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1.
Adv Sci (Weinh) ; 11(28): e2404073, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38757622

RESUMO

Ferroptosis plays important roles both in normal physiology and multiple human diseases. It is well known that selenoprotein named glutathione peroxidase 4 (GPX4) is a crucial regulator for ferroptosis. However, it remains unknown whether other selenoproteins responsible for the regulation of ferroptosis, particularly in gut diseases. In this study, it is observed that Selenoprotein I (Selenoi) prevents ferroptosis by maintaining ether lipids homeostasis. Specific deletion of Selenoi in intestinal epithelial cells induced the occurrence of ferroptosis, leading to impaired intestinal regeneration and compromised colonic tumor growth. Mechanistically, Selenoi deficiency causes a remarkable decrease in ether-linked phosphatidylethanolamine (ePE) and a marked increase in ether-linked phosphatidylcholine (ePC). The imbalance of ePE and ePC results in the upregulation of phospholipase A2, group IIA (Pla2g2a) and group V (Pla2g5), as well as arachidonate-15-lipoxygenase (Alox15), which give rise to excessive lipid peroxidation. Knockdown of PLA2G2A, PLA2G5, or ALOX15 can reverse the ferroptosis phenotypes, suggesting that they are downstream effectors of SELENOI. Strikingly, GPX4 overexpression cannot rescue the ferroptosis phenotypes of SELENOI-knockdown cells, while SELENOI overexpression can partially rescue GPX4-knockdown-induced ferroptosis. It suggests that SELENOI prevents ferroptosis independent of GPX4. Taken together, these findings strongly support the notion that SELENOI functions as a novel suppressor of ferroptosis during colitis and colon tumorigenesis.


Assuntos
Colite , Neoplasias Colorretais , Ferroptose , Selenoproteínas , Ferroptose/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Camundongos , Animais , Selenoproteínas/metabolismo , Selenoproteínas/genética , Colite/metabolismo , Colite/genética , Humanos , Modelos Animais de Doenças , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Transdução de Sinais/genética
2.
BMC Cancer ; 24(1): 465, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38622522

RESUMO

BACKGROUND: Gastric cancer (GC) lacks serum biomarkers with clinical diagnostic value. Multi-omics analysis is an important approach to discovering cancer biomarkers. This study aimed to identify and validate serum biomarkers for GC diagnosis by cross-analysis of proteomics and transcriptomics datasets. METHODS: A cross-omics analysis was performed to identify overlapping differentially expressed genes (DEGs) between our previous aptamer-based GC serum proteomics dataset and the GC tissue RNA-Seq dataset in The Cancer Genome Atlas (TCGA) database, followed by lasso regression and random forest analysis to select key overlapping DEGs as candidate biomarkers for GC. The mRNA levels and diagnostic performance of these candidate biomarkers were analyzed in the original and independent GC datasets to select valuable candidate biomarkers. The valuable candidate biomarkers were subjected to bioinformatics analysis to select those closely associated with the biological behaviors of GC as potential biomarkers. The clinical diagnostic value of the potential biomarkers was validated using serum samples, and their expression levels and functions in GC cells were validated using in vitro cell experiments. RESULTS: Four candidate biomarkers (ILF2, PGM2L1, CHD7, and JCHAIN) were selected. Their mRNA levels differed significantly between tumor and normal tissues and showed different diagnostic performances for GC, with areas under the receiver operating characteristic curve (AUROCs) of 0.629-0.950 in the TCGA dataset and 0.736-0.840 in the Gene Expression Omnibus (GEO) dataset. In the bioinformatics analysis, only ILF2 (interleukin enhancer-binding factor 2) gene levels were associated with immune cell infiltration, some checkpoint gene expression, chemotherapy sensitivity, and immunotherapy response. Serum levels of ILF2 were higher in GC patients than in controls, with an AUROC of 0.944 for the diagnosis of GC, and it was also detected in the supernatants of GC cells. Knockdown of ILF2 by siRNA significantly reduced the proliferation and colony formation of GC cells. Overexpression of ILF2 significantly promotes the proliferation and colony formation of gastric cancer cells. CONCLUSIONS: Trans-omics analysis of proteomics and transcriptomics is an efficient approach for discovering serum biomarkers, and ILF2 is a potential diagnostic biomarker and therapeutic target of gastric cancer.


Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Biomarcadores Tumorais/metabolismo , Perfilação da Expressão Gênica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína do Fator Nuclear 45/genética
3.
J Med Virol ; 96(5): e29634, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38682578

RESUMO

Metabolic reprogramming induced by Epstein-Barr virus (EBV) often mirrors metabolic changes observed in cancer cells. Accumulating evidence suggests that lytic reactivation is crucial in EBV-associated oncogenesis. The aim of this study was to explore the role of metabolite changes in EBV-associated malignancies and viral life cycle control. We first revealed that EBV (LMP1) accelerates the secretion of the oncometabolite D-2HG, and serum D-2HG level is a potential diagnostic biomarker for NPC. EBV (LMP1)-driven metabolite changes disrupts the homeostasis of global DNA methylation and demethylation, which have a significantly inhibitory effect on active DNA demethylation and 5hmC content. We found that loss of 5hmC indicates a poor prognosis for NPC patients, and that 5hmC modification is a restriction factor of EBV reactivation. We confirmed a novel EBV reactivation inhibitor, α-KG, which inhibits the expression of EBV lytic genes with CpG-containing ZREs and the latent-lytic switch by enhancing 5hmC modification. Our results demonstrate a novel mechanism of which metabolite abnormality driven by EBV controls the viral lytic reactivation through epigenetic modification. This study presents a potential strategy for blocking EBV reactivation, and provides potential targets for the diagnosis and therapy of NPC.


Assuntos
Metilação de DNA , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Ativação Viral , Humanos , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/fisiologia , Carcinoma Nasofaríngeo/virologia , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/virologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/complicações , Proteínas da Matriz Viral/metabolismo , Proteínas da Matriz Viral/genética , Epigênese Genética , Progressão da Doença
4.
Sci China Life Sci ; 67(6): 1242-1254, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38478296

RESUMO

RNA N6-methyladenosine (m6A), as the most abundant modification of messenger RNA, can modulate insect behaviors, but its specific roles in aggregation behaviors remain unexplored. Here, we conducted a comprehensive molecular and physiological characterization of the individual components of the methyltransferase and demethylase in the migratory locust Locusta migratoria. Our results demonstrated that METTL3, METTL14 and ALKBH5 were dominantly expressed in the brain and exhibited remarkable responses to crowding or isolation. The individual knockdown of methyltransferases (i.e., METTL3 and METTL14) promoted locust movement and conspecific attraction, whereas ALKBH5 knockdown induced a behavioral shift toward the solitary phase. Furthermore, global transcriptome profiles revealed that m6A modification could regulate the orchestration of gene expression to fine tune the behavioral aggregation of locusts. In summary, our in vivo characterization of the m6A functions in migratory locusts clearly demonstrated the crucial roles of the m6A pathway in effectively modulating aggregation behaviors.


Assuntos
Adenosina , Locusta migratoria , Metiltransferases , Animais , Adenosina/metabolismo , Adenosina/análogos & derivados , Locusta migratoria/genética , Locusta migratoria/fisiologia , Locusta migratoria/metabolismo , Metiltransferases/metabolismo , Metiltransferases/genética , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Encéfalo/fisiologia , Transcriptoma , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Regulação da Expressão Gênica , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Gafanhotos/genética , Gafanhotos/fisiologia , Gafanhotos/metabolismo
5.
FASEB J ; 38(5): e23532, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38451470

