RESUMO
Genome organization can regulate gene expression and promote cell fate transitions. The differentiation of germline stem cells (GSCs) to oocytes in Drosophila involves changes in genome organization mediated by heterochromatin and the nuclear pore complex (NPC). Heterochromatin represses germ cell genes during differentiation, and NPCs anchor these silenced genes to the nuclear periphery, maintaining silencing to allow for oocyte development. Surprisingly, we found that genome organization also contributes to NPC formation, mediated by the transcription factor Stonewall (Stwl). As GSCs differentiate, Stwl accumulates at boundaries between silenced and active gene compartments. Stwl at these boundaries plays a pivotal role in transitioning germ cell genes into a silenced state and activating a group of oocyte genes and nucleoporins (Nups). The upregulation of these Nups during differentiation is crucial for NPC formation and further genome organization. Thus, cross-talk between genome architecture and NPCs is essential for successful cell fate transitions.
Assuntos
Diferenciação Celular , Proteínas de Drosophila , Genoma de Inseto , Poro Nuclear , Oogênese , Animais , Oogênese/genética , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Diferenciação Celular/genética , Poro Nuclear/metabolismo , Poro Nuclear/genética , Genoma de Inseto/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Feminino , Drosophila melanogaster/genética , Oócitos/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Drosophila/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/genéticaRESUMO
Intrinsic complement C3 activity is integral to human T helper type 1 (Th1) and cytotoxic T cell responses. Increased or decreased intracellular C3 results in autoimmunity and infections, respectively. The mechanisms regulating intracellular C3 expression remain undefined. We identified complement, including C3, as among the most significantly enriched biological pathway in tissue-occupying cells. We generated C3-reporter mice and confirmed that C3 expression was a defining feature of tissue-immune cells, including T cells and monocytes, occurred during transendothelial diapedesis, and depended on integrin lymphocyte-function-associated antigen 1 (LFA-1) signals. Immune cells from patients with leukocyte adhesion deficiency type 1 (LAD-1) had reduced C3 transcripts and diminished effector activities, which could be rescued proportionally by intracellular C3 provision. Conversely, increased C3 expression by T cells from arthritis patients correlated with disease severity. Our study defines integrins as key controllers of intracellular complement, demonstrates that perturbations in the LFA-1-C3-axis contribute to primary immunodeficiency, and identifies intracellular C3 as biomarker of severity in autoimmunity.
Assuntos
Complemento C3/imunologia , Integrinas/imunologia , Antígeno-1 Associado à Função Linfocitária/imunologia , Linfócitos/imunologia , Monócitos/imunologia , Migração Transendotelial e Transepitelial/imunologia , Adulto , Idoso , Animais , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Criança , Pré-Escolar , Complemento C3/genética , Complemento C3/metabolismo , Feminino , Humanos , Integrinas/metabolismo , Antígeno-1 Associado à Função Linfocitária/metabolismo , Linfócitos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Monócitos/metabolismo , Transdução de Sinais/imunologiaRESUMO
BACKGROUND: Wellens syndrome complicates acute coronary syndrome and, if unmanaged, can lead to immanent myocardial infarction. This study aimed towards determining the prevalence of Wellens syndrome among acute coronary syndrome patients while focusing on both types and identifying the associated risk factors, then exploring the variation in affected coronary arteries within patients fulfilling Wellens syndrome criteria. METHODS: Implementing a descriptive cross sectional hospital based observational study design, at Ahmed Gasim Teaching Hospital for Cardiac Surgery and Renal Transplantation in Khartoum North, Sudan, the study was conducted following using a non probability convenience sampling of patients fitting the inclusion criteria. Data was collected using closed ended structured questionnaires. Ethical clearance was obtained from relevant authorities. Statistical analysis was done using descriptive and comparative data analysis with the aid of the SPSS software, and STROBE guidelines were followed. RESULTS: A total of 120 patients were included, 70 males and 50 females, majority in their fifth decade. 