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Camellia perpetua has the excellent characteristic of flowering multiple times throughout the year, which is of great importance to solve the problem of "short flowering period" and "low fresh flower yield" in the yellow Camellia industry at present. Observations of flowering phenology have demonstrated that most floral buds of C. perpetua were formed by the differentiation of axillary buds in the scales at the base of the terminal buds of annual branches. However, the molecular mechanism of flowering in C. perpetua is still unclear. In this study, we conducted a comparative transcriptomic study of the terminal buds and their basal flower buds in March (spring) and September (autumn) using RNA-seq and found that a total of 11,067 genes were significantly differentially expressed in these two periods. We identified 27 genes related to gibberellin acid (GA) synthesis, catabolism, and signal transduction during floral bud differentiation. However, treatment of the terminal buds and axillary buds of C. perpetua on annual branch with GA3 did not induce floral buds at the reproductive growth season (in August) but promoted shoot sprouting. Moreover, 203 flowering genes were identified from the C. perpetua transcriptome library through homology alignment, including flowering integrators LEAFY (LFY) and UNUSUAL FLORAL ORGANS (UFO), as well as MADS-box, SQUAMOSA PROMOTER BINDING PROTEIN-box (SBP-box), and TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR (TCP) genes, which were specifically upregulated in floral buds and were likely involved in flowering in C. perpetua. The floral inhibitor CperTFL1b was identified and cloned from C. perpetua, and its expression level was specifically regulated in terminal buds in autumn. Ectopic overexpression of CperTFL1b delayed flowering time and produced abnormal inflorescence and floral organs in Arabidopsis, suggesting that CperTFL1b inhibits flowering. In conclusion, this study deepens our understanding of the molecular mechanism of blooms throughout the year in C. perpetua and provides a helpful reference for cultivating new varieties of yellow Camellia with improved flowering traits.
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Camellia , Transcriptoma , Camellia/genética , Perfilación de la Expresión Génica , RNA-Seq , Flores , Regulación de la Expresión Génica de las PlantasRESUMEN
OBJECTIVE: Renal clear cell carcinoma (ccRCC) is the most common type of renal cancer. Here we aim to explore the prognosis and immunotherapeutic value of copper death-related gene Dihydrolipoamide S-acetyltransferase (DLAT) in ccRCC. METHODS: The mRNA and protein expressions and methylation level of DLAT, as well as the relation of DLAT to survival prognosis, clinical characteristics, biological function, and immune microenvironment and responses in patients with ccRCC were evaluated using multiple databases. In addition, 75 paired ccRCC tissue samples and 3 kinds of cell lines were tested for experimental validation. RESULTS: Bioinformatics analysis of multiple databases, qRT-PCR, and western blot verified that DLAT expression in ccRCC was lower than that in paracancerous tissues. Patients with low expression of DLAT had a lower survival rate, worse clinical prognosis, stronger immune cell infiltration and expression of immunosuppressive points, and higher tumor immune dysfunction and exclusion (TIDE) scores. CONCLUSIONS: DLAT was identified as an independent prognostic factor in ccRCC and was closely related to the prognosis and immune responses of patients with ccRCC.
