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Background: Hepatitis B, often leading to Hepatocellular carcinoma (HCC), poses a major global health challenge. While Tenofovir (TDF) and Entecavir (ETV) are potent treatments, their comparative effectiveness in improving recurrence-free survival (RFS) and overall survival (OS) rates in HBV-related HCC is not well-established. Methods: We conducted an individual patient data meta-analysis using survival data from randomized trials and high-quality propensity score-matched studies to compare the impact of Tenofovir (TDF) and Entecavir (ETV) on RFS and OS in HBV-related HCC patients. Data from six databases and gray literature up to 30 August 2023, were analyzed, utilizing Kaplan-Meier curves, stratified Cox models, and shared frailty models for survival rate assessment and to address between-study heterogeneity. The study employed restricted mean survival time analysis to evaluate differences in RFS and OS between TDF-treated and ETV-treated patients. Additionally, landmark analyses compared early (<2 years) and late (≥2 years) tumor recurrence in these cohorts. Results: This study incorporated seven research articles, covering 4,602 patients with HBV-related HCC (2,082 on TDF and 2,520 on ETV). Within the overall cohort, TDF recipients demonstrated significantly higher RFS (p = 0.042) and OS (p < 0.001) than those on ETV. The stratified Cox model revealed significantly improved OS for the TDF group compared to the ETV group (hazard ratio, 0.756; 95% confidence interval, 0.639-0.896; p = 0.001), a result corroborated by the shared frailty model. Over a follow-up period of 1-8 years, no significant difference was noted in the mean time to death between the TDF and ETV groups. The rates of early recurrence did not significantly differ between the groups (p = 0.735). However, TDF treatment was significantly associated with a reduced risk of late recurrence compared to ETV (p < 0.001). In the HCC resection subgroup, the disparities in OS, early, and late recurrence rates between the two treatments paralleled those seen in the overall cohort. Conclusion: Compared to ETV, TDF may enhance OS and reduce late tumor recurrence risk in HBV-related HCC patients receiving curative treatment. However, there was no statistically significant distinction in the timing of tumor recurrence and mortality between patients administered TDF and those prescribed ETV. Systematic Review Registration: http://www.crd.york.ac.uk/prospero/.
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Multiple myeloma (MM) is a malignancy of plasma cells that can cause anemia due to renal failure and bone marrow failure. Secondary polycythemia (SE) is a clinically rare disease that involves the overproduction of red blood cells. To our knowledge, the association of multiple myeloma and polycythemia has been reported, but the association of SE and multiple myeloma is rare and has been infrequently reported in literature. In contrast to anemia, the presence of polycythemia in multiple myeloma patients is a rare finding. A patient of IgA-λ multiple myeloma with secondary erythrocytosis recently admitted to our department is now reported as follows and relevant literature is reviewed to improve clinicians' awareness of such rare comorbidities.
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Acute promyelocytic leukemia (APL), especially cases of high-risk with complex chromosomes (CK), is rare in individuals infected with human immunodeficiency virus (HIV), making the establishment of therapeutic approaches challenging; often the treatment is individualized. This report describes a 49-year-old female patient with HIV who was diagnosed with high-risk APL with a new CK translocation and presents a literature review. At diagnosis, the patient presented with typical t(15;17)(q24;q21) with additional abnormalities, including add(5)(q15), add(5)(q31), add(7)(q11.2) and add(12) (p13). The results of acute myeloid leukemia mutation analysis suggested positivity for calreticulin and lysine methyltransferase 2C genes. The patient received all-trans retinoic acid combined with arsenic trioxide and chemotherapy, with morphologically complete remission after the first cycle of chemotherapy. The present report provided preliminary data for future clinical research.