RESUMO

Although elevated glycolysis has been widely recognized as a hallmark for highly proliferating cells like stem cells and cancer, its regulatory mechanisms are still being updated. Here, we found a previously unappreciated mechanism of mammalian target of rapamycin complex 2 (mTORC2) in regulating glycolysis in intestinal stem cell maintenance and cancer progression. mTORC2 key subunits expression levels and its kinase activity were specifically upregulated in intestinal stem cells, mouse intestinal tumors, and human colorectal cancer (CRC) tissues. Genetic ablation of its key scaffolding protein Rictor in both mouse models and cell lines revealed that mTORC2 played an important role in promoting intestinal stem cell proliferation and self-renewal. Moreover, utilizing mouse models and organoid culture, mTORC2 loss of function was shown to impair growth of gut adenoma and tumor organoids. Based on these findings, we performed RNA-seq and noticed significant metabolic reprogramming in Rictor conditional knockout mice. Among all the pathways, carbohydrate metabolism was most profoundly altered, and further studies demonstrated that mTORC2 promoted glycolysis in intestinal epithelial cells. Most importantly, we showed that a rate-limiting enzyme in regulating glycolysis, 6-phosphofructo-2-kinase (PFKFB2), was a direct target for the mTORC2-AKT signaling. PFKFB2 was phosphorylated upon mTORC2 activation, but not mTORC1, and this process was AKT-dependent. Together, this study has identified a novel mechanism underlying mTORC2 activated glycolysis, offering potential therapeutic targets for treating CRC.


Assuntos
Neoplasias , Proteínas Proto-Oncogênicas c-akt , Animais , Humanos , Camundongos , Modelos Animais de Doenças , Células Epiteliais , Glicólise , Mamíferos , Alvo Mecanístico do Complexo 2 de Rapamicina , Camundongos Knockout , Fosfofrutoquinase-2 , Sirolimo
6.
J Hepatocell Carcinoma ; 11: 317-325, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38348099

RESUMO

Purpose: The differential diagnosis of atypical hepatocellular carcinoma (aHCC) and atypical benign focal hepatic lesions (aBFHL) usually depends on pathology. This study aimed to develop non-invasive approaches based on conventional blood indicators for the differential diagnosis of aHCC and aBFHL. Patients and Methods: Hospitalized patients with pathologically confirmed focal hepatic lesions and their clinical data were retrospectively collected, in which patients with HCC with serum alpha-fetoprotein (AFP) levels of ≤200 ng/mL and atypical imaging features were designated as the aHCC group (n = 224), and patients with benign focal hepatic lesions without typical imaging features were designated as the aBFHL group (n = 178). The performance of indexes (both previously reported and newly constructed) derived from conventional blood indicators by four mathematical operations in distinguishing aHCC and aBFHL was evaluated using the receiver operating characteristic (ROC) curve and diagnostic validity metrics. Results: Among ten previously reported derived indexes related to HCC, the index GPR, the ratio of γ-glutamyltransferase (GGT) to platelet (PLT), showed the best performance in distinguishing aHCC from aBFHL with the area under ROC curve (AUROC) of 0.853 (95% CI 0.814-0.892), but the other indexes were of little value (AUROCs from 0.531 to 0.700). A new derived index, sAGP [(standardized AFP + standardized GGT)/standardized PLT], was developed and exhibited AUROCs of 0.905, 0.894, 0.891, 0.925, and 0.862 in differentiating overall, BCLC stage 0/A, TNM stage I, small, and AFP-negative aHCC from aBFHL, respectively. Conclusion: The sAGP index is an efficient, simple, and practical metric for the non-invasive differentiation of aHCC from aBFHL.

