RESUMO
Nitrogen is the primary nutrient for plants. Low nitrogen generally affects plant growth and fruit quality. Melon, as an economic crop, is highly dependent on nitrogen. However, the response mechanism of its self-rooted and grafted seedlings to low-nitrogen stress has not been reported previously. Therefore, in this study, we analyzed the transcriptional differences between self-rooted and grafted seedlings under low-nitrogen stress using fluorescence characterization and RNA-Seq analysis. It was shown that low-nitrogen stress significantly inhibited the fluorescence characteristics of melon self-rooted seedlings. Analysis of differentially expressed genes showed that the synthesis of genes related to hormone signaling, such as auxin and brassinolide, was delayed under low-nitrogen stress. Oxidative stress response, involved in carbon and nitrogen metabolism, and secondary metabolite-related differentially expressed genes (DEGs) were significantly down-regulated. It can be seen that low-nitrogen stress causes changes in many hormonal signals in plants, and grafting can alleviate the damage caused by low-nitrogen stress on plants, ameliorate the adverse effects of nitrogen stress on plants, and help them better cope with environmental stresses.
Assuntos
Cucurbitaceae , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Nitrogênio , Estresse Fisiológico , Transcriptoma , Nitrogênio/metabolismo , Estresse Fisiológico/genética , Cucurbitaceae/genética , Cucurbitaceae/crescimento & desenvolvimento , Cucurbitaceae/metabolismo , Perfilação da Expressão Gênica/métodos , Plântula/genética , Plântula/crescimento & desenvolvimento , Plântula/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Reguladores de Crescimento de Plantas/metabolismoRESUMO
BACKGROUND AND AIMS: Therapeutic blockade of the programmed cell death protein-1 (PD-1) immune checkpoint pathways has resulted in significant reactivation of T cell-mediated antitumor immunity and is a promising clinical anticancer treatment modality in several tumor types, but the durable response rate remains relatively low (15%-20%) in most patients with HCC for unknown reasons. Evidence reveals that the interferon signaling pathway plays a critical role in modulating the efficacy and sensitivity of anti-PD-1 therapy against multiple tumor types, but the mechanisms are unclear. APPROACH AND RESULTS: Using Kaplan-Meier survival analysis based on HCC databases, we found that deceased expression of interferon regulatory factor (IRF) 8 in HCC, among all the nine IRF members that regulate interferon signals, was associated with poor prognosis of patients with HCC. Moreover, gene set enrichment analysis identified the interferon-gamma and PD-1 signaling signatures as the top suppressed pathways in patients with IRF8-low HCC. Contrarily, overexpression of IRF8 in HCC cells significantly enhanced antitumor effects in immune-competent mice, modulating infiltration of tumor-associated macrophages (TAMs) and T cell exhaustion in tumor microenvironment. We further demonstrated that IRF8 regulated recruitment of TAMs by inhibiting the expression of chemokine (C-C motif) ligand 20 (CCL20). Mechanically, IRF8-mediated repression of c-fos transcription resulted in decreased expression of CCL20, rather than directly bound to CCL20 promoter region. Importantly, adeno-associated virus 8-mediated hepatic IRF8 rescue significantly suppressed HCC progression and enhanced the response to anti-PD-1 therapy. CONCLUSIONS: This work identified IRF8 as an important prognostic biomarker in patients with HCC that predicted the response and sensitivity to anti-PD-1 therapy and uncovered it as a therapeutic target for enhancing the efficacy of immune therapy.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Camundongos , Animais , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Fatores Reguladores de Interferon/metabolismo , Microambiente Tumoral , Interferon gama/metabolismo , Morte CelularRESUMO
Erlotinib, an EGFR tyrosine kinase inhibitor has been introduced into cancer chemotherapy. However, the therapeutic effects of erlotinib in hepatocellular carcinoma (HCC) remain vaguely understood. Our previous study found that a hypoxia-mediated PLAGL2-EGFR-HIF-1/2α signaling loop in HCC decreased response to erlotinib. The current study has demonstrated that the combination of erlotinib and 2ME2 exerted synergistic antitumor effects against HCC. Further investigation showed that erlotinib increased the expression level of EGFR, HIF-2α, and PLAGL2, which contributes to the insensitivity of hypoxic HCC cells to erlotinib. The simultaneous exposure to 2ME2 effectively inhibited the expression level of EGFR, HIF-2α, and PLAGL2 that was induced by erlotinib. This contributes to the synergistic effect of the two therapeutic agents. Furthermore, the combination of erlotinib and 2ME2 induced apoptosis and inhibited the stemness of hypoxic HCC cells. Our findings potentially explain the mechanism of HCC insensitivity to erlotinib and provide a new strategy of combining EGFR and HIF1/2α inhibitors for HCC treatment.
