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1.
BMJ Open Diabetes Res Care ; 12(5)2024 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-39366717

RESUMO

INTRODUCTION: This study aimed to assess recent trends in the US use of glucagon-like peptide-1 receptor agonist (GLP-1 RA) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) in people with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD), including incident use following newly diagnosed ASCVD. RESEARCH DESIGN AND METHODS: This real-world, retrospective observational study used de-identified data from the TriNetX Dataworks-USA network. A longitudinal analysis of cross-sectional data (interval: January 01, 2018 to December 31, 2022) assessed the yearly prevalent use of GLP-1 RA and SGLT2i. A nested cohort study (January 01, 2017 to January 31, 2023) assessed the proportions of patients with T2D newly prescribed GLP-1 RAs and SGLT2is after incident ASCVD diagnosis. RESULTS: Prevalent use of GLP-1 RA and/or SGLT2i increased from 9.2% of patients in 2018 to 27.1% in 2022, with eligible annual patient numbers ranging from 279,474 to 348,997. GLP-1 RA-alone use rose from 5.2% to 9.9% and SGLT2i-alone use rose from 2.8% to 12.2% over this interval. Incident use of GLP-1 RA and/or SGLT2i within the year following ASCVD diagnosis increased from 5.9% to 17.0% (2018-2022). For GLP-1 RA alone, this increase was from 3.6% to 7.8%, while for SGLT2i alone, it was from 1.8% to 7.0%. CONCLUSIONS: Use of GLP-1 RAs/SGLT2is in patients with T2D and ASCVD has increased in recent years in the USA, but remains suboptimal given the prevalence of ASCVD and its high morbidity and mortality.


Assuntos
Aterosclerose , Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Feminino , Masculino , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Estudos Retrospectivos , Aterosclerose/epidemiologia , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Idoso , Estudos Transversais , Hipoglicemiantes/uso terapêutico , Estudos Longitudinais , Seguimentos
2.
Pragmat Obs Res ; 15: 173-183, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39386162

RESUMO

Purpose: Observational research provides valuable insights into treatments used in patient populations in real-world settings. However, confounding is likely to occur if there are differences in patient characteristics associated with both the exposure and outcome between the groups being evaluated. One approach to reduce confounding and facilitate unbiased comparisons is inverse probability of treatment weighting (IPTW) using propensity scores. Machine learning (ML) and entropy balancing can potentially be used in generating propensity scores for IPTW, but there is limited literature on this application. We aimed to assess the feasibility of applying these methods for reducing confounding in observational studies. These methods were assessed in a study comparing cardiovascular outcomes in adults with type 2 diabetes and established atherosclerotic cardiovascular disease taking once-weekly glucagon-like peptide-1 receptor agonists or dipeptidyl peptidase-4 inhibitors. Methods: We applied advanced methods to generate the propensity scores compared to the original logistic regression method in terms of covariate balance. After calculating weights, a weighted Cox proportional hazards model was used to calculate the sample average treatment effect. Support Vector Classification, Support Vector Regression, XGBoost, and LightGBM were the ML models used. Entropy balancing was also performed on features identified in the original cardiovascular outcomes study. Results: Accuracy (range: 0.71 to 0.73), area under the curve (0.77 to 0.79), precision (0.53 to 0.60), recall (0.66 to 0.68), and F1 score (0.60 to 0.64) were similar between all of the advanced propensity score methods and traditional logistic regression. Among ML models, only XGBoost achieved balance in all measured baseline characteristics between the two treatment groups, closely approximating the performance of the original logistic regression. Entropy balancing weights provided the best performance among all models in balancing baseline characteristics, achieving near perfect balancing. Conclusion: Among the advanced methods examined, entropy balancing weights performed the best for optimizing balancing and can produce similar results compared to traditional logistic regression.

3.
BMC Cardiovasc Disord ; 24(1): 553, 2024 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-39395939

RESUMO

BACKGROUND: Among heart failure patients with obesity, the prognosis is better than those with normal weight, a phenomenon known as the obesity paradox. However, it is unclear whether lipoprotein levels play a mediating role in the machine of the obesity paradox. METHODS: The study included 1663 heart failure patients hospitalized from January, 2019 through August, 2022. Kaplan-Meier survival analysis and Log-rank tests were performed for three endpoints in order to determine cumulative event-free survival. We investigated the correlation between Body Max Index (BMI) and outcomes by multifactorial Cox models. Mediation analysis was applied to study the presence and magnitude of mediation effects of triglyceride, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein A1 and apolipoprotein B, with the association between BMI and endpoints. RESULTS: In MACCEs, the median follow-up period was 679 days. In Cox model, compared with the underweight group, a high BMI level was significantly associated with lower all-cause mortality (HR=0.47, 95%CI 0.31~0.69, p<0.001, obese vs underweight), cardiovascular mortality (HR=0.46, 95%CI 0.30~0.73, p<0.001, obese vs underweight) and the incidence of MACCEs (HR=0.68, 95%CI 0.53~0.88, p=0.003, obese vs underweight). Mediation analysis revealed that TG was the strongest mediator between BMI and endpoints, with proportions of mediated effects of 6.6% (95%CI 2.2%~18.0%, p=0.0258, in all-cause death),7.0% (95%CI 2.3%~18.9%, p=0.0301, in cardiovascular death) and 10.2% (95%CI 3.3%~27.4%, p=0.0185, in MACCEs). CONCLUSIONS: There is an "obesity paradox" in patients with heart failure, and lipoprotein levels especially triglyceride mediate the association between BMI and cardiovascular outcomes.


