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1.
Toxicol Appl Pharmacol ; 486: 116933, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38631520

RESUMO

"White pollution" has a significant impact on male reproduction. Di-n-butyl phthalate (DBP) is one of the most important factors in this type of pollution. Currently, research from international sources has demonstrated the significant reproductive toxicity of DBP. However, most of these studies have focused mainly on hormones expression at the protein and mRNA levels and the specific molecular targets of DBP and its mechanisms of action remain unclear. In this study, we established a Sprague Dawley pregnant mouse model exposed to DBP, and all male offspring were immediately euthanized at birth and bilateral testes were collected. We found through transcriptome sequencing that cell apoptosis and MAPK signaling pathway are the main potential pathways for DBP induced reproductive toxicity. Molecular biology analyses revealed a significant increase in the protein levels of JNK1(MAPK8) and BAX, as well as a significant increase in the BAX/BCL2 ratio after DBP exposure. Therefore, we propose that DBP induces reproductive toxicity by regulating JNK1 expression to activate the MAPK signaling pathway and induce reproductive cell apoptosis. In conclusion, our study provides the first evidence that the MAPK signaling pathway is involved in DBP-induced reproductive toxicity and highlights the importance of JNK1 as a potential target of DBP in inducing reproductive toxicity.

2.
Med Oncol ; 41(5): 113, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38602586

RESUMO

Leukemia is a malignant disease of the hematopoietic system, in which clonal leukemia cells accumulate and inhibit normal hematopoiesis in the bone marrow and other hematopoietic tissues as a result of uncontrolled proliferation and impaired apoptosis, among other mechanisms. In this study, the anti-leukemic effect of a compound (SGP-17-S) extracted from Chloranthus multistachys, a plant with anti-inflammatory, antibacterial and anti-tumor effects, was evaluated. The effect of SGP-17-S on the viability of leukemic cell was demonstrated by MTT assay, cell cycle, and apoptosis were assessed by flow cytometry using PI staining and Annexin V/PI double staining. Combinations of network pharmacology and cellular thermal shift assay (CETSA) with western blot were used to validate agents that act on leukemia targets. The results showed that SGP-17-S inhibited the growth of leukemia cells in a time- and dose-dependent manner. SGP-17-S blocked HEL cells in the G2 phase, induced apoptosis, decreased Bcl-2 and caspase-8 protein expression, and increased Bax and caspase-3 expression. In addition, CETSA revealed that PARP1 is an important target gene for the inhibition of HEL cell growth, and SGP-17-S exerted its action on leukemia cells by targeting PARP1. Therefore, this study might provide new solutions and ideas for the treatment of leukemia.


Assuntos
Leucemia , Humanos , Leucemia/tratamento farmacológico , Ciclo Celular , Proliferação de Células , Divisão Celular , Anexina A5 , Poli(ADP-Ribose) Polimerase-1
3.
Chem Biodivers ; : e202301776, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38602834

RESUMO

A novel series of trifluoromethyl-containing quinazoline derivatives with a variety of functional groups was designed, synthesized, and tested for their antitumor activity by following a pharmacophore hybridization strategy. Most of the 20 compounds displayed moderate to excellent antiproliferative activity against five different cell lines (PC3, LNCaP, K562, HeLa, and A549). After three rounds of screening and structural optimization, compound 10 b was identified as the most potent one, with IC50 values of 3.02, 3.45, and 3.98 µM against PC3, LNCaP, and K562 cells, respectively, which were comparable to the effect of the positive control gefitinib. To further explore the mechanism of action of 10 b against cancer, experiments focusing on apoptosis induction, cell cycle arrest, and cell migration assay were conducted. The results showed that 10 b was able to induce apoptosis and prevent tumor cell migration, but had no effect on the cell cycle of tumor cells.

