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Jee Myung Yang, Edward T Wei, Seong Jin Kim, Kyung Chul Yoon
Transient receptor potential (TRP) channels transduce signals of chemical irritation and temperature change from the ocular surface to the brain. Dry eye disease (DED) is a multifactorial disorder wherein the eyes react to trivial stimuli with abnormal sensations, such as dryness, blurring, presence of foreign body, discomfort, irritation, and pain. There is increasing evidence of TRP channel dysfunction (i.e., TRPV1 and TRPM8) in DED pathophysiology. Here, we review some of this literature and discuss one strategy on how to manage DED using a TRPM8 agonist...
November 15, 2018: Pharmaceuticals
Brian Chiou, James R Connor
Ferritin, a ubiquitously expressed protein, has classically been considered the main iron cellular storage molecule in the body. Owing to the ferroxidase activity of the H-subunit and the nucleation ability of the L-subunit, ferritin can store a large amount of iron within its mineral core. However, recent evidence has demonstrated a range of abilities of ferritin that extends well beyond the scope of iron storage. This review aims to discuss novel functions and biomedical uses of ferritin in the processes of iron delivery, delivery of biologics such as chemotherapies and contrast agents, and the utility of ferritin as a biomarker in a number of neurological diseases...
November 13, 2018: Pharmaceuticals
Simona Camorani, Monica Fedele, Antonella Zannetti, Laura Cerchia
Compared to other breast cancers, triple-negative breast cancer (TNBC) usually affects younger patients, is larger in size, of higher grade and is biologically more aggressive. To date, conventional cytotoxic chemotherapy remains the only available treatment for TNBC because it lacks expression of the estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2), and no alternative targetable molecules have been identified so far. The high biological and clinical heterogeneity adds a further challenge to TNBC management and requires the identification of new biomarkers to improve detection by imaging, thus allowing the specific treatment of each individual TNBC subtype...
November 13, 2018: Pharmaceuticals
David J Kopsky, Jan M Keppel Hesselink
BACKGROUND: Phenytoin cream applied topically has been explored in neuropathic pain conditions. In several case series, phenytoin 5% and 10% cream could reduce pain in a clinically relevant way with a fast onset of action within 30 min, and with positive effects on sleep. OBJECTIVE: To evaluate a single-blind placebo-controlled response test (SIBRET) for use in clinical practice. MATERIALS AND METHODS: Patients with localized neuropathic pain, having an equal pain intensity in at least 2 areas (e...
November 12, 2018: Pharmaceuticals
Matteo Tacelli, Ciro Celsa, Bianca Magro, Aurora Giannetti, Grazia Pennisi, Federica Spatola, Salvatore Petta
Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common cause of chronic liver disease in Western countries, accounting for 20⁻30% of general population and reaching a prevalence of 55% in patients with type 2 diabetes mellitus (T2DM). Insulin resistance plays a key role in pathogenic mechanisms of NAFLD. Many drugs have been tested but no medications have yet been approved. Antidiabetic drugs could have a role in the progression reduction of the disease. The aim of this review is to summarize evidence on efficacy and safety of antidiabetic drugs in patients with NAFLD...
November 8, 2018: Pharmaceuticals
Fadi Bou-Abdallah, John J Paliakkara, Galina Melman, Artem Melman
Ferritins are highly conserved supramolecular protein nanostructures composed of two different subunit types, H (heavy) and L (light). The two subunits co-assemble into a 24-subunit heteropolymer, with tissue specific distributions, to form shell-like protein structures within which thousands of iron atoms are stored as a soluble inorganic ferric iron core. In-vitro (or in cell free systems), the mechanisms of iron(II) oxidation and formation of the mineral core have been extensively investigated, although it is still unclear how iron is loaded into the protein in-vivo...
November 5, 2018: Pharmaceuticals
Isadora T S Bastos, Pedro de Sena M Pinheiro, Fanny N Costa, Miguel D Rocha, Carlos Mauricio R Sant'Anna, Delson Braz, Everton T Souza, Marco A Martins, Eliezer J Barreiro, Fabio F Ferreira, Regina C Barroso, Carlos A M Fraga
Pulmonary arterial hypertension (PAH) is a chronic cardiovascular disease that displays inflammatory components, which contributes to the difficulty of adequate treatment with the available therapeutic arsenal. In this context, the N -acylhydrazone derivative LASSBio-1359 was previously described as a multitarget drug candidate able to revert the events associated with the progression of PAH in animal models. However, in spite of having a dual profile as PDE4 inhibitor and adenosine A2A receptor agonist, LASSBio-1359 does not present balanced potencies in the modulation of these two targets, which difficult its therapeutic use...