Assuntos
Biomarcadores , Índice de Massa Corporal , Insuficiência Cardíaca , Lipoproteínas , Análise de Mediação , Obesidade , Humanos , Masculino , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Feminino , Idoso , Obesidade/sangue , Obesidade/diagnóstico , Obesidade/mortalidade , Obesidade/epidemiologia , Obesidade/complicações , Pessoa de Meia-Idade , Medição de Risco , Biomarcadores/sangue , Lipoproteínas/sangue , Fatores de Tempo , Fatores de Risco , Prognóstico , Intervalo Livre de Progressão , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Incidência
4.
Front Cell Dev Biol ; 12: 1435718, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39282473

RESUMO

Hematogenous metastasis involves cancer cell migration to different locations from the primary tumor through the blood circulation. Von Willebrand factor (VWF) has been shown to play an important role in tumor cell adhesion to and extravasation from the endothelial cell lining of blood vessel walls during cancer metastasis. VWF may contribute to this process by interacting with tumor cells, endothelial cells, and platelets through various cell membrane receptors, such as platelet glycoprotein (GP)Ibα, P-selectin, ανß3 and αIIbß3 integrins, and glycocalyx. Blood flow can mechanically extend and activate VWF to bind platelets and associate intermolecularly with other VWF molecules in plasma or on the surface of endothelial cells, cancer cells, or platelets. This suggests a mechanoregulatory role of VWF in mediating the interactions between VWF and these cells to promote cancer cell adhesion to blood vessels. In this review, we will summarize the current knowledge of VWF function and the role of hydrodynamic forces in hematogenous cancer metastasis.

5.
BMC Microbiol ; 24(1): 345, 2024 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-39271978

RESUMO

BACKGROUND: Saccharomyces cerevisiae has been considered a harmless yeast, but in recent years, increasing evidence has shown that it can cause disease in humans, especially invasive infections in infants/children and vulvovaginal infections in women. This study aimed to investigate the clinical information and antifungal susceptibility of clinical cases with S. cerevisiae and establish a foundation for the prevention and treatment of fungal infections. METHODS: This study was conducted from May 2018 to May 2023 at a national regional medical center in Southwest China for women and children. The demographic and clinical characteristics of patients isolated with S. cerevisiae were collected and analyzed. All the isolates were cultured on Sabouraud medium plates and identified by MALDI-TOF MS. The antifungal susceptibility of S. cerevisiae to 10 agents (amphotericin B, fluconazole, itraconazole, voriconazole, micafungin, caspofungin, terbinafine and 5-flucytosine) was determined via the microdilution broth method to determine the minimum inhibitory concentrations (MICs). RESULTS: A total of 75 cases of S. cerevisiae isolated from patients with vulvovaginal candidiasis (VVC, 44 cases), pneumonia (13 cases), or diarrhea (18 cases) were included after data review. The MICs of voriconazole and flucytosine for S. cerevisiae isolated from different body sites differed, with higher resistance in intestinal isolates. In this study, S. cerevisiae caused VVC, but there was no clear evidence that it was involved in pneumonia or diarrhea. Compared with those of Candida albicans, the primary pathogen of VVC, the MICs of fluconazole (11.96 ± 5.78 µg/mL vs. 67.64 ± 16.62 µg/mL, p = 0.002), itraconazole (0.77 ± 0.19 µg/mL vs. 2.31 ± 0.53 µg/mL, p = 0.008), voriconazole (0.22 ± 0.09 µg/mL vs. 5.02 ± 1.09 µg/mL, p < 0.001), and terbinafine (10.41 ± 0.84 µg/mL vs. 14.93 ± 4.77 µg/mL, p < 0.001) for S. cerevisiae (isolated from the genital tract) were significantly lower, while those of micafungin (0.14 ± 0.01 µg/mL vs. 0.06 ± 0.01 µg/mL, p < 0.001) and caspofungin (0.27 ± 0.04 µg/mL vs. 0.06 ± 0.01 µg/mL, p < 0.001) were significantly greater. CONCLUSION: Azoles remain the recommended regimen for S. cerevisiae-related VVC, and the use of amphotericin B vaginal effervescent tablets could be considered for the treatment of azole-resistant isolates. The antifungal susceptibility of S. cerevisiae varies according to the isolated source, and the pathogenicity trend of S. cerevisiae should be studied.


