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1.
Transl Oncol ; 46: 101994, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38776708

RESUMO

Cervical cancer ranks fourth in women in terms of incidence and mortality. The RNA-binding protein YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2) contributes to cancer progression by incompletely understood mechanisms. We show how YTHDF2 controls the fate of cervical cancer cells and whether YTHDF2 could be a valid target for the therapy of cervical cancer. Sphere formation and alkaline phosphatase staining assays were performed to evaluate tumor stemness of cervical cancer cells following YTHDF2 knockdown. Apoptosis was detected by flow cytometry and TUNEL assay. The compounds 4PBA and SP600125 were used to investigate the correlation between JNK, endoplasmic reticulum stress, tumor stemness, and apoptosis. Data from The Cancer Genome Atlas (TCGA) databases and Gene Expression Omnibus (GEO) revealed that GLI family zinc finger 2 (GLI2) might be the target of YTHDF2. The transcription inhibitor actinomycin D and dual-luciferase reporter gene assays were employed to investigate the association between the GLI2 mRNA and YTHDF2. Nude mouse xenografts were generated to assess the effects of YTHDF2 knockdown on cervical cancer growth in vivo. Knockdown of YTHDF2 up-regulated the expression of GLI2, leading to JNK phosphorylation and endoplasmic reticulum stress. These processes inhibited the proliferation of cervical cancer cells and their tumor cell stemness and promotion of apoptosis. In conclusion, the knockdown of YTHDF2 significantly affects the progression of cervical cancer cells, making it a potential target for treating cervical cancer.

2.
Int Immunopharmacol ; 135: 112286, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38776849

RESUMO

Ulcerative colitis (UC) is a subtype of inflammatory bowel disease. Previous studies have suggested a link between senescence process and the body's inflammatory reaction, indicating that senescence may exacerbate UC, yet the relation between UC and senescence remains unclear. Tedizolid Phosphate (TED), a novel oxazolidinone antimicrobial, is indicated in acute bacterial skin infections, its impact on senescence is not known. Our research revealed that the UC inducer dextran sulfate sodium (DSS) triggers senescence in both colon epithelial NCM460 cells and colon tissues, and TED that screened from a compound library demonstrated a strong anti-senescence effect on DSS treated NCM460 cells. As an anti-senescence medication identified in this research, TED efficiently alleviated UC and colonic senescence in mice caused by DSS. By proteomic analysis and experimental validation, we found that DSS significantly inhibits the AMPK signaling pathway, while TED counteracts senescence by restoring AMPK activity. This research verified that the development of UC is accompanied with colon tissue senescence, and TED, an anti-senescence medication, can effectively treat UC caused by DSS and alleviate colon senescence. Our work suggests anti-senescence strategy is an effective approach for UC treatment.

3.
Invest Ophthalmol Vis Sci ; 65(5): 31, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38771572

RESUMO

Purpose: Although effective amblyopia treatments are available, treatment outcome is unpredictable, and the condition recurs in up to 25% of the patients. We aimed to evaluate whether a large-scale quantitative contrast sensitivity function (CSF) data source, coupled with machine learning (ML) algorithms, can predict amblyopia treatment response and recurrence in individuals. Methods: Visual function measures from traditional chart vision acuity (VA) and novel CSF assessments were used as the main predictive variables in the models. Information from 58 potential predictors was extracted to predict treatment response and recurrence. Six ML methods were applied to construct models. The SHapley Additive exPlanations was used to explain the predictions. Results: A total of 2559 consecutive records of 643 patients with amblyopia were eligible for modeling. Combining variables from VA and CSF assessments gave the highest accuracy for treatment response prediction, with the area under the receiver operating characteristic curve (AUC) of 0.863 and 0.815 for outcome predictions after 3 and 6 months, respectively. Variables from the VA assessment alone predicted the treatment response, with AUC values of 0.723 and 0.675 after 3 and 6 months, respectively. Variables from the CSF assessment gave rise to an AUC of 0.909 for recurrence prediction compared to 0.539 for VA assessment alone, and adding VA variables did not improve predictive performance. The interocular differences in CSF features are significant contributors to recurrence risk. Conclusions: Our models showed CSF data could enhance treatment response prediction and accurately predict amblyopia recurrence, which has the potential to guide amblyopia management by enabling patient-tailored decision making.


