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1.
Bioorg Med Chem ; 98: 117584, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38168629

RESUMO

Transient receptor potential melastatin 4 (TRPM4) is considered to be a potential target for cancer and other human diseases. Herein, a series of 2-(naphthalen-1-yloxy)-N-phenylacetamide derivatives were designed and synthesized as new TRPM4 inhibitors, aiming to improve cellular potency. One of the most promising compounds, 7d (ZX08903), displayed promising antiproliferative activity against prostate cancer cell lines. 7d also suppressed colony formation and the expression of androgen receptor (AR) protein in prostate cancer cells. Furthermore, 7d can concentration-dependently induce cell apoptosis in prostate cancer cells. Collectively, these findings indicated that compound 7d may serve as a promising lead compound for further anticancer drug development.


Assuntos
Antineoplásicos , Neoplasias da Próstata , Canais de Cátion TRPM , Masculino , Humanos , Linhagem Celular Tumoral , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Proliferação de Células , Relação Estrutura-Atividade , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular
2.
Bioorg Chem ; 144: 107115, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38232684

RESUMO

Ferroptosis is an iron-dependent form of oxidative cell death induced by lipid peroxidation accumulation. Glutathione peroxidase 4 (GPX4) plays a key role in the regulation of ferroptosis and is considered to be a promising therapeutic target for cancer and other human diseases. Herein, we describe our design, synthesis, and biological evaluation of a series of HyT-based degraders of the GPX4. One of the most promising compounds, 7b (ZX782), effectively induces dose- and time-dependent degradation of GPX4 protein and potently suppresses the growth of human fibrosarcoma HT1080 cells, which are highly sensitive to ferroptosis and widely used for evaluating compound specificity in ferroptosis. Mechanism investigation indicated that 7b depletes GPX4 through both the ubiquitin-proteasome and the autophagy-lysosome. Furthermore, the degradation of GPX4 induced by 7b could significantly increase the accumulation of lipid reactive oxygen species (ROS) in HT1080 cells, ultimately leading to ferroptosis. Overall, compound 7b exhibits robust potency in depleting endogenous GPX4, thereby modulating ferroptosis in cancer cells.


Assuntos
Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Humanos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Glutationa Peroxidase/metabolismo , Morte Celular , Peroxidação de Lipídeos , Oxirredução
3.
Appl Opt ; 63(15): 4165-4174, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38856510

RESUMO

Currently, computer-generated holograms (CGHs) based on ray tracing technology are generated faster and faster, and the reconstructed scenes are getting bigger and bigger and contain more and more information. Based on this situation, there are also more applications of using CGHs to hide information, but there is a lack of research on the ability to hide information. To address this issue, this paper proposes a point-sampling CGH method based on ray tracing. Our method utilizes ray tracing techniques to rapidly sample text information at different depths in the scene and hides the depth-encoded text information in the carrier image using discrete cosine transform. The reconstructed image after embedding shows good results, with a peak signal-to-noise ratio (PSNR) of 29.56 dB between the hidden images before and after embedding. The PSNR value between the embedded carrier image and the original carrier image is 51.66 dB, making it difficult for the human eye to distinguish, thereby effectively protecting the generated CGH. We also analyzed the maximum information density and observed that computational holograms obtain the maximum information density at 200×200 resolution.

4.
J Environ Manage ; 363: 121374, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38843734

RESUMO

Cotton is a major cash crop globally, playing a pivotal role in the textile sector. However, cotton growers in Xinjiang region are experiencing cotton yield penalty caused by limited heat environment. In this region, limited heat conditions strongly arrest cotton plant growth and development resulting in recued productivity. To counteract this problem, there is an urgent need to robustly identify efficient management strategies to improve plant performance and increase cotton yield under heat-limited situations. This will hold crucial implications for agricultural sustainability and global cotton supply. This review article identified challenges faced by cotton producers under heat limited environments with potential solutions to enhance cotton productivity. Specifically, we focused on the implementation of two life history strategies including planting early maturing and cold tolerant cultivars, and adjusting sowing date that can promote early maturity and increase cold stress tolerance. These strategies have shown promising results in protecting cotton plants from limited heat injury and consequently improved cotton productivity. By focusing on Xinjiang province unique climate and associated agronomic practices, valuable insights can be gained, which may have broader applications in other heat-limited cotton-growing regions globally. This comprehensive review endeavors to provide a foundation for future research and practical interventions aimed at boosting cotton yields under limited heat areas.


