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1.
2.
Nature ; 630(8016): 466-474, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38839952

RESUMO

Histone acetylation regulates gene expression, cell function and cell fate1. Here we study the pattern of histone acetylation in the epithelial tissue of the Drosophila wing disc. H3K18ac, H4K8ac and total lysine acetylation are increased in the outer rim of the disc. This acetylation pattern is controlled by nuclear position, whereby nuclei continuously move from apical to basal locations within the epithelium and exhibit high levels of H3K18ac when they are in proximity to the tissue surface. These surface nuclei have increased levels of acetyl-CoA synthase, which generates the acetyl-CoA for histone acetylation. The carbon source for histone acetylation in the rim is fatty acid ß-oxidation, which is also increased in the rim. Inhibition of fatty acid ß-oxidation causes H3K18ac levels to decrease in the genomic proximity of genes involved in disc development. In summary, there is a physical mark of the outer rim of the wing and other imaginal epithelia in Drosophila that affects gene expression.


Assuntos
Acetilcoenzima A , Núcleo Celular , Cromatina , Drosophila melanogaster , Ácidos Graxos , Histonas , Asas de Animais , Animais , Acetilcoenzima A/metabolismo , Cromatina/metabolismo , Cromatina/genética , Histonas/metabolismo , Drosophila melanogaster/metabolismo , Drosophila melanogaster/genética , Acetilação , Núcleo Celular/metabolismo , Asas de Animais/metabolismo , Ácidos Graxos/metabolismo , Discos Imaginais/metabolismo , Discos Imaginais/citologia , Oxirredução , Lisina/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Acetato-CoA Ligase/metabolismo , Acetato-CoA Ligase/genética
3.
ACS Chem Biol ; 19(6): 1376-1386, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38829775

RESUMO

Histone lysine acetylation (Kac) and crotonylation (Kcr) marks mediate the recruitment of YEATS domains to chromatin. In this way, YEATS domain-containing proteins such as AF9 participate in the regulation of DNA-templated processes. Our previous study showed that the replacement of Kac/Kcr by a 2-furancarbonyllysine (Kfu) residue led to greatly enhanced affinity toward the AF9 YEATS domain, rendering Kfu-containing peptides useful chemical tools to probe the AF9 YEATS-Kac/Kcr interactions. Here, we report the genetic incorporation of Kfu in Escherichia coli and mammalian cells through the amber codon suppression technology. We develop a Kfu-containing epitope tag, termed RAY-tag, which can robustly and selectively engage with the AF9 YEATS domain in vitro and in cellulo. We further demonstrate that the fusion of RAY-tag to different protein modules, including fluorescent proteins and DNA binding proteins, can facilitate the interrogation of the histone lysine acylation-mediated recruitment of the AF9 YEATS domain in different biological contexts.


Assuntos
Epitopos , Lisina , Lisina/metabolismo , Lisina/química , Acilação , Humanos , Epitopos/metabolismo , Epitopos/química , Escherichia coli/genética , Escherichia coli/metabolismo , Histonas/metabolismo , Histonas/química , Histonas/genética , Ligação Proteica , Acetilação
4.
Amino Acids ; 56(1): 41, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38851640

RESUMO

Periodontitis is an inflammatory condition of supporting structures of teeth leading to attachment and bone loss. Cigarette smoking is the single most important and modifiable risk factor with 5 to 20-fold susceptibility for periodontal diseases. Reverse smoking is a peculiar habit of smoking where the lit end is kept inside the mouth, which is predominant in the northern coastal districts of Andhra Pradesh. Polyamines are biologically active amines involved in tissue regeneration and modulation of inflammation. The study aimed to evaluate polyamines and check their utility as a marker in detection of periodontitis among different groups. Total polyamine levels showed significant increase in reverse smokers with periodontitis when compared to the other groups. Qualitative analysis by thin layer chromatography showed three polyamine bands with varying intensity among the different groups. Mass spectrometric and NMR analyses of the three bands identified them as N1, N8-diacetyl spermidine, N-acetyl cadaverine and lysine. Most significantly elevated levels of lysine was observed in the smoker and reverse smoker periodontitis groups when compared to healthy and non-smoker periodontitis groups. The significantly elevated levels of N-acetyl cadaverine could be responsible for the more destruction of periodontium in the reverse smoker group. Antioxidant potential decreased significantly in different smoker periodontitis groups. The present study suggests that the quantitative analysis of salivary polyamines, lysine and N-acetyl cadaverine can aid as an easy noninvasive diagnostic method for assessing the periodontal status, especially in smokers.