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Chronic myeloid leukemia (CML), a clonal myeloproliferative disorder of pluripotent hematopoietic stem cells, results from the Philadelphia chromosome (Ph) chromosome. The Ph is from a translocation, t(9;22)(q34q11), that creates a BCR-ABL fusion gene, which is transcribed into proteins with abnormal tyrosine kinase activity, driving the abnormal proliferation of white blood cells. Multiple myeloma (MM) is a proliferation disorder of plasma cells derived from a single clone, which may lead to uncontrolled growth, kidney injury, destructive bone lesions, hypercalcemia and anemia. It is extremely rare that MM and CML should occur in the same patient either synchronously or metachronously. To date, MM accompanied with CML has only been reported in limited studies, and the the cause behind the occurrence of both malignancies together is not understood. With the advent of novel therapies, the survival time in patients with CML and MM has improved. Therefore, the further investigation of the pathophysiology and clinical characteristics of these cases is valuable. The present study reports the case of a 79-year-old male who had been diagnosed with CML and treated with tyrosine kinase inhibitor, and then developed immunoglobulin G-κ MM after 6 years. This report should provide valid raw data for clinical research.
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Despite the remarkable clinical responses achieved with immune checkpoint blockade therapy, the response rate is relatively low and only a subset of patients can benefit from the treatment. Aberrant RNA accumulation can mediate IFN signaling and stimulate an immune response, suggesting that targeting RNA decay machinery might sensitize tumor cells to immunotherapy. With this in mind, we identified an RNA exoribonuclease, XRN1, as a potential therapeutic target to suppress RNA decay and stimulate antitumor immunity. Silencing of XRN1 suppressed tumor growth in syngeneic immunocompetent mice and potentiated immunotherapy efficacy, while silencing of XRN1 alone did not affect tumor growth in immunodeficient mice. Mechanistically, XRN1 depletion activated IFN signaling and the viral defense pathway; both pathways play determinant roles in regulating immune evasion. Aberrant RNA-sensing signaling proteins (RIG-I/MAVS) mediated the expression of IFN genes, as depletion of each of them blunted the elevation of antiviral/IFN signaling in XRN1-silenced cells. Analysis of pan-cancer CRISPR-screening data indicated that IFN signaling triggered by XRN1 silencing is a common phenomenon, suggesting that the effect of XRN1 silencing may be extended to multiple types of cancers. Overall, XRN1 depletion triggers aberrant RNA-mediated IFN signaling, highlighting the importance of the aberrant RNA-sensing pathway in regulating immune responses. These findings provide the molecular rationale for developing XRN1 inhibitors and exploring their potential clinical application in combination with cancer immunotherapy. SIGNIFICANCE: Targeting XRN1 activates an intracellular innate immune response mediated by RNA-sensing signaling and potentiates cancer immunotherapy efficacy, suggesting inhibition of RNA decay machinery as a novel strategy for cancer treatment.
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Neoplasias , ARN , Animales , Ratones , Exonucleasas/metabolismo , Exorribonucleasas/genética , Exorribonucleasas/metabolismo , Inmunoterapia , Neoplasias/genética , Neoplasias/terapia , Estabilidad del ARN , Transducción de SeñalRESUMEN
Introduction: Parkinson's disease (PD) is related to renal insufficiency. The purpose of this study was to explore the correlation between PD and blood urea nitrogen, creatinine, and proteinuria. Methods: The case-control study method was adopted in this study. In total, 200 patients with PD who were hospitalized in the Department of Neurology of the Second Affiliated Hospital of Anhui Medical University were selected as the PD group, and 110 healthy patients during the same period were selected as the control group. The differences in clinical data and laboratory results between the two groups were compared. Logistic regression analysis, ROC curve, and Spearman correlation analysis were used to determine the correlation between PD and blood urea nitrogen, creatinine, and urine protein. Results: The levels of cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL-C), and apolipoprotein B in the PD group were lower than those in the control group. The levels of creatinine, urea nitrogen, and proteinuria in the PD group were higher than those in the control group. Multivariate logistic regression analysis showed that elevated blood urea nitrogen, creatinine, and urine protein levels were risk factors for PD, and elevated LDL-C levels were protective factors for PD. The blood urea nitrogen level of patients with PD was positively correlated with the course of PD, Hoehn-Yahr staging, and UPDRS exercise score (r = 0.309, 0.434, and 0.540, respectively; P < 0.01). Serum creatinine level was positively correlated with the course of PD, Hoehn-Yahr staging, and UPDRS exercise score (r = 0.139, 0.320, and 0.290, respectively; P < 0.01). Conclusion: Blood urea nitrogen, creatinine levels, and proteinuria can be regarded as the onset of PD and a biomarker of disease progression.
