Chloroquine commonly induces hormetic dose responses

The use of chloroquine in the treatment of COVID-19 has received considerable attention. The recent intense focus on this application of chloroquine stimulated an investigation into the effects of chloroquine at low doses on highly biologically-diverse models and whether it may induce hormetic-biphasic dose response effects. The assessment revealed that hormetic effects have been commonly induced by chloroquine, affecting numerous cell types, including tumor cell lines (e.g. human breast and colon) and non-tumor cell lines, enhancing viral replication, spermmotility, various behavioral endpoints aswell as decreasing risks of convulsions, and enhancing a spectrum of neuroprotective responses within a preconditioning experimental framework. These diverse and complex findings indicate that hormetic dose responses commonly occur with chloroquine treatment with a range of biologicalmodels and endpoints. These findings have implications concerning study design features including the number and spacing of doses, and suggest a range of possible clinical concerns and opportunities depending on the endpoint considered. (C) 2020 Elsevier B.V. All rights reserved

Cytotoxicity models of Huntington's disease and relevance of hormetic mechanisms: A critical assessment of experimental approaches and strategies.

Abstract This paper assesses in vivo cytotoxicity models of Huntington's disease (HD). Nearly 150 agents were found to be moderately to highly effective in mitigating the pathological sequelae of cytotoxic induction of HD features in multiple rodent models. Typically, rodents are treated with a prospective HD-protective agent before, during, or after the application of a chemical or transgenic process for inducing histopathological and behavioral symptoms of HD. Although transgenic and knockout rodent models (1) display relatively high construct and face validity, and (2) are ever more routinely employed to mimic genetic-to-phenotypic expression of HD features, toxicant models are also often employed, and have served as valuable test beds for the elucidation of biochemical processes and discovery of therapeutic targets in HD. Literature searches of the toxicant HD rodent models yielded nearly 150 agents that were moderately to highly effective in mitigating pathological sequelae in multiple mouse and rat HD models. Experimental models, study designs, and exposure protocols (e.g., pre- and post-conditioning) used in testing these agents were assessed, including dosing strategies, endpoints, and dose-response features. Hormetic-like biphasic dose responses, chemoprotective mechanisms, and the translational relevance of the preclinical studies and their therapeutic implications are critically analyzed in the present report. Notably, not one of the 150 agents that successfully delayed onset and progression of HD in the experimental models has been successfully translated to the treatment of humans in a clinical setting. Potential reasons for these translational failures are (1) the inadequacy of dose-response analyses and subsequent lack of useful dosing data; (2) effective rodent doses that are too high for safe human application; (3) key differences between the experimental models and humans in pharmacokinetic/pharmacodynamic features, ages and routes of agent administration; (4) lack of robust pharmacokinetic, mechanistic or systematic approaches to probe novel treatment strategies; and (5) inadequacies of the chemically induced HD model in rats to mimic accurately the complex genetic and developmental origin and progression of HD in humans. These deficiencies need to be urgently addressed if pharmaceutical agents for the treatment of HD are going to be successfully developed in experimental models and translated with fidelity to the clinic

WINISIS – A Practical Guide: In Hindi Language

This WINISIS Training Manual in Hindi language contains three self-learning modules: WINISIS – A Practical Guide; Creating Web Interface for CDS/ISIS Databases using GenisisWeb; and Publishing CDS/ISIS Databases on CD-ROM using GenisisCD. These self-learning modules are the outcome of the Advanced Workshop on CDS-ISIS for Windows, held at the Thapar University on 14-18 May 2007. The Training Manual covers all aspects of WINISIS: installation of software, creation of the database, database operations, customization of search interfaces and display formatting language. Advanced features, such as hyper-linking, web interfacing, full-text document processing and automation of libraries, are also present in this document. Target audience of this Manual is library professionals working in academic, special and public libraries as well as students of library science courses. The Manual will also be helpful to small organizations, which are building digital archives in local library setup or on CD-ROMs. After practicing the laboratory exercises given in the Manual, the learners will be able to install WINISIS software and its web application tools GENISIS; create and manage bibliographic or full-text databases. This Manual is particularly useful in the South Asian region, where availability of training material in local languages is crucial for providing public information services with the help of free and open source software (FOSS)

