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BACKGROUND: Oral squamous cell carcinoma (OSCC), the predominant malignancy of the oral cavity, is characterized by high incidence and low survival rates. Emerging evidence suggests a link between circadian rhythm disruptions and cancer development. The circadian gene TIMELESS, known for its specific expression in various tumors, has not been extensively studied in the context of OSCC. This study aims to explore the influence of TIMELESS on OSCC, focusing on cell growth and metabolic alterations. METHODS: We analyzed TIMELESS expression in OSCC using western blot, immunohistochemistry, qRT-PCR, and data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE). The role of TIMELESS in OSCC was examined through clone formation, MTS, cell cycle, and EdU assays, alongside subcutaneous tumor growth experiments in nude mice. We also assessed the metabolic impact of TIMELESS by measuring glucose uptake, lactate production, oxygen consumption, and medium pH, and investigated its effect on key metabolic proteins including silent information regulator 1 (SIRT1), hexokinase 2 (HK2), pyruvate kinase isozyme type M2 (PKM2), recombinant lactate dehydrogenase A (LDHA) and glucose transporter-1 (GLUT1). RESULTS: Elevated TIMELESS expression in OSCC tissues and cell lines was observed, correlating with reduced patient survival. TIMELESS overexpression enhanced OSCC cell proliferation, increased glycolytic activity (glucose uptake and lactate production), and suppressed oxidative phosphorylation (evidenced by reduced oxygen consumption and altered pH levels). Conversely, TIMELESS knockdown inhibited these cellular and metabolic processes, an effect mirrored by manipulating SIRT1 levels. Additionally, SIRT1 was positively associated with TIMELESS expression. The expression of SIRT1, HK2, PKM2, LDHA and GLUT1 increased with the overexpression of TIMELESS levels and decreased with the knockdown of TIMELESS. CONCLUSION: TIMELESS exacerbates OSCC progression by modulating cellular proliferation and metabolic pathways, specifically by enhancing glycolysis and reducing oxidative phosphorylation, largely mediated through the SIRT1 pathway. This highlights TIMELESS as a potential target for OSCC therapeutic strategies.
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Péptidos y Proteínas de Señalización del Ritmo Circadiano , Glucosa , Neoplasias de la Boca , Carcinoma de Células Escamosas de Cabeza y Cuello , Animales , Humanos , Ratones , Línea Celular Tumoral , Proliferación Celular/genética , Glucosa/metabolismo , Transportador de Glucosa de Tipo 1 , Lactatos , Ratones Desnudos , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Sirtuina 1/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Péptidos y Proteínas de Señalización del Ritmo Circadiano/genéticaRESUMEN
BACKGROUND: Ultrasound-targeted microbubble destruction (UTMD) has emerged as a promising strategy for the targeted delivery of bone marrow mesenchymal stem cells (MSCs) to the ischemic myocardium. However, the limited migration capacity and poor survival of MSCs remains a major therapeutic barrier. The present study was performed to investigate the synergistic effect of UTMD with platelet-derived growth factor BB (PDGF-BB) on the homing of MSCs for acute myocardial infarction (AMI). METHODS: MSCs from male donor rats were treated with PDGF-BB, and a novel microbubble formulation was prepared using a thin-film hydration method. In vivo, MSCs with or without PDGF-BB pretreatment were transplanted by UTMD after inducing AMI in experimental rats. The therapeutic efficacy of PDGF-BB-primed MSCs on myocardial apoptosis, angiogenesis, cardiac function and scar repair was estimated. The effects and molecular mechanisms of PDGF-BB on MSC migration and survival were explored in vitro. RESULTS: The results showed that the biological effects of UTMD increased the local levels of stromal-derived factor-1 (SDF-1), which promoted the migration of transplanted MSCs to the ischemic region. Compared with UTMD alone, UTMD combined with PDGF-BB pretreatment significantly increased the cardiac homing of MSCs, which subsequently reduced myocardial apoptosis, promoted neovascularization and tissue repair, and increased cardiac function 30 days after MI. The vitro results demonstrated that PDGF-BB enhanced MSC migration and protected these cells from H2O2-induced apoptosis. Mechanistically, PDGF-BB pretreatment promoted MSC migration and inhibited H2O2-induced MSC apoptosis via activation of the phosphatidylinositol 3-kinase/serine-threonine kinase (PI3K/Akt) pathway. Furthermore, crosstalk between PDGF-BB and stromal-derived factor-1/chemokine receptor 4 (SDF-1/CXCR4) is involved in the PI3K/AKT signaling pathway. CONCLUSION: The present study demonstrated that UTMD combined with PDGF-BB treatment could enhance the homing ability of MSCs, thus alleviating AMI in rats. Therefore, UTMD combined with PDGF-BB pretreatment may offer exciting therapeutic opportunities for strengthening MSC therapy in ischemic diseases.
