scholarly journals Distinct molecular targets for macrocyclic lactone and isoxazoline insecticides in the human louse: new prospects for the treatment of pediculosis

2020 ◽  
Author(s):  
Nicolas Lamassiaude ◽  
Berthine Toubate ◽  
Cédric Neveu ◽  
Pierre Charnet ◽  
Catherine Dupuy ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Chloride Channels ◽  
Macrocyclic Lactone ◽  
Control Strategies ◽  
Molecular Targets ◽  
Drug Repurposing ◽  
Health Concern ◽  
The Novel ◽  
Pediculus Humanus ◽  
Significant Public Health

AbstractBackgroundControl of infestation by cosmopolitan lice (Pediculus humanus) is increasingly difficult due to the transmission of resistant parasites to pediculicides. However, since the targets for pediculicides have no been identified in human lice so far, their mechanism of action remain largely unknown. The macrocyclic lactone, ivermectin is active against a broad range of insects including human lice. Isoxazolines are a recent new chemical class targeting the γ-aminobutyric acid (GABA) receptor made of the resistant to dieldrin (RDL) subunit and exhibiting a strong insecticidal potential. Here, we addressed the pediculicidal potential of isoxazolines and deciphered the molecular targets of ivermectin and the novel ectoparasiticide lotilaner in the human body louse species Pediculus humanus humanus.Methods and findingsUsing toxicity bioassays, we showed that fipronil, ivermectin and lotilaner are efficient pediculicides on adult lice. The RDL (Phh-RDL) and glutamate-gated chloride channel subunits (Phh-GluCl) were cloned and characterized by two-electrode voltage clamp electrophysiology in Xenopus laevis oocytes. Phh-RDL and Phh-GluCl formed functional homomeric receptors respectively gated by GABA and L-glutamate with EC50 values of 6.4 µM and 9.3 µM. Importantly, ivermectin displayed a super agonist action on Phh-Glucl whereas Phh-RDL receptors were weakly affected. Reversally, lotilaner strongly inhibited the GABA-evoked currents in Phh-RDL with an IC50 value 0.5 µM, whereas it had no effect on Phh-GluCl.ConclusionsWe report here for the first time the pediculicidal potential of isoxazolines and reveal the distinct mode of action of ivermectin and lotilaner on GluCl and RDL channels from human lice. These results emphasize the clear repurposing future of the isoxazoline drug class to provide new pediculicidal agents to tackle resistant-louse infestations in humans.Autorship summaryWhy was this study done?Human cosmopolitan lice are responsible for pediculosis, which represent a significant public health concern. Resistant lice against insecticides and lack of safety of the treatments for human and environment is a growing issue worldwide. Here we investigated the efficacy on lice of the classical macrocyclic lactone drug, ivermectin, and the novel isoxazoline drug, lotilaner. This study was done to decipher their mode of action at the molecular and funtional levels in order to propose new strategies to control lice infestation.What did the researchers do and find?Our bioassay results indicate that ivermectin and lotilaner were potent at killing human adult lice, with lotilaner showing a higher efficacy than ivermectin. Furthermore, we identified and pharmacologically characterized the first glutamate- and GABA-gated chloride channels ever described in human lice yet. Mechanistically, our molecular biology and electrophysiology findings demonstrate that ivermectin acted preferentially at glutamate channels while lotilaner specifically targeted GABA channels.What do these findings mean?These results provide new insights in the understanding of the insecticide mode of action and highlight the isoxazolines as a new drug-repurposing opportunity for pest control strategies.

scholarly journals The molecular targets of ivermectin and lotilaner in the human louse Pediculus humanus humanus: New prospects for the treatment of pediculosis

2021 ◽  
Vol 17 (2) ◽  
pp. e1008863
Author(s):  
Nicolas Lamassiaude ◽  
Berthine Toubate ◽  
Cédric Neveu ◽  
Pierre Charnet ◽  
Catherine Dupuy ◽  
...  
Keyword(s):  
Chloride Channels ◽  
Molecular Targets ◽  
Pediculus Humanus ◽  
Agonist Action ◽  
Electrode Voltage ◽  
Louse Species ◽  
Rdl Subunit ◽  
First Time ◽  
Human Body Louse ◽  
Chemical Class

