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Current Pharmacology Reports

Obeid M Malekshah, Xuguang Chen, Alireza Nomani, Siddik Sarkar, Arash Hatefi
The use of enzyme/prodrug system has gained attention because it could help improve the efficacy and safety of conventional cancer chemotherapies. In this approach, cancer cells are first transfected with a gene that can express an enzyme with ability to convert a non-toxic prodrug into its active cytotoxic form. As a result, the activated prodrug could kill the transfected cancer cells. Despite the significant progress of different suicide gene therapy protocols in preclinical studies and early clinical trials, none has reached the clinic due to several shortcomings...
December 2016: Current Pharmacology Reports
Eileen N Oni, Ronald P Hart
Several recent publications sought to investigate the effects of ethanol treatment on models of central nervous system development, specifically through changes in DNA methylation. Regulation of DNA methylation causes a long-lasting, epigenetic change in the capacity of the genome to respond to developmental or metabolic stimuli. Changes in technologies for quantifying DNA methylation have increased the ability to identify and interpret potential effects of ethanol. Here, we review these recent studies in order to evaluate the detection technologies and bioinformatic analyses...
October 2016: Current Pharmacology Reports
Yuan Wei, Chenxiao Tang, Vinayak Sant, Song Li, Samuel M Poloyac, Wen Xie
Pregnane X receptor (PXR, NR112) is a xenobiotic receptor whose primary function is to regulate the expression of drug-metabolizing enzymes (DMEs) and drug transporters. Drug-induced PXR activation and subsequent enzyme and transporter induction has been proposed to be an important mechanism for the drug-drug interactions. In addition to activating PXR, many pharmaceutical chemicals can also function as reversible or irreversible inhibitors of DMEs, which may also impact the pharmacokinetics and pharmacodynamics (PK/PD) of drugs...
August 2016: Current Pharmacology Reports
Balaraman Kalyanaraman, Micael Hardy, Jacek Zielonka
In this review, potential fluorescent probe applications for detecting reactive oxygen and nitrogen species (ROS/RNS) generated from NADPH oxidases (e.g., Nox2) and nitric oxide synthase enzymes are discussed in the context of pesticide toxicology. Identification of the specific marker products derived from the interaction between ROS/RNS and the fluorescent probes (e.g., hydroethidine and coumarin boronate) is critical. Due to the complex nature of reactions between the probes and ROS/RNS, we suggest avoiding the use of fluorescence microscopy for detecting oxidizing/nitrating species...
August 2016: Current Pharmacology Reports
Lei Wang, James T F Wise, Zhuo Zhang, Xianglin Shi
Carcinogenesis induced by environmental metal exposure is a major public health concern. The exact mechanisms underlying metal carcinogenesis remain elusive. In the past few decades, the relationship between metal induced generation of reactive oxygen species (ROS) and the mechanism of metal carcinogenesis has been established. The carcinogenic process is a very complex one. In the early stage of metal carcinogenesis or cell transformation high levels of ROS are oncogenic by causing DNA damage, genetic instability, epigenetic alteration, and metabolic reprogramming, leading to malignant transformation...
August 2016: Current Pharmacology Reports
Ioannis P Androulakis
Quantitative Systems Pharmacology (QSP) is receiving increased attention. As the momentum builds and the expectations grow it is important to (re)assess and formalize the basic concepts and approaches. In this short review, I argue that QSP, in addition to enabling the rational integration of data and development of complex models, maybe more importantly, provides the foundations for developing an integrated framework for the assessment of drugs and their impact on disease within a broader context expanding the envelope to account in great detail for physiology, environment and prior history...
June 2016: Current Pharmacology Reports
Neal K Bennett, Anandika Dhaliwal, Prabhas V Moghe
Biophysical and biochemical cues from the cellular microenvironment initiate intracellular signaling through cellular membrane receptors and trigger specific cell developmental programs. Extracellular substrates and matrix scaffolds engineered to mimic cell's native physiological environment must incorporate the multifactorial parameters (composition, micro and nanoscale organization and topography) of the extracellular matrix as well as the dynamic nature of the matrix. The design of such engineered biomaterials is challenged by the inherent complexity and dynamic nature of the cell-extracellular matrix reciprocity, while the validation of robust microenvironments requires a deeper, higher content phenotypic resolution of cell-matrix interactions alongside a rapid screening capability...