Assuntos
Antifúngicos , Testes de Sensibilidade Microbiana , Saccharomyces cerevisiae , Antifúngicos/farmacologia , Humanos , Feminino , China , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/isolamento & purificação , Criança , Pré-Escolar , Lactente , Adulto , Candidíase Vulvovaginal/microbiologia , Masculino , Adolescente , Farmacorresistência Fúngica , Pessoa de Meia-Idade , Adulto Jovem , Micoses/microbiologia
6.
Oncogene ; 43(38): 2868-2884, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39154122

RESUMO

The dysregulation of long non-coding RNAs (lncRNAs) are involved in regulating tumor progression in multiple manner. However, little is known about whether lncRNA is involved in the translation regulation of proteins. Here, we identified that the suppressor of inflammatory macrophage apoptosis lncRNA (SIMALR) was highly expressed in nasopharyngeal carcinoma (NPC) tissues by analyzing the lncRNA microarray. Clinically, the high expression of SIMALR served as an independent predictor for inferior prognosis in NPC patients. SIMALR functioned as an oncogenic lncRNA that promoted the proliferation and metastasis of NPC cells in vitro and in vivo. Mechanistically, SIMALR served as a critical accelerator of protein synthesis by binding to eEF1A2 (eukaryotic translation elongation factor 1 alpha 2), one of the most crucial regulators in the translation machinery of the eukaryotic cells, and enhancing its endogenous GTPase activity. Furthermore, SIMALR mediated the activation of eEF1A2 phosphorylation to accelerate the translation of ITGB4/ITGA6, ultimately promoting the malignant phenotype of NPC cells. In addition, N-acetyltransferase 10 (NAT10) enhanced the stability of SIMALR and caused its overexpression in NPC through the N4-acetylcytidine (ac4C) modification. In sum, our results illustrate SIMALR functions as an accelerator for protein translation and highlight the oncogenic role of NAT10-SIMALR-eEF1A2-ITGB4/6 axis in NPC.


Assuntos
Regulação Neoplásica da Expressão Gênica , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Fator 1 de Elongação de Peptídeos , RNA Longo não Codificante , Animais , Feminino , Humanos , Masculino , Camundongos , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Camundongos Nus , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/metabolismo , Fator 1 de Elongação de Peptídeos/genética , Fator 1 de Elongação de Peptídeos/metabolismo , Prognóstico , Biossíntese de Proteínas , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
7.
Stem Cell Res Ther ; 15(1): 242, 2024 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-39098899

RESUMO

BACKGROUND: Mesenchymal stromal cell (MSC)-derived exosomes (MSC-Exo) have been recognized for their significant role in regulating macrophage polarization, a process crucial to the pathogenesis of abdominal aortic aneurysm (AAA). However, the therapeutic effects of MSC-Exo on AAA remain largely unexplored. Therefore, this study aimed to investigate the functional and mechanistic aspects of MSC-Exo in the progression of AAA. METHODS: The MSC-derived exosomes were characterized using Transmission Electron Microscopy, Nanoparticle Tracking Analysis, and Western blotting. An experimental mouse model of AAA was established through the administration of angiotensin II (Ang II) in male apoe-/- mice and calcium chloride (CaCl2) in male C57/B6 mice, with subsequent tail vein injection of exosomes to evaluate their efficacy against AAA. Macrophage polarization was assessed using immunofluorescence staining and WB analysis. Mechanistic analysis was performed using 4D Label-free Proteomics analysis. RESULTS: We found that intravenous administration of MSC-Exo induced M2 polarization of macrophages within an inflammatory environment, effectively impeding AAA development in Ang II or CaCl2-induced AAA model. The therapeutic efficacy of MSC-Exo treatment was dependent on the presence of macrophages. Mechanistically, MSC-Exo suppressed the levels of cluster of differentiation 74 (CD74), modulating macrophage polarization through the TSC2-mTOR-AKT pathway. These findings highlight the potential of MSC-Exo as a therapeutic strategy for AAA by modulating macrophage polarization.


Assuntos
Aneurisma da Aorta Abdominal , Exossomos , Macrófagos , Células-Tronco Mesenquimais , Camundongos Endogâmicos C57BL , Animais , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Exossomos/metabolismo , Camundongos , Células-Tronco Mesenquimais/metabolismo , Macrófagos/metabolismo , Macrófagos/imunologia , Masculino , Modelos Animais de Doenças , Angiotensina II/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Antígenos de Histocompatibilidade Classe II/genética , Cloreto de Cálcio
8.
JACC Asia ; 4(8): 609-620, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39156513

