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1.
bioRxiv ; 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39026790

RESUMO

The ability of an organism to overcome infectious diseases has traditionally been linked to killing invading pathogens. Accumulating evidence, however, indicates that, apart from restricting pathogen loads, organismal survival is coupled to an additional yet poorly understood mechanism called disease tolerance. Here we report that p16High immune cells play a key role in establishing disease tolerance. We found that the FDA-approved BNT162b2 mRNA COVID-19 vaccine is a potent and rapid inducer of p16High immune subsets both in mice and humans. In turn, p16High immune cells were indispensable for counteracting different lethal conditions, including LPS-induced sepsis, acute SARS-CoV-2 infection and ionizing irradiation. Mechanistically, we propose that activation of TLR7 or a low physiological activity of STING is sufficient to induce p16High immune subset that, in turn, establishes a low adenosine environment and disease tolerance. Furthermore, containing these signals within a beneficial range by deleting MDA5 that appeared sufficient to maintain a low activity of STING, induces p16High immune cells and delays organ deterioration upon aging with improved healthspan. Our data highlight the beneficial role of p16High immune subsets in establishing a low adenosine environment and disease tolerance.

2.
Nat Cell Biol ; 25(9): 1265-1278, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37652981

RESUMO

Despite advances in four-factor (4F)-induced reprogramming (4FR) in vitro and in vivo, how 4FR interconnects with senescence remains largely under investigated. Here, using genetic and chemical approaches to manipulate senescent cells, we show that removal of p16High cells resulted in the 4FR of somatic cells into totipotent-like stem cells. These cells expressed markers of both pluripotency and the two-cell embryonic state, readily formed implantation-competent blastoids and, following morula aggregation, contributed to embryonic and extraembryonic lineages. We identified senescence-dependent regulation of nicotinamide N-methyltransferase as a key mechanism controlling the S-adenosyl-L-methionine levels during 4FR that was required for expression of the two-cell genes and acquisition of an extraembryonic potential. Importantly, a partial 4F epigenetic reprogramming in old mice was able to reverse several markers of liver aging only in conjunction with the depletion of p16High cells. Our results show that the presence of p16High senescent cells limits cell plasticity, whereas their depletion can promote a totipotent-like state and histopathological tissue rejuvenation during 4F reprogramming.


Assuntos
Plasticidade Celular , Reprogramação Celular , Animais , Camundongos , Reprogramação Celular/genética , Envelhecimento/genética , Implantação do Embrião , Epigenômica
3.
Biology (Basel) ; 11(3)2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-35336777

RESUMO

Glucuronidation, catalyzed by UDP-glucuronosyltransferase UGT2B enzymes, is a major inactivating and elimination pathway for androgen hormones in humans. Whether Ugt2b enzymes from mice are also reactive with these hormones have never been investigated. The present study aimed at evaluating the capability of murine tissues and Ugt2b enzymes to glucuronidated androgens. The 7 murine Ugt2b (Ugt2b1, 2b5, 2b34, 2b35, 2b36, 2b37 and 2b38) enzymes were cloned and stably expressed into HEK293 cells. In vitro glucuronidation assays were performed with microsomal proteins or homogenates from mice tissues (liver, kidney, intestine, adipose, testis, prostate, epididymis, bulbo, seminal vesicle, mammary glands, uterus, and ovary) and from Ugt2b-HEK293 cells. Male and female livers, as well as male kidneys, are the major sites for androgen glucuronidation in mice. The male liver is highly efficient at glucuronidation of dihydrotestosterone (DHT) and testosterone and is enriched in Ugt2b1 and 2b5 enzymes. Androsterone and 3α-Diol are conjugated in the male kidney through an Ugt2b37-dependent process. Interestingly, castration partially abolished hepatic Ugt2b1 expression and activity, while Ugt2b37 was totally repressed. DHT injection partially corrected these changes. In conclusion, these observations revealed the substrate- and tissue-specific manner in which murine Ugt2b enzymes conjugate androgens. They also evidence how androgens modulate their own glucuronide conjugation in mice.

4.
Cell Metab ; 32(1): 87-99.e6, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32485135

RESUMO

The accumulation of senescent cells can drive many age-associated phenotypes and pathologies. Consequently, it has been proposed that removing senescent cells might extend lifespan. Here, we generated two knockin mouse models targeting the best-characterized marker of senescence, p16Ink4a. Using a genetic lineage tracing approach, we found that age-induced p16High senescence is a slow process that manifests around 10-12 months of age. The majority of p16High cells were vascular endothelial cells mostly in liver sinusoids (LSECs), and to lesser extent macrophages and adipocytes. In turn, continuous or acute elimination of p16High senescent cells disrupted blood-tissue barriers with subsequent liver and perivascular tissue fibrosis and health deterioration. Our data show that senescent LSECs are not replaced after removal and have important structural and functional roles in the aging organism. In turn, delaying senescence or replacement of senescent LSECs could represent a powerful tool in slowing down aging.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Envelhecimento/metabolismo , Animais , Células Cultivadas , Senescência Celular/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Células Endoteliais/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
5.
Aging (Albany NY) ; 12(11): 11152-11160, 2020 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-32535553

