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1.
PLoS One ; 19(3): e0299595, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38451972

RESUMO

OBJECTIVE: Glycolytic inhibition via 2-deoxy-D-glucose (2DG) has potential therapeutic benefits for a range of diseases, including cancer, epilepsy, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), and COVID-19, but the systemic effects of 2DG on gene function across different tissues are unclear. METHODS: This study analyzed the transcriptional profiles of nine tissues from C57BL/6J mice treated with 2DG to understand how it modulates pathways systemically. Principal component analysis (PCA), weighted gene co-network analysis (WGCNA), analysis of variance, and pathway analysis were all performed to identify modules altered by 2DG treatment. RESULTS: PCA revealed that samples clustered predominantly by tissue, suggesting that 2DG affects each tissue uniquely. Unsupervised clustering and WGCNA revealed six distinct tissue-specific modules significantly affected by 2DG, each with unique key pathways and genes. 2DG predominantly affected mitochondrial metabolism in the heart, while in the small intestine, it affected immunological pathways. CONCLUSIONS: These findings suggest that 2DG has a systemic impact that varies across organs, potentially affecting multiple pathways and functions. The study provides insights into the potential therapeutic benefits of 2DG across different diseases and highlights the importance of understanding its systemic effects for future research and clinical applications.


Assuntos
Desoxiglucose , Epilepsia , Camundongos , Animais , Desoxiglucose/farmacologia , Desoxiglucose/metabolismo , Camundongos Endogâmicos C57BL , Glucose/metabolismo , Perfilação da Expressão Gênica
2.
J Cardiothorac Surg ; 19(1): 46, 2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38310273

RESUMO

OBJECTIVE: To investigate the independent risk factors for postoperative prolonged ICU stay in patients with Stanford type A aortic dissection (TAAD) and assess the clinical outcomes of prolonged ICU stay. METHOD: The clinical data of 100 patients with TAAD admitted to the Department of Cardiovascular Surgery, First Affiliated Hospital of Anhui Medical University from December 2018 to September 2022 were retrospectively collected and analyzed. Patients were divided into two groups, based on the postoperative ICU stay (7 days as the threshold), regular ICU stay group (< 7 days) and prolonged ICU stay group (≥ 7 days). First, preoperative and intraoperative materials were collected for univariate analysis. Then, the significant variables after univariate analysis were analyzed using logistic regression, and the final independent risk factors for prolonged ICU stay were determined. Meanwhile, the postoperative clinical outcomes were analyzed with the aim of assessing the clinical outcomes due to prolonged ICU stay. RESULTS: There were 65 and 35 patients in the regular ICU stay group and the prolonged ICU stay group, respectively. In accordance with the result of univariate analysis in the two groups, emergency surgery (χ2 = 13.598; P < 0.001), preoperative urea nitrogen (t = 3.006; P = 0.004), cardiopulmonary bypass (CPB) time (t = 2.671; P = 0.001) and surgery time (t = 2.630; P = 0.010) were significant. All significant variates were analyzed through logistic regression, and it was found that emergency surgery (OR = 0.192; 95% CI: 0.065-0.561), preoperative urea nitrogen (OR = 0.775; 95% CI: 0.634-0.947) and cardiopulmonary time (OR = 0.988; 95% CI: 0.979-0.998) were independent risk factors for prolonged postoperative ICU stay. The Receiver Operating Characteristic (ROC) curves of these three factors were also effective in predicting postoperative prolonged ICU stay (Emergency surgery, AUC = 0.308, 95% CI: 0.201-0.415; Preoperative urea nitrogen, AUC = 0.288, 95% CI: 0.185-0.392; cardiopulmonary time, AUC = 0.340, 95% CI: 0.223-0.457). Moreover, compared with a single factor, the predictive value of combined factors was more significant (AUC = 0.810, 95% CI: 0.722-0.897). For the comparison of postoperative data in the two groups,, compared with the regular ICU stay group, the incidence of adverse events in the prolonged ICU stay group increased significantly, including limb disability of limbs (χ2 = 22.182; P < 0.001), severe organ injury (χ2 = 23.077; P < 0.001), tracheotomy (χ2 = 17.582; P < 0.001), reintubation (χ2 = 28.020; P < 0.001), 72 h tracheal extubation after surgery (χ2 = 29.335; P < 0.001), 12 h consciousness recovery after surgery (χ2 = 18.445; P < 0.001), ICU re-entering (χ2 = 9.496; P = 0.002) and irregular discharging (χ2 = 24.969; P < 0.001). CONCLUSION: Emergency surgery, preoperative urea nitrogen, and CPB time are risk factors for postoperative prolonged ICU stay after TAAD surgery. Furthermore, prolonged ICU stay is associated with worse clinical outcomes. Hence, a reasonable strategy should be adopted proactively focusing on the risk factors to shorten ICU stays and improve clinical outcomes.