4.
Front Psychol ; 15: 1356554, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38533221

RESUMO

Background: The increasing prevalence of mental health issues among children and adolescents has prompted a growing number of researchers and practitioners to explore digital technology interventions, which offer convenience, diversity, and proven effectiveness in addressing such problems. However, the existing literature reveals a significant gap in comprehensive reviews that consolidate findings and discuss the potential of digital technologies in enhancing mental health. Methods: To clarify the latest research progress on digital technology to promote mental health in the past decade (2013-2023), we conducted two studies: a systematic review and meta-analysis. The systematic review is based on 59 empirical studies identified from three screening phases, with basic information, types of technologies, types of mental health issues as key points of analysis for synthesis and comparison. The meta-analysis is conducted with 10 qualified experimental studies to determine the overall effect size of digital technology interventions and possible moderating factors. Results: The results revealed that (1) there is an upward trend in relevant research, comprising mostly experimental and quasi-experimental designs; (2) the common mental health issues include depression, anxiety, bullying, lack of social emotional competence, and mental issues related to COVID-19; (3) among the various technological interventions, mobile applications (apps) have been used most frequently in the diagnosis and treatment of mental issues, followed by virtual reality, serious games, and telemedicine services; and (4) the meta-analysis results indicated that digital technology interventions have a moderate and significant effect size (g = 0.43) for promoting mental health. Conclusion: Based on these findings, this study provides guidance for future practice and research on the promotion of adolescent mental health through digital technology. Systematic review registration: https://inplasy.com/inplasy-2023-12-0004/, doi: 10.37766/inplasy2023.12.0004.

5.
Small Methods ; : e2400336, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38517268

RESUMO

Industrializing water electrolyzers demands better electrocatalysts, especially for the anodic oxygen evolution reaction (OER). The prevailing OER catalysts are Ir or Ru-based nanomaterials, however, they still suffer from insufficient stability. An alternative yet considerably less explored approach is to upgrade Rh, a known stable but moderately active element for OER electrocatalysis, via rational structural engineering. Herein, a precise synthesis of assembled RhRuFe trimetallenes (RhRuFe TMs) with an average thickness of 1 nm for boosting overall water splitting catalysis is reported. Favorable mass transport and optimized electronic structure collectively render RhRuFe TMs with an improved OER activity of an overpotential of 330 mV to deliver 10 mA cm-2, which is significantly lower than the Rh/C control (by 601 mV) and reported Rh-based OER electrocatalysts. In particular, the RhRuFe TMs-based water splitting devices can achieve the current density of 10 mA cm-2 at a low voltage of 1.63 V, which is among the best in the Rh-based bifunctional catalysts for electrolyzers. The addition of Fe in RhRuFe TMs can modulate the strain/electron distribution of the multi-alloy, which regulates the binding energies of H* and OH* in hydrogen and oxygen evolution reactions for achieving the enhanced bifunctional OER and HER catalysis is further demonstrated.

6.
Sci Rep ; 14(1): 7423, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38548882

RESUMO

This study investigates the impact of macroprudential policies on ecological footprint (EF) in the top 11 largest countries. This study uses country-level panel data from these countries, covering the period from 1992 to 2020. Findings indicate that macroprudential policies alleviates ecological footprint in the sample. Macroprudential policies primarily reduce the ecological footprint before medium quantile (50%) while the environmental benefits of the policies end in the later quantiles. Moreover, environmental policy stringency (EPS) amplifies the positive influence of macroprudential policies on environmental sustainability. Estimate results stay the same with basic regression results in the post-global financial crisis (GFC) period while the impact is positive in the pre-GFC period. Finally, other robust tests validate the findings reported in basic regression model. This study suggests that governments should customize various types of macroprudential policies while also considering environmental concerns. The achievement of a sustainable environment can be facilitated by the combined effects of macroprudential policies and EPS.

7.
J Biol Chem ; 300(4): 107139, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38447792

RESUMO

Androgen receptor (AR) is one of the key targets for the treatment of castration-resistant prostate cancer (CRPC). Current endocrine therapy can greatly improve patients with CRPC. However, with the change of pathogenic mechanism, acquired resistance often leads to the failure of treatment. Studies have shown that tanshinone IIA (TS-IIA) and its derivatives have significant antitumor activity, and have certain AR-targeting effects, but the mechanism is unknown. In this study, the TS-IIA analog TB3 was found to significantly inhibit the growth of CRPC in vitro and in vivo. Molecular docking, cellular thermal shift assay, and cycloheximide experiments confirmed that AR was the target of TB3 and promoted the degradation of AR. Furthermore, TB3 can significantly inhibit glycolysis metabolism by targeting the AR/PKM2 axis. The addition of pyruvic acid could significantly alleviate the inhibitory effect of TB3 on CRPC cells. Besides, the knockdown of AR or PKM2 also could reverse the effect of TB3 on CRPC cells. Taken together, our study suggests that TS-IIA derivative TB3 inhibits glycolysis to prevent the CRPC process by targeting the AR/PKM2 axis.

