Multi-therapeutic strategy targeting parasite and inflammation-related alterations to improve prognosis of chronic Chagas cardiomyopathy: a hypothesis-based approach*

Lannes‐Vieira, Joseli

doi:10.1590/0074-02760220019

Cited by 9 publications

(11 citation statements)

References 53 publications

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“…Network pharmacology along with the system biology paradigm have both provided a breakthrough in drug discovery research by establishing the relationship between drug molecules and disease, and the potential therapeutic targets [75]. The development of multi-target therapeutics drug compounds is likely to be a promising paradigm for discovering drugs and offer a greater efficacy level with minimal or no adverse effects and toxicity compared to monotheraputic drug compounds [76]. A study has reported herbal medicine to be characterized by multi-components/compounds and multi-targets with promising prospects for the discovery of new lead drug compounds with multi-therapeutic use [68].…”

Section: Discussionmentioning

confidence: 99%

An Efficient Weighted Network Centrality Approach for Exploring Mechanisms of Action of the RP-RB Herbal Formula for Treating Rheumatoid Arthritis

Ochieng

Dombi

Hussain

2022

Preprint

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Aim : This study presents an efficient weighted network centrality measureapproach and its application in network pharmacology for exploring mechanismsof action of the Ruellia prostrata (RP) and Ruellia bignoniiflora (RB) herbalformula for treating rheumatoid arthritis. Method: A tripartite network of RP-RB compositive compound-knowntherapeutic targets-putative target genes was first built. The interconnectivityscore was used to prioritizes network candidate network components based ontheir overall connectivity with shared neighborhood network components. A newinterconnectivity based weighted centrality score calculated from traditionalnetwork centrality measure was used identify and explore relationships of themajor network components. The functionality of our proposed method wasdemonstrated by an application in network pharmacology. Result : Network pharmacology results revealed that out of 196 compounds 22were actively interacting with known rheumatoid arthritis therapeutic targets andputative target genes. A multi-level network simulation identifies 33 majorcandidate targets including 8 compositive compounds, 10 therapeutic targets and15 putative target genes. The gene ontology and KEGG pathway enrichmenttarget validation demonstrated that candidate putative target genes were frequently involved in TNF, CCR5, IL-17 and G-protein coupled receptorssignaling pathways which are critical in the progression of rheumatoid arthritis.The molecular docking simulation and molecular descriptor analysis indicatedthat Glyceryl diacetate-2-Oleate, Hexadecanoic acid, 2,3-bis(acetyloxy)propylester, Glycidyl oleate, and Oleoyl chloride had a high binding affinity on theirmajor targets with their molecular descriptor properties indicating their potentialdrug likeliness for the treatment of rheumatoid arthritis. Conclusion : The findings of this study provides promising results that couldlead to design and discovery alternative drug compounds for management andtreatment of rheumatoid arthritis. Although our approach is purely based on insilico method, clinical experiments are still needed to test and validate thehypotheses of our computational methods.

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Section: Discussionmentioning

confidence: 99%

An Efficient Weighted Network Centrality Approach for Exploring Mechanisms of Action of the RP-RB Herbal Formula for Treating Rheumatoid Arthritis

Ochieng

Dombi

Hussain

2022

Preprint

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“…There is a bulk of evidence that parasite persistence in tissues associated with ill-adapted homeostatic mechanisms, such as oxidative/anti-oxidative and pro-inflammatory/anti-inflammatory processes, are critical for the pathogenesis and progression of organ dysfunction in CD. 18 , 19 …”

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confidence: 99%

“… 19 In Chagas’ heart disease, low-level cardiac inflammation is linked to low-grade parasite persistence, tissue injury, progressive fibrosis, electrical abnormalities, and dysfunction, potentially evolving to heart failure. 18 , 19 The progression from IND to CARD form, and its severity (mild, moderate, severe), have been directly associated with the levels of the systemic inflammatory profile, revealed as increased serum levels of inflammatory (TNF, IL-6, IL-17, IFNγ, CCL2/MCP1) and regulatory/anti-inflammatory (IL-4, IL-10, TGFβ) cytokines, inflammatory mediators as nitric oxide, and reduced anti-oxidant enzymes as superoxide dismutase (SOD) and glutathione peroxidase (GPx), supporting inflammatory/anti-inflammatory and oxidant/anti-oxidant imbalance. 62 , 63 This is a quite relevant trait.…”

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confidence: 99%

“… 68 , 69 , 70 These preclinical models were used to study aspects of CD pathogenesis, trials of immunoregulatory drugs, 68 , 69 therapeutic vaccines, 71 and combined multi-therapeutic strategy targeting parasite and inflammation-related alterations in chronic T. cruzi infection, 72 , 73 opening opportunities to test new therapeutic schemes aiming to improve the prognosis of chronic Chagas cardiomyopathy. 19 While performing these experiments we observed that chronically T. cruzi -infected mice were not interested in the objects used to enrich the cage as paper tubes and plastic igloo, compared with non-infected controls. More broadly, these findings led us to consider the presence of behavioural changes in preclinical models of chronic T. cruzi infection, opening new pathways to be explored.…”