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Apoptosis , Carcinoma de Células Renales , Carcinoma , Neoplasias Renales , Humanos , Biomarcadores , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/terapia , Acetiltransferasa de Residuos Dihidrolipoil-Lisina , Inmunoterapia , Neoplasias Renales/genética , Neoplasias Renales/terapia , Pronóstico , Microambiente Tumoral/genética , CobreRESUMEN
Solamargine (SM), an active compound derived from Solanum nigrum, triggers apoptosis and inhibits the metastatic and oxidative activities of various types of tumor cells. However, the effect of SM on human renal carcinoma cells remains unknown. In the present study, the molecular mechanisms underlying the antitumor effects of SM on ACHN and 786-O cells were elucidated. Specifically, MTT and colony formation assays were conducted to evaluate the impact of SM treatment on the proliferation of ACHN and 786-O cells, and flow cytometry was conducted to determine the influence of SM on the apoptosis rates of these cells. In addition, the expression of target proteins was determined by western blotting. The results revealed that SM not only inhibited cell viability but also promoted the apoptosis of ACHN and 786-O cells in a time- and dose-dependent manner. Moreover, treatment of ACHN and 786-O cells with SM significantly enhanced the caspase-3, caspase-8 and caspase-9 activities. Furthermore, SM downregulated the expression of phosphorylated signal transducer and activator of transcription-3 (p-STAT3) and Bcl-2 but increased the expression of cleaved caspase-3, -8, -9 and Bax. BAY2353, a p-STAT3 inhibitor, inhibited the viability of ACHN and 786-O cells, increased the expression of cleaved caspase-9 and Bax and decreased the expression of p-STAT3 and Bcl-2. Further experiments demonstrated that SM inhibited tumor growth in xenograft nude mice without causing specific toxicity to the major organs. Collectively, these findings indicated that SM not only inhibited the viability but also promoted the apoptosis of ACHN and 786-O cells, through a mechanism involving downregulation of p-STAT3 expression.
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BACKGROUND: Cuproptosis is a novel cell death mechanism, and FDX1 is a key gene associated with cuproptosis. However, it is unclear whether FDX1 has prognostic and immunotherapeutic value for clear cell renal carcinoma (ccRCC). METHODS: Data on FDX1 expression in ccRCC were extracted from various databases and validated using qRT-PCR and western blotting. Moreover, the survival prognosis, clinical features, methylation, and biological functions of FDX1 were evaluated, and the tumor immune dysfunction and exclusion (TIDE) score was used to explore the immunotherapy response to FDX1 in ccRCC. RESULTS: The expression of FDX1 in ccRCC tissues was significantly lower than that in normal tissues, as validated by qRT-PCR and western blotting of patient samples (P < 0.01). Moreover, low FDX1 expression was related to shorter survival time and high immune activation, as indicated by alterations in the tumor mutational burden and tumor microenvironment, stronger immune cell infiltration and immunosuppression point expression, and a higher TIDE score. CONCLUSIONS: FDX1 could serve as a novel and accessible biomarker for predicting survival prognosis, tumor immune landscape, and immune responses in ccRCC.
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Apoptosis , Carcinoma de Células Renales , Neoplasias Renales , Humanos , Western Blotting , Carcinoma de Células Renales/genética , Muerte Celular , Neoplasias Renales/genética , Reacción en Cadena de la Polimerasa , Pronóstico , Microambiente Tumoral , CobreRESUMEN
Background: Myopia is an increasingly serious public concern, particularly among primary school students. The prevalence of myopia and its influencing factors in primary school pupils in Eastern China during the COVID-19 pandemic had not been explored. Methods: A randomly clustered sampling method was performed, and selected pupils from grade 1 to grade 3 in 15 primary schools in the Fenghua District of Zhejiang Province were included and given myopia screening and uniform questionnaire survey 1 year later. Results: A total of 4,213 students completed the myopia screening and questionnaire survey. Myopia was diagnosed in 1,356 pupils, with a myopia incidence of 32.19%. The spherical equivalent (SE) refraction of the included pupils decreased on average by 0.50 ± 2.15 D 1 year later. The myopia rate was positively correlated with the increase of grade, in which the myopia rate among grade 3 students was the highest at 39.69%. The myopia rate among female students was higher than that among male students. Students residing in urban areas had a higher myopia rate than in rural areas. Maintaining an near work distance ≥33 cm was a significant protective factor (OR = 0.84, 95% CI: 0.74-0.96). Students with two myopic parents had a higher risk of myopia (OR = 1.61, 95% CI: 1.34-1.92). Conclusion: During the COVID-19 pandemic, the myopia rate among early primary school students in Eastern China was high. More attention and implementation of interventions from health and education departments, such as training the development of good eye behavior, should be considered to strengthen the intervention of myopia in primary school students.