Assuntos
Biomarcadores , Cadaverina , Lisina , Periodontite , Humanos , Periodontite/metabolismo , Periodontite/diagnóstico , Cadaverina/metabolismo , Cadaverina/análise , Biomarcadores/metabolismo , Biomarcadores/análise , Lisina/análogos & derivados , Lisina/análise , Lisina/metabolismo , Adulto , Masculino , Fumantes , Feminino , Pessoa de Meia-Idade , Fumar , Saliva/química , Saliva/metabolismo
5.
Crit Rev Eukaryot Gene Expr ; 34(5): 31-43, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38842202

RESUMO

Breast cancer is one of the most common malignant tumors worldwide. SLC7A2 is abnormally expressed in multiple cancers. However, its potential in triple negative breast cancer (TNBC) is still unclear. The purpose of this study was to investigate the roles of SLC7A2 and its underlying molecular mechanisms in TNBC. mRNA expression was detected by RT-qPCR. Protein expression was detected by western blot. Co-localization of ACOX1 and TCF1 was determined using FISH assay. Histone crotonylation was performed using in vitro histone crotonylation assay. Functional analysis was performed using CCK-8 and flow cytometry assays. Xenograft assay was conducted to further verify the role of SLC7A2 in TNBC. CD8A expression was detected using immunohistochemistry. We found that SLC7A2 is downregulated in TNBC tumors. Low levels are associated with advanced stages and lymph node metastasis. SLC7A2 expression is positively correlated with CD8A. SLC7A2-mediated lysine catabolism drives the activation of CD8+ T cells. Moreover, SLC7A2 promotes histone crotonylation via upregulating ACOX1. It also promotes interaction between ACOX1 and TCF1, thus promoting antitumor T cell immunity. Additionally, overexpression of SLC7A2 activates CD8+ T cells and enhances the chemosensitivity of anti-PD-1 therapies in vivo. In conclusion, SLC7A2 may function as an antitumor gene in TNBC by activating antitumor immunity, suggesting SLC7A2/ACOX1/TCF1 signaling as a promising therapeutic strategy.


Assuntos
Lisina , Neoplasias de Mama Triplo Negativas , Animais , Feminino , Humanos , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Transportador 1 de Aminoácidos Neutros Grandes/genética , Lisina/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
6.
Nat Commun ; 15(1): 4962, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38862536

RESUMO

In all eukaryotes, acetylation of histone lysine residues correlates with transcription activation. Whether histone acetylation is a cause or consequence of transcription is debated. One model suggests that transcription promotes the recruitment and/or activation of acetyltransferases, and histone acetylation occurs as a consequence of ongoing transcription. However, the extent to which transcription shapes the global protein acetylation landscapes is not known. Here, we show that global protein acetylation remains virtually unaltered after acute transcription inhibition. Transcription inhibition ablates the co-transcriptionally occurring ubiquitylation of H2BK120 but does not reduce histone acetylation. The combined inhibition of transcription and CBP/p300 further demonstrates that acetyltransferases remain active and continue to acetylate histones independently of transcription. Together, these results show that histone acetylation is not a mere consequence of transcription; acetyltransferase recruitment and activation are uncoupled from the act of transcription, and histone and non-histone protein acetylation are sustained in the absence of ongoing transcription.


Assuntos
Histonas , Transcrição Gênica , Ubiquitinação , Acetilação , Histonas/metabolismo , Humanos , Fatores de Transcrição de p300-CBP/metabolismo , Processamento de Proteína Pós-Traducional , Histona Acetiltransferases/metabolismo , Histona Acetiltransferases/genética , Lisina/metabolismo
7.
Clin Genitourin Cancer ; 22(4): 102108, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38843766

RESUMO

PURPOSE: The role of elective pelvic nodal irradiation in salvage radiotherapy (sRT) remains controversial. Utilizing 18F-DCFPyL PET/CT, this study aimed to investigate differences in disease distribution after whole pelvic (WPRT) or prostate bed (PBRT) radiotherapy and to identify risk factors for pelvic lymph node (LN) relapse. METHODS: This retrospective study included patients with PSA > 0.1 ng/mL post-radical prostatectomy (RP) or post-RP and sRT who underwent 18F-DCFPyL PET/CT. Disease distribution on 18F-DCFPyL PET/CT after sRT was compared using Chi-square tests. Risk factors were tested for association with pelvic LN relapse after RP and salvage PBRT using logistic regression. RESULTS: 979 18F-DCFPyL PET/CTs performed at our institution between 1/1/2022 - 3/24/2023 were analyzed. There were 246 patients meeting criteria, of which 84 received salvage RT after RP (post-salvage RT group) and 162 received only RP (post-RP group). Salvage PBRT patients (n = 58) had frequent pelvic nodal (53.6%) and nodal-only (42.6%) relapse. Salvage WPRT patients (n = 26) had comparatively lower rates of pelvic nodal (16.7%, p = 0.002) and nodal-only (19.2%, p = 0.04) relapse. The proportion of distant metastases did not differ between the two groups. Multiple patient characteristics, including ISUP grade and seminal vesicle invasion, were associated with pelvic LN disease in the post-RP group. CONCLUSION: At PSA persistence or progression, salvage WPRT resulted in lower rates of nodal involvement than salvage PBRT, but did not reduce distant metastases. Certain risk factors increase the likelihood of pelvic LN relapse after RP and can help inform salvage RT field selection.


