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2.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(6): 593-598, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34130781

RESUMO

OBJECTIVE: To evaluate the clinical features of preterm infants with a birth weight less than 1 500 g undergoing different intensities of resuscitation. METHODS: A retrospective analysis was performed for the preterm infants with a birth weight less than 1 500 g and a gestational age less than 32 weeks who were treated in the neonatal intensive care unit of 20 hospitals in Jiangsu, China from January 2018 to December 2019. According to the intensity of resuscitation in the delivery room, the infants were divided into three groups:non-tracheal intubation (n=1 184), tracheal intubation (n=166), and extensive cardiopulmonary resuscitation (ECPR; n=116). The three groups were compared in terms of general information and clinical outcomes. RESULTS: Compared with the non-tracheal intubation group, the tracheal intubation and ECPR groups had significantly lower rates of cesarean section and use of antenatal corticosteroid (P < 0.05). As the intensity of resuscitation increased, the Apgar scores at 1 minute and 5 minutes gradually decreased (P < 0.05), and the proportion of infants with Apgar scores of 0 to 3 at 1 minute and 5 minutes gradually increased (P < 0.05). Compared with the non-tracheal intubation group, the tracheal intubation and ECPR groups had significantly higher mortality rate and incidence rates of moderate-severe bronchopulmonary dysplasia and serious complications (P < 0.05). The incidence rates of grade Ⅲ-Ⅳ intracranial hemorrhage and retinopathy of prematurity (stage Ⅲ or above) in the tracheal intubation group were significantly higher than those in the non-tracheal intubation group (P < 0.05). CONCLUSIONS: For preterm infants with a birth weight less than 1 500 g, the higher intensity of resuscitation in the delivery room is related to lower rate of antenatal corticosteroid therapy, lower gestational age, and lower birth weight. The infants undergoing tracheal intubation or ECRP in the delivery room have an increased incidence rate of adverse clinical outcomes. This suggests that it is important to improve the quality of perinatal management and delivery room resuscitation to improve the prognosis of the infants.


Assuntos
Cesárea , Recém-Nascido Prematuro , Peso ao Nascer , China , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Gravidez , Estudos Retrospectivos
3.
Cell Discov ; 7(1): 37, 2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031383

RESUMO

Treatment options for COVID-19 remain limited, especially during the early or asymptomatic phase. Here, we report a novel SARS-CoV-2 viral replication mechanism mediated by interactions between ACE2 and the epigenetic eraser enzyme LSD1, and its interplay with the nuclear shuttling importin pathway. Recent studies have shown a critical role for the importin pathway in SARS-CoV-2 infection, and many RNA viruses hijack this axis to re-direct host cell transcription. LSD1 colocalized with ACE2 at the cell surface to maintain demethylated SARS-CoV-2 spike receptor-binding domain lysine 31 to promote virus-ACE2 interactions. Two newly developed peptide inhibitors competitively inhibited virus-ACE2 interactions, and demethylase access to significantly inhibit viral replication. Similar to some other predominantly plasma membrane proteins, ACE2 had a novel nuclear function: its cytoplasmic domain harbors a nuclear shuttling domain, which when demethylated by LSD1 promoted importin-α-dependent nuclear ACE2 entry following infection to regulate active transcription. A novel, cell permeable ACE2 peptide inhibitor prevented ACE2 nuclear entry, significantly inhibiting viral replication in SARS-CoV-2-infected cell lines, outperforming other LSD1 inhibitors. These data raise the prospect of post-exposure prophylaxis for SARS-CoV-2, either through repurposed LSD1 inhibitors or new, nuclear-specific ACE2 inhibitors.

