scholarly journals Nitro-Deficient Niclosamide Confers Reduced Genotoxicity and Retains Mitochondrial Uncoupling Activity for Cancer Therapy

2021 ◽  
Vol 22 (19) ◽  
pp. 10420
Author(s):  
Tsz Wai Ngai ◽  
Gamal Ahmed Elfar ◽  
Pearlyn Yeo ◽  
Nicholas Phua ◽  
Jin Hui Hor ◽  
...  
Keyword(s):  
Nitro Group ◽  
Calcium Signalling ◽  
Treatment Strategies ◽  
Metabolite Profile ◽  
Arachidonic Acid Metabolism ◽  
Dna Breaks ◽  
Mitochondrial Uncoupling ◽  
Alternative Drug ◽  
Personalised Treatment ◽  
Quantitative Scoring

Niclosamide is an oral anthelmintic drug, approved for use against tapeworm infections. Recent studies suggest however that niclosamide may have broader clinical applications in cancers, spurring increased interest in the functions and mechanisms of niclosamide. Previously, we reported that niclosamide targets a metabolic vulnerability in p53-deficient tumours, providing a basis for patient stratification and personalised treatment strategies. In the present study, we functionally characterised the contribution of the aniline 4′-NO2 group on niclosamide to its cellular activities. We demonstrated that niclosamide induces genome-wide DNA damage that is mechanistically uncoupled from its antitumour effects mediated through mitochondrial uncoupling. Elimination of the nitro group in ND-Nic analogue significantly reduced γH2AX signals and DNA breaks while preserving its antitumour mechanism mediated through a calcium signalling pathway and arachidonic acid metabolism. Lipidomics profiling further revealed that ND-Nic-treated cells retained a metabolite profile characteristic of niclosamide-treated cells. Notably, quantitative scoring of drug sensitivity suggests that elimination of its nitro group enhanced the target selectivity of niclosamide against p53 deficiency. Importantly, the results also raise concern that niclosamide may impose a pleiotropic genotoxic effect, which limits its clinical efficacy and warrants further investigation into alternative drug analogues that may ameliorate any potential unwanted side effects.

Selected natural and synthetic agents effective against Parkinson’s disease with diverse mechanisms

2021 ◽  
Vol 21 ◽  
Author(s):  
Hayrettin Ozan Gulcan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Dopamine Metabolism ◽  
Dopaminergic Agonists ◽  
Alternative Drug ◽  
Synthetic Agents ◽  
Disease Modifying

: Similar to other neurodegenerative diseases, Parkinson’s disease (PD) has been extensively investigated with respect to its neuropathological background and possible treatment options. Since the symptomatic outcomes are generally related to dopamine deficiency, the current treatment strategies towards PD mainly employ dopaminergic agonists as well as the compounds acting on dopamine metabolism. These drugs do not provide disease modifying properties; therefore alternative drug discovery studies focus on targets involved in the progressive neurodegenerative character of PD. This study has aimed to present the pathophysiology of PD concomitant to the representation of drugs and promising molecules displaying activity against the validated and non-validated targets of PD.

scholarly journals Aberrant PARP1 Activity Couples DNA Breaks to Deregulated Presynaptic Calcium Signalling and Lethal Seizures

2018 ◽  
Author(s):  
Emilia Komulainen ◽  
Jack Badman ◽  
Stephanie Rey ◽  
Stuart Rulten ◽  
Limei Ju ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Ex Vivo ◽  
Calcium Signalling ◽  
Strand Break ◽  
Parp Inhibition ◽  
Dna Breaks ◽  
Single Strand Break ◽  
Presynaptic Calcium ◽  
Dna Strand

AbstractDefects in DNA single-strand break repair result in cerebellar ataxia which in Xrcc1Nes-Cre mice is promoted by hyperactivity of the DNA strand break sensor protein, Parp1. Here, we show that Parp1 hyperactivity extends beyond the cerebellum in Xrcc1-defective brain, resulting in lethal seizures and shortened lifespan. We demonstrate that aberrant Parp1 activation triggers seizure-like activity in Xrcc1-defective hippocampus ex vivo and aberrant presynaptic calcium signalling in isolated hippocampal neurons in vitro. Moreover, we show that these defects are prevented by Parp1 inhibition and/or deletion. Collectively, these data identify aberrant Parp1 activity at unrepaired DNA breaks as a cell-autonomous source of deregulated presynaptic calcium signalling, and highlight PARP inhibition as a possible therapeutic approach in XRCC1-mutated neurodegenerative disease.SummaryPARP1 activity and presynaptic Ca2+ signalling

scholarly journals Stability in eosinophil categorisation during subsequent severe exacerbations of COPD