Assuntos
2-Metoxiestradiol/uso terapêutico , Antineoplásicos/uso terapêutico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Proteínas de Ligação a DNA/metabolismo , Cloridrato de Erlotinib/uso terapêutico , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , 2-Metoxiestradiol/administração & dosagem , 2-Metoxiestradiol/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Sinergismo Farmacológico , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/administração & dosagem , Cloridrato de Erlotinib/farmacologia , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Nus , Transplante de NeoplasiasRESUMO
AIM OF STUDY: To evaluate the feasibility of transplantation of embryonic stem cell (ESC)-derived retinal cells in the treatment of retinal degeneration. MATERIALS AND METHODS: Rat ESCs were isolated and induced into retinal progenitor cells (RPCs) in vitro, which were subsequently induced into retinal pigment epithelium cells (RPEs) and photoreceptors (PRCs). All cells were identified by Western blot detection of their specific markers. RPEs and PRCs were, respectively, injected into the retina of Royal College of Surgeons (RCSs) rats. Control group was injected with PBS. Post-transplantation visual function was determined by electroretinography (ERG). The histology of the whole eye was compared by H&E staining. RESULTS: RPEs and PRCs were successfully derived from rat ESCs through the two-step differentiation as indicated by the presence of ESC- (Oct-3/4, Nanog, TRA-1-60 and TRA-1-81), RPC- (Rx, Mitf, Pax6 and Chx10), RPE- (RPE65 and keratin) and PRC-specific markers (blue opsin, red/green opsin, recoverin and rhodopsin) in Western blot. The amplitude of ERG a- and b-wave in RPE- and PRC-transplanted groups at week 2 and 10 after transplantation was markedly higher compared with PBS controls. Retinal injury and vascular stress response was not detected in any of the RCS rats after transplantation. CONCLUSION: The developed stepwise protocol can derive retinal cells from ESCs. Transplantation of these retinal cells can restore visual function of RCS rats. Our study provides evidence for potential clinical application of ESC-based cell therapy for retinal degeneration.
Assuntos
Células-Tronco Embrionárias/transplante , Células Fotorreceptoras de Vertebrados/transplante , Degeneração Retiniana/cirurgia , Epitélio Pigmentado da Retina/citologia , Transplante de Células-Tronco/métodos , Animais , Biomarcadores/análise , Modelos Animais de Doenças , Eletrorretinografia , Oftalmopatias Hereditárias , Ratos , Ratos Mutantes , Retina/fisiologia , Degeneração Retiniana/fisiopatologia , Opsinas de Bastonetes , Transtornos da Visão , Visão Ocular/fisiologiaRESUMO
Persistent organic pollutants (POPs) are known to converge into the ocean and accumulate in the sediment, posing great threats to marine organisms such as the sessile bottom burrowing bivalves. However, the immune toxicity of POPs, such as B[a]P, under future ocean acidification scenarios remains poorly understood to date. Therefore, in the present study, the impacts of B[a]P exposure on the immune responses of a bivalve species, Tegillarca granosa, under present and future ocean acidification scenarios were investigated. Results obtained revealed an increased immune toxicity of B[a]P under future ocean acidification scenarios in terms of reduced THC, altered haemocyte composition, and hampered phagocytosis, which may attribute to the synergetic effects of B[a]P and ocean acidification. In addition, the gene expressions of pathogen pattern recognition receptors (TLR1, TLR2, TLR4, TLR6), pathway mediators (TRAF6, TAK1, TAB2, IKKα and Myd88), and effectors (NF-ĸB) of the important immune related pathways were significantly down-regulated upon exposure to B[a]P under future ocean acidification scenarios. Results of the present study suggested an increased immune toxicity of B[a]P under future ocean acidification scenarios, which will significantly hamper the immune responses of T. granosa and subsequently render individuals more susceptible to pathogens challenges.