Assuntos
Dissecção Aórtica , Azidas , Desoxiglucose/análogos & derivados , Humanos , Estudos Retrospectivos , Dissecção Aórtica/cirurgia , Fatores de Risco , Unidades de Terapia Intensiva , Nitrogênio , Ureia , Tempo de Internação
3.
J Cardiovasc Surg (Torino) ; 65(1): 69-75, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38300164

RESUMO

BACKGROUND: Type A aortic dissection (TAAD) surgical management is still under debate. The purpose of this study was to demonstrate the feasibility and safety of the aortic valve-sparing root reconstruction (AVSR) procedure in 92 consecutive patients operated for TAAD, even when preoperative condition was severe (malperfusion, shock or both). METHODS: Our hospital database was reviewed to identify all patients who underwent an AVSR procedure for TAAD over 14 years. From May 2000 to June 2014, 92 consecutive patients were studied regarding to their preoperative condition. RESULTS: Age (61±13 years) and logistic Euroscore (23.4±15.3%) as well as cross-clamping (113±39 min), cardiopulmonary bypass (142±49 min) and circulatory arrest (22±13 min) times were collected. Hospital mortality was 16.3%. Mean follow-up was complete for a mean period of 27.6 months. One patient had early reoperation for aortic insufficiency. Actuarial survival at 1 year was 82.5%. The analysis of each group showed comparable mortality and morbidity in between patients. CONCLUSIONS: Based upon our experience in the management of TAAD, a reimplantation procedure could be performed regardless preoperative malperfusion or shock, with an acceptable postoperative over mortality or morbidity. A word of caution should be brought to patients over 70 years old.


Assuntos
Aneurisma Aórtico , Dissecção Aórtica , Insuficiência da Valva Aórtica , Azidas , Desoxiglucose/análogos & derivados , Humanos , Pessoa de Meia-Idade , Idoso , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Aneurisma Aórtico/diagnóstico por imagem , Aneurisma Aórtico/cirurgia , Resultado do Tratamento , Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/cirurgia , Insuficiência da Valva Aórtica/diagnóstico por imagem , Insuficiência da Valva Aórtica/cirurgia , Reoperação , Reimplante/efeitos adversos , Contraindicações , Estudos Retrospectivos
4.
Am J Physiol Cell Physiol ; 326(2): C647-C658, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38189133

RESUMO

Thoracic aortic aneurysm/dissection (TAAD) is a lethal vascular disease, and several pathological factors participate in aortic medial degeneration. We previously discovered that the complement C3a-C3aR axis in smooth muscle cells promotes the development of thoracic aortic dissection (TAD) through regulation of matrix metalloproteinase 2. However, discerning the specific complement pathway that is activated and elucidating how inflammation of the aortic wall is initiated remain unknown. We ascertained that the plasma levels of C3a and C5a were significantly elevated in patients with TAD and that the levels of C3a, C4a, and C5a were higher in acute TAD than in chronic TAD. We also confirmed the activation of the complement in a TAD mouse model. Subsequently, knocking out Cfb (Cfb) or C4 in mice with TAD revealed that the alternative pathway and Cfb played a significant role in the TAD process. Activation of the alternative pathway led to generation of the anaphylatoxins C3a and C5a, and knocking out their receptors reduced the recruitment of inflammatory cells to the aortic wall. Moreover, we used serum from wild-type mice or recombinant mice Cfb as an exogenous source of Cfb to treat Cfb KO mice and observed that it exacerbated the onset and rupture of TAD. Finally, we knocked out Cfb in the FBN1C1041G/+ Marfan-syndrome mice and showed that the occurrence of TAA was reduced. In summary, the alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD.NEW & NOTEWORTHY The alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD.


Assuntos
Aneurisma da Aorta Torácica , Dissecção Aórtica , Azidas , Desoxiglucose/análogos & derivados , Humanos , Camundongos , Animais , Via Alternativa do Complemento , Metaloproteinase 2 da Matriz , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Dissecção Aórtica/genética , Inflamação
5.
Eur J Cardiothorac Surg ; 65(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38212996