8.
Bioorg Med Chem ; 102: 117660, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38442524

RESUMO

Werner (WRN) syndrome protein is a multifunctional enzyme with helicase, ATPase, and exonuclease activities that are necessary for numerous DNA-related transactions in the human cell. Recent studies identified WRN as a synthetic lethal target in cancers. In this study, a series of new N-arylquinazoline-4-amine analogs were designed and synthesized based on structure optimization of quinazoline. The structures of the thirty-two newly synthesized compounds were confirmed by 1H NMR, 13C NMR and ESI-MS. The anticancer activity in vitro against chronic myeloid leukemia cells (K562), non-small cell lung cancer cells (A549), human prostate cancer cells (PC3), and cervical cancer cells (HeLa) of the target compounds was evaluated. Among them, the inhibition ratio of compounds 17d, 18a, 18b, 11 and 23a against four cancer cells at 5 µM concentration were more than 50 %. The IC50 values of compounds 18a and 18b were 0.3 ± 0.01 µM and 0.05 ± 0.02 µM in K562 cells respectively, compared with HeLa and A549 cells, 18a and 18b were more sensitive to K562 cells. In addition, the PC3 cells with WRN overexpression (PC3-WRN) was constructed, 18a and 18b and 23a were more sensitive to PC3-WRN cells compared with the control group cells (PC3-NC). Then, the cell viability of the novel WRN inhibitors were further assessed by colony formation assay. Compared with PC3-NC cells, 18b and 23a had obvious inhibitory effect on PC3-WRN cell at 1000 nM. In summary, these results indicated that the compounds 18b and 23a could be WRN protein inhibitor with potent anticancer properties in vitro.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , RecQ Helicases , Exodesoxirribonucleases/metabolismo , Células HeLa
9.
Heliyon ; 10(6): e27905, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38509991

RESUMO

This study examined the impact of economic uncertainty (EU) on Islamic banks (IBs) and conventional banks' (CBs) efficiency in countries that meet a standard where 1% share of Islamic banking assets is part of their total domestic banking sector assets. In addition, this study explored the moderating effect of country governance (CG) by employing the quantitative methodology based on secondary data from 2006 to 2021. The data analysis was done through ordinary least square, fixed effect model, and the random effect model. EU was found to enhance bank efficiency based on the basic regression results. CG moderated the positive effect of EU on bank efficiency. Additional robustness tests showed that EU was positively related to both types of banks' efficiency. The value of the paper is unique in that few papers have investigated the moderating effect of CG on the impact of EU on banks' efficiency, which enhances comprehension of EU and CG. These results highlight important policy implications whereby banks should continue to invest in and improve their risk management strategies. In addition, governments and regulatory bodies should prioritise good governance practices as these can improve banks' efficiency.

10.
Sci Rep ; 14(1): 4529, 2024 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-38402320

RESUMO

The increasing prevalence of antibiotic resistance in Cutibacterium acnes (C. acnes) requires the search for alternative therapeutic strategies. Antimicrobial peptides (AMPs) offer a promising avenue for the development of new treatments targeting C. acnes. In this study, to design peptides with the specific inhibitory activity against C. acnes, we employed a deep learning pipeline with generators and classifiers, using transfer learning and pretrained protein embeddings, trained on publicly available data. To enhance the training data specific to C. acnes inhibition, we constructed a phylogenetic tree. A panel of 42 novel generated linear peptides was then synthesized and experimentally evaluated for their antimicrobial selectivity and activity. Five of them demonstrated their high potency and selectivity against C. acnes with MIC of 2-4 µg/mL. Our findings highlight the potential of these designed peptides as promising candidates for anti-acne therapeutics and demonstrate the power of computational approaches for the rational design of targeted antimicrobial peptides.