4.
Front Immunol ; 11: 1228, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32612611

RESUMO

Lysine specific demethylase 1 (LSD1) is a key epigenetic eraser enzyme implicated in cancer metastases and recurrence. Nuclear LSD1 phosphorylated at serine 111 (nLSD1p) has been shown to be critical for the development of breast cancer stem cells. Here we show that circulating tumor cells isolated from immunotherapy-resistant metastatic melanoma patients express higher levels of nLSD1p compared to responders, which is associated with co-expression of stem-like, mesenchymal genes. Targeting nLSD1p with selective nLSD1 inhibitors better inhibits the stem-like mesenchymal signature than traditional FAD-specific LSD1 catalytic inhibitors such as GSK2879552. We also demonstrate that nLSD1p is enriched in PD-1+CD8+ T cells from resistant melanoma patients and 4T1 immunotherapy-resistant mice. Targeting the LSD1p nuclear axis induces IFN-γ/TNF-α-expressing CD8+ T cell infiltration into the tumors of 4T1 immunotherapy-resistant mice, which is further augmented by combined immunotherapy. Underpinning these observations, nLSD1p is regulated by the key T cell exhaustion transcription factor EOMES in dysfunctional CD8+ T cells. EOMES co-exists with nLSD1p in PD-1+CD8+ T cells in resistant patients, and nLSD1p regulates EOMES nuclear dynamics via demethylation/acetylation switching of critical EOMES residues. Using novel antibodies to target these post-translational modifications, we show that EOMES demethylation/acetylation is reciprocally expressed in resistant and responder patients. Overall, we show for the first time that dual inhibition of metastatic cancer cells and re-invigoration of the immune system requires LSD1 inhibitors that target the nLSD1p axis.


Assuntos
Reprogramação Celular/efeitos dos fármacos , Reprogramação Celular/genética , Histona Desmetilases/genética , Neoplasias/etiologia , Proteínas com Domínio T/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Animais , Biomarcadores , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Feminino , Citometria de Fluxo , Imunofluorescência , Expressão Gênica , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Histona Desmetilases/metabolismo , Humanos , Imunoterapia , Camundongos , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Proteínas com Domínio T/genética , Linfócitos T/imunologia , Resultado do Tratamento
5.
BMC Immunol ; 21(1): 22, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32316916

RESUMO

BACKGROUND: Cancer cells subvert natural immunosuppression by upregulating the expression of checkpoint proteins and their ligands. For example, tumor cells expressing programmed death-ligand 1 (PD-L1) induce immune cell tolerance to cancers, thereby facilitating tumor progression. The recent clinical success of immunotherapy, particularly checkpoint blockade, represents a significant advance in cancer therapy. However, many cancers develop resistance to immunotherapies, and the underlying mechanisms and how these might be exploited to overcome resistance still need to be determined. METHODS: T cell dysfunction, in part caused by chronic T cell receptor stimulation, diminishes the capacity for durable responses to checkpoint blockade. Furthermore, T cell populations are phenotypically and functionally heterogeneous, resulting in varying responses to checkpoint blockade. Recent molecular studies of T cell heterogeneity have shown that checkpoint blockade on its own does not alter the epigenetic landscape of T cells, despite epigenetic changes governing T cell phenotype. CONCLUSION: Here we argue that epigenetic modifiers can be used to prime and sensitize T cells to immunotherapy. Administering epitherapy in conjunction with checkpoint blockade could decrease T cell exhaustion and immunotherapy resistance in many cancer types.


Assuntos
Epigênese Genética/imunologia , Inibidores de Checkpoint Imunológico/imunologia , Linfócitos T/imunologia , Animais , Antígeno B7-H1/imunologia , Humanos , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia
6.
Neural Regen Res ; 14(4): 642-648, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30632504

RESUMO

Resting-state functional magnetic resonance imaging has revealed disrupted brain network connectivity in adults and teenagers with cerebral palsy. However, the specific brain networks implicated in neonatal cases remain poorly understood. In this study, we recruited 14 term-born infants with mild hypoxic ischemic encephalopathy and 14 term-born infants with severe hypoxic ischemic encephalopathy from Changzhou Children's Hospital, China. Resting-state functional magnetic resonance imaging data showed efficient small-world organization in whole-brain networks in both the mild and severe hypoxic ischemic encephalopathy groups. However, compared with the mild hypoxic ischemic encephalopathy group, the severe hypoxic ischemic encephalopathy group exhibited decreased local efficiency and a low clustering coefficient. The distribution of hub regions in the functional networks had fewer nodes in the severe hypoxic ischemic encephalopathy group compared with the mild hypoxic ischemic encephalopathy group. Moreover, nodal efficiency was reduced in the left rolandic operculum, left supramarginal gyrus, bilateral superior temporal gyrus, and right middle temporal gyrus. These results suggest that the topological structure of the resting state functional network in children with severe hypoxic ischemic encephalopathy is clearly distinct from that in children with mild hypoxic ischemic encephalopathy, and may be associated with impaired language, motion, and cognition. These data indicate that it may be possible to make early predictions regarding brain development in children with severe hypoxic ischemic encephalopathy, enabling early interventions targeting brain function. This study was approved by the Regional Ethics Review Boards of the Changzhou Children's Hospital (approval No. 2013-001) on January 31, 2013. Informed consent was obtained from the family members of the children. The trial was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR1800016409) and the protocol version is 1.0.

