RESUMEN
Cyprodinil, a globally utilized broad-spectrum pyrimidine amine fungicide, has been observed to elicit cardiac abnormality. Resveratrol (RSV), a naturally occurring polyphenolic compound, showcases remarkable defensive properties in nurturing cardiac development. To investigate whether RSV could protect against cyprodinil-induced cardiac defects, we exposed zebrafish embryos to cyprodinil (500 µg/L) in the presence or absence of RSV (1 µM). Our results showed that RSV significantly mitigated the decrease of survival rate and embryo movement and the hatching delay induced by cyprodinil. In addition, RSV also improved cyprodinil-induced zebrafish cardiac developmental toxicity, including pericardial edema and cardiac function impairment. In mechanism, RSV attenuated the cyprodinil-induced changes in mRNA expression involved in cardiac development, such as myh6, myl7, tbx5, and gata4, and calcium ion channels, such as ncx1h, slc8a4a, and atp2a2b. We further showed that RSV might inhibit the activity of aryl hydrocarbon receptor (AhR) signaling pathways induced by cyprodinil. In summary, our findings establish that the protective effects of RSV against the cardiac developmental toxicity are induced by cyprodinil due to its remarkable ability to inhibit AhR activity. Our findings not only shed light on a new avenue for regulating and ensuring the safe utilization of cyprodinil but also presents a novel concept to promote its responsible use.
Asunto(s)
Corazón , Pirimidinas , Receptores de Hidrocarburo de Aril , Resveratrol , Pez Cebra , Animales , Pez Cebra/embriología , Resveratrol/farmacología , Pirimidinas/toxicidad , Pirimidinas/farmacología , Corazón/efectos de los fármacos , Embrión no Mamífero/efectos de los fármacosRESUMEN
BACKGROUND: Gastric cancer (GC) is a deadly disease with poor overall survival and limited therapeutic options. Genetic alterations such as mutations and/or deletions in chromatin remodeling gene AT-rich interactive domain 1 A (ARID1A) occur frequently in GC. Although ARID1A mutations/deletions are not a druggable target for conventional treatments, novel therapeutic strategies based on a synthetic lethal approach may be effective for the treatment of ARID1A-deficient cancers. METHODS: A kinase inhibitor library containing 551 compounds was screened in ARID1A isogenic GC cells for the ability to induce synthetic lethality effect. Selected hits' activity was validated, and the mechanism of the most potent candidate drug, AKT inhibitor AD5363 (capivasertib), on induction of the synthetic lethality with ARID1A deficiency was investigated. RESULTS: After robust vulnerability screening of 551 diverse protein kinase inhibitors, we identified the AKT inhibitor AZD5363 as being the most potent lead compound in inhibiting viability of ARID1A-/- cells. A synthetic lethality between loss of ARID1A expression and AKT inhibition by AZD5363 was validated in both GC cell model system and xenograft model. Mechanistically, AZD5363 treatment induced pyroptotic cell death in ARID1A-deficient GC cells through activation of the Caspase-3/GSDME pathway. Furthermore, ARID1A occupied the AKT gene promoter and regulated its transcription negatively, thus the GC cells deficient in ARID1A showed increased expression and phosphorylation of AKT. CONCLUSIONS: Our study demonstrates a novel synthetic lethality interaction and unique mechanism between ARID1A loss and AKT inhibition, which may provide a therapeutic and mechanistic rationale for targeted therapy on patients with ARID1A-defective GC who are most likely to be beneficial to AZD5363 treatment.