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Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , Creatinina , Estudios de Casos y Controles , Nitrógeno de la Urea Sanguínea , LDL-Colesterol , Proteinuria/etiologíaRESUMEN
INTRODUCTION: Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), and provides a target for a dendritic cell (DC) vaccine. CD137 ligand (CD137L) expressed on antigen presenting cells, costimulates CD137-expressing T cells, and reverse CD137L signaling differentiates monocytes to CD137L-DC, a type of DC, which is more potent than classical DC in stimulating T cells. METHODS: In this phase I study, patients with locally recurrent or metastatic NPC were administered CD137L-DC pulsed with EBV antigens (CD137L-DC-EBV-VAX). RESULTS: Of the 12 patients treated, 9 received full 7 vaccine doses with a mean administered cell count of 23.9 × 106 per dose. Treatment was well tolerated with only 4 cases of grade 1 related adverse events. A partial response was obtained in 1 patient, and 4 patients are still benefitting from a progression free survival (PFS) of currently 2-3 years. The mean pre-treatment neutrophil: lymphocyte ratio was 3.4 and a value of less than 3 was associated with prolonged median PFS. Progressors were characterized by a high frequency of naïve T cells but a low frequency of CD8+ effector T cells while patients with a clinical benefit (CB) had a high frequency of memory T cells. Patients with CB had lower plasma EBV DNA levels, and a reduction after vaccination. CONCLUSION: CD137L-DC-EBV-VAX was well tolerated. The use of CD137L-DC-EBV-VAX is demonstrated to be safe. Consistent results were obtained from all 12 patients, indicating that CD137L-DC-EBV-VAX induces an anti-EBV and anti-NPC immune response, and warranting further studies in patients post effective chemotherapy. PRECIS: The first clinical testing of CD137L-DC, a new type of monocyte-derived DC, finds that CD137L-DC are safe, and that they can induce an immune response against Epstein-Barr virus-associated nasopharyngeal carcinoma that leads to tumor regression or prevents tumor progression.
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Infecciones por Virus de Epstein-Barr , Neoplasias Nasofaríngeas , Ligando 4-1BB/genética , Células Dendríticas , Herpesvirus Humano 4 , Humanos , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/terapiaRESUMEN
Drainage severely changes the environment and ecological process in peatlands, but how does it affect the germinability of Sphagnum spores in peat remains unclear. In this study, we took two peat cores from a near-pristine stand dominated by Sphagnum and a drained stand dominated by dwarf shrubs in Baijianghe Peatland in the Changbai Mountains as experimental materials. Those peat cores were cut into slices. Physicochemical characteristics were measured while Sphagnum spores from each slice were extracted to count spore density and test spore germinability. After dating and determining relationship between peat depth and age, we tried to figure out the mechanism underlying the responses of Sphagnum spore germinability to drainage. The average number of spores in the near-pristine stand was slightly higher than that in the drained stand. There was no difference in average spore germinability between the two stands. The drained stand showed higher peat bulk density, total carbon and total nitrogen relative to the near-pristine stand. Upper peat core showed no significant difference in spore accumulation rate between the two stands after drainage (in 1987), with lower average spore germinability (34%) in the near-pristine stand relative to the drained stand (72%). For the whole peat cores, C/N was positively correlated with spore ger-minability in the near-pristine stand while total carbon, pH and burial time were negatively correlated with spore germinability in the drained stand. The drainage 30 years ago had limited effect on spore accumulation, but improved germinability of spores in shallow peat by changing physicochemical properties of peat due to accelerating decomposition, and thus reduced the persistence of spore bank. This may reduce the persistent regeneration potential of Sphagnum after catastrophic distur-bances.