14 patients had no documented risk factors. 42.5% had STEMI, 34.2% had NSTEMI and 23.3% had unstable angina. Patients fulfilling Wellens syndrome criteria were 18 (15%), 55.6% of them were type A and 44.4% were type B. Most frequently encountered risk factor among Wellens syndrome patients was Diabetes (50%). Out of 16 Wellens syndrome patients who underwent coronary angiography, 50% had mid LAD involvement, most were type A; 25% had proximal LAD involvement and 25% had normal coronary angiography. There was some association between Wellens syndrome and NSTEMI, but no significant association with any specific risk factor. CONCLUSION: Wellens syndrome complicates 15% of acute coronary syndrome patients with a 55.6% possibility of becoming type A, it can present even without a specific predisposing risk factor and coronary angiographic variation other than the proximal part of the LAD artery may occur, including multiple vessels involvement. This is a descriptive cross sectional study conducted at Ahmed Gasim Teaching Hospital in Sudan, to determine the prevalence and risk factors of Wellens syndrome. Data was collected using questionnaires and analyzed with the SPSS software. Out of 120 patients, 14 patients had no documented risk factors. 34.2% had NSTEMI and 23.3% had unstable angina. Patients fulfilling Wellens syndrome criteria were 18 (15%). The commonest risk factor among Wellens syndrome patients was Diabetes (50%). 50% of Wellens syndrome patients had mid LAD involvement. The study concluded that Wellens syndrome is not rare, it can present without specific risk factor and coronary angiographic variation other than the proximal LAD artery can occur.
Assuntos
Síndrome Coronariana Aguda , Diabetes Mellitus , Infarto do Miocárdio sem Supradesnível do Segmento ST , Masculino , Feminino , Humanos , Estudos Transversais , Angiografia Coronária , Síndrome Coronariana Aguda/diagnóstico por imagem , Síndrome Coronariana Aguda/epidemiologia , Eletrocardiografia , Prevalência , Arritmias Cardíacas , Fatores de Risco , Angina InstávelRESUMO
The fourth universal definition of MI defines requires presence of j point elevation in two contiguous leads except v2-3 where the elevation should be equal to or >2 mm in men (2.5 mm in <40 years) and 1.5 mm in women.(1) We present two cases of patients who presented with electrocardiographic manifestations of occlusion of septal perforator of left anterior descending artery and discuss the salient feature of ECG in such patients. We also present the limitations of STEMI criteria given the dynamic nature of acute coronary occlusion and stress on early recognition of this MI.
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Oclusão Coronária , Eletrocardiografia , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Oclusão Coronária/diagnóstico , Angiografia Coronária , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Adulto , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/fisiopatologia , IdosoRESUMO
This systematic review investigates the diagnostic and prognostic utility of coronary flow reserve (CFR) assessment through echocardiography in patients with left bundle branch block (LBBB), a condition known to complicate the clinical evaluation of coronary artery disease (CAD). The literature search was performed on PubMed, EMBASE, Web of Science, Scopus, and Google Scholar, was guided by PRISMA standards up to March 2024, and yielded six observational studies that met inclusion criteria. These studies involved a diverse population of patients with LBBB, employing echocardiographic protocols to clarify the impact of LBBB on coronary flow dynamics. The findings emphasize the importance of CFR in stratifying cardiovascular risk and guiding clinical decision-making in patients with LBBB. Pooled results reveal that patients with LBBB and significant left anterior descending (LAD) artery stenosis exhibited a marked decrease in stress-peak diastolic velocity (MD = -19.03 [-23.58; -14.48] cm/s; p < .0001) and CFR (MD = -.60 [-.71; -.50]; p < .0001), compared to those without significant LAD lesions, suggesting the efficacy of stress echocardiography CFR assessment in the identification of clinically significant CAD among the LBBB population. This review highlights the clinical relevance of echocardiography CFR assessment as a noninvasive tool for evaluating CAD and stratifying risk in the presence of LBBB and underscores the need for standardized protocols in CFR measurement.
