An update on emerging drugs for the treatment of idiopathic pulmonary fibrosis

Introduction: Idiopathic pulmonary fibrosis is a chronic, progressive fibrotic lung disease of unknown etiology associated with a high morbidity and mortality. The hallmark of the disease is impaired healing after alveolar epithelial injury in the setting of a genetic predisposition. Development of two new drugs has changed the landscape of the treatment of IPF but more work is needed to improve outcomes and improve survival.

Areas covered: The development of two antifibrotic agents, nintedanib and pirfenidone has been an exciting landmark in the treatment of IPF. Current research efforts are focused on developing new drugs, as well as combination of new agents with currently available therapies. New molecules in development target not only the deposition of extracellular matrix, but also upstream pathways including those mediated by immunity.

Expert opinion: IPF is a complex and a heterogeneous disease involving several different pathways culminating in fibrosis. Efforts are underway to develop drugs targeting the different pathways. The key to the successful treatment of IPF will require identification of better end-points for research as well as precision medicine involving the use of multidrug therapy personalized to specific patients based on endomolecular genotyping.     

Atg7- and Keap1-dependent autophagy protects breast cancer cell lines against mitoquinone-induced oxidative stress

The interplay between oxidative stress and autophagy is critical for determining the fate of cancer cells exposed to redox-active and cytotoxic chemotherapeutic agents. Mitoquinone (MitoQ), a mitochondrially-targeted redox-active ubiquinone conjugate, selectively kills breast cancer cells over healthy mammary epithelial cells. We reported previously that MitoQ, although a derivative of the antioxidant ubiquinone, can generate excess ROS and trigger the Keap1-Nrf2 antioxidant response in the MDA-MB-231 cell line. Following MitoQ treatment, a greater number of cells underwent autophagy than apoptosis. However, the relationship between MitoQ-induced oxidative stress and autophagy as a primary cellular response was unclear. In this report, we demonstrate that MitoQ induces autophagy related gene 7 (Atg7)-dependent, yet Beclin-1-independent, autophagy marked by an increase in LC3-II. Both the ATG7-deficient human MDA-MB-231 cells and Atg7-knockout mouse embryonic fibroblasts exhibited lower levels of autophagy following MitoQ treatment than their respective wild-type counterparts. Increased apoptosis was confirmed in these autophagy-deficient isogenic cell line pairs, indicating that autophagy was attempted for survival in wild type cell lines. Furthermore, we observed higher levels of ROS in Atg7-deficient cells, as measured by hydroethidine oxidation. In Atg7-deficient cells, redox-sensitive Keap1 degradation was decreased, suggesting autophagy- and Atg7-dependent degradation of Keap1. Conversely, downregulation of Keap1 decreased autophagy levels, increased Nrf2 activation, upregulated cytoprotective antioxidant gene expression, and caused accumulation of p62, suggesting a feedback loop between ROS-regulated Keap1-Nrf2 and Atg7-regulated autophagy. Our data indicate that excessive ROS causes the upregulation of autophagy, and autophagy acts as an antioxidant feedback response triggered by cytotoxic levels of MitoQ.     

Differential regulation of MeCP2 phosphorylation in the CNS by dopamine and serotonin

Systemic administration of amphetamine (AMPH) induces phosphorylation of MeCP2 at Ser421 (pMeCP2) in select populations of neurons in the mesolimbocortical brain regions. Because AMPH simultaneously activates multiple monoamine neurotransmitter systems, here we examined the ability of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) to induce pMeCP2. Selective blockade of the DA transporter (DAT) or the 5-HT transporter (SERT), but not the NE transporter (NET), was sufficient to induce pMeCP2 in the CNS. DAT blockade induced pMeCP2 in the prelimbic cortex (PLC) and nucleus accumbens (NAc), whereas SERT blockade induced pMeCP2 only in the NAc. Administration of selective DA and 5-HT receptor agonists was also sufficient to induce pMeCP2; however, the specific combination of DA and 5-HT receptors activated determined the regional- and cell-type specificity of pMeCP2 induction. The D(1)-class DA receptor agonist SKF81297 induced pMeCP2 widely; however, coadministration of the D(2)-class agonist quinpirole restricted the induction of pMeCP2 to GABAergic interneurons of the NAc. Intra-striatal injection of the adenylate cyclase activator forskolin was sufficient to induce pMeCP2 in medium-spiny neurons, suggesting that the combinatorial regulation of cAMP by different classes of DA and 5-HT receptors may contribute to the cell-type specificity of pMeCP2 induction. Consistent with the regulation of pMeCP2 by multiple monoamine neurotransmitters, genetic disruption of any single monoamine transporter in DAT-, SERT-, and NET-knockout mice failed to eliminate AMPH-induced pMeCP2 in the NAc. Together, these studies indicate that combinatorial signaling through DA and 5-HT receptors can regulate the brain region- and cell-type specific pMeCP2 in the CNS.     

