FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2

Nature, Год журнала: 2022, Номер 615(7950), С. 134 - 142

Опубликована: Дек. 5, 2022

Abstract Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2) 1 , could represent a new chemoprophylactic approach for COVID-19 that complements vaccination 2,3 . However, the mechanisms control expression of ACE2 remain unclear. Here we show farnesoid X receptor (FXR) is direct regulator transcription in several tissues affected COVID-19, including gastrointestinal and respiratory systems. We then use over-the-counter compound z-guggulsterone off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling downregulate human lung, cholangiocyte intestinal organoids corresponding mice hamsters. UDCA-mediated downregulation reduces susceptibility vitro, vivo lungs livers perfused ex situ. Furthermore, reveal UDCA nasal epithelium humans. Finally, identify correlation between treatment positive clinical outcomes after using retrospective registry data, confirm these findings an independent validation cohort recipients liver transplants. In conclusion, has role controlling provide evidence modulation this pathway be beneficial reducing infection, paving way future trials.

Язык: Английский

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COVID-19 and cellular senescence

Nature reviews. Immunology, Год журнала: 2022, Номер 23(4), С. 251 - 263

Опубликована: Окт. 5, 2022

Язык: Английский

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SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence

Nature Cell Biology, Год журнала: 2023, Номер 25(4), С. 550 - 564

Опубликована: Март 9, 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the RNA virus responsible for disease 2019 (COVID-19) pandemic. Although SARS-CoV-2 was reported to alter several cellular pathways, its impact on DNA integrity and mechanisms involved remain unknown. Here we show that causes damage elicits an altered response. Mechanistically, proteins ORF6 NSP13 cause degradation of response kinase CHK1 through proteasome autophagy, respectively. loss leads deoxynucleoside triphosphate (dNTP) shortage, causing impaired S-phase progression, damage, pro-inflammatory pathways activation senescence. Supplementation deoxynucleosides reduces that. Furthermore, N-protein impairs 53BP1 focal recruitment by interfering with damage-induced long non-coding RNAs, thus reducing repair. Key observations are recapitulated in SARS-CoV-2-infected mice patients COVID-19. We propose SARS-CoV-2, boosting ribonucleoside levels promote replication at expense dNTPs hijacking RNAs' biology, threatens genome activation, induction inflammation

Язык: Английский

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SARS-CoV-2 and innate immunity: the good, the bad, and the “goldilocks”

Cellular and Molecular Immunology, Год журнала: 2023, Номер 21(2), С. 171 - 183

Опубликована: Ноя. 20, 2023

Abstract An ancient conflict between hosts and pathogens has driven the innate adaptive arms of immunity. Knowledge about this interplay can not only help us identify biological mechanisms but also reveal pathogen vulnerabilities that be leveraged therapeutically. The humoral response to SARS-CoV-2 infection been focus intense research, role immune system received significantly less attention. Here, we review current knowledge various means employs evade defense systems. We consider immunity in vaccines phenomenon long COVID.

Язык: Английский

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Challenges in developing Geroscience trials

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Авг. 19, 2023

Abstract Geroscience is becoming a major hope for preventing age-related diseases and loss of function by targeting biological mechanisms aging. This unprecedented paradigm shift requires optimizing the design future clinical studies related to aging in humans. Researchers will face number challenges, including ideal populations study, which lifestyle Gerotherapeutic interventions test initially, selecting key primary secondary outcomes such trials, biomarkers are most valuable both predicting or monitoring responses (“Gerodiagnostics”). article reports main results Task Force experts Geroscience.

Язык: Английский

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Cellular senescence: Neither irreversible nor reversible

The Journal of Experimental Medicine, Год журнала: 2024, Номер 221(4)

Опубликована: Фев. 22, 2024

Cellular senescence is a critical stress response program implicated in embryonic development, wound healing, aging, and immunity, it backs up apoptosis as an ultimate cell-cycle exit mechanism. In analogy to replicative exhaustion of telomere-eroded cells, premature types senescence—referring oncogene-, therapy-, or virus-induced senescence—are widely considered irreversible growth arrest states well. We discuss here that entry into full-featured not necessarily permanent endpoint, but dependent on essential maintenance components, potentially transient. Unlike binary state switch, we view with its extensive epigenomic reorganization, profound cytomorphological remodeling, distinctive metabolic rewiring rather journey toward condition variable strength depth. Senescence-underlying maintenance-essential molecular mechanisms may allow reentry if continuously provided. Importantly, senescent cells resumed proliferation fundamentally differ from those never entered senescence, hence would reflect reversion dynamic progression post-senescent comes distinct functional clinically relevant ramifications.