Assuntos
Gossypium , Gossypium/crescimento & desenvolvimento , Temperatura Alta , Agricultura/métodos , China
5.
World J Surg Oncol ; 21(1): 353, 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-37968641

RESUMO

PURPOSE: To investigate the clinical features and survival outcomes of primary gastrointestinal non-Hodgkin lymphomas (PGINHL) in pediatric and adolescent population, we conducted a population-based cohort study. METHODS: All pediatric and adolescent patients with PGINHL diagnosed between 2000 and 2019 were identified using the Surveillance, Epidemiology, and End Results (SEER) database. Kaplane-Meier estimations were used to generate survival curves based on various criteria. To compare survival curves, the log-rank test was applied. A multivariate Cox proportional hazards model was developed to investigate the effect of each component on overall survival. RESULTS: A total of 334 pediatric and adolescent with PGINHL patients were identified. The median age at diagnosis was 12 years (range 1.0-19 years). Tumors were most commonly found in the small bowel (47.3%), followed by the large bowel (42.8%) and the stomach (9.9%). Overall, the most common histological subtype was Burkitt lymphoma (56.9%), followed by diffuse large B-cell lymphoma (DLBCL) (27.8%). Overall survival rates for all patients were 92.2% at 5- year and 91.6% at 10- year, respectively. The Cox proportional hazard regression revealed that only chemotherapy was an important independent predictor in this model. Patients with chemotherapy have a higher survival rate than those without. CONCLUSIONS: Our study revealed that only chemotherapy was found to be the most important predictor of the OS in pediatric and adolescent PGINHL, providing critical information for therapeutic care.


Assuntos
Neoplasias Gastrointestinais , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Humanos , Criança , Adolescente , Lactente , Pré-Escolar , Adulto Jovem , Adulto , Prognóstico , Estudos de Coortes , Linfoma não Hodgkin/epidemiologia , Linfoma não Hodgkin/terapia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Neoplasias Gastrointestinais/terapia , Neoplasias Gastrointestinais/tratamento farmacológico , Estômago/patologia , Estudos Retrospectivos
6.
Chemistry ; 26(53): 12086-12100, 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32207184

RESUMO

The O-linked ß-N-acetylglucosamine (O-GlcNAc) modification, termed O-GlcNAcylation, is an essential and dynamic post-translational modification in cells. O-GlcNAc transferase (OGT) installs this modification on serine and threonine residues, whereas O-GlcNAcase (OGA) hydrolyzes it. O-GlcNAc modifications are found on thousands of intracellular proteins involved in diverse biological processes. Dysregulation of O-GlcNAcylation and O-GlcNAc cycling enzymes has been detected in many diseases, including cancer, diabetes, cardiovascular and neurodegenerative diseases. Here, recent advances in the development of molecular tools to investigate OGT and OGA functions and substrate recognition are discussed. New chemical approaches to study O-GlcNAc dynamics and its potential roles in the immune system are also highlighted. It is hoped that this minireview will encourage more research in these areas to advance the understanding of O-GlcNAc in biology and diseases.