7.
Blood Adv ; 2(6): 656-668, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29563122

RESUMO

Immune reconstitution following hematopoietic stem cell transplantation (HSCT) is critical in preventing harmful sequelae in recipients with cytomegalovirus (CMV) infection. To understand the molecular mechanisms underlying immune reconstitution kinetics, we profiled the transcriptome-chromatin accessibility landscape of CMV-specific CD8+ T cells from HCST recipients with different immune reconstitution efficiencies. CMV-specific T cells from HSCT recipients with stable antiviral immunity expressed higher levels of interferon/defense response and cell cycle genes in an interconnected network involving PI3KCG, STAT5B, NFAT, RBPJ, and lower HDAC6, increasing chromatin accessibility at the enhancer regions of immune and T-cell receptor signaling pathway genes. By contrast, the transcriptional and epigenomic signatures of CMV-specific T cells from HSCT recipients with unstable immune reconstitution showed commonalities with T-cell responses in other nonresolving chronic infections. These signatures included higher levels of EGR and KLF factors that, along with lower JARID2 expression, maintained higher accessibility at promoter and CpG-rich regions of genes associated with apoptosis. Furthermore, epigenetic targeting via inhibition of HDAC6 or JARID2 enhanced the transcription of genes associated with differential responses, suggesting that drugs targeting epigenomic modifiers may have therapeutic potential for enhancing immune reconstitution in HSCT recipients. Taken together, these analyses demonstrate that transcription factors and chromatin modulators create different chromatin accessibility landscapes in T cells of HSCT recipients that not only affect immediate gene expression but also differentially prime cells for responses to additional signals. Epigenetic therapy may be a promising strategy to promote immune reconstitution in HSCT recipients.


Assuntos
Reprogramação Celular/genética , Reprogramação Celular/imunologia , Epigênese Genética , Reconstituição Imune , Linfócitos T/imunologia , Linfócitos T/metabolismo , Montagem e Desmontagem da Cromatina , Citomegalovirus/imunologia , Infecções por Citomegalovirus/etiologia , Regulação da Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Especificidade do Receptor de Antígeno de Linfócitos T , Fatores de Transcrição/metabolismo , Transcriptoma , Transplantados , Replicação Viral
8.
Neural Regen Res ; 12(4): 603-609, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28553341

RESUMO

With improvements in care of at-risk neonates, more and more children survive. This makes it increasingly important to assess, soon after birth, the prognosis of children with hypoxic-ischemic encephalopathy. Computed tomography, ultrasound, and conventional magnetic resonance imaging are helpful to diagnose brain injury, but cannot quantify white matter damage. In this study, ten full-term infants without brain injury and twenty-two full-term neonates with hypoxic-ischemic encephalopathy (14 moderate cases and 8 severe cases) underwent diffusion tensor imaging to assess its feasibility in evaluating white matter damage in this condition. Results demonstrated that fractional anisotropy, voxel volume, and number of fiber bundles were different in some brain areas between infants with brain injury and those without brain injury. The correlation between fractional anisotropy values and neonatal behavioral neurological assessment scores was closest in the posterior limbs of the internal capsule. We conclude that diffusion tensor imaging can quantify white matter injury in neonates with hypoxic-ischemic encephalopathy.

9.
Sci Rep ; 7: 44825, 2017 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-28317936

RESUMO

Memory T cells exhibit transcriptional memory and "remember" their previous pathogenic encounter to increase transcription on re-infection. However, how this transcriptional priming response is regulated is unknown. Here we performed global FAIRE-seq profiling of chromatin accessibility in a human T cell transcriptional memory model. Primary activation induced persistent accessibility changes, and secondary activation induced secondary-specific opening of previously less accessible regions associated with enhanced expression of memory-responsive genes. Increased accessibility occurred largely in distal regulatory regions and was associated with increased histone acetylation and relative H3.3 deposition. The enhanced re-stimulation response was linked to the strength of initial PKC-induced signalling, and PKC-sensitive increases in accessibility upon initial stimulation showed higher accessibility on re-stimulation. While accessibility maintenance was associated with ETS-1, accessibility at re-stimulation-specific regions was linked to NFAT, especially in combination with ETS-1, EGR, GATA, NFκB, and NR4A. Furthermore, NFATC1 was directly regulated by ETS-1 at an enhancer region. In contrast to the factors that increased accessibility, signalling from bHLH and ZEB family members enhanced decreased accessibility upon re-stimulation. Interplay between distal regulatory elements, accessibility, and the combined action of sequence-specific transcription factors allows transcriptional memory-responsive genes to "remember" their initial environmental encounter.


