Current Pharmaceutical Design - Volume 26, Issue 18, 2020

High-risk human papillomavirus strains are widely known to be the causative agents responsible for cervical cancer development. Aggregated damage caused by papillomaviruses solely is estimated in at least 5% of all malignancies of the human body and 16% in cancers that affect the female genital area. Enhanced understanding of the complex issue on how the high extent of carcinogenicity is eventually formed due to the infection by the Papoviridae family would contribute to enhancing current prevention strategies not only towards cervical cancer, but also other HPV associated cancers. This review article is aimed at presenting the key points in two directions: the current cervical cancer prevention and related aspects of HPV behavior. Virtually all applied technologies related to HPV diagnostics and screening programs, such as HPV tests, colposcopy-based tests (VIA/VILI), conventional and liquid-based cytology, currently available are presented. Issues of availability, advantages, and drawbacks of the screening programs, as well as vaccination strategies, are also reviewed in the article based on the analyzed sources. The current point of view regarding HPV is discussed with emphasis on the most problematic aspect of the HPV family concerning the observed increasing number of highly carcinogenic types. Present trends in HPV infection diagnostics throughout the human fluids and tissues are also reported, including the latest novelties in this field, such as HPV assay/self-sample device combinations. Besides, a brief outline of the related prevention issues in Kazakhstan, the leading country of Central Asia, is presented. Kazakhstan, as one of the post-soviet middle-income countries, may serve as an example of the current situation in those terrains, concerning the implementation of globally accepted cervical cancer prevention strategies. Along with positive achievements, such as the development of a nationwide screening program, a range of drawbacks is also analyzed and discussed.

Premature ovarian failure (POF), which may be undetectable for a long time, is associated with impaired fertility. The mechanisms involved in the pathogenesis of POF as well as the concomitant treatments are still unclear. Although many data exist, mainly produced by the study of transgenic animals under various experimental conditions, they remain fragmented. A systematic review of the pathways involved in premature ovarian failure was conducted. Data extraction was performed from experimental studies until 2019. The molecular processes and their correlation with the follicular developmental stage have been described. Furthermore, the effects in other cells, such as oocytes, granulosa and theca cells have been reported. An overall estimation was conducted.

The human intermediate conductance calcium-activated potassium channel, KCa3.1, is involved in several pathophysiological conditions playing a critical role in cell secretory machinery and calcium signalling. The recent cryo-EM analysis provides new insights for understanding the modulation by both endogenous and pharmacological agents. A typical feature of this channel is the low open probability in saturating calcium concentrations and its modulation by potassium channel openers (KCOs), such as benzo imidazolone 1-EBIO, without changing calcium-dependent activation. In this paper, we proposed a model of KCOs action in the modulation of channel activity. The KCa3.1 channel has a very rich pharmacological profile with several classes of molecules that selectively interact with different binding sites of the channel. Among them, benzo imidazolones can be openers (positive modulators such as 1-EBIO, DC-EBIO) or blockers (negative modulators such as NS1619). Through computation modelling techniques, we identified the 1,4-benzothiazin-3-one as a promising scaffold to develop new KCa3.1 channel modulators. Further studies are needed to explore the potential use of 1-4 benzothiazine- 3-one in KCa3.1 modulation and its pharmacological application.