Asunto(s)
Proteínas de Unión al ADN , Proteínas Proto-Oncogénicas c-akt , Piroptosis , Neoplasias Gástricas , Mutaciones Letales Sintéticas , Factores de Transcripción , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Humanos , Factores de Transcripción/genética , Factores de Transcripción/antagonistas & inhibidores , Animales , Ratones , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas de Unión al ADN/genética , Piroptosis/efectos de los fármacos , Piroptosis/genética , Mutaciones Letales Sintéticas/efectos de los fármacos , Línea Celular Tumoral , Pirimidinas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/farmacologíaRESUMEN
Thrombosis is a major health concern that contributes to the development of several cardiovascular diseases and a significant number of fatalities worldwide. While stent surgery is the current recommended treatment according to the guidelines, percutaneous coronary intervention (PCI) is the optimal approach for acute myocardial infarction (AMI). However, in remote areas with limited resources, PCI procedures may not be feasible, leading to a delay in treatment and irreversible outcomes. In such cases, preoperative thrombolysis becomes the primary choice for managing AMI in remote settings. The market for thrombolytic drugs is continuously evolving, and identifying a safe and effective thrombolytic agent for treating AMI is crucial. This study evaluated Urokinase, Alteplase, and Recombinant Human TNK Tissue-type Plasminogen Activator for Injection (rhTNK) as representatives of first-, second-, and third-generation thrombolytic drugs, respectively. The research included in vitro thrombolysis experiments, exposure of human cardiomyocytes, zebrafish tail vein injections, and vascular endothelial transgenic zebrafish models. The findings revealed that rhTNK is the most effective thrombolytic drug with the least adverse effects and lowest bleeding rate, highlighting its potential as the preferred treatment option for AMI. The order of thrombolytic effectiveness was Urokinase < Alteplase < rhTNK, with adverse effects on cardiomyocytes post-thrombolytic therapy ranking similarly as Urokinase < Alteplase < rhTNK, while the bleeding rate after thrombolysis followed the order of Urokinase > Alteplase > rhTNK.
RESUMEN
The Epstein-Barr virus (EBV) is implicated in several cancers, including EBV-associated gastric cancer (EBVaGC). This study focuses on EBV-encoded BALF1 (BamH1 A fragment leftward reading frame 1), a key apoptosis regulator in EBV-related cancers, whose specific impact on EBVaGC was previously unknown. Our findings indicate that BALF1 overexpression in gastric cancer cells significantly enhances their proliferation, migration, and resistance to chemotherapy-induced apoptosis, confirming BALF1's oncogenic potential. A novel discovery is that BALF1 undergoes degradation via the ubiquitin-proteasome pathway. Through analysis of 69 deubiquitinating enzymes (DUBs), ovarian tumor protease (OTU) domain-containing protein 1 (OTUD1) emerged as a vital regulator for maintaining BALF1 protein stability. Furthermore, BALF1 was found to play a role in regulating the stability of the B-cell lymphoma-2 (Bcl-2) protein, increasing its levels through deubiquitination. This mechanism reveals BALF1's multifaceted oncogenic role in gastric cancer, as it contributes both directly and indirectly to cancer progression, particularly by stabilizing Bcl-2, known for its anti-apoptotic characteristics. These insights significantly deepen our understanding of EBV's involvement in the pathogenesis of gastric cancer. The elucidation of OTUD1's role in BALF1 regulation and its influence on Bcl-2 stabilization provide new avenues for therapeutic intervention in EBVaGC, bridging the gap between viral oncogenesis and cellular protein regulation and offering a more holistic view of gastric cancer development under the influence of EBV.