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Sphagnopsida , Carbono , China , Suelo , EsporasRESUMEN
Tumor-specific antibody drugs can serve as cancer therapy with minimal side effects. A humanized antibody, PRL3-zumab, specifically binds to an intracellular oncogenic phosphatase PRL3, which is frequently expressed in several cancers. Here we show that PRL3-zumab specifically inhibits PRL3+ cancer cells in vivo, but not in vitro. PRL3 antigens are detected on the cell surface and outer exosomal membranes, implying an 'inside-out' externalization of PRL3. PRL3-zumab binds to surface PRL3 in a manner consistent with that in classical antibody-dependent cell-mediated cytotoxicity or antibody-dependent cellular phagocytosis tumor elimination pathways, as PRL3-zumab requires an intact Fc region and host FcγII/III receptor engagement to recruit B cells, NK cells and macrophages to PRL3+ tumor microenvironments. PRL3 is overexpressed in 80.6% of 151 fresh-frozen tumor samples across 11 common cancers examined, but not in patient-matched normal tissues, thereby implicating PRL3 as a tumor-associated antigen. Targeting externalized PRL3 antigens with PRL3-zumab may represent a feasible approach for anti-tumor immunotherapy.
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Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Antineoplásicos Inmunológicos/farmacología , Carcinoma Hepatocelular/metabolismo , Citofagocitosis/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Microambiente Tumoral/efectos de los fármacos , Animales , Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales de Origen Murino , Antígenos de Neoplasias/metabolismo , Linfocitos B , Línea Celular Tumoral , Células Hep G2 , Hepatocitos/metabolismo , Humanos , Inmunoterapia , Células Asesinas Naturales , Macrófagos , Ratones , Terapia Molecular Dirigida , Proteínas de Neoplasias/metabolismo , Trasplante de Neoplasias , Neoplasias/metabolismo , Proteínas Oncogénicas/metabolismo , Proteínas Tirosina Fosfatasas/metabolismo , Receptores de IgG , Microambiente Tumoral/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Gap junctions (GJs) are novel molecular targets for pain therapeutics due to their pain-promoting function. INI-0602, a new GJ inhibitor, exerts a neuroprotective role, while its role in neuropathic pain is unclear. The objective was to investigate the analgesic role and mechanisms of INI-0602 in neuropathic pain induced by spared nerve injury (SNI), and whether INI-0602 attenuated pain-induced depression-like behaviors. Rats were randomly assigned to saline treatment groups (sham+NS and SNI+NS) or INI-0602 treatment groups (sham+INI-0602 and SNI+INI-0602). The von Frey test was used to assess pain behavior, and the sucrose preference test, the forced swimming test, and the tail suspension test were used to assess depression-like behaviors. Gap junction intercellular communication (GJIC) was measured by parachute assay. Western blots were used to determine the protein expression. In vitro, INI-0602 significantly suppressed GJIC by decreasing connexin43 and connexin32 expression. In vivo, INI-0602 significantly suppressed mechanical allodynia during initiation (7 days after SNI) and the maintenance phase (21 days after SNI) and simultaneously attenuated accompanying depression-like behaviors. Furthermore, INI-0602 markedly suppressed the activation of astrocytes and microglia on days 7 and 21 by reducing GJIC. Finally, INI-0602 reversed the changes in the brain-derived neurotrophic factor and Nr2b subunits of the N-methyl-D-aspartate receptor in SNI rats, suggesting that these effects of INI-0602 were related to its analgesic effect. Our findings demonstrated that blocking GJs with INI-0602 attenuated mechanical pain hypersensitivity and related depression-like behaviors in SNI rats by reducing glial activation.