Язык: Английский

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Cellular senescence and cardiovascular diseases: moving to the “heart” of the problem

Physiological Reviews, Год журнала: 2022, Номер 103(1), С. 609 - 647

Опубликована: Сен. 1, 2022

Cardiovascular diseases (CVDs) constitute the prime cause of global mortality, with an immense impact on patient quality life and disability. Clinical evidence has revealed a strong connection between cellular senescence worse cardiac outcomes in majority CVDs concerning both ischemic nonischemic cardiomyopathies. Cellular is characterized by cell cycle arrest accompanied alterations several metabolic pathways, resulting morphological functional changes. Metabolic rewiring senescent cells results marked paracrine activity, through unique secretome, often exerting deleterious effects neighboring cells. Here, we recapitulate hallmarks key molecular pathways involved context summarize different roles CVDs. In last few years, possibility eliminating various pathological conditions been increasingly explored, giving rise to field senotherapeutics. Therefore, additionally attempt clarify current state this focus discuss potential implementing senolytics as treatment option heart disease.

Язык: Английский

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Human lungs show limited permissiveness for SARS-CoV-2 due to scarce ACE2 levels but virus-induced expansion of inflammatory macrophages

European Respiratory Journal, Год журнала: 2022, Номер 60(6), С. 2102725 - 2102725

Опубликована: Июнь 21, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilises the angiotensin-converting enzyme (ACE2) transmembrane peptidase as cellular entry receptor. However, whether SARS-CoV-2 in alveolar compartment is strictly ACE2-dependent and to what extent virus-induced tissue damage and/or direct immune activation determines early pathogenesis still elusive.Spectral microscopy, single-cell/-nucleus RNA sequencing or ACE2 "gain-of-function" experiments were applied infected human lung explants adult stem cell derived organoids correlate related host factors with tropism, propagation, virulence compared SARS-CoV, influenza Middle East (MERS-CoV). Coronavirus disease 2019 (COVID-19) autopsy material was used validate ex vivo results.We provide evidence that expression must be considered scarce, thereby limiting propagation alveolus. Instead, lungs COVID-19 samples showed macrophages frequently positive for SARS-CoV-2. Single-cell/-nucleus transcriptomics further revealed nonproductive virus uptake a inflammatory anti-viral activation, especially "inflammatory macrophages", comparable those induced by SARS-CoV MERS-CoV, but different from NL63 infection.Collectively, our findings indicate severe injury probably results macrophage-triggered rather than viral of compartment.

Язык: Английский

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Removal of senescent cells reduces the viral load and attenuates pulmonary and systemic inflammation in SARS-CoV-2-infected, aged hamsters

Nature Aging, Год журнала: 2023, Номер 3(7), С. 829 - 845

Опубликована: Июль 6, 2023

Abstract Older age is one of the strongest risk factors for severe COVID-19. In this study, we determined whether age-associated cellular senescence contributes to severity experimental Aged golden hamsters accumulate senescent cells in lungs, and senolytic drug ABT-263, a BCL-2 inhibitor, depletes these at baseline during SARS-CoV-2 infection. Relative young hamsters, aged had greater viral load acute phase infection displayed higher levels sequelae post-acute phase. Early treatment with ABT-263 lowered pulmonary (but not young) animals, an effect associated lower expression ACE2, receptor SARS-CoV-2. also led systemic senescence-associated secretory phenotype amelioration early late lung disease. These data demonstrate causative role pre-existing on COVID-19 have clear clinical relevance.

Язык: Английский

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Escape from senescence: molecular basis and therapeutic ramifications

The Journal of Pathology, Год журнала: 2023, Номер 260(5), С. 649 - 665

Опубликована: Авг. 1, 2023

Abstract Cellular senescence constitutes a stress response mechanism in reaction to plethora of stimuli. Senescent cells exhibit cell‐cycle arrest and altered function. While withdrawal has been perceived as permanent, recent evidence cancer research introduced the so‐called escape‐from‐senescence concept. In particular, under certain conditions, senescent may resume proliferation, acquiring highly aggressive features. As such, they have associated with tumour relapse, rendering less effective inhibiting progression. Thus, conventional treatments, incapable eliminating senescence, benefit if revisited include senolytic agents. To this end, it is anticipated that assessment burden everyday clinical material by pathologists will play crucial role near future, laying foundation for more personalised approaches. Here, we provide an overview investigations phenomenon, identified mechanisms, well major implications pathology therapy. © 2023 The Authors. Journal Pathology published John Wiley & Sons Ltd on behalf Pathological Society Great Britain Ireland.

Язык: Английский

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