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COVID-19 , Miopía , Humanos , Masculino , Femenino , Pandemias , COVID-19/epidemiología , Miopía/epidemiología , China/epidemiología , EstudiantesRESUMEN
Delta-shaped gastroduodenostomy (DSGD) and overlap gastroduodenostomy (OGD) are the two most widely used intracorporeal Billroth I anastomosis methods after distal gastrectomy. In this study, we compared the short-term outcomes of DSGD and OGD in total laparoscopic distal gastrectomy (TLDG). In a retrospective cohort study, we examined 92 gastric cancer patients who underwent TLDG performed by the same surgeon between January 2014 and June 2018. All patients underwent Billroth I reconstruction (OGD, n = 45; DSGD, n = 47) and D2 lymph node dissection. We retrospectively reviewed the surgical outcomes, clinical pathological results, and endoscopy results. Laparoscopic surgery was successfully performed in both groups without conversion to open surgery. The demographic and clinical characteristics were similar between the two groups (P > 0.05). There were no significant differences between the two groups in operation time (158.9 ± 13.6 min vs. 158.8 ± 14.8 min, P=0.955), anastomotic time (19.4 ± 3.0 min vs. 18.8 ± 2.9 min, P=0.354), intraoperative blood loss (88.9 ± 25.4 mL vs. 83.7 ± 24.3 mL, P=0.321), number of lymph node dissections (31.0 ± 7.1 vs. 29.2 ± 7.5, P=0.229), length of hospital stay (8.8 ± 2.7 days vs. 9.1 ± 3.0 days, P=0.636), fluid intake time (3.1 ± 0.7 days vs. 3.2 ± 0.7 days, P=0.914), and morbidity of postoperative complications (6.7% [3/45] vs. 10.6% [5/47], P=0.499). Endoscopy performed 6 months postoperatively showed that the residual food (P=0.033), gastritis (P=0.029), and bile (P=0.022) classification score significantly decreased in the OGD group, and there were no significant differences 12 months postoperatively. OGD is a safe and effective reconstruction technique with comparable postoperative surgical outcomes and endoscopy results when compared with those of DSGD.
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Laparoscopía , Neoplasias Gástricas , Anastomosis Quirúrgica/métodos , Gastrectomía/métodos , Gastroenterostomía/métodos , Humanos , Laparoscopía/métodos , Estudios Retrospectivos , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Resultado del TratamientoRESUMEN
Peroxynitrite anion (ONOO-), a product derived from reaction between reactive oxygen species (ROS) and nitric oxide (NO), is considered to be a more toxic reactive species than most ROS for cancer photodynamic therapy (PDT). To promote the PDT effect, a viable method is to develop rational strategies for efficient ONOO- generation at targeted tumor sites. Herein, a heterostructure nanocomposite containing ZnO-coated lanthanide nanoparticles (LnNPs) is reported for ONOO--based PDT. In this nanocomposite, Nd3+-doped LnNPs are employed to realize efficient NIR-light-triggered ROS generation by activating the triplet state of chlorin-e6 (Ce6) photosensitizers via a direct lanthanide-to-triplet sensitization mechanism. Meanwhile, ZnO in the composite catalyzes the decomposition of S-nitrosoglutathione (GSNO) to generate NO in the tumor microenvironment. The coupled system allows the combination of photo-induced ROS and NO to produce ONOO-, leading to drastically promoted cancer cell apoptosis and tumor growth inhibition. This study establishes a new apoptosis-inducing PDT agent, which is potentially active in drug resistant malignancies.