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Analgésicos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Neuralgia/fisiopatología , Animales , Depresión/etiología , Uniones Comunicantes/efectos de los fármacos , Hiperalgesia/etiología , Masculino , Neuralgia/etiología , Traumatismos de los Nervios Periféricos/complicaciones , Traumatismos de los Nervios Periféricos/fisiopatología , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
[This corrects the article DOI: 10.18632/oncotarget.23356.].
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Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells. dBET6 treatment drastically reduces BET protein genomic occupancy, RNA-Pol2 activity, and permissive chromatin marks. Subsequently, dBET6 represses the proliferation, self-renewal, and tumorigenic ability of GBM cells. Moreover, dBET6-induced degradation of BET proteins exerts superior antiproliferation effects compared to conventional BBIs and overcomes both intrinsic and acquired resistance to BBIs in GBM cells. Our study reveals crucial functions of BET proteins and provides the rationale and therapeutic merits of targeted degradation of BET proteins in GBM.
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Antineoplásicos/farmacología , Factor de Transcripción E2F1 , Glioblastoma , Proteínas Serina-Treonina Quinasas , Proteínas de Unión al ARN , Proteínas de Ciclo Celular , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Factor de Transcripción E2F1/antagonistas & inhibidores , Factor de Transcripción E2F1/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Dominios Proteicos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas de Unión al ARN/antagonistas & inhibidores , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Due to higher technical requirements, laparoscopic major hepatectomy (LMH) for primary hepatolithiasis have been limited to a few institutions. This retrospective study was performed to evaluate the therapeutic safety, and perioperative and long-term outcomes of LMH versus open major hepatectomy (OMH) for hepatolithiasis. METHODS: From January 2012 to December 2016, 61 patients with hepatolithiasis who underwent major hepatectomy were enrolled, including 29 LMH and 32 OMH. The perioperative outcomes and postoperative complications, as well as long-term outcomes, including the stone clearance and recurrence rate, were evaluated. RESULTS: There was no difference of surgical procedures between the two groups. The mean operation time was (262 ± 83) min in the LMH group and (214 ± 66) min in the OMH group (p = 0.05). There is no difference of intra-operative bleeding (310 ± 233) ml versus (421 ± 359) ml (p = 0.05). In the LMH group, there were shorter time to postoperative oral intake ((1.1 ± 0.6) days versus (3.1 ± 1.8) days, p = 0.01) and shorter hospital stay [(7.2 ± 2.3) days versus (11.8 ± 5.5) days, p = 0.03] than the open group. The LMH group had comparable stone clearance rate with the OMH group during the initial surgery (82.8% vs. 84.4%, p = 0.86). CONCLUSIONS: LMH could be an effective and safe treatment for selected patients with hepatolithiasis, with an advantage over OMH in the field of less intra-operative blood loss, less intra-operative transfusion, less overall complications, and faster postoperative recovery.
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Cálculos/cirugía , Hepatectomía/métodos , Laparoscopía/métodos , Hepatopatías/cirugía , Anciano , Pérdida de Sangre Quirúrgica , Transfusión Sanguínea , Femenino , Hepatectomía/efectos adversos , Humanos , Laparoscopía/efectos adversos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Tempo Operativo , Complicaciones Posoperatorias , Recurrencia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Oncogenesis is a multistep process mediated by a variety of factors including epigenetic modifications. Global epigenetic post-translational modifications have been detected in almost all cancers types. Epigenetic changes appear briefly and do not involve permanent changes to the primary DNA sequence. These epigenetic modifications occur in key oncogenes, tumor suppressor genes, and transcription factors, leading to cancer initiation and progression. The most commonly observed epigenetic changes include DNA methylation, histone lysine methylation and demethylation, histone lysine acetylation and deacetylation. However, there are several other novel post-translational modifications that have been observed in recent times such as neddylation, sumoylation, glycosylation, phosphorylation, poly-ADP ribosylation, ubiquitination as well as transcriptional regulation and these have been briefly discussed in this article. We have also highlighted the diverse epigenetic changes that occur during the process of tumorigenesis and described the role of histone modifications that can occur on tumor suppressor genes as well as oncogenes, which regulate tumorigenesis and can thus form the basis of novel strategies for cancer therapy.