Assuntos
Recidiva Local de Neoplasia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prostatectomia , Neoplasias da Próstata , Terapia de Salvação , Humanos , Masculino , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/diagnóstico por imagem , Recidiva Local de Neoplasia/radioterapia , Estudos Retrospectivos , Idoso , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Pessoa de Meia-Idade , Fatores de Risco , Metástase Linfática , Pelve/diagnóstico por imagem , Pelve/efeitos da radiação , Linfonodos/patologia , Linfonodos/diagnóstico por imagem , Linfonodos/efeitos da radiação , Lisina/análogos & derivados , Ureia/análogos & derivados
8.
J Dig Dis ; 25(4): 255-265, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38837552

RESUMO

OBJECTIVES: In this study we aimed to assess the impact of acetylation of hepatocyte nuclear factor 4α (HNF4α) on lysine 458 on the differentiation therapy of hepatocellular carcinoma (HCC). METHODS: Periodic acid-Schiff (PAS) staining, Dil-acetylated low-density lipoprotein (Dil-Ac-LDL) uptake, and senescence-associated ß-galactosidase (SA-ß-gal) activity analysis were performed to assess the differentiation of HCC cells. HNF4α protein was detected by western blot and immunohistochemistry (IHC). The effects of HNF4α-K458 acetylation on HCC malignancy were evaluated in HCC cell lines, a Huh-7 xenograft mouse model, and an orthotopic model. The differential expression genes in Huh-7 xenograft tumors were screened by RNA-sequencing analysis. RESULTS: K458R significantly enhanced the inhibitory effect of HNF4α on the malignancy of HCC cells, whereas K458Q reduced the inhibitory effects of HNF4α. Moreover, K458R promoted, while K458Q decreased, HNF4α-induced HCC cell differentiation. K458R stabilized HNF4α, while K458Q accelerated the degradation of HNF4α via the ubiquitin proteasome system. K458R also enhanced the ability of HNF4α to inhibit cell growth of HCC in the Huh-7 xenograft mouse model and the orthotopic model. RNA-sequencing analysis revealed that inhibiting K458 acetylation enhanced the transcriptional activity of HNF4α without altering the transcriptome induced by HNF4α in HCC. CONCLUSION: Our data revealed that inhibiting K458 acetylation of HNF4α might provide a more promising candidate for differential therapy of HCC.


Assuntos
Carcinoma Hepatocelular , Diferenciação Celular , Fator 4 Nuclear de Hepatócito , Neoplasias Hepáticas , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Acetilação , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Lisina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
9.
BMC Genomics ; 25(1): 557, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834972

RESUMO

Reducing the levels of dietary protein is an effective nutritional approach in lowering feed cost and nitrogen emissions in ruminants. The purpose of this study was to evaluate the effects of dietary Lys/Met ratio in a low protein diet (10%, dry matter basis) on the growth performance and hepatic function (antioxidant capacity, immune status, and glycolytic activity) in Tibetan lambs. Ninety two-month-old rams with an average weight of 15.37 ± 0.92 kg were randomly assigned to LP-L (dietary Lys/Met = 1:1), LP-M (dietary Lys/Met = 2:1) and LP-H (dietary Lys/Met = 3:1) treatments. The trial was conducted over 100 d, including 10 d of adaption to the diets. Hepatic phenotypes, antioxidant capacity, immune status, glycolytic activity and gene expression profiling was detected after the conclusion of the feeding trials. The results showed that the body weight was higher in the LP-L group when compared to those on the LP-M group (P < 0.05). In addition, the activities of the catalase (CAT) and glutathione peroxidase (GSH-Px) in the LP-L group were significantly increased compared with the LP-M group (P < 0.05), while the malondialdehyde (MDA) levels in LP-H group were significantly decreased (P < 0.05). Compared with LP-H group, both hepatic glycogen (P < 0.01) and lactate dehydrogenase (LDH) (P < 0.05) were significantly elevated in LP-L group. For the LP-L group, the hepatocytes were arranged radially with the central vein in the center, and hepatic plates exhibited tight arrangement. Transcriptome analysis identified 29, 179, and 129 differentially expressed genes (DEGs) between the LP-M vs. LP-L, LP-H vs. LP-M, and LP-H vs. LP-L groups, respectively (Q-values < 0.05 and |log2Fold Change| > 1). Gene Ontology (GO) and correlation analyses showed that in the LP-L group, core genes (C1QA and JUNB) enriched in oxidoreductase activity were positively correlated with antioxidant indicators, while the MYO9A core gene enriched in the immune response was positively associated with immune indicators, and core genes enriched in molecular function (PDK3 and PDP2) were positively correlated with glycolysis indicators. In summary, low-protein diet with a low Lys/Met ratio (1:1) could reduce the hepatic oxidative stress and improve the glycolytic activity by regulating the expression of related genes of Tibetan sheep.