Assuntos
Ambliopia , Sensibilidades de Contraste , Recidiva , Acuidade Visual , Humanos , Ambliopia/terapia , Ambliopia/fisiopatologia , Ambliopia/diagnóstico , Acuidade Visual/fisiologia , Masculino , Feminino , Sensibilidades de Contraste/fisiologia , Criança , Resultado do Tratamento , Pré-Escolar , Curva ROC , Aprendizado de Máquina , Estudos Retrospectivos , Adolescente , Privação Sensorial , Algoritmos
4.
Asia Pac J Clin Nutr ; 33(2): 247-271, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38794984

RESUMO

BACKGROUND AND OBJECTIVES: Sarcopenia has garnered extensive attention in clinical practice since its high prevalence and significant impact on clinical outcomes. Multiple organizations have published guidance documents on sarcopenia, offering evidence-based recommendations for clinical practice and/or research. We aimed to appraise the methodological quality of the included documents and synthesize available recommendations for the screening, diagnosis, and intervention of sarcopenia. METHODS AND STUDY DESIGN: We conducted a search on PubMed, Embase, Scopus, Cochrane Library, China National Knowledge Infrastructure, guideline database, and guideline organizations and professional societies websites for clinical practices, consensus statements and position papers in terms of sarcopenia, muscle atrophy or muscle loss published before April 17, 2023. The AGREE II instrument was used by three independent reviewers to assess the methodological quality of these documents. RESULTS: Thirty-six guidance documents published between 2010 and 2023 were included. Seven documents fulfilled ≥ 50% of all the AGREE II domains. Seven underwent a Delphi process and six graded the strength of the recommendations. The process of screening (n=21), early diagnosis of sarcopenia (n=12), diagnosis of sarcopenia and severe sarcopenia (n=10), and management (n=21) were increasingly recommended. SARC-F (n=14) was the most recommended screening tool, and the assessment of muscle function was considered the first step in diagnosing sarcopenia. The management strategy for both age-related and disease-related sarcopenia mainly focused on exercise and nutrition intervention. CONCLUSIONS: The guidance documents have provided referential recommendations that have great guiding significance. But the inconsistency in recommendations and variation in methodological rigour suggests that high-quality evidence is lacking yet.


Assuntos
Força Muscular , Músculo Esquelético , Sarcopenia , Sarcopenia/diagnóstico , Sarcopenia/terapia , Humanos , Guias de Prática Clínica como Assunto
5.
BMC Genomics ; 25(1): 460, 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38730330

RESUMO

BACKGROUND: Zingiber officinale Roscoe, colloquially known as ginger, is a crop of significant medicinal and culinary value that frequently encounters adversity stemming from inhospitable environmental conditions. The MYB transcription factors have garnered recognition for their pivotal role in orchestrating a multitude of plant biological pathways. Nevertheless, the enumeration and characterization of the MYBs within Z. officinale Roscoe remains unknown. This study embarks on a genome-wide scrutiny of the MYB gene lineage in ginger, with the aim of cataloging all ZoMYB genes implicated in the biosynthesis of gingerols and curcuminoids, and elucidating their potential regulatory mechanisms in counteracting abiotic stress, thereby influencing ginger growth and development. RESULTS: In this study, we identified an MYB gene family comprising 231 members in ginger genome. This ensemble comprises 74 singular-repeat MYBs (1R-MYB), 156 double-repeat MYBs (R2R3-MYB), and a solitary triple-repeat MYB (R1R2R3-MYB). Moreover, a comprehensive analysis encompassing the sequence features, conserved protein motifs, phylogenetic relationships, chromosome location, and gene duplication events of the ZoMYBs was conducted. We classified ZoMYBs into 37 groups, congruent with the number of conserved domains and gene structure analysis. Additionally, the expression profiles of ZoMYBs during development and under various stresses, including ABA, cold, drought, heat, and salt, were investigated in ginger utilizing both RNA-seq data and qRT-PCR analysis. CONCLUSION: This work provides a comprehensive understanding of the MYB family in ginger and lays the foundation for the future investigation of the potential functions of ZoMYB genes in ginger growth, development and abiotic stress tolerance of ginger.