RESUMO

Data obtained from genetically modified mouse models suggest a detrimental role for p16High senescent cells in physiological aging and age-related pathologies. Our recent analysis of aging mice revealed a continuous and noticeable accumulation of liver sinusoid endothelial cells (LSECs) expressing numerous senescence markers, including p16. At early stage, senescent LSECs show an enhanced ability to clear macromolecular waste and toxins including oxidized LDL (oxLDL). Later in life, however, the efficiency of this important detoxifying function rapidly declines potentially due to increased endothelial thickness and senescence-induced silencing of scavenger receptors and endocytosis genes. This inability to detoxify toxins and macromolecular waste, which can be further exacerbated by increased intestinal leakiness with age, might be an important contributing factor to animal death. Here, we propose how LSEC senescence could serve as an endogenous clock that ultimately controls longevity and outline some of the possible approaches to extend the lifespan.


Assuntos
Envelhecimento/fisiologia , Senescência Celular/fisiologia , Células Endoteliais/metabolismo , Fígado/citologia , Animais , Lipoproteínas LDL/metabolismo , Fígado/metabolismo , Longevidade/fisiologia , Camundongos , Modelos Animais
6.
Cancer Res ; 73(23): 6963-71, 2013 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24121496

RESUMO

Androgen deprivation therapy (ADTh) remains a mainstay of prostate cancer treatment, but its efficacy is bypassed by mechanisms that are not fully understood. In human prostate cancer cells, androgen glucuronidation, catalyzed by the two UDP-glucuronosyltransferase (UGT) enzymes UGT2B15 and UGT2B17, is the major androgen inactivation pathway. In this study, we investigated the effect of ADTh on androgen glucuronidation to evaluate its potential clinical utility for prostate cancer prognosis or therapy. UGT2B15 and UGT2B17 expression was evaluated in prostate cancer specimens from untreated or treated patients and in cell models of prostate cancer exposed to clinically relevant antiandrogens. UGT2B15 and UGT2B17 protein levels in prostate were increased after 5 months of ADTh when compared with specimens from untreated patients. UGT2B15 expression remained elevated for up to 12 months, but UGT2B17 returned to initial levels as soon as after 6 months. Several androgen receptor (AR) antagonists tested caused a dose- and time-dependent stimulation of UGT2B15 and UGT2B17 expression and androgen glucuronidation in prostate cancer cell lines. The role of AR in these regulatory events was confirmed using AR-deficient LNCaP cells, in which UGT2B attenuation reduced the antiproliferative effects of AR pharmacologic antagonists. Through this combination of clinical and functional investigations, our work revealed that ADTh stimulates a local androgen metabolism in prostate cells, establishing a foundation to evaluate the potential of UGT2B15 and UGT2B17 as drug targets and/or molecular markers for ADTh responsiveness and maintenance in prostate cancer.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Androgênios/metabolismo , Antineoplásicos Hormonais/uso terapêutico , Glucuronosiltransferase/metabolismo , Terapia de Alvo Molecular/métodos , Neoplasias da Próstata/tratamento farmacológico , Antagonistas de Androgênios/farmacologia , Detecção Precoce de Câncer/métodos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ácido Glucurônico/metabolismo , Glucuronosiltransferase/antagonistas & inibidores , Glucuronosiltransferase/genética , Humanos , Masculino , Antígenos de Histocompatibilidade Menor , Prognóstico , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/genética , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Células Tumorais Cultivadas
7.
Basic Clin Pharmacol Toxicol ; 113(2): 92-102, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23527766

RESUMO

Bicalutamide (Casodex(®) ) is a non-steroidal pure anti-androgen used in the treatment of localized prostate cancer. It is a racemate drug, and its activity resides in the (R)-enantiomer, with little in the (S)-enantiomer. A major metabolic pathway for bicalutamide is glucuronidation catalysed by UDP-glucuronosyltransferase (UGT) enzymes. While (S)bicalutamide is directly glucuronidated, (R)bicalutamide requires hydroxylation prior to glucuronidation. The contribution of human tissues and UGT isoforms in the metabolism of these enantiomers has not been extensively investigated. In this study, both (R) and/or (S)bicalutamide were converted into glucuronide (-G) derivatives after incubation of pure and racemic solutions with microsomal extracts from human liver and kidney. Intestinal microsomes exhibited only low reactivity with these substrates. Km values of liver and kidney samples for (S)bicalutamide glucuronidation were similar, and lower than values obtained with the (R)-enantiomer. Among the 16 human UGTs tested, UGT1A8 and UGT1A9 were able to form both (S) and (R)bicalutamide-G from pure or racemic substrates. UGT2B7 was also able to form (R)bicalutamide-G. Kinetic parameters of the recombinant UGT2B7, UGT1A8 and UGT1A9 enzymes support a predominant role of the UGT1A9 isoform in bicalutamide metabolism. Accordingly, (S)bicalutamide inhibited the ability of human liver and kidney microsomes to glucuronidate the UGT1A9 probe substrate, propofol. In conclusion, the present study provides the first comprehensive analysis of in vitro bicalutamide glucuronidation by human tissues and UGTs and identifies UGT1A9 as a major contributor for (R) and (S) glucuronidation in the human liver and kidney.


