Τρίτη 31 Οκτωβρίου 2017

Bilateral vestibulopathy: Diagnostic criteria Consensus document of the Classification Committee of the Bárány Society.

Bilateral vestibulopathy: Diagnostic criteria Consensus document of the Classification Committee of the Bárány Society.

J Vestib Res. 2017;27(4):177-189

Authors: Strupp M, Kim JS, Murofushi T, Straumann D, Jen JC, Rosengren SM, Della Santina CC, Kingma H

Abstract
This paper describes the diagnostic criteria for bilateral vestibulopathy (BVP) by the Classification Committee of the Bárány Society. The diagnosis of BVP is based on the patient history, bedside examination and laboratory evaluation. Bilateral vestibulopathy is a chronic vestibular syndrome which is characterized by unsteadiness when walking or standing, which worsen in darkness and/or on uneven ground, or during head motion. Additionally, patients may describe head or body movement-induced blurred vision or oscillopsia. There are typically no symptoms while sitting or lying down under static conditions.The diagnosis of BVP requires bilaterally significantly impaired or absent function of the vestibulo-ocular reflex (VOR). This can be diagnosed for the high frequency range of the angular VOR by the head impulse test (HIT), the video-HIT (vHIT) and the scleral coil technique and for the low frequency range by caloric testing. The moderate range can be examined by the sinusoidal or step profile rotational chair test.For the diagnosis of BVP, the horizontal angular VOR gain on both sides should be <0.6 (angular velocity 150-300°/s) and/or the sum of the maximal peak velocities of the slow phase caloric-induced nystagmus for stimulation with warm and cold water on each side <6°/s and/or the horizontal angular VOR gain <0.1 upon sinusoidal stimulation on a rotatory chair (0.1 Hz, Vmax = 50°/sec) and/or a phase lead >68 degrees (time constant of <5 seconds). For the diagnosis of probable BVP the above mentioned symptoms and a bilaterally pathological bedside HIT are required.Complementary tests that may be used but are currently not included in the definition are: a) dynamic visual acuity (a decrease of ≥0.2 logMAR is considered pathological); b) Romberg (indicating a sensory deficit of the vestibular or somatosensory system and therefore not specific); and c) abnormal cervical and ocular vestibular-evoked myogenic potentials for otolith function.At present the scientific basis for further subdivisions into subtypes of BVP is not sufficient to put forward reliable or clinically meaningful definitions. Depending on the affected anatomical structure and frequency range, different subtypes may be better identified in the future: impaired canal function in the low- or high-frequency VOR range only and/or impaired otolith function only; the latter is evidently very rare.Bilateral vestibulopathy is a clinical syndrome and, if known, the etiology (e.g., due to ototoxicity, bilateral Menière's disease, bilateral vestibular schwannoma) should be added to the diagnosis. Synonyms include bilateral vestibular failure, deficiency, areflexia, hypofunction and loss.

PMID: 29081426 [PubMed - in process]



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New developments and clinical transition of hyaluronic acid-based nanotherapeutics for treatment of cancer: reversing multidrug resistance, tumour-specific targetability and improved anticancer efficacy.

New developments and clinical transition of hyaluronic acid-based nanotherapeutics for treatment of cancer: reversing multidrug resistance, tumour-specific targetability and improved anticancer efficacy.

Artif Cells Nanomed Biotechnol. 2017 Oct 30;:1-14

Authors: Safdar MH, Hussain Z, Abourehab MAS, Hasan H, Afzal S, Thu HE

Abstract
This review aims to overview and critically analyses recent developments in achieving tumour-specific delivery of anticancer agents, maximizing anticancer efficacy, and mitigating tumour progression and off-target effects. Stemming from critical needs to develop target-specific delivery vehicles in cancer therapy, various hyaluronic acid (HA)-conjugated nanomedicines have been fabricated owing to their biocompatibility, safety, tumour-specific targetability of drugs and genes, and proficient interaction with cluster-determinant-44 (CD44) receptors over-expressed on the surface of tumour cells. HA-based conjugation or surface modulation of anticancer drugs encapsulated nanocarriers have shown promising efficacy against the various types of carcinomas of liver, breast, colorectal, pancreatic, lung, skin, ovarian, cervical, head and neck and gastric. The success of this emerging platform is assessed in achieving the rapid internalization of anticancer payloads into the tumour cells, impeding cancer cells division and proliferation, induction of cancer-specific apoptosis and prevention of metastasis (tumour progression). This review extends detailed insight into the engineering of HA-based nanomedicines, characterization, utilization for the diagnosis or treatment of CD44 over-expressing cancer subtypes and emphasizing the transition of nanomedicines to clinical cancer therapy.