Assuntos
Acetilglucosamina/química , N-Acetilglucosaminiltransferases , beta-N-Acetil-Hexosaminidases , Acetilglucosamina/metabolismo , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Processamento de Proteína Pós-Traducional , Serina/química , Treonina/química
7.
J Org Chem ; 85(19): 12408-12417, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-32885655

RESUMO

In view of the importance of both fluorinated synthons and homoenolate equivalents, synthetic application of difluorocyclopropanols is desired but remains challenging due to their thermodynamic instability. Herein, we use siloxydifluorocyclopropanes as difluorocyclopropanol precursors to carry out new Cu-catalyzed ring-opening defluorinative alkylation. With α-bromo carboxylic esters as coupling partners, the reaction affords γ-fluoro-δ-ketoesters via a CuI/CuII catalytic cycle. Interestingly, by the use of α-bromoamides, the ring-opening defluorinative alkylation is followed by an additional intramolecular C-N oxidative coupling to deliver a lactam intermediate, which further undergoes defluorination, hydrolysis, ring opening, and dehydration cascade via a CuI/CuII/CuIII catalytic pathway, leading to γ,δ-diketonitriles as the final products.

8.
Med Sci Monit ; 26: e925591, 2020 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-32917849

RESUMO

BACKGROUND Beginning in the 2020 spring semester, due to the COVID-19 pandemic, all school-age children in China were homeschooled via live/recorded broadcasts, online group communication, and software-based homework submission. This study assessed the effects of and proper preparation for this educational approach. MATERIAL AND METHODS The homeschooling behaviors and feelings of school-age children were assessed with 2010 online surveys obtained separately from students, parents, and teachers of grades 1-9 in 15 Chinese provinces. Answers were compared among low- (grades 1-3), middle- (grades 4-6), and high- (grades 7-9) grade groups. The chi-square test was used to identify significant differences between groups. RESULTS We found that 76% of the respondents thought the homeschooling style was acceptable. However, teachers were concerned that students' interest, focus, and academic performance would decline. Sixty-nine percent of the parents reported their children had more than 3 hours of daily screen time, and 82% of students had less than 2 hours of daily outdoor activity. Ninety-five percent of the parents were concerned about their children's eyesight. Additionally, 17.6% of the students were suspected to have emotional or behavioral problems according to the parent-rated Strengths and Difficulties Questionnaire (SDQ) results. The Self-Rating Anxiety Scale (SAS) results of parents and teachers showed higher levels of anxiety than usual. CONCLUSIONS Students should continue the going-to-school rhythm at home to cope with changes caused by the COVID-19 pandemic. Integrated grade-specific approaches are needed. Because long screen time and insufficient outdoor activities can severely affect children's eyesight, appropriate eye-protection measures should be implemented.


Assuntos
Betacoronavirus , Infecções por Coronavirus/psicologia , Educação a Distância , Pandemias , Pais/psicologia , Pneumonia Viral/psicologia , Professores Escolares/psicologia , Estudantes/psicologia , Adolescente , Adulto , COVID-19 , Distribuição de Qui-Quadrado , Criança , Transtornos do Comportamento Infantil/etiologia , Emoções , Feminino , Humanos , Relações Interpessoais , Masculino , Pessoa de Meia-Idade , Psicologia da Criança , Quarentena/psicologia , SARS-CoV-2 , Transtornos do Sono-Vigília/etiologia , Inquéritos e Questionários , Transtornos da Visão/etiologia
9.
J Cell Physiol ; 234(9): 16517-16525, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30805928

RESUMO

Renal cell carcinoma (RCC) is a common urinary system cancer with high morbidity and mortality rate. Clear cell renal cell carcinoma (ccRCC) is a highly aggressive and common type of RCC. More and effective therapeutic targets are badly needed for the treatment of ccRCC. Kinesin family protein (KIF)20B, also named M-phase phosphoprotein 1, was reported as a microtubule-associated, plus-end-directed kinesin. KIF20B was involved in multiple cellular processes such as cytokinesis. Multiple studies indicated the oncogenic role for KIF20B in several types of tumors, including breast cancer and bladder cancer. However, the possible role of KIF20B in the progression of renal carcinoma is still unknown. Herein, our study demonstrated that KIF20B was relatively highly expressed in ccRCC tissues. In addition, KIF20B was inversely related to the clinical features including tumor size and T stage. We further found that inhibition of the KIF20B expression by a specific short hairpin RNA obviously reduces proliferation of ccRCC cells both in vitro and in vivo. Our study reveals the involvement of KIF20B in ccRCC progression. Generally, KIF20B is a promising novel therapeutic for the treatment of clear cell RCC.