Assuntos
Arcidae/efeitos dos fármacos , Benzo(a)pireno/toxicidade , Regulação da Expressão Gênica , Imunidade Inata/efeitos dos fármacos , Água do Mar/química , Poluentes Químicos da Água/toxicidade , Animais , Mudança Climática , Concentração de Íons de Hidrogênio , NF-kappa B/genética , NF-kappa B/metabolismo , Distribuição Aleatória , Transdução de Sinais , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismoRESUMO
MicroRNA-21 (miR-21) was reported to act as an oncogene during the development of many human tumors. However, little was revealed about the function of miR-21 in retinoblastoma (RB). In this study, we examined the expression of miR-21 in RB tissues and explored the relationship between miR-21 and phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3-OH kinase (PI3K)/AKT signal. Quantitative real-time PCR (qRT-PCR) results showed that the level of miR-21 in RB tissues was higher than that in retinal normal tissues. In Weri-Rb-1 cells, miR-21 inhibitor suppressed the expression of miR-21 and cell viability, but improved cell apoptotic rates by modulating the levels of PDCD4, Bax, and Bcl-2. Meanwhile, miR-21 inhibitor suppressed cell migration and invasion via inhibiting the protein levels of MMP2 and MMP9 and significantly affected the expression of PTEN, PI3K, and p-AKT. Taken together, miR-21 inhibitor suppressed cell proliferation, migration, and invasion via the PTEN/PI3K/AKT signal. These findings revealed the molecular basis of miR-21 functioning in the progression of RB and provided a new means for cell therapy in RB.
Assuntos
MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Retinoblastoma/genética , Retinoblastoma/patologia , Transdução de Sinais , Apoptose , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Criança , Pré-Escolar , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Lactente , MicroRNAs/genética , Invasividade Neoplásica , Proteínas de Neoplasias/metabolismoRESUMO
BACKGROUND: Macular retinoschisis in patients with high myopia is one of the main reasons for a decline in visual function and the perceived deformation of visual objects. OBJECTIVE: This study aimed to investigate the therapeutic effect of cataract phacoemulsification and foldable intraocular lens implantation (FILI) combined with internal limiting membrane stripping (ILMS) in the treatment of macular retinoschisis in patients with high myopia. METHODS: A total of 52 patients (55 eyes) who had been diagnosed with macular retinoschisis with high myopia between June 2019 and June 2020 were enrolled in the present study. Patients in the control group (25 eyes) received 23G vitreous surgery and macular ILMS and long-term inert gas (C3F8) filling of the vitreous cavity; patients in the research group (30 eyes) were additionally treated with cataract phacoemulsification and soft intraocular lens on the same treatment basis as the control group. RESULTS: The difference in average BCVA between the control and the research groups was not statistically significant before the surgery (P> 0.05) but was statistically significant 12 months after the procedure (P< 0.05). The minimum foveal thickness was significantly decreased in the two groups after the surgery compared with before the procedure (P< 0.05). CONCLUSION: Cataract phacoemulsification and FILI further improved the therapeutic effect of ILMS in the treatment of macular retinoschisis in patients with high myopia.
Assuntos
Catarata , Lentes Intraoculares , Miopia , Retinosquise , Humanos , Retinosquise/cirurgia , Vitrectomia/métodos , Estudos Retrospectivos , Miopia/cirurgia , Retina , Catarata/complicaçõesRESUMO
Stimulator of interferon genes (STING) agonism presents a powerful weapon for cancer immunotherapy. This study reports a novel dimerized STING agonist diBSP01, which exhibited promising STING binding and activation properties in vitro, based on the benzo[b]selenophene scaffold. Meanwhile, shielding the pharmacophores of diBSP01 with photoremovable protecting groups (PPGs) resulted in the generation of the first photoactivatable STING agonist, caged-diBSP01, that exerted no biological potency in the absence of light stimulation while regaining its STING agonistic activity after 400 nm irradiation. Optically controlled in vivo anticancer activity was also proven with caged-diBSP01 in a zebrafish xenograft model. Our study provides insights into developing novel STING agonists for cancer treatment and a solution for precise STING activation to avoid the on-target systemic inflammatory response responsible for normal cell damage caused by systemic STING agonism.