Control of infestation by cosmopolitan lice (Pediculus humanus) is increasingly difficult due to the transmission of parasites resistant to pediculicides. However, since the targets for pediculicides have no been identified in human lice so far, their mechanisms of action remain largely unknown. The macrocyclic lactone ivermectin is active against a broad range of insects including human lice. Isoxazolines are a new chemical class exhibiting a strong insecticidal potential. They preferentially act on the γ-aminobutyric acid (GABA) receptor made of the resistant to dieldrin (RDL) subunit and, to a lesser extent on glutamate-gated chloride channels (GluCls) in some species. Here, we addressed the pediculicidal potential of isoxazolines and deciphered the molecular targets of ivermectin and the ectoparasiticide lotilaner in the human body louse species Pediculus humanus humanus. Using toxicity bioassays, we showed that fipronil, ivermectin and lotilaner are efficient pediculicides on adult lice. The RDL (Phh-RDL) and GluCl (Phh-GluCl) subunits were cloned and characterized by two-electrode voltage clamp electrophysiology in Xenopus laevis oocytes. Phh-RDL and Phh-GluCl formed functional homomeric receptors respectively gated by GABA and L-glutamate with EC50 values of 16.0 μM and 9.3 μM. Importantly, ivermectin displayed a super agonist action on Phh-GluCl, whereas Phh-RDL receptors were weakly affected. Reversally, lotilaner strongly inhibited the GABA-evoked currents in Phh-RDL with an IC50 value of 40.7 nM, whereas it had no effect on Phh-GluCl. We report here for the first time the insecticidal activity of isoxazolines on human ectoparasites and reveal the mode of action of ivermectin and lotilaner on GluCl and RDL channels from human lice. These results emphasize an expected extension of the use of the isoxazoline drug class as new pediculicidal agents to tackle resistant-louse infestations in humans.

scholarly journals Functional investigation of conserved glutamate receptor subunits reveals a new mode of action of macrocyclic lactones in nematodes

2020 ◽  
Author(s):  
Nicolas Lamassiaude ◽  
Elise Courtot ◽  
Angélique Corset ◽  
Claude L. Charvet ◽  
Cédric Neveu
Keyword(s):  
Caenorhabditis Elegans ◽  
Mode Of Action ◽  
Chloride Channels ◽  
Parasitic Nematode ◽  
Expression System ◽  
Molecular Targets ◽  
Parasitic Nematodes ◽  
Pharmacological Properties ◽  
Macrocyclic Lactones ◽  
C Elegans

AbstractGlutamate-gated chloride channels receptors (GluCls) are involved in the inhibition of neurotransmission in invertebrates and represent major molecular targets for therapeutic drugs. Among these drugs, macrocyclic lactones (MLs) are widely used as anthelmintic to treat parasitic nematodes impacting both human and animal health. Despite massive use of MLs since the 80’s, the exact molecular targets of these drugs are still unknown in many important parasite species. Among the GluCl subunit encoding genes, avr-14, glc-2, glc-3 and glc-4 are highly conserved throughout the nematode phylum. Using the Xenopus oocyte as an expression system, we pharmacologically characterized these GluCl subunits from the model nematode Caenorhabditis elegans, the human filarial nematode Brugia malayi and the horse parasitic nematode Parascaris univalens. In contrast with C. elegans, expression of parasitic nematode subunits as homomeric receptors was not reliable and needed glutamate application at the mM range to induce low currents at the nA range. However, the co-expression of GLC-2 and AVR-14B lead to the robust expression of ML-sensitive receptors for the three nematode species. In addition, we demonstrated that for C. elegans and P. univalens, GLC-2 co-assembled with GLC-3 to form a new GluCl subtype with distinct pharmacological properties. Whereas 1μM ivermectin, moxidectin and eprinomectin acted as agonist of the GLC-2/GLC-3 receptor from C. elegans, they did not directly activate GLC-2/GLC-3 of P. univalens. In contrast, these MLs potentialized glutamate elicited currents thus representing a unique pharmacological property. Our results highlight the importance of GLC-2 as a key subunit in the composition of heteromeric channels in nematodes and demonstrate that MLs act on novel GluCl subtypes that show unusual pharmacological properties, providing new insights about MLs mode of action.Author summaryThe filarial and ascarid parasitic nematodes include some of the most pathogenic or invalidating species in humans, livestock and companion animals. Whereas the control of these worms is critically dependent on macrocyclic lactones (MLs) such as ivermectin, the mode of action of this anthelmintic class remains largely unknown in these parasites. In the model nematode Caenorhabditis elegans, MLs target GluCl pentameric glutamate-sensitive chloride channels (GluCl). Because MLs are potent anthelmintics on C. elegans, ascarid and filarial nematodes, in the present study we investigated GluCl subunits highly conserved between these distantly related worms. Using the Xenopus oocyte as a heterologous expression system, we identified and performed the pharmacological characterization of novel GluCl receptors from C. elegans, the human filarial parasite Brugia malayi and the horse parasite Parascaris univalens. Our results highlight heteromeric GluCls from parasites as molecular targets for a wide range of MLs. We report an original mode of action of MLs on a new GluCl subtype made of the GLC-2/GLC-3 subunit combination. This study brings new insights about the diversity of GluCl subtypes in nematodes and opens the way for rational drug screening for the identification of next generation anthelmintic compounds.