Assuntos
Bloqueio de Ramo , Circulação Coronária , Ecocardiografia , Humanos , Bloqueio de Ramo/fisiopatologia , Bloqueio de Ramo/diagnóstico por imagem , Bloqueio de Ramo/complicações , Circulação Coronária/fisiologia , Ecocardiografia/métodos , Reserva Fracionada de Fluxo Miocárdico/fisiologia , Doença da Artéria Coronariana/fisiopatologia , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/complicações , Velocidade do Fluxo Sanguíneo/fisiologia , Vasos Coronários/fisiopatologia , Vasos Coronários/diagnóstico por imagemRESUMO
Roots are the hidden and most important part of plants. They serve as stabilizers and channels for uptaking water and nutrients and play a crucial role in the growth and development of plants. Here, two-dimensional image data were used to identify quantitative trait loci (QTL) controlling root traits in an interspecific mapping population derived from a cross between wild soybean 'PI366121' and cultivar 'Williams 82'. A total of 2830 single-nucleotide polymorphisms were used for genotyping, constructing genetic linkage maps, and analyzing QTLs. Forty-two QTLs were identified on twelve chromosomes, twelve of which were identified as major QTLs, with a phenotypic variation range of 36.12% to 39.11% and a logarithm of odds value range of 12.01 to 17.35. Two significant QTL regions for the average diameter, root volume, and link average diameter root traits were detected on chromosomes 3 and 13, and both wild and cultivated soybeans contributed positive alleles. Six candidate genes, Glyma.03G027500 (transketolase/glycoaldehyde transferase), Glyma.03G014500 (dehydrogenases), Glyma.13G341500 (leucine-rich repeat receptor-like protein kinase), Glyma.13G341400 (AGC kinase family protein), Glyma.13G331900 (60S ribosomal protein), and Glyma.13G333100 (aquaporin transporter) showed higher expression in root tissues based on publicly available transcriptome data. These results will help breeders improve soybean genetic components and enhance soybean root morphological traits using desirable alleles from wild soybeans.
Assuntos
Mapeamento Cromossômico , Glycine max , Raízes de Plantas , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Glycine max/genética , Glycine max/anatomia & histologia , Glycine max/crescimento & desenvolvimento , Raízes de Plantas/genética , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/anatomia & histologia , Mapeamento Cromossômico/métodos , Fenótipo , Cromossomos de Plantas/genética , Ligação Genética , GenótipoRESUMO
BACKGROUND: The optimal management strategy for significant unprotected ostial left anterior descending artery (LAD) disease remains undefined. Merits of the two most common percutaneous approaches are considered in this quantitative synthesis. METHOD: A meta-analysis was performed to compare ostial stenting (OS) and crossover stenting (CS) in the treatment of unprotected ostial LAD stenosis. The primary outcome is the disparity in target lesion revascularisation (TLR). The Mantel-Haenszel method was employed with random effect model, chosen a priori to account for heterogeneity among the included studies. RESULTS: Seven studies comprising 1,181 patients were included in the analyses. Of these, 482 (40.8%) patients underwent CS. Overall, there was a statistically significant trend in favour of CS (odds ratio 0.51, 95% confidence interval 0.30-0.86, p=0.01) with respect to the rate of TLR at follow-up. This remained true when TLR involving the left circumflex artery (LCx) was considered, even when there was a greater need for unintended intervention to the LCx during the index procedure (odds ratio 6.68, 95% confidence interval: 1.69-26.49, p=0.007). Final kissing balloon inflation may reduce the need for acute LCx intervention. Imaging guidance appeared to improve clinical outcomes irrespective of approach chosen. CONCLUSIONS: In the percutaneous management of unprotected ostial LAD disease, CS into the left main coronary artery (LMCA) appeared to reduce future TLR. Integration of intracoronary imaging was pivotal to procedural success. The higher incidence of unintended LCx intervention in the CS arm may be mitigated by routine final kissing balloon inflation, although the long-term implication of this remains unclear. In the absence of randomised trials, clinicians' discretion remains critical.