Assuntos
Antioxidantes , Glicólise , Fígado , Metionina , Animais , Fígado/metabolismo , Fígado/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Antioxidantes/metabolismo , Ovinos , Metionina/farmacologia , Metionina/administração & dosagem , Metionina/metabolismo , Lisina/metabolismo , Dieta com Restrição de Proteínas/veterinária , Suplementos Nutricionais , Ração Animal/análise , Masculino
10.
Artigo em Inglês | MEDLINE | ID: mdl-38862432

RESUMO

Lysine post-translational modifications (PTMs) are widespread and versatile protein PTMs that are involved in diverse biological processes by regulating the fundamental functions of histone and non-histone proteins. Dysregulation of lysine PTMs is implicated in many diseases, and targeting lysine PTM regulatory factors, including writers, erasers, and readers, has become an effective strategy for disease therapy. The continuing development of mass spectrometry (MS) technologies coupled with antibody-based affinity enrichment technologies greatly promotes the discovery and decoding of PTMs. The global characterization of lysine PTMs is crucial for deciphering the regulatory networks, molecular functions, and mechanisms of action of lysine PTMs. In this review, we focus on lysine PTMs, and provide a summary of the regulatory enzymes of diverse lysine PTMs and the proteomics advances in lysine PTMs by MS technologies. We also discuss the types and biological functions of lysine PTM crosstalks on histone and non-histone proteins and current druggable targets of lysine PTM regulatory factors for disease therapy.


Assuntos
Histonas , Lisina , Processamento de Proteína Pós-Traducional , Lisina/metabolismo , Humanos , Histonas/metabolismo , Animais , Proteômica/métodos
11.
FASEB J ; 38(11): e23715, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38837260

RESUMO

Impaired intestinal permeability induces systemic inflammation and metabolic disturbance. The effect of a leaky gut on metabolism in skeletal muscle, a major nutrient consumer, remains unclear. In this study, we aimed to investigate the glucose metabolic function of the whole body and skeletal muscles in a mouse model of diet-induced intestinal barrier dysfunction. At Week 2, we observed higher intestinal permeability in mice fed a titanium dioxide (TiO2)-containing diet than that of mice fed a normal control diet. Subsequently, systemic glucose and insulin tolerance were found to be impaired. In the skeletal muscle, glucose uptake and phosphorylation levels in insulin signaling were lower in the TiO2 group than those in the control group. Additionally, the levels of pro-inflammatory factors were higher in TiO2-fed mice than those in the control group. We observed higher carboxymethyl-lysin (CML) levels in the plasma and intestines of TiO2-fed mice and lower insulin-dependent glucose uptake in CML-treated cultured myotubes than those in the controls. Finally, soluble dietary fiber supplementation improved glucose and insulin intolerance, suppressed plasma CML, and improved intestinal barrier function. These results suggest that an impaired intestinal barrier leads to systemic glucose intolerance, which is associated with glucose metabolism dysfunction in the skeletal muscles due to circulating CML derived from the intestine. This study highlights that the intestinal condition regulates muscle and systemic metabolic health.


Assuntos
Lisina , Músculo Esquelético , Titânio , Animais , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Masculino , Lisina/análogos & derivados , Lisina/metabolismo , Camundongos Endogâmicos C57BL , Aditivos Alimentares/farmacologia , Insulina/sangue , Insulina/metabolismo , Glucose/metabolismo , Intolerância à Glucose/metabolismo , Mucosa Intestinal/metabolismo
12.
Am J Physiol Renal Physiol ; 327(1): F128-F136, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38695076