Assuntos
Acne Vulgar , Anti-Infecciosos , Aprendizado Profundo , Humanos , Peptídeos Antimicrobianos , Filogenia , Anti-Infecciosos/farmacologia , Acne Vulgar/microbiologia , Propionibacterium acnes , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico
11.
Transl Lung Cancer Res ; 13(1): 34-45, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38405006

RESUMO

Background: Immunotherapy has opened up a new era of individualized treatment for non-small cell lung cancer (NSCLC) with negative driver gene mutations. Anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibodies have been the main options for immunotherapy over the past decade. Screening for predictive markers of anti-PD-1/PD-L1-responsive patients remains a focus in the field of immunotherapy, especially on the protein level in which relevant proteomic biomarkers are still lacking. Methods: We collected samples from 23 patients with NSCLC who received anti-PD-1/PD-L1 monotherapy and were followed up for three years. The proteomic profile of the tumor was obtained by mass spectrometry (MS). Meanwhile, we combined the RNA sequencing (RNA-seq) data of 27 patients treated with anti-PD-1/PD-L1 therapy in a previous study to establish an integrated gene network. Weighted correlation network analysis (WGCNA) and elastic network were implemented to screen the top gene modules for predicting treatment-responsive patients. Gene expression related mutational patterns were also retrieved for validation in the Memorial Sloan-Kettering Cancer Center (MSKCC) cohort. Results: Our results showed the gene expression profile of MOXD1, PHAF1, KRT7, ANKRD30A, TMEM184A, KIR3DL1, and KCNK4 could better predict the durable response to anti-PD-1/PD-L1 therapy, with the specificity and sensitivity of 0.76 and 0.6, respectively. Besides, the mutational gene profile associated with these genes also suggested an association with favorable response in the MSKCC cohort. Patient-specific protein-protein interaction (PPI) network also indicated strong correlation among KRT7, TMEM184A and ANKRD30A. Conclusions: Our study indicated that key gene signatures identified by machine learning model could be utilized for clinical screening of patients who might benefit from anti-PD-1 therapy. Further mechanistic investigations around these genes are warranted.

12.
Surg Endosc ; 38(4): 1709-1722, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38413470

RESUMO

BACKGROUND: Postoperative anastomotic leakage (PAL) is a serious complication of gastric cancer surgery. Although perioperative management has made considerable progress, anastomotic leakage (AL) cannot always be avoided. The purpose of this study is to evaluate whether intraoperative leak testing (IOLT) can reduce the incidence of PAL and other postoperative outcomes in gastric cancer surgery. MATERIALS AND METHODS: In this meta-analysis, we searched the PubMed, Embase, and Cochrane Library databases for clinical trials to assess the application of IOLT in gastric cancer surgery. All patients underwent laparoscopic radical gastrectomy for gastric cancer surgery. Studies comparing the postoperative outcomes of IOLT and no intraoperative leak testing (NIOLT) were included. Quality assessment, heterogeneity, risk of bias, and the level of evidence of the included studies were evaluated. PAL, anastomotic-related complications, 30-day mortality, and reoperation rates were compared between the IOLT and NIOLT group. RESULTS: Our literature search returned 721 results, from which six trials (a total of 1,666 patients) were included in our meta-analysis. Statistical heterogeneity was low. The primary outcome was PAL. IOLT reduced the incidence of PAL [2.09% vs 6.68%; (RR = 0.31, 95% Cl 0.19-0.53, P < 0.0001]. Anastomotic-related complications, which included bleeding, leakage, and stricture, were significantly higher in the NIOLT group than in the IOLT group [3.24% VS 10.85%; RR = 0.30, 95% Cl 0.18-0.53, P < 0.0001]. Moreover, IOLT was associated with lower reoperation rates [0.94% vs 6.83%; RR = 0.18, 95% CI 0.07-0.43, P = 0.0002]. CONCLUSION: Considering the observed lower incidence of postoperative anastomotic leakage (PAL), anastomotic-related complications, and reoperation rates, IOLT appears to be a promising option for gastric cancer surgery. It warrants further study before potential inclusion in future clinical guidelines.