Glioblastoma (GB) represents the most common and malignant form of glioma cancer. The Gold Standard in Glioblastoma is neurosurgical tumor removal and radiotherapy treatment in concomitant with temozolomide (TMZ). Unfortunately, because of tumor chemo and radio-resistance during this therapy, the patient’s outcome remains very poor, with a median overall survival of about 14.6 months. Resveratrol is a natural polyphenol with a stilbene structure with chemopreventive and anticancer properties. In the present review, we evaluated data from preclinical studies conducted with resveratrol as a possible adjuvant during the standard protocol of GB. Resveratrol can reach the brain parenchyma at sub-micromolar concentrations when administrated through conventional routes. In this way, resveratrol reduces cell invasion and increases the efficacy of radiotherapy (radiosensitizer effects) and temozolomide. The molecular mechanism of the adjuvant action of resveratrol may depend upon the reduction of PI3K/AKT/NF-ΚB axis and downstream targets O-6-methylguanine-DNA methyltransferase (MGMT) and metalloproteinase-2 (MMP-2). It has been reported that redox signaling plays an important role in the regulation of autophagy. Resveratrol administration by External Carotid Artery (ECA) injection or by Lumbar Puncture (LP) can reach micromolar concentrations in tumor mass where it would inhibit tumor growth by STAT-3 dependent mechanisms. Preclinical evidences indicate a positive effect on the use of resveratrol as an adjuvant in anti-GB therapy. Ameliorated formulations of resveratrol with a favorable plasmatic profile for a better brain distribution and timing sequences during radio and chemotherapy could represent a critical aspect for resveratrol use as an adjuvant for a clinical evaluation.

Discovery and selection of the potential targets are some of the important issues in pharmacology. Even when all the reactions and the proteins in a biological network are known, how does one choose the optimal target? Here, we review and discuss the application of the computational methods to address this problem using the blood coagulation cascade as an example. The problem of correct antithrombotic targeting is critical for this system because, although several anticoagulants are currently available, all of them are associated with bleeding risks. The advantages and the drawbacks of different sensitivity analysis strategies are considered, focusing on the approaches that emphasize: 1) the functional modularity and the multi-tasking nature of this biological network; and 2) the need to normalize hemostasis during the anticoagulation therapy rather than completely suppress it. To illustrate this effect, we show the possibility of the differential regulation of lag time and endogenous thrombin potential in the thrombin generation. These methods allow to identify the elements in the blood coagulation cascade that may serve as the targets for the differential regulation of this system.

Thrombospondin-1, an extracellular matrix protein, is the first identified natural angiogenesis inhibitor. Thrombospondin-1 participates in a great number of physiological and pathological processes, including cell-cell and cell-matrix interactions via a number of cell receptors, including CD36 and CD47, which plays a vital role in mediating inflammation and performs a promoting effect in pulmonary arterial vasculopathy and diabetes. Thrombospondin-1 consists of six domains, which combine with different molecules and participate in various functions in cancers, serving as a critical member in diverse pathways in cancers. Thrombospondin-1 works as a cancer promotor in some pathways but as a cancer suppressor in others, which makes it highly possible that its erroneous functioning might lead to opposite effects. Therefore, subdividing the roles of thrombospondin-1 and distinguishing them in cancers are necessary. Complex structure and multiple roles take disadvantage of the research and application of thrombospondin-1. Compared with the whole thrombospondin-1 protein, each thrombospondin- 1 active peptide performs an uncomplicated structure and, nevertheless, a specific role. In other words, various thrombospondin-1 active peptides may function differently. For instance, thrombospondin-1 could both promote and inhibit glioblastoma, which is significantly inhibited by the three type I repeats, a thrombospondin-1 active peptide but promoted by the fragment 167-569, a thrombospondin-1 active peptide consisting of the procollagen homology domain and the three type I repeats. Further studies of the functions of thrombospondin-1 active peptides and applying them reasonably are necessary. In addition to mediating cancerogenesis, thrombospondin-1 is also affected by cancer development, as reflected by its expression in plasma and the cancer tissue. Therefore, thrombospondin-1 may be a potential biomarker for pre-clinical and clinical application. This review summarizes findings on the multiple roles of thrombospondin-1 in cancer processes, with a focus on its use as a potential therapeutic target.

In vitro screening for anti-cancer agents currently uses mainly cell lines in 2D culture. It is generally assumed that 3D culture, namely spheroids, represents physiologically more relevant models for tumors. Unfortunately, drug testing in spheroids is not as easy and reproducible as in 2D culture because there are factors that limit the universal use of spheroids as screening platforms. Technical problems in the generation of uniform spheroids, cell/tumor-specific differences in the ability to form spheroids, and more complex readout parameters are the main reasons for differences between spheroid data. The review discusses requirements for cancer spheroids to be representative models, suitable methodologies to generate spheroids for the screening and readout parameters for the evaluation of anti-cancer agents.