RESUMO

Acute kidney injury (AKI) is extremely prevalent among hospitalizations and presents a significant risk for the development of chronic kidney disease and increased mortality. Ischemia caused by shock, trauma, and transplant are common causes of AKI. To attenuate ischemic AKI therapeutically, we need a better understanding of the physiological and cellular mechanisms underlying damage. Instances of ischemia are most damaging in proximal tubule epithelial cells (PTECs) where hypoxic signaling cascades, and perhaps more rapidly, posttranslational modifications (PTMs), act in concert to change cellular metabolism. Here, we focus on the effects of the understudied PTM, lysine succinylation. We have previously shown a protective effect of protein hypersuccinylation on PTECs after depletion of the desuccinylase sirtuin5. General trends in the results suggested that hypersuccinylation led to upregulation of peroxisomal activity and was protective against kidney injury. Included in the list of changes was the Parkinson's-related deglycase Park7. There is little known about any links between peroxisome activity and Park7. In this study, we show in vitro and in vivo that Park7 has a crucial role in protection from AKI and upregulated peroxisome activity. These data in combination with published results of Park7's protective role in cardiovascular damage and chronic kidney disease lead us to hypothesize that succinylation of Park7 may ameliorate oxidative damage resulting from AKI and prevent disease progression. This novel mechanism provides a potential therapeutic mechanism that can be targeted.NEW & NOTEWORTHY Succinylation is an understudied posttranslational modification that has been shown to increase peroxisomal activity. Furthermore, increased peroxisomal activity has been shown to reduce oxidative stress and protect proximal tubules after acute kidney injury. Analysis of mass spectrometry succinylomic and proteomic data reveals a novel role for Parkinson's related Park7 in mediating Nrf2 antioxidant response after kidney injury. This novel protection pathway provides new insights for kidney injury prevention and development of novel therapeutics.


Assuntos
Injúria Renal Aguda , Túbulos Renais Proximais , Proteína Desglicase DJ-1 , Animais , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/patologia , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Proteína Desglicase DJ-1/metabolismo , Proteína Desglicase DJ-1/genética , Processamento de Proteína Pós-Traducional , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Masculino , Sirtuínas/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Camundongos , Estresse Oxidativo , Lisina/metabolismo
13.
mBio ; 15(6): e0016224, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38695580

RESUMO

Herpesvirus genomes are maintained as extrachromosomal plasmids within the nuclei of infected cells. Some herpesviruses persist within dividing cells, putting the viral genome at risk of being lost to the cytoplasm during mitosis because karyokinesis (nuclear division) requires nuclear envelope breakdown. Oncogenic herpesviruses (and papillomaviruses) avoid genome loss during mitosis by tethering their genomes to cellular chromosomes, thereby ensuring viral genome uptake into newly formed nuclei. These viruses use viral proteins with DNA- and chromatin-binding capabilities to physically link viral and cellular genomes together in a process called tethering. The known viral tethering proteins of human papillomavirus (E2), Epstein-Barr virus (EBNA1), and Kaposi's sarcoma-associated herpesvirus (LANA) each contain two independent domains required for genome tethering, one that binds sequence specifically to the viral genome and another that binds to cellular chromatin. This latter domain is called a chromatin tethering domain (CTD). The human cytomegalovirus UL123 gene encodes a CTD that is required for the virus to productively infect dividing fibroblast cells within the S phase of the cell cycle, presumably by tethering the viral genome to cellular chromosomes during mitosis. The CTD-containing UL123 gene product that supports S-phase infections is the IE19 protein. Here, we define two motifs in IE19 required for S-phase infections: an N-terminal triple lysine motif and a C-terminal nucleosome-binding motif within the CTD.IMPORTANCEThe IE19 protein encoded by human cytomegalovirus (HCMV) is required for S-phase infection of dividing cells, likely because it tethers the viral genome to cellular chromosomes, thereby allowing them to survive mitosis. The mechanism through which IE19 tethers viral genomes to cellular chromosomes is not understood. For human papillomavirus, Epstein-Barr virus, and Kaposi's sarcoma-associated herpesvirus, viral genome tethering is required for persistence (latency) and pathogenesis (oncogenesis). Like these viruses, HCMV also achieves latency, and it modulates the properties of glioblastoma multiforme tumors. Therefore, defining the mechanism through which IE19 tethers viral genomes to cellular chromosomes may help us understand, and ultimately combat or control, HCMV latency and oncomodulation.


Assuntos
Citomegalovirus , Nucleossomos , Humanos , Citomegalovirus/genética , Citomegalovirus/metabolismo , Citomegalovirus/fisiologia , Nucleossomos/metabolismo , Nucleossomos/genética , Fase S , Lisina/metabolismo , Lisina/genética , Infecções por Citomegalovirus/virologia , Infecções por Citomegalovirus/metabolismo , Proteínas Virais/metabolismo , Proteínas Virais/genética , Ligação Proteica , Proteínas Imediatamente Precoces/metabolismo , Proteínas Imediatamente Precoces/genética , Motivos de Aminoácidos
14.
Cell Signal ; 120: 111211, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38705504

