Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases

Al‐Bari, Md. Abdul Alim

doi:10.1093/jac/dkv018

Cited by 373 publications

(322 citation statements)

References 136 publications

Supporting

Mentioning

306

Contrasting

Unclassified

Order By: Relevance

“…Moreover, signaling via TLR coreceptors may have bypassed the inhibited pathways (55). Importantly, although it is widely used as a TLR inhibitor, chloroquine is thought to directly interfere with multiple physiological cell functions, including chemotaxis, phagocytosis, and ROS release, by alkalizing lysosomes and phagolysosomes (56,57). Our results do not support an inhibitory effect of chloroquine on these functions at the concentrations applied in the present study, as no significant differences between neutrophils treated with chloroquine and negative controls were seen.…”

Section: Figmentioning

confidence: 99%

Modulation of Neutrophil Extracellular Trap and Reactive Oxygen Species Release by Periodontal Bacteria

et al. 2017

View full text Add to dashboard Cite

Oral bacteria are the main trigger for the development of periodontitis, and some species are known to modulate neutrophil function. This study aimed to explore the release of neutrophil extracellular traps (NETs), associated antimicrobial proteins, and reactive oxygen species (ROS) in response to periodontal bacteria, as well as the underlying pathways. Isolated peripheral blood neutrophils were stimulated with 19 periodontal bacteria. NET and ROS release, as well as the expression of NET-bound antimicrobial proteins, elastase, myeloperoxidase, and cathepsin G, in response to these species was measured using fluorescence-based assays. NET and ROS release was monitored after the addition of NADP (NADPH) oxidase pathway modulators and inhibitors of Toll-like receptors (TLRs). Moreover, bacterial entrapment by NETs was visualized microscopically, and bacterial killing was assessed by bacterial culture. Certain microorganisms, e.g., Veillonella parvula and Streptococcus gordonii, stimulated higher levels of ROS and NET release than others. NETs were found to entrap, but not kill, all periodontal bacteria tested. NADPH oxidase pathway modulators decreased ROS production but not NET production in response to the bacteria. Interestingly, TLR inhibitors did not impact ROS and NET release. These data suggest that the variability in the neutrophil response toward different bacteria may contribute to the pathogenesis of periodontal diseases by mechanisms such as bacterial avoidance of host responses and activation of neutrophils. Moreover, our results indicate that bacterium-stimulated NET release may arise in part via NADPH oxidase-independent mechanisms. The role of TLR signaling in bacterium-induced ROS and NET release needs to be further elucidated.KEYWORDS neutrophils, NETs, reactive oxygen species, periodontitis, oral bacteria P eriodontitis is initiated by the accumulation of microbial biofilms at and below the gingival margin. Indeed, it has been estimated that ϳ700 oral bacterial species and ϳ1,200 predominant phylotypes exist (1-3). Of these bacterial species, 5 major bacterial complexes (red, orange, yellow, green, and purple) have been identified by Socransky et al. using DNA probes (4) and are referred to here as Socransky complexes. The clustering and ordination analysis allowed them to assign microbial species to a color complex on the basis of the strength of the association with each other and the clinical staging of periodontitis. The biofilms which develop during disease are orchestrated to maximize their adherence, communication, and survival. The accumulation of bacterial species within the biofilm enables its development and perseverance, and certain bacteria, such as Fusobacterium nucleatum, are key orchestrators of biofilm formation and maturation (5).In susceptible individuals, dysbiosis and an aberrant host-microbe equilibrium can result in the onset of disease (6), where the microbial biofilm thrives by exploiting the

show abstract

Section: Figmentioning

confidence: 99%

Modulation of Neutrophil Extracellular Trap and Reactive Oxygen Species Release by Periodontal Bacteria

et al. 2017

View full text Add to dashboard Cite

show abstract

“…AM drugs, such as CQ and HCQ, are acidophile substances that can freely pass through the cell membrane and accumulate up to 100 times in the acidic organelles like lysosomes, so that they are indicated as lysosomotropic agents [65][66][67]. Once in the lysosomes, these drugs are protonated and retained in these organelles where they are able to alter morphology and pH, thus resulting in an impaired functionality.…”

