RESUMEN
Targeted delivery and precise release of toxins is a prospective strategy for the treatment of triple-negative breast cancer (TNBC), yet the flexibility to incorporate both properties simultaneously remains tremendously challenging in the X-drug conjugate fields. As critical components in conjugates, linkers could flourish in achieving optimal functionalities. Here, we pioneered a pH-hypersensitive tumor-targeting aptamer AS1411-triptolide conjugate (AS-TP) to achieve smart release of the toxin and targeted therapy against TNBC. The multifunctional acetal ester linker in the AS-TP site-specifically blocked triptolide toxicity, quantitatively sustained aptamer targeting, and ensured the circulating stability. Furthermore, the aptamer modification endowed triptolide with favorable water solubility and bioavailability and facilitated endocytosis of conjugated triptolide by TNBC cells in a nucleolin-dependent manner. The integrated superiorities of AS-TP promoted the preferential intra-tumor triptolide accumulation in xenografted TNBC mice and triggered the in-situ triptolide release in the weakly acidic tumor microenvironment, manifesting striking anti-TNBC efficacy and virtually eliminated toxic effects beyond clinical drugs. This study illustrated the therapeutic potential of AS-TP against TNBC and proposed a promising concept for the development of nucleic acid-based targeted anticancer drugs.
Asunto(s)
Aptámeros de Nucleótidos , Diterpenos , Compuestos Epoxi , Fenantrenos , Neoplasias de la Mama Triple Negativas , Diterpenos/farmacología , Diterpenos/uso terapéutico , Diterpenos/química , Compuestos Epoxi/farmacología , Compuestos Epoxi/uso terapéutico , Compuestos Epoxi/química , Fenantrenos/farmacología , Fenantrenos/uso terapéutico , Fenantrenos/química , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Animales , Humanos , Ratones , Femenino , Aptámeros de Nucleótidos/farmacología , Aptámeros de Nucleótidos/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéuticoRESUMEN
Colorectal cancer (CRC) is among the most common gastrointestinal malignancies worldwide. eIF3a is highly expressed in a variety of cancer types, yet its role in CRC remains unclear. We introduced ectopic eIF3a expression in CRC cells to investigate its relevance to various malignant behaviors. Further, we silenced eIF3a to explore its effect on tumor growth in a nude mouse tumor xenograft model. Finally, the molecular mechanisms through which eIF3a regulates malignancy in CRC cells were explored through bioinformatics analysis combined with the use of a specific PI3K inhibitor (LY294002). eIF3a was highly expressed in the peripheral blood and cancer tissue of CRC patients. Malignancy and tumor growth were significantly inhibited by silencing eIF3a, while overexpression promoted malignant behaviors, with a positive correlation between PI3K/AKT activation and eIF3a expression. Taken together, eIF3a plays an oncogenic role in CRC by regulating PI3K/AKT signaling and is a potential biomarker for CRC diagnosis and prognostic monitoring.
Asunto(s)
Neoplasias Colorrectales , Factor 3 de Iniciación Eucariótica , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Humanos , Factor 3 de Iniciación Eucariótica/metabolismo , Factor 3 de Iniciación Eucariótica/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Animales , Ratones , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Ratones Desnudos , Línea Celular Tumoral , Proliferación Celular , Ensayos Antitumor por Modelo de Xenoinjerto , Femenino , Masculino , Regulación Neoplásica de la Expresión GénicaRESUMEN
BACKGROUND: Acrylamide (ACR) is a widely used compound that is known to be neurotoxic to both experimental animals and humans, causing nerve damage. The widespread presence of ACR in the environment and food means that the toxic risk to human health can no longer be ignored. Rosmarinic acid (RA), a natural polyphenolic compound extracted from the perilla plant, exhibits anti-inflammatory, antioxidant, and other properties. It has also been demon strated to possess promising potential in neuroprotection. However, its role and potential mechanism in treating ACR induced neurotoxicity are still elusive. PURPOSE: This study explores whether RA can improve ACR induced neurotoxicity and its possible mechanism. METHODS: The behavioral method was used to study RA effect on ACR exposed mice's neurological function. We studied its potential mechanism through metabolomics, Nissl staining, HE staining, immunohistochemical analysis, and Western blot. RESULTS: RA pretreatment reversed the increase in mouse landing foot splay and decrease in spontaneous activity caused by 3 weeks of exposure to 50 mg/kg/d ACR. Further experiments demonstrated that RA could prevent ACR induced neuronal apoptosis, significantly downregulate nuclear factor-κB and tumor necrosis factor-α expression, and inhibit NOD-like receptor protein 3 inflammasome activation, thereby reducing inflammation as confirmed by metabolomics results. Additionally, RA treatment prevented endoplasmic reticulum stress (ERS) caused by ACR exposure, as evidenced by the reversal of significant P-IRE1α,TRAF2,CHOP expression increase. CONCLUSION: RA alleviates ACR induced neurotoxicity by inhibiting ERS and inflammation. These results provide a deeper understanding of the mechanism of ACR induced neurotoxicity and propose a potential new treatment method.