SARS-COV2 virus and Coronavirus disease (COVID-19)

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 977-982
Author(s):  
Mohamed J. Saadh ◽  
Bashar Haj Rashid M ◽  
Roa’a Matar ◽  
Sajeda Riyad Aldibs ◽  
Hala Sbaih ◽  
...  
Keyword(s):  
Close Contact ◽  
Antiviral Agents ◽  
Health Concern ◽  
The Novel ◽  
Global Public Health ◽  
Fatal Disease ◽  
Mild Disease ◽  
Life Threatening ◽  
Novel Coronavirus

SARS-COV2 virus causes Coronavirus disease (COVID-19) and represents the causative agent of a potentially fatal disease that is of great global public health concern. The novel coronavirus (2019) was discovered in 2019 in Wuhan, the market of the wet animal, China with viral pneumonia cases and is life-threatening. Today, WHO announces COVID-19 outbreak as a pandemic. COVID-19 is likely to be zoonotic. It is transmitted from bats as intermediary animals to human. Also, the virus is transmitted from human to human who is in close contact with others. The computerized tomographic chest scan is usually abnormal even in those with no symptoms or mild disease. Treatment is nearly supportive; the role of antiviral agents is yet to be established. The SARS-COV2 virus spreads faster than its two ancestors, the SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), but has lower fatality. In this article, we aimed to summarize the transmission, symptoms, pathogenesis, diagnosis, treatment, and vaccine to control the spread of this fatal disease.

The Antiviral and Antimalarial Drug Repurposing in Quest of Chemotherapeutics to Combat COVID-19 Utilizing Structure-Based Molecular Docking

2020 ◽  
Vol 23 ◽  
Author(s):  
Sisir Nandi ◽  
Mohit Kumar ◽  
Mridula Saxena ◽  
Anil Kumar Saxena
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Drug Repurposing ◽  
Clinical Settings ◽  
The Novel ◽  
In Silico Docking ◽  
Biochemical Mechanisms ◽  
Novel Coronavirus ◽  
In Silico Molecular Docking

Background: The novel coronavirus disease (COVID-19) is caused by a new strain (SARS-CoV-2) erupted in 2019. Nowadays, it is a great threat that claims uncountable lives worldwide. There is no specific chemotherapeutics developed yet to combat COVID-19. Therefore, scientists have been devoted in the quest of the medicine that can cure COVID- 19. Objective: Existing antivirals such as ASC09/ritonavir, lopinavir/ritonavir with or without umifenovir in combination with antimalarial chloroquine or hydroxychloroquine have been repurposed to fight the current coronavirus epidemic. But exact biochemical mechanisms of these drugs towards COVID-19 have not been discovered to date. Method: In-silico molecular docking can predict the mode of binding to sort out the existing chemotherapeutics having a potential affinity towards inhibition of the COVID-19 target. An attempt has been made in the present work to carry out docking analyses of 34 drugs including antivirals and antimalarials to explain explicitly the mode of interactions of these ligands towards the COVID-19protease target. Results: 13 compounds having good binding affinity have been predicted towards protease binding inhibition of COVID-19. Conclusion: Our in silico docking results have been confirmed by current reports from clinical settings through the citation of suitable experimental in vitro data available in the published literature.

Role of Cytochrome P450 in Prostate Cancer and its Therapy

2020 ◽  
Vol 16 (1) ◽  
pp. 63-73 ◽  
Author(s):  
Rishabh Kaushik ◽  
Sheeza Khan ◽  
Meesha Sharma ◽  
Srinivasan Hemalatha ◽  
Zeba Mueed ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cytochrome P450 ◽  
Drug Discovery ◽  
Cholesterol Metabolism ◽  
Molecular Targets ◽  
Health Concern ◽  
Metabolic Functions ◽  
Novel Drugs ◽  
Genes Encoding ◽  
Causes Of Mortality