RESUMO

OBJECTIVES: In the last decades, 4 different scores for the prediction of mortality following surgery for type A acute aortic dissection (TAAD) were proposed. We aimed to validate these scores in a large external multicentre cohort. METHODS: We retrospectively analysed patients who underwent surgery for TAAD between 2000 and 2020. Patients were enrolled from 10 centres from 2 European countries. Outcomes were the early (30-day and/or in-hospital) and 1-year mortality. Discrimination, calibration and observed/expected (O/E) ratio were evaluated. RESULTS: A total of 1895 patients (31.7% females, mean age 63.72 ± 12.8 years) were included in the study. Thirty-day mortality and in-hospital mortality were 21.7% (n = 412) and 22.5% (n = 427) respectively. The German Registry of Acute Aortic Dissection Type A (GERAADA) score shows to have the best discrimination [area under the curve (AUC) 0.671 and 0.672] in predicting as well the early and the 1-year mortality, followed by the International Registry of Acute Aortic Dissection (IRAD) model 1 (AUC 0.658 and 0.672), the Centofanti (AUC 0.645 and 0.66) and the UK aortic score (AUC 0.549 and 0.563). According to Hosmer-Lemeshow and Brier tests, the IRAD model I and GERAADA, respectively, were well calibrated for the early mortality, while the GERAADA and Centofanti for the 1-year mortality. The O/E analysis showed a marked underestimation for patients labelled as low-risk for UK aortic score and IRAD model I for both outcomes. CONCLUSIONS: The GERAADA score showed the best performance in comparison with other scores. However, none of them achieved together a fair discrimination and a good calibration for predicting either the early or the 1-year mortality.


Assuntos
Dissecção Aórtica , Azidas , Desoxiglucose/análogos & derivados , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Masculino , Estudos Retrospectivos , Dissecção Aórtica/cirurgia , Mortalidade Hospitalar , Europa (Continente) , Sistema de Registros , Fatores de Risco , Resultado do Tratamento
6.
Pharmacol Res Perspect ; 12(1): e1173, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38294142

RESUMO

Our previous work has shown a synergistic tumoricidal efficacy of combining the hexokinase (HK) inhibitor 2-deoxyglucose (2-DG) and the autophagy inhibitor chloroquine (CQ) through intraperitoneal injections on HK2-addicted prostate cancers in animal models. The pharmacokinetic (PK) behaviors of these oral drugs after simultaneous oral administration have not been reported. We developed high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) analytical methods for 2-DG and the clinically favored drug hydroxychloroquine (HCQ) for sera samples. Using a jugular vein-cannulated male rat model with serial blood collection before and after a single gavage dose of each drug alone or in combination, we examined their PK metrics for drug-drug interactions. The data demonstrated a rapid and complete separation of 2-DG from common monosaccharides by HPLC-MS-MS multi-reaction monitoring. Application of the HPLC-MS-MS 2-DG and HCQ methods to sera samples of nine rats showed a peak time (Tmax ) for 2-DG of 0.5 h after 2-DG alone or with HCQ and identical post-peak half-life of approximately 1 h. With a seemingly bi-modal time course for HCQ, the Tmax for HCQ alone (1.2 h) was faster than that for the combination (2 h; p = .017). After combination dosing, the peak concentration (Cmax ) and area under the curve (AUC0-4h ) of 2-DG were decreased by 53.8% (p = .0004) and 53.7% (p = .0001), whereas AUC0-8h for HCQ was decreased by 30.8% (p = .0279) from the respective single dosing. Without changing the mean residence time (MRT0-∞ ) of each drug, the combination affected the apparent volume of distribution (Vd ) and clearance (CL) of 2-DG, and CL for HCQ without affecting its Vd . We observed significant negative PK interactions, probably at the intestinal absorption level, between 2-DG and HCQ taken simultaneously by mouth. Future optimization efforts are warranted for their combination regimen for clinical translation.


Assuntos
Hidroxicloroquina , Masculino , Ratos , Animais , Hidroxicloroquina/farmacocinética , Cromatografia Líquida de Alta Pressão , Administração Oral , Desoxiglucose
7.
EMBO Mol Med ; 16(1): 132-157, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38177536

RESUMO

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition associated with Marfan syndrome (MFS), a disease caused by fibrillin-1 gene mutations. While various conditions causing TAAD exhibit aortic accumulation of the proteoglycans versican (Vcan) and aggrecan (Acan), it is unclear whether these ECM proteins are involved in aortic disease. Here, we find that Vcan, but not Acan, accumulated in Fbn1C1041G/+ aortas, a mouse model of MFS. Vcan haploinsufficiency protected MFS mice against aortic dilation, and its silencing reverted aortic disease by reducing Nos2 protein expression. Our results suggest that Acan is not an essential contributor to MFS aortopathy. We further demonstrate that Vcan triggers Akt activation and that pharmacological Akt pathway inhibition rapidly regresses aortic dilation and Nos2 expression in MFS mice. Analysis of aortic tissue from MFS human patients revealed accumulation of VCAN and elevated pAKT-S473 staining. Together, these findings reveal that Vcan plays a causative role in MFS aortic disease in vivo by inducing Nos2 via Akt activation and identify Akt signaling pathway components as candidate therapeutic targets.


