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Current Opinion in Pharmacology

Alyson P Black, Anand S Mehta
Hepatocellular carcinoma (HCC) is the 5th most common cancer, but the 3rd leading cause of cancer death globally with approximately 700,000 fatalities annually. The severity of this cancer arises from its difficulty to detect and treat. The major etiologies of HCC are liver fibrosis or cirrhosis from chronic viral infections, as well as metabolic conditions. Since most cases arise from prior pathologies, biomarker surveillance in high-risk individuals is an essential approach for early detection and improved patient outcome...
May 14, 2018: Current Opinion in Pharmacology
T C Guillette, Thomas W Jackson, Scott M Belcher
The physiological actions of estrogens are primarily mediated by the nuclear hormone receptors estrogen receptor alpha (ERα) and beta (ERβ). Activities of these nuclear steroid hormone receptors in etiology and progression of many hormone-responsive cancers are well-established, yet the specific role of each receptor, and their various expressed isoforms, in estrogen-responsive cancers remains unclear. Recent advances in nuclear receptor profiling, characterization of expressed splice variants, and the availability of new experimental cancer models, has extended the understanding of the complex interplay between the differentially expressed nuclear estrogen receptors...
May 14, 2018: Current Opinion in Pharmacology
Maria Gabriella Matera, Clive Page, Barbara Rinaldi
Inhaled selective β2-agonists are the most widely used treatment for obstructive airway diseases. The classical mechanism of action of these drugs is considered as their ability to activate β2-adrenergic receptors (β2-AR) on airway smooth muscle leading to G-protein activation and subsequent generation of c-AMP causing bronchodilation. However, there is now growing evidence to suggest that binding of β2-agonists to β2-AR is pleotropically coupled to many intracellular pathways whereby depending on the state of the β2-AR when activated, a subset of different intracellular responses can be triggered...
May 12, 2018: Current Opinion in Pharmacology
Roland Baron, Francesca Gori
Osteoporosis is a widespread chronic disease characterized by low bone density, altered microstructure and bone fragility, leading to low impact fractures in affected individuals. The discovery of a few mutations that cause extremely rare human diseases has identified the WNT signaling pathway as a candidate for therapeutic intervention aimed at increasing bone mass and strength. In particular, inhibition of sclerostin, a WNT antagonist secreted by osteocytes, has proven in clinical trials to be a very efficient osteo-anabolic approach...
May 9, 2018: Current Opinion in Pharmacology
Mariska Pm van den Berg, Herman Meurs, Reinoud Gosens
In the airways, arginase and NOS compete for the common substrate l-arginine. In chronic airway diseases, such as asthma and COPD, elevated arginase expression contributes to airway contractility, hyperresponsiveness, inflammation and remodeling. The disrupted l-arginine homeostasis, through changes in arginase and NOS expression and activity, does not only play a central role in the development of various airways diseases such as asthma or COPD. It possibly also affects l-arginine homeostasis throughout the body contributing to the emergence of co-morbidities...
May 2, 2018: Current Opinion in Pharmacology
Reynold A Panettieri, Tonio Pera, Stephen B Liggett, Jeffrey L Benovic, Raymond B Penn
Current therapies to treat asthma and other airway diseases primarily include anti-inflammatory agents and bronchodilators. Anti-inflammatory agents target trafficking and resident immunocytes and structural cells, while bronchodilators act to prevent or reverse shortening of airway smooth muscle (ASM), the pivotal tissue regulating bronchomotor tone. Advances in our understanding of the biology of G protein-coupled receptors (GPCRs) and biased agonism offers unique opportunities to modulate GPCR function that include the use of pepducins and allosteric modulators...
May 2, 2018: Current Opinion in Pharmacology
Jamie N Mills, Alex C Rutkovsky, Antonio Giordano
Several mechanisms of resistance have been identified, underscoring the complex nature of estrogen receptor (ER) signaling and the many connections between this pathway and other essential signaling pathways in breast cancer cells. Many therapeutic targets of cell signaling and cell cycle pathways have met success with endocrine therapy and remain an ongoing area of investigation. This review focuses on two major pathways that have recently emerged as important opportunities for therapeutic intervention in endocrine resistant breast tumors: PI3K/AKT/mTOR cell signaling and cyclinD1/cyclin-dependent kinase 4/6 cell cycle pathways...