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Trasplante de Células Madre Mesenquimatosas , Infarto del Miocardio , Ratas , Masculino , Animales , Trasplante de Células Madre Mesenquimatosas/métodos , Becaplermina/farmacología , Microburbujas , Peróxido de Hidrógeno , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Infarto del Miocardio/terapia , MiocardioRESUMEN
Inflammatory granuloma is a rare non neoplastic benign disease that rarely reported in the heart tissue, and surgical resection is the final treatment with satisfactory results. Hereinafter, we report a case of inflammatory granuloma in the right ventricle of a 25-year-old man who underwent multimodality imaging and successful resection of the mass. Results of the case suggested that when evaluating patients with cardiac mass in unusual locations, it was necessary to comprehensively consider multiple imaging features and combine laboratory examination to make clinical suspicion.
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Ecocardiografía , Ventrículos Cardíacos , Masculino , Humanos , Adulto , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/cirugía , Granuloma/diagnóstico por imagen , Granuloma/cirugía , Diagnóstico DiferencialRESUMEN
Angiosarcoma is an extremely rare primary cardiac malignant tumor, with characteristics of early blood metastasis and radiochemotherapy resistance. Early diagnosis and timely treatment are of great significance to the prognosis of patients. Hereinafter, we report a case of angiosarcoma in the left atrium of a 61-year-old woman who underwent multimodality imaging and successful resection of the angiosarcoma. Results of the present case suggest that multimodal imaging plays an important role in detecting angiosarcoma and determining the treatment plan and prognosis for patients after treatment.
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Neoplasias Encefálicas , Neoplasias Cardíacas , Hemangiosarcoma , Femenino , Humanos , Persona de Mediana Edad , Hemangiosarcoma/diagnóstico por imagen , Hemangiosarcoma/patología , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/patología , Neoplasias Cardíacas/diagnóstico por imagen , Neoplasias Cardíacas/patología , Imagen Multimodal , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patologíaRESUMEN
Lipomas occuring within the heart are rare tumors, and invasive cardiac lipomas are even rare. Hereinafter we reported a case of a 51-year-old woman with a left ventricular transmural invasive lipoma, and summarized the imaging characteristics and main sites of it. Comprehensive imaging investigations appears valuable for early detection, intraoperative monitoring, and postoperative follow-up of invasive cardiac lipomas.
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Neoplasias Cardíacas , Lipoma , Femenino , Humanos , Persona de Mediana Edad , Ventrículos Cardíacos/patología , Neoplasias Cardíacas/diagnóstico por imagen , Neoplasias Cardíacas/cirugía , Corazón , Ecocardiografía , Lipoma/diagnóstico por imagen , Lipoma/cirugíaRESUMEN
Thyroid nodule is a common and frequently occurring disease in the neck in recent years, and ultrasound has become the preferred imaging diagnosis method for thyroid nodule due to its advantages of noninvasive, nonradiation, real-time, and repeatable. The thyroid imaging, reporting and data system (TI-RADS) classification standard scores suspicious nodules that are difficult to determine benign and malignant as grade 4, and further pathological puncture is recommended clinically, which may lead to a large number of unnecessary biopsies and operations. Including conventional ultrasound, ACR TI-RADS, shear wave elastography, super microvascular imaging, contrast enhanced ultrasound, "firefly," artificial intelligence, and multimodal ultrasound imaging used in combination. In order to identify the most clinically significant malignant tumors when reducing invasive operations. This article reviews the application and research progress of multimodal ultrasound imaging in the diagnosis of TI-RADS 4 thyroid nodules.