Assuntos
Fístula Anastomótica , Neoplasias Gástricas , Humanos , Fístula Anastomótica/epidemiologia , Fístula Anastomótica/etiologia , Fístula Anastomótica/prevenção & controle , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/complicações , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Gastrectomia/efeitos adversos , Gastrectomia/métodos , Anastomose Cirúrgica/efeitos adversos
13.
PLoS One ; 19(1): e0296363, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38181052

RESUMO

This study investigates the impact of macroprudential policies on CO2 emissions in G7 and BRIC countries using country-level panel data from 11 countries, covering the period from 1992 to 2020. The findings indicate that macroprudential policies alleviate CO2 emissions in the sample. Quantile regression results reveal that policies can exacerbate CO2 emissions in countries with high levels of CO2 emissions due to carbon leakage. The positive impact of macroprudential policies on sustainable development can be strengthened by high level of globalisation. Moreover, the influence of macroprudential policies stayed the same based on the basic regression results during the post-global financial crisis (GFC) period, while the impact was positive in the pre-GFC period. Finally, robust tests validated the findings reported in the basic regression model. From this, policymakers should prioritise sustainable economic growth when implementing macroprudential policies and leverage the influence of globalisation to amplify their impact on CO2 emissions. Furthermore, it is crucial to strengthen environmental regulations to prevent carbon leakage that result from industries seeking lenient standards.


Assuntos
Dióxido de Carbono , Carbono , Desenvolvimento Econômico , Indústrias , Políticas
14.
Science ; 383(6680): 305-311, 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38236973

RESUMO

On 6 February 2023, two large earthquakes (moment magnitude 7.8 and 7.6) shocked a vast area of southeastern Türkiye and northern Syria, leading to heavy casualties and economic loss. To investigate the rupture process over multiple fault segments, we performed a comprehensive analysis of local seismic and geodetic data and determined supershear ruptures on the initial branch and the Pazarcik and Erkenek segments and subshear ruptures on the Amanos segment of event 1. The bilateral rupture of event 2 also presents distinct sub- and supershear velocities. The dynamic stress of the branch fault rupture triggered the Pazarcik segment initial rupture at a point 9 kilometers west of the junction of these two faults, boosting the supershear rupture of the Pazarcik segment of the main fault. The geometry and prestress level of multiple segments controlled the rupture behaviors and influenced the ground shaking intensity.

15.
Eur J Pharm Sci ; 194: 106706, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38244809

RESUMO

Cervical cancer is the leading cause of death among gynecological malignant tumors, especially due to the poor prognosis of patients with advanced tumors due to recurrence, metastasis, and chemotherapy resistance. Therefore, exploring new antineoplastic drugs with high efficacy and low toxicity may bring new expectations in patients with cervical cancer. Natural products and their derivatives exert an antitumor activity. Therefore, in this work, combined with network pharmacology analysis and experimental validation, we investigated the anti-cervical cancer activity and molecular mechanism of a new trifluoromethyl quinoline (FKL) derivative in vivo and in vitro. FKL117 inhibited the proliferation of cervical cancer cells in a dose and time-dependent manner, induced apoptosis in HeLa cells, arrested the cell cycle in the G2/M phase, and regulated the expression of the apoptotic and cell cycle-related proteins Bcl-2, Bax, cyclin B1, and CDC2. We used online databases to obtain HDAC1 as one of the possible targets of FKL117 and the target binding and binding affinity were modeled by molecular docking. The results showed that FKL117 formed a hydrogen bond with HDAC1 and had good binding ability. We found that FKL117 targeted to inhibit the expression and function of HDAC1 and increased the acetylation of histone H3 and H4, which was also confirmed in vivo. The migration of HMGB1 from the nucleus to the cytoplasm further verified the above results. In conclusion, our study suggested that FKL117 might be used as a novel candidate for targeting the inhibition of HDAC1 against cervical cancer.