November 1, 2018: Pharmaceuticals
Claire Desfrançois, Rachel Auzély, Isabelle Texier
Several drug delivery systems already exist for the encapsulation and subsequent release of lipophilic drugs that are well described in the scientific literature. Among these, lipid nanoparticles (LNP) have specifically come up for dermal, transdermal, mucosal, intramuscular and ocular drug administration routes in the last twenty years. However, for some of them (especially dermal, transdermal, mucosal), the LNP aqueous dispersions display unsuitable rheological properties. They therefore need to be processed as semi-solid formulations such as LNP-hydrogel composites to turn into versatile drug delivery systems able to provide precise spatial and temporal control of active ingredient release...
November 1, 2018: Pharmaceuticals
M Mofizul Islam, Dennis Wollersheim
The study examined the relationship between dispensing patterns of prescription opioids, neighborhood-disadvantage-index, and standardized doses dispensed. Three-year's dispensing data drawn from 80 local government areas (LGAs) within Victoria, Australia's second most populous state, was analyzed. Quantities dispensed in defined daily dose (DDD)/1000-people/day were computed for LGAs of low, moderate, high, and very high socio-economic disadvantage. LGAs with various levels of dispensing, and neighborhood disadvantage were identified and mapped...
November 1, 2018: Pharmaceuticals
Ari Koivisto, Niina Jalava, Raymond Bratty, Antti Pertovaara
Here, we review the literature assessing the role of transient receptor potential ankyrin 1 (TRPA1), a calcium-permeable non-selective cation channel, in various types of pain conditions. In the nervous system, TRPA1 is expressed in a subpopulation of nociceptive primary sensory neurons, astroglia, oligodendrocytes and Schwann cells. In peripheral terminals of nociceptive primary sensory neurons, it is involved in the transduction of potentially harmful stimuli and in their central terminals it is involved in amplification of nociceptive transmission...
November 1, 2018: Pharmaceuticals
Antonella Roetto, Mariarosa Mezzanotte, Rosa Maria Pellegrino
Iron homeostasis is a tightly regulated process in all living organisms because this metal is essential for cellular metabolism, but could be extremely toxic when present in excess. In mammals, there is a complex pathway devoted to iron regulation, whose key protein is hepcidin (Hepc), which is a powerful iron absorption inhibitor mainly produced by the liver. Transferrin receptor 2 (Tfr2) is one of the hepcidin regulators, and mutations in TFR2 gene are responsible for type 3 hereditary hemochromatosis (HFE3), a genetically heterogeneous disease characterized by systemic iron overload...
October 23, 2018: Pharmaceuticals
Naiara Santana-Codina, Joseph D Mancias
Nuclear receptor coactivator 4 (NCOA4) is a selective cargo receptor that mediates the autophagic degradation of ferritin ("ferritinophagy"), the cytosolic iron storage complex. NCOA4-mediated ferritinophagy maintains intracellular iron homeostasis by facilitating ferritin iron storage or release according to demand. Ferritinophagy is involved in iron-dependent physiological processes such as erythropoiesis, where NCOA4 mediates ferritin iron release for mitochondrial heme synthesis. Recently, ferritinophagy has been shown to regulate ferroptosis, a newly described form of iron-dependent cell death mediated by excess lipid peroxidation...
October 23, 2018: Pharmaceuticals
Stephanie Rockfield, Ravneet Chhabra, Michelle Robertson, Nabila Rehman, Richa Bisht, Meera Nanjundan
Maintenance of iron homeostasis is critical to cellular health as both its excess and insufficiency are detrimental. Likewise, lipids, which are essential components of cellular membranes and signaling mediators, must also be tightly regulated to hinder disease progression. Recent research, using a myriad of model organisms, as well as data from clinical studies, has revealed links between these two metabolic pathways, but the mechanisms behind these interactions and the role these have in the progression of human diseases remains unclear...
