether PPARγ can serve as a suitable radiomodification target. Conclusion: Through this review, we have justified that PPARγ having both radioprotective as wells as radiotherapeutic potential, may serve as an attractive target for the development of novel and more effective therapies.

Background: Cell signaling through nitric oxide (NO) is a multifaceted mechanism, which regulates metabolic activities and fate in different tissues. The peroxynitrite (ONOO-) formed as reaction product of nitric oxide radical and superoxide interacts with cell membrane phospholipids and proteins causing damage. Objective: The reaction kinetics to form nitrotyrosine (ONOO-tyrosine) and/or nitrosylated cysteine (ONOO-cysteine) in protein molecules during posttranslational modification and nitration of lipids are therefore critical in determining cells' signaling mechanism for survival or apoptosis. Results: The nitrosylation was found to modulate GPCRs and activation of guanylate cyclase as well as regulate NF-ΚB activation. The recent findings have shown the neuroprotective effects of S- nitrosylation, though mechanism is unclear. Conclusion: While keeping the background in mind, we address here the biological function of NO derivatives in medicine. We target four known compounds: SNAP, SIN- 1 chloride, SNP and GSNO to understand the effect of NO in different tissues. Here we analyze the existing findings to assess therapeutic relevance of NO-signaling during inflammation, vasodilation and tolerance.

Background: Drug toxicity and inefficacy are commonly experienced problems with drug therapy failure. To face these problems, extensive research work took place aiming to design new dosage forms for drug delivery especially nanoparticulate systems. These systems are designed to increase the quantity of the therapeutic molecule delivered to the desired site concurrently with reduced side effects. In order to achieve this objective, nanocarriers must principally display suitable drug vehiculization abilities and a controlled biological destiny of drug molecules. Only the intelligent design of the nanomedicine will accomplish these fundamentals. Methods: The present review article is dedicated to the discussion of the important fundamentals to be considered in the fabrication of nanomedicines. These include the therapeutic agent, the imaging agent, the nanocarrier and the functionalization moieties. Special consideration is devoted to the explanation and compilation of highly potential fabrication approaches assisting how to control the in vivo destiny of the nanomedicine. Finally, some nanotechnology-based drug delivery systems, for the development of nanomedicine, are also discussed. Results: The nanotechnology-based drug delivery systems show remarkable outcomes based on passive and active targeting as well as improvement of the drug pharmacodynamic and pharmacokinetic profiles. Multifunctional nanocarrier concept affords a revolutionary drug delivery approach for maximizing the efficacy, safety and monitoring the biological fate of the therapeutic molecule. Conclusion: Nanomedicines may enhance the efficacy of therapeutic molecules and reduce their toxic effects. Meanwhile, further research works are required to rightly optimize (and define) the effectiveness, nanotoxicity, in vivo destiny and feasibility of these nanomedicines which, from a preclinical standpoint, are actually promising.

Considerable progress has been made in learning about the physiology and biochemistry of the sebaceous glands and several of the diseases that affect this component of the skin. Of these diseases, acne has particular importance. It is associated with adolescence, and because of the hormonal changes that take place in this stage, when it is severe it can cause depression. Moreover, in a considerable proportion of acne sufferers both adolescent and adult, it can produce tumors and deformation of the sebaceous glands. This seriously affects the sufferers to the point where it may limit their professional activities because they do not want to be seen in public. Several important issues from classic studies on the sebaceous gland will be reviewed in this document to report the state of the art of current treatments for the pathology of these glands. The sebaceous gland is an intracrine organ, capable of synthesizing and metabolizing different steroidal hormones. The role of each of the enzymes involved in these processes of the skin will be analyzed. The presence of different hormone receptors in the scientific literature will be also reviewed, due to the role of the sebaceous gland in lipogenesis at different ages. We also describe the mechanism of action of androgens and progestins in relation to coregulators recruited for lipogenesis in this gland. We propose several new steroidal compounds based on their mechanism of action to block lipogenesis in the sebaceous glands. These molecules offer potential for new treatment options for skin diseases.

Epothilones are a class of macrolide compounds. Their activities of tubulin polymerization and microtubule depolymerization inhibition like paclitaxel make them a new generation of antimitotic drugs. The mechanism of action is similar to that of paclitaxel, which can bind to tubulin and cause cancer cells to fail to undergo mitosis, thereby causing apoptosis in cancer cells. Epothilone is superior to paclitaxel in anti-tumor spectrum, anti-tumor activity, safety, water solubility and synthetic methods. It is expected to develop into a more effective anti-tumor drug than paclitaxel. Herein, the synthesis methods and activity of epothilone D were summarized and analyzed.