RESUMO
CDK9 plays a vital role in regulating RNA transcription and significantly impacts the expression of short-lived proteins such as Mcl-1 and c-Myc. Thus, targeting CDK9 holds great promise for the development of antitumor drugs. Natural flavonoid derivatives have recently gained considerable attention in the field of antitumor drug research due to their broad bioactivity and low toxicity. In this study, the PROTAC strategy was used to perform structural modifications of the flavonoid derivative LWT-111 to design a series of flavonoid-based CDK9 degraders. Notably, compound CP-07 emerged as a potent CDK9 degrader, effectively suppressing the proliferation and colony formation of 22RV1 cells by downregulating Mcl-1 and c-Myc. Moreover, CP-07 exhibited significant tumor growth inhibition with a TGI of 75.1% when administered at a dose of 20 mg/kg in the 22RV1 xenograft tumor model. These findings demonstrated the potential of CP-07 as a powerful flavonoid-based CDK9 degrader for prostate cancer therapy.
Assuntos
Neoplasias da Próstata , Masculino , Animais , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides , Neoplasias da Próstata/tratamento farmacológico , Modelos Animais de Doenças , Flavonoides/farmacologia , Xenoenxertos , Quinase 9 Dependente de CiclinaRESUMO
Effectiveness of epidermal growth factor receptor (EGFR) inhibitors, including Osimertinib, for treating non-small-cell lung cancer (NSCLC) is limited due to the continuous emergence of drug resistance. Hence, it is urgent to develop new therapeutic approaches. CDK9, a key regulator of RNA transcription, has emerged as a promising target for the development of antitumor drugs due to its crucial role in modulating the levels of antiapoptotic protein Mcl-1. Herein, we present the synthesis, optimization, and evaluation of selective CDK9 inhibitors with a macrocyclic scaffold that effectively suppresses the growth of NSCLC cells. Notably, compound Z11, a potent CDK9 inhibitor (IC50 = 3.20 nM) with good kinase selectivity, significantly inhibits cell proliferation and colony formation and induces apoptosis in Osimertinib-resistant H1975 cells. Furthermore, Z11 demonstrates a significant suppression of tumor growth in six patient-derived organoids, including three organoids resistant to Osimertinib. Overall, Z11 served as a promising macrocycle-based CDK9 inhibitor for treating Osimertinib-resistant NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Compostos Macrocíclicos , Inibidores de Proteínas Quinases , Humanos , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Quinase 9 Dependente de Ciclina , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/uso terapêuticoRESUMO
Diabetic retinopathy (DR) is the leading clinical cause of blindness in diabetic patients. Mitophagy participates in the pathogenesis of DR. Dynamin related protein 1 (Drp1) is associated with mitophagy. Here, we investigated whether Drp1 can regulate mitophagy to affect the progression of DR. We constructed DR rat model by administration of streptozocin. Primary rat retinal endothelial cells (RECs) were treated with high glucose (HG) as a DR cell model. Drp1 was highly expressed in the retinal tissues of DR rats and HG-treated RECs. Drp1 knockdown inhibited HG-mediated increase of reactive oxygen species (ROS) levels and apoptosis in RECs. Moreover, Drp1 silencing inhibited the expression of autophagy-related proteins LC3-II/LC3-1 and Beclin-1 and reduced LC3 puncta in HG-treated RECs. The expression of mitochondrial marker Tom20 was reduced and the levels of mitophagy were increased in the HG-treated RECs, which was rescued by Drp1 silencing. Drp1 knockdown repressed LC3-II expression in HG-treated RECs, indicating that autophagy flux was inhibited. Rapamycin (autophagy activator) enhanced ROS levels and apoptosis in HG-treated RECs by activating autophagy, which was rescued by Drp1 knockdown. In conclusion, these data demonstrated that Drp1 knockdown repressed apoptosis of rat retinal endothelial cells by inhibiting mitophagy. Thus, this work suggests that targeted regulation of Drp1 may become a treatment for DR.