June 2016: Current Pharmacology Reports
Yongqun He
Compared with controlled terminologies (e.g., MedDRA, CTCAE, and WHO-ART), the community-based Ontology of AEs (OAE) has many advantages in adverse event (AE) classifications. The OAE-derived Ontology of Vaccine AEs (OVAE) and Ontology of Drug Neuropathy AEs (ODNAE) serve as AE knowledge bases and support data integration and analysis. The Immune Response Gene Network Theory explains molecular mechanisms of vaccine-related AEs. The OneNet Theory of Life treats the whole process of a life of an organism as a single complex and dynamic network (i...
June 2016: Current Pharmacology Reports
Montserrat Rojo de la Vega, Matthew Dodson, Christine Gross, Heidi Manzour, R Clark Lantz, Eli Chapman, Ting Wang, Stephen M Black, Joe G N Garcia, Donna D Zhang
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the clinical manifestations of severe lung damage and respiratory failure. Characterized by severe inflammation and compromised lung function, ALI/ARDS result in very high mortality of affected individuals. Currently, there are no effective treatments for ALI/ARDS, and ironically, therapies intended to aid patients (specifically mechanical ventilation, MV) may aggravate the symptoms. Key events contributing to the development of ALI/ARDS are: increased oxidative and proteotoxic stresses, unresolved inflammation, and compromised alveolar-capillary barrier function...
April 2016: Current Pharmacology Reports
Jun He, Bing-Hua Jiang
Since both reactive oxygen species (ROS) production and microRNAs expression signature have been associated with tumor development, progression, metastasis and therapeutic response, it is important to understand the crosstalk between ROS and microRNAs. Indeed, growing evidence suggests a reciprocal connection between ROS signaling and microRNAs pathway, resulting in diverse biological effects in cancer cells. In this mini review, we discussed the ROS-responsive microRNAs that have implications in cancer and the possible mechanisms in which ROS regulate microRNAs...
April 2016: Current Pharmacology Reports
Lingzhi Li, Fei Chen
The carcinogenic role of arsenic has been extensively studied for more than half century. How arsenic causes human cancer, however, remains to be fully elucidated. In this brief review, we focus our attentions on the most recent discoveries by us and others on the capabilities of arsenic in inducing generation of reactive oxygen species (ROS), expression of microRNAs (miRNAs) and the generation of the cancer stem cells. We believe that these new understandings on the mechanisms of arsenic-induced carcinogenesis will shed light on the prevention and treatment of human cancers resulted from environmental or occupational arsenic exposure...
April 2016: Current Pharmacology Reports
Am Sashi Papu John, Murali K Ankem, Chendil Damodaran
Cancer is a leading cause of death worldwide, and treating advanced stages of cancer remains clinically challenging. Epidemiological studies have shown that oxidants and free radicals induced DNA damage is one of the predominant causative factors for cancer pathogenesis. Hence, oxidants are attractive targets for chemoprevention as well as therapy. Dietary agents are known to exert an anti-oxidant property which is one of the most efficient preventive strategy in cancer progression. In this article, we highlight dietary agents can potentially target oxidative stress, in turn delaying, preventing, or treating cancer development...
April 2016: Current Pharmacology Reports
Lakshmanan Jagannathan, Suresh Cuddapah, Max Costa
Oxygen (O2) levels range from 2-9% in vivo. However, cell culture experiments are performed at atmospheric O2 levels (21%). Oxidative stress due to generation of reactive oxygen species (ROS) in cells cultured at higher than physiological levels is implicated in multitude of deleterious effects including DNA damage, genomic instability and senescence. In addition, oxidative stress activates redox sensitive transcription factors related to inflammatory signaling and apoptotic signaling. Furthermore, several chromatin-modifying enzymes are affected by ROS, potentially impacting epigenetic regulation of gene expression...
April 2016: Current Pharmacology Reports
Jay Morris, Yuan Fang, Keya De Mukhopdhyay, Michael J Wargovich
Aerodigestive cancers are on an increasing level in both occurrence and mortality. A major cause in many of these cancers is disruption of the inflammatory pathway, leading to increased cell proliferation, and epigenetic silencing of normal regulatory genes. Here we review the research on several natural products: silibinin, silymarin, quercetin, neem & nimbolide, gingerol, epigallatecatechin-3- gallate, curcumin, genistein and resveratrol conducted on aerodigestive cancers. These types of cancers are primarily those from oral cavity, esophagus/windpipe, stomach, small and large intestine, colon/rectum and bile/pancreas tissues...