2021 ◽  
Vol 8 (1) ◽  
pp. e000960
Author(s):  
Emanuel Citgez ◽  
Job van der Palen ◽  
Paul van der Valk ◽  
Huib A M Kerstjens ◽  
Marjolein Brusse-Keizer
Keyword(s):  
Treatment Strategies ◽  
Stable State ◽  
Total Leucocyte Count ◽  
Chronic Obstructive ◽  
Blood Eosinophil ◽  
Obstructive Pulmonary Disease ◽  
Blood Eosinophil Count ◽  
Acute Exacerbations ◽  
The Stability ◽  
Personalised Treatment

BackgroundThe blood eosinophil count has been shown to be a promising biomarker for establishing personalised treatment strategies to reduce corticosteroid use, either inhaled or systemic, in chronic obstructive pulmonary disease (COPD). Eosinophil levels seem relatively stable over time in stable state, but little is known whether this is also true in subsequent severe acute exacerbations of COPD (AECOPD).Aims and objectivesTo determine the stability in eosinophil categorisation between two subsequent severe AECOPDs employing frequently used cut-off levels.MethodsDuring two subsequent severe AECOPDs, blood eosinophil counts were determined at admission to the hospital in 237 patients in the Cohort of Mortality and Inflammation in COPD Study. The following four cut-off levels were analysed: absolute counts of eosinophils ≥0.2×10⁹/L (200 cells/µL) and ≥0.3×10⁹/L (300 cells/µL) and relative eosinophil percentage of ≥2% and ≥3% of total leucocyte count. Categorisations were considered stable if during the second AECOPD their blood eosinophil status led to the same classification: eosinophilic or not.ResultsDepending on the used cut-off, the overall stability in eosinophil categorisation varied between 70% and 85% during two subsequent AECOPDs. From patients who were eosinophilic at the first AECOPD, 34%–45% remained eosinophilic at the subsequent AECOPD, while 9%–21% of patients being non-eosinophilic at the first AECOPD became eosinophilic at the subsequent AECOPD.ConclusionsThe eosinophil variability leads to category changes in subsequent AECOPDs, which limits the eosinophil categorisation stability. Therefore, measurement of eosinophils at each new exacerbation seems warranted.

scholarly journals Dutch patients, caregivers and healthcare professionals generate first nationwide research agenda for juvenile idiopathic arthritis

2020 ◽  
Author(s):  
Anouk Verwoerd ◽  
Wineke Armbrust ◽  
Katherine Cowan ◽  
Lotte van den Berg ◽  
Joke de Boer ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Focus Groups ◽  
Research Agenda ◽  
Healthcare Professionals ◽  
Treatment Strategies ◽  
Research Priorities ◽  
Nationwide Survey ◽  
James Lind Alliance ◽  
Research Questions ◽  
Personalised Treatment

Abstract Background Involving the end-users of scientific research (patients, carers and clinicians) in setting research priorities is important to formulate research questions that truly make a difference and are in tune with the needs of patients. We therefore aimed to generate a national research agenda for Juvenile Idiopathic Arthritis (JIA) together with patients, their caregivers and healthcare professionals through conducting a nationwide survey among these stakeholders.Methods The James Lind Alliance method was used, tailored with additional focus groups held to involve younger patients. First, research questions were gathered through an online and hardcopy survey. The received questions that were in scope were summarised and a literature search was performed to verify that questions were unanswered. Questions were ranked in the interim survey, and the final top 10 was chosen during a prioritisation workshop. Results Two hundred and seventy-eight respondents submitted 604 questions, of which 519 were in scope. Of these 604 questions, 81 were generated in the focus groups with younger children. The questions were summarised into 53 summary questions. An evidence checking process verified that all questions were unanswered. A total of 303 respondents prioritised the questions in the interim survey. Focus groups with children generated a top 5 of their most important questions. Combining this top 5 with the top 10s of patients, carers, and clinicians led to a top 21. Out of these, the top 10 research priorities were chosen during a final workshop. Research into pain and fatigue, personalised treatment strategies and aetiology were ranked high in the Top 10.Conclusions Through this study, the top 10 research priorities for JIA of patients, their caregivers and clinicians were identified to inform researchers and research funders of the research topics that matter most to them. The top priority involves the treatment and mechanisms behind persisting pain and fatigue when the disease is in remission.

scholarly journals Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures

EMBO Reports ◽  
2021 ◽  
Author(s):  
Emilia Komulainen ◽  
Jack Badman ◽  
Stephanie Rey ◽  
Stuart Rulten ◽  
Limei Ju ◽  
...  
Keyword(s):  
Calcium Signalling ◽  
Dna Breaks

scholarly journals The Role of the Cutaneous Microbiome in Hidradenitis Suppurativa—Light at the End of the Microbiological Tunnel