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Elementos de la Serie de los Lantanoides , Nanopartículas del Metal , Neoplasias , Fotoquimioterapia , Óxido de Zinc , Aniones/uso terapéutico , Humanos , Elementos de la Serie de los Lantanoides/farmacología , Elementos de la Serie de los Lantanoides/uso terapéutico , Neoplasias/tratamiento farmacológico , Ácido Peroxinitroso , Fotoquimioterapia/métodos , Especies Reactivas de Oxígeno , Microambiente TumoralRESUMEN
Resistance to apoptosis induced by chemotherapy is still an obstacle for the treatment of chronic myeloid leukemia (CML). Numerous studies have indicated that upregulation of hepatocyte growth factor (HGF) protein expression reduced apoptosis induced by various factors. However, whether HGF has any effect on apoptosis induced by VP-16 (etoposide) in CML cells and its underlying mechanisms are unclear. HGF was overexpressed in the K562 cell line using transfection. The protein and mRNA expression levels, and the concentration of HGF were measured using western blot analysis, reverse transcription-quantitative (RT-qPCR) and ELISA respectively. Apoptosis in the K562 cell line was determined using flow cytometry and western blot analysis. Changes in cell viability were measured using a MTT assay. RT-qPCR and western blot analysis revealed that HGF was successfully upregulated at both the mRNA and protein expression levels in the K562 cell line, respectively. After VP-16 treatment, the number of apoptotic cells overexpressing HGF was lower compared with that in cells transfected with the empty vector. Mechanistic investigation revealed that overexpression of HGF led to the increase in Bcl-2 protein expression level and inhibition of caspase-3/9 activation. Furthermore, HGF overexpression resulted in activation of the PI3K/Akt signaling pathway. Therefore, the results of the present study revealed that targeting HGF could be used as a strategy to overcome VP-16 resistance in CML.
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GRP75 (75-kDA glucose-regulated protein), defined as a major component of both the mitochondrial quality control system and mitochondria-associated membrane, plays a key role in mitochondrial homeostasis. In this study, we assessed the roles of GRP75, other than as a component, in insulin action in both in vitro and in vivo models with insulin resistance. We found that GRP75 was downregulated in mice fed a high-fat diet (HFD) and that induction of Grp75 in mice could prevent HFD-induced obesity and insulin resistance. Mechanistically, GRP75 influenced insulin sensitivity by regulating mitochondrial function through its modulation of mitochondrial-supercomplex turnover rather than mitochondria-associated membrane communication: GRP75 was negatively associated with respiratory chain complex activity and was essential for mitochondrial-supercomplex assembly and stabilization. Moreover, mitochondrial dysfunction in Grp75-knockdown cells might further increase mitochondrial fragmentation, thus triggering cytosolic mtDNA release and activating the cGAS/STING-dependent proinflammatory response. Therefore, GRP75 can serve as a potential therapeutic target of insulin resistant-related diabetes or other metabolic diseases.
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Proteínas HSP70 de Choque Térmico/fisiología , Resistencia a la Insulina/genética , Proteínas de la Membrana/fisiología , Mitocondrias/metabolismo , Células 3T3-L1 , Animales , Células Cultivadas , ADN Mitocondrial/metabolismo , Transporte de Electrón/fisiología , Técnicas de Silenciamiento del Gen , Proteínas HSP70 de Choque Térmico/genética , Humanos , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Dinámicas Mitocondriales/genética , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismoRESUMEN
Mitochondria are crucial metabolic organelles involved in tumorigenesis and tumor progression, and the induction of abnormal mitochondria metabolism is recognized as a strategy with strong potential for the exploration of advanced tumor therapeutics. Herein, hierarchical manganese silicate nanoclusters modified with triphenylphosphonium (MSNAs-TPP) were designed and synthesized for mitochondria-targeted tumor theranostics. The as-prepared MSNAs-TPP retains considerable dimensional and structural stability in the neutral physiological environment, favoring its accumulation at the tumor site. More interestingly, MSNAs-TPP may disassemble in a responsive manner to an acidic tumor microenvironment into ultrasmall manganese silicate nanocapsules (â¼6 nm), enabling deep tumor penetration and mitochondria targeting. When reaching the mitochondria, the nanocapsules effectively deplete mitochondrial glutathione (GSH), and simultaneously release catalytic Mn2+ ions to induce amplified oxidative stress in the structure with the enriched CO2 and H2O2 from mitochondria metabolism. As a result, MSNAs-TPP presents considerable antitumor effect without a clear side effect, both in vitro and in vivo. The study may provide an alternative concept in the development of intelligent nanotherapeutics for tumor treatment with high efficacy.
