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Structurally ordered L10-PtM (M = Fe, Co, Ni and so on) intermetallic nanocrystals, benefiting from the chemically ordered structure and higher stability, are one of the best electrocatalysts used for fuel cells. However, their practical development is greatly plagued by the challenge that the high-temperature (>600 °C) annealing treatment necessary for realizing the ordered structure usually leads to severe particle sintering, morphology change and low ordering degree, which makes it very difficult for the gram-scale preparation of desirable PtM intermetallic nanocrystals with high Pt content for practical fuel cell applications. Here we report a new concept involving the low-melting-point-metal (M' = Sn, Ga, In)-induced bond strength weakening strategy to reduce Ea and promote the ordering process of PtM (M = Ni, Co, Fe, Cu and Zn) alloy catalysts for a higher ordering degree. We demonstrate that the introduction of M' can reduce the ordering temperature to extremely low temperatures (≤450 °C) and thus enable the preparation of high-Pt-content (≥40 wt%) L10-Pt-M-M' intermetallic nanocrystals as well as ten-gram-scale production. X-ray spectroscopy studies, in situ electron microscopy and theoretical calculations reveal the fundamental mechanism of the Sn-facilitated ordering process at low temperatures, which involves weakened bond strength and consequently reduced Ea via Sn doping, the formation and fast diffusion of low-coordinated surface free atoms, and subsequent L10 nucleation. The developed L10-Ga-PtNi/C catalysts display outstanding performance in H2-air fuel cells under both light- and heavy-duty vehicle conditions. Under the latter condition, the 40% L10-Pt50Ni35Ga15/C catalyst delivers a high current density of 1.67 A cm-2 at 0.7 V and retains 80% of the current density after extended 90,000 cycles, which exceeds the United States Department of Energy performance metrics and represents among the best cathodic electrocatalysts for practical proton-exchange membrane fuel cells.
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Cellular communication mediated by messenger molecules plays an important role in the progression of cancer. Herein, pH-sensitive zeolitic imidazolate framework-8 (ZIF-8) loaded with PtCl2(OH)2(NH3)2 [i.e., Pt(IV)] bimetallic nanoplatforms were developed for prostate cancer therapy by interfering inositol-1, 4, 5-trisphosphate (IP3)-mediated cellular communication. As an important messenger in cells, the function of IP3 was found to be efficiently interfered with by the Pt(IV)-binding inositol unit. This finding effect of Pt(IV) is totally different from its traditional function as a prodrug of cis-platinum for chemotherapy. The decreased IP3 signal further downregulated the cytoplasmic Ca2+ concentration and downstream signal transduction to inhibit proliferation and invasion of tumor cells. Meanwhile, Zn2+ released from ZIF-8 under an acidic tumor microenvironment decreased adenosine triphosphate biosynthesis, which could further limit the cellular communication. Such a proposed strategy of interfering cellular communication has demonstrated its feasibility in this study, which may provide new perspectives for cancer therapy.
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Antineoplásicos , Neoplasias da Próstata , Humanos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Masculino , Antineoplásicos/farmacologia , Antineoplásicos/química , Comunicação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Inositol 1,4,5-Trifosfato/metabolismo , Inositol 1,4,5-Trifosfato/química , Concentração de Íons de Hidrogênio , Imidazóis/química , Imidazóis/farmacologia , Zinco/química , Zinco/farmacologiaRESUMO
Surface polarization under harsh electrochemical environments usually puts catalysts in a thermodynamically unstable state, which strictly hampers the thermodynamic stability of Pt-based catalysts in high-performance fuel cells. Here, we report a strategy by introducing electron buffers (variable-valence metals, M = Ti, V, Cr, and Nb) into intermetallic Pt alloy nanoparticle catalysts to suppress the surface polarization of Pt shells using the structurally ordered L10-M-PtFe as a proof of concept. Operando X-ray absorption spectra analysis suggests that with the potential increase, electron buffers, especially Cr, could facilitate an electron flow to form a electron-enriched Pt shell and thus weaken the surface polarization and tensile Pt strain. The best-performing L10-Cr-PtFe/C catalyst delivers superb oxygen reduction reaction (ORR) activity (mass activity = 1.41/1.02 A mgPt-1 at 0.9 V, rated power density = 14.0/9.2 W mgPt-1 in H2-air under a total Pt loading of 0.075/0.125 mgPt cm-2, respectively) and stability (20 mV voltage loss at 0.8 A cm-2 after 60,000 cycles of accelerated durability test) in a fuel cell cathode, representing one of the best reported ORR catalysts. Density functional theory calculations reveal that the optimized surface strain by introducing Cr on L10-PtFe/C accounts for the enhanced ORR activity, and the durability enhancement stems from the charge transfer contribution of Cr to the Pt shells and the increased kinetic energy barrier for Pt dissolution/Fe diffusion.