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Nódulo Tiroideo , Humanos , Nódulo Tiroideo/patología , Inteligencia Artificial , Estudios Retrospectivos , Ultrasonografía/métodosRESUMEN
Androgen receptor (AR) and its constitutively active splice variant, AR Variant 7 (AR-V7), regulate genes essential for the development and progression of prostate cancer. Degradation of AR and AR-V7 by the ubiquitination proteasomal pathway is important for the regulation of both their protein stability. Our published results demonstrate that the interaction of TM4SF3 with either AR or AR-V7 leads to mutual stabilization due to a reduction in their ubiquitination and proteasomal degradation. These results led us to search for a common E3 ligase for AR, AR-V7, and TM4SF3. Depletion by siRNA of several E3 ligases identified MDM2 as the common E3 ligase. MDM2 inhibition by siRNA depletion or using a pharmacological inhibitor (MDM2i) of its E3 ligase activity led to elevated levels of endogenous AR, AR-V7, and TM4SF3 in prostate cancer cells. MDM2 knockdown in PC-3 cells, which do not express AR, also increased TM4SF3, demonstrating that MDM2 affects the TM4SF3 protein independent of AR. We further demonstrate that MDM2i treatment reduced the ubiquitination of AR and TM4SF3, suggesting that MDM2 can induce the ubiquitination of these proteins. Increased AR and AR-V7 protein levels induced by MDM2i treatment resulted in the expected increased expression of AR-regulated genes and enhanced proliferation and migration of both LNCaP and Enzalutamide-resistant CWR-22Rv1 prostate cancer cells. Thus, our study expands the known roles of MDM2 in prostate cancer to include its potential involvement in the important mutual stabilization that TM4SF3 exhibits when interacting with either AR or AR-V7.
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Polyethylene terephthalate (PET) is widely used for various industrial applications. However, owing to its extremely slow breakdown rate, PET accumulates as plastic trash, which negatively affects the environment and human health. Here, we report two novel PET hydrolases: PpPETase from Pseudomonas paralcaligenes MRCP1333, identified in human feces, and ScPETase from Streptomyces calvus DSM 41452. These two enzymes can decompose various PET materials, including semicrystalline PET powders (Cry-PET) and low-crystallinity PET films (gf-PET). By structure-guided engineering, two variants, PpPETaseY239R/F244G/Y250G and ScPETaseA212C/T249C/N195H/N243K were obtained that decompose Cry-PET 3.1- and 1.9-fold faster than their wild-type enzymes, respectively. The co-expression of ScPETase and mono-(2-hydroxyethyl) terephthalate hydrolase from Ideonella sakaiensis (IsMHETase) resulted in 1.4-fold more degradation than the single enzyme system. This engineered strain degraded Cry-PET and gf-PET by more than 40% and 6%, respectively, after 30 d. The concentrations of terephthalic acid (TPA) in the Cry-PET and gf-PET degradation products were 37.7% and 25.6%, respectively. The discovery of these two novel PET hydrolases provides opportunities to create more powerful biocatalysts for PET biodegradation.
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Heces , Hidrolasas , Tereftalatos Polietilenos , Streptomyces , Tereftalatos Polietilenos/metabolismo , Tereftalatos Polietilenos/química , Streptomyces/enzimología , Streptomyces/genética , Hidrolasas/metabolismo , Hidrolasas/genética , Hidrolasas/química , Humanos , Heces/microbiología , Pseudomonas/enzimología , Pseudomonas/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , BurkholderialesRESUMEN
ß-1,3-Galactanases selectively degrade ß-1,3-galactan, thus it is an attractive enzyme technique to map high-galactan structure and prepare galactooligosaccharides. In this work, a gene encoding exo-ß-1,3-galactanase (PxGal43) was screened form Paenibacillus xylanexedens, consisting of a GH43 domain, a CBM32 domain and α-L-arabinofuranosidase B (AbfB) domain. Using ß-1,3-galactan (AG-II-P) as substrate, the recombined enzyme expressed in Escherichia coli BL21 (DE3) exhibited an optimal activity at pH 7.0 and 30 °C. The enzyme was thermostable, retaining >70 % activity after incubating at 50 °C for 2 h. In addition, it showed high tolerance to various metal ions, denaturants and detergents. Substrate specificity indicated that PxGal43 hydrolysis only ß-1,3-linked galactosyl oligosaccharides and polysaccharides, releasing galactose as an exo-acting manner. The function of the CBM32 and AbfB domain was revealed by their sequential deletion and suggested that their connection to the catalytic domain was crucial for the oligomerization, catalytic activity, substrate binding and thermal stability of PxGal43. The substrate docking and site-directed mutagenesis proposed that Glu191, Gln244, Asp138 and Glu81 served as the catalytic acid, catalytic base, pKa modulator, and substrate identifier in PxGal43, respectively. These results provide a better understanding and optimization of multi-domain bacterial GH43 ß-1,3-galactanase for the degradation of arabinogalactan.
