Therapeutic strategies for COVID-19: progress and lessons learned

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(6), P. 449 - 475

Published: April 19, 2023

Language: Английский

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Human topoisomerases and their roles in genome stability and organization

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(6), P. 407 - 427

Published: Feb. 28, 2022

Human topoisomerases comprise a family of six enzymes: two type IB (TOP1 and mitochondrial TOP1 (TOP1MT), IIA (TOP2A TOP2B) IA (TOP3A TOP3B) topoisomerases. In this Review, we discuss their biochemistry roles in transcription, DNA replication chromatin remodelling, highlight the recent progress made understanding TOP3A TOP3B. Because advances elucidating high-order organization genome through loops topologically associating domains (TADs), integrate functions with organization. We also physiological pathological formation irreversible topoisomerase cleavage complexes (TOPccs) as they generate DNA–protein crosslinks (TOP-DPCs) coupled breaks. expanding number redundant pathways that repair TOP-DPCs, defects those pathways, which are increasingly recognized source genomic damage leading to neurological diseases cancer. Topoisomerases have essential replication, remodelling and, recently revealed, 3D However, breaks, disease-causing damage.

Language: Английский

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Alterations in microbiota of patients with COVID-19: potential mechanisms and therapeutic interventions

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: April 29, 2022

The global coronavirus disease 2019 (COVID-19) pandemic is currently ongoing. It caused by severe acute respiratory syndrome 2 (SARS-CoV-2). A high proportion of COVID-19 patients exhibit gastrointestinal manifestations such as diarrhea, nausea, or vomiting. Moreover, the and tracts are primary habitats human microbiota targets for SARS-CoV-2 infection they express angiotensin-converting enzyme-2 (ACE2) transmembrane protease serine (TMPRSS2) at levels. There accumulating evidence that significantly altered in with post-acute (PACS). Microbiota powerful immunomodulatory factors various diseases, diabetes, obesity, cancers, ulcerative colitis, Crohn's disease, certain viral infections. In present review, we explore associations between host terms their clinical relevance. Microbiota-derived metabolites components main mediators microbiota-host interactions influence immunity. Hence, discuss potential mechanisms which microbiota-derived modulate immune responses to infection. Finally, review a variety possible microbiota-based prophylaxes therapies PACS, including fecal transplantation (FMT), probiotics, prebiotics, metabolites, engineered symbiotic bacteria. This treatment strategy could mitigate virus-induced inflammation.

Language: Английский

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SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry

Nature, Journal Year: 2022, Volume and Issue: 610(7931), P. 381 - 388

Published: Oct. 5, 2022

Language: Английский

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Longitudinal metabolomics of human plasma reveals prognostic markers of COVID-19 disease severity

Cell Reports Medicine, Journal Year: 2021, Volume and Issue: 2(8), P. 100369 - 100369

Published: July 21, 2021

There is an urgent need to identify which COVID-19 patients will develop life-threatening illness so that medical resources can be optimally allocated and rapid treatment administered early in the disease course, when clinical management most effective. To aid prognostic classification of severity, we perform untargeted metabolomics on plasma from 339 patients, with samples collected at six longitudinal time points. Using temporal metabolic profiles machine learning, build a predictive model severity. We discover panel metabolites measured study entry successfully determines Through analysis samples, confirm these markers are directly related progression their levels return baseline upon recovery. Finally, validate also altered hamster COVID-19.

Language: Английский

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Pharmacological inhibition of fatty acid synthesis blocks SARS-CoV-2 replication

Nature Metabolism, Journal Year: 2021, Volume and Issue: 3(11), P. 1466 - 1475

Published: Sept. 27, 2021

Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19 is a virus-induced inflammatory disease of the airways and lungs that leads to multi-organ damage death. Here we show cellular lipid synthesis required for SARS-CoV-2 replication offers an opportunity pharmacological intervention. Screening short-hairpin RNA sublibrary targets metabolic genes, identified genes either inhibit or promote viral infection, including two key candidate ACACA FASN, which operate in same pathway. We further screened several potent inhibitors fatty acid synthase (encoded FASN), US Food Drug Administration-approved anti-obesity drug orlistat, found it inhibits vitro variants, more contagious new such as Delta. In mouse model infection (K18-hACE2 transgenic mice), injections orlistat resulted lower levels lung, reduced lung pathology increased survival. Our findings identify candidates prevention treatment inhibiting replication. Clinical trials are needed evaluate efficacy repurposing humans. Pharmacological synthase, approved shown vivo.

Language: Английский

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SARS-CoV-2 restructures host chromatin architecture

Nature Microbiology, Journal Year: 2023, Volume and Issue: 8(4), P. 679 - 694

Published: March 23, 2023

Language: Английский

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Stress, epigenetics, and aging: Unraveling the intricate crosstalk

Molecular Cell, Journal Year: 2023, Volume and Issue: 84(1), P. 34 - 54

Published: Nov. 13, 2023

Language: Английский

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COVID-19 drug discovery and treatment options

Nature Reviews Microbiology, Journal Year: 2024, Volume and Issue: 22(7), P. 391 - 407

Published: April 15, 2024

Language: Английский

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ATM and IRAK1 orchestrate two distinct mechanisms of NF-κB activation in response to DNA damage

Nature Structural & Molecular Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Language: Английский

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