RESUMO

Vascular calcification (VC) is a characteristic feature in patients with diabetes mellitus (DM) and is closely associated with the osteogenic differentiation of vascular smooth muscle cells (VSMCs). Ubiquitin-Specific Protease 10 (USP10) has been shown to regulate multiple cellular processes; however, its relationship with diabetic VC remains unclear. This study aims to elucidate the role of USP10 in VC development and the underlying regulatory mechanisms. Nε-carboxymethyl lysine (CML) was significantly increased in calcified ateries from diabetic atherosclerosis ApoE-/- mice fed with high-fat diets. CML downregulated USP10 expression in VSMCs and calcified mice coronary arteries, as assessd by Western blotting, RT-qPCR,immunofluorescence and immunohistochemistry. Loss-and gain-of-function experiments were conducted both in vitro and in vivo to verify the biological functions of USP10. Ectopic expression of USP10 mitigated the severity of VC. With regard to the mechanism, the interaction between USP10 and AMPKα was investigated through double-label immunofluorescence and Co-immunoprecipitation. In vitro ubiquitination assay revealed that USP10 was capable of mediating AMPKα ubiquitination and caused increased AMPKα phosphorylation level at Thr172. Moreover, the anticalcification effect of USP10 was reversed by pharmacological inhibition of AMPK signaling pathway. The current fundings suggest an important role of USP10 in diabetic VC progression, at least in part, via mediating the ubiquitination and activation of AMPKα. USP10 may serve as a novel therapeutic target for the treatment of diabetic VC.


Assuntos
Proteínas Quinases Ativadas por AMP , Aterosclerose , Lisina , Ubiquitina Tiolesterase , Calcificação Vascular , Animais , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genética , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia , Camundongos , Aterosclerose/metabolismo , Aterosclerose/patologia , Lisina/metabolismo , Lisina/análogos & derivados , Proteínas Quinases Ativadas por AMP/metabolismo , Masculino , Ubiquitinação , Camundongos Endogâmicos C57BL , Humanos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia
15.
Clin Nucl Med ; 49(7): e338-e339, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38739487

RESUMO

ABSTRACT: Peripheral T-cell lymphomas are a heterogenous group of lymphomas with a high rate of extranodal disease. We present a case of increased 18 F-DCFPyL uptake in peripheral T-cell lymphoma of subcutaneous tissue and bone. Familiarity with the increased 18 F-DCFPyL uptake and extranodal presentation of peripheral T-cell lymphomas can avoid misinterpretation for metastatic disease.


Assuntos
Antígenos de Superfície , Glutamato Carboxipeptidase II , Linfoma de Células T Periférico , Lisina , Humanos , Linfoma de Células T Periférico/diagnóstico por imagem , Linfoma de Células T Periférico/tratamento farmacológico , Glutamato Carboxipeptidase II/metabolismo , Masculino , Lisina/análogos & derivados , Lisina/metabolismo , Antígenos de Superfície/metabolismo , Ureia/análogos & derivados , Ureia/farmacologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Transporte Biológico , Pessoa de Meia-Idade
16.
Cell Signal ; 120: 111228, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38750680

RESUMO

Cancer cells tend to live in hypoxic environment characterized by enhanced glycolysis and accumulation of lactate. Intracellular lactate is shown to drive a novel type of post-translational modification (PTM), lysine lactylation (Kla). Kla has been confirmed to affect the malignant progression of tumors such as hepatocellular carcinoma (HCC) and colon cancer, whereas the global lactylomic profiling of oral squamous cell carcinoma (OSCC) is unclear. Here, the integrative lactylome and proteome analyses by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified 1011 Kla sites within 532 proteins and 1197 Kla sites within 608 proteins in SCC25 cells under normoxic and hypoxic environments, respectively. Among these lactylated proteins, histones accounted for only a small fraction, suggesting the presence of Kla modification of OSCC in a large number of non-histone proteins. Notably, Kla preferred to enrich in spliceosome, ribosome and glycolysis/gluconeogenesis pathway in both normoxic and hypoxic cultures. Compared with normoxia, 589 differential proteins with 898 differentially lactylated sites were detected under hypoxia, which were mainly associated with the glycolysis/gluconeogenesis pathway by KEGG analysis. Importantly, we verified the presence of lactylation modification in the spliceosomal proteins hnRNPA1, SF3A1, hnRNPU and SLU7, as well as in glycolytic enzyme PFKP. In addition, the differential alternative splicing analysis described the divergence of pre-mRNA splicing patterns in the presence or absence of sodium lactate and at different oxygen concentrations. Finally, a negative correlation between tissue Kla levels and the prognosis of OSCC patients was revealed by immunohistochemistry. Our study is the first report to elucidate the lactylome and its biological function in OSCC, which deepens our understanding of the mechanisms underlying OSCC progression and provides a novel strategy for targeted therapy for OSCC.