10.
Chembiochem ; 20(14): 1783-1788, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30942519

RESUMO

Crenolanib (CP-868,596), a potent inhibitor of FLT3 and PDGFRα/ß, is currently under phase III clinical investigation for the treatment of acute myeloid leukemia. However, the protein targets of Crenolanib in cancer cells remain obscure, which results in difficulties in understanding the mechanism of actions and side effects. To alleviate this issue, in this study, a photoaffinity probe and two fluorescent probes were created based on Crenolanib, followed by competitive protein profiling and bioimaging studies, with the aim of characterizing the cellular targets. A series of unknown protein hits, such as MAPK1, SHMT2, SLC25A11, and HIGD1A, were successfully identified by means of pull-down/LC-MS/MS; these might provide valuable clues for understanding drug action and potential toxicities. Moreover, the fluorescent probes are suitable for imaging drug distribution at the single-cell level.


Assuntos
Benzimidazóis/farmacologia , Corantes Fluorescentes/farmacologia , Marcadores de Fotoafinidade/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Humanos , Microscopia de Fluorescência/métodos , Simulação de Acoplamento Molecular , Marcadores de Fotoafinidade/síntese química , Marcadores de Fotoafinidade/metabolismo , Piperidinas/síntese química , Piperidinas/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/química , Tirosina Quinase 3 Semelhante a fms/metabolismo
11.
Chemistry ; 25(40): 9491-9497, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-30817040

RESUMO

A series of 1,1'-spirobiindane-7,7'-diol (SPINOL) analogues bearing a 2,2'-dimethyl-, cyclopentyl-, or cyclohexyl-fused ring were synthesized, and their distinct structural features were elucidated by X-ray crystallography. On the basis of these scaffolds, chiral monophosphoramidite ligands 6 a-m were synthesized, which demonstrated excellent enantioselectivity in RhI -catalyzed asymmetric hydrogenation of a dehydro amino acid methyl ester. Ligands 6 a-m were also successfully applied in the RhI -catalyzed enantioselective [4+2] cycloaddition of α,ß-unsaturated imines with isocyanates, which afforded the corresponding pyrimidinones in good yields (60-92 %) with high enantioselectivities (75-92 % ee).

12.
J Am Chem Soc ; 140(32): 10374-10381, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30036064

RESUMO

1,1'-Spirobiindane has been one type of privileged skeleton for chiral ligand design, and 1,1'-spirobiindane-based chiral ligands have demonstrated outstanding performance in various asymmetric catalysis. However, the access to enantiopure spirobiindane is quite tedious, which obstructs its practical application. In the present article, a facile enantioselective synthesis of cyclohexyl-fused chiral spirobiindanes has been accomplished, in high yields and excellent stereoselectivities (up to >99% ee), via a sequence of Ir-catalyzed asymmetric hydrogenation of α,α'-bis(arylidene)ketones and TiCl4 promoted asymmetric spiroannulation of the hydrogenated chiral ketones. The protocol can be performed in one pot and is readily scalable, and has been utilized in a 25 g scale asymmetric synthesis of cyclohexyl-fused spirobiindanediol (1 S,2 S,2' S)-5, in >99% ee and 67% overall yield for four steps without chromatographic purification. Facile derivations of (1 S,2 S,2' S)-5 provided straightforward access to chiral monodentate phosphoramidites 6a-c and a tridentate phosphorus-amidopyridine 11, which were evaluated as chiral ligands in several benchmark enantioselective reactions (hydrogenation, hydroacylation, and [2 + 2] reaction) catalyzed by transition metal (Rh, Au, or Ir). Preliminary results from comparative studies showcased the excellent catalytic performances of these ligands, with a competency essentially equal to the corresponding well-established privileged ligands bearing a regular spirobiindane backbone. X-ray crystallography revealed a close resemblance between the structures of the precatalysts 20 and 21 and their analogues, which ultimately help to rationalize the almost identical stereochemical outcomes of reactions catalyzed by metal complexes of spirobiindane-derived ligands with or without a fused cyclohexyl ring on the backbone. This work is expected to stimulate further applications of this type of readily accessible skeletons in development of chiral ligands and functional molecules.