RESUMO

Background: Homocysteine (Hcy) is a recognized cardiovascular disease (CVD) risk factor linked with atherosclerosis. However, the association between Hcy and myocardial injury is little known. Objectives: This study aimed to examine the associations between Hcy metabolism, subclinical myocardial injury, and cardiovascular mortality. Methods: We included 10,871 participants without diagnosed CVD. Generalized linear regression was used to investigate the relationship between Hcy-related indicators (plasma total Hcy [tHcy], vitamin B12, and folate) and myocardial injury biomarkers (high-sensitivity troponin T [hs-cTnT], high-sensitivity troponin I [hs-cTnI] measured using 3 assays [Abbott, Siemens, and Ortho], and N-terminal pro-B-type natriuretic peptide [NT-proBNP]). Results: Among 10,871 participants, the weighted mean levels for tHcy, folate, and vitamin B12 were 8.58 µmol/L, 32.43 nmol/L, and 447.08 pmol/L, respectively. Plasma tHcy levels were positively associated with elevated hs-cTnT, hs-cTnI, and NT-proBNP, whereas folate and vitamin B12 were not inversely related to myocardial injury biomarkers. Multivariable-adjusted odds ratios for elevated hs-cTnT (19 ng/L) and NT-proBNP (125 pg/mL) per doubling of tHcy were 2.80 (95% CI: 1.17-6.73; P < 0.001) and 1.58 (95% CI: 1.20-2.08; P < 0.001), respectively. The associations of tHcy levels with elevated hs-cTnI (Abbott: 28 ng/L; Siemens: 46.5 ng/L; Ortho: 11 ng/L) were consistent. Indirect effects of tHcy on cardiovascular mortality risk via hs-cTnT and NT-proBNP explained up to 26.6% and 12.3% of the total effect, respectively. Conclusions: Plasma tHcy, not folate or vitamin B12, is significantly associated with elevated hs-cTnT, hs-cTnI, and NT-proBNP in adults without CVD. Subclinical myocardial injury may substantially mediate Hcy-related cardiovascular mortality risk.

9.
Cell Rep ; 43(8): 114527, 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39046873

RESUMO

The paracrine actions of adipokine plasminogen activator inhibitor-1 (PAI-1) are implicated in obesity-associated tumorigenesis. Here, we show that PAI-1 mediates extracellular matrix (ECM) signaling via epigenetic repression of DKK1 in endometrial epithelial cells (EECs). While the loss of DKK1 is known to increase ß-catenin accumulation for WNT signaling activation, this epigenetic repression causes ß-catenin release from transmembrane integrins. Furthermore, PAI-1 elicits the disengagement of TIMP2 and SPARC from integrin-ß1 on the cell surface, lifting an integrin-ß1-ECM signaling constraint. The heightened interaction of integrin-ß1 with type 1 collagen (COL1) remodels extracellular fibrillar structures in the ECM. Consequently, the enhanced nanomechanical stiffness of this microenvironment is conducive to EEC motility and neoplastic transformation. The formation of extensively branched COL1 fibrils is also observed in endometrial tumors of patients with obesity. The findings highlight PAI-1 as a contributor to enhanced integrin-COL1 engagement and extensive ECM remodeling during obesity-associated neoplastic development.


Assuntos
Matriz Extracelular , Integrina beta1 , Obesidade , Inibidor 1 de Ativador de Plasminogênio , beta Catenina , Humanos , Obesidade/metabolismo , Obesidade/patologia , Feminino , Inibidor 1 de Ativador de Plasminogênio/metabolismo , beta Catenina/metabolismo , Integrina beta1/metabolismo , Matriz Extracelular/metabolismo , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Animais , Osteonectina/metabolismo , Osteonectina/genética , Colágeno/metabolismo , Endométrio/metabolismo , Endométrio/patologia , Colágeno Tipo I/metabolismo , Membrana Celular/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Peptídeos e Proteínas de Sinalização Intercelular
10.
Syst Rev ; 13(1): 172, 2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-38971762

RESUMO

BACKGROUND: Allergic rhinitis (AR) is a common inflammatory disease of the nasal mucosa that is characterized by symptoms such as sneezing, nasal congestion, nasal itching, and rhinorrhoea. In recent years, acupoint herbal patching (AHP) therapy has gained a growing interest as a potential management option for AR. This systematic review and meta-analysis will evaluate the clinical research evidence on the effectiveness and safety of AHP as a treatment option for AR outside of the Sanfu or Sanjiu days (summer or winter solstice). The results of this review will provide up-to-date evidence-based guidance for healthcare providers and individuals seeking alternative treatments for AR. METHODS: A comprehensive search of electronic databases (PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, China National Knowledge Infrastructure (CNKI), CQVIP, Sino-Med, and Wanfang Databases) will be conducted from their inception to June 2023. The inclusion criteria will be limited to randomized controlled trials that evaluate the effectiveness or efficacy of non-Sanfu or non-Sanjiu AHP for AR. The primary outcome measure will be the total nasal symptom score. The methodological quality of included studies will be assessed using the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2), and meta-analyses will be performed using RevMan (V.5.3) statistical software. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach will be used to determine the certainty of evidence. DISCUSSION: This systematic review and meta-analysis will provide valuable insights into the effectiveness and safety of non-Sanfu or non-Sanjiu AHP as a treatment option for AR. The study aims to produce a high-quality review by adhering to PRISMA-P guidelines and using clinical guideline recommended outcome measures. The results of this review may offer additional treatment options for AR patients who seek complementary and alternative therapies, and hold significant implications for future research in this field. Overall, this study has the potential to inform clinical practice and improve patient outcomes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022181322.