7.
Proc Natl Acad Sci U S A ; 121(1): e2307395120, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38157451

RESUMO

Oxidative stress, which can be activated by a variety of environmental risk factors, has been implicated as an important pathogenic factor for inflammatory bowel disease (IBD). However, how oxidative stress drives IBD onset remains elusive. Here, we found that oxidative stress was strongly activated in inflamed tissues from both ulcerative colitis patients and Crohn's disease patients, and it caused nuclear-to-cytosolic TDP-43 transport and a reduction in the TDP-43 protein level. To investigate the function of TDP-43 in IBD, we inducibly deleted exons 2 to 3 of Tardbp (encoding Tdp-43) in mouse intestinal epithelium, which disrupted its nuclear localization and RNA-processing function. The deletion gave rise to spontaneous intestinal inflammation by inducing epithelial cell necroptosis. Suppression of the necroptotic pathway with deletion of Mlkl or the RIP1 inhibitor Nec-1 rescued colitis phenotypes. Mechanistically, disruption of nuclear TDP-43 caused excessive R-loop accumulation, which triggered DNA damage and genome instability and thereby induced PARP1 hyperactivation, leading to subsequent NAD+ depletion and ATP loss, consequently activating mitochondrion-dependent necroptosis in intestinal epithelial cells. Importantly, restoration of cellular NAD+ levels with NAD+ or NMN supplementation, as well as suppression of ALKBH7, an α-ketoglutarate dioxygenase in mitochondria, rescued TDP-43 deficiency-induced cell death and intestinal inflammation. Furthermore, TDP-43 protein levels were significantly inversely correlated with γ-H2A.X and p-MLKL levels in clinical IBD samples, suggesting the clinical relevance of TDP-43 deficiency-induced mitochondrion-dependent necroptosis. Taken together, these findings identify a unique pathogenic mechanism that links oxidative stress to intestinal inflammation and provide a potent and valid strategy for IBD intervention.


Assuntos
Doenças Inflamatórias Intestinais , Necroptose , Humanos , Animais , Camundongos , NAD/metabolismo , Estruturas R-Loop , Doenças Inflamatórias Intestinais/metabolismo , Células Epiteliais/metabolismo , Mucosa Intestinal/metabolismo , Inflamação/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Mitocôndrias/metabolismo
8.
Front Chem ; 11: 1144347, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37228865

RESUMO

Introduction: Aptamers are valuable for bioassays, but aptamer-target binding is susceptible to reaction conditions. In this study, we combined thermofluorimetric analysis (TFA) and molecular dynamics (MD) simulations to optimize aptamer-target binding, explore underlying mechanisms and select preferred aptamer. Methods: Alpha-fetoprotein (AFP) aptamer AP273 (as the model) was incubated with AFP under various experimental conditions, and melting curves were measured in a real-time PCR system to select the optimal binding conditions. The intermolecular interactions of AP273-AFP were analysed by MD simulations with these conditions to reveal the underlying mechanisms. A comparative study between AP273 and control aptamer AP-L3-4 was performed to validate the value of combined TFA and MD simulation in selecting preferred aptamers. Results: The optimal aptamer concentration and buffer system were easily determined from the dF/dT peak characteristics and the melting temperature (Tm) values on the melting curves of related TFA experiments, respectively. A high Tm value was found in TFA experiments performed in buffer systems with low metal ion strength. The molecular docking and MD simulation analyses revealed the underlying mechanisms of the TFA results, i.e., the binding force and stability of AP273 to AFP were affected by the number of binding sites, frequency and distance of hydrogen bonds, and binding free energies; these factors varied in different buffer and metal ion conditions. The comparative study showed that AP273 was superior to the homologous aptamer AP-L3-4. Conclusion: Combining TFA and MD simulation is efficient for optimizing the reaction conditions, exploring underlying mechanisms, and selecting aptamers in aptamer-target bioassays.

9.
Nutrients ; 15(8)2023 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-37111049

RESUMO

During aging, the protective function of mucus barrier is significantly reduced among which changes in colonic mucus barrier function received the most attention. Additionally, the incidence of colon-related diseases increases significantly in adulthood, posing a threat to the health of the elderly. However, the specific changes in colonic mucus barrier with aging and the underlying mechanisms have not been fully elucidated. To understand the effects of aging on the colonic mucus barrier, changes in the colonic mucus layer were evaluated in mice aged 2, 12, 18, and 24 months. Microbial invasion, thickness, and structure of colonic mucus in mice at different months of age were analyzed by in situ hybridization fluorescence staining, AB/PAS staining, and cryo-scanning electron microscopy. Results showed that the aged colon exhibited intestinal mucus barrier dys-function and altered mucus properties. During aging, microorganisms invaded the mucus layer to reach epithelial cells. Compared with young mice, the thickness of mucus layer in aged mice in-creased by 11.66 µm. And the contents of the main components and glycosylation structure of colon changed. Among them, the proportion of goblet cells decreased significantly in older mice, and the expression of spdef genes that regulate goblet cell differentiation decreased. Further, the expression of key enzymes involved in mucin core structure formation and glycan modification also changed with aging. The expression of core 1 ß1,3-galactosyltransferase (C1GalT1) which is the key enzyme forming the main core structure increased by one time, while core 2 ß1,6 N-acetylglucosaminyltransferase (C2GnT) and core 3 ß1,3 N-acetylglucosaminyltransferase (C3GnT) decreased 2 to 6- and 2-fold, respectively. Also, the expression of sialyltransferase, one of the mucin-glycan modifying enzymes, was decreased by 1-fold. Overall, our results indicate that the goblet cells/glycosyltransferase/O-glycan axis plays an important role in maintaining the physicochemical properties of colonic mucus and the stability of intestinal environment.