13.
Angew Chem Int Ed Engl ; 57(30): 9284-9289, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-29768700

RESUMO

Venetoclax (ABT-199) and idasanutlin (RG7388) are efficient anticancer drugs targeting two essential apoptosis markers, Bcl-2 and MDM2, respectively. Recent studies have shown that the combination of these two drugs leads to remarkable enhancement of anticancer efficacy, both in vitro and in vivo. In an attempt to disclose the relationships of their protein targets, competitive affinity-based proteome profiling coupled with bioimaging was employed to characterize their protein targets in the same cancer cell line and tumor tissue. A series of protein hits, including ITPR1, GSR, RER1, PDIA3, Apoa1, and Tnfrsf17 were simultaneously identified by pull-down/LC-MS/MS with the two sets of affinity-based probes. Dual imaging was successfully carried out, with the simultaneous detection of Bcl-2 and MDM2 expression in various cancer cells. This could facilitate the novel diagnostic and therapeutic strategies of dual targeting of Bcl-2/MDM2.


Assuntos
Antineoplásicos/química , Biomarcadores Tumorais/análise , Neoplasias da Mama/tratamento farmacológico , Compostos Bicíclicos Heterocíclicos com Pontes/química , Corantes Fluorescentes/química , Proteoma/análise , Pirrolidinas/química , Sulfonamidas/química , para-Aminobenzoatos/química , Antineoplásicos/farmacologia , Apoptose , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Imagem Óptica , Proteoma/antagonistas & inibidores , Proteoma/genética , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-mdm2/análise , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/genética , Pirrolidinas/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , para-Aminobenzoatos/farmacologia
14.
Zhonghua Nan Ke Xue ; 23(3): 217-222, 2017 Mar.
Artigo em Zh | MEDLINE | ID: mdl-29706041

RESUMO

OBJECTIVE: To compare the clinical effect of diode laser enucleation of the prostate (DIOD) with that of transurethral resection of the prostate (TURP) on benign prostate hyperplasia (BPH) with different prostate volumes. METHODS: This retrospective study included 256 BPH patients treated by DIOD (n = 141) or TURP (n = 115) from March 2012 to August 2015. According to the prostate volume, we divided the patients into three groups: <60 ml (42 for DIOD and 31 for TURP), 60-80 ml (51 for DIOD and 45 for TURP), and >80 ml (48 for DIOD and 39 for TURP). We obtained the relevant data from the patients before, during and at 6 months after surgery, and compared the two surgical strategies in operation time, perioperative levels of hemoglobin and sodium ion, post-operative urethral catheterization time and bladder irrigation time, pre- and post-operative serum PSA levels, International Prostate Symptoms Score (IPSS), post-void residual urine (PVR) volume and maximum urinary flow rate (Qmax), and incidence of post-operative complications among different groups. RESULTS: In the <60 ml group, there were no remarkable differences in the peri- and post-operative parameters between the two surgical strategies. In the 60-80 ml group, DIOD exhibited a significant superiority over TURP in the perioperative levels of hemoglobin (ï¼»3.25 ± 1.53ï¼½ g/L vs ï¼»4.77 ± 1.67ï¼½ g/L, P <0.05) and Na+ (ï¼»3.58 ± 1.27ï¼½mmol/L vs ï¼»9.67 ± 2.67ï¼½ mmol/L, P <0.01), bladder irrigation time (ï¼»30.06 ± 6.22ï¼½h vs ï¼»58.32 ± 10.25ï¼½ h, P <0.01), and urethral catheterization time (ï¼»47.61 ± 13.55ï¼½ h vs ï¼»68.01 ± 9.69ï¼½ h, P <0.01), but a more significant decline than the latter in the postoperative PSA level (ï¼»2.34 ± 1.29ï¼½ ng/ml vs ï¼»1.09 ± 0.72ï¼½ ng/ml, P <0.05), and similar decline was also seen in the >80 ml group (ï¼»3.35 ± 1.39ï¼½ ng/ml vs ï¼»1.76 ± 0.91ï¼½ ng/ml, P <0.05). No blood transfusion was necessitated and nor postoperative transurethral resection syndrome or urethral stricture observed in DIOD. However, the incidence rate of postoperative pseudo-urinary incontinence was significantly higher in the DIOD (22.7%, 32/141) than in the TURP group (7.83%, 9/115) (P <0.05). CONCLUSIONS: DIOD, with its obvious advantages of less blood loss, higher safety, faster recovery, and more definite short-term effectiveness, is better than TURP in the treatment of BPH with medium or large prostate volume and similar to the latter with small prostate volume.