2020 ◽  
Vol 21 (4) ◽  
pp. 1205 ◽  
Author(s):  
Langan ◽  
Recke ◽  
Bokor-Billmann ◽  
Billmann ◽  
Kahle ◽  
...  
Keyword(s):  
Skin Diseases ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Acne Inversa ◽  
Inflammatory Skin Diseases ◽  
Microbial Dysbiosis ◽  
Inflammatory Skin ◽  
Personalised Treatment ◽  
Generation Sequencing

The development of next generation sequencing, coupled with advances in bio-informatics, has provided new insights into the role of the cutaneous microbiome in the pathophysiology of a range of inflammatory skin diseases. In fact, it has even been suggested that the identification of specific skin microbial signatures may not only be useful in terms of diagnosis of skin diseases but they may also ultimately help inform personalised treatment strategies. To date, research investigating the role of microbiota in the development of inflammatory skin diseases has largely focused on atopic eczema and psoriasis vulgaris. The role of the microbiome in Hidradenits suppurativa (HS)—also known as acne inversa—a chronic auto-inflammatory skin disease associated with significant morbidity, has received comparatively little attention. This is despite the fact that antimicrobial therapy plays a central role in the treatment of HS. After briefly outlining the clinical features of HS and current treatment strategies, we move on to review the evidence of microbial dysbiosis in HS pathophysiology. We conclude by outlining the potential for metagenomic studies to deepen our understanding of HS biology but more importantly to identify novel and much needed treatment strategies.

scholarly journals Can serum biomarkers predict the outcome of systemic therapy for atopic dermatitis?

2020 ◽  
Author(s):  
Guillem Hurault ◽  
Evelien Roekevisch ◽  
Mandy E. Schram ◽  
Krisztina Szegedi ◽  
Sanja Kezic ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Systemic Therapy ◽  
Measurement Errors ◽  
Treatment Strategies ◽  
Predictive Performance ◽  
Historical Record ◽  
Statistical Machine Learning ◽  
Minimum Detectable Change ◽  
Severity Scores ◽  
Personalised Treatment

SUMMARYBackgroundAtopic dermatitis (AD or eczema) is a most common chronic skin disease. Designing personalised treatment strategies for AD based on patient stratification, rather than the “one-size-fits-all” treatments, is of high clinical relevance. It has been hypothesised that the measurement of biomarkers could help predict therapeutic response for individual patients.ObjectiveWe aim to assess whether biomarkers can predict the outcome of systemic therapy.MethodsWe developed a statistical machine learning predictive model using the data of an already published longitudinal study of 42 patients who received systemic therapy. The data contained 26 serum cytokines measured before the therapy. The model described the dynamics of the latent disease severity and measurement errors to predict AD severity scores (EASI, (o)SCORAD and POEM) two-weeks ahead. We conducted feature selection to identify the most important biomarkers for predicting the AD severity scores.ResultsWe validated our model and confirmed that it outperformed standard time-series forecasting models. Adding biomarkers did not improve predictive performance. Our estimates of the minimum detectable change for the AD severity scores were larger than already published estimates of the minimal clinically important difference.ConclusionsBiomarkers had a negligible and non-significant effect for predicting the future AD severity scores and the outcome of the systemic therapy. Instead, a historical record of severity scores provides rich and insightful dynamical information required for prediction of therapeutic responses.

scholarly journals Population Graph GNNs for Brain Age Prediction

2020 ◽  
Author(s):  
Kamilė Stankevičiūtė ◽  
Tiago Azevedo ◽  
Alexander Campbell ◽  
Richard Bethlehem ◽  
Pietro Liò
Keyword(s):  
Treatment Strategies ◽  
Brain Disorders ◽  
Graph Data ◽  
Entire Cohort ◽  
Wide Range ◽  
Age Trends ◽  
Personalised Treatment ◽  
Brain Age ◽  
The Brain ◽  
Age Prediction

AbstractMany common neurological and neurodegenerative disorders, such as Alzheimer’s disease, dementia and multiple sclerosis, have been associated with abnormal patterns of apparent ageing of the brain. Discrepancies between the estimated brain age and the actual chronological age (brain age gaps) can be used to understand the biological pathways behind the ageing process, assess an individual’s risk for various brain disorders and identify new personalised treatment strategies. By flexibly integrating minimally preprocessed neuroimaging and non-imaging modalities into a population graph data structure, we train two types of graph neural network (GNN) architectures to predict brain age in a clinically relevant fashion as well as investigate their robustness to noisy inputs and graph sparsity. The multimodal population graph approach has the potential to learn from the entire cohort of healthy and affected subjects of both sexes at once, capturing a wide range of confounding effects and detecting variations in brain age trends between different sub-populations of subjects.