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BACKGROUND: Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) is a novel laparoscopic intraperitoneal chemotherapy technique, with advantages such as homogeneous distribution of aerosol and deeper tissue penetration. Thus far, PIPAC oxaliplatin has been administered at an arbitrary dose of 92âmg/m2. AIM: We aim to determine the dose-related safety profile and tolerability of PIPAC oxaliplatin using an evidence-based approach. The secondary aim is to evaluate clinic-pathologic response and the pharmacokinetic profile. METHODS: This is a phase I 3+3 dose escalation study for gastric and colorectal cancer with predominant peritoneal metastasis starting at a dose of 45âmg/m2. Safety is assessed according to Clavien-Dindo Classification and Common Terminology Criteria for Adverse Events (version 4.0). Clinico-pathologic response is assessed using the Peritoneal Regression Grading Score, Peritoneal Cancer Index, and Response Evaluation Criteria In Solid Tumour criteria (version 1.1). Pharmacokinetic analysis is performed using Inductively Coupled Plasma-Mass Spectrometry assay. This trial is registered on ClinicalTrials.gov (NCT03172416). CONCLUSIONS: This phase I study can provide the scientific basis to identify the optimal dose for PIPAC with oxaliplatin such that the benefits of this novel and promising intraperitoneal chemotherapy delivery technique can be maximized.
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Oligopeptides are one of the the key pharmaceutical effective constituents of traditional Chinese medicine(TCM). Systematic study on composition and efficacy of TCM oligopeptides is essential for the analysis of material basis and mechanism of TCM. In this study, the potential anti-hypertensive oligopeptides from Glycine max and their endothelin receptor A (ETA) antagonistic activity were discovered and predicted based on in silico technologies.Main protein sequences of G. max were collected and oligopeptides were obtained using in silico gastrointestinal tract proteolysis. Then, the pharmacophore of ETA antagonistic peptides was constructed and included one hydrophobic feature, one ionizable negative feature, one ring aromatic feature and five excluded volumes. Meanwhile, three-dimensional structure of ETA was developed by homology modeling methods for further docking studies. According to docking analysis and consensus score, the key amino acid of GLN165 was identified for ETA antagonistic activity. And 27 oligopeptides from G. max were predicted as the potential ETA antagonists by pharmacophore and docking studies.In silico proteolysis could be used to analyze the protein sequences from TCM. According to combination of in silico proteolysis and molecular simulation, the biological activities of oligopeptides could be predicted rapidly based on the known TCM protein sequence. It might provide the methodology basis for rapidly and efficiently implementing the mechanism analysis of TCM oligopeptides.
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Antihipertensivos/química , Glycine max/química , Oligopéptidos/química , Receptor de Endotelina A/química , Simulación por Computador , Antagonistas de los Receptores de la Endotelina A , Medicina Tradicional China , Simulación del Acoplamiento Molecular , ProteolisisRESUMEN
Type 2 diabetes, which features ß-cell failure, is caused by the decrease of ß-cell mass and insulin secretory function. Current treatments fail to halt the decrease of functional ß-cell mass. Strategies to prevent ß-cell apoptosis and dysfunction are highly desirable. Recently, our group and others have reported that blockade of N-methyl-d-aspartate receptors (NMDARs) in the islets has been proposed to prevent the progress of type 2 diabetes through improving ß-cell function. It suggests that a sustained activation of the NMDARs may exhibit deleterious effect on ß-cells. However, the exact functional impact and mechanism of the sustained NMDAR stimulation on islet ß-cells remains unclear. Here, we identify a sustained activation of pancreatic NMDARs as a novel factor of apoptotic ß-cell death and function. The sustained treatment with NMDA results in an increase of intracellular [Ca2+] and reactive oxygen species, subsequently induces mitochondrial membrane potential depolarization and a decrease of oxidative phosphorylation expression, and then impairs the mitochondrial function of ß-cells. NMDA specifically induces the mitochondrial-dependent pathway of apoptosis in ß-cells through upregulation of the proapoptotic Bim and Bax, and downregulation of antiapoptotic Bcl-2. Furthermore, a sustained stimulation of NMDARs impairs ß-cell insulin secretion through decrease of pancreatic duodenal homeobox-1 (Pdx-1) and adenosine triphosphate synthesis. The activation of nuclear factor-κB partly contributes to the reduction of Pdx-1 expression induced by overstimulation of NMDARs. In conclusion, we show that the sustained stimulation of NMDARs is a novel mediator of apoptotic signaling and ß-cell dysfunction, providing a mechanistic insight into the pathological role of NMDARs activation in diabetes.