PMID: 29082766 [PubMed - as supplied by publisher]



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Development of docetaxel liposome surface modified with CD133 aptamers for lung cancer targeting.

Development of docetaxel liposome surface modified with CD133 aptamers for lung cancer targeting.

Artif Cells Nanomed Biotechnol. 2017 Oct 30;:1-8

Authors: Ma J, Zhuang H, Zhuang Z, Lu Y, Xia R, Gan L, Wu Y

Abstract
The aim of the present study was to prepare a novel CD133 aptamer modified DTX liposome system and investigate its characteristics in vitro and in vivo studies. In this study, the CD133-DTX LP was prepared by the thin-film hydration method and with the particle size of 100-120 nm. The TEM photomicrographs were smooth, sub-spherical in shape and aggregated to form small clusters. In vitro, a relatively slower DTX release profile was observed in CD133-DTX LP due to the presence of CD133 aptamers on the outer surface which might hinder the drug release. The drug release mechanism fit well with the Higuchi equation better. In cytotoxicity study, CD133 aptamers modified DTX LP significantly decreased cell proliferation and improved the therapeutic efficiency. In vivo imaging result indicated that CD133-DTX LP had very good tumour targeting ability. In vivo antitumour activity indicated that the CD133-DTX LP showed a significant antitumour activity in A549 tumour mice, with a very low systemic toxicity.

PMID: 29082764 [PubMed - as supplied by publisher]



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Ternary complex of plasmid DNA with NLS-Mu-Mu protein and cationic niosome for biocompatible and efficient gene delivery: a comparative study with protamine and lipofectamine.

Ternary complex of plasmid DNA with NLS-Mu-Mu protein and cationic niosome for biocompatible and efficient gene delivery: a comparative study with protamine and lipofectamine.

Artif Cells Nanomed Biotechnol. 2017 Oct 28;:1-11

Authors: Nematollahi MH, Torkzadeh-Mahanai M, Pardakhty A, Ebrahimi Meimand HA, Asadikaram G

Abstract
Non-viral gene delivery methods are considered due to safety and simplicity in human gene therapy. Since the use of cationic peptide and niosome represent a promising approach for gene delivery purposes we used recombinant fusion protein and cationic niosome as a gene carrier. A multi-domain fusion protein including nuclear localization motif (NLS) and two DNA-binding (Mu) domains, namely NLS-Mu-Mu (NMM) has been designed, cloned and expressed in E. coli DE3 strain. Afterward, the interested protein was purified by affinity chromatography. Binary vectors based on protein/DNA and ternary vectors based on protein/DNA/niosome were prepared. Protamine was used as a control. DNA condensing properties of NMM and protamine were evaluated by various experiments. Furthermore, we examined cytotoxicity, hemolysis and transfection potential of the binary and ternary complexes in HEK293T and MCF-7 cell lines. Protamine and Lipofectamine™2000 were used as positive controls, correspondingly. The recombinant NMM was expressed and purified successfully and DNA was condensed efficiently at charge ratios that were not harmful to cells. Peptidoplexes showed transfection efficiency (TE) but ternary complexes had higher TE. Additionally, NMM ternary complex was more efficient compared to protamine ternary vectors. Our results showed that niosomal ternary vector of NMM is a promising non-viral gene carrier to achieve an effective and safe carrier system for gene therapy.

PMID: 29081256 [PubMed - as supplied by publisher]



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Glutaraldehyde inactivation of enveloped DNA viruses in the preparation of haemoglobin-based oxygen carriers.

Glutaraldehyde inactivation of enveloped DNA viruses in the preparation of haemoglobin-based oxygen carriers.