Assuntos
Família Multigênica , Filogenia , Proteínas de Plantas , Estresse Fisiológico , Fatores de Transcrição , Zingiber officinale , Zingiber officinale/genética , Estresse Fisiológico/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regulação da Expressão Gênica de Plantas
6.
Int J Mol Sci ; 25(10)2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38791126

RESUMO

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common metabolic disease of the liver, characterized by hepatic steatosis in more than 5% of hepatocytes. However, despite the recent approval of the first drug, resmetirom, for the management of metabolic dysfunction-associated steatohepatitis, decades of target exploration and hundreds of clinical trials have failed, highlighting the urgent need to find new druggable targets for the discovery of innovative drug candidates against MASLD. Here, we found that glutathione S-transferase alpha 1 (GSTA1) expression was negatively associated with lipid droplet accumulation in vitro and in vivo. Overexpression of GSTA1 significantly attenuated oleic acid-induced steatosis in hepatocytes or high-fat diet-induced steatosis in the mouse liver. The hepatoprotective and anti-inflammatory drug bicyclol also attenuated steatosis by upregulating GSTA1 expression. A detailed mechanism showed that GSTA1 directly interacts with fatty acid binding protein 1 (FABP1) and facilitates the degradation of FABP1, thereby inhibiting intracellular triglyceride synthesis by impeding the uptake and transportation of free fatty acids. Conclusion: GSTA1 may be a good target for the discovery of innovative drug candidates as GSTA1 stabilizers or enhancers against MASLD.


Assuntos
Proteínas de Ligação a Ácido Graxo , Fígado Gorduroso , Glutationa Transferase , Regulação para Cima , Glutationa Transferase/metabolismo , Glutationa Transferase/genética , Animais , Humanos , Camundongos , Proteínas de Ligação a Ácido Graxo/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/tratamento farmacológico , Regulação para Cima/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Fígado/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos Endogâmicos C57BL , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Ácido Oleico/metabolismo , Células Hep G2 , Triglicerídeos/metabolismo , Isoenzimas
7.
Infect Dis Ther ; 13(6): 1359-1378, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38733495

RESUMO

INTRODUCTION: Listeriosis is a severe food-borne disease caused by Listeria monocytogenes infection. The data of listeriosis in Xi'an population are limited. The aim of this study is to evaluate the clinical features and fatality risk factors for listeriosis in three tertiary-care hospitals in Xi'an, China METHODS: The characteristics of demographic data, underlying diseases, clinical manifestations, laboratory indicators, cranial imaging examination, antibiotics therapeutic schemes, and clinical outcomes were collected between 2011 and 2023. Logistic regression analysis was performed. RESULTS: Seventy-one etiologically confirmed listeriosis patients were enrolled, including 12 neonatal and 59 non-neonatal cases. The majority of neonatal listeriosis presented as preterm (50%) and fetal distress (75%). The main clinical manifestations of non-neonatal listeriosis included fever (88%), headache (32%), disorder of consciousness (25%), vomiting (17%), abdominal pain (12%), and convulsions (8%). The fatality rate in neonatal cases was higher than in non-neonatal listeriosis (42 vs. 17%). Although no deaths were reported in maternal listeriosis, only two of 23 patients had an uneventful obstetrical outcome. Five maternal listeriosis delivered culture-positive neonates, three of whom decreased within 1 week post-gestation due to severe complications. Twenty-eight cases were neurolisteriosis and 43 cases were bacteremia. Neurolisteriosis had a higher fatality rate compared with bacteremia listeriosis (36 vs. 12%). The main neuroradiological images were cerebral edema/hydrocephalus, intracranial infection, and cerebral hernia. Listeria monocytogenes showed extremely low resistance to ampicillin (two isolates) and penicillin (one isolate). The fatality risk factors were the involvement of the central nervous system, hyperbilirubinemia, and hyponatremia for all enrolled subjects. Hyperuricemia contributed to the elevation of fatality risk in non-neonatal listeriosis. CONCLUSIONS: When the patients suffered with symptoms of fever and central nervous system infection, they should be alert to the possibility of listeriosis. Early administration of ampicillin- or penicillin-based therapy might be beneficial for recovery of listeriosis.