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Glicósido Hidrolasas , Paenibacillus , Paenibacillus/enzimología , Paenibacillus/genética , Glicósido Hidrolasas/genética , Glicósido Hidrolasas/metabolismo , Glicósido Hidrolasas/química , Especificidad por Sustrato , Dominios Proteicos , Concentración de Iones de Hidrógeno , Estabilidad de Enzimas , Cinética , Hidrólisis , Galactanos/metabolismo , Secuencia de Aminoácidos , TemperaturaRESUMEN
Purpose: Kidney transplantation (KT) has the potential to reverse the cardiac changes caused by end-stage renal disease, and it may be inaccurate to analysis the left ventricular function by conventional echocardiography due to afterload. This study aimed to investigate the utility of pressure strain loops (PSLs) in evaluating left ventricular performance in patients underwent KT. Methods: We enrolled 60 patients with end-stage renal disease who underwent KT between January 2022 and July 2023, and 60 healthy controls with a similar distribution of gender and age to the patients. All participants underwent conventional echocardiography and three-dimensional speckle tracking echocardiography (3D-STE). Long axis, short axis, and four cavity images were collected and cardiac parameters were measured. The echocardiographic changes of cardiac structure and function of all patients before KT and about 12 months after KT were recorded. Left ventricular myocardial work parameters were acquired by PSLs, including the global work index (GWI), global constructive work (GCW), global wasted work (GWW), global work efficiency (GWE) and global longitudinal strain (GLS). In addition, the correlation between PSLs and clinical data were explored. Results: Compared with controls, the conventional echocardiographic parameters, myocardial function indicators GWI and GCW appeared no difference in post-KT group, while the GWE and GLS decreased (p < 0.05), and the GWW increased (p < 0.05). Compared with pre-KT, the GLS, GWI, GCW and GWE increased in post-KT group, while the GWW decreased (all p < 0.05). The above indicators were correlated with left ventricular GLS and left ventricular ejection fraction. Conclusion: PSLs were more sensitive than traditional echocardiographic indicators in detecting changes in myocardial work and predicting left ventricular myocardial damage. This indicator could quantitatively evaluate myocardial work and provide a new and reliable non-invasive reference for clinical diagnosis and treatment of patients underwent KT.
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BACKGROUND: Erectile dysfunction and atherosclerosis are common cardiovascular complications in diseases. Clinical associations between erectile dysfunction and atherosclerosis have been noticed, but the specific mechanisms are not illustrated adequately. OBJECTIVES: The aim of the study was to further mine associated pathological mechanisms and genetic alterations of atherosclerosis in diabetes mellitus-related erectile dysfunction. MATERIALS AND METHODS: Significant atherosclerosis-related genes were identified from transcriptome data of diabetes mellitus-related erectile dysfunction and atherosclerosis-related gene sets from DisGeNET and GeneCard databases. Functional enrichment and immune infiltration analyses were performed to clarify the biological roles and pathways as well as immune responses of significant atherosclerosis-related gene sets. A protein-protein interaction network was constructed, and gene clusters were performed. Then, data of diabetic plaques and high-glucose cavernosum endothelial cells were analyzed for validation. And hub atherosclerosis-related gene sets were identified. Finally, expressed pattern of hub atherosclerosis-related gene sets were explored by single-cell profiling and immune analysis. RESULTS: In total, 202 significant atherosclerosis-related gene sets including 100 upregulated and 102 downregulated genes were identified. These genes were related to endothelial cell migration, inflammatory response, regulation of oxidative stress, and immune response. In immune infiltration, immature dendritic cells and monocytes showed differential expression between the diabetes mellitus-related erectile dysfunction and control groups, A protein-protein interaction network containing 135 nodes was constructed. A hub atherosclerosis-related gene set signature consisting of HBEGF, LOX, NQO1, and VLDLR was obtained by multi-omics validation. In addition, Functional enrichment analysis revealed that hub atherosclerosis-related gene sets were involved in oxidoreductase activity and extracellular matrix organization. DISCUSSION AND CONCLUSION: We explored atherosclerosis-related genetic changes and signaling pathways in diabetes mellitus-related erectile dysfunction. HBEGF, LOX, NQO1, and VLDLR were identified as hub atherosclerosis-related gene sets. These may serve as potential biomarkers for the clinical management of atherosclerosis and preventing further cardiovascular risks in diabetes mellitus-related erectile dysfunction.