Assuntos
Lasers Semicondutores/uso terapêutico , Hiperplasia Prostática/cirurgia , Ressecção Transuretral da Próstata/métodos , Humanos , Lasers Semicondutores/efeitos adversos , Masculino , Duração da Cirurgia , Tamanho do Órgão , Complicações Pós-Operatórias/etiologia , Próstata/patologia , Hiperplasia Prostática/patologia , Qualidade de Vida , Estudos Retrospectivos , Irrigação Terapêutica , Ressecção Transuretral da Próstata/efeitos adversos , Ressecção Transuretral da Próstata/estatística & dados numéricos , Resultado do Tratamento , Estreitamento Uretral/etiologia , Cateterismo Urinário , Incontinência Urinária/etiologia
15.
J Org Chem ; 80(17): 8910-5, 2015 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-26249672

RESUMO

A direct N-trifluoromethylation method has been developed by the use of the in situ generated [ArICF3](+) species as the electrophilic trifluoromethyl source. Upon treatment of N-H ketimines with Ruppert-Prakash reagent in the presence of PhI(OAc)2 and KF, or with Togni's reagent II catalyzed by copper salt, N-trifluoromethylated imine products were obtained in moderate to good yields.

16.
Sci Rep ; 14(1): 12728, 2024 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-38830934

RESUMO

To clarify the impact of SETD2 on macrophage function in pediatric patients with acute suppurative osteomyelitis and to elucidate the precise underlying mechanism. To gain insights into the potential functions of SETD2, a comprehensive study was conducted utilizing a co-culture model of human bone mesenchymal stem cells (hBMSCs) and bone marrow-derived macrophages (THP-1). A range of techniques were employed, including quantitative polymerase chain reaction, western blotting, ELISA, alkaline phosphatase activity assays, alizarin red S staining, luciferase reporter gene assays, and chromatin immunoprecipitation, to unravel the intricate interactions and molecular mechanisms involving SETD2 in this system. It was observed that SETD2 expression was reduced in THP-1 cells stimulated by staphylococcal protein A (SPA). Furthermore, the downregulation of SETD2 resulted in elevated M1 macrophage polarization and glycolysis, effects that were mitigated by SPA stimulation. Notably, SPA-stimulated THP-1 cells exhibited an increase in HIF-1α expression, which exhibited an inverse correlation with SETD2 levels. Moreover, it was discovered that SETD2 functioned as a catalyst for H3K36me3 and bound to the HIF-1α gene, which, in turn, regulated HIF-1α expression. Furthermore, the suppression of HIF-1α abrogated the consequences of SETD2 downregulation on glycolysis and M1 macrophage polarization. Lastly, the study demonstrated that M1 macrophage polarization serves as a mediator for BMP4's inhibitory effect on osteogenic differentiation of hBMSCs. This research has uncovered a previously unknown role of SETD2 in macrophages during osteomyelitis, revealing its significance in the pathogenesis of this condition. These findings suggest SETD2 as a novel target for the treatment of osteomyelitis.