A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression

Introduction

We hypothesized that common Alzheimer's disease (AD)-associated variants within the triggering receptor expressed on myeloid (TREM) gene cluster influence disease through gene expression.

Effect of Hg, As and Pb on biomass production, photosynthetic rate, nutrients uptake and phytochelatin induction in Pfaffia glomerata

Plantlets of Pfaffia glomerata (Spreng.) were exposed for 28 days to three different metal/metalloid (Hg, Pb and As) with different levels (Hg 1; As 25, 50, 100 and Pb 100 and 400 μM) to analyze the possible phytochelatin initiation and affects on growth and photosynthetic pigments vis-à-vis metal accumulation potential of plants. The plantlets showed significant Hg, As and Pb accumulation in roots (150, 1267.67 and 2129 μg g^?1 DW respectively); however, a low root to shoot metal translocation was observed. It was interesting to note that all tested macronutrient (Mg, K, Ca) was higher in shoots and just opposite in case of micronutrients (Cu, Fe, Zn), was recorded highest in roots. The growth of plantlets (analyzed in terms of length and dry weight) was negatively affected by various metal treatments. In addition, the level of photosynthetic pigments alters significantly in response to all metal/metalloid treatment. In response to all tested metal/metalloids in plants only As induced phytochelatins (PC2, PC3 and PC4) in roots, and in shoots, GSH was observed in all tested metal/metalloids. In conclusion, P. glomerata plantlets could not cooperatively induce phytochelatins under any of Hg and Pb levels.     

Apnea testing with continuous positive airway pressure for the diagnosis of brain death in a patient with poor baseline oxygenation status

Apnea testing is a key component in the clinical diagnosis of brain death. Patients with poor baseline oxygenation may not tolerate the standard 8-10 min apnea testing with oxygen insufflation through tracheal tube. No studies have assessed the safety and feasibility of other methods of oxygenation during apnea testing in these types of patients. Here, we safely performed apnea testing in a patient with baseline PaO₂ of 99.1 mm Hg at 100% oxygen. We used continuous positive airway pressure (CPAP) of 10 cm of H₂O and 100% oxygen at the flow rate of 12 L/min using the circle system of anesthesia machine. After 10 min of apnea testing, PaO₂ decreased to 75.7 mm Hg. There was a significant rise in PaCO₂ and fall in pH, but without hemodynamic instability, arrhythmias, or desaturation. Thus, the apnea test was declared positive. CPAP can be a valuable, feasible and safe means of oxygenation during apnea testing in patients with poor baseline oxygenation, thus avoiding the need for ancillary tests.     

Is there a set of histologic changes that are invariably reflux associated?

Many histologic changes have been described in the esophageal squamous mucosa in patients with gastroesophageal reflux disease (GERD), including dilated intercellular spaces, balloon cells, intrapapillary vessel dilation, elongated papillae, basal cell hyperplasia, acanthosis, intraepithelial eosinophils, Langerhans cells, and p53 protein overexpression. To define a set of histologic changes that are invariably reflux associated, we examined the histologic changes in esophageal specimens from normal controls, patients with GERD, patients without GERD but with a suspicion of other pathology, and patients with esophageal carcinoma. We also examined biopsy specimens from sites with differing endoscopic features, including cloudy white and reddened mucosa. A definitive set of reflux-associated histologic changes could not be defined from the small number of biopsy specimens examined in the present study. Histologic changes indicative of GERD are likely to be found somewhere in the esophagus in all patients with GERD, but these changes are nonspecific. A set of histologic changes that are invariably reflux associated may exist, but these changes are nonspecific. To develop a set of characteristic reflux-associated features, endoscopists may perform targeted biopsies from several sites with various endoscopic features and at different stages of disease.