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Aterosclerosis , Diabetes Mellitus Experimental , Disfunción Eréctil , Masculino , Animales , Humanos , Disfunción Eréctil/etiología , Células Endoteliales/metabolismo , Aterosclerosis/complicaciones , Aterosclerosis/genética , Transcriptoma , Diabetes Mellitus Experimental/complicaciones , Perfilación de la Expresión GénicaRESUMEN
Prostate cancer transitions from an early treatable form to the lethal castration-resistant prostate cancer (CRPC). Androgen receptor (AR) and constitutively active AR splice variants, such as AR-V7, may be major drivers of CRPC. Our laboratory recently identified a novel mechanism of AR regulation via the transmembrane protein transmembrane 4 superfamily 3 (TM4SF3), which exhibits a physical interaction, nuclear colocalization, and mutual stabilization with AR. Here, we have mapped the interaction domains within AR and TM4SF3 and discovered that TM4SF3 also physically interacts with AR-V7, regulating its protein stability and the viability of CRPC cells expressing AR-V7. Ubiquitination of TM4SF3 and AR-V7 was detected for the first time and TM4SF3 interaction with either AR or AR-V7 resulted in mutual deubiquitination of both proteins, showing that mutual stabilization results from deubiquitination. Interestingly, nuclear TM4SF3 was co-recruited to the promoters of AR- and AR-V7-regulated genes and required for their expression, showing that TM4SF3 interaction is critical for their transcriptional functions. The results collectively show the multiple critical regulatory functions of TM4SF3 on AR or AR-V7 in prostate cancer cells.
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Neoplasias de la Próstata Resistentes a la Castración , Receptores Androgénicos , Humanos , Masculino , Línea Celular Tumoral , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Próstata/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Isoformas de Proteínas/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismoRESUMEN
Background: Clinical associations between erectile dysfunction and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) have been noticed, but the common pathogenic mechanisms between them remain elusive. The aim of the study was to mine shared genetic alterations between ED and chronic prostatitis/chronic pelvic pain syndrome. Method: Transcriptome data of ED and chronic prostatitis/chronic pelvic pain syndrome-related genes (CPRGs) were retrieved from relevant databases and differentially expressed analysis was used to obtain significant CPRGs. Then function enrichment and interaction analyses were performed to show shared transcriptional signature, including gene ontology and pathway enrichment, the construction of protein-protein interaction (PPI) network, cluster analysis, and co-expression analysis. Hub CPRGs and key cross-link were selected by validating these genes in clinical samples, chronic prostatitis/chronic pelvic pain syndrome and ED-related datasets. Then the miRNA-OSRGs co-regulatory network was predicted and validated. Subpopulation distribution and disease association of hub CPRGs were further identified. Result: Differentially expressed analysis revealed 363 significant CPRGs between ED and chronic prostatitis/chronic pelvic pain syndrome, functioning in inflammatory reaction, oxidative stress, apoptosis, smooth muscle cell proliferation, and extracellular matrix organization. A PPI network containing 245 nodes and 504 interactions was constructed. Module analysis depicted that multicellular organismal process and immune metabolic process were enriched. 17 genes were screened in PPI via topological algorithms, and reactive oxygen species as well as interleukin-1 metabolism were regarded as the bridging interactive mechanism. After screening and validation, a hub-CPRG signature consisting of COL1A1, MAPK6, LPL, NFE2L2 and NQO1 were identified and associated miRNA were verified. These miRNAs played an important role in immune and inflammatory response likewise. Finally, NQO1 was identified as a key genetic link between ED and chronic prostatitis/chronic pelvic pain syndrome. It was predominately enriched in corpus cavernosum endothelial cell, and correlated with other male urogenital and immune system diseases tightly. Conclusion: We identified the genetic profiles as well as corresponding regulatory network underlying interaction between ED and chronic prostatitis/chronic pelvic pain syndrome via multi-omics analysis. These findings expanded a new understanding for the molecular mechanism of ED with chronic prostatitis/chronic pelvic pain syndrome.