Asunto(s)
Estrés Oxidativo , Ácido Rosmarínico , Ratones , Humanos , Animales , Acrilamida/toxicidad , Endorribonucleasas , Proteínas Serina-Treonina Quinasas , Hipocampo , Inflamación/tratamiento farmacológico , Estrés del Retículo EndoplásmicoRESUMEN
Currently, there is no effective treatment for Parkinson's disease (PD), and the regenerative treatment of neural stem cells (NSCs) is considered the most promising method. This study aimed to investigate the protective effect and mechanism of NSCs on neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced cynomolgus monkey (Macaca fascicularis) model of PD. We first found that injecting NSCs into the subarachnoid space relieved motor dysfunction in PD cynomolgus monkeys, as well as reduced dopaminergic neuron loss and neuronal damage in the substantia nigra (SN) and striatum. Besides, NSCs decreased 17-estradiol (E2) level, an estrogen, in the cerebrospinal fluid (CSF) of PD cynomolgus monkeys, which shows NSCs may provide neuro-protection by controlling estrogen levels in the CSF. Furthermore, NSCs elevated proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a), mitofusin 2 (MFN2), and optic atrophy 1 (OPA1) expression, three genes mediating mitochondrial biogenesis, in the SN and striatum of PD monkeys. In addition, NSCs suppress reactive oxygen species (ROS) production caused by MPTP, as well as mitochondrial autophagy, therefore preserving dopaminergic neurons. In summary, our findings show that NSCs may preserve dopaminergic and neuronal cells in an MPTP-induced PD cynomolgus monkey model. These protective benefits might be attributed to NSCs' ability of modulating estrogen balance, increasing mitochondrial biogenesis, and limiting oxidative stress and mitochondrial autophagy. These findings add to our understanding of the mechanism of NSC treatment and shed light on further clinical treatment options.
Asunto(s)
Intoxicación por MPTP , Células-Madre Neurales , Enfermedad de Parkinson , Animales , Humanos , Macaca fascicularis/metabolismo , Intoxicación por MPTP/terapia , Intoxicación por MPTP/metabolismo , Células-Madre Neurales/metabolismo , Enfermedad de Parkinson/metabolismo , Neuronas Dopaminérgicas , Dopamina/metabolismo , Estrógenos/farmacologíaRESUMEN
BACKGROUND: The most common causes of scrotal enlargement in patients include primary tumor of the scrotum, inflammation, hydrocele of the tunica vaginalis, and indirect inguinal hernia; scrotal enlargement caused by external tumors of the scrotum is rare. The patient had both a greater omentum tumor and an inguinal hernia, and the tumor protruded into the scrotum through the hernia sac, which is even rarer. Moreover, omental tumors are mostly metastatic, and primary omental fibroma is rare. CASE SUMMARY: Here, we report a rare case of a 25-year-old young man with scrotal enlargement and pain for 3 months. Preoperative examination and multidisciplinary discussions considered intra-abdominal tumor displacement and inguinal hernia, and intraoperative exploration confirmed that the greater omentum tumor protruded into the scrotum. Therefore, tumor resection and tension-free inguinal hernia repair were performed. The final diagnosis was benign fibroma of the greater omentum accompanied by an indirect inguinal hernia. CONCLUSION: This unusual presentation of a common inguinal hernia disease illustrates the necessity of performing detailed history taking, physical examination, and imaging before surgery.