Screening and identification of novel compounds with potential anti-proliferative effects on gallium-resistant lung cancer through an AXL kinase pathway

The clinical application of gallium compounds as anticancer agents is hampered by development of resistance. As a potential strategy to overcome the limitation, eight series of compounds were identified through virtual screening of AXL kinase homology model. Anti-proliferative studies were carried using gallium-sensitive (S) and gallium-resistant (R) human lung adenocarcinoma (A549) cells. Compounds 5476423 and 7919469 were identified as leads. The IC₅₀ values from treating R-cells showed compounds 5476423 and 7919469 had 80 fold and 13 fold increased potency, respectively, compared to gallium acetylacetonate (GaAcAc). The efficacy of GaAcAc against R-cells was increased 2 fold and 1.2 fold when combined with compounds 5476423 and 7919469, respectively. Compared with S-cells, R-cells showed elevated expression of AXL protein, which was significantly suppressed through treatments with the lead compounds. It is anticipated that the lead compounds could be applied in virtual screening programs to identify novel scaffolds for new therapeutic agents as well as combinatorial therapy agents in gallium resistant lung cancer.     

Oleocanthal-rich extra-virgin olive oil enhances donepezil effect by reducing amyloid-β load and related toxicity in a mouse model of Alzheimer’s disease

Previous evidence suggested that extra-virgin olive oil (EVOO) is linked to attenuating amyloid-β (Aβ) pathology and improving cognitive function in Alzheimer’s disease (AD) mouse models. In addition, we recently reported the beneficial effect of oleocanthal, a phenolic compound in EVOO, against AD pathology. Currently, medications available to target AD pathology are limited. Donepezil is an acetylcholine esterase inhibitor approved for use for all AD stages. Donepezil has been reported to have limited Aβ-targeting mechanisms beside its acetylcholine esterase inhibition. The aim of this study was to investigate the consumption of EVOO rich with oleocanthal (hereafter EVOO) as a medical food on enhancing the effect of donepezil on attenuating Aβ load and related toxicity in 5xFAD mouse model of AD. Our results showed that EVOO consumption in combination with donepezil significantly reduced Aβ load and related pathological changes. Reduced Aβ load could be explained, at least in part, by enhancing Aβ clearance pathways including blood–brain barrier (BBB) clearance and enzymatic degradation, and shifting amyloid precursor protein processing toward the nonamyloidogenic pathway. Furthermore, EVOO combination with donepezil up-regulated synaptic proteins, enhanced BBB tightness and reduced neuroinflammation associated with Aβ pathology. In conclusion, EVOO consumption as a medical food combined with donepezil offers an effective therapeutic approach by enhancing the noncholinergic mechanisms of donepezil and by providing additional mechanisms to attenuate Aβ-related pathology in AD patients.     

Preboreal oscillations inferred from Arctica islandica sclerochronology

An increasingly important source of annually resolved palaeoenvironmental proxy data originates from cross-dated incremental chronologies summarizing the shell growth of several individuals. Here, we have analysed annual increment variations in a collection of radiocarbon-dated shells of ocean quahog (Arctica islandica) from early Holocene prodelta deposits in north Norway. Radiocarbon dating of the shell material showed that the increments were formed contemporaneously during Preboreal times. The biologically youngest shell contains 35 annual increments, whereas the oldest shell shows 169 increments. Time-series of annual increments demonstrated clear age trends with the widest increments during the very early years of bivalve life, followed by a notable decline in increment widths as the bivalves aged. Subsequent to removing these biological trends from the series, a sclerochronological cross-dating was carried out and resolved the temporal alignments of the shell growth increment records relative to each other. The resulting shell growth increment chronology evidences vigorous growth variations. Spectral analysis of the chronology revealed 3.7- and 4.3-year periodicities, indicative of Preboreal environmental oscillations. Periodicities of longer period were not detected. Our results prove the value of radiocarbon-dated shell assemblages to build “floating” geochronologies for periods and regions where dead shells from museum collections or seabed are not obtainable. Increasing constructions of such chronologies enhance the potential of sclerochronological cross-dating of annual shell growth increment chronologies to depict and detail annually-resolved climate variability not only for late Holocene, as previously illustrated, but also for early Holocene times, when large-scale oscillations punctuated the global climate dynamics. Development of longer chronologies with higher sample replication remains an attainable interdisciplinary target.     