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Androgen receptor (AR) plays a vital role in the development and progression of prostate cancer from the primary stage to the usually lethal stage known as castration-resistant prostate cancer (CRPC). Constitutively active AR splice variants (AR-Vs) lacking the ligand-binding domain are partially responsible for the abnormal activation of AR and may be involved in resistance to AR-targeting drugs occurring in CRPC. There is increasing consensus on the potential of drugs targeting protein-protein interactions. Our lab has recently identified transmembrane 4 superfamily 3 (TM4SF3) as a critical interacting partner for AR and AR-V7 and mapped the minimal interaction regions. Thus, we hypothesized that these interaction domains can be used to design peptides that can disrupt the AR/TM4SF3 interaction and kill prostate cancer cells. Peptides TA1 and AT1 were designed based on the TM3SF3 or AR interaction domain, respectively. TA1 or AT1 was able to decrease AR/TM4SF3 protein interaction and protein stability. Peptide TA1 reduced the recruitment of AR and TM4SF3 to promoters of androgen-regulated genes and subsequent activation of these AR target genes. Peptides TA1 and AT1 were strongly cytotoxic to prostate cancer cells that express AR and/or AR-V7. Peptide TA1 inhibited the growth and induced apoptosis of both enzalutamide-sensitive and importantly enzalutamide-resistant prostate cancer cells. TA1 also blocked the migration and malignant transformation of prostate cancer cells. Our data clearly demonstrate that using peptides to target the important interaction AR has with TM4SF3 provides a novel method to kill enzalutamide-resistant prostate cancer cells that can potentially lead to new more effective therapy for CRPC.
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Prostate cancer starts as a treatable hormone-dependent disease, but often ends in a drug-resistant form called castration-resistant prostate cancer (CRPC). Despite the development of the antiandrogens enzalutamide and abiraterone for CRPC, which target the androgen receptor (AR), drug resistance usually develops within 6 months and metastatic CRPC (mCRPC) leads to lethality. EZH2, found with SUZ12, EED, and RbAP48 in Polycomb repressive complex 2 (PRC2), has emerged as an alternative target for the treatment of deadly mCRPC. Unfortunately, drugs targeting EZH2 have shown limited efficacy in mCRPC. To address these failures, we have developed novel, dual-acting peptide inhibitors of PRC2 that uniquely target the SUZ12 protein component, resulting in the inhibition of both PRC2 canonical and noncanonical functions in prostate cancer. These peptides were found to inhibit not only the EZH2 methylation activity, but also block its positive effect on AR gene expression in prostate cancer cells. Since the peptide effect on AR levels is transcriptional, the inhibitory peptides can block the expression of both full-length AR and its splicing variants including AR-V7, which plays a significant role in the development of drug resistance. This dual-mode action provides the peptides with the capability to kill enzalutamide-resistant CRPC cells. These peptides are also more cytotoxic to prostate cancer cells than the combination of enzalutamide and an EZH2 inhibitory drug, which was recently suggested to be an effective treatment of mCRPC disease. Our data show that such a dual-acting therapeutic approach can be more effective than the existing front-line drug therapies for treating deadly mCRPC.