Assuntos
Mucosa Intestinal , Mucinas , Camundongos , Animais , Mucinas/metabolismo , Mucosa Intestinal/metabolismo , N-Acetilglucosaminiltransferases/metabolismo , Colo/metabolismo , Mucina-2/genética , Mucina-2/metabolismo , Células Caliciformes/metabolismo , Muco/metabolismo , Polissacarídeos/metabolismo
10.
J Org Chem ; 88(4): 2140-2157, 2023 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-36701175

RESUMO

Here, we demonstrate that α-C-H and C-N bonds of unactivated secondary amides can be activated simultaneously by the copper catalyst to synthesize α-ketoamides or α-ketoesters in one step, which is a challenging and underdeveloped transformation. Using copper as a catalyst and air as an oxidant, the reaction is compatible with a broad range of acetoamides, amines, and alcohols. The preliminary mechanism studies and density functional theory calculation indicated that the reaction process may undergo first radical α-oxygenation and then transamidation with the help of the resonant six-membered N,O-chelation and molecular oxygen plays a role as an initiator to trigger the transamidation process. The combination of chelation assistance and dioxygen selective oxygenation strategy would substantially extend the modern mild synthetic amide cleavage toolbox, and we envision that this broadly applicable method will be of great interest in the biopharmaceutical industry, synthetic chemistry, and agrochemical industry.

11.
Theranostics ; 12(16): 6865-6882, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36276637

RESUMO

Rationale: Dysregulation of signaling that governs self-renewal and differentiation of intestinal stem cells (ISCs) is a major cause of colorectal cancer (CRC) initiation and progression. Methods: qRT-PCR, western blotting, in situ hybridization, immunohistochemistry and immunofluorescence assays were used to detect the expression levels of MEX3A, KLF4 and E2F3 in CRC tissues. The biological functions of MEX3A were studied using Mex3a knockout (KO) and intestinal epithelium specific conditional knockout (cKO) mice, AOM-DSS mouse colorectal tumor model, Apc floxed mouse tumor model and intestinal and tumor organoids. Transcriptomic RNA sequencing (RNA-seq), RNA crosslinking immunoprecipitation (CLIP) and luciferase reporter assays were performed to explore the molecular mechanisms of MEX3A. Results: RNA-binding protein MEX3A, a specific ISC marker gene, becomes ectopically upregulated upon CRC and its levels negatively correlate with patient survival prognosis. MEX3A functions as an oncoprotein that retains cancer cells in undifferentiated and proliferative status and it enhances their radioresistance to DNA damage. Mechanistically, a rate limiting factor of cellular proliferation E2F3 induces MEX3A, which in turn activates WNT pathway by directly suppressing expression of its pro-differentiation transcription factor KLF4. Knockdown of MEX3A with siRNA or addition of KLF4 agonist significantly suppressed tumor growth both by increasing differentiation status of cancer cells and by suppressing their proliferation. Conclusions: It identifies E2F3-MEX3A-KLF4 axis as an essential coordinator of cancer stem cell self-renewal and differentiation, representing a potent new druggable target for cancer differentiation therapy.