Assuntos
Diferenciação Celular , Histona-Lisina N-Metiltransferase , Macrófagos , Células-Tronco Mesenquimais , Osteogênese , Osteomielite , Humanos , Osteomielite/metabolismo , Osteomielite/patologia , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/genética , Macrófagos/metabolismo , Macrófagos/imunologia , Células-Tronco Mesenquimais/metabolismo , Células THP-1 , Técnicas de Cocultura , Glicólise , Subunidade alfa do Fator 1 Induzível por Hipóxia
17.
Int Urol Nephrol ; 56(7): 2117-2123, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38300450

RESUMO

PURPOSE: Primary intrascrotal rhabdomyosarcoma (RMS) is a rare and aggressive tumor. The purpose of this study was to investigate the prognostic factors of intrascrotal RMS in children. METHODS: All pediatric patients with intrascrotal RMS diagnosed between 2000 and 2018 were identified using the Surveillance, Epidemiology, and End Results (SEER) database. To compare survival curves, the log-rank test was employed. A multivariate Cox proportional hazards model was developed to investigate the effect of each factor on overall survival (OS). A nomogram was created using the outcomes of the Cox regression model. RESULTS: A total of 102 pediatric patients with intrascrotal RMS were identified. Overall survival rates for all patients were 90.6% at 3-year and 87.2% at 5-year, respectively. Survival rates differed significantly by SEER stage and surgery; however, chemotherapy and removal of lymph nodes showed no significant difference. The outcome of Cox proportional hazard regression revealed that SEER stage and surgery were important independent predictors in this model. Furthermore, we developed a nomogram for predicting OS in pediatric intrascrotal RMS based on the Cox regression model. The risk of death increased with stage in patients. Additionally, patients who underwent surgery had a lower mortality risk than those who did not. CONCLUSIONS: Our findings show that SEER stage and surgery are the most important indicators of OS in children with intrascrotal RMS, providing critical epidemiological information for clinical therapy.


Assuntos
Neoplasias dos Genitais Masculinos , Rabdomiossarcoma , Escroto , Humanos , Masculino , Rabdomiossarcoma/terapia , Rabdomiossarcoma/mortalidade , Criança , Pré-Escolar , Prognóstico , Neoplasias dos Genitais Masculinos/terapia , Neoplasias dos Genitais Masculinos/patologia , Neoplasias dos Genitais Masculinos/mortalidade , Lactente , Taxa de Sobrevida , Programa de SEER , Nomogramas , Adolescente , Estudos Retrospectivos
18.
World J Clin Cases ; 12(14): 2332-2341, 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38765747

RESUMO

BACKGROUND: Up until now, no research has been reported on the association between the clinical growth rate of multilocular cystic renal neoplasm of low malignant potential (MCRNLMP) and computed tomography (CT) imaging characteristics. Our study sought to examine the correlation between them, with the objective of distinguishing unique features of MCRNLMP from renal cysts and exploring effective management strategies. AIM: To investigate optimal management strategies of MCRNLMP. METHODS: We retrospectively collected and analyzed data from 1520 patients, comprising 1444 with renal cysts and 76 with MCRNLMP, who underwent renal cyst decompression, radical nephrectomy, or nephron-sparing surgery for renal cystic disease between January 2013 and December 2021 at our institution. Detection of MCRNLMP utilized the Bosniak classification for imaging and the 2016 World Health Organization criteria for clinical pathology. RESULTS: Our meticulous exploration has revealed compelling findings on the occurrence of MCRNLMP. Precisely, it comprises 1.48% of all cases involving simple renal cysts, 5.26% of those with complex renal cysts, and a noteworthy 12.11% of renal tumors coexisting with renal cysts, indicating a statistically significant difference (P = 0.001). Moreover, MCRNLMP constituted a significant 22.37% of the patient population whose cysts demonstrated a rapid growth rate of ≥ 2.0 cm/year, whereas it only represented 0.66% among those with a growth rate below 2.0 cm/year. Of the 76 MCRNLMP cases studied, none of the nine patients who underwent subsequent nephron-sparing surgery or radical nephrectomy following renal cyst decompression experienced recurrence or metastasis. In the remaining 67 patients, who were actively monitored over a 3-year postoperative period, only one showed suspicious recurrence on CT scans. CONCLUSION: MCRNLMP can be tentatively identified and categorized into three types based on CT scanning and growth rate indicators. In treating MCRNLMP, partial nephrectomy is preferred, while radical nephrectomy should be minimized. After surgery, active monitoring is advisable to prevent unnecessary nephrectomy.