Asunto(s)
Apoptosis , Proteínas Proto-Oncogénicas c-bcl-2 , Neoplasias Gástricas , Ubiquitinación , Humanos , Neoplasias Gástricas/patología , Neoplasias Gástricas/virología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Línea Celular Tumoral , Herpesvirus Humano 4/metabolismo , Herpesvirus Humano 4/genética , Proteínas Virales/metabolismo , Proteínas Virales/genética , Proliferación Celular , Proteasas Ubiquitina-Específicas/metabolismo , Proteasas Ubiquitina-Específicas/genética , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/metabolismo , Infecciones por Virus de Epstein-Barr/patología , Infecciones por Virus de Epstein-Barr/genética , Estabilidad Proteica , Movimiento Celular , Animales , Enzimas Desubicuitinizantes/metabolismo , Enzimas Desubicuitinizantes/genética , Proteínas Reguladoras y Accesorias ViralesRESUMEN
The monocyte to high-density lipoprotein-cholesterol (HDL-C) ratio (monocyte-to-HDL-C ratio) was proposed as a marker of atherosclerosis. Osteoporosis and atherosclerosis share common risk factors and pathophysiological mechanisms. This study aimed to assess the relationship between monocyte-to-HDL-C ratio and osteoporosis. Participants aged ≥50 years with complete bone mineral density (BMD), monocyte, and HDL-C examination data from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 were included. Descriptive analysis was performed separately according to males and females. Weight linear regression and weight logistic regression analyses were used to analyze the association between the monocyte-to-HDL-C ratio and BMD and osteopenia and osteoporosis and vertebral fracture. A total of 1804 participants were included. Among the participants with osteopenia, 398 (48.31%) were males and 466 (51.91%) were females. Among those with osteoporosis, 38 (2.77%) were males and 95 (9.50%) were females. In females, monocyte-to-HDL-C ratio was negatively associated with femoral neck BMD (regression coefficient (ß) = -0.18; 95% confidence interval (CI): (-0.29, -0.07)) and high monocyte-to-HDL-C ratio was associated with higher odds of osteopenia (odds ratio (OR) = 1.22; 95% CI: (1.01, 1.47)) and osteoporosis (OR = 1.68; 95% CI: (1.13, 2.49)) after adjusting for confounders. In males, only monocyte-to-HDL-C ratio >0.35 was observed to be associated with higher odds of osteoporosis (OR = 1.96; 95% CI: (1.02, 3.79)). Stratified analyses showed that similar results were also found in different populations. This study showed that the monocyte-to-HDL-C ratio was negatively associated with BMD and the risk of osteopenia and osteoporosis in females. The monocyte-to-HDL-C ratio may be a new marker of osteoporosis or osteopenia.
Asunto(s)
Aterosclerosis , Enfermedades Óseas Metabólicas , Osteoporosis , Masculino , Femenino , Humanos , Encuestas Nutricionales , HDL-Colesterol , Monocitos , Osteoporosis/complicaciones , Densidad Ósea , Enfermedades Óseas Metabólicas/epidemiología , Enfermedades Óseas Metabólicas/complicaciones , Enfermedades Óseas Metabólicas/diagnóstico , Aterosclerosis/complicacionesRESUMEN
Pyrrolizidine alkaloids (PAs) are a class of phytotoxins that are widely distributed and can be consumed by humans through their daily diets. Echimidine is one of the most abundant PAs, but its safety, particularly its effects on development, is not fully understood. In this study, we used a zebrafish model to assess the developmental toxicity of echimidine. Zebrafish embryos were exposed to echimidine at concentrations of 0.02, 0.2, and 2 mg/L for 96 h. Our study revealed that embryonic exposure to echimidine led to developmental toxicity, characterized by delayed hatching and reduced body length. Additionally, echimidine exposure had a notable impact on heart development in larvae, causing tachycardia and reducing stroke volume (SV)and cardiac output (CO). Upon exposing the transgenic zebrafish strain Tg(cmlc2:EGFP) to echimidine, we observed atrial dilation and thinning of the atrial wall in developing embryos. Moreover, our findings indicated abnormal expression of genes associated with cardiac development (including gata4, tbx5, nkx2.5 and myh6) and genes involved in calcium signaling pathways (such as cacna1aa, cacna1sa, ryr2a, ryr2b, atp2a2a, atp2a2b, slc8a1, slc8a3 and slc8a4a). In summary, our findings demonstrate that echimidine may impair cardiac development and function in zebrafish larvae by disrupting calcium transport, leading to developmental toxicity. These findings provide insights regarding the safety of products containing PAs in food and medicine.