8.
J Affect Disord ; 358: 474-482, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38735578

RESUMO

BACKGROUND: An association between the menopause and depression is widely reported. This review aims to determine the global prevalence of depression in menopausal women (this includes women in perimenopause and postmenopause). METHODS: PubMed, Web of Science, Embase, and PsycINFO databases were systematically searched from database inception until March 1, 2024. Studies with validated methods for assessing the prevalence of depression in perimenopausal and postmenopausal women were included. Two authors independently extracted relevant data. Random effects meta-analysis and Meta-regression analysis were performed using Stata software. RESULTS: Total of 55 studies (76,817 participants) were included in the review. A random effects model was used to calculate pooled prevalence. The pooled depression prevalence in menopausal women was 35.6 % (95 % CI: 32.0-39.2 %), with 33.9 % (95 % CI: 27.8-40.0 %) in perimenopausal women, and 34.9 % (95 % CI: 30.7-39.1 %) in postmenopausal women. Subgroup analyses indicated that region, screening tool, study design, and setting moderated the prevalence of depression. Meta-regression indicated that smaller sample sizes and poorer study quality were significantly associated with a higher prevalence. LIMITATIONS: There was a high degree of heterogeneity across the included studies. Only articles published in English were included. There was significant publication bias in this meta-analysis. There is insufficient information about many risk factors of menopausal depression in current meta-analysis. CONCLUSIONS: Depression is common among menopausal women worldwide. To reduce the negative impact of depression on health outcomes in menopausal women, regular screening and the availability of effective prevention and treatment measures should be made available for this population.


Assuntos
Depressão , Menopausa , Humanos , Feminino , Prevalência , Menopausa/psicologia , Depressão/epidemiologia , Saúde Global/estatística & dados numéricos , Pessoa de Meia-Idade , Pós-Menopausa/psicologia , Perimenopausa/psicologia
9.
Radiother Oncol ; 197: 110324, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38735537

RESUMO

PURPOSE: To determine the prevalence of anxiety and depression in patients with nasopharyngeal carcinoma (NPC) and to identify central symptoms and bridge symptoms among psychiatric disorders. METHODS: This cross-sectional study recruited patients with NPC in Guangzhou, China from May 2022, to October 2022. The General Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9) were used for screening anxiety and depression, respectively. Network analysis was conducted to evaluate the centrality and connectivity of the symptoms of anxiety, depression, quality of life (QoL) and insomnia. RESULTS: A total of 2806 respondents with complete GAD-7 and PHQ-9 scores out of 3828 were enrolled. The incidence of anxiety in the whole population was 26.5% (depression, 28.5%; either anxiety or depression, 34.8%). Anxiety was highest at caner diagnosis (34.2%), while depression reached a peak at late-stage radiotherapy (48.5%). Both moderate and severe anxiety and depression were exacerbated during radiotherapy. Coexisting anxiety and depression occurred in 58.3% of those with either anxiety or depression. The generated network showed that anxiety and depression symptoms were closely connected; insomnia was strongly connected with QoL. "Sad mood", "Lack of energy", and "Trouble relaxing" were the most important items in the network. Insomnia was the most significant bridge item that connected symptom groups. CONCLUSION: Patients with NPC are facing alarming disturbances of psychiatric disorders; tailored strategies should be implemented for high-risk patients. Besides, central symptoms (sad mood, lack of energy, and trouble relaxing) and bridge symptoms (insomnia) may be potential interventional targets in future clinical practice.