Assuntos
Pontos de Acupuntura , Metanálise como Assunto , Rinite Alérgica , Revisões Sistemáticas como Assunto , Humanos , Rinite Alérgica/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Projetos de Pesquisa
11.
J Dermatol Sci ; 115(1): 33-41, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38955622

RESUMO

BACKGROUND: Tryptophan metabolism dysregulation has been observed in vitiligo. However, drawing a mechanistic linkage between this metabolic disturbance and vitiligo pathogenesis remains challenging. OBJECTIVE: Aim to reveal the characterization of tryptophan metabolism in vitiligo and investigate the role of tryptophan metabolites in vitiligo pathophysiology. METHODS: LC-MS/MS, dual-luciferase reporter assay, ELISA, qRT-PCR, small interfering RNA, western blotting, and immunohistochemistry were employed. RESULTS: Kynurenine pathway activation and KYAT enzyme-associated deviation to kynurenic acid (KYNA) in the plasma of stable non-segmental vitiligo were determined. Using a public microarray dataset, we next validated the activation of kynurenine pathway was related with inflammatory-related genes expression in skin of vitiligo patients. Furthermore, we found that KYNA induced CXCL10 upregulation in keratinocytes via AhR activation. Moreover, the total activity of AhR agonist was increased while the AhR concentration per se was decreased in the plasma of vitiligo patients. Finally, higher KYAT, CXCL10, CYP1A1 and lower AhR expression in vitiligo lesional skin were observed by immunohistochemistry staining. CONCLUSION: This study depicts the metabolic and genetic characterizations of tryptophan metabolism in vitiligo and proposes that KYNA, a tryptophan-derived AhR ligand, can enhance CXCL10 expression in keratinocytes.


Assuntos
Quimiocina CXCL10 , Queratinócitos , Ácido Cinurênico , Receptores de Hidrocarboneto Arílico , Pele , Triptofano , Regulação para Cima , Vitiligo , Humanos , Vitiligo/metabolismo , Vitiligo/genética , Vitiligo/sangue , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Triptofano/metabolismo , Triptofano/sangue , Ácido Cinurênico/sangue , Ácido Cinurênico/metabolismo , Masculino , Queratinócitos/metabolismo , Pele/metabolismo , Pele/patologia , Adulto , Feminino , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cinurenina/metabolismo , Cinurenina/sangue , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Pessoa de Meia-Idade , Estudos de Casos e Controles , Transdução de Sinais , Adulto Jovem
12.
J Am Chem Soc ; 146(25): 17103-17113, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38869216

RESUMO

Understanding the interfacial hydrogen evolution reaction (HER) is crucial to regulate the electrochemical behavior in aqueous zinc batteries. However, the mechanism of HER related to solvation chemistry remains elusive, especially the time-dependent dynamic evolution of the hydrogen bond (H-bond) under an electric field. Herein, we combine in situ spectroscopy with molecular dynamics simulation to unravel the dynamic evolution of the interfacial solvation structure. We find two critical change processes involving Zn-electroplating/stripping, including the initial electric double layer establishment to form an H2O-rich interface (abrupt change) and the subsequent dynamic evolution of an H-bond (gradual change). Moreover, the number of H-bonds increases, and their strength weakens in comparison with the bulk electrolyte under bias potential during Zn2+ desolvation, forming a diluted interface, resulting in massive hydrogen production. On the contrary, a concentrated interface (H-bond number decreases and strength enhances) is formed and produces a small amount of hydrogen during Zn2+ solvation. The insights on the above results contribute to deciphering the H-bond evolution with competition/corrosion HER during Zn-electroplating/stripping and clarifying the essence of electrochemical window widened and HER suppression by high concentration. This work presents a new strategy for aqueous electrolyte regulation by benchmarking the abrupt change of the interfacial state under an electric field as a zinc performance-enhancement criterion.