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Nanocápsulas , Neoplasias , Humanos , Peróxido de Hidrógeno , Imagen por Resonancia Magnética , Mitocondrias , Neoplasias/tratamiento farmacológico , Microambiente TumoralRESUMEN
Although immunotherapy such as immune checkpoint inhibitors has shown promising efficacy in cancer treatment, the responsiveness among patients is relatively limited. Activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase/interferon gene stimulator (cGAS/STING) signaling pathway to upregulate innate immunity has become an emerging strategy for enhancing tumor immunotherapy. Herein, ZnS@BSA (bovine serum albumin) nanoclusters synthesized via a self-assembly approach are reported, where the released zinc ions under acidic tumor microenvironment significantly enhance cGAS/STING signals. Meanwhile, intracellular zinc ions can produce reactive oxygen species, which is further facilitated by the generated H2 S gas from ZnS@BSA via specifically inhibiting catalase in hepatocellular carcinoma cells. It is found that the nanoclusters activate the cGAS/STING signals in mice, which promotes the infiltration of CD8+ T cells at the tumor site and cross-presentation of dendritic cells, leading to an improved immunotherapy efficacy against hepatocellular carcinoma.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Compuestos de Zinc , Animales , Linfocitos T CD8-positivos , Carcinoma Hepatocelular/terapia , Humanos , Inmunoterapia , Neoplasias Hepáticas/terapia , Proteínas de la Membrana/metabolismo , Nanopartículas del Metal , Ratones , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Sulfuros , Microambiente Tumoral , Compuestos de Zinc/farmacologíaRESUMEN
Emerging evidence has shown that open reading frames inside long noncoding RNAs (lncRNAs) could encode micropeptides. However, their roles in cellular energy metabolism and tumor progression remain largely unknown. Here, we identified a 94 amino acid-length micropeptide encoded by lncRNA LINC00467 in colorectal cancer. We also characterized its conservation across higher mammals, localization to mitochondria, and the concerted local functions. This peptide enhanced the ATP synthase construction by interacting with the subunits α and γ (ATP5A and ATP5C), increased ATP synthase activity and mitochondrial oxygen consumption rate, and thereby promoted colorectal cancer cell proliferation. Hence, this micropeptide was termed ATP synthase-associated peptide (ASAP). Furthermore, loss of ASAP suppressed patient-derived xenograft growth with attenuated ATP synthase activity and mitochondrial ATP production. Clinically, high expression of ASAP and LINC00467 predicted poor prognosis of colorectal cancer patients. Taken together, our findings revealed a colorectal cancer-associated micropeptide as a vital player in mitochondrial metabolism and provided a therapeutic target for colorectal cancer.
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Adenosina Trifosfato/biosíntesis , Neoplasias Colorrectales/etiología , Proteínas Mitocondriales/fisiología , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Péptidos/farmacología , ARN Largo no Codificante/fisiología , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Humanos , Mitocondrias/metabolismo , Fosforilación Oxidativa , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND AND AIMS: Accumulating evidence suggests that the primary and acquired resistance of hepatocellular carcinoma (HCC) to sorafenib is mediated by multiple molecular, cellular, and microenvironmental mechanisms. Understanding these mechanisms will enhance the likelihood of effective sorafenib therapy. METHODS: In vitro and in vivo experiments were performed and clinical samples and online databases were acquired for clinical investigation. RESULTS: In this study, we found that a circular RNA, circRNA-SORE, which is up-regulated in sorafenib-resistant HCC cells, was necessary for the maintenance of sorafenib resistance, and that silencing circRNA-SORE substantially increased the efficacy of sorafenib-induced apoptosis. Mechanistic studies determined that circRNA-SORE sequestered miR-103a-2-5p and miR-660-3p by acting as a microRNA sponge, thereby competitively activating the Wnt/ß-catenin pathway and inducing sorafenib resistance. The increased level of circRNA-SORE in sorafenib-resistant cells resulted from increased RNA stability. This was caused by an increased level of N6-methyladenosine (m6A) at a specific adenosine in circRNA-SORE. In vivo delivery of circRNA-SORE interfering RNA by local short hairpin RNA lentivirus injection substantially enhanced sorafenib efficacy in animal models. CONCLUSIONS: This work indicates a novel mechanism for maintaining sorafenib resistance and is a proof-of-concept study for targeting circRNA-SORE in sorafenib-treated HCC patients as a novel pharmaceutical intervention for advanced HCC.