Assuntos
Montagem e Desmontagem da Cromatina , Cromatina/genética , Memória Imunológica/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcrição Genética , Acetilação , Sítios de Ligação , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Fatores de Transcrição GATA/metabolismo , Perfilação da Expressão Gênica , Histonas/metabolismo , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Fatores de Transcrição NFATC/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica
10.
Oncotarget ; 7(31): 49027-49041, 2016 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-27448985

RESUMO

The urotensin II/urotensin receptor (UII/UT) system can mediate inflammatory liver injury in acute liver failure (ALF); however; the related mechanism is not clear. In this study, we confirmed that lipopolysaccharide/D-galactosamine (LPS/D-GalN) induced up-regulation of liver interferon regulatory factor 3 (IRF3) in ALF mice, whereas the UT antagonist urantide inhibited the up-regulated liver IRF3. LPS stimulation induced IRF3 transcription and nuclear translocation and promoted the secretion of interleukin-6 (IL-6), interferon (IFN)-ß, and IFN-γ in Kupffer cells (KCs); these effects in LPS-stimulated KCs were inhibited by urantide. Knockdown of IRF3 using an adenovirus expressing an IRF3 shRNA inhibited IFN-ß transcription and secretion as well as tumor necrosis factor (TNF)-α and IL-1ß secretion from LPS-stimulated KCs; additionally, IL-10 transcription and secretion were promoted in response to LPS. However, LPS-stimulated TNF-α and IL-1ß mRNA was not affected in the KCs. The IRF3 shRNA also did not have a significant effect on the NF-κB p65 subunit and p38MAPK protein phosphorylation levels in the nuclei of LPS-stimulated KCs. Therefore, IRF3 expression and activation depended on the signal transduction of the UII/UT system, and played important roles in UII/UT-mediated immune inflammatory injury in the liver but did not affect NF-κB and p38 MAPK activity.


Assuntos
Inflamação , Fator Regulador 3 de Interferon/metabolismo , Falência Hepática Aguda/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Urotensinas/metabolismo , Transporte Ativo do Núcleo Celular , Adenoviridae , Animais , Galactosamina/metabolismo , Interferon beta/metabolismo , Interferon gama/metabolismo , Interleucina-6/metabolismo , Macrófagos do Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fragmentos de Peptídeos/química , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Transcrição RelA/metabolismo , Urotensinas/química , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
J Cell Sci ; 129(12): 2448-61, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27149922

RESUMO

Memory T cells are characterized by their rapid transcriptional programs upon re-stimulation. This transcriptional memory response is facilitated by permissive chromatin, but exactly how the permissive epigenetic landscape in memory T cells integrates incoming stimulatory signals remains poorly understood. By genome-wide ChIP-sequencing ex vivo human CD4(+) T cells, here, we show that the signaling enzyme, protein kinase C theta (PKC-θ) directly relays stimulatory signals to chromatin by binding to transcriptional-memory-responsive genes to induce transcriptional activation. Flanked by permissive histone modifications, these PKC-enriched regions are significantly enriched with NF-κB motifs in ex vivo bulk and vaccinia-responsive human memory CD4(+) T cells. Within the nucleus, PKC-θ catalytic activity maintains the Ser536 phosphorylation on the p65 subunit of NF-κB (also known as RelA) and can directly influence chromatin accessibility at transcriptional memory genes by regulating H2B deposition through Ser32 phosphorylation. Furthermore, using a cytoplasm-restricted PKC-θ mutant, we highlight that chromatin-anchored PKC-θ integrates activating signals at the chromatin template to elicit transcriptional memory responses in human memory T cells.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Núcleo Celular/enzimologia , Histonas/metabolismo , Memória Imunológica/genética , Isoenzimas/metabolismo , Proteína Quinase C/metabolismo , Fator de Transcrição RelA/metabolismo , Transcrição Genética , Sequência de Aminoácidos , Cromatina/metabolismo , Regulação da Expressão Gênica , Histonas/química , Humanos , Células Jurkat , Fosforilação , Fosfosserina/metabolismo , Proteína Quinase C-theta , Transdução de Sinais
12.
Artigo em Inglês | MEDLINE | ID: mdl-27087823