13.
Integr Cancer Ther ; 23: 15347354241259182, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38845538

RESUMO

BACKGROUND: The prescription of Chinese herbal medicine (CHM) consists of multiple herbs that exhibit synergistic effects due to the presence of multiple components targeting various pathways. In clinical practice, the combination of Erchen decoction and Huiyanzhuyu decoction (EHD) has shown promising outcomes in treating patients with laryngeal squamous cell carcinoma (LSCC). However, the underlying mechanism by which EHD exerts its therapeutic effects in LSCC remains unknown. METHODS: Online databases were utilized for the analysis and prediction of the active constituents, targets, and key pathways associated with EHD in the treatment of LSCC. The protein-protein interaction (PPI) network of common targets was constructed and visualized using Cytoscape 3.8.1 software. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to investigate the functional roles of core targets within the PPI network. Protein clustering was conducted utilizing the MCODE plug-in. The obtained results highlight the principal targets and pathways involved. Subsequently, clinical samples were collected to validate alterations in the levels of these main targets through Western blotting (WB) and immunohistochemistry (IHC). Furthermore, both in vivo and in vitro experiments were conducted to investigate the therapeutic effects of EHD on healing LSCC and elucidate its underlying mechanism. Additionally, to ensure experimental reliability and reproducibility, quality control measures utilizing HPLC were implemented for EHD herbal medicine. RESULTS: The retrieval and analysis of databases in EHD medicine and LSCC disease yielded a total of 116 overlapping targets. The MCODE plug-in methods were utilized to acquire 8 distinct protein clusters through protein clustering. The findings indicated that both the first and second clusters exhibited a size greater than 6 scores, with key genes PI3K and ErbB occupying central positions, while the third and fourth clusters were associated with proteins in the PI3K, STAT3, and Foxo pathways. GO functional analysis reported that these targets had associations mainly with the pathway of p53 mediated DNA damage and negative regulation of cell cycle in terms of biological function; the death-induced signaling complex in terms of cell function; transcription factor binding and protein kinase activity in terms of molecular function. The KEGG enrichment analysis demonstrated that these targets were correlated with several signaling pathways, including PI3K-Akt, FoxO, and ErbB2 signaling pathway. On one hand, we observed higher levels of key genes such as P-STAT3, P-PDK1, P-Akt, PI3K, and ErbB2 in LSCC tumor tissues compared to adjacent tissues. Conversely, FOXO3a expression was lower in LSCC tumor tissues. On the other hand, the key genes mentioned above were also highly expressed in both LSCC xenograft nude mice tumors and LSCC cell lines, while FOXO3a was underexpressed. In LSCC xenograft nude mice models, EHD treatment resulted in downregulation of P-STAT3, P-PDK1, PI3K, P-AKT, and ErbB2 protein levels but upregulated FOXO3a protein level. EHD also affected the levels of P-STAT3, P-PDK1, PI3K, P-AKT, FOXO3a, and ErbB2 proteins in vitro: it inhibited P-STAT3, P-AKT, and ErbB2, while promoting FOXO3a; however, it had no effect on PDK1 protein. In addition, HPLC identified twelve compounds accounting for more than 30% within EHD. The findings from this study can serve as valuable guidance for future experimental investigations. CONCLUSION: The possible mechanism of EHD medicine action on LSCC disease is speculated to be closely associated with the ErbB2/PI3K/AKT/FOXO3a signaling pathway.


Assuntos
Medicamentos de Ervas Chinesas , Neoplasias Laríngeas , Farmacologia em Rede , Mapas de Interação de Proteínas , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Farmacologia em Rede/métodos , Animais , Neoplasias Laríngeas/tratamento farmacológico , Camundongos , Carcinoma de Células Escamosas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Masculino , Linhagem Celular Tumoral , Camundongos Nus , Feminino , Proliferação de Células/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Drug Resist Updat ; 76: 101111, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38908233

RESUMO

Gemcitabine (GEM) based induction chemotherapy is a standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). However, approximately 15 % of patients are still resistant to GEM-containing chemotherapy, which leads to treatment failure. Nevertheless, the underlying mechanisms of GEM resistance remain poorly understood. Herein, based on a microarray analysis, we identified 221 dysregulated lncRNAs, of which, DYNLRB2-AS1 was one of the most upregulated lncRNAs in GEM-resistance NPC cell lines. DYNLRB2-AS1 was shown to function as contain an oncogenic lncRNA that promoted NPC GEM resistance, cell proliferation, but inhibited cell apoptosis. Mechanistically, DYNLRB2-AS1 could directly bind to the DHX9 protein and prevent its interaction with the E3 ubiquitin ligase PRPF19, and thus blocking PRPF19-mediated DHX9 degradation, which ultimately facilitated the repair of DNA damage in the presence of GEM. Clinically, higher DYNLRB2-AS1 expression indicated an unfavourable overall survival of NPC patients who received induction chemotherapy. Overall, this study identified the oncogenic lncRNA DYNLRB2-AS1 as an independent prognostic biomarker for patients with locally advanced NPC and as a potential therapeutic target for overcoming GEM chemoresistance in NPC.