Artif Cells Nanomed Biotechnol. 2017 Oct 28;:1-6

Authors: Ma H, Li Q, Feng K, Zhang Y, Zhu H, Chen C, Yan K

Abstract
Glutaraldehyde (GA), used medically as a disinfectant and as a crosslinker for haemoglobin (Hb)-based oxygen carriers (HBOCs), was investigated for its ability to inactivate viruses during the preparation of these artificial blood substitutes. Porcine parvovirus (PPV; a non-enveloped DNA virus) and porcine pseudorabies virus (PRV; an enveloped DNA virus) were used as the virus indicators. Upon treatment with 0.1 mM GA, the titer of PRV decreased from 9.62 log10 to 2.62 log10 within 0.5 h, whereas that of PPV decreased from 7.00 log10 to 2.30 log10 in 5 h. Following treatment with 1.0 mM GA, the titer of PRV decreased from 11.00 log10 to 1.97 log10 within 0.5 h, whereas that of PPV decreased from 7.50 log10 to 3.43 log10 in 4.5 h. During the polymerization of Hb with GA, the GA concentration decreased to 1.0 and 0.1 mM within 30 and 50 min, respectively, at a GA:Hb molar ratio of 10:1, whereas at a GA:Hb molar ratio of 30:1, GA decreased to those same concentrations in 1.5 and 2.5 h, respectively. This rapid decrease in GA concentration during its polymerization with Hb indicates that GA must be added into the Hb solution in a short time in order to get as high a initial concentration as possible. In this study, the GA can only inactivate PRV effectively, given that a longer time (4.5 h) was required for it to inactivate the PPV titer. This study therefore demonstrates that GA inactivates the enveloped DNA virus only during the preparation of HBOCs.

PMID: 29081252 [PubMed - as supplied by publisher]



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Novel therapeutic modalities and drug delivery - erlotinib liposomes modified with galactosylated lipid: in vitro and in vivo investigations.

Novel therapeutic modalities and drug delivery - erlotinib liposomes modified with galactosylated lipid: in vitro and in vivo investigations.

Artif Cells Nanomed Biotechnol. 2017 Oct 28;:1-6

Authors: Xu H, He C, Liu Y, Jiang J, Ma T

Abstract
The aim of this study to develop galactosylated erlotinib liposomes for treatment of lung cancer. The liposomes were prepared by using solvent evaporation method. Various parameters such as particle size, zeta potential, entrapment efficiency, stability and in vitro drug release were determined. The size of liposomes (both conventional and modified) was 103.5 and 121.4 nm. The zeta potential and EE of both liposomes were -7.1 ± 1.3 mV, -1.2 ± 0.5 mV and (82.3 ± 1.9)%, (83.4 ± 1.5)%, respectively. It was found that modified liposomes increase the size of particles. The in vitro release results indicated that the release of erlotinib from galactosylated liposomes was similar to that of conventional liposome, demonstrating that the modification did not affect erlotinib release. From the result of in vivo, it proved that erlotinib liposomes can significantly improve the drug targeting, rapidly distribute the drug in the body, prolong the drug circulation time and significantly increase the relative bioavailability of the drug. Biodistribution studies showed that erlotinib from galactosylated liposomes had higher AUC inside liver than the injection group and no histological change occurred to the rat liver after the administration of erlotinib conventional and galactosylated liposomes.

PMID: 29081246 [PubMed - as supplied by publisher]



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Chitosan delaying human fibroblast senescence through downregulation of TGF-β signaling pathway.

Chitosan delaying human fibroblast senescence through downregulation of TGF-β signaling pathway.

Artif Cells Nanomed Biotechnol. 2017 Oct 30;:1-12

Authors: Tsai CW, Chiang IN, Wang JH, Young TH

Abstract
This study evaluated the effect of chitosan, poly vinyl alcohol (PVA) and poly (2-hydroxyethyl methacrylate) (pHEMA) on delaying the human fibroblast senescence. Cells could form suspending multicellular spheroids on these biomaterials, but only chitosan was capable of decreasing the SA β-gal activity and increasing the proliferation ability of senescent fibroblasts. Therefore, in addition to the structure of multicellular spheroids, chitosan itself should play an important role in delaying fibroblast senescence. The main difference of senescence-related protein expressions for cells cultured on chitosan, PVA and pHEMA occurred on the TGF-β signaling pathway. In addition to the intracellular TGF-β expression, the extracellular TGF-β expression was also downregulated. Chitosan with cationic amino structure was assumed to bind with anionic TGF-β by forming polyelectrolyte complexes. This assumption was demonstrated by directly adding chitosan into the medium to downregulate the cell TGF-β expression and further to delay cell senescence, indicating TGF-β signaling pathway was involved in the chitosan-mediating fibroblast senescence process. Finally, the delaying cell senescence ability of chitosan increased with increasing the amount of amino groups in chitosan and its ionization degree. In summary, these results provide important information for considering the application of chitosan in the future cell therapy and regeneration medicine.