February 2016: Current Pharmacology Reports
Yan Wang, Ying Xie, David Oupický
This review discusses the potential of CXCR4 chemokine receptor in the design of anticancer and antimetastatic drug delivery systems. The role of CXCR4 in cancer progression and metastasis is discussed in the context of the development of several types of drug delivery strategies. Overview of drug delivery systems targeted to cancers that overexpress CXCR4 is provided, together with the main types of CXCR4-binding ligands used in targeting applications. Drug delivery applications that take advantage of CXCR4 inhibition to achieve enhanced anticancer and antimetastatic activity of combination treatments are also discussed...
February 2016: Current Pharmacology Reports
Barbara Wiśniowska, Sebastian Polak
Computational modelling is a cornerstone of Comprehensive In Vitro Proarrhythmia Assay and is re-increasingly being used in drug development. Electrophysiological effects of drug-drug interactions can be predicted in silico, e.g. with the use of in vitro cardiac ion channel data, PK profiles and human ventricular cardiomyocyte models. There are, however, several approaches with different assumptions used to assess the combined effect of multiple drugs, and there is no agreed standard interaction model. The aim of this study was to assess whether the choice of the drug-drug interaction (DDI) model (Bliss independence, Loewe additivity, or simple sum) influences the results of QT interval simulation trial...
2016: Current Pharmacology Reports
Zofia Tylutki, Sebastian Polak, Barbara Wiśniowska
Cardiac safety is an issue causing early terminations at various stages of drug development. Efforts are put into the elimination of false negatives as well as false positives resulting from the current testing paradigm. In silico approaches offer mathematical system and data description from the ion current, through cardiomyocytes level, up to incorporation of inter-individual variability at the population level. The article aims to review three main modelling and simulation approaches, i.e. "top-down" which refers to models built on the observed data, "bottom-up", which stands for a mechanistic description of human physiology, and "middle-out" which combines both strategies...
2016: Current Pharmacology Reports
Masoud Jamei
There is a renewed surge of interest in applications of physiologically-based pharmacokinetic (PBPK) models by the pharmaceutical industry and regulatory agencies. Developing PBPK models within a systems pharmacology context allows separation of the parameters pertaining to the animal or human body (the system) from that of the drug and the study design which is essential to develop generic drug-independent models used to extrapolate PK/PD properties in various healthy and patient populations. This has expanded the classical paradigm to a 'predict-learn-confirm-apply' concept...
2016: Current Pharmacology Reports
Shiv Ram Krishn, Surinder K Batra, Sukhwinder Kaur
MicroRNAs (miRNAs) are an important class of small non-coding RNAs that direct post-transcriptional gene regulation by different mechanisms. Mounting evidences from numerous studies in the last decade have unraveled that deregulated miRNAs, and their cognate target expressions are strongly implicated in the carcinogenesis. Recent advances have highlighted miRNA-mediated regulation of mucins that have critical role in inflammation and cancer biology. The aberrant expression and differential glycosylation of mucins cause tumorigenesis, metastasis, chemoresistance and poor outcome of cancer patients, thus recognizing them as attractive therapeutic targets...
December 2015: Current Pharmacology Reports
Noriko N Yokoyama, Andria Denmon, Edward M Uchio, Mark Jordan, Dan Mercola, Xiaolin Zi
Recent evidence has strongly supported that the rate of aging is controlled, at least to some extent, by evolutionarily conserved nutrient sensing pathways (e.g. the insulin/IGF-1-signaling, mTOR, AMPK, and sirtuins) from worms to humans. These pathways are also commonly involved in carcinogenesis and cancer metabolism. Agents (e.g. metformin, resveratrol, and Rhodiola) that target these nutrient sensing pathways often have both anti-aging and anti-cancer efficacy. These agents not only reprogram energy metabolism of malignant cells, but also target normal postmitotic cells by suppressing their conversion into senescent cells, which confers systematic metabolism benefits...
December 1, 2015: Current Pharmacology Reports
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