RESUMO

The present study aimed to assess the effects and mechanisms of genistin in the rat model of myocardial ischemia reperfusion injury. The rat hearts were exposed to the left anterior descending coronary artery (LAD) ligation for 30 min followed by 1 h of reperfusion. In the rat of myocardial ischemia/reperfusion (MI/R), it was found that genistin pretreatment reduced myocardial infarct size, improved the heart rate, and decreased creatine kinase (CK) and lactate dehydrogenase (LDH) levels in coronary flow. This pretreatment also increased catalase (CAT), superoxide dismutase (SOD) activities but decreased glutathione (GSH), malondialdehyde (MDA) levels. Furthermore, we determined that genistin can ameliorate the impaired mitochondrial morphology and oxidation system; interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α) levels were also recovered. Besides, related-proteins of nuclear factor kappa-B (NF-κB) signal pathway activated by P2X7 were investigated to determine the molecular mechanism of genistin and their expressions were measured by western blot. These results presented here demonstrated that genistin enhanced the protective effect on the rats with myocardial ischemia reperfusion injury. Therefore, the cardioprotective effects of genistin may rely on its antioxidant and anti-inflammatory activities via suppression of P2X7/NF-κB pathways.

13.
Front Immunol ; 6: 530, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26528291

RESUMO

One of the major goals in immunology research is to understand the regulatory mechanisms that underpin the rapid switch on/off of robust and efficient effector (Teffs) or regulatory (Tregs) T-cell responses. Understanding the molecular mechanisms underlying the regulation of such responses is critical for the development of effective therapies. T-cell activation involves the engagement of T-cell receptor and co-stimulatory signals, but the subsequent recruitment of serine/threonine-specific protein Kinase C-theta (PKC-θ) to the immunological synapse (IS) is instrumental for the formation of signaling complexes, which ultimately lead to a transcriptional network in T cells. Recent studies demonstrated that major differences between Teffs and Tregs occurred at the IS where its formation induces altered signaling pathways in Tregs. These pathways are characterized by reduced recruitment of PKC-θ, suggesting that PKC-θ inhibits Tregs suppressive function in a negative feedback loop. As the balance of Teffs and Tregs has been shown to be central in several diseases, it was not surprising that some studies revealed that PKC-θ plays a major role in the regulation of this balance. This review will examine recent knowledge on the role of PKC-θ in T-cell transcriptional responses and how this protein can impact on the function of both Tregs and Teffs.

14.
BMC Immunol ; 16: 27, 2015 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-25943594

RESUMO

BACKGROUND: Immunological memory is the ability of the immune system to respond more rapidly and effectively to previously encountered pathogens, a key feature of adaptive immunity. The capacity of memory T cells to "remember" previous cellular responses to specific antigens ultimately resides in their unique patterns of gene expression. Following re-exposure to an antigen, previously activated genes are transcribed more rapidly and robustly in memory T cells compared to their naïve counterparts. The ability for cells to remember past transcriptional responses is termed "adaptive transcriptional memory". RESULTS: Recent global epigenome studies suggest that epigenetic mechanisms are central to establishing and maintaining transcriptional memory, with elegant studies in model organisms providing tantalizing insights into the epigenetic programs that contribute to adaptive immunity. These epigenetic mechanisms are diverse, and include not only classical acetylation and methylation events, but also exciting and less well-known mechanisms involving histone structure, upstream signalling pathways, and nuclear localisation of genomic regions. CONCLUSIONS: Current global health challenges in areas such as tuberculosis and influenza demand not only more effective and safer vaccines, but also vaccines for a wider range of health priorities, including HIV, cancer, and emerging pathogens such as Ebola. Understanding the multi-layered epigenetic mechanisms that underpin the rapid recall responses of memory T cells following reactivation is a critical component of this development pathway.