11.
J Dig Dis ; 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38779802

RESUMO

OBJECTIVES: As a serious complication of moderately severe acute pancreatitis (MSAP) and severe acute pancreatitis (SAP), infected pancreatic necrosis (IPN) can lead to a prolonged course of interventional therapy. Most predictive models designed to identify such patients are complex or lack validation. The aim of this study was to develop a predictive model for the early detection of IPN in MSAP and SAP. METHODS: A total of 594 patients with MSAP or SAP were included in the study. To reduce dimensionality, least absolute shrinkage and selection operator regression analysis was used to screen potential predictive variables, a nomogram was then constructed using logistic regression analysis. The receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to evaluate the discrimination, accuracy, and clinical efficacy of the model. External data were also obtained to further validate the constructed model. RESULTS: There were 476, 118, and 82 patients in the training, internal validation, and external validation cohorts, respectively. Platelet count, hematocrit, albumin/globulin, severity of acute pancreatitis, and modified computed tomography severity index score were independent factors for predicting IPN in MSAP and SAP. The area under the ROC curves were 0.923, 0.940, and 0.817, respectively, in the three groups. There was a good consistency between the actual probabilities and the predicted probabilities. DCA revealed excellent clinical utility. CONCLUSION: The constructed nomogram is a simple and feasible model that has good clinical predictive value and efficacy in clinical decision-making for IPN in MSAP and SAP.

12.
Small ; : e2401308, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773889

RESUMO

Incorporating ultralow loading of nanoparticles into polymers has realized increases in dielectric constant and breakdown strength for excellent energy storage. However, there are still a series of tough issues to be dealt with, such as organic solvent uses, which face enormous challenges in scalable preparation. Here, a new strategy of dual in situ synthesis is proposed, namely polymerization of polyethylene terephthalate (PET) synchronizes with growth of calcium borate nanoparticles, making polyester nanocomposites from monomers directly. Importantly, this route is free of organic solvents and surface modification of nanoparticles, which is readily accessible to scalable synthesis of polyester nanocomposites. Meanwhile, uniform dispersion of as ultralow as 0.1 wt% nanoparticles and intense bonding at interfaces have been observed. Furthermore, the PET-based nanocomposite displays obvious increases in both dielectric constant and breakdown strength as compared to the neat PET. Its maximum discharged energy density reaches 15 J cm-3 at 690 MV m-1 and power density attains 218 MW cm-3 under 150 Ω resistance at 300 MV m-1, which is far superior to the current dielectric polymers that can be produced at large scales. This work presents a scalable, safe, low-cost, and environment-friendly route toward polymer nanocomposites with superior capacitive performance.

13.
Int J Biol Macromol ; 269(Pt 2): 132215, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38729482

RESUMO

Food allergy has a significant impact on the health and well-being of individuals, affecting both their physical and mental states. Research on natural bioactive compounds, such as polysaccharides extracted from seaweeds, holds great promise in the treatment of food allergies. In this study, fermented Gracilaria lemaneiformis polysaccharides (F-GLSP) were prepared using probiotic fermentation. Probiotic fermentation of Gracilaria lemaneiformis reduces the particle size of polysaccharides. To compare the anti-allergic activity of F-GLSP with unfermented Gracilaria lemaneiformis polysaccharides (UF-GLSP), an OVA-induced mouse food allergy model was established. F-GLSP exhibited a significant reduction in OVA-specific IgE and mMCP levels in allergic mice. Moreover, it significantly inhibited Th2 differentiation and IL-4 production and significantly promoted Treg differentiation and IL-10 production in allergic mice. In contrast, UF-GLSP only reduced OVA-specific IgE and mMCP in the serum of allergic mice. Furthermore, F-GLSP demonstrated a more pronounced regulation of intestinal flora abundance compared to UF-GLSP, significantly influencing the populations of Firmicutes, Bacteroidetes, Lactobacillus, and Clostridiales in the intestines of mice with food allergy. These findings suggest that F-GLSP may regulate food allergies in mice through multiple pathways. In summary, this study has promoted further development of functional foods with anti-allergic properties based on red algae polysaccharides.