Assuntos
Carcinoma de Células Escamosas , Lisina , Neoplasias Bucais , Processamento de Proteína Pós-Traducional , Humanos , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Lisina/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Hipóxia Celular , Proteoma/metabolismo
17.
Cell Death Dis ; 15(5): 360, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38789414

RESUMO

Disseminated intravascular coagulation (DIC) is considered to be the most common and lethal complication of sepsis. NLR-family pyrin domain-containing-3 (NLRP3) inflammasome plays an important role in host defense against microbial pathogens, and its deregulation may cause coagulation cascade and should be strictly managed. Here, we identified the deubiquitinase YOD1, which played a vital role in regulating coagulation in a NLRP3 inflammasome-dependent manner in sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA). YOD1 interacted with NLRP3 to remove K33-linked ubiquitination of NLRP3 based on its deubiquitinating enzyme activity and specifically inhibited expression of NLRP3 as well as activation of NLRP3 inflammasome. Deficiency of YOD1 expression enhanced NLRP3 inflammasome activation and coagulation both in vitro and in vivo. In addition, pharmacological inhibition of the NLRP3 effectively improved coagulation and alleviated organ injury in Yod1-/- mice infected with MRSA. Thus, our study reported that YOD1 is a key regulator of coagulation during MRSA infection, and provided YOD1 as a potential therapeutic target for the treatment of NLRP3 inflammasome-related diseases, especially MRSA sepsis-induced DIC.


Assuntos
Coagulação Intravascular Disseminada , Inflamassomos , Staphylococcus aureus Resistente à Meticilina , Proteína 3 que Contém Domínio de Pirina da Família NLR , Sepse , Ubiquitinação , Animais , Humanos , Masculino , Camundongos , Coagulação Intravascular Disseminada/metabolismo , Coagulação Intravascular Disseminada/patologia , Coagulação Intravascular Disseminada/microbiologia , Células HEK293 , Inflamassomos/metabolismo , Lisina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sepse/microbiologia , Sepse/complicações , Sepse/metabolismo , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/metabolismo
18.
J Med Chem ; 67(10): 8186-8200, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38733345

RESUMO

The ATPase family AAA+ domain containing 2 (ATAD2) protein and its paralog ATAD2B have a C-terminal bromodomain (BRD) that functions as a reader of acetylated lysine residues on histone proteins. Using a structure-function approach, we investigated the ability of the ATAD2/B BRDs to select acetylated lysine among multiple histone post-translational modifications. The ATAD2B BRD can bind acetylated histone ligands that also contain adjacent methylation or phosphorylation marks, while the presence of these modifications significantly weakened the acetyllysine binding activity of the ATAD2 BRD. Our structural studies provide mechanistic insights into how ATAD2/B BRD-binding pocket residues coordinate the acetyllysine group in the context of adjacent post-translational modifications. Furthermore, we investigated how sequence changes in amino acids of the histone ligands impact the recognition of an adjacent acetyllysine residue. Our study highlights how the interplay between multiple combinations of histone modifications influences the reader activity of the ATAD2/B BRDs, resulting in distinct binding modes.


Assuntos
ATPases Associadas a Diversas Atividades Celulares , Proteínas de Ligação a DNA , Histonas , Lisina , Histonas/metabolismo , Histonas/química , ATPases Associadas a Diversas Atividades Celulares/metabolismo , ATPases Associadas a Diversas Atividades Celulares/química , Humanos , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/química , Lisina/metabolismo , Lisina/química , Acetilação , Processamento de Proteína Pós-Traducional , Adenosina Trifosfatases/metabolismo , Adenosina Trifosfatases/química , Ligação Proteica , Domínios Proteicos , Modelos Moleculares , Sítios de Ligação
19.
J Food Sci ; 89(6): 3455-3468, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38700315

RESUMO

Excessive accumulation of advanced glycation end products (AGEs) in the body is associated with diabetes and its complications. In this study, we aimed to explore the potential and mechanism of coffee leaf extract (CLE) in inhibiting the generation of AGEs and their precursors in an in vitro glycation model using bovine serum albumin and glucose (BSA-Glu) for the first time. High-performance liquid chromatography analysis revealed that CLE prepared with ultrasound pretreatment (CLE-U) contained higher levels of trigonelline, mangiferin, 3,5-dicaffeoylquinic acid, and γ-aminobutyric acid than CLE without ultrasound pretreatment (CLE-NU). The concentrations of these components, along with caffeine and rutin, were dramatically decreased when CLE-U or CLE-NU was incubated with BSA-Glu reaction mixture. Both CLE-U and CLE-NU exhibited a dose-dependent inhibition of fluorescent AGEs, carboxymethyllysine, fructosamine, 5-hydroxymethylfurfural, 3-deoxyglucosone, glyoxal, as well as protein oxidation products. Notably, CLE-U exhibited a higher inhibitory capacity compared to CLE-NU. CLE-U effectively quenched fluorescence intensity and increased the α-helix structure of the BSA-Glu complex. Molecular docking results suggested that the key bioactive compounds present in CLE-U interacted with the arginine residues of BSA, thereby preventing its glycation. Overall, this research sheds light on the possible application of CLE as a functional ingredient in combating diabetes by inhibiting the generation of AGEs.