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Adenosina/análogos & derivados , Carcinoma Hepatocelular/tratamiento farmacológico , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , ARN Circular/genética , Sorafenib/farmacología , beta Catenina/metabolismo , Adenosina/química , Animales , Antineoplásicos/farmacología , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Movimiento Celular , Proliferación Celular , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , ARN Circular/química , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , beta Catenina/genéticaRESUMEN
Abnormal tumor microenvironment, such as hypoxia, interstitial hypertension and low pH, leads to unexpected resistance for current tumor treatment. The development of versatile drug delivery systems which present responsive characteristics to tumor microenvironment (TME) has been extensively carried out, but remains challenging. In this study, zeolitic imidazolate framework-8 (ZIF-8) coated ZnS nanoparticles have been designed and prepared for co-delivery of ICG/TPZ molecules, denoted as ZSZIT, for H2S-amplified synergistic therapy. Methods: The ZSZ nanoparticles were characterized using SEM, TEM and XRD. The in vitro viabilities of cancer cells cultured with ZSZIT under normoxia/hypoxia conditions were evaluated by cell counting kit-8 (CCK-8) assay. In addition, in vivo anti-tumor effect was also performed using male Balb/c nude mice as animal model. Results: ZSZIT shows cascade PDT and hypoxia-activated chemotherapeutic effect under an 808nm NIR irradiation. Meanwhile, ZSZIT degrades under tumor acidic environment, and H2S produced by ZnS cores could inhibit the expression of catalase, which subsequently favors the hypoxia and antitumor effect of TPZ drug. Both in vitro and in vivo studies demonstrate the H2S-sensitized synergistic antitumor effect based on cascade PDT/chemotherapy. Conclusion: This cascade H2S-sensitized synergistic nanoplatform has enabled more effective and lasting anticancer treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Portadores de Fármacos/química , Nanopartículas del Metal/química , Neoplasias/tratamiento farmacológico , Fotoquimioterapia/métodos , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Línea Celular Tumoral , Composición de Medicamentos/métodos , Sinergismo Farmacológico , Humanos , Sulfuro de Hidrógeno/química , Verde de Indocianina/administración & dosificación , Masculino , Estructuras Metalorgánicas/química , Ratones , Neoplasias/patología , Profármacos/administración & dosificación , Profármacos/farmacocinética , Tirapazamina/administración & dosificación , Hipoxia Tumoral/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Zeolitas/químicaRESUMEN
Localized drug delivery systems (LDDSs), in the forms of fibers or hydrogel, have emerged as an alternative approach for effective cancer treatment, but suffer challenges in the limited efficacy originated from sole therapeutic functionality. Herein, a multifunctional LDDS, showing feasibility for minimally-invasive implantation, was designed and synthesized for on-site chemo-photothermal synergistic therapy. In this system, polydopamine (PDA) nanoparticles, loaded with doxorubicin (DOX), were assembled at the surface of electrospun PCL-gelatin (PG) fibers (PG@PDA-DOX). The composite PG@PDA-DOX nanofibers could effectively transform NIR light into heat and present excellent photostability. In addition, low pH and NIR irradiation enabled remarkably accelerated DOX release. The in vitro study of PG@PDA-DOX fibers showed effective anti-cancer effect with irradiation of 808â¯nm NIR by inducing cell apoptosis and suppressing cell proliferation. The in vivo study, by implanting PG@PDA-DOX nanofibers in the patient derived xenograft (PDX) model via minimally-invasive surgery, presented that the composite fibers can effectively inhabit tumor growth by the combined chemo-photothermal effect without clear systematic side-effects. This study has therefore demonstrated a minimally-invasive platform, in a fibrous mesh form, with both high therapeutic efficacy and considerable potential in clinical translation for liver cancer treatment.