P21-activated kinase in inflammatory and cardiovascular disease

P-21 activated kinases, or PAKs, are serine–threonine kinases that serve a role in diverse biological functions and organ system diseases. Although PAK signaling has been the focus of many investigations, still our understanding of the role of PAK in inflammation is incomplete. This review consolidates what is known about PAK1 across several cell types, highlighting the role of PAK1 and PAK2 in inflammation in relation to NADPH oxidase activation. This review explores the physiological functions of PAK during inflammation, the role of PAK in several organ diseases with an emphasis on cardiovascular disease, and the PAK signaling pathway, including activators and targets of PAK. Also, we discuss PAK1 as a pharmacological anti-inflammatory target, explore the potentials and the limitations of the current pharmacological tools to regulate PAK1 activity during inflammation, and provide indications for future research. We conclude that a vast amount of evidence supports the idea that PAK is a central molecule in inflammatory signaling, thus making PAK1 itself a promising prospective pharmacological target.     

Role of cAMP and phosphodiesterase signaling in liver health and disease

Liver disease is a significant health problem worldwide with mortality reaching around 2 million deaths a year. Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the major causes of chronic liver disease. Pathologically, NAFLD and ALD share similar patterns of hepatic disorders ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. It is becoming increasingly important to identify new pharmacological targets, given that there is no FDA-approved therapy yet for either NAFLD or ALD. Since the evolution of liver diseases is a multifactorial process, several mechanisms involving parenchymal and non-parenchymal hepatic cells contribute to the initiation and progression of liver pathologies. Moreover, certain protective molecular pathways become repressed during liver injury including signaling pathways such as the cyclic adenosine monophosphate (cAMP) pathway. cAMP, a key second messenger molecule, regulates various cellular functions including lipid metabolism, inflammation, cell differentiation and injury by affecting gene/protein expression and function. This review addresses the current understanding of the role of cAMP metabolism and consequent cAMP signaling pathway(s) in the context of liver health and disease. The cAMP pathway is extremely sophisticated and complex with specific cellular functions dictated by numerous factors such abundance, localization and degradation by phosphodiesterases (PDEs). Furthermore, because of the distinct yet divergent roles of both of its effector molecules, the cAMP pathway is extensively targeted in liver injury to modify its role from physiological to therapeutic, depending on the hepatic condition. This review also examines the behavior of the cAMP-dependent pathway in NAFLD, ALD and in other liver diseases and focuses on PDE inhibition as an excellent therapeutic target in these conditions.     

Epigenetic silencing of TIMP4 in heart failure

Tissue inhibitor of matrix metalloprotease 4 (TIMP4) is endogenously one of the key modulators of matrix metalloprotease 9 (MMP9) and we have reported earlier that cardiac specific TIMP4 instigates contractility and helps in differentiation of cardiac progenitor cells. Although studies show that the expression of TIMP4 goes down in heart failure but the mechanism is unknown. This study aims to determine the mechanism of silencing of TIMP4 in heart failure progression created by aorta‐vena cava (AV) fistula. We hypothesize that there is epigenetic silencing of TIMP4 in heart failure. To validate this hypothesis, we created heart failure model by creating AV fistula in C57BL/6 mice and looked into the promoter methylation (methylation specific PCR, high resolution melting, methylation sensitive restriction enzyme and Na bisulphite treatment followed by sequencing), histone modification (ChIP assay) and microRNAs that regulate TIMP4 (mir122a) and MMP9 (mir29b and mir455‐5p). The physiological parameters in terms of cardiac function after AV fistula were assessed by echocardiography. We observed that there are 7 CpG islands in the TIMP4 promoter which get methylated during the progression of heart failure which leads to its epigenetic silencing. In addition, the up‐regulated levels of mir122a in part, contribute to regulation of TIMP4. Consequently, MMP9 gets up‐regulated and leads to cardiac remodeling. This is a novel report to explain the epigenetic silencing of TIMP4 in heart failure.     

ATG5 provides host protection acting as a switch in the atg8ylation cascade between autophagy and secretion

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