scholarly journals Dutch patients, caregivers and healthcare professionals generate first nationwide research agenda for juvenile idiopathic arthritis

2020 ◽  
Author(s):  
Anouk Verwoerd ◽  
Wineke Armbrust ◽  
Katherine Cowan ◽  
Lotte van den Berg ◽  
Joke de Boer ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Focus Groups ◽  
Research Agenda ◽  
Healthcare Professionals ◽  
Treatment Strategies ◽  
Research Priorities ◽  
Nationwide Survey ◽  
James Lind Alliance ◽  
Research Questions ◽  
Personalised Treatment

Abstract Background: Involving the end-users of scientific research (patients, carers and clinicians) in setting research priorities is important to formulate research questions that truly make a difference and are in tune with the needs of patients. We therefore aimed to generate a national research agenda for Juvenile Idiopathic Arthritis (JIA) together with patients, their caregivers and healthcare professionals through conducting a nationwide survey among these stakeholders.Methods: The James Lind Alliance method was used, tailored with additional focus groups held to involve younger patients. First, research questions were gathered through an online and hardcopy survey. The received questions that were in scope were summarised and a literature search was performed to verify that questions were unanswered. Questions were ranked in the interim survey, and the final top 10 was chosen during a prioritisation workshop.Results: Two hundred and seventy-eight respondents submitted 604 questions, of which 519 were in scope. Of these 604 questions, 81 were generated in the focus groups with younger children. The questions were summarised into 53 summary questions. An evidence checking process verified that all questions were unanswered. A total of 303 respondents prioritised the questions in the interim survey. Focus groups with children generated a top 5 of their most important questions. Combining this top 5 with the top 10 s of patients, carers, and clinicians led to a top 21. Out of these, the top 10 research priorities were chosen during a final workshop. Research into pain and fatigue, personalised treatment strategies and aetiology were ranked high in the Top 10.Conclusions: Through this study, the top 10 research priorities for JIA of patients, their caregivers and clinicians were identified to inform researchers and research funders of the research topics that matter most to them. The top priority involves the treatment and mechanisms behind persisting pain and fatigue when the disease is in remission.

scholarly journals Inhibition of tryptophan 2,3-dioxygenase impairs DNA damage tolerance and repair in glioma cells

2020 ◽  
Author(s):  
Megan R. Reed ◽  
Leena Maddukuri ◽  
Amit Ketkar ◽  
Stephanie D. Byrum ◽  
Maroof K. Zafar ◽  
...  
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Protein A ◽  
Treatment Strategies ◽  
Glioma Cells ◽  
Replication Stress ◽  
Dna Breaks ◽  
Aberrant Expression ◽  
Aryl Hydrocarbon ◽  
Proliferative Effect

ABSTRACTAberrant expression of tryptophan 2,3-dioxygenase (TDO) is a determinant of malignancy and immune response in gliomas in part through kynurenine (KYN)-mediated activation of the aryl hydrocarbon receptor (AhR). In the current study, we investigated the hypothesis that TDO activation in gliomas has a broad impact upon genome maintenance - promoting tolerance of replication stress (RS) and repair of DNA damage. We report that inhibition of TDO activity attenuated recovery from hydroxyurea (HU)-induced RS and increased the genotoxic effects of bis-chloroethylnitrosourea (BCNU), as fork progress was impeded when TDO-deficient glioma cells were treated with BCNU. Activation of the Chk1 arm of the replication stress response (RSR) was reduced when TDO activity was blocked prior to treatment with BCNU, whereas phosphorylation of serine 33 (pS33) on replication protein A (RPA) was enhanced – indicative of increased fork collapse. Restoration of KYN levels protected against some replication-associated effects of BCNU. Inhibition of TDO activity had a strong anti-proliferative effect on glioma-derived cells – enhancing the cytotoxic effects of BCNU. Analysis of results obtained using quantitative proteomics revealed TDO-dependent changes in several signaling pathways – including down-regulation of DNA repair factors and sirtuin signaling. Consistent with these observations, inhibition of TDO diminished SIRT7 recruitment to chromatin, which increased histone H3K18 acetylation – a key mark involved in 53BP1 recruitment to sites of DNA damage. Cells lacking TDO activity exhibited defective recruitment of 53BP1 to gH2AX foci, which corresponded with delayed repair of BCNU-induced DNA breaks. Addition of exogenous KYN increased the rate of break repair. The discovery that TDO activity modulates sensitivity to DNA damage by fueling SIRT7/53BP1 localization to chromatin and repair of BCNU-induced DNA damage highlights the potential for tumor-specific metabolic changes to influence genome stability and may have implications for glioma biology and treatment strategies.

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