Assuntos
Intervenção Coronária Percutânea , Humanos , Intervenção Coronária Percutânea/métodos , Vasos Coronários/cirurgia , Vasos Coronários/diagnóstico por imagem , Doença da Artéria Coronariana/cirurgia , Doença da Artéria Coronariana/terapia , Stents , Estenose Coronária/cirurgia , Estenose Coronária/terapia , FemininoRESUMO
In 15 Turkish LAD-1 patients and controls, we assessed the impact of pathogenic ITGB2 mutations on Th17/Treg differentiation and functions, and innate lymphoid cell (ILC) subsets. The percentage of peripheral blood Treg cells, in vitro-generated induced Tregs differentiated from naive CD4+ T cells were decreased despite the elevated absolute counts of CD4+ cells in LAD-1 patients. Serum IL-23 levels were elevated in LAD-1 patients. Post-curdlan stimulation, LAD-1 patient-derived PBMCs produced more IL-17A. Additionally, the percentages of CD18-deficient Th17 cells expanded from total or naïve CD4+ T cells were higher. The blood ILC3 subset was significantly elevated in LAD-1. Finally, LAD-1 PBMCs showed defects in trans-well migration and proliferation and were more resistant to apoptosis. Defects in de novo generation of Tregs from CD18-deficient naïve T cells and elevated Th17s, and ILC3s in LAD-1 patients' peripheral blood suggest a type 3-skewed immunity and may contribute to LAD-1-associated autoimmune symptoms.
Assuntos
Síndrome da Aderência Leucocítica Deficitária , Linfócitos T Reguladores , Humanos , Imunidade Inata , Linfócitos T CD4-Positivos , Células Th17RESUMO
Leukocyte adhesion deficiency (LAD) is an immunodeficiency caused by defects in the adhesion of leukocytes (especially neutrophils) to the blood vessel wall. As a result, patients with LAD suffer from severe bacterial infections and impaired wound healing, accompanied by neutrophilia. In LAD-I, characterized directly after birth by delayed separation of the umbilical cord, mutations are found in ITGB2, the gene that encodes the ß subunit (CD18) of the ß2 integrins. In the rare LAD-II disease, the fucosylation of selectin ligands is disturbed, caused by mutations in SLC35C1, the gene that encodes a GDP-fucose transporter of the Golgi system. LAD-II patients lack the H and Lewis Lea and Leb blood group antigens. Finally, in LAD-III, the conformational activation of the hematopoietically expressed ß integrins is disturbed, leading to leukocyte and platelet dysfunction. This last syndrome is caused by mutations in FERMT3, encoding the kindlin-3 protein in all blood cells, involved in the regulation of ß integrin conformation. This article contains an update of the mutations that we consider to be relevant for the various forms of LAD.
Assuntos
Síndrome da Aderência Leucocítica Deficitária , Humanos , Adesão Celular/genética , Síndrome da Aderência Leucocítica Deficitária/genética , Antígenos CD18/genética , Antígenos CD18/metabolismo , Leucócitos , MutaçãoRESUMO
BACKGROUND: Ladinin-1 (LAD1), an anchoring filament protein, has been associated with several cancer types, including cancers of the colon, lungs, and breast. However, it is still unclear how and why LAD1 causes gastric cancer (GC). METHODS: Multiple in vitro and in vivo, functional gains and loss experiments were carried out in the current study to confirm the function of LAD1. Mass spectrometry was used to find the proteins that interact with LAD1. Immunoprecipitation analyses revealed the mechanism of LAD1 involved in promoting aggressiveness. RESULTS: The results revealed that the LAD1 was overexpressed in GC tissues, and participants with increased LAD1 expression exhibited poorer disease-free survival (DFS) and overall survival (OS). Functionally, LAD1 promotes cellular invasion, migration, proliferation, and chemoresistance in vivo and in vitro in the subcutaneous patient-and cell-derived xenograft (PDX and CDX) tumor models. Mechanistically, LAD1 competitively bound to Vimentin, preventing it from interacting with the E3 ubiquitin ligase macrophage erythroblast attacher (MAEA), which led to a reduction in K48-linked ubiquitination of Vimentin and an increase in Vimentin protein levels in GC cells. CONCLUSIONS: In conclusion, the current investigation indicated that LAD1 has been predicted as a possible prognostic biomarker and therapeutic target for GC due to its ability to suppress Vimentin-MAEA interaction.