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Coiled-coil domain containing 88C (CCDC88C) is a component of non-canonical Wnt signaling, and its dysregulation causes colorectal cancer metastasis. Dysregulated expression of CCDC88C was observed in lymph node metastatic tumor tissues of breast cancer. However, the role of CCDC88C in breast cancer metastasis remains unclear. To address this, the stable BT549 and SKBR3 cell lines with CCDC88C overexpression or knockdown were developed. Loss/gain-of-function experiments suggested that CCDC88C drove breast cancer cell motility in vitro and lung and liver metastasis in vivo. We found that CCDC88C led to c-JUN-induced transcription activation. Overlapping genes were identified from the genes modulated by CCDC88C and c-JUN. CEMIP, one of these overlapping genes, has been confirmed to confer breast cancer metastasis. We found that CCDC88C regulated CEMIP mRNA levels via c-JUN and it exerted pro-metastatic capabilities in a CEMIP-dependent manner. Moreover, we identified the CCDC88C as a substrate of polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6). GALNT6 was positively correlated with CCDC88C protein abundance in the normal breast and breast cancer tissues, indicating that GALNT6 might be associated with expression patterns of CCDC88C in breast cancer. Our data demonstrated that GALNT6 maintained CCDC88C stability by promoting its O-linked glycosylation, and the modification was critical for the pro-metastatic potential of CCDC88C. CCDC88C also could mediate the pro-metastatic potential of GALNT6 in breast cancer. Collectively, our findings uncover that CCDC88C may increase the risk of breast cancer metastasis and elucidate the underlying molecular mechanisms.
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The annexin superfamily (ANXA) is made up of 12 calcium (Ca2+) and phospholipid binding protein members that have a high structural homology and play a key function in cancer cells. However, little research has been done on the annexin family's function in pan-cancer. We examined the ANXA family's expression in various tumors through public databases using bioinformatics analysis, assessed the differences in ANXA expression between tumor and normal tissues in pan-cancer, and then investigated the relationship between ANXA expression and patient survival, prognosis, and clinicopathologic traits. Additionally, we investigated the relationships among TCGA cancers' mutations, tumor mutation burden (TMB), microsatellite instability (MSI), immunological subtypes, immune infiltration, tumor microenvironment, immune checkpoint genes, chemotherapeutics sensitivity, and ANXAs expression. cBioPortal was also used to uncover pan-cancer genomic anomalies in the ANXA family, study relationships between pan-cancer ANXA mRNA expression and copy number or somatic mutations, and assess the prognostic values of these variations. Moreover, we investigated the relationship between ANXAs expression and effectiveness of immunotherapy in multiple cohorts, including one melanoma (GSE78220), one renal cell carcinoma (GSE67501), and three bladder cancer cohorts (GSE111636, IMvigor210 and our own sequencing dataset (TRUCE-01)), and further analyzed the changes of ANXAs expression before and after treatment (tislelizumab combined with nab-paclitaxel) of bladder cancer. Then, we explored the biological function and potential signaling pathway of ANXAs using gene set enrichment analysis (GSEA), and first conducted immune infiltration analysis with ANXAs family genes expression, copy number, or somatic mutations of bladder cancer by TIMER 2.0. Most cancer types and surrounding normal tissues expressed ANXA differently. ANXA expression was linked to patient survival, prognosis, clinicopathologic features, mutations, TMB, MSI, immunological subtypes, tumor microenvironment, immune cell infiltration, and immune checkpoint gene expression in 33 TCGA cancers, with ANXA family members varied. The anticancer drug sensitivity analysis showed that ANXAs family members were significantly related to a variety of drug sensitivities. In addition, we also discovered that the expression level of ANXA1/2/3/4/5/7/9/10 was positively or negatively correlated with objective responses to anti-PD-1/PD-L1 across multiple immunotherapy cohorts. The immune infiltration analysis of bladder cancer further showed the significant relationships between ANXAs copy number variations or mutation status, and infiltration level of different immune cells. Overall, our analyses confirm the importance of ANXAs expression or genomic alterations in prognosis and immunological features of various cancer and identified ANXA-associated genes that may serve as potential therapeutic targets.