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Neoplasias de la Próstata Resistentes a la Castración , Receptores Androgénicos , Masculino , Humanos , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Feniltiohidantoína/farmacología , Feniltiohidantoína/uso terapéutico , Nitrilos/farmacología , Péptidos/farmacología , Resistencia a Antineoplásicos , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismoRESUMEN
Ultrasound is not only the most widely used medical imaging mode for diagnostics owing to its real-time, non-radiation, portable and low-cost merits, but also a promising targeted drug/gene delivery technique by producing a series of powerful bioeffects. The development of micron-sized or nanometer-sized ultrasound agents or delivery carriers further makes ultrasound a distinctive modality in accurate diagnosis and effective treatment. In this review, we introduce one kind of unique biogenic gas-filled protein nanostructures called gas vesicles, which present some unique characteristics beyond the conventional microbubbles. Gas vesicles can not only serve as ultrasound contrast agent with innovative imaging methods such as cross-amplitude modulation harmonic imaging, but also can further be adjusted and optimized via genetic engineered techniques. Moreover, they could not only serve as acoustic gene reporters, acoustic biosensors to monitor the cell metabolism, but also serve as cavitation nuclei and drug carrier for therapeutic purpose. We focus on the latest development and applications in the area of ultrasound imaging and targeted therapeutics, and also give a brief introduction to the corresponding mechanisms. In summary, these biogenic gas vesicles show some advantages over conventional MBs that deserve making more efforts to promote their development.
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Microburbujas , Nanoestructuras , Medios de Contraste/química , Técnicas de Transferencia de Gen , Humanos , UltrasonografíaRESUMEN
[This corrects the article DOI: 10.7150/thno.43233.].
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BACKGROUND: Severe functional tricuspid regurgitation is associated with adverse clinical outcomes. Conventional surgical risk for patients with advanced tricuspid regurgitation stage is high. Alternative approaches are therefore required. AIMS: The purpose of this study was to investigate the feasibility, technical details, and midterm outcomes of implantation of a novel radial force-independent orthotopic transcatheter tricuspid valve -the LuX-Valve- in patients with severe functional tricuspid regurgitation. METHODS: The implantations of the LuX-Valve were performed in six patients with left-sided valvular surgery and secondary massive tricuspid regurgitation. The anatomy of the tricuspid valve and right heart measurements were evaluated by echocardiography and computed tomography in all patients. Conventional right ventricular (RV) function parameters and RV global longitudinal strain were obtained at baseline and 12-month follow-up. LuX-Valve implantation was performed under the guidance of digital subtraction angiography and transoesophageal echocardiography. RESULTS: All patients had successful implantations of LuX-Valves through the right atrium with a substantial reduction in the degree of tricuspid regurgitation. Although one patient with moderate paravalvular leakage died because of right heart failure during three-month follow-up, the five patients who lived had no significant paravalvular leakage, and displayed significant improvements in mean transvalvular gradient, right heart sizes, conventional RV function indices and RV global longitudinal strain, and a reduction in New York Heart Association Functional Class during 12-month follow-up. CONCLUSIONS: Transcatheter tricuspid valve replacement with the LuX-Valve was feasible and safe for patients with severe functional tricuspid regurgitation. This strategy seems a promising treatment option for patients at high surgical risk.
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Implantación de Prótesis de Válvulas Cardíacas , Insuficiencia de la Válvula Tricúspide , Cateterismo Cardíaco , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Humanos , Resultado del Tratamiento , Válvula Tricúspide/diagnóstico por imagen , Válvula Tricúspide/cirugía , Insuficiencia de la Válvula Tricúspide/diagnóstico por imagen , Insuficiencia de la Válvula Tricúspide/cirugíaRESUMEN
Myocarditis is a type of inflammatory cardiomyopathy that has no specific treatment. Accumulating evidence suggests that Th17 cells play a prominent role in the pathogenesis of myocarditis. Interleukin-(IL)-6-mediated signal transducer and activation of transcription 3 (STAT3) signaling is essential for Th17 cell differentiation and secretion of inflammatory cytokines. Bazedoxifene inhibits IL-6/STAT3 signaling in cancer cells, but its effect on the Th17 immune response induced by myocarditis remains unknown. Here we explore the effect of Bazedoxifene on Th17 immune response and cardiac inflammation in a mouse model of experimental autoimmune myocarditis, which has been used to mimic human inflammatory heart disease. After eliciting an immune response, we found Bazedoxifene ameliorated cardiac inflammatory injury and dysfunction. Th17 cells and related inflammatory factors in splenic CD4+ T cells at day 14 and in the heart at day 21 were increased, which were reduced by Bazedoxifene. Furthermore, Bazedoxifene could regulate autophagy induction in polarized Th17 cells. In conclusion, Bazedoxifene affected STAT3 signaling and prevented cardiac inflammation deterioration, so may provide a promising therapeutic strategy for the treatment of experimental autoimmune myocarditis (EAM).