Assuntos
Neoplasias Gástricas , Humanos , Animais , Ubiquitina , Vimentina , Ubiquitinação , Mama , Modelos Animais de DoençasRESUMO
In this paper we propose a new robust estimation of precision matrices for high-dimensional data when the number of variables is larger than the sample size. Different from the existing methods in literature, the proposed model combines the technique of modified Cholesky decomposition (MCD) with the robust generalized M-estimators. The MCD reparameterizes a precision matrix and transforms its estimation into solving a series of linear regressions, in which the commonly used robust techniques can be conveniently incorporated. Additionally, the proposed method adopts the model averaging idea to address the ordering issue in the MCD approach, resulting in an accurate estimation for precision matrices. Simulations and real data analysis are conducted to illustrate the merits of the proposed estimator.
Assuntos
Modelos Lineares , Humanos , Tamanho da Amostra , CausalidadeRESUMO
BACKGROUND: There is a paucity of information about the clinical features and angiographic findings in young patients with acute myocardial infarction (MI), especially in the Arab Peninsula countries. OBJECTIVE: The aim of this study was to assess the proposed risk factors, clinical presentation, and angiographic findings of acute myocardial infarction in young adults. METHODS: This prospective study included young (range, 18 to 45 years) patients who presented with acute MI based on clinical evaluation, laboratory investigation, and electrocardiogram, and they underwent a coronary angiography procedure. KEY FINDINGS: Data of 109 patients with a diagnosis of acute MI were collected. Patients' mean age was 39.98 ± 7.52 years (range, 31 to 45 years), and 92.7% (101) were male. Smoking was the highest risk factor in 67% of patients, obesity and overweight in 66%, sedentary lifestyle in 64%, dyslipidaemia in 33%, and hypertension in 28%. Smoking was the most common risk factor for acute MI in males (p = 0.009), whereas sedentary lifestyle was the most common risk factor in females (p = 0.028). Chest pain typical of acute MI was the most common presenting symptom in 96% of patients (p < 0.001). On admission, 96% of patients were conscious, and 95% were oriented. On angiography, the left anterior descending artery (LAD) was affected in 57%, the right coronary artery (RCA) was affected in 42%, and the left circumflex artery (LCX) was affected in 32% of patients. The LAD was severely affected in 44%, the RCA was severely affected in 25.7%, and the LCX was severely affected in 19.26% of patients (p < 0.001). CONCLUSION: Smoking, obesity, sedentary lifestyle, dyslipidaemia, and hypertension were the most common risk factors for acute MI. Smoking was the most common risk factor in males and sedentary lifestyle in females. The LAD was the most commonly affected coronary artery, followed by the RCA and LCX arteries, with the same order for severity of stenosis.