PMID: 29081244 [PubMed - as supplied by publisher]



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Angiogenesis inhibitor; +36 new citations

36 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

Angiogenesis inhibitor

These pubmed results were generated on 2017/10/31

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.



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Stop the Spam! Conference Ethics and Decoding the Subtext in Post-Truth Science. What Would Denis Diderot Say?

Stop the Spam! Conference Ethics and Decoding the Subtext in Post-Truth Science. What Would Denis Diderot Say?

OMICS. 2017 Oct 30;:

Authors: Özdemir V, Dandara C, Hekim N, Birch K, Springer S, Kunej T, Endrenyi L

Abstract
Science and its practice always had a subtext, subject to influence by scientists', funders', and other innovation actors' values and assumptions. The recent emergence of post-truth, authoritarian and populist penchants, in both developed and developing countries, has further blurred the already fluid boundaries between material scientific facts and their social construction/shaping by scientific subtext, human values, powers, and hegemony. While there are certain checks, balances, and oversight mechanisms for publication ethics, other pillars of science communication, most notably, scientific conferences and their governance, are ill prepared for post-truth science. Worrisomely, the proliferation of spam conferences is a major cause for concern for integrative biology and postgenomic science. The current gaps in conference ethics are important beyond science communication because conferences help build legitimacy of emerging technologies and frontiers of science and, thus, bestows upon the organizers, funders, enlisted scientific advisors, speakers, among others, power, which in turn needs to be checked. Denis Diderot (1713-1784), a prominent intellectual during the Enlightenment period, has aptly observed that the very act of organizing brings about power, influence, and control. If the subtext of conference practices is left unchecked, it can pave the way for hegemony, and yet more volatile and violent authoritarian governance systems in science and society. This begs for innovative solutions to increase accountability, resilience, and capacity of technology experts and scientists to discern and decode the subtext in science and its communication in the current post-truth world. We propose that the existing undergraduate and graduate programs in life and physical sciences and medicine could be redesigned to include a rotation for exposure to and training in political science. Such innovative PhD+ programs straddling technical and political science scholarship would best equip future students and citizens to grasp and respond to subtext and embedded opaque value and power systems in scientific practices in an increasingly post-truth world. Political science scholarship unpacks the inner workings, subtext, and power dynamics in science and society. Thus, knowledge of political science competency is akin to molecular biology in life sciences. Both make the invisible (e.g., cell biology versus subtext of knowledge) visible. The ability to read subtext in science and claims of post-truth knowledge is a new and essential form of societal literacy in 21(st) century science and integrative biology.

PMID: 29083982 [PubMed - as supplied by publisher]



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Mapping the small molecule interactome by mass spectrometry.

Mapping the small molecule interactome by mass spectrometry.

Biochemistry. 2017 Oct 30;:

Authors: Flaxman HA, Woo CM

Abstract
Mapping small molecule interactions throughout the proteome provides the critical structural basis for functional analysis of their impact on biochemistry. However, translation of mass spectrometry-based proteomics methods to directly profile the interaction between a small molecule and the whole proteome is challenging due to the substoichiometric nature of many interactions, the diversity of covalent and noncovalent interactions involved, and the subsequent computational complexity associated with spectral assignment. Recent advances in mass spectrometry and chemical tools have begun to provide a structural basis for the breadth of small molecule-protein interactions in the whole proteome. Innovations enabling direct characterization of the small molecule interactome have centered on faster, more sensitive instrumentation coupled to chemical conjugation, enrichment, and labeling methods that facilitate detection and assignment. These methods have started to measure molecular interaction hot spots due to inherent differences in local amino acid reactivity and binding affinity throughout the proteome. Measurement of the small molecule interactome is producing structural insights into protein biochemistry that yields small molecule probes, therapeutic targets, and engineered modifications to the proteome. Direct structural characterization of the small molecule interactome is a rapidly emerging area that is producing new frontiers in biochemistry at the interface of small molecules and the proteome.

PMID: 29083874 [PubMed - as supplied by publisher]



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Frontiers in sperm function testing: DNA fragmentation analysis shows promise.

Frontiers in sperm function testing: DNA fragmentation analysis shows promise.