14.
World J Gastroenterol ; 30(16): 2209-2219, 2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38690022

RESUMO

Laryngopharyngeal reflux disease (LPRD) is an inflammatory condition in the laryngopharynx and upper aerodigestive tract mucosa caused by reflux of stomach contents beyond the esophagus. LPRD commonly presents with sym-ptoms such as hoarseness, cough, sore throat, a feeling of throat obstruction, excessive throat mucus. This complex condition is thought to involve both reflux and reflex mechanisms, but a clear understanding of its molecular mechanisms is still lacking. Currently, there is no standardized diagnosis or treatment protocol. Therapeutic strategies for LPRD mainly include lifestyle modifications, proton pump inhibitors and endoscopic surgery. This paper seeks to provide a comprehensive overview of the existing literature regarding the mechanisms, patho-physiology and treatment of LPRD. We also provide an in-depth exploration of the association between LPRD and gastroesophageal reflux disease.


Assuntos
Refluxo Gastroesofágico , Refluxo Laringofaríngeo , Inibidores da Bomba de Prótons , Humanos , Refluxo Laringofaríngeo/fisiopatologia , Refluxo Laringofaríngeo/diagnóstico , Refluxo Laringofaríngeo/terapia , Refluxo Gastroesofágico/fisiopatologia , Refluxo Gastroesofágico/terapia , Refluxo Gastroesofágico/diagnóstico , Inibidores da Bomba de Prótons/uso terapêutico , Resultado do Tratamento , Estilo de Vida
15.
Adv Sci (Weinh) ; : e2400594, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38689503

RESUMO

Proteolysis targeting chimeras (PROTACs) have emerged as a promising strategy for drug discovery and exploring protein functions, offering a revolutionary therapeutic modality. Currently, the predominant approach to PROTACs discovery mainly relies on an empirical design-synthesis-evaluation process involving numerous cycles of labor-intensive synthesis-purification and bioassay data collection. Therefore, the development of innovative methods to expedite PROTAC synthesis and exploration of chemical space remains highly desired. Here, a direct-to-biology strategy is reported to streamline the synthesis of PROTAC libraries on plates, enabling the seamless transfer of reaction products to cell-based bioassays without the need for additional purification. By integrating amide coupling and light-induced primary amines and o-nitrobenzyl alcohols cyclization (PANAC) photoclick chemistry into a plate-based synthetic process, this strategy produces PROTAC libraries with high efficiency and structural diversity. Moreover, by employing this platform for PROTACs screening, we smoothly found potent PROTACs effectively inhibit triple-negative breast cancer (TNBC) cell growth and induce rapid, selective targeted degradation of cyclin-dependent kinase 9 (CDK9). The study introduces a versatile platform for assembling PROTACs on plates, followed by direct biological evaluation. This approach provides a promising opportunity for high-throughput synthesis of PROTAC libraries, thereby enhancing the efficiency of exploring chemical space and accelerating the discovery of PROTACs.

16.
Genes Genomics ; 46(6): 647-657, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38573409

RESUMO

BACKGROUND: Helicobacter pylori (Hp) infection is considered to be the strongest risk factor for gastric cancer (GC). Long non-coding RNA HOXA cluster antisense RNA 2 (HOXA-AS2) has been indicated to be significantly related to Hp infection in GC patients. OBJECTIVE: To investigate the detailed role and molecular mechanism of lncRNA HOXA-AS2 in Hp-induced GC. METHODS: GC cells were treated with Hp filtrate for cell infection. Bioinformatics tools were utilized for survival analysis and prediction of HOXA-AS2 downstream molecules. Western blotting and RT-qPCR were utilized for assessing protein and RNA levels, respectively. Flow cytometry, colony formation and CCK-8 assays were implemented for testing HOXA-AS2 functions in Hp-infected GC cells. HOXA-AS2 localization in cells was determined by subcellular fractionation assay. The relationship between RNAs were measured by luciferase reporter assay. RESULTS: Hp infection induced HOXA-AS2 upregulation in GC cells. Knocking down HOXA-AS2 restrained cell proliferation but promoted cell apoptosis with Hp infection. HOXA-AS2 bound to miR-509-3p, and miR-509-3p targeted monocyte to macrophage differentiation associated 2 (MMD2). Overexpressing MMD2 reversed HOXA-AS2 depletion-mediated suppression on cell aggressiveness with Hp infection. CONCLUSION: Hp infection induces the aggressiveness of GC cells by regulating HOXA-AS2/miR-509-3p/MMD2 axis.