Prostate cancer has become a global health concern as it is one of the leading causes of mortality in males. With the emerging drug resistance to conventional therapies, it is imperative to unravel new molecular targets for disease prevention. Cytochrome P450 (P450s or CYPs) represents a unique class of mixed-function oxidases which catalyses a wide array of biosynthetic and metabolic functions including steroidogenesis and cholesterol metabolism. Several studies have reported the overexpression of the genes encoding CYPs in prostate cancer cells and how they can be used as molecular targets for drug discovery. But due to functional redundancy and overlapping expression of CYPs in several other metabolic pathways there are several impediments in the clinical efficacy of the novel drugs reported till now. Here we review the most crucial P450 enzymes which are involved in prostate cancer and how they can be used as molecular targets for drug discovery along with the clinical limitations of the currently existing CYP inhibitors.

Old Drugs with New Tricks; Paradigm in Drug Development Pipeline for Alzheimer’s Disease

2020 ◽  
Vol 20 ◽  
Author(s):  
Tanay Dalvi ◽  
Bhaskar Dewangan ◽  
Rudradip Das ◽  
Jyoti Rani ◽  
Suchita Dattatray Shinde ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Development ◽  
Molecular Targets ◽  
Drug Repurposing ◽  
Phase Iii ◽  
Complex Nature ◽  
New Drug ◽  
Development Pipeline ◽  
Old Drugs

: The most common reason behind dementia is Alzheimer’s disease (AD) and it is predicted to be the third lifethreatening disease apart from stroke and cancer for the geriatric population. Till now only four drugs are available in the market for symptomatic relief. The complex nature of disease pathophysiology and lack of concrete evidences of molecular targets are the major hurdles for developing new drug to treat AD. The the rate of attrition of many advanced drugs at clinical stages, makes the de novo discovery process very expensive. Alternatively, Drug Repurposing (DR) is an attractive tool to develop drugs for AD in a less tedious and economic way. Therefore, continuous efforts are being made to develop a new drug for AD by repursing old drugs through screening and data mining. For example, the survey in the drug pipeline for Phase III clinical trials (till February 2019) which has 27 candidates, and around half of the number are drugs which have already been approved for other indications. Although in the past the drug repurposing process for AD has been reviewed in the context of disease areas, molecular targets, there is no systematic review of repurposed drugs for AD from the recent drug development pipeline (2019-2020). In this manuscript, we are reviewing the clinical candidates for AD with emphasis on their development history including molecular targets and the relevance of the target for AD.

scholarly journals Assessing the Molecular Targets and Mode of Action of Furanone C-30 on Pseudomonas aeruginosa Quorum Sensing

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1620
Author(s):  
Victor Markus ◽  
Karina Golberg ◽  
Kerem Teralı ◽  
Nazmi Ozer ◽  
Esti Kramarsky-Winter ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Quorum Sensing ◽  
Conformational Changes ◽  
Mode Of Action ◽  
Pathogenic Bacteria ◽  
Molecular Targets ◽  
Resistant Bacteria ◽  
Public Healthcare ◽  
C 30

Quorum sensing (QS), a sophisticated system of bacterial communication that depends on population density, is employed by many pathogenic bacteria to regulate virulence. In view of the current reality of antibiotic resistance, it is expected that interfering with QS can address bacterial pathogenicity without stimulating the incidence of resistance. Thus, harnessing QS inhibitors has been considered a promising approach to overriding bacterial infections and combating antibiotic resistance that has become a major threat to public healthcare around the globe. Pseudomonas aeruginosa is one of the most frequent multidrug-resistant bacteria that utilize QS to control virulence. Many natural compounds, including furanones, have demonstrated strong inhibitory effects on several pathogens via blocking or attenuating QS. While the natural furanones show no activity against P. aeruginosa, furanone C-30, a brominated derivative of natural furanone compounds, has been reported to be a potent inhibitor of the QS system of the notorious opportunistic pathogen. In the present study, we assess the molecular targets and mode of action of furanone C-30 on P. aeruginosa QS system. Our results suggest that furanone C-30 binds to LasR at the ligand-binding site but fails to establish interactions with the residues crucial for the protein’s productive conformational changes and folding, thus rendering the protein dysfunctional. We also show that furanone C-30 inhibits RhlR, independent of LasR, suggesting a complex mechanism for the agent beyond what is known to date.

scholarly journals The intersection of COVID-19 and cancer: signaling pathways and treatment implications

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Zhi Zong ◽  
Yujun Wei ◽  
Jiang Ren ◽  
Long Zhang ◽  
Fangfang Zhou
Keyword(s):  
Signaling Pathways ◽  
Health Concern ◽  
Type I ◽  
The Novel ◽  
Checkpoint Signaling ◽  
Patients With Cancer ◽  
Advantages And Disadvantages ◽  
Anticancer Treatment ◽  
Severe Infections ◽  
Novel Coronavirus