Assuntos
Hipertensão , Infarto do Miocárdio , Feminino , Humanos , Masculino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Estudos Prospectivos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Angiografia Coronária , Hipertensão/complicações , Hipertensão/epidemiologia , Obesidade/complicações , Obesidade/epidemiologiaRESUMO
BACKGROUND AND OBJECTIVE: The usefulness of the mast cell activation test (MAT) in diagnosing patients with uninterpretable basophil activation test (BAT) caused by nonresponding basophils has not yet been addressed. It should be further evaluated if the results of MAT are associated with the severity of the allergic reaction. METHODS: We recruited 39 Hymenoptera venom allergic (HVA) patients, 22 non-sensitized controls, and 37 BAT nonresponding HVA patients. Specific IgE levels for honey bee venom (HBV), yellow jacket venom (YJV) and total IgEs were quantified using the Immulite system. BAT and MAT with LAD2 cells in response to HBV and YJV were performed. RESULTS: We first optimized the susceptibility of LAD2 cells to IgE-mediated degranulation in HVA and showed that prestimulation with IL-33 and IL-6 significantly increased the LAD2 cells´ responsiveness to allergen stimulation (P<0.01). LAD2 MAT results correlated with BAT results, and patients with severe sting reactions (Mueller grades IV or III) had a median 2-fold higher LAD2 MAT than the patients with nonsevere sting reactions (Mueller grades II, I or LLR) (P<0.05). Further, LAD2 MAT provided conclusive results in 54.1% (20 of 37) of HVA patients with nonresponding basophils in the BAT. CONCLUSION: The LAD2 MAT represents a new diagnostic tool for HVA patients with nonresponding basophils. Further, LAD2 MAT can identify patients at risk of severe sting reactions and thus can help guide recommendations for venom immunotherapy and improve the management of patients with HVA.
RESUMO
In view of the significance of circular RNA (circRNA) in multiple carcinogeneses, our study focused on circ_0060937 and investigated its function and molecular mechanism in lung cancer. Quantitative real-time PCR (qPCR) and western blot assays were applied for expression analysis of circ_0060937, miR-1304-5p, LAD1, and several marker proteins. Functional experiments, including colony formation assay, EdU assay, transwell analysis, sphere formation assay, and flow cytometry experiment, were conducted for cell behavior analysis. The putative binding relationship between circ_0060937 and miR-1304-5p was validated by dual-luciferase reporter experiment and pull-down analysis. Animal models were established to ascertain the role of circ_0060937. Upregulation of circ_0060937 was shown in lung cancer tissues and cell lines. Circ_0060937 downregulation repressed A549 and H1299 cell proliferative, migratory, invasive, and sphere formation abilities, and circ_0060937 absence also decelerated tumorigenesis in animal models. Circ_0060937 bound to miR-1304-5p to positively regulate LAD1 expression. The inhibitory effects of circ_0060937 absence on A549 and H1299 cell malignant behaviors were largely reversed by miR-1304-5p inhibition or LAD1 overexpression, hinting that circ_0060937 affected lung cancer progression via modulating the miR-1304-5p/LAD1 axis. Circ_0060937 downregulation decreased the expression of LAD1 by releasing miR-1304-5p to effectively repress lung cancer cell growth and in vivo tumorigenesis.