Assuntos
Aneurisma da Aorta Torácica , Doenças da Aorta , Dissecção Aórtica , Azidas , Desoxiglucose , Síndrome de Marfan , Animais , Humanos , Camundongos , Aneurisma da Aorta Torácica/complicações , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/metabolismo , Doenças da Aorta/complicações , Desoxiglucose/análogos & derivados , Síndrome de Marfan/complicações , Síndrome de Marfan/genética , Síndrome de Marfan/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Versicanas/metabolismo
8.
J Cardiothorac Surg ; 19(1): 16, 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38254116

RESUMO

BACKGROUND: Delirium is a common postoperative complication among patients who undergo Stanford Type A aortic dissection (TAAD). It is associated with increased mortality, as well as other serious surgical outcomes. This study aimed to analyze the risk factors for delirium in TAAD patients. METHODS: Pubmed, Web of science, Embase, the Cochrane Library and CINAHL were searched by computer to collect literatures on risk factors for postoperative delirium (POD) after TAAD. The retrieval period was from the establishment of the database to September 2022. After literature screening, two reviewers independently assessed the quality of the included studies using the Newcastle-Ottawa Scale (NOS). Data were extracted according to standard protocols, and then meta-analysis was performed using Revman 5.3 software. RESULTS: A total of 9 articles, comprising 7 case-control studies and 2 cohort studies, were included in this analysis. The sample size consisted of 2035 patients. POD was associated with increased length of ICU stay (MD 3.24, 95% CI 0.18-6.31, p = 0.04) and length of hospital stay (MD 9.34, 95% CI 7.31-11.37, p < 0.0001) in TAAD patients. Various perioperative risk factors were identified, including age (MD 4.40, 95% CI 2.06-6.73, p = 0.0002), preoperative low hemoglobin levels (MD - 4.44, 95% CI - 7.67 to - 1.20, p = 0.007), body mass index (MD 0.92, 95% CI 0.22-1.63, p = 0.01), history of cardiac surgery (OR 3.06, 95% CI 1.20-7.83, p = 0.02), preoperative renal insufficiency (OR 2.50, 95% CI 1.04-6.04, p = 0.04), cardiopulmonary bypass (CPB) duration (MD 19.54, 95% CI 6.34-32.74, p = 0.004), surgery duration (MD 44.88, 95% CI 5.99-83.78, p = 0.02), mechanical ventilation time (SMD 1.14, 95% CI 0.34-1.94, p = 0.005), acute physiology and chronic health evaluation (APACHE II) score (MD 2.67, 95% CI 0.37-4.98, p = 0.02), postoperative renal insufficiency (OR 2.82, 95% CI 1.40-5.68, p = 0.004), electrolyte disturbance (OR 6.22, 95% CI 3.08-12.54, p < 0.0001) and hypoxemia (OR 3.56, 95% CI 1.70-7.44, p = 0.0007). CONCLUSIONS: POD can prolong ICU stay and hospital stay in TAAD patients. This study identified a number of risk factors for POD after TAAD, suggesting the possibility of early identification of high-risk patients using relevant data.


Assuntos
Dissecção Aórtica , Azidas , Desoxiglucose/análogos & derivados , Delírio do Despertar , Insuficiência Renal , Humanos , Fatores de Risco , Dissecção Aórtica/cirurgia
9.
Sci Rep ; 14(1): 1522, 2024 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-38233509

RESUMO

Acute type A aortic dissection (a-TAAD) is a severe disease characterized by high mortality, which can be fatal in elderly patients. The objective of this study was to investigate the safety and efficacy of two-stage type II hybrid aortic arch repair (HAR) in elderly patients with acute type A aortic dissection (a-TAAD). This was a single-center, retrospective study involving 119 patients with a-TAAD, including 82 males and 37 females, aged 22-81 years old. Eighty-eight patients underwent total aortic arch replacement (TAR) with frozen elephant trunk (FET) implantation (TAR with FET group) and 31 patients underwent two-stage type II HAR (HAR group). Propensity score matching was applied to adjust for preoperative data, and match 25 pairs. The preoperative, perioperative, postoperative and follow-up data were recorded. Fifteen patients died during the perioperative period; 13 cases were in the TAR with FET group and 2 cases were in the HAR group. The age, body mass index, cerebral infarction, renal insufficiency were significantly higher, and the 24-h fluid drainage, the incidence of acute liver injury, acute kidney injury and pulmonary infection were lower in the HAR group (all P < 0.05). Moreover, the mechanical ventilation time, intensive care unit time, hospital stay time were shorter in the HAR group (all P < 0.05). The follow-up period ranged from 12 to 54 months, with 7 deaths (9.3%) in the TAR with FET group and 2 deaths (6.9%) in the HAR group. The true lumen of the aortic arch and the middle descending thoracic aorta were larger and the false lumen thrombosis rates of the middle descending thoracic aorta and renal artery level were higher in the HAR group (all P < 0.05). Two-stage type II HAR is a safe and effective method for the treatment of elderly patients with a-TAAD. It may be a good choice for elderly patients with a-TAAD and comorbidities.