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confidence: 99%

“… 124 Considering the putative effect of benznidazole on biological mechanisms contributing to stroke, our studies in chronically T. cruzi -infected mice showed that benznidazole therapy abrogated atrial fibrillation and reduced the expression of chemokines and cytokines (such as CCL3, TNF, and IFNγ) in the cardiac and the systemic inflammatory profile, as decreased the TNF and nitric oxide serum levels. 19 , 72 , 73 …”

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Anxiety, depression, and memory loss in Chagas disease: a puzzle far beyond neuroinflammation to be unpicked and solved*

Lannes‐Vieira

Vilar-Pereira

Barrios

et al. 2023

Mem. Inst. Oswaldo Cruz

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Mental disorders such as anxiety, depression, and memory loss have been described in patients with chronic Chagas disease (CD), a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. Social, psychological, and biological stressors may take part in these processes. There is a consensus on the recognition of an acute nervous form of CD. In chronic CD patients, a neurological form is associated with immunosuppression and neurobehavioural changes as sequelae of stroke. The chronic nervous form of CD has been refuted, based on the absence of histopathological lesions and neuroinflammation; however, computed tomography shows brain atrophy. Overall, in preclinical models of chronic T. cruzi infection in the absence of neuroinflammation, behavioural disorders such as anxiety and depression, and memory loss are related to brain atrophy, parasite persistence, oxidative stress, and cytokine production in the central nervous system. Interferon-gamma (IFNγ)-bearing microglial cells are colocalised with astrocytes carrying T. cruzi amastigote forms. In vitro studies suggest that IFNγ fuels astrocyte infection by T. cruzi and implicate IFNγ-stimulated infected astrocytes as sources of TNF and nitric oxide, which may also contribute to parasite persistence in the brain tissue and promote behavioural and neurocognitive changes. Preclinical trials in chronically infected mice targeting the TNF pathway or the parasite opened paths for therapeutic approaches with a beneficial impact on depression and memory loss. Despite the path taken, replicating aspects of the chronic CD and testing therapeutic schemes in preclinical models, these findings may get lost in translation as the chronic nervous form of CD does not fulfil biomedical model requirements, as the presence of neuroinflammation, to be recognised. It is hoped that brain atrophy and behavioural and neurocognitive changes are sufficient traits to bring the attention of researchers to study the biological and molecular basis of the central nervous system commitment in chronic CD.

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An efficient weighted network centrality approach for exploring mechanisms of action of the Ruellia herbal formula for treating rheumatoid arthritis

et al. 2023

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Aim This study outlines an efficient weighted network centrality measure approach and its application in network pharmacology for exploring mechanisms of action of the Ruellia prostrata (RP) and Ruellia bignoniiflora (RB) herbal formula for treating rheumatoid arthritis. Method In our proposed method we first calculated interconnectivity scores all the network targets then computed weighted centrality score for all targets to identify of major network targets based on centrality score. We apply our technology to network pharmacology by constructing herb-compound-putative target network; compound-putative targets-RA target network; and imbalance multi-level herb-compound-putative target-RA target-PPI network. We then identify the major targets in the network based on our centrality measure approach. Finally we validated the major identified network targets using the enrichment analysis and a molecular docking simulation. Result The results reveled our proposed weighted network centrality approach outperform classical centrality measure in identification of influential nodes in four real complex networks based on SI model simulation. Application of our approach to network pharmacology shows that 57 major targets of which 33 targets including 8 compositive compounds, 15 putative target and 10 therapeutic targets played an important role in the network and directly linked to rheumatoid arthritis. Enrichment analysis confirmed that putative targets were frequently involved in TNF, CCR5, IL-17 and G-protein coupled receptors signaling pathways which are critical in the progression of rheumatoid arthritis. The molecular docking simulation indicated four targets had significant binding affinity to major protein targets. Glyceryl diacetate-2-Oleate and Oleoyl chloride showed the best binding affinity to all targets proteins and were within Lipinski limits. ADMET prediction also confirm both compounds had no toxic effect on human hence potential lead drug compounds for treating rheumatoid arthritis. Conclusion This study developed an efficient weighted network centrality approach as tool for identification of major network targets. Network pharmacology findings provides promising results that could lead us to design and discover of alternative drug compounds. Though our approach is a purely in silico method, clinical experiments are required to test and validate the hypotheses of our computational methods.

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Multi-therapeutic strategy targeting parasite and inflammation-related alterations to improve prognosis of chronic Chagas cardiomyopathy: a hypothesis-based approach*

Cited by 9 publications

References 53 publications

An Efficient Weighted Network Centrality Approach for Exploring Mechanisms of Action of the RP-RB Herbal Formula for Treating Rheumatoid Arthritis

An Efficient Weighted Network Centrality Approach for Exploring Mechanisms of Action of the RP-RB Herbal Formula for Treating Rheumatoid Arthritis

Anxiety, depression, and memory loss in Chagas disease: a puzzle far beyond neuroinflammation to be unpicked and solved*

An efficient weighted network centrality approach for exploring mechanisms of action of the Ruellia herbal formula for treating rheumatoid arthritis

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