Assuntos
Neoplasias Colorretais , Fator de Transcrição E2F3 , Fator 4 Semelhante a Kruppel , Proteínas de Ligação a RNA , Animais , Camundongos , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , RNA Interferente Pequeno , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Via de Sinalização Wnt , Fator 4 Semelhante a Kruppel/genética , Fator 4 Semelhante a Kruppel/metabolismo , Fator de Transcrição E2F3/genética , Fator de Transcrição E2F3/metabolismo
12.
Chaos ; 32(9): 093120, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36182378

RESUMO

In this paper, a Riemann-Hilbert approach to a two-component modified short-pulse (mSP) system on the line with zero boundary conditions is developed. A parametric representation of the solution to the related Cauchy problem is obtained. Four nonlocal integrable reductions, namely, the real reverse space-time nonlocal focusing and defocusing mSP equations and the complex reverse space-time nonlocal focusing and defocusing mSP equations, are studied in detail. For each case, soliton solutions are presented, and, unlike their local counterparts, the nonlocal equations exhibit certain novel properties induced by the impact of nonlocality.

13.
Opt Express ; 30(22): 40144-40160, 2022 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-36298952

RESUMO

A new interim and connection space (ICS) and its reconstruction method are proposed. The proposed ICS,tD65A, consists of six colorimetric values or two sets of tristimulus values under CIE illuminant D65 and A respectively. In addition, a new spectral decomposition based on the tD65A ICS and the Wiener Estimation matrix MW was introduced for an improved spectral reconstruction. Accompanying the tD65A ICS, m important basis vectors for the metameric black space based on the new spectral decomposition, and a mapping matrix MP,k via a polynomial model of order k, were trained so that both the spectral and colorimetric accuracies for the reconstructed reflectance can be further enhanced. The proposed ICS and its reconstruction method can ensure exact colorimetric matches under two (real rather than synthetic) illuminants D65 and A, which is an advantage compared with other ICSs. The performance of the proposed method was tested and compared with five other ICSs using the NCS dataset and three spectral images respectively, using RMSE and GFC to measure the spectral accuracy, and using CIEDE2000 colour differences to measure the colorimetric accuracy under three types of illuminants (continuous, fluorescent, and LED). Performance test results showed the proposed methods outperform other ICSs in terms of both spectral accuracy and colorimetric measures (RMSE, GFC, and CIEDE2000 colour difference). Therefore, it is expected the proposed ICS and its reconstruction method can play an important role in spectral image compression and reproduction applications.

14.
iScience ; 25(3): 103982, 2022 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-35310332

RESUMO

The Mammary gland undergoes complicated epithelial remodeling to form lobuloalveoli during pregnancy, in which basal epithelial cells remarkably increase to form a basket-like architecture. However, it remains largely unknown how dormant mammary basal stem/progenitor cells involve in lobuloalveolar development. Here, we show that Nfatc1 expression marks a rare population of mammary epithelial cells with the majority being basal epithelial cells. Nfatc1 reporter-marked basal epithelial cells are relatively dormant mammary stem/progenitor cells. Although Nfatc1 reporter-marked basal epithelial cells have limited contribution to the homeostasis of mammary epithelium, they divide rapidly during pregnancy and contribute to lobuloalveolar development. Furthermore, Nfatc1 reporter-marked basal epithelial cells are preferentially used for multiple pregnancies. Using single-cell RNA-seq analysis, we identify multiple functionally distinct clusters within the Nfatc1 reporter-marked cell-derived progeny cells during pregnancy. Taken together, our findings underscore Nfatc1 reporter-marked basal cells as dormant stem/progenitor cells that contribute to mammary lobuloalveolar development during pregnancy.

15.
Cell Res ; 32(7): 670-686, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35296796

RESUMO

Diet can impact on gut health and disease by modulating intestinal stem cells (ISCs). However, it is largely unknown if and how the ISC niche responds to diet and influences ISC function. Here, we demonstrate that Lepr+ mesenchymal cells (MCs) surrounding intestinal crypts sense diet change and provide a novel niche signal to maintain ISC and progenitor cell proliferation. The abundance of these MCs increases upon administration of a high-fat diet (HFD) but dramatically decreases upon fasting. Depletion of Lepr+ MCs resulted in fewer intestinal stem/progenitor cells, compromised the architecture of crypt-villus axis and impaired intestinal regeneration. Furthermore, we showed that IGF1 secreted by Lepr+ MCs is an important effector that promotes proliferation of ISCs and progenitor cells in the intestinal crypt. We conclude that Lepr+ MCs sense diet alterations and, in turn, modulate intestinal stem/progenitor cell function via a stromal IGF1-epithelial IGF1R axis. These findings reveal that Lepr+ MCs are important mediators linking systemic diet changes to local ISC function and might serve as a novel therapeutic target for gut diseases.