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HCC is a common malignancy worldwide and surgery or reginal treatments are deemed insufficient for advanced-stage disease. Sorafenib is an inhibitor of many kinases and was shown to benefit advanced HCC patients. However, resistance emerges soon after initial treatment, limiting the clinical benefit of sorafenib, and the mechanisms still remain elusive. Thus, this study aims to investigate the mechanisms of sorafenib resistance and to provide possible targets for combination therapies. Through miRNA sequencing, we found that miR-486-3p was downregulated in sorafenib resistant HCC cell lines. Cell viability experiments showed increased miR-486-3p expression could induce cell apoptosis while miR-486-3p knockdown by CRISPR-CAS9 technique could reduce cell apoptosis in sorafenib treatment. Clinical data also indicated that miR-486-3p level was downregulated in tumor tissue compared with adjacent normal tissue in HCC patients. Mechanism dissections showed that FGFR4 and EGFR were the targets of miR-486-3p, which was verified by luciferase reporter assay. Importantly, FGFR4 or EGFR selective inhibitor could enhance sorafenib efficacy in the resistant cells. Moreover, in vivo sorafenib resistant model identified that over-expressing miR-486-3p by lentivirus injection could overcome sorafenib resistance by significantly suppressing tumor growth in combination with the treatment of sorafenib. In conclusion, we found miR-486-3p was an important mediator regulating sorafenib resistance by targeting FGFR4 and EGFR, thus offering a potential target for HCC treatment.
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Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroARNs/genética , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/genética , Carcinoma Hepatocelular/patología , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Hepáticas/patología , Inhibidores de Proteínas Quinasas/farmacología , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
Developing drug delivery platforms that can modulate a tumor microenvironment and deliver multiple therapeutics to targeted tumors is critical for efficient cancer treatment. Achieving these platforms still remains a great challenge. Herein, biodegradable nanocapsules based on MnFe hydroxides (H-MnFe(OH)x) have been developed as a new type of cargo delivery with high loading capacity and catalytic activity, enabling synergetic therapy with promoted efficacy by relieving hypoxia in tumor tissues. As a proof of concept, a photosensitizer (indocyanine green, ICG) and a chemotherapeutic drug (doxorubicin, DOX) are co-loaded in nanocapsules and selectively released upon degradation of the nanocapsules in the acidic tumor microenvironment, and are promoted by near infrared irradiation. Meanwhile, Mn2+/Fe3+ ions released from the degradation of nanocapsules catalyze the conversion of H2O2 in a tumor microenvironment into oxygen, which modulates tumor hypoxia and dramatically boosts multimodal therapies. Remarkable synergistic anticancer outcomes have been demonstrated both in vitro and in vivo, paving the way towards future multifunctional therapeutic platforms.