October 22, 2018: Pharmaceuticals
Wanting Shu, Joshua L Dunaief
Iron is essential for life, while excess iron can be toxic. Iron generates hydroxyl radical, which is the most reactive free radical, causing oxidative stress. Since iron is absorbed through the diet but not excreted from the body, it accumulates with age in tissues, including the retina, consequently leading to age-related toxicity. This accumulation is further promoted by inflammation. Hereditary diseases such as aceruloplasminemia, Friedreich's ataxia, pantothenate kinase-associated neurodegeneration, and posterior column ataxia with retinitis pigmentosa involve retinal degeneration associated with iron dysregulation...
October 22, 2018: Pharmaceuticals
Mayra Vera-Aviles, Eleni Vantana, Emmy Kardinasari, Ngat L Koh, Gladys O Latunde-Dada
Anemia is a major health condition associated with chronic kidney disease (CKD). A key underlying cause of this disorder is iron deficiency. Although intravenous iron treatment can be beneficial in correcting CKD-associated anemia, surplus iron can be detrimental and cause complications. Excessive generation of reactive oxygen species (ROS), particularly by mitochondria, leads to tissue oxidation and damage to DNA, proteins, and lipids. Oxidative stress increase in CKD has been further implicated in the pathogenesis of vascular calcification...
October 21, 2018: Pharmaceuticals
Maria Rangel, Tânia Moniz, André M N Silva, Andreia Leite
Controlling the sources of Fe available to pathogens is one of the possible strategies that can be successfully used by novel antibacterial drugs. We focused our interest on the design of chelators to address Mycobacterium avium infections. Taking into account the molecular structure of mycobacterial siderophores and considering that new chelators must be able to compete for Fe(III), we selected ligands of the 3-hydroxy-4-pyridinone class to achieve our purpose. After choosing the type of chelating unit it was also our objective to design chelators that could be monitored inside the cell and for that reason we designed chelators that could be functionalized with fluorophores...
October 20, 2018: Pharmaceuticals
Marco T Nuñez, Pedro Chana-Cuevas
Iron chelation has been introduced as a new therapeutic concept for the treatment of neurodegenerative diseases with features of iron overload. At difference with iron chelators used in systemic diseases, effective chelators for the treatment of neurodegenerative diseases must cross the blood⁻brain barrier. Given the promissory but still inconclusive results obtained in clinical trials of iron chelation therapy, it is reasonable to postulate that new compounds with properties that extend beyond chelation should significantly improve these results...
October 19, 2018: Pharmaceuticals
Mario M Soldevilla, Daniel Meraviglia-Crivelli de Caso, Ashwathi P Menon, Fernando Pastor
Aptamers are single-stranded oligonucleotides (ssDNA or ssRNA) that bind and recognize their targets with high affinity and specificity due to their complex tertiary structure. Aptamers are selected by a method called SELEX (Systematic Evolution of Ligands by EXponential enrichment). This method has allowed the selection of aptamers to different types of molecules. Since then, many aptamers have been described for the potential treatment of several diseases including cancer. It has been described over the last few years that aptamers represent a very useful tool as therapeutics, especially for cancer therapy...
October 18, 2018: Pharmaceuticals
Enikő Balogh, György Paragh, Viktória Jeney
Bone homeostasis is a complex process, wherein osteoclasts resorb bone and osteoblasts produce new bone tissue. For the maintenance of skeletal integrity, this sequence has to be tightly regulated and orchestrated. Iron overload as well as iron deficiency disrupt the delicate balance between bone destruction and production, via influencing osteoclast and osteoblast differentiation as well as activity. Iron overload as well as iron deficiency are accompanied by weakened bones, suggesting that balanced bone homeostasis requires optimal-not too low, not too high-iron levels...
October 18, 2018: Pharmaceuticals
Leila Hassanzadeh, Suxiang Chen, Rakesh N Veedu
Aptamers are short single-stranded DNA or RNA oligonucleotide ligand molecules with a unique three-dimensional shape, capable of binding to a defined molecular target with high affinity and specificity. Since their discovery, aptamers have been developed for various applications, including molecular imaging, particularly nuclear imaging that holds the highest potential for the clinical translation of aptamer-based molecular imaging probes. Their easy laboratory production without any batch-to-batch variations, their high stability, their small size with no immunogenicity and toxicity, and their flexibility to incorporate various functionalities without compromising the target binding affinity and specificity make aptamers an attractive class of targeted-imaging agents...
October 15, 2018: Pharmaceuticals
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