Assuntos
Leptina , Células-Tronco Mesenquimais , Dieta , Mucosa Intestinal , Células-Tronco/fisiologia
16.
J Gastroenterol Hepatol ; 37(4): 734-740, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35102609

RESUMO

BACKGROUND AND AIM: Colonic stem cells play important roles in both normal epithelial turnover and injury repair. Lgr5+ colonic stem cells are highly susceptible to DSS-induced damage. However, it is still unclear how colonic stem cells regenerate injured epithelium during colitis. Here, we explored the functions of a new population of NFATc1+ colonic stem cells in experimental colitis. METHODS: Nfatc1+ colonic stem cells were labeled using Nfatc1CreERT2 ;R26mTmG reporter mice. Immunostaining assays were used to detect Goblet cells, enteroendocrine cells, and intestinal stem/progenitor cells. We performed lineage tracing assay to investigate whether Nfatc1+ cells are real colonic stem cells using Nfatc1CreERT2 ;R26mTmG mice. The contribution of Nfatc1+ stem cells on epithelial regeneration was detected in experimental colitis induced by DSS. RESULTS: Nfatc1-reporter marked cells are enriched for +3 to +5 position in colonic crypts, and they are overlapped with Sox9+ cells and Hopx+ cells that have been identified as stem cells in small intestine. However, Nfatc1-reporter marked cells are not overlapped with Lgr5+ colonic stem cells, as well as differentiated goblet cells and enteroendocrine cells. Furthermore, Nfatc1-reporter marked cells are able to give rise to all lineages of the colonic epithelium, and they preferentially contribute to the regeneration of colonic epithelium in DSS-induced experimental colitis. CONCLUSION: Nfatc1+ cells were identified as a novel population of colonic stem cells that are primarily located at +3 to +5 position and contribute to epithelial regeneration during colitis.


Assuntos
Colite , Fatores de Transcrição NFATC , Células-Tronco , Animais , Colite/induzido quimicamente , Mucosa Intestinal/fisiologia , Camundongos , Fatores de Transcrição NFATC/genética , Regeneração , Células-Tronco/fisiologia
17.
J Anal Test ; 6(3): 247-273, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35039787

RESUMO

Point-of-care testing (POCT), as a portable and user-friendly technology, can obtain accurate test results immediately at the sampling point. Nowadays, microfluidic paper-based analysis devices (µPads) have attracted the eye of the public and accelerated the development of POCT. A variety of detection methods are combined with µPads to realize precise, rapid and sensitive POCT. This article mainly introduced the development of electrochemistry and optical detection methods on µPads for POCT and their applications on disease analysis, environmental monitoring and food control in the past 5 years. Finally, the challenges and future development prospects of µPads for POCT were discussed.

18.
Food Funct ; 12(21): 10700-10713, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34605504

RESUMO

Inflammatory bowel disease (IBD) is a chronic intestinal inflammation that is currently incurable. Increasing evidence indicates that supplementation with probiotics could improve the symptoms of IBD. It is scientifically significant to identify novel and valid strains for treating IBD. It has been reported that the probiotic Lactobacillus paracasei L9 (L9), which is identified from the gut of healthy centenarians, can modulate host immunity and plays an anti-allergic role. Here, we demonstrated that L9 alleviates the pathological phenotypes of experimental colitis by expanding the abundance of butyrate-producing bacteria. Oral administration of sodium butyrate in experimental colitis recapitulates the L9 anti-inflammatory phenotypes. Mechanistically, sodium butyrate ameliorated the inflammatory responses by inhibiting the IL-6/STAT3 signaling pathway in colitis. Overall, these findings demonstrated that L9 alleviates the DSS-induced colitis development by enhancing the abundance of butyrate-producing bacterial strains that produce butyrate to suppress the IL-6/STAT3 signaling pathway, providing new insight into a promising therapeutic target for the remission of IBD.