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Apoptosis/efectos de los fármacos , Diabetes Mellitus Tipo 2/fisiopatología , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/fisiología , N-Metilaspartato/farmacología , Receptores de N-Metil-D-Aspartato/agonistas , Animales , Células Cultivadas , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Diabetes Mellitus Tipo 2/inducido químicamente , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Masculino , Ratones , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
The lateral habenula plays a central role in reward and punishment processing and has been suggested to drive the cardinal symptom of anhedonia in depression. This hypothesis is largely based on observations of habenula hypermetabolism in animal models of depression, but the activity of habenula and its relationship with clinical symptoms in patients with depression remains unclear. High-resolution functional magnetic resonance imaging (fMRI) and computational modelling were used to investigate the activity of the habenula during a probabilistic reinforcement learning task with rewarding and punishing outcomes in 21 unmedicated patients with major depression and 17 healthy participants. High-resolution anatomical scans were also acquired to assess group differences in habenula volume. Healthy individuals displayed the expected activation in the left habenula during receipt of punishment and this pattern was confirmed in the computational analysis of prediction error processing. In depressed patients, there was a trend towards attenuated left habenula activation to punishment, while greater left habenula activation was associated with more severe depressive symptoms and anhedonia. We also identified greater habenula volume in patients with depression, which was associated with anhedonic symptoms. Habenula dysfunction may contribute to abnormal response to punishment in patients with depression, and symptoms such as anhedonia.
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Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Mayor/psicología , Habénula/fisiopatología , Motivación , Adulto , Anhedonia , Potenciales Evocados , Femenino , Lateralidad Funcional , Humanos , Aprendizaje , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Castigo , Refuerzo en Psicología , Recompensa , Adulto JovenRESUMEN
Increasing evidence has indicated that epithelial-to-mesenchymal transition (EMT) at the advanced stage of liver cancer not only has the ability to self-renew and progress cancer, but also enables greater resistance to conventional chemo- and radiotherapies. Here, we report that ascochlorin (ASC), an isoprenoid antibiotic, could potentiate the cytotoxic effect of doxorubicin on HCCLM3, SNU387, SNU49, and SK-Hep-1 hepatocellular carcinoma cells, which had a predominantly mesenchymal signature with low expression of E-cadherin but high expression of N-cadherin. Co-administration of ASC reduced doxorubicin-induced invasion/migration and modulated EMT characteristics in mesenchymal cells. This process was probably mediated by the E-cadherin repressors Snail and Slug. In addition, ASC increased sensitivity to doxorubicin treatment by directly inhibiting STAT3 binding to the Snail promoter. We also observed that ASC significantly enhanced the effect of doxorubicin against tumor growth and inhibited metastasis in an HCCLM3_Luc orthotopic mouse model. Collectively, our data demonstrate that ASC can increase sensitivity to doxorubicin therapy and reverse the EMT phenotype via the downregulation of STAT3-Snail expression, which could form the basis of a novel therapeutic approach against hepatocellular carcinoma. Mol Cancer Ther; 15(12); 2966-76. ©2016 AACR.