Assuntos
Injúria Renal Aguda , Aneurisma da Aorta Torácica , Dissecção Aórtica , Azidas , Implante de Prótese Vascular , Desoxiglucose/análogos & derivados , Masculino , Idoso , Feminino , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Aorta Torácica/cirurgia , Estudos Retrospectivos , Implante de Prótese Vascular/métodos , Resultado do Tratamento , Dissecção Aórtica/cirurgia , Injúria Renal Aguda/cirurgia , Aneurisma da Aorta Torácica/cirurgia
10.
Ecotoxicol Environ Saf ; 269: 115767, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38039851

RESUMO

Inhaling silica causes the occupational illness silicosis, which mostly results in the gradual fibrosis of lung tissue. Previous research has demonstrated that hypoxia-inducible factor-1α (HIF-1α) and glycolysis-related genes are up-regulated in silicosis. The role of 2-deoxy-D-glucose (2-DG) as an inhibitor of glycolysis in silicosis mouse models and its molecular mechanisms remain unclear. Therefore, we used 2-DG to observe its effect on pulmonary inflammation and fibrosis in a silicosis mouse model. Furthermore, in vitro cell experiments were conducted to explore the specific mechanisms of HIF-1α. Our study found that 2-DG down-regulated HIF-1α levels in alveolar macrophages induced by silica exposure and reduced the interleukin-1ß (IL-1ß) level in pulmonary inflammation. Additionally, 2-DG reduced silica-induced pulmonary fibrosis. From these findings, we hypothesize that 2-DG reduced glucose transporter 1 (GLUT1) expression by inhibiting glycolysis, which inhibits the expression of HIF-1α and ultimately reduces transcription of the inflammatory cytokine, IL-1ß, thus alleviating lung damage. Therefore, we elucidated the important regulatory role of HIF-1α in an experimental silicosis model and the potential defense mechanisms of 2-DG. These results provide a possible effective strategy for 2-DG in the treatment of silicosis.


Assuntos
Pneumonia , Fibrose Pulmonar , Silicose , Animais , Camundongos , Desoxiglucose/farmacologia , Desoxiglucose/metabolismo , Glucose/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/metabolismo , Macrófagos Alveolares , Pneumonia/metabolismo , Fibrose Pulmonar/metabolismo , Dióxido de Silício/toxicidade , Silicose/tratamento farmacológico , Silicose/metabolismo
11.
Am J Med Genet A ; 194(3): e63458, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37921548

RESUMO

Pathogenic variants in several genes involved in the function or regulation of smooth muscle cells (SMC) are known to predispose to congenital heart disease and thoracic aortic aneurysm and dissection (TAAD). Variants in MYLK are primarily known to predispose to TAAD, but a growing body of evidence points toward MYLK also playing an essential role in the regulation of SMC contraction outside the aorta. In this case report, we present a patient with co-occurrence of persistent ductus arteriosus (PDA) and thoracic aortic dissection. Genetic analyses revealed a novel splice acceptor variant (c.3986-1G > A) in MYLK, which segregated with disease in the family. RNA-analyses on fibroblasts showed that the variant induced skipping of exon 24, which resulted in an in-frame deletion of 101 amino acids. These findings suggest that MYLK-associated disease could include a broader phenotypic spectrum than isolated TAAD, including PDA and obstructive pulmonary disease. Genetic analyses could be considered in families with TAAD and PDA or obstructive pulmonary disease.


Assuntos
Aneurisma da Aorta Torácica , Dissecção Aórtica , Azidas , Desoxiglucose/análogos & derivados , Permeabilidade do Canal Arterial , Canal Arterial , Pneumopatias Obstrutivas , Humanos , Masculino , Canal Arterial/diagnóstico por imagem , Canal Arterial/metabolismo , Canal Arterial/patologia , Linhagem , Dissecção Aórtica/genética , Permeabilidade do Canal Arterial/genética , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/genética , Proteínas de Ligação ao Cálcio/genética , Quinase de Cadeia Leve de Miosina/genética , Quinase de Cadeia Leve de Miosina/metabolismo
13.
J Mech Behav Biomed Mater ; 150: 106306, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38091923