Assuntos
RNA Helicases DEAD-box , Desoxicitidina , Gencitabina , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , RNA Longo não Codificante , Animais , Humanos , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , RNA Helicases DEAD-box/metabolismo , RNA Helicases DEAD-box/genética , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/metabolismo , Proteínas de Neoplasias , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ubiquitinação/efeitos dos fármacos
16.
Nat Commun ; 15(1): 5300, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38906860

RESUMO

Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in nasopharyngeal carcinoma remains to be elucidated. Here, we identify PJA1 as a key E3 ubiquitin ligase involved in nasopharyngeal carcinoma chemoresistance that is highly expressed in nasopharyngeal carcinoma patients with nonresponse to docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find that PJA1 facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis in nasopharyngeal carcinoma cells. Mechanistically, PJA1 promotes the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, which further facilitates DRP1 phosphorylation at S637 and reduced mitochondrial reactive oxygen species production, resulting in suppression of GSDME-mediated pyroptosis and the antitumour immune response. PGAM5 knockdown fully restores the docetaxel sensitization effect of PJA1 knockdown. Moreover, pharmacological targeting of PJA1 with the small molecule inhibitor RTA402 enhances the docetaxel sensitivity of nasopharyngeal carcinoma in vitro and in vivo. Clinically, high PJA1 expression indicates inferior survival and poor clinical efficacy of TPF IC in nasopharyngeal carcinoma patients. Our study emphasizes the essential role of E3 ligases in regulating chemoresistance and provides therapeutic strategies for nasopharyngeal carcinoma based on targeting the ubiquitin-proteasome system.


Assuntos
Docetaxel , Resistencia a Medicamentos Antineoplásicos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Piroptose , Ubiquitina-Proteína Ligases , Ubiquitinação , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Dinaminas/metabolismo , Dinaminas/genética , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Gasderminas , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Fosfoproteínas Fosfatases/metabolismo , Fosfoproteínas Fosfatases/genética , Fosforilação/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Piroptose/genética , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Eur J Histochem ; 68(2)2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38742403

RESUMO

Chronic kidney disease (CKD) is a leading public health issue associated with high morbidity worldwide. However, there are only a few effective therapeutic strategies for CKD. Emodin, an anthraquinone compound from rhubarb, can inhibit fibrosis in tissues and cells. Our study aims to investigate the antifibrotic effect of emodin and the underlying molecular mechanism. A unilateral ureteral obstruction (UUO)-induced rat model was established to evaluate the effect of emodin on renal fibrosis development. Hematoxylin and eosin staining, Masson's trichrome staining, and immunohistochemistry staining were performed to analyze histopathological changes and fibrotic features after emodin treatment. Subsequently, a transforming growth factor-beta 1 (TGF-ß1)-induced cell model was used to assess the inhibition of emodin on cell fibrosis in vitro. Furthermore, Western blot analysis and real-time quantitative reverse transcription-polymerase chain reaction were performed to validate the regulatory mechanism of emodin on renal fibrosis progression. As a result, emodin significantly improved histopathological abnormalities in rats with UUO. The expression of fibrosis biomarkers and mitochondrial biogenesis-related proteins also decreased after emodin treatment. Moreover, emodin blocked TGF-ß1-induced fibrotic phenotype, lipid accumulation, and mitochondrial homeostasis in NRK-52E cells. Conversely, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) silencing significantly reversed these features in emodin-treated cells. Collectively, emodin plays an important role in regulating PGC-1α-mediated mitochondria function and energy homeostasis. This indicates that emodin exhibits great inhibition against renal fibrosis and acts as a promising inhibitor of CKD.


Assuntos
Emodina , Fibrose , Mitocôndrias , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Insuficiência Renal Crônica , Animais , Emodina/farmacologia , Emodina/uso terapêutico , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Fibrose/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Homeostase/efeitos dos fármacos , Rim/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Obstrução Ureteral/patologia , Obstrução Ureteral/tratamento farmacológico , Fator de Crescimento Transformador beta1/metabolismo , Linhagem Celular
18.
World J Clin Cases ; 12(9): 1634-1643, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38576748

RESUMO

BACKGROUND: Low-molecular-weight heparins (LMWH) are the most commonly used anticoagulants during pregnancy. It is considered to be the drug of choice due to its safety in not crossing placenta. Considering the beneficial effect in the improvement of microcirculation, prophylactic application of LMWH in patients with preeclampsia became a trend. However, the bleeding risk related with LMWH in preeclampsia patients has seldomly been evaluated. This current study aimed to identify the potential risks regarding LMWH application in patients with preeclampsia. CASE SUMMARY: Herein we present a case series of three pregnant women diagnosed with preeclampsia on LMWH therapy during pregnancy. All the cases experienced catastrophic hemorrhagic events. After reviewing the twenty-one meta-analyses, the bleeding risk related with LMWH seems ignorable. Only one study analyzed the bleeding risk of LMWH and found a significantly higher risk of developing PPH in women receiving LMWH. Other studies reported minor bleeding risks, none of these were serious enough to stop LMWH treatment. Possibilities of bleeding either from uterus or from intrabdominal organs in preeclampsia patients on LMWH therapy should not be ignored. Intensive management of blood pressure even after delivery and homeostasis suture in surgery are crucial. CONCLUSION: Consideration should be given to the balance between benefits and risks of LMWH in patients with preeclampsia.