Assuntos
Quinolinas , Neoplasias do Colo do Útero , Feminino , Humanos , Histonas/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Células HeLa , Acetilação , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Apoptose , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Proliferação de Células , Histona Desacetilase 1/metabolismo
16.
Nano Lett ; 24(5): 1602-1610, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38286023

RESUMO

Metallene materials with atomic thicknesses are receiving increasing attention in electrocatalysis due to ultrahigh surface areas and distinctive surface strain. However, the continuous strain regulation of metallene remains a grand challenge. Herein, taking advantage of autocatalytic reduction of Cu2+ on biaxially strained, carbon-intercalated Ir metallene, we achieve control over the carbon extraction kinetics, enabling fine regulation of carbon intercalation concentration and continuous tuning of (111) in-plane (-2.0%-2.6%) and interplanar (3.5%-8.8%) strains over unprecedentedly wide ranges. Electrocatalysis measurements reveal the strain-dependent activity toward hydrogen evolution reaction (HER), where weakly strained Ir metallene (w-Ir metallene) with the smallest lattice constant presents the highest mass activity of 2.89 A mg-1Ir at -0.02 V vs reversible hydrogen electrode (RHE). Theoretical calculations validated the pivotal role of lattice compression in optimizing H binding on carbon-intercalated Ir metallene surfaces by downshifting the d-band center, further highlighting the significance of strain engineering for boosted electrocatalysis.

17.
Eur J Pharm Sci ; 192: 106660, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38052256

RESUMO

A series of novel prenylated chalcone derivatives with broad spectrum anticancer potential were designed and synthesized. Some of the synthesized target compounds showed potent anti-proliferative activities toward LNCaP (prostate cancer cell line), K562 (human leukemia cells), A549 (human lung carcinoma cell line) and HeLa (cervical cancer cell line) cell lines. Among of the active compounds, (E)-1-(4-(2-(diethylamino)ethoxy)-2-hydroxy-6-methoxy-3-(3-methylbut-2-en-1-yl)phenyl)-3-(pyridin-3-yl)prop-2-en-1-one (C36) was directly interacted with protein kinase B (PKB), also known as AKT, significantly inhibited the pPI3K, pAKT(Ser473) protein levels to repress the growth of cancer cells by inducing apoptosis, arresting cell cycle. Our studies provide support for prenylated chalcone derivatives potential applications in cancer treatment as a potential AKT inhibitor.


Assuntos
Antineoplásicos , Chalcona , Chalconas , Humanos , Chalconas/farmacologia , Proteínas Proto-Oncogênicas c-akt/farmacologia , Proliferação de Células , Chalcona/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Apoptose , Relação Estrutura-Atividade
18.
Biochem Pharmacol ; 219: 115960, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38049008

RESUMO

Prostate cancer is the most common malignant tumor among men worldwide. Currently, the main treatments are radical prostatectomy, radiotherapy, chemotherapy, and endocrine therapy. However, most of them are poorly effective and induce side effects. Polo-like kinase 1 (PLK1) regulates cell cycle and mitosis. Its inhibitor BI2536 promotes the therapeutic effect of nilotinib in chronic myeloid leukemia, enhances the sensitivity of neural tube cell tumors to radiation therapy and PLK1 silencing enhances the sensitivity of squamous cell carcinoma to cisplatin. Therefore, the aim of this study was to evaluate the effect of the PLK1 inhibitor L-shaped ortho-quinone analog TE6 on prostate cancer. In vitro on prostate cancer cells showed that TE6 inhibited PLK1 protein expression and consequently cell proliferation by blocking the cell cycle at G2 phase. In vivo on a subcutaneous tumor model in nude mice confirmed that TE6 effectively inhibited tumor growth in nude mice, inhibited PLK1 expression and regulated the expression of cell cycle proteins such as p21, p53, CDK1, Cdc25C, and cyclinB1. Thus, PLK1 was identified as the target protein of TE6, these results reveal the critical role of PLK1 in the growth and survival of prostate cancer and point out the ability of TE6 on targeting PLK1, being a potential drug for prostate cancer therapy.