RESUMO

At present, simple anti-tumor drugs are ineffective at targeting bone tissue and are not purposed to treat patients with bone metastasis. In this study, zoledronic acid (ZOL) demonstrated excellent bone-targeting properties as a bone-targeting ligand. The metal-organic framework (MOF) known as ZIF-90 was modified with ZOL to construct a bone-targeting-based drug delivery system. Chlorin e6 (Ce6) was loaded in the bone-targeted drug delivery system and combined with 2-deoxy-D-glucose (2-DG), which successfully treated bone tumors when enhanced photodynamic therapy was applied. The Ce6@ZIF-PEG-ZOL (Ce6@ZPZ) nanoparticles were observed to have uniform morphology, a particle size of approximately 210 nm, and a potential of approximately -30.4 mV. The results of the bone-targeting experiments showed that Ce6@ZPZ exhibited a superior bone-targeted effect when compared to Ce6@ZIF-90-PEG. The Ce6@ZPZ solution was subjected to 660 nm irradiation and the resulting production of reactive oxygen species increased over time, which could be further increased when Ce6@ZPZ was used in combination with 2-DG. Their combination had a stronger inhibitory capacity against tumor cells than either 2-DG or Ce6@ZPZ alone, increasing the rate of tumor cell apoptosis. The apoptosis rate caused by HGC-27 was 61.56% when 2-DG was combined with Ce6@ZPZ. In vivo results also showed that Ce6@ZPZ combined with 2-DG maximally inhibited tumor growth and prolonged mice survival compared to the other experimental groups. Therefore, the combination of PDT and glycolytic inhibitors serves as a potential option for the treatment of cancer.


Assuntos
Neoplasias Ósseas , Nanopartículas , Fotoquimioterapia , Humanos , Animais , Camundongos , Fotoquimioterapia/métodos , Linhagem Celular Tumoral , Glucose , Neoplasias Ósseas/tratamento farmacológico , Osso e Ossos , Desoxiglucose/farmacologia
14.
Biochem Biophys Res Commun ; 693: 149376, 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38104523

RESUMO

Peritoneal dialysis (PD) and prolonged exposure to PD fluids (PDF) induce peritoneal membrane (PM) fibrosis and hypervascularity, leading to functional PM degeneration. 2-deoxy-glucose (2-DG) has shown potential as PM antifibrotic by inhibiting hyper-glycolysis induced mesothelial-to-mesenchymal transition (MMT). We investigated whether administration of 2-DG with several PDF affects the permeability of mesothelial and endothelial barrier of the PM. The antifibrotic effect of 2-DG was confirmed by the gel contraction assay with embedded mesothelial (MeT-5A) or endothelial (EA.hy926) cells cultured in Dianeal® 2.5 % (CPDF), BicaVera® 2.3 % (BPDF), Balance® 2.3 % (LPDF) with/without 2-DG addition (0.2 mM), and qPCR for αSMA, CDH2 genes. Moreover, 2-DG effect was tested on the permeability of monolayers of mesothelial and endothelial cells by monitoring the transmembrane resistance (RTM), FITC-dextran (10, 70 kDa) diffusion and mRNA expression levels of CLDN-1 to -5, ZO1, SGLT1, and SGLT2 genes. Contractility of MeT-5A cells in CPDF/2-DG was decreased, accompanied by αSMA (0.17 ± 0.03) and CDH2 (2.92 ± 0.29) gene expression fold changes. Changes in αSMA, CDH2 were found in EA.hy926 cells, though αSMA also decreased under LPDF/2-DG incubation (0.42 ± 0.02). Overall, 2-DG mitigated the PDF-induced alterations in mesothelial and endothelial barrier function as shown by RTM, dextran transport and expression levels of the CLDN-1 to -5, ZO1, and SGLT2. Thus, supplementation of PDF with 2-DG not only reduces MMT but also improves functional permeability characteristics of the PM mesothelial and endothelial barrier.


Assuntos
Diálise Peritoneal , Fibrose Peritoneal , Humanos , Transportador 2 de Glucose-Sódio/metabolismo , Desoxiglucose/farmacologia , Desoxiglucose/metabolismo , Células Endoteliais , Diálise Peritoneal/efeitos adversos , Peritônio/patologia , Soluções para Diálise/metabolismo , Soluções para Diálise/farmacologia , Fibrose Peritoneal/metabolismo , Glucose/metabolismo , Células Epiteliais/metabolismo , Células Cultivadas
15.
Adv Healthc Mater ; 12(30): e2302099, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37666241