19.
Zhongguo Zhong Yao Za Zhi ; 49(4): 1044-1051, 2024 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-38621911

RESUMO

The animal and cell models were used in this study to investigate the mechanism of Astragali Radix-Curcumae Rhizoma(HQEZ) in inhibiting colon cancer progression and enhancing the efficacy of 5-fluorouracil(5-FU) by regulating hypoxia-inducible factors and tumor stem cells. The animal model was established by subcutaneous transplantation of colon cancer HCT116 cells in nude mice, and 24 successfully modeled mice were randomized into model, 5-FU, HQEZ, and 5-FU+HQEZ groups. The tumor volume was measured every two days. Western blot was employed to measure the protein levels of epidermal growth factor receptor(EGFR), dihydropyrimidine dehydrogenase(DPYD), and thymidylate synthase(TYMS), the key targets of the hypoxic core region, as well as the hypoxia-inducible factors HIF-1α and HIF-2α and the cancer stem cell surface marker CD133 and SRY-box transcription factor 2(SOX2). The results of animal experiments showed that HQEZ slowed down the tumor growth and significantly increased the tumor inhibition rate of 5-FU. Compared with the model group, HQEZ significantly down-regulated the protein levels of EGFR and DPYD, and 5-FU+HQEZ significantly down-regulated the protein levels of EGFR and TYMS in tumors. Compared with the model group, HQEZ significantly down-regulated the protein levels of HIF-1α, HIF-2α, SOX2, and CD133 in the hypoxic core region. Compared with the 5-FU group, 5-FU+HQEZ lowered the protein levels of HIF-1α, HIF-2α, and SOX2. The cell experiments showed that the protein le-vels of HIF-1α and HIF-2α in HCT116 cells elevated significantly after low oxygen treatment. Compared with 5-FU(1.38 µmol·L~(-1)) alone, HQEZ(40 mg·mL~(-1)) and 5-FU+HQEZ significantly down-regulated the protein levels of HIF-1α, HIF-2α, and TYMS. In conclusion, HQEZ can inhibit the expression of hypoxia-responsive molecules in colon cancer cells and reduce the properties of cancer stem cells, thereby enhancing the therapeutic effect of 5-FU on colon cancer.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Neoplasias do Colo , Camundongos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Camundongos Nus , Fluoruracila/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Hipóxia , Receptores ErbB , Células-Tronco Neoplásicas , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Linhagem Celular Tumoral
20.
Front Cell Infect Microbiol ; 14: 1356353, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38601741

RESUMO

Carbapenem-resistant Acinetobacter baumannii (CRAB) is resistant to almost all antibiotics. Eravacycline, a newer treatment option, has the potential to treat CRAB infections, however, the mechanism by which CRAB isolates develop resistance to eravacycline has yet to be clarified. This study sought to investigate the features and mechanisms of eravacycline heteroresistance among CRAB clinical isolates. A total of 287 isolates were collected in China from 2020 to 2022. The minimum inhibitory concentration (MIC) of eravacycline and other clinically available agents against A. baumannii were determined using broth microdilution. The frequency of eravacycline heteroresistance was determined by population analysis profiling (PAP). Mutations and expression levels of resistance genes in heteroresistant isolates were determined by polymerase chain reaction (PCR) and quantitative real-time PCR (qRT-PCR), respectively. Antisense RNA silencing was used to validate the function of eravacycline heteroresistant candidate genes. Twenty-five eravacycline heteroresistant isolates (17.36%) were detected among 144 CRAB isolates with eravacycline MIC values ≤4 mg/L while no eravacycline heteroresistant strains were detected in carbapenem-susceptible A. baumannii (CSAB) isolates. All eravacycline heteroresistant strains contained OXA-23 carbapenemase and the predominant multilocus sequence typing (MLST) was ST208 (72%). Cross-resistance was observed between eravacycline, tigecycline, and levofloxacin in the resistant subpopulations. The addition of efflux pump inhibitors significantly reduced the eravacycline MIC in resistant subpopulations and weakened the formation of eravacycline heteroresistance in CRAB isolates. The expression levels of adeABC and adeRS were significantly higher in resistant subpopulations than in eravacycline heteroresistant parental strains (P < 0.05). An ISAba1 insertion in the adeS gene was identified in 40% (10/25) of the resistant subpopulations. Decreasing the expression of adeABC or adeRS by antisense RNA silencing significantly inhibited eravacycline heteroresistance. In conclusion, this study identified the emergence of eravacycline heteroresistance in CRAB isolates in China, which is associated with high expression of AdeABC and AdeRS.


Assuntos
Acinetobacter baumannii , Tetraciclinas , Tipagem de Sequências Multilocus , Antibacterianos/farmacologia , beta-Lactamases/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Carbapenêmicos/farmacologia , RNA Antissenso , China/epidemiologia , Testes de Sensibilidade Microbiana
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