Assuntos
Proliferação de Células , Infecções por Helicobacter , Helicobacter pylori , MicroRNAs , RNA Longo não Codificante , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Helicobacter pylori/genética , Infecções por Helicobacter/genética , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/complicações , Linhagem Celular Tumoral , Proliferação de Células/genética , Apoptose/genética , Regulação Neoplásica da Expressão Gênica
17.
Front Biosci (Landmark Ed) ; 29(4): 160, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38682208

RESUMO

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignant tumor associated with Epstein-Barr virus (EBV) infection. Chemoradiotherapy is the mainstream treatment for locally advanced NPC, and chemotherapeutic drugs are an indispensable part of NPC treatment. However, the toxic side-effects of chemotherapy drugs limit their therapeutic value, and new chemotherapy drugs are urgently needed for NPC. Silvestrol, an emerging natural plant anticancer molecule, has shown promising antitumor activity in breast cancer, melanoma, liver cancer, and other tumor types by promoting apoptosis in cancer cells to a greater extent than in normal cells. However, the effects of silvestrol on NPC and its possible molecular mechanisms have yet to be fully explored. METHODS: Cell counting kit-8 (CCK-8), cell scratch, flow cytometry, 5-ethynyl-2'-deoxyuridine (EdU), and Western blot (WB) assays were used to evaluate the effects of silvestrol on the cell viability, cell cycle, apoptosis, and migration of NPC cells. RNA sequencing (RNA-Seq) was used to study the effect of extracellular signal-regulated kinase (ERK) inhibitors on the cell transcriptome, and immunohistochemistry (IHC) to assess protein expression levels in patient specimens. RESULTS: Silvestrol inhibited cell migration and DNA replication of NPC cells, while promoting the expression of cleaved caspase-3, apoptosis, and cell cycle arrest. Furthermore, silvestrol altered the level of ERK phosphorylation. The ERK-targeted inhibitor LY3214996 attenuated silvestrol-mediated inhibition of NPC cell proliferation but not migration. Analysis of RNA-Seq data and WB were used to identify and validate the downstream regulatory targets of silvestrol. Expression of GADD45A, RAP1A, and hexokinase-II (HK2) proteins was inhibited by silvestrol and LY3214996. Finally, IHC revealed that GADD45A, RAP1A, and HK2 protein expression was more abundant in cancer tissues than in non-tumor tissues. CONCLUSIONS: Silvestrol inhibits the proliferation of NPC cells by targeting ERK phosphorylation. However, the inhibition of NPC cell migration by silvestrol was independent of the Raf-MEK-ERK pathway. RAP1A, HK2, and GADD45A may be potential targets for the action of silvestrol.


Assuntos
Benzofuranos , Proteínas GADD45 , Hexoquinase , Sistema de Sinalização das MAP Quinases , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Proteínas rap1 de Ligação ao GTP , Humanos , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Hexoquinase/genética , Hexoquinase/metabolismo , Proteínas rap1 de Ligação ao GTP/genética , Proteínas rap1 de Ligação ao GTP/metabolismo , Proteínas GADD45/genética , Proteínas GADD45/metabolismo
18.
Life Sci ; 345: 122604, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38580196