The delivery of drugs, via different layers of skin, is challenging because it acts as a natural barrier and exerts hindrance against molecules to permeate into or through it. To overcome such obstacles, different noninvasive methods, like vehicle-drug interaction, modifications of the horny layer and nanoparticles have been suggested. The aim of the present review is to highlight some of the non-invasive methods for topical, diadermal and transdermal delivery of drugs. Special emphasis has been made on the information available in numerous research articles that put efforts in overcoming obstacles associated with barrier functions imposed by various layers of skin. Advances have been made in improving patient compliance that tends to avoid hitches involved in oral administration. Of particular interest is the use of lipid-based vesicles and nanoparticles for dermatological applications. These particulate systems can effectively interact and penetrate into the stratum corneum via lipid exchange and get distributed in epidermis and dermis. They also have the tendency to exert a systemic effect by facilitating the absorption of an active moiety into general circulation.

Background: Cancer is a set of diseases formed by abnormal growth of cells leading to the formation of the tumor. The diagnosis can be made through symptoms’ evaluation or imaging tests, however, the techniques are limited and the tumor detection may be late. Thus, pharmaceutical nanotechnology has emerged to optimize the cancer diagnosis through nanostructured contrast agent’s development. Objective: This review aims to identify commercialized nanomedicines and patents for cancer diagnosis. Methods: The databases used for scientific articles research were Pubmed, Science Direct, Scielo and Lilacs. Research on companies’ websites and articles for the recognition of commercial nanomedicines was performed. The Derwent tool was applied for patent research. Results: This article aimed to research on nanosystems based on nanoparticles, dendrimers, liposomes, composites and quantum dots, associated to imaging techniques. Commercialized products based on metal and composite nanoparticles, associated with magnetic resonance and computed tomography, have been observed. The research conducted through Derwent tool displayed a small number of patents using nanotechnology for cancer diagnosis. Among these patents, the most significant number was related to the use of systems based on metal nanoparticles, composites and quantum dots. Conclusion: Although few systems are found in the market and patented, nanotechnology appears as a promising field for the development of new nanosystems in order to optimize and accelerate the cancer diagnosis.

Introduction: The pulmonary inflammatory response results from exposure to injurious factors and is associated with oxidative stress, which intensifies the pathological reaction. In this context, limonene, a monoterpene found in citrus fruits, can be a therapeutic alternative for the treatment of this pathology, as it presents known anti-inflammatory and antioxidant actions. Objective: The purpose of this article is to provide an overview of the anti-inflammatory activity of limonene and its capacity to prevent and control respiratory system injuries. Search strategy: A comprehensive literature search of the Cochrane, Scopus, MEDLINE-PubMed, Web of Science, and Lilacs databases was performed using the keywords: "limonene", “lung”, “pulmonary”, “airway”, “trachea”, “lung injury”, "respiratory system", “respiratory tract diseases”. Selection criteria: Studies on the use of limonene in disorders of the respiratory system, published until August 2019, were included. Those that did not use limonene alone or treated lesions in different systems other than the respiratory system, without targeting its anti-inflammatory action were excluded. In addition, review articles, meta-analyses, abstracts, conference papers, editorials/letters and case reports were also excluded. Results: Of the 561 articles found, 64 were in the Cochrane database, 235 in Scopus, 99 in Web of science, 150 in PubMed and 13 in Lilacs. After completing the systematic steps, 25 articles were selected for full reading, after which 7 papers remained in the review. An article was added after a manual literature search, resulting in a total of 8 papers. There was a high level of agreement on inclusion/exclusion among the researchers who examined the papers (Kappa index > 88%). Conclusion: Limonene has effective anti-inflammatory activity in both preventing and controlling respiratory system injuries.