April 29, 2018: Current Opinion in Pharmacology
Olivia Manfrini, Peter Louis Amaduzzi, Edina Cenko, Raffaele Bugiardini
Prevalence of peripheral arterial disease in patients with coronary artery disease is considerably higher than in the general population. A graded increase in the risk of major cardiovascular events in a variety of clinical settings is associated with the number of arterial beds affected by peripheral arterial disease. This is not surprising, considering that both coronary artery disease and peripheral arterial disease are linked to a higher prevalence of cardiovascular risk factors and a greater incidence of atherosclerotic burden...
April 26, 2018: Current Opinion in Pharmacology
Vera P Mourits, Jac Chm Wijkmans, Leo Ab Joosten, Mihai G Netea
Recent studies have shown that upon certain vaccinations or infections human innate immune cells can undergo extensive metabolic and epigenetic reprogramming, which results in enhanced immune responses upon heterologous re-infection, a process termed trained immunity. Trained immunity has also been shown to be inappropriately activated in inflammatory diseases. This provides the potential for identifying novel therapeutic targets: potentiation of trained immunity could protect from secondary infections and reverse immunotolerant states, while inhibition of trained immunity might reduce excessive immune activation in chronic inflammatory conditions...
April 24, 2018: Current Opinion in Pharmacology
Yoshiya Tanaka, Takeshi Ohira
Rheumatoid arthritis (RA), a chronic inflammatory disorder, causes swelling, bone erosion, and joint deformity. Bone erosion in RA-affected joints arises from activation of osteoclasts by inflammatory processes. RA patients may also have primary, disease-related, or glucocorticoid-induced osteoporosis, caused by a disrupted balance between osteoclasts and osteoblasts. Disease-modifying antirheumatic drugs (DMARDs) interfere with the processes causing inflammation in the joint but do not sufficiently treat bone erosion and osteoporosis...
April 24, 2018: Current Opinion in Pharmacology
Spyridon G Deftereos, Dimitrios A Vrachatis, Christos Tolis, Georgios Giannopoulos
Invasive treatment in peripheral artery disease (PAD) has evolved as a viable alternative to surgical treatment. However, beyond the common pathophysiological substrate, as far as treatment is concerned, each site of atherosclerotic disease (subclavian and vertebral arteries; carotid arteries; intracranial arterial tree; renal arteries; lower extremity arteries) features unique characteristics. Treatment options include medical treatment, endovascular management and/or surgery. Sound clinical evaluation is required as individual patient assessment often limits intervention options, while available data regarding benefits of invasive and surgical management are questioned by advances in medical treatment...
April 20, 2018: Current Opinion in Pharmacology
Nils Lycke, Cristina Lebrero-Fernández
Most infections are caused by pathogens that access the body at mucosal sites. Hence, development of mucosal vaccines to prevent local infection or invasion of pathogens appears highly warranted, especially since only mucosal immunization will stimulate strong local IgA responses and tissue resident memory CD4 and CD8 T cells. The most significant obstacle to developing such vaccines is the lack of approved adjuvants that can effectively and safely enhance relevant mucosal and systemic immune responses. The most potent mucosal adjuvants known today are the adenosine diphosphate (ADP)-ribosylating bacterial enterotoxins cholera toxin (CT) and Escherichia coli heat-labile toxins (LTs)...
April 19, 2018: Current Opinion in Pharmacology
Georgia Vogiatzi, Evangelos Oikonomou, Spyridon Deftereos, Gerasimos Siasos, Dimitris Tousoulis
Peripheral artery disease (PAD) is a vascular problem of diffuse atherosclerosis and is a major cause of cardiovascular morbidity and mortality. Many studies have tried to gain insight into the molecular mechanisms involved in PAD. Lately, highly stable circulating small noncoding RNAs, microRNAs (miRNAs), seem to have disease-specific expression. Thus, miRNAs are emerging as new measurable diagnostic biomarkers and a start point for individualized treatment. To date, the association of miRNA regulation in angiogenesis and maintenance of vascular integrity in PAD has attracted little interest...