RESUMO

Synergistic chemotherapy and photothermal therapy (PTT) have emerged as a promising anticancer paradigm to achieve expected therapeutic effects while mitigating side effects. However, the chemo/PTT combination therapy suffers from limited penetration depth, thermoresistance performance of tumor cells, and low drug bioavailability. Herein, multifunctional nanoparticles (BTP/DOX/2DG NPs) coloaded with near-infrared region II (NIR-II) light excitation donor-acceptor-donor (D-A-D) small molecules, doxorubicin (DOX), and 2-deoxy-d-glucose (2-DG) are developed for reinforced starvation/chemo/NIR-II PTT combination therapy. The synthesized phenylboronic acid (PBA)-modified water-soluble D-A-D molecule (BBT-TF-PBA) not only exhibits high binding ability to DOX and 2-DG through donor-acceptor coordination interactions PBA-diol bonds but also serves as a photoactive agent for NIR-II fluorescence imaging, NIR-II photoacoustic imaging, and NIR-II PTT. Under the acidic and oxidizing conditions in the tumor microenvironment, donor-acceptor coordination interactions and PBA-diol bond are decomposed, simultaneously releasing DOX and 2-DG from BTP/DOX/2DG NPs to achieve effective chemotherapy and starvation therapy. 2-DG also effectively inhibits the expression of heat shock protein and further enhances NIR-II PTT and chemotherapy efficiency. In vitro and in vivo experiments demonstrate the combination effect of BTP/DOX/2DG NPs for chemotherapy, NIR-II PTT, and starvation therapy.


Assuntos
Nanopartículas , Terapia Fototérmica , Fototerapia/métodos , Glucose , Doxorrubicina/química , Desoxiglucose , Nanopartículas/química , Linhagem Celular Tumoral
16.
Int J Mol Sci ; 24(15)2023 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-37569428

RESUMO

Melanoma is the most aggressive and treatment-resistant form of skin cancer. It is phenotypically characterized by aerobic glycolysis that provides higher proliferative rates and resistance to cell death. The glycolysis regulation in melanoma cells by means of effective metabolic modifiers represents a promising therapeutic opportunity. This work aimed to assess the metabolically oriented effect and mechanism of action of fucoidan from the brown alga Saccharina cichorioides (ScF) and its carboxymethylated derivative (ScFCM) in combination with 2-deoxy-D-glucose (2-DG) on the proliferation and colony formation of human melanoma cell lines SK-MEL-28, SK-MEL-5, and RPMI-7951. The metabolic profile of melanoma cells was determined by the glucose uptake and Lactate-GloTM assays. The effect of 2-DG, ScF, ScFCM, and their combination on the proliferation, colony formation, and activity of glycolytic enzymes was assessed by the MTS, soft agar, and Western blot methods, respectively. When applied separately, 2-DG (IC50 at 72 h = 8.7 mM), ScF (IC50 at 72 h > 800 µg/mL), and ScFCM (IC50 at 72 h = 573.9 µg/mL) inhibited the proliferation and colony formation of SK-MEL-28 cells to varying degrees. ScF or ScFCM enhanced the inhibiting effect of 2-DG at low, non-toxic concentrations via the downregulation of Glut 1, Hexokinase II, PKM2, LDHA, and pyruvate dehydrogenase activities. The obtained results emphasize the potential of the use of 2-DG in combination with algal fucoidan or its derivative as metabolic modifiers for inhibition of melanoma SK-MEL-28 cell proliferation.


Assuntos
Laminaria , Melanoma , Humanos , Glucose/metabolismo , Laminaria/metabolismo , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Proliferação de Células , Desoxiglucose/farmacologia , Desoxiglucose/uso terapêutico , Linhagem Celular Tumoral
17.
Am J Physiol Regul Integr Comp Physiol ; 325(3): R229-R237, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37424401

RESUMO

To investigate the role of glial cells in the regulation of glucoprivic responses in rats, a chemogenetic approach was used to activate astrocytes neighboring catecholamine (CA) neurons in the ventromedial medulla (VLM) where A1 and C1 CA cell groups overlap (A1/C1). Previous results indicate that activation of CA neurons in this region is necessary and sufficient for feeding and corticosterone release in response to glucoprivation. However, it is not known whether astrocyte neighbors of CA neurons contribute to glucoregulatory responses. Hence, we made nanoinjections of AAV5-GFAP-hM3D(Gq)-mCherry to selectively transfect astrocytes in the A1/C1 region with the excitatory designer receptor exclusively activated by designer drugs (DREADDs), hM3D(Gq). After allowing time for DREADD expression, we evaluated the rats for increased food intake and corticosterone release in response to low systemic doses of the antiglycolytic agent, 2-deoxy-d-glucose (2DG), alone and in combination with the hM3D(Gq) activator clozapine-n-oxide (CNO). We found that DREADD-transfected rats ate significantly more food when 2DG and CNO were coadministered than when either 2DG or CNO was injected alone. We also found that CNO significantly enhanced 2DG-induced FOS expression in the A1/C1 CA neurons, and that corticosterone release also was enhanced when CNO and 2DG were administered together. Importantly, CNO-induced activation of astrocytes in the absence of 2DG did not trigger food intake or corticosterone release. Our results indicate that during glucoprivation, activation of VLM astrocytes cells markedly increases the sensitivity or responsiveness of neighboring A1/C1 CA neurons to glucose deficit, suggesting a potentially important role for VLM astrocytes in glucoregulation.