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Antibióticos Antineoplásicos/farmacología , Hipoxia de la Célula/efectos de los fármacos , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Verde de Indocianina/farmacología , Fármacos Fotosensibilizantes/farmacología , Animales , Antibióticos Antineoplásicos/síntesis química , Antibióticos Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/síntesis química , Doxorrubicina/química , Femenino , Humanos , Hidróxidos/química , Hidróxidos/farmacología , Verde de Indocianina/química , Hierro/química , Hierro/farmacología , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Manganeso/química , Manganeso/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanocápsulas/química , Tamaño de la Partícula , Fármacos Fotosensibilizantes/química , Terapia Fototérmica , Porosidad , Propiedades de Superficie , Microambiente Tumoral/efectos de los fármacosRESUMEN
Therapeutic systems to induce reactive oxygen species (ROS) have received tremendous success in the research of tumor theranostics, but suffered daunting challenges in limited efficacy originating from low presence of reactants and reaction kinetics within cancer cells. Here, ferrous sulfide-embedded bovine serum albumin (FeS@BSA) nanoclusters, in an amorphous nature, are designed and synthesized via a self-assembly approach. In acidic conditions, the nanoclusters degrade and simultaneously release H2S gas and Fe2+ ions. The in vitro study using Huh7 cancer cells reveals that Fe2+ released from FeS@BSA nanoclusters induces the toxic hydroxyl radical (·OH) effectively via the Fenton reaction. More interestingly, H2S gas released intracellularly presents the specific suppression effect to catalase activity of cancer cells, resulting in the promoted presence of H2O2 that facilitates the Fenton reaction of Fe2+ and consequently promotes ROS induction within the cells remarkably. After intravenous administration, the nanoclusters accumulate in the tumors of mice via the enhanced permeability and retention effect and present strong magnetic resonance imaging (MRI) signals. The findings confirm this therapeutic system can enable superior anti-tumor performance with MRI guidance and negligible side effects. This study, therefore, offers an alternative gas-amplified ROS-based therapeutic platform for synergetic tumor treatment.
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For the first time, we report the design and fabrication of a ZnS nanoparticle-decorated silica fibre mesh (ZnS@SiO2) for localized H2S-amplified chemotherapy. With incorporation of DOX, implanted ZnS@SiO2 fibres enable sufficient on-site drug dosage and intracellular H2S content, inducing significant in vitro and in vivo tumour inhibition.
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Antineoplásicos/farmacología , Doxorrubicina/farmacología , Sulfuro de Hidrógeno/farmacología , Nanopartículas del Metal/química , Sulfuros/química , Compuestos de Zinc/química , Animales , Catalasa/antagonistas & inhibidores , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Sinergismo Farmacológico , Inhibidores Enzimáticos/farmacología , Humanos , Nanopartículas del Metal/toxicidad , Ratones , Pruebas de Sensibilidad Microbiana , Nanofibras/química , Nanofibras/toxicidad , Dióxido de Silicio/química , Dióxido de Silicio/toxicidad , Sulfuros/toxicidad , Compuestos de Zinc/toxicidadRESUMEN
PURPOSE: Gallbladder neuroendocrine neoplasm (GB-NEN) is a relatively rare neoplasm, accounting for 0.5% of all neuroendocrine neoplasm cases and 2.1% of gallbladder cancers. Because of the limited understanding of GB-NEN, the aim of this study was to explore the clinicopathology and survival of GB-NEN patients selected from the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: A total of 248 GB-NEN patients from the SEER database diagnosed between 2004 and 2015 were included. Kaplan-Meier curves were used to examine the survival time. Multivariate Cox proportional hazard models were used to estimate hazard ratios with 95% confidence intervals to analyze the impact of factors on overall survival and cancer-specific survival. RESULTS: The majority of the GB-NEN patients were women (67.3%), white (77%), and married (61.7%). Most tumors were <2 cm in size (31.0%), G3 stage (25.8%), and distant SEER stage (41.1%). 62.9% and 64.5% of cases showed an absence of lymph node metastasis and tumor metastasis, respectively. Patients who received gallbladder surgery had significantly better survival outcomes (P < 0.001). However, patients who received both gallbladder surgery and lymph node resection did not have better survival outcome compared with patients who received only gallbladder surgery. Multivariate Cox proportional hazard models indicated that older age, unmarried status, large tumor size (>5 cm), and distant SEER stage were significant independent predictors for decreased overall survival time and cancer-specific survival time (P < 0.05). CONCLUSION: Age, marital status, tumor size, and SEER stage were predictors for the survival of GB-NEN patients. Gallbladder surgery was associated with better survival, but the combination of gallbladder surgery and lymphadenectomy had no effect on survival outcomes.