Assuntos
Epigênese Genética , Memória Imunológica/genética , Linfócitos T/metabolismo , Transcrição Genética , Animais , Cromatina/metabolismo , Histonas/metabolismo , Humanos
15.
PLoS One ; 10(3): e0121383, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25803040

RESUMO

The urotensin II (UII)/UII receptor (UT) system is closely related to immune inflammation. In acute liver failure (ALF), the UII/UT system can promote the production and release of proinflammatory cytokines, inducing an inflammatory injury response in liver tissue. However, the mechanism by which the hepatic UII/UT system promotes proinflammatory cytokine production and release is not clear. To solve this problem, we used primary Kupffer cells (KCs) as the model system in the current study. The results showed that after lipopolysaccharide (LPS) stimulation, KCs showed significantly increased expression and release of UII/UT and proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß). Pretreatment with urantide, which is a UT receptor antagonist, significantly inhibited the LPS-stimulated expression and release of UII/UT, TNF-α, and IL-1ß by KCs. In addition, LPS stimulation induced nuclear p38 mitogen-activated protein kinase (MAPK) protein phosphorylation and expression of the nuclear nuclear factor κB (NF-κB) p65 subunit in KCs and enhanced the binding activity of NF-κB to DNA molecules, whereas urantide pretreatment significantly inhibited the LPS-stimulated nuclear expression and activity of these molecules in KCs. Therefore, our conclusion is that the UII/UT system mediates LPS-stimulated production and release of proinflammatory cytokine by KCs, and this mediating effect at least partially relies on the inflammatory signaling pathway molecules p38 MAPK and NF-κB.


Assuntos
Citocinas/metabolismo , Macrófagos do Fígado/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , NF-kappa B/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Urotensinas/metabolismo , Análise de Variância , Animais , Western Blotting , Primers do DNA/genética , Ensaio de Desvio de Mobilidade Eletroforética , Interleucina-1beta/metabolismo , Macrófagos do Fígado/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Masculino , Fragmentos de Peptídeos/farmacologia , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/metabolismo , Urotensinas/farmacologia
16.
World J Gastroenterol ; 21(11): 3239-44, 2015 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-25805930

RESUMO

AIM: To investigate urotensin-II (UII) and its effects on tumor necrosis factor (TNF)-α and interleukin (IL)-1ß in early acute liver failure (ALF). METHODS: We investigated the time-dependent alteration in UII levels and its effects on TNF-α and IL-1ß in liver and blood in the early stage of lipopolysaccharide/D-galactosamine-induced ALF. RESULTS: After lipopolysaccharide/D-galactosamine challenge, UII rose very rapidly and reached a maximal level 0.5 h, and the level remained significantly elevated after 2 h (P < 0.05). Six hours after challenge, UII began to degrade, but remained higher than at 0 h (P < 0.05). Pretreatment with urantide, an inhibitor of the UII receptor, suppressed the degree of UII increase in liver and blood at 6 h after challenge (P < 0.05 vs paired controls). In addition, liver and blood TNF-α increased from 1 to 6 h, and reached a peak at 1 and 2 h, respectively; however, IL-1ß did not rise until 6 h after challenge. Urantide pretreatment inhibited the degree of TNF-α and IL-1ß increase following downregulation of UII post-challenge (all P < 0.05). CONCLUSION: UII plays a role in the pathogenesis and priming of ALF by triggering an inflammatory cascade and driving the early release of cytokines in mice.


Assuntos
Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Falência Hepática Aguda/metabolismo , Fígado/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Urotensinas/metabolismo , Animais , Modelos Animais de Doenças , Galactosamina , Lipopolissacarídeos , Fígado/metabolismo , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/prevenção & controle , Masculino , Camundongos Endogâmicos BALB C , Fragmentos de Peptídeos/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Urotensinas/farmacologia
17.
Mol Cell Biol ; 34(16): 2961-80, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24891615

RESUMO

Epithelial to mesenchymal transition (EMT) is activated during cancer invasion and metastasis, enriches for cancer stem cells (CSCs), and contributes to therapeutic resistance and disease recurrence. Signal transduction kinases play a pivotal role as chromatin-anchored proteins in eukaryotes. Here we report for the first time that protein kinase C-theta (PKC-θ) promotes EMT by acting as a critical chromatin-anchored switch for inducible genes via transforming growth factor ß (TGF-ß) and the key inflammatory regulatory protein NF-κB. Chromatinized PKC-θ exists as an active transcription complex and is required to establish a permissive chromatin state at signature EMT genes. Genome-wide analysis identifies a unique cohort of inducible PKC-θ-sensitive genes that are directly tethered to PKC-θ in the mesenchymal state. Collectively, we show that cross talk between signaling kinases and chromatin is critical for eliciting inducible transcriptional programs that drive mesenchymal differentiation and CSC formation, providing novel mechanisms to target using epigenetic therapy in breast cancer.