Section: Lysosome and Autophagy Impairmentmentioning

confidence: 99%

“…Once in the lysosomes, these drugs are protonated and retained in these organelles where they are able to alter morphology and pH, thus resulting in an impaired functionality. This implies altered processing of proteins and ingested antigens, and this is a significant effect particularly for cells like macrophages, monocytes or dendritic cells since the activity of antigen presentation and MHC loading results strongly defective [67,68]. It seems that the impairment in lysosomal function can lead to an altered immune function and subsequent lowered production of pro-inflammatory cytokines, such as IL-1, IL-6, TNF-a or IFN-g [68,69].…”

Section: Lysosome and Autophagy Impairmentmentioning

confidence: 99%

Reappraisal of Antimalarials in Interferonopathies: New Perspectives for Old Drugs

Piscianz

Cuzzoni

Sharma

et al. 2018

CMC

View full text Add to dashboard Cite

The story of antimalarials as antinflammatory drugs dates back few centuries. Chinin, the extract of the Cinchona bark, has been exploited since the 18th century for its antimalarial and antifebrile properties. Later, during the Second World War, the broad use of antimalarials allowed arguing their antirheumatic effect on soldiers. Since then, these drugs have been broadly used to treat Systemic Lupus Erythematosus, but, only recently, the molecular mechanisms of action have been partly clarified.The inhibitory action on vacuole function and trafficking has been considered for decades the main mechanism of the action of antimalarials, affecting the activation of phagocytes and dendritic cells. In addition, chloroquine is also as a potent inhibitor of autophagy, providing another possible explanation of its antinflammatory action. However, much attention has been recently devoted to the action of antimalarials on the so-called cGAS-STING pathway deputed to the sensing of nucleic acid and to the production of type 1 interferons. This pathway is a fundamental mechanism for host defence, since it is able to detect microbial DNA and RNA and induce the immune response that will lead to the production of interferons. Of note, genetic defects in disposal of nucleic acids lead to inappropriate activation of the cGAS-STING pathway and inflammation. These disorders, named type I interferonopathies, represent a valuable model to study the antinflammatory potential of antimalarials.We will discuss possible development of antimalarials to improve the treatment of type I interferonopathies and, likely multifactorial disorders characterised by interferon inflammation, such as systemic lupus erythematosus.

show abstract

“…They act by lowering the upregulated expression of regulatory T cells [15]. This is a report of 4 disease association cases and their response to hydroxychloroquine.…”

Section: Introductionmentioning

confidence: 99%

Frontal Fibrosing Alopecia Coexisting with Lupus Erythematosus: Poor Response to Hydroxychloroquine

Contin

Marques

Noriega

2016

Skin Appendage Disord

View full text Add to dashboard Cite

Lupus erythematosus, especially the discoid form, and lichen planopilaris may be associated and can occur in different topographies (coexistence) or in the same lesion (lupus eythematosus/lichen planus overlap syndrome). Frontal fibrosing alopecia is considered a variant form of lichen planopilaris and is characterized by frontotemporal hairline and eyebrow involvement. Of the association with lupus erythematosus we have only a few descriptions. Hydroxychloroquine and chloroquine diphosphate are antimalarial drugs described as viable treatment options for both diseases, due to an antilymphocytic effect. The association between frontal fibrosing alopecia and lupus erythematosus (discoid or systemic) is reported in this article, showing a progressive alopecia in the frontotemporal hairline despite treatment with hydroxychloroquine.

show abstract

Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases

Cited by 373 publications

References 136 publications

Modulation of Neutrophil Extracellular Trap and Reactive Oxygen Species Release by Periodontal Bacteria

Modulation of Neutrophil Extracellular Trap and Reactive Oxygen Species Release by Periodontal Bacteria

Reappraisal of Antimalarials in Interferonopathies: New Perspectives for Old Drugs

Frontal Fibrosing Alopecia Coexisting with Lupus Erythematosus: Poor Response to Hydroxychloroquine

Contact Info

Product

Resources

About