Assuntos
Fase G2 , Neoplasias da Próstata , Quinonas , /antagonistas & inibidores , Quinonas/química , Quinonas/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Fase G2/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Xenoenxertos , Humanos , Animais , Camundongos , Masculino , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Linhagem Celular Tumoral , Estrutura Molecular
19.
Int J Biol Macromol ; 255: 128305, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37992942

RESUMO

Leukemia is a type of malignant hematological disease that is generally resistant to chemotherapy and has poor therapeutic outcomes. Werner (WRN) DNA helicase, an important member of the RecQ family of helicases, plays an important role in DNA repair and telomere stability maintenance. WRN gene dysfunction leads to premature aging and predisposes humans to various types of cancers. However, the biological function of WRN in cancer remains unknown. In this study, the expression of this RecQ family helicase was investigated in different types of leukemia cells, and the leukemia cell line K562 with high WRN expression was selected to construct a WRN knockdown cell line. The results showed that WRN knockdown inhibited leukemia occurrence and development by regulating the proliferation, cell cycle, differentiation, and aging of cells and other biological processes. The results of transcriptome sequencing revealed that WRN promoted the sensitivity of leukemia cells to the DNA damage inducer Etoposide by regulating cell cycle-related proteins, such as CDC2, cyclin B1, p16, and p21, as well as key proteins in DNA damage repair pathways, such as p53, RAD50, RAD51, and MER11. Our findings show that WRN helicase is a promising potential target for leukemia treatment, providing new ideas for the development of targeted drugs against leukemia.


Assuntos
Exodesoxirribonucleases , Leucemia , Humanos , Helicase da Síndrome de Werner/genética , Helicase da Síndrome de Werner/metabolismo , Exodesoxirribonucleases/genética , Exodesoxirribonucleases/metabolismo , RecQ Helicases/genética , RecQ Helicases/metabolismo , Ciclo Celular/genética , Reparo do DNA , Dano ao DNA , Leucemia/genética
20.
Int J Surg ; 110(2): 1196-1205, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37988416

RESUMO

OBJECTIVE: Postoperative staple line leakage (SLL) after sleeve gastrectomy (SG) is a rare but serious complication. Many surgeons routinely test anastomosis with an intraoperative leak test (IOLT) as part of the SG procedure. This meta-analysis aims to determine whether an IOLT plays a role in reducing the rate of postoperative staple line related complications in patients who underwent SG. METHODS: The authors searched the PubMed, Web of science, the Cochrane Library, and Clinical Trials.gov databases for clinical studies assessing the application of IOLT in SG. The primary endpoint was the development of postoperative SLL. Secondary endpoints included the postoperative bleeding, 30 days mortality rates, and 30 days readmission rates. RESULTS: Six studies totaling 469 588 patients met the inclusion criteria. Our review found that the SLL rate was 0.38% (1221/ 324 264) in the IOLT group and 0.31% (453/ 145 324) in the no intraoperative leak test (NIOLT) group. Postoperative SLL decreased in the NIOLT group compared with the IOLT group (OR=1.27; 95% CI: 1.14-1.42, P =0.000). Postoperative bleeding was fewer in the IOLT group than that in the NIOLT group (OR 0.79; 95% CI: 0.72-0.87, P =0.000). There was no significant difference between the IOLT group and the NIOLT group regarding 30 days mortality rates and 30 days readmission rates ( P >0.05). CONCLUSION: IOLT was correlated with an increase in SLL when included as a part of the SG procedure. However, IOLT was associated with a lower rate of postoperative bleeding. Thus, IOLT should be considered in SG in the situation of suspected postoperative bleeding.


Assuntos
Laparoscopia , Obesidade Mórbida , Humanos , Fístula Anastomótica/diagnóstico , Fístula Anastomótica/etiologia , Fístula Anastomótica/prevenção & controle , Estudos Retrospectivos , Obesidade Mórbida/cirurgia , Grampeamento Cirúrgico/efeitos adversos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Hemorragia Pós-Operatória/etiologia , Gastrectomia/efeitos adversos , Gastrectomia/métodos , Laparoscopia/métodos , Resultado do Tratamento
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