Assuntos
Células Endoteliais , Mitofagia , Animais , Apoptose , Dinaminas/metabolismo , Células Endoteliais/metabolismo , Humanos , Ratos , Retina/metabolismoRESUMO
Objective: To evaluate the feasibility and practicability of intraoperative optical coherence tomography (IOCT) in the surgery of idiopathic macular epiretinal membrane (IMM) without internal limiting membrane staining in all patients. Methods: Patients were selected from July 2018 to June 2020, and 32 patients (32 eyes) with IMM were operated with the use of IOCT. All patients underwent standard 23g vitrectomy. The internal limiting membrane was peeled off if there were obvious retinal folds. Intraoperative and postoperative complications, macular microstructural changes, and integrity of the detached membranes were recorded. The preoperative and postoperative best corrected visual acuity were compared. Results: The macular epiretinal membrane was completely removed in 75% (24 eyes) patients without internal limiting membrane staining, and in 15.6% (5 eyes) patients with combined internal limiting membrane stripping. The "starting point" of macular epiretinal membrane stripping was found in 75% (24 eyes), and the time required to find the best starting point ranged from 28s to 140s (mean 66 ± 15s). At 3 months after operation, 96.8% of the patients had stable or improved BCVA (p < 0.05). The central macular thickness of the affected eyes decreased significantly at 1 and 3 months after operation (p < 0.05). Conclusion: IOCT can significantly reduce the use of internal limiting membrane staining in idiopathic macular epiretinal membrane surgery, and it is safe, feasible and practical in idiopathic macular epiretinal membrane surgery without internal limiting membrane staining in all patients.
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Enzalutamide (ENZ) is a second-generation androgen receptor (AR) antagonist used for the treatment of castration-resistant prostate cancer (CRPC) and reportedly prolongs survival time within a year of starting therapy. However, CRPC patients can develop ENZ resistance (ENZR), mainly driven by abnormal reactivation of AR signaling, involving increased expression of the full-length AR (ARfl) or dominantly active androgen receptor splice variant 7 (ARv7) and ARfl/ARv7 heterodimers. There is currently no efficient treatment for ENZR in CRPC. Herein, a small molecule LLU-206 was rationally designed based on the ENZ structure and exhibited potent inhibition of both ARfl and constitutively active ARv7 to inhibit PCa proliferation and suppress ENZR in CRPC. Mechanically, LLU-206 promoted ARfl/ARv7 protein degradation and decreased ARfl/ARv7 heterodimers through mouse double minute 2-mediated ubiquitination. Finally, LLU-206 exhibited favorable pharmacokinetic properties with poor permeability across the blood-brain barrier, leading to a lower prevalence of adverse effects, including seizure and neurotoxicity, than ENZ-based therapies. In a nutshell, our findings demonstrated that LLU-206 could effectively inhibit ARfl/ARv7-driven CRPC by dual-targeting of ARfl/ARv7 heterodimers and protein degradation, providing new insights for the design of new-generation AR inhibitors to overcome ARfl/ARv7-driven CRPC.
RESUMO
Computer assisted movement tracking was used to characterize the motility of two marine microalgae, Isochrysis galbana and Tetraselmis chui, and to investigate the toxicity of Cu, Pb, and Cd on motile percentage, curvilinear velocity, average path velocity, straight line velocity, linearity, straightness, and wobble. Except for motile percentage, all other motility parameters differed significantly between I. galbana and T. chui. Based on relative motile percentage data, the median effective concentration (EC50) of Cu on the motility of I. galbana and T. chui was 31.4 and 1.3 micromol/L, respectively, while for Pb it was 37.8 and 10.9 micromol/L and for Cd it was 121.6 and 37.8 micromol/L, respectively. Compared to I. galbana, T. chui was more sensitive to all tested metals. The toxic effect of the heavy metals on motility exhibited the following decreasing order for both species: Cu > Pb > Cd. Our results indicate that L. galbana and T. chui motility is sensitive to heavy metals and can be used as an indicator for toxicology bioassays.