Transl Androl Urol. 2017 Sep;6(Suppl 4):S457-S458

Authors: Herati AS, Lamb DJ

PMID: 29082161 [PubMed]



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Frontiers in clinical andrology.

Frontiers in clinical andrology.

Transl Androl Urol. 2017 Sep;6(Suppl 4):S343-S345

Authors: Agarwal A, Cho CL, Majzoub A, Esteves SC

PMID: 29082143 [PubMed]



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Inner ear manifestations in CHARGE: Abnormalities, treatments, animal models, and progress toward treatments in auditory and vestibular structures.

Inner ear manifestations in CHARGE: Abnormalities, treatments, animal models, and progress toward treatments in auditory and vestibular structures.

Am J Med Genet C Semin Med Genet. 2017 Oct 30;:

Authors: Choo DI, Tawfik KO, Martin DM, Raphael Y

Abstract
The inner ear contains the sensory organs for hearing and balance. Both hearing and balance are commonly affected in individuals with CHARGE syndrome (CS), an autosomal dominant condition caused by heterozygous pathogenic variants in the CHD7 gene. Semicircular canal dysplasia or aplasia is the single most prevalent feature in individuals with CHARGE leading to deficient gross motor skills and ambulation. Identification of CHD7 as the major gene affected in CHARGE has enabled acceleration of research in this field. Great progress has been made in understanding the role of CHD7 in the development and function of the inner ear, as well as in related organs such as the middle ear and auditory and vestibular neural pathways. The goals of current research on CHD7 and CS are to (a) improve our understanding of the pathology caused by CHD7 pathogenic variants and (b) to provide better tools for prognosis and treatment. Current studies utilize cells and whole animals, from flies to mammals. The mouse is an excellent model for exploring mechanisms of Chd7 function in the ear, given the evolutionary conservation of ear structure, function, Chd7 expression, and similarity of mutant phenotypes between mice and humans. Newly recognized developmental functions for mouse Chd7 are shedding light on how abnormalities in CHD7 might lead to CS symptoms in humans. Here we review known human inner ear phenotypes associated with CHD7 pathogenic variants and CS, summarize progress toward diagnosis and treatment of inner ear-related pathologies, and explore new avenues for treatment based on basic science discoveries.

PMID: 29082607 [PubMed - as supplied by publisher]



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Psychological Predictors of Postconcussive Symptoms Following Traumatic Injury.

Psychological Predictors of Postconcussive Symptoms Following Traumatic Injury.

J Head Trauma Rehabil. 2017 Oct 27;:

Authors: Sullivan KA, Edmed SL, Greenslade JH, White M, Chu K, Lukin B, Lange RT, Lurie JK

Abstract
OBJECTIVE: To determine the contribution of demographics, injury type, pain, and psychological factors on postconcussive symptoms.
SETTING AND PARTICIPANTS: Recently injured (n = 54) and noninjured (n = 184) adults were recruited from a hospital emergency department or the community. Thirty-eight individuals met the diagnostic criteria for a mild traumatic brain injury and 16 individuals received treatment for a minor traumatic non-brain injury.
MAIN MEASURES: Standardized tests were administered to assess 4 postconcussion symptom types and theorized predictors including a "physiogenic" variable (injury type) and "psychogenic" variables (symptoms of anxiety, depression, and stress) within 1 month of the injury.
RESULTS: In the injured sample, after controlling for injury type, demographics, and pain (chronic and current), a hierarchical regression analysis revealed that the combination of psychological symptoms predicted affective (F10,42 = 2.80, P = .009, Rchange = 0.27) but not other postconcussion symptoms types. Anxiety (β = .48), stress (β = .18), and depression (β = -.07) were not statistically significant individual predictors (P > .05). Cognitive and vestibular postconcussion symptoms were not predicted by the modeled factors, somatic sensory postconcussion symptoms were predicted by demographic factors only, and the pattern of predictors for the symptom types differed for the samples.
CONCLUSIONS: Traditional explanatory models do not account for these findings. The predictors are multifactorial, different for injured versus noninjured samples, and symptom specific.

PMID: 29084098 [PubMed - as supplied by publisher]



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Adaptive equipment use by people with motor neuron disease in Australia: a prospective, observational consecutive cohort study.

Adaptive equipment use by people with motor neuron disease in Australia: a prospective, observational consecutive cohort study.