Assuntos
Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal/genética , Isoenzimas/genética , Proteína Quinase C/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Antígeno CD24/biossíntese , Antígeno CD24/genética , Diferenciação Celular/genética , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Receptores de Hialuronatos/biossíntese , Receptores de Hialuronatos/genética , Células MCF-7 , Subunidade p50 de NF-kappa B/biossíntese , Subunidade p50 de NF-kappa B/genética , Invasividade Neoplásica , Metástase Neoplásica , Células-Tronco Neoplásicas/patologia , Proteína Quinase C-theta , Interferência de RNA , RNA Mensageiro/biossíntese , RNA Interferente Pequeno , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Transdução de Sinais/genética , Esferoides Celulares/patologia , Fator de Transcrição RelA/biossíntese , Fator de Transcrição RelA/genética , Fator de Crescimento Transformador beta/genética
18.
Zhonghua Yi Xue Za Zhi ; 93(24): 1881-5, 2013 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-24124739

RESUMO

OBJECTIVE: To explore the pathophysiological changes in the functional connectivity of posterior cingulate cortex (PCC) with other brain regions in children with attention-deficit or hyperactivity disorder (ADHD) on resting-state functional magnetic resonance imaging(fMRI) and explore the neural mechanisms of ADHD at the point of relationships between brain regions. METHODS: Thirty children with ADHD from the Third Affiliated Hospital of Soochow University from June 2008 to April 2010 and another 30 age-and-gender-matched controls from a normal primary school over the same period underwent resting-state fMRI scans. And blood oxygenation level dependent (BOLD) signal was acquired to calculate the functional connectivity of PCC with other brain regions controls. Significant differences of connectivity between groups were analyzed with REST software. RESULTS: The pattern of functional connectivity of PCC for the ADHD group was similar to that of the control group. Significant positive functional connectivity with PCC was observed in the default mode of network (DMN) while negative functional connectivity was present in dorsolateral prefrontal cortex, anterior cingulate, parietal cortex and basal ganglia(all P < 0.05, corrected). Compared to the controls, the ADHD group exhibited decreased positive connectivity with PCC in bilateral medial prefrontal cortex (0.07 ± 0.20 vs 0.33 ± 0.23, t = -5.47), right posterior cingulate gyrus(0.25 ± 0.28 vs 0.48 ± 0.30, t = -3.44), right inferior temporal gyrus (-0.05 ± 0.19 vs 0.22 ± 0.22, t = -4.61) and cerebellar posterior lobe (-0.04 ± 0.21 vs 0.17 ± 0.16, t = -3.99), while decreased negative functional connectivity with PCC was observed in left insula (-0.10 ± 0.26 vs -0.30 ± 0.19, t = 3.71), right inferior parietal lobule (0.02 ± 0.18 vs -0.23 ± 0.17, t = 5.20), left postcentral gyrus (0.08 ± 0.26 vs -0.17 ± 0.25, t = 4.06), left superior temporal gyrus (-0.04 ± 0.25 vs -0.27 ± 0.17, t = 4.27), right superior temporal gyrus (-0.08 ± 0.25 vs -0.31 ± 0.21, t = 3.80) and left fusiform gyrus (-0.01 ± 0.25 vs -0.18 ± 0.17, t = 3.57)(all P < 0.05, corrected). CONCLUSIONS: The connectivity of DMN between brain regions is abnormal in ADHD group. And the strengthen of negative relationship between DMN and task activated network becomes reduced. It is surmised that the decreased internal synchronization of default network and disrupted balance between DMN and prefrontal-parietal attentional networks may be important neural mechanisms of ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Giro do Cíngulo/fisiopatologia , Imageamento por Ressonância Magnética , Adolescente , Estudos de Casos e Controles , Criança , Humanos , Vias Neurais
19.
Zhonghua Yi Xue Za Zhi ; 93(20): 1555-8, 2013 May 28.
Artigo em Chinês | MEDLINE | ID: mdl-24028722