Assuntos
Neoplasias Pulmonares , MicroRNAs , Animais , Neoplasias Pulmonares/genética , Carcinogênese , Linhagem Celular , Movimento Celular , Proliferação de Células , MicroRNAs/genéticaRESUMO
Anchoring filament protein ladinin-1 (LAD1) codes for an anchor filament protein in the basement membrane. Here, we have aimed to determine its potential role in LUAD. According to the comprehensive analyses conducted in this study, we studied the expression, prognostic significance, function, methylation, copy number variations, and the immune cell infiltration of LAD1 in LUAD. A higher level of LAD1 gene expression was observed in the LUAD tumor tissues compared to the normal lung tissues (p < 0.001). Furthermore, the multivariate analysis indicated that a higher LAD1 gene expression level was the independent prognostic factor. Additionally, the DNA methylation level of the LAD1 was inversely linked to its expression (p < 0.001). We noted that the patients affected due to LAD1 hypomethylation showed a very low overall survival rate compared to the patients with a higher LAD1 methylation score (p < 0.05). Moreover, the results of the immunity analysis indicated that the LAD1 expression might be inversely linked to the immune cell infiltration degree, expression of the infiltrated immune cells, and the PD-L1 levels. Lastly, we supplemented some verification to increase the rigor of the study. The results suggested that high expression of LAD1 may be related to cold tumors. Hence, this indirectly reflects that the immunotherapy effect of LUAD patients with high LAD1 expression might be worse. Based on the role played by the LAD1 in the tumor immune microenvironment, it can be considered a potential biomarker for predicting the immunotherapy response to LUAD.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Variações do Número de Cópias de DNA , Adenocarcinoma de Pulmão/genética , Metilação de DNA , Neoplasias Pulmonares/genética , Microambiente TumoralRESUMO
Safflower (Carthamus tinctorius. L) possesses anti-tumor, anti-thrombotic, anti-oxidative, immunoregulatory, and cardio-cerebral protective effects. It is used clinically for the treatment of cardio-cerebrovascular disease in China. This study aimed to investigate the effects and mechanisms of action of safflower extract on myocardial ischemia-reperfusion (MIR) injury in a left anterior descending (LAD)-ligated model based on integrative pharmacology study and ultra-performance liquid chromatography-quadrupole time-of-flight-tandem mass spectrometer (UPLC-QTOF-MS/MS). Safflower (62.5, 125, 250 mg/kg) was administered immediately before reperfusion. Triphenyl tetrazolium chloride (TTC)/Evans blue, echocardiography, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, lactate dehydrogenase (LDH) ability, and superoxide dismutase (SOD) levels were determined after 24 h of reperfusion. Chemical components were obtained using UPLC-QTOF-MS/MS. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to analyze mRNA and protein levels, respectively. Safflower dose-dependently reduced myocardial infarct size, improved cardiac function, decreased LDH levels, and increased SOD levels in C57/BL6 mice. A total of 11 key components and 31 hub targets were filtered based on the network analysis. Comprehensive analysis indicated that safflower alleviated inflammatory effects by downregulating the expression of NFκB1, IL-6, IL-1ß, IL-18, TNFα, and MCP-1 and upregulating NFκBia, and markedly increased the expression of phosphorylated PI3K, AKT, PKC, and ERK/2, HIF1α, VEGFA, and BCL2, and decreased the level of BAX and phosphorylated p65. Safflower shows a significant cardioprotective effect by activating multiple inflammation-related signaling pathways, including the NFκB, HIF-1α, MAPK, TNF, and PI3K/AKT signaling pathways. These findings provide valuable insights into the clinical applications of safflower.
Assuntos
Carthamus tinctorius , Traumatismo por Reperfusão Miocárdica , Camundongos , Animais , Traumatismo por Reperfusão Miocárdica/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Espectrometria de Massas em Tandem , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Superóxido Dismutase/farmacologia , ApoptoseRESUMO
Heterochromatin and euchromatin form different spatial compartments in the interphase nucleus, with heterochromatin being localized mainly at the nuclear periphery. The mechanisms responsible for peripheral localization of heterochromatin are still not fully understood. The nuclear lamina and nuclear pore complexes were obvious candidates for the role of heterochromatin binders. This review is focused on recent studies showing that heterochromatin interactions with the nuclear lamina and nuclear pore complexes maintain its peripheral localization. Differences in chromatin interactions with the nuclear envelope in cell populations and in individual cells are also discussed.