April 18, 2018: Current Opinion in Pharmacology
Saleha B Vuyyuri, Chris Shidal, Keith R Davis
The health benefits of soy consumption have long been recognized. An important potential benefit is the linkage of soy consumption with reduced cancer risk. One emerging factor that may confer the anticancer effects of soy is the peptide lunasin. Lunasin has both chemopreventive and therapeutic activities against a variety of carcinogens and cancer types. A novel feature of lunasin is that it contains multiple functional domains that can modulate gene expression through effects on histone acetylation and integrin signaling...
April 18, 2018: Current Opinion in Pharmacology
Halley B Rycenga, David T Long
DNA crosslinking agents make up a broad class of chemotherapy agents that target rapidly dividing cancer cells by disrupting DNA synthesis. These drugs differ widely in both chemical structure and biological effect. In cells, crosslinking agents can form multiple types of DNA lesions with varying efficiencies. Inter-strand crosslinks (ICLs) are considered to be the most cytotoxic lesion, creating a covalent roadblock to replication and transcription. Despite over 50 years in the clinic, the use of crosslinking agents that specialize in the formation of ICLs remains limited, largely due to high toxicity in patients...
April 18, 2018: Current Opinion in Pharmacology
Birgit Weinberger
Immunosenescence contributes to increased incidence and severity of many infections in old age and is responsible for impaired immunogenicity and efficacy of vaccines. Adjuvants are one strategy to enhance immunogenicity of vaccines. The oil-in-water emulsions MF59TM and AS03, as well as a virosomal vaccine have been licensed in seasonal or pandemic influenza vaccines and are/were used successfully in the elderly. AS01, a liposome-based adjuvant comprising two immunostimulants has recently been approved in a recombinant protein vaccine for older adults, which showed very high efficacy against herpes zoster in clinical trials...
April 17, 2018: Current Opinion in Pharmacology
Timothy M Hall, Marie-Pier Tétreault, Kathryn E Hamilton, Kelly A Whelan
Esophageal squamous cell carcinoma (ESCC) is amongst the most aggressive human malignancies, representing a significant health burden worldwide. Autophagy is an evolutionarily conserved catabolic process that degrades and recycles damaged organelles and misfolded proteins to maintain cellular homeostasis. Alterations in autophagy are associated with cancer pathogenesis, including ESCC; however, the functional role of autophagy in ESCC remains elusive. Here, we discuss the clinical relevance of autophagy effectors in ESCC and review current knowledge regarding the molecular mechanisms through which autophagy contributes to ESCC...
April 17, 2018: Current Opinion in Pharmacology
Melissa O'Brien, Jason J McDougall
Cannabis has been used for millennia to treat a multitude of medical conditions including chronic pain. Osteoarthritis (OA) pain is one of the most common types of pain and patients often turn to medical cannabis to manage their symptoms. While the majority of these reports are anecdotal, there is a growing body of scientific evidence which supports the analgesic potential of cannabinoids to treat OA pain. OA pain manifests as a combination of inflammatory, nociceptive, and neuropathic pain, each requiring modality-specific analgesics...
April 7, 2018: Current Opinion in Pharmacology
Maria Drakopoulou, Carmen Moldovan, Konstantinos Toutouzas, Dimitris Tousoulis
Atherosclerosis of the internal carotid artery is an important cause of disabling ischemic stroke and therefore constitutes a major medical, social, and economic issue. Although advances in vascular imaging modalities during the last decades allow to risk stratify patients not solely on the degree of carotid artery stenosis but also based on 'high risk' features, there still remains a controversy over patient selection for carotid artery revascularization. Among other features of plaque vulnerability, there is an increasing body of evidence that inflammation is a key factor in the initiation, progression and destabilization of atherosclerotic plaques...
April 6, 2018: Current Opinion in Pharmacology
Luigino Calzetta, Maria Gabriella Matera, Mario Cazzola
Long-acting β2 adrenoceptor agonists (LABAs) in combination with long-acting muscarinic antagonists (LAMAs) can elicit functional and clinical benefits in chronic obstructive pulmonary disease (COPD). LABA/LAMA combinations synergistically relax human isolated airways at the level of the medium and small bronchi. LABAs and LAMAs both modulate the bronchial tone via different pathways localized at the level of presynaptic parasympathetic fibers and airway smooth muscle cells. The exact nature of the interactions between these pathways is not completely understood, but there is cross-talk at many levels in airway smooth muscle cells that is also regulated by the activity of calcium-activated potassium channels and protein tyrosine kinases...
April 4, 2018: Current Opinion in Pharmacology
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