Assuntos
Produtos Finais de Glicação Avançada , Extratos Vegetais , Folhas de Planta , Soroalbumina Bovina , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Folhas de Planta/química , Soroalbumina Bovina/química , Coffea/química , Alcaloides/farmacologia , Furaldeído/análogos & derivados , Furaldeído/farmacologia , Frutosamina , Cromatografia Líquida de Alta Pressão , Glioxal , Glucose/metabolismo , Simulação de Acoplamento Molecular , Glicosilação/efeitos dos fármacos , Ácido Quínico/análogos & derivados , Ácido Quínico/farmacologia , Rutina/farmacologia , Lisina/análogos & derivados , Cafeína/farmacologia , Desoxiglucose/análogos & derivados , Desoxiglucose/farmacologia , Xantonas
20.
J Anim Sci ; 1022024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38795007

RESUMO

The present study sought to assess the effects of manganese complexes with lysine and glutamic acid (Mn-LG) as manganese (Mn) sources on growth performance, trace element deposition, antioxidant capacity, and metacarpal strength in weaned piglets. The study involved 288 healthy Duroc × Landrace × Yorkshire piglets that were weaned at 25 to 28 d of age and weighed 8.66 ±â€…0.96 kg. These piglets were randomly divided into six groups: a control group (Mn-LG-0, receiving a basal diet without Mn supplementation), a Mn sulfate group (basal diet supplemented with 40 mg·kg-1 diet of Mn, Mn-S-40 group), and four Mn-LG groups (Mn-LG-20, Mn-LG-40, Mn-LG-60, Mn-LG-80, supplemented with 20, 40, 60, and 80 mg·kg-1 Mn from Mn-LG in the basal diet). Grouping began at weaning on the 0th day of the experiment. The corn-soybean-based basal diet during the early (days 0 to 14) and late (days 15 to 42) phases of the experiment contained 20.88 and 30.12 mg·kg-1 Mn, respectively. Blood samples were collected on days 14 and 42, and pigs were sacrificed for sample collection on day 42. The results indicated no significant differences in average daily gain, average daily feed intake, or feed-to-gain ratio among the groups (P > 0.05). The diarrhea rates of all Mn-LG groups and the Mn-S-40 group were significantly lower in the 0 to 14 d and during the entire experimental period than in the Mn-LG-0 group (P < 0.001). The Mn-LG-40 group exhibited a significant increase in liver Mn concentration and serum Mn superoxide dismutase (Mn-SOD) activity on day 42 (P < 0.01), as well as a significant decrease in fecal Mn concentration (P < 0.05), compared to those of the Mn-S-40 group. Significant differences (P < 0.05) were detected in the serum, liver, and fecal Mn concentrations, as well as in the serum and liver Mn-SOD activity, across the different Mn-LG groups. The serum and fecal Mn concentrations and serum Mn-SOD activity increased linearly or quadratically (P < 0.01) with increasing Mn-LG supplementation. No significant differences (P > 0.05) were found in kidney, heart, or metacarpal bone Mn concentrations or in bone strength indices. In summary, compared with the Mn-LG-0 diet, dietary supplementation with Mn-LG enhanced serum Mn deposition and Mn-SOD activity and decreased the incidence of diarrhea. Additionally, the fecal Mn concentration was lower in the Mn-LG group than in the inorganic group at equivalent dosages.


This research explored the effects of a manganese complex containing lysine and glutamic acid (Mn-LG) on various health parameters in weaned piglets. Utilizing samples of 288 piglets, the study investigated how Mn-LG supplementation influences growth performance, Mn deposition and emission, antioxidant capacity, and metacarpal strength. Key findings include an increase in serum Mn levels and Mn superoxide dismutase (Mn-SOD) activity, a reduction in diarrhea incidence, and no significant effects in bone strength indices in piglets receiving Mn-LG. Additionally, the fecal Mn concentration was notably lower in the Mn-LG group than in the group receiving inorganic Mn at equivalent dosages.


Assuntos
Ração Animal , Antioxidantes , Dieta , Suplementos Nutricionais , Ácido Glutâmico , Lisina , Manganês , Animais , Lisina/farmacologia , Lisina/administração & dosagem , Lisina/metabolismo , Ração Animal/análise , Manganês/farmacologia , Manganês/administração & dosagem , Manganês/metabolismo , Dieta/veterinária , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Suplementos Nutricionais/análise , Suínos/crescimento & desenvolvimento , Ácido Glutâmico/farmacologia , Ácido Glutâmico/metabolismo , Masculino , Feminino , Fenômenos Fisiológicos da Nutrição Animal , Desmame , Distribuição Aleatória , Ossos Metacarpais/metabolismo , Ossos Metacarpais/efeitos dos fármacos
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