Assuntos
Cádmio/toxicidade , Cobre/toxicidade , Chumbo/toxicidade , Biologia Marinha , Microalgas/efeitos dos fármacos , Microalgas/classificação , Especificidade da EspécieRESUMO
Prostate cancer (PCa) is one of the most common malignancies affecting men worldwide. Androgen receptor (AR) has been a target of PCa treatment for nearly six decades. AR antagonists/degraders can effectively treat PCa caused by increased AR overexpression. However, all approved AR antagonists have similar chemical structures and exhibit the same mode of action on the protein. Although initially effective, resistance to these AR antagonists usually develops. Therefore, this calls for the identification of novel chemical structures of AR antagonists to overcome the resistance. Herein, we employed the synergetic combination of virtual and experimental screening to identify a flavonoid compound which not only effectively inhibits AR transcriptional activity, but also induces the degradation of the protein. Based on this compound, we designed and synthesized a series of derivatives. We discovered that the most potent compound 10e could effectively inhibit AR transcriptional activity, and possessed a profound ability to cause degradation of both full length- and ARv7 truncated forms of human AR. Notably, 10e efficiently inhibited the growth of ARv7 dependent prostate cancer cell-lines, which are completely resistant to all current anti-androgens. Compound 10e also showed strong antitumor activity in the LNCaP (androgen dependent prostate cancer cell line) in vivo xenograft model. These results provide a foundation for the development of a new class of AR antagonists.
Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Antineoplásicos/farmacologia , Flavonoides/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Antagonistas de Receptores de Andrógenos/síntese química , Antagonistas de Receptores de Andrógenos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Flavonoides/síntese química , Flavonoides/química , Humanos , Masculino , Estrutura Molecular , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/genética , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Purpose: Exploring and studying the novel target of hepatocellular carcinoma (HCC) has been extremely important for its treatment. The principal objective of this project is to investigate whether myeloid derived growth factor (MYDGF) could accelerate the progression of HCC, and how it works. Methods: Cell proliferation, clonal formation, sphere formation and xenograft tumor experiments were used to prove the critical role of MYDGF in HCC progression. Tumor angiogenesis, immune cell infiltration, macrophage chemotaxis and inflammatory cytokines detection were utilized to clarify how MYDGF remodeled the tumor microenvironment (TME) to accelerate the progress of HCC. Results: Here, we reported a secretory protein MYDGF, which could be induced by hypoxia, was significantly upregulated in HCC and associated with poor clinical outcomes. Using bioinformatics and experimental approaches, we found that MYDGF promotes cell proliferation in vitro and in vivo through a mechanism that might involve enhanced self-renewal of liver CSCs. Furthermore, MYDGF can also promote tumor angiogenesis, induce macrophages to chemotaxis into tumor tissue, and then release various inflammatory cytokines, including IL-6 and TNF-α, which ultimately aggravate inflammation of tumor microenvironment and accelerate HCC progression. Conclusions: We provided evidence that MYDGF could directly affect the self-renewal of liver CSCs, and indirectly aggravate the inflammatory microenvironment to accelerate the progression of HCC.
Assuntos
Carcinoma Hepatocelular/genética , Interleucinas/genética , Neoplasias Hepáticas/genética , Neovascularização Patológica/genética , Hipóxia Tumoral/genética , Microambiente Tumoral/genética , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Progressão da Doença , Técnicas de Silenciamento de Genes , Humanos , Interleucinas/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Transplante de Neoplasias , Neovascularização Patológica/patologiaRESUMO
Hepatic ischemia/reperfusion (I/R) injury is an inevitable complication of hepatic surgery occasioned by liver transplantation and resection. The progression from liver ischemia to reperfusion injury is accompanied by abnormal metabolism, Kupffer cell activation, neutrophil recruitment and the release of cytokines. Activation of several interferon regulatory factors (IRFs) has been reported to either enhance or restrict I/R progression, but the role of IRF8 in the regulation of I/R injury progression is still unknown. In this study, we explore the IRF8 function in the I/R-mediated liver injury using overexpressed hepatic IRF8 and knockout mice. According to our results, IRF8 knockout mice had significantly lower inflammatory cells infiltration, inflammatory cytokines release and serum aspartate aminotransferase/alanine aminotransferase levels that improved the necrotic injury after I/R, unlike the control mice. Conversely, the overexpression of IRF8 in WT mice markedly aggravated the liver structure damage and its abnormal function. We further showed that IRF8-mediated inflammatory cells infiltration were partly dependent on early autophagy and NF-κΒ signal pathway during I/R. AAV8-IRF8-I/R mice pretreated with autophagy inhibitor hydroxychloroquine and NF-κΒ signal pathway inhibitor secukinumab could drastically reverse the IRF8-mediated increase of neutrophil infiltration and chemokine release at different degrees. This work uncovered a critical role of IRF8 in the modulation of the hepatic microenvironment and as a potential target in the initial treatment of I/R injury.