WINISIS - A Practical Guide: In Hindi Language

This WINISIS Training Manual in Hindi language contains three self-learning modules: WINISIS â A Practical Guide; Creating Web Interface for CDS/ISIS Databases using GenisisWeb; and Publishing CDS/ISIS Databases on CD-ROM using GenisisCD. These self-learning modules are the outcome of the Advanced Workshop on CDS-ISIS for Windows, held at the Thapar University on 14-18 May 2007. The Training Manual covers all aspects of WINISIS: installation of software, creation of the database, database operations, customization of search interfaces and display formatting language. Advanced features, such as hyper-linking, web interfacing, full-text document processing and automation of libraries, are also present in this document. Target audience of this Manual is library professionals working in academic, special and public libraries as well as students of library science courses. The Manual will also be helpful to small organizations, which are building digital archives in local library setup or on CD-ROMs. After practicing the laboratory exercises given in the Manual, the learners will be able to install WINISIS software and its web application tools GENISIS; create and manage bibliographic or full-text databases. This Manual is particularly useful in the South Asian region, where availability of training material in local languages is crucial for providing public information services with the help of free and open source software (FOSS)

HORMESIS: A fundamental concept with widespread biological and biomedical applications

Hormesis is a biphasic dose response with specific quantitative features for the amplitude and width of the stimulation. It is highly generalizable and independent of biological model, endpoint, inducing agent, level of biological organization and mechanism. Hormesis may be induced via a direct stimulation or by overcompensation to a disruption of homeostasis. The induction of hormesis by low-level stressor agents not only rapidly upregulates adaptive processes to repair damage but also protects the adapted system from damage due to a subsequent challenging dose (toxic) within a definable temporal window. The striking consistency of the amplitude of hormetic response suggests that hormesis provides a quantitative description of biological plasticity. Knowledge of hormesis has particular potential biomedical significance with respect to slowing or retarding both normal aging processes and the progression of severe neurological diseases

Synergistic repression of anaerobic genes by Mot3 and Rox1 in Saccharomyces cerevisiae

Two groups of anaerobic genes (genes induced in anaerobic cells and repressed in aerobic cells) are negatively regulated by heme, a metabolite present only in aerobic cells. Members of both groups, the hypoxic genes and the DAN/TIR/ERG genes, are jointly repressed under aerobic conditions by two factors. One is Rox1, an HMG protein, and the second, originally designated Rox7, is shown here to be Mot3, a global C2H2 zinc finger regulator. Repression of anaerobic genes results from co-induction of Mot3 and Rox1 in aerobic cells. Repressor synthesis is triggered by heme, which de-represses a mechanism controlling expression of both MOT3 and ROX1 in anaerobic cells; it includes Hap1, Tup1, Ssn6 and a fourth unidentified factor. The constitutive expression of various anaerobic genes in aerobic rox1Δ or mot3Δ cells directly implies that neither factor can repress by itself at endogenous levels and that stringent aerobic repression results from the concerted action of both. Mot3 and Rox1 are not essential components of a single complex, since each can repress independently in the absence of the other, when artificially induced at high levels. Moreover, the two repression mechanisms appear to be distinct: as shown here repression of ANB1 by Rox1 alone requires Tup1–Ssn6, whereas repression by Mot3 does not. Though artificially high levels of either factor can repress well, the absolute efficiency observed in normal cells when both are present—at much lower levels—demonstrates a novel inhibitory synergy. Evidently, expression levels for the two mutually dependent repressors are calibrated to permit a range of variation in basal aerobic expression at different promoters with differing operator site combinations