RESUMO

AIMS: Intestinal barrier dysfunction is the initial and propagable factor of sepsis in which acute kidney injury (AKI) has been considered as a common life-threatening complication. Our recent study identifies the regulatory role of Pellino1 in tubular death under inflammatory conditions in vitro. The objective of our current study is to explore the impact of Pellino1 on gut-kidney axis during septic AKI and uncover the molecular mechanism (s) underlying this process. MATERIALS AND METHODS: Immunohistochemistry (IHC) was conducted to evaluate Pellino1 and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) levels in renal biopsies from critically ill patients with a clinical diagnosis of sepsis. Functional and mechanistic studies were characterized in septic models of the Peli-knockout (Peli1-/-) mice by histopathological staining, enzyme-linked immunosorbent assay (ELISA), flow cytometry, immunofluorescence, biochemical detection, CRISPR/Cas9-mediated gene editing and intestinal organoid. KEY FINDINGS: Pellino1, together with NLRP3, are highly expressed in renal biopsies from critically ill patients diagnosed with sepsis and kidney tissues of septic mice. The Peli1-/- mice with sepsis become less prone to develop AKI and have markedly compromised NLRP3 activation in kidney. Loss of Peli1 endows septic mice refractory to intestinal inflammation, barrier permeability and enterocyte apoptosis that requires stimulator of interferons genes (STING) pathway. Administration of STING agonist DMXAA deteriorates AKI and mortality of septic Peli1-/- mice in the presence of kidney-specific NLRP3 reconstitution. SIGNIFICANCE: Our studies suggest that Pellino1 has a principal role in orchestrating gut homeostasis towards renal pathophysiology, thus providing a potential therapeutic target for septic AKI.


Assuntos
Injúria Renal Aguda , Sepse , Animais , Humanos , Camundongos , Injúria Renal Aguda/metabolismo , Estado Terminal , Inflamassomos/metabolismo , Rim/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas Nucleares/metabolismo , Sepse/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
19.
Mater Horiz ; 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38567484

RESUMO

Discovering new negative thermal expansion (NTE) materials is a great challenge in experiment. Meanwhile, the machine learning (ML) method can be another approach to explore NTE materials using the existing material databases. Herein, we adopt the multi-step ML method with efficient data augmentation and cross-validation to identify around 1000 materials, including oxides, fluorides, and cyanides, with bulk framework structures as new potential NTE candidate materials from ICSD and other databases. Their corresponding coefficients of negative thermal expansion (CNTE) and temperature ranges are also well predicted. Among them, about 57 materials are predicted to have an NTE probability of 100%. Some predicted NTE materials were tested by the first-principles calculations with quasi-harmonic approximation (QHA), which indicates that the ML results are in good agreement with the first principles calculation results. Based on the comprehensive analysis of the existing and predicted NTE materials, we established three universal relationships of CNTE with an average electronegativity, porosity, and temperature range. From these, we also identified some important critical values characterizing the NTE property, which can serve as an important criterion for designing new NTE materials.

20.
Front Cell Neurosci ; 18: 1292969, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38628398

RESUMO

During the development of neural circuits, axons are guided by a variety of molecular cues to navigate through the brain and establish precise connections with correct partners at the right time and place. Many axon guidance cues have been identified and they play pleiotropic roles in not only axon guidance but also axon fasciculation, axon pruning, and synaptogenesis as well as cell migration, angiogenesis, and bone formation. In search of receptors for Sema3E in axon guidance, we unexpectedly found that Plexin B3 is highly expressed in retinal ganglion cells of zebrafish embryos when retinal axons are crossing the midline to form the chiasm. Plexin B3 has been characterized to be related to neurodevelopmental disorders. However, the investigation of its pathological mechanisms is hampered by the lack of appropriate animal model. We provide evidence that Plexin B3 is critical for axon guidance in vivo. Plexin B3 might function as a receptor for Sema3E while Neuropilin1 could be a co-receptor. The intracellular domain of Plexin B3 is required for Semaphorin signaling transduction. Our data suggest that zebrafish could be an ideal animal model for investigating the role and mechanisms of Sema3E and Plexin B3 in vivo.

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