19.
J Inorg Biochem ; 257: 112599, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38749082

RESUMO

The urgent global health problem of antimicrobial resistance (AMR) calls for the discovery of new antibiotics with innovative modes of action while considering the low toxicity to mammalian cells. This paper proposes a novel strategy for designing antibiotics with selective bacterial toxicity by exploiting the positional differences of electron transport chains (ETC) in bacterial and mammalian cells. The focus is on cytochrome c (cyt C) and its maturation system in E. coli. The catalytic oxidative activity of metallophthalocyanine (MPc), which have a distinctive M-N4 structure, is being investigated. Unlike previous applications based on light-activated reactive oxygen species (ROS) generation, this study exploits the ability of MPcs to oxidize Fe2+ to Fe3+ in cyt C and catalyze the formation of disulfide bonds between cysteine residues to interfere with cyt C maturation, disrupt the bacterial respiratory chain and selectively kills bacteria. In contrast, in mammalian cells, these MPcs are located in the lysosomes and cannot access the ETC in the mitochondria, thus achieving selective bacterial toxicity. Two MPcs that showed effective antibacterial activity in a wound infection model were identified. This study provides a valuable reference for the design of novel antibiotics based on M-N4-based metal complex molecules.


Assuntos
Antibacterianos , Escherichia coli , Indóis , Antibacterianos/farmacologia , Antibacterianos/química , Escherichia coli/efeitos dos fármacos , Indóis/química , Indóis/farmacologia , Animais , Citocromos c/metabolismo , Citocromos c/química , Isoindóis , Humanos , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Espécies Reativas de Oxigênio/metabolismo , Oxirredução
20.
Chem Biol Drug Des ; 103(1): e14429, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38230769

RESUMO

Considering the therapeutic efficacy of Stachydrine on breast cancer (BC), this study aims to decipher the relevant mechanism. The effects of Stachydrine on BC cell viability, proliferation and apoptosis were firstly investigated. Then, Bioinformatics was applied to sort out the candidate interacting with Stachydrine as well as its expression and downstream target in BC. Relative expressions of genes of interest as well as proliferation- and apoptosis-related factors in BC cells were quantified through quantitative reverse-transcription PCR and western blot as appropriate. As a result, Stachydrine inhibited the proliferation, down-regulated the expressions of proliferating cell nuclear antigen and CyclinD1, enhanced cell cycle arrest and apoptosis, and up-regulated the levels of Cleaved caspase-3 and Cleaved caspase-9 in BC cells. Phospholipase A2 Group IIA (PLA2G2A) was predicted as the candidate interacting with Stachydrine and to be lowly expressed in BC. PLA2G2A silencing reversed while PLA2G2A overexpression reinforced the effects of Stachydrine. Decorin (DCN) was the downstream target of PLA2G2A and also lowly expressed in BC. PLA2G2A silencing counteracted yet overexpressed PLA2G2A strengthened the promoting effects of Stachydrine on DCN level. Collectively, Stachydrine inhibits the growth of BC cells to promote cell cycle arrest and apoptosis via PLA2G2A/DCN axis.


Assuntos
Neoplasias da Mama , MicroRNAs , Prolina/análogos & derivados , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Apoptose , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Linhagem Celular Tumoral , Fosfolipases A2 do Grupo II , Decorina/farmacologia
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