Assuntos
Antagonistas de Androgênios/farmacologia , Anilidas/farmacologia , Glucuronosiltransferase/metabolismo , Rim/enzimologia , Fígado/enzimologia , Nitrilas/farmacologia , Compostos de Tosil/farmacologia , Cromatografia Líquida , Humanos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Microssomos/enzimologia , Neoplasias da Próstata/tratamento farmacológico , Estereoisomerismo , Espectrometria de Massas em Tandem , UDP-Glucuronosiltransferase 1A
8.
J Clin Endocrinol Metab ; 97(3): E428-32, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22170718

RESUMO

CONTEXT: Androgens play major roles in prostate cancer initiation and development. In prostate cells, the human uridine diphosphate-glucuronosyltransferase (UGT)2B15 and UGT2B17 enzymes inactivate androgens. OBJECTIVE: We investigated in vivo how UGT2B15 and UGT2B17 expressions are affected during prostate cancer development. DESIGN: We conducted an observational study of the UGT2B15 and UGT2B17 mRNA and protein levels. SETTING: The study was conducted at Laval University (Québec, Canada) and at the University of British Columbia (Vancouver, Canada). PATIENTS/PARTICIPANTS: Participants were from a cohort of prostate cancer patients from the Hôtel-Dieu de Québec hospital (Québec; mRNA analyses) and from the Vancouver Prostate Centre tissue bank (Vancouver; tissue microarray experiments). MAIN OUTCOME MEASURES: UGT mRNA and protein levels were determined using real-time PCR and immunohistochemical analyses, respectively. RESULTS: Both UGT2B15 and UGT2B17 mRNA and protein levels were not significantly associated with Gleason score stratification. However, when protein levels were compared to benign prostatic hyperplasia, UGT2B17 was significantly more abundant in all Gleason-scored tumors. By contrast, UGT2B15 levels were significantly reduced in naive and castration-resistant tumors and undetectable in lymph node metastases. Finally, UGT2B17 proteins were 5-fold more abundant in metastases than in benign samples. CONCLUSIONS: The current study reveals that UGT2B15 and UGT2B17 are differentially regulated during prostate cancer progression. Furthermore, this study also identifies the UGT2B15 gene as a negatively regulated target gene in castration-resistant prostate cancer and lymph node metastases.


Assuntos
Regulação Neoplásica da Expressão Gênica , Glucuronosiltransferase/genética , Próstata/enzimologia , Neoplasias da Próstata/genética , Progressão da Doença , Glucuronosiltransferase/metabolismo , Humanos , Masculino , Antígenos de Histocompatibilidade Menor , Gradação de Tumores , Próstata/patologia , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia
9.
Drug Metab Rev ; 42(1): 110-22, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19831728

RESUMO

Recent progresses in molecular pharmacology approaches have allowed the identification and characterization of a series of nuclear receptors (NR) which efficiently control the level UDP-glucuronosyltransferase (UGT) genes expression. These regulatory processes ensure optimized UGT expression in response to specific endogenous and/or exogenous stimuli. Interestingly, numerous endogenous activators of these NRs are conjugated by the UGT enzymes they regulate. In such a case, the NR-dependent regulation of UGT genes corresponds to a feedforward/feedback mechanism by which a bioactive molecule controls its own concentrations. In the present review, we will discuss i) how bilirubin reduces its circulating levels by activating AhR in the liver; ii) how bile acids modulate their hepatic glucuronidation via PXR- and FXR-dependent processes in enterohepatic tissues; and iii) how androgens inhibit their cellular metabolism in prostate cancer cells through an AR-dependent mechanism. Subsequently, with further discussion of the same examples (bilirubin and bile acids), we will illustrate how NR-dependent regulation of UGT enzymes may contribute to the beneficial effects of pharmacological activators of nuclear receptors, such as CAR and PPARa.


Assuntos
Fatores Ativadores da Transcrição/fisiologia , Ácidos e Sais Biliares/metabolismo , Bilirrubina/sangue , Fígado/metabolismo , Receptores Citoplasmáticos e Nucleares/fisiologia , Fatores Ativadores da Transcrição/metabolismo , Células Cultivadas , Glucuronídeos/metabolismo , Glucuronosiltransferase/metabolismo , Regiões Promotoras Genéticas , Transdução de Sinais/fisiologia
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