Assuntos
Astrócitos , Corticosterona , Ratos , Animais , Astrócitos/metabolismo , Desoxiglucose/farmacologia , Ratos Sprague-Dawley , Bulbo/metabolismo , Glucose/metabolismo , Catecolaminas/metabolismo
18.
J Reprod Immunol ; 159: 104123, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37487312

RESUMO

The proper invasion of trophoblasts is crucial for embryo implantation and placental development, which is helpful to establish a correct maternal-fetal relationship. Trophoblasts can produce a large amount of lactate through aerobic glycolysis during early pregnancy. Lactate creates a low pH microenvironment around the embryo to help uterine tissue decompose and promote the invasion of trophoblasts. The purpose of this study is to reveal the the potential mechanism of aerobic glycolysis regulating the invasiveness of trophoblasts by investigating the effect of 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor, on the biological function of HTR-8/SVneo trophoblast cells, the expressions of epithelial mesenchymal transformation (EMT) markers and invasion-related factors. 2-DG could inhibit the aerobic glycolysis of trophoblasts and decrease the activity of trophoblasts in a dose-dependent manner. Moreover, 2-DG inhibited the EMT of HTR-8/SVneo cells, down-regulated the expression of invasion-related factors matrix metalloproteinase 2/9 (MMP2/9) and up-regulated the expression of tissue inhibitor of matrix metalloproteinases 1/2 (TIMP1/2), thus inhibiting cell migration and invasion. This paper provides a foundation in the significance of aerobic glycolysis of trophoblasts in the process of invasion, and also provides ideas and insights for the promotion of embryo implantation.


Assuntos
Placenta , Trofoblastos , Humanos , Gravidez , Feminino , Trofoblastos/metabolismo , Placenta/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Transdução de Sinais , Linhagem Celular , Desoxiglucose/farmacologia , Desoxiglucose/metabolismo , Lactatos/metabolismo , Lactatos/farmacologia , Movimento Celular
19.
Neuron ; 111(18): 2831-2846.e10, 2023 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-37453419

RESUMO

Intermittent fasting (IF) is a diet with salutary effects on cognitive aging, Alzheimer's disease (AD), and stroke. IF restricts a number of nutrient components, including glucose. 2-deoxyglucose (2-DG), a glucose analog, can be used to mimic glucose restriction. 2-DG induced transcription of the pro-plasticity factor, Bdnf, in the brain without ketosis. Accordingly, 2-DG enhanced memory in an AD model (5xFAD) and functional recovery in an ischemic stroke model. 2-DG increased Bdnf transcription via reduced N-linked glycosylation, consequent ER stress, and activity of ATF4 at an enhancer of the Bdnf gene, as well as other regulatory regions of plasticity/regeneration (e.g., Creb5, Cdc42bpa, Ppp3cc, and Atf3) genes. These findings demonstrate an unrecognized role for N-linked glycosylation as an adaptive sensor to reduced glucose availability. They further demonstrate that ER stress induced by 2-DG can, in the absence of ketosis, lead to the transcription of genes involved in plasticity and cognitive resilience as well as proteostasis.


Assuntos
Doença de Alzheimer , Cetose , Acidente Vascular Cerebral , Humanos , Desoxiglucose/farmacologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Glucose/metabolismo , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo
20.
Epilepsy Res ; 193: 107169, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37263021

RESUMO

2-deoxy-D-glucose (2DG) is a glucose analog and reversible inhibitor of glycolysis with anticonvulsant and antiepileptic effects in multiple seizure models. 2DG at a dose of 250 mg/kg intraperitoneally (IP) delays progression of repeated seizures evoked by kindling in rats when administered 30 min prior to twice daily kindling stimulation. As toxicological studies have demonstrated that repeated daily oral administration of 2DG at doses of 60-375 mg/kg/day in rats induces dose-dependent, reversible cardiac myocyte vacuolation, it was of interest to determine if 2DG also slowed kindling progression when administered at or below doses causing cardiac toxicity and at various time points after evoked seizures. We found that: (1) 2DG slowed kindling progression nearly 2-fold when administered at a dose of 37.5 mg/kg given IP 30 min prior to kindling stimulation, and (2) 2DG 37.5 mg/kg IP also slowed kindling progression when given immediately after, and for as long as 10 min after evoked (kindled) seizures. These observations suggest potential clinical usefulness of post-seizure administration of 2DG to reduce seizure clusters and long-term consequences of repeated seizures at human equivalent doses that are likely to be safe and well tolerated in patients.


Assuntos
Glucose , Excitação Neurológica , Ratos , Humanos , Animais , Convulsões/tratamento farmacológico , Convulsões/etiologia , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Desoxiglucose/farmacologia , Desoxiglucose/uso terapêutico
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