Assuntos
Colite/induzido quimicamente , Colite/terapia , Interleucina-6/metabolismo , Lacticaseibacillus paracasei , Probióticos/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Butiratos , Ácido Butírico/administração & dosagem , Ácido Butírico/farmacologia , Sulfato de Dextrana/toxicidade , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/administração & dosagem , Antagonistas dos Receptores Histamínicos/farmacologia , Inflamação/tratamento farmacológico , Interleucina-6/genética , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Fator de Transcrição STAT3/genética
19.
Front Cell Dev Biol ; 9: 691050, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34336839

RESUMO

Myoepithelial and luminal cells synergistically expand in the mammary gland during pregnancy, and this process is precisely governed by hormone-related signaling pathways. The bone morphogenetic protein (BMP) signaling pathway is now known to play crucial roles in all organ systems. However, the functions of BMP signaling in the mammary gland remain unclear. Here, we found that BMPR1a is upregulated by hormone-induced Sp1 at pregnancy. Using a doxycycline (Dox)-inducible BMPR1a conditional knockout mouse model, we demonstrated that loss of BMPR1a in myoepithelium results in compromised myoepithelial integrity, reduced mammary stem cells and precocious alveolar differentiation during pregnancy. Mechanistically, BMPR1a regulates the expression of p63 and Slug, two key regulators of myoepithelial maintenance, through pSmad1/5-Smad4 complexes, and consequently activate P-cadherin during pregnancy. Furthermore, we observed that loss of BMPR1a in myoepithelium results in the upregulation of a secreted protein Spp1 that could account for the precocious alveolar differentiation in luminal layer, suggesting a defective basal-to-luminal paracrine signaling mechanism. Collectively, these findings identify a novel role of BMP signaling in maintaining the identity of myoepithelial cells and suppressing precocious alveolar formation.

20.
Theranostics ; 11(8): 3607-3623, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33664851

RESUMO

Background: Brown adipose tissue (BAT) dissipates chemical energy as heat and has the potential to be a protective strategy to prevent obesity. microRNAs (miRNAs) are emerging as important posttranscriptional factors affecting the thermogenic function of BAT. However, the regulatory mechanism underlying miRNA-mediated energy metabolism in BAT is not fully understood. Here, we explored the roles of miR-22 in BAT thermogenesis and energy metabolism. Methods: Using global and conditional knockout mice as in vivo models and primary brown adipocytes as an in vitro system, we investigated the function of miR-22 in BAT thermogenesis in vivo and in vitro. Results: miR-22 expression was upregulated in BAT in response to cold exposure and during brown preadipocyte differentiation. Both global and conditional knockout mice displayed BAT whitening, impaired cold tolerance, and decreased BAT thermogenesis. Moreover, we found that miR-22 deficiency impaired BAT glycolytic capacity, which is critical for thermogenesis. The mechanistic results revealed that miR-22 activated the mTORC1 signaling pathway by directly suppressing Tsc1 and concomitantly directly suppressing Hif1an, an inhibitor of Hif1α, which promotes glycolysis and maintains thermogenesis. Conclusions: Our findings identify miR-22 as a critical regulator in the control of thermogenesis in BAT and as a potential therapeutic target for human metabolic disorders.


Assuntos
Adipócitos Marrons/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , MicroRNAs/genética , Termogênese/genética , Tecido Adiposo Marrom/metabolismo , Animais , Células Cultivadas , Temperatura Baixa , Dieta Hiperlipídica/efeitos adversos , Glicólise , Técnicas In Vitro , Resistência à Insulina/genética , Masculino , Camundongos , Camundongos Knockout , MicroRNAs/metabolismo , Oxigenases de Função Mista/metabolismo , Medicina de Precisão , Transdução de Sinais , Termogênese/fisiologia , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo , Regulação para Cima
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