Assuntos
Fatores Reguladores de Interferon/biossíntese , Hepatopatias/metabolismo , Hepatopatias/prevenção & controle , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Animais , Fatores Reguladores de Interferon/genética , Fígado/lesões , Fígado/metabolismo , Hepatopatias/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Traumatismo por Reperfusão/genéticaRESUMO
Diabetic retinopathy (DR) is a diabetic complication which affects retinal function and results in severe loss of vision and relevant retinal diseases. Retinal vascular dysfunction caused by multifactors, such as advanced glycosylation end products and receptors, pro-inflammatory cytokines and chemokines, proliferator-activated receptor-γ disruption, growth factors, oxidative stress, and microRNA. These factors promote retinal endothelial dysfunction, which results in the development of DR. In this review, we summarize the contributors in the pathophysiology of DR for a better understanding of the molecular and cellular mechanism in the development of DR with a special emphasis on retinal endothelial dysfunction.
Assuntos
Retinopatia Diabética/metabolismo , Endotélio Vascular/metabolismo , Estresse Oxidativo/fisiologia , Retina/metabolismo , Transdução de Sinais/fisiologia , Citocinas/metabolismo , Retinopatia Diabética/fisiopatologia , Células Endoteliais/metabolismo , Endotélio Vascular/fisiopatologia , Humanos , PPAR gama/metabolismo , Retina/fisiopatologiaRESUMO
Prostate cancer (PC) is the most diagnosed type of malignancy in men and the major frequently cause of cancer-related death worldwide. The androgen receptor (AR) has become a promising drug target for the treatment of PC. Here, we reported the design, optimization and evaluation of pyridine tetrahydroisoquinoline thiohydantoin derivatives with improved activity and safety as potent AR antagonists. The most promising compound 42f exhibited potent inhibitory activity on AR and strongly blocked AR nuclear translocation. Moreover, 42f displayed promising in vitro antitumor activity toward AR-dependent prostate cancer cell lines (LNCaP) and also demonstrated therapeutic effects in LNCaP xenograft tumor model in mice (TGI: 79%) with no apparent toxicity observed in vivo. More importantly, 42f showed negligible penetration of the brain-blood barrier (BBB) compared with enzalutamide. These results provide a foundation for the development of a new class of androgen receptor antagonists for potential therapeutics against PC with lower seizurogenic risk for patients.
Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Antineoplásicos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Piridinas/farmacologia , Receptores Androgênicos/metabolismo , Tetra-Hidroisoquinolinas/farmacologia , Tioidantoínas/farmacologia , Antagonistas de Receptores de Andrógenos/síntese química , Antagonistas de Receptores de Andrógenos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/química , Tioidantoínas/síntese química , Tioidantoínas/química , Células Tumorais CultivadasRESUMO
In incurable castration-resistant prostate cancer (CRPC), resistance to the novel androgen receptor (AR) antagonist enzalutamide is driven mainly by AR overexpression. Here we report that the expression of interferon regulatory factor 8 (IRF8) is increased in primary prostate cancer but decreased in CRPC compared with normal prostate tissue. Decreased expression of IRF8 positively associated with CRPC progression and enzalutamide resistance. IRF8 interacted with AR and promoted its degradation via activation of the ubiquitin/proteasome systems. Epigenetic knockdown of IRF8 promoted AR-mediated prostate cancer progression and enzalutamide resistance in vitro and in vivo. Furthermore, IFNα increased expression of IRF8 and improved the efficacy of enzalutamide in CRPC by targeting the IRF8-AR axis. We also provide preliminary evidence for the efficacy of IFNα with hormonotherapy in a clinical study. Collectively, this study identifies IRF8 both as a tumor suppressor in prostate cancer pathogenesis and a potential alternative therapeutic option to overcome enzalutamide resistance. SIGNIFICANCE: These findings identify IRF8-mediated AR degradation as a mechanism of resistance to AR-targeted therapy, highlighting the therapeutic potential of IFNα in targeting IRF8-AR axis in CRPC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/13/2927/F1.large.jpg.