Disabil Rehabil Assist Technol. 2017 Oct 28;:1-6

Authors: Connors KA, Mahony LM, Morgan P

Abstract
PURPOSE: People with motor neuron sisease require adaptive equipment to enhance life quality. This study aimed to examine total and concurrent equipment items prescribed with phenotype consideration.
METHODS: A prospective, observational consecutive cohort study was undertaken. Data regarding Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, phenotype, symptom onset and Functional Independence Measure (inpatients only) was recorded. Equipment utilized was coded by therapist as: speech devices; transfer devices; mobility devices (including power wheelchairs); orthoses; activities of daily living equipment; assisted technology and home modification equipment.
RESULTS: Two hundred and seventy-three people with motor neuron disease participated, mean age 67 years, mean amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score 32, a moderate level of disability. Equipment items per participant ranged from 0 to 20, median 5. The electric lift recliner chair was the most commonly used equipment item, used by 51.2% of the cohort. There was a statistically significant difference in equipment use between flail leg and bulbar (Md 11, 3 items, respectively; p = .005), and flail leg and cervical phenotypes (Md 11, 3.5 items respectively; p = .009).
CONCLUSIONS: People with motor neuron disease have high equipment needs to optimize quality of life. Information regarding phenotype relative to equipment requirement, and most frequently prescribed equipment items can assist health-care providers anticipate equipment needs, burden and intensity for those with motor neuron disease. Implications for rehabilitation People with motor neuron disease have high concurrent equipment needs. Electric recliner lift chairs are the most frequently prescribed equipment item by those with motor neuron disease. There is variation in concurrent equipment needs relative to motor neuron disease phenotype.

PMID: 29082797 [PubMed - as supplied by publisher]



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Tools to Measure Autophagy Using High Content Imaging and Analysis.

Tools to Measure Autophagy Using High Content Imaging and Analysis.

Methods Mol Biol. 2018;1683:59-71

Authors: Dolman NJ, Samson BA, Chambers KM, Janes MS, Mandavilli BS

Abstract
Macroautophagy, hereafter referred to as autophagy, is a predominately pro-survival catabolic process responsible for the degradation of long-lived or aggregated proteins, invading microorganisms and damaged or redundant intracellular organelles. Removal of these entities is achieved through encompassment of the target by the autophagosome and subsequent delivery to the lysosome. The use of fluorescence microscopy is a common method to investigate autophagy through monitoring the spatial and temporal recruitment both of autophagosomal markers and cargo to the autophagosome. In this section, we will discuss the use of high content imaging (HCI) and analysis in the study of autophagy with reference to commonly used markers of autophagosomal formation.

PMID: 29082487 [PubMed - in process]



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NRF2-targeted therapeutics: New targets and modes of NRF2 regulation.

NRF2-targeted therapeutics: New targets and modes of NRF2 regulation.

Curr Opin Toxicol. 2016 Dec;1:62-70

Authors: de la Vega MR, Dodson M, Chapman E, Zhang DD

Abstract
Pharmacological activation of the transcription factor nuclear factor-erythroid derived 2-like 2 (NRF2), the key regulator of the cellular antioxidant response, has been recognized as a feasible strategy to reduce oxidative/electrophilic stress and prevent carcinogenesis or other chronic illnesses, such as diabetes and chronic kidney disease. In contrast, due to the discovery of the "dark side" of NRF2, where prolonged activation of NRF2 causes tissue damage, cancer progression, or chemoresistance, efforts have been devoted to identify inhibitors. Currently, only one NRF2 activator has been approved for use in the clinic, while no specific NRF2 inhibitors have been discovered. Future development of NRF2-targeted therapeutics should be based on our current understanding of the regulatory mechanisms of this protein. In addition to the KEAP1-dependent mechanisms, the recent discovery of other pathways involved in the degradation of NRF2 have opened up new possibilities for the development of safe and specific therapeutics. Here, we review available and putative NRF2-targeted therapeutics and discuss their modes of action as well as their potential for disease prevention and treatment.

PMID: 29082352 [PubMed]



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Non-canonical activation of NRF2: New insights and its relevance to disease.

Non-canonical activation of NRF2: New insights and its relevance to disease.