Assuntos
Lâmina Nuclear , Poro Nuclear , Heterocromatina , Cromatina , Núcleo Celular , Membrana NuclearRESUMO
The oncogenic role of Ladinin-1 (LAD1), an anchoring filament protein, is largely unknown. In this study, we conducted a series of studies on the oncogenic role of LAD1 in lung adenocarcinoma (LUAD). Firstly, we analyzed the aberrant expression of LAD1 in LUAD and its correlation with patient survival, tumor immune infiltration, and the activation of cancer signaling pathways. Furthermore, the relationship between LAD1 expression and K-Ras and EGF signaling activation, tumor cell proliferation, migration, and colony formation was studied by gene knockout/knockout methods. We found that LAD1 was frequently overexpressed in LUAD, and high LAD1 expression predicts a poor prognosis. LAD1 exhibits promoter hypomethylation in LUAD, which may contribute to its mRNA upregulation. Single-sample gene set enrichment analysis (ssGSEA) showed that acquired immunity was negatively correlated with LAD1 expression, which was verified by the downregulated GO terms of "Immunoglobulin receptor binding" and "Immunoglobulin complex circulating" in the LAD1 high-expression group through Gene Set Variation Analysis (GSVA). Notably, the Ras-dependent signature was the most activated signaling in the LAD1 high-expression group, and the phosphorylation of downstream effectors, such as ERK and c-jun, was strongly inhibited by LAD1 deficiency. Moreover, we demonstrated that LAD1 depletion significantly inhibited the proliferation, migration, and cell-cycle progression of LUAD cells and promoted sensitivity to Gefitinib, K-Ras inhibitor, and paclitaxel treatments. We also confirmed that LAD1 deficiency remarkably retarded tumor growth in the xenograft model. Conclusively, LAD1 is a critical prognostic biomarker for LUAD and has potential as an intervention target.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Imunidade Adaptativa , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Carcinogênese , Imunoglobulinas , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genéticaRESUMO
Periodontitis is a common human inflammatory disease. In this condition, microbiota trigger excessive inflammation in oral mucosal tissues surrounding the dentition, resulting in destruction of tooth-supporting structures (connective tissue and bone). While susceptibility factors for common forms of periodontitis are not clearly understood, studies in patients with single genetic defects reveal a critical role for tissue neutrophils in disease susceptibility. Indeed, various genetic defects in the development, egress from the bone marrow, chemotaxis, and extravasation are clearly linked to aggressive/severe periodontitis at an early age. Here, we provide an overview of genetic defects in neutrophil biology that are linked to periodontitis. In particular, we focus on the mechanisms underlying Leukocyte Adhesion Deficiency-I, the prototypic Mendelian defect of impaired neutrophil extravasation and severe periodontitis.
Assuntos
Síndromes de Imunodeficiência/genética , Selectina L/genética , Mutação/genética , Neutrófilos/fisiologia , Periodontite/genética , Animais , Diferenciação Celular , Quimiotaxia , Humanos , Síndromes de Imunodeficiência/imunologia , Periodontite/imunologiaRESUMO
Several models have been used to assess temporal cover change trends by using remote and proximal sensing tools. Particularly, from the point of hydrologic and erosional processes and sustainable land and soil management, it is crucial to determine and understand the variation of protective canopy cover change within a development period. Concordantly, leaf angle distribution (LAD) is a crucial parameter when using the vegetation indices (VIs) to define the radiation reflected by the canopy when estimating the cover-management factor (C-factor). This research aims to assess the C-factor of cultivated lands with sunflower and wheat that have different leaf orientations (planophile and erectophile, respectively) with the help of reduced models of NDVI and LAI for estimating crop-stage SLR values with the help of a stepwise linear regression. Those equations with R-squared values of 0.85 and 0.93 were obtained for sunflower and wheat-planted areas, respectively. The Normalized Difference Vegetation Index (NDVI), one of the two plant indices used in this study, was measured by remote and proximal sensing tools. At the same time, the Leaf Area Index (LAI) was obtained by a proximal hand-held crop sensor alone. Soil loss ratio (SLR) was upscaled for the establishment period (1P) of sunflower and the maturing period (3P) of wheat to present different growth stages simultaneously with plant-specific equations that can be easily adapted to those aforementioned crops instead of doing field measurements with conventional techniques in semi-arid cropping systems.