RESUMO

OBJECTIVE: To explore the mathematics cognitive function of children with attention deficit hyperactivity disorder and explore neural mechanisms with event-related potential(ERP) and behaviors. METHODS: Behavior data and ERP elicited by performing mental calculation tasks were recorded in 27 children with ADHD and 29 normal controls from July to October 2012 at Third Affiliated Hospital of Soochow University.The differences of behaviors and N2 component of ERP were compared and analyzed. RESULTS: The reaction time of the children with ADHD were longer than the control group in addition, subtraction and multiplication ((949 ± 144) vs (829 ± 166) ms, (981 ± 129) vs (856 ± 170) ms, (944 ± 136) vs (825 ± 172) ms, all P < 0.05). While the correct rate were less than normal control in all three arithmetic operations (0.80% (0.72%, 0.88%) vs 0.90% (0.85%,0.96%), 0.78% (0.64%,0.85%) vs 0.90% (0.84%,0.93%), 0.86% (0.74%,0.92%) vs 0.93%(0.90%,0.98%), all P < 0.05). N2 component could be elicited by all subjects in forehead. The amplitude of N2 of children with ADHD were significantly lower than control group in all three arithmetic operations at left frontal (F3: (-3.5 ± 5.2) vs (-6.7 ± 3.5)µV, (-3.8 ± 4.0) vs (-7.4 ± 4.5)µV, -5.8 (-7.6,1.6) vs -6.4(-10.3, -4.9) µV, all P < 0.05) and Fz ((-4.3 ± 6.4) vs ( -7.4 ± 4.2) µV, (-5.0 ± 5.4) vs (-7.9 ± 4.6)µV, -5.2(-9.7, -0.6) vs -7.9 (-10.5, -5.1)µV, all P < 0.05), the latency of ADHD group were prolonger than controls in subtraction operations at right and left frontal ((328 ± 36) vs (307 ± 27)ms, 325 (307,354)vs 309 (280, 330)ms) and frontal electrodes ((331 ± 35) vs (311 ± 30) ms, all P < 0.05). In addition and multiplication operations, there was no significant difference in latency (all P > 0.05). CONCLUSIONS: The children with ADHD have weak capacities of inhibition irrelevant information and paying attention to control. Their deficits in mental arithmetics may be due to the difficulties of selecting the best strategy during cognitive tasks.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Cognição , Estudos de Casos e Controles , Criança , Potenciais Evocados , Feminino , Humanos , Masculino , Matemática
20.
Biochem Pharmacol ; 77(8): 1358-63, 2009 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-19426674

RESUMO

Glutathione transferase Zeta (GSTZ1-1) is identical to maleylacetoacetate isomerase and catalyses a significant step in the catabolism of phenylalanine and tyrosine. Exposure of GSTZ1-1 deficient mice to high dietary phenylalanine causes a rapid loss of circulating white blood cells (WBCs). The loss was significant (P<0.05) after 2 days and total WBCs were reduced by 60% after 6 days. The rapid loss of WBCs was attributed to the accumulation of the catabolic intermediates maleylacetoacetate or maleylacetone (MA) in the circulation. Serum from GSTZ1-1 deficient mice treated with phenylalanine was cytotoxic to splenocytes from normal BALB/c mice and direct incubation of normal splenocytes with MA caused a rapid loss of viability. Dichloroacetic acid (DCA) has been used therapeutically to treat lactic acidosis and is potentially of use in cancer chemotherapy. Since DCA can inactivate GSTZ1-1 there is a possibility that long-term treatment of patients with DCA could cause GSTZ1-1 deficiency and susceptibility to oxidative stress and phenylalanine/tyrosine-induced WBC loss. However, although we found that DCA at 200mg/(kg day) causes a severe loss of hepatic GSTZ1-1 activity in BALB/c mice, it did not induce WBC cytotoxicity when combined with high dietary phenylalanine.


Assuntos
Ácido Dicloroacético/efeitos adversos , Glutationa Transferase/deficiência , Leucopenia/induzido quimicamente , Fenilalanina/efeitos adversos , Animais , Sobrevivência Celular , Células Cultivadas , Meios de Cultura , Ácido Dicloroacético/farmacologia , Contagem de Eritrócitos , Glutationa/sangue , Glutationa Transferase/genética , Contagem de Leucócitos , Leucócitos/citologia , Leucopenia/sangue , Leucopenia/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Fenilalanina/sangue , Fenilalanina/farmacologia , Baço/citologia
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