AbstractThe outbreak of the novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a serious public health concern. Patients with cancer have been disproportionately affected by this pandemic. Increasing evidence has documented that patients with malignancies are highly susceptible to severe infections and mortality from COVID-19. Recent studies have also elucidated the molecular relationship between the two diseases, which may not only help optimize cancer care during the pandemic but also expand the treatment for COVID-19. In this review, we highlight the clinical and molecular similarities between cancer and COVID-19 and summarize the four major signaling pathways at the intersection of COVID-19 and cancer, namely, cytokine, type I interferon (IFN-I), androgen receptor (AR), and immune checkpoint signaling. In addition, we discuss the advantages and disadvantages of repurposing anticancer treatment for the treatment of COVID-19.

scholarly journals Risk factors associated with Ctenocephalides felis flea infestation of peri-urban goats: a neglected parasite in an under-appreciated host

2021 ◽  
Vol 53 (1) ◽  
Author(s):  
Julia Rose Dahm ◽  
Jordana Burdon Bailey ◽  
Robert F. Kelly ◽  
Patrick Chikungwa ◽  
Julius Chulu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Urban Communities ◽  
Control Strategies ◽  
Animal Health ◽  
Animal Husbandry ◽  
Ctenocephalides Felis ◽  
Disease Spread ◽  
Health Concern ◽  
Cross Sectional ◽  
Flea Infestation

AbstractGoats are critical in mixed smallholder agricultural systems in lower and middle-income countries, while fleas are important human and animal health concerns around the world. Convenience sampling was used to describe and consider risk factors for flea infestations of peri-urban goats, with the aim of informing the iterative development of animal husbandry and management based control strategies. Seven hundred and ninety-two goats were examined in 228 households across 10 peri-urban communities surrounding Blantyre in southern Malawi. The prevalence of Ctenocephalides felis fleas was 18.3, 37.1 and 100% at the levels of individual goats, households and communities, respectively, highlighting a neglected human and animal health concern. Constant introduction of new livestock coupled to a lack of biosecurity within communities, the ubiquitous presence of dog and cat hosts for C. felis, the frequency and thoroughness of cleaning overnight goat accommodation, and goat age less than 12 months old were identified as risk factors for flea infestation. This focal cross-sectional study highlights the significance of fleas in peri-urban communities and uncovers trends and commonalities that are needed to inform sustainable disease management. The majority of the peri-urban goat keepers were female, had resided in the same community throughout their whole life and had primary level education. Advice on the planned management of fleas in livestock needs to be tailored towards this demographic group. This approach affords an opportunity to promote public health measures to address household flea infestations and zoonotic disease spread.

Biomarkers of Stress in Music Interventions: A Systematic Review

2021 ◽  
Author(s):  
Melanie Mitsui Wong ◽  
Talha Tahir ◽  
Michael Mitsui Wong ◽  
Annilee Baron ◽  
Rachael Finnerty
Keyword(s):  
Psychological Stress ◽  
Acute Stress ◽  
Well Being ◽  
Health Concern ◽  
Music Intervention ◽  
P Values ◽  
Stress Biomarkers ◽  
Study Protocols ◽  
Significant Public Health ◽  
Meta Analyses

Abstract Psychological stress is a significant public health concern as it is associated with various comorbidities and long-term health implications. Music interventions are emerging therapies for alleviating psychological stress and improving one’s physical and mental well-being. We conducted a systematic literature review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement guidelines for reporting to identify all neuroendocrine biomarkers used to evaluate psychological stress in randomized control trials involving music interventions. We identified 18 unique biomarkers of stress from 14 full-text randomized controlled trials studies. Only one of the 14 music studies included a music therapy intervention. The most frequently used biomarkers across the studies were plasma cortisol, salivary cortisol, and salivary α-amylase. Of the 14 studies, 12 included in this review assessed at least one of these three biomarkers. Of these 12 studies, five papers reported p-values for changes in both stress biomarkers and psychological stress outcome measures. Four of the five studies found significant p-values for the reduction of both stress biomarkers and psychological stress in music intervention groups. The variety of stress biomarkers used and the variance in study protocols makes it difficult to assess the magnitude of effect of music interventions on psychological stress. However, our findings suggest that music interventions have the potential for reducing both stress biomarker levels and psychological stress in acute stress situations.

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