Curr Pathobiol Rep. 2017 Jun;5(2):171-176

Authors: Dodson M, Zhang DD

Abstract
PURPOSE OF REVIEW: The goal of this review is to summarize the current knowledge in the field regarding the non-canonical activation of the NRF2 pathway. Specifically, we address what role p62 plays in mediating this pathway, which pathologies have been linked to the p62-dependent activation of NRF2, as well as what therapeutic strategies could be used to treat diseases associated with the non-canonical pathway.
RECENT FINDINGS: It has recently been shown that autophagic dysfunction leads to the aggregation or autophagosomal accumulation of p62, which sequesters KEAP1, resulting in prolonged activation of NRF2. The ability of p62 to outcompete NRF2 for KEAP1 binding depends on its abundance, or post-translational modifications to its key domains. Furthermore, the relevance of the p62-dependent activation of NRF2 in disease has been demonstrated in human hepatocellular carcinomas, as well as neurodegenerative diseases.
SUMMARY: These findings indicate that targeting p62, or the enzymes that modify it, could prove to be an advantageous strategy for treating diseases associated with autophagy dysregulation and prolonged activation of NRF2. Other therapeutic possibilities include restoring proper autophagic function, or directly inhibiting NRF2 or its targets, to restore redox and metabolic homeostasis. Future studies will help further clarify the mechanisms, regulation, and relevance of the non-canonical pathway in driving disease pathogenesis.

PMID: 29082113 [PubMed]



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A Case of Beta-propeller Protein-associated Neurodegeneration due to a Heterozygous Deletion of WDR45.

A Case of Beta-propeller Protein-associated Neurodegeneration due to a Heterozygous Deletion of WDR45.

Tremor Other Hyperkinet Mov (N Y). 2017;7:465

Authors: Hermann A, Kitzler HH, Pollack T, Biskup S, Krüger S, Funke C, Terrile C, Haack TB

Abstract
BACKGROUND: Static encephalopathy of childhood with neurodegeneration in adulthood is a phenotypically distinctive, X-linked dominant subtype of neurodegeneration with brain iron accumulation (NBIA). WDR45 mutations were recently identified as causal. WDR45 encodes a beta-propeller scaffold protein with a putative role in autophagy, and the disease has been renamed beta-propeller protein-associated neurodegeneration (BPAN).
CASE REPORT: Here we describe a female patient suffering from a classical BPAN phenotype due to a novel heterozygous deletion of WDR45. An initial gene panel and Sanger sequencing approach failed to uncover the molecular defect. Based on the typical clinical and neuroimaging phenotype, quantitative polymerase chain reaction of the WDR45 coding regions was undertaken, and this showed a reduction of the gene dosage by 50% compared with controls.
DISCUSSION: An extended search for deletions should be performed in apparently WDR45-negative cases presenting with features of NBIA and should also be considered in young patients with predominant intellectual disabilities and hypertonia/parkinsonism/dystonia.

PMID: 29082105 [PubMed - in process]



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Curcumin Induces Autophagy, Apoptosis, and Cell Cycle Arrest in Human Pancreatic Cancer Cells.

Curcumin Induces Autophagy, Apoptosis, and Cell Cycle Arrest in Human Pancreatic Cancer Cells.

Evid Based Complement Alternat Med. 2017;2017:5787218

Authors: Zhu Y, Bu S

Abstract
OBJECTIVE: Curcumin is an active extract from turmeric. The aim of this study was to identify the underlying mechanism of curcumin on PCa cells and the role of autophagy in this process.
METHODS: The inhibitory effect of curcumin on the growth of PANC1 and BxPC3 cell lines was detected by CCK-8 assay. Cell cycle distribution and apoptosis were tested by flow cytometry. Autophagosomes were tested by cell immunofluorescence assay. The protein expression was detected by Western blot. The correlation between LC3II/Bax and cell viability was analyzed.
RESULTS: Curcumin inhibited the cell proliferation in a dose- and time-dependent manner. Curcumin could induce cell cycle arrest at G2/M phase and apoptosis of PCa cells. The autophagosomes were detected in the dosing groups. Protein expression of Bax and LC3II was upregulated, while Bcl2 was downregulated in the high dosing groups of curcumin. There was a significant negative correlation between LC3II/Bax and cell viability.
CONCLUSIONS: Autophagy could be triggered by curcumin in the treatment of PCa. Apoptosis and cell cycle arrest also participated in this process. These findings imply that curcumin is a multitargeted agent for PCa cells. In addition, autophagic cell death may predominate in the high concentration groups of curcumin.

PMID: 29081818 [PubMed]



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