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Multiômica , Neoplasias da Bexiga Urinária , Humanos , Variações do Número de Cópias de DNA , Imunoterapia , Anexinas , Microambiente Tumoral/genéticaRESUMO
Cervical cancer (CC) is the primary cancer-related cause of morbidity and mortality in women. Previous studies have shown that placenta-specific 8 (PLAC8) has different functions in multiple malignancies. This study aimed to explore the function and regulatory mechanism of PLAC8 in CC. Bioinformatics and immunohistochemical analyses demonstrated that PLAC8 was significantly upregulated in CC tissues compared with normal tissues. Gain/loss-of-function experiments showed that siRNA-mediated knockdown of PLAC8 suppressed cell migration and invasion, while PLAC8 overexpression promoted cell motility. Moreover, PLAC8 was revealed to affect the epithelial-mesenchymal transition (EMT) process by upregulating epithelial (E)-cadherin and decreasing the expression of mesenchymal markers of EMT, including vimentin, zinc finger E-box binding homeobox 1 (ZEB1), neural (N)-cadherin, matrix metalloproteinase-9 (MMP-9), and MMP-2 in PLAC8-silenced cells. PLAC8 activated the AKT pathway, as proven by the downregulation of p-AKTSer473 and p-AKTThr308 expression after PLAC8 knockdown. Furthermore, PLAC8 overexpression upregulated the expression of sex-determining region Y-related high-mobility group box transcription factor 4 (SOX4), which is reported to mediate the activation of the AKT pathway, and SOX4 deficiency reversed the cellular functions caused by PLAC8 overexpression. Overall, the present study indicates that PLAC8 may facilitate CC development by activating the SOX4-mediated AKT pathway, suggesting that PLAC8 may serve as a potential biomarker for CC treatment.
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Proteínas Proto-Oncogênicas c-akt , Neoplasias do Colo do Útero , Humanos , Feminino , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Caderinas/metabolismo , Transição Epitelial-Mesenquimal , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo , Proteínas/metabolismoRESUMO
PURPOSE: Patients who have been diagnosed with prostate cancer (PCa) typically have a dismal outlook and few therapeutic choices available to them, because the precise pathogenesis of the disease is not yet fully understood. The presence of HP1α, also known as the heterochromatin protein 1α, is required for the creation of higher-order chromatin structures. However, little is known about HP1α that serves roles in the pathogenesis of PCa. The primary purpose of our research was to investigate alterations in the levels of HP1α expression and to plan a series of tests to validate the function of HP1α in PCa. METHOD: Information on HP1α expression in PCa and benign prostatic hyperplasia (BPH) tissues were gathered using the Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) databases. RT-qPCR, western blotting, and immunohistochemistry (IHC) were used to assess HP1α mRNA and protein expression in several human PCa tissues and cell lines. The CCK8 assay, clone formation assay, and transwell assay were used to examine biological activities including cell proliferation, migration, and invasion. The expression of proteins connected to apoptosis and the epithelial-mesenchymal transition (EMT) was examined using Western blot. The tumorigenic effect of HP1α was also verified by in vivo experiments. RESULT: HP1α expression was much higher in PCa than in BPH tissues and cells, and was positively correlated with the Gleason score of PCa. In vitro experiments showed that HP1α knockdown could inhibit the ability of proliferation, invasion, and migration of PC3 and LNCaP cells, and promote cell apoptosis and EMT. In vivo experiments showed that HP1α knockdown inhibited tumorigenesis in mice. CONCLUSION: Our findings indicate that HP1α expression promotes PCa development and might be a novel therapeutic target for the diagnosis or treatment of PCa.
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Hiperplasia Prostática , Neoplasias da Próstata , Masculino , Humanos , Animais , Camundongos , Hiperplasia Prostática/genética , Hiperplasia Prostática/metabolismo , Linhagem Celular Tumoral , Neoplasias da Próstata/metabolismo , Fatores de Transcrição/genética , Proliferação de Células/genética , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Transição Epitelial-Mesenquimal/genéticaRESUMO
The benefits of excess PbI2 on perovskite crystal nucleation and growth are countered by the photoinstability of interfacial PbI2 in perovskite solar cells (PSCs). Here we report a simple chemical polishing strategy to rip PbI2 crystals off the perovskite surface to decouple these two opposing effects. The chemical polishing results in a favorable perovskite surface exhibiting enhanced luminescence, prolonged carrier lifetimes, suppressed ion migration, and better energy level alignment. These desired benefits translate into increased photovoltages and fill factors, leading to high-performance mesostructured formamidinium lead iodide-based PSCs with a champion efficiency of 24.50%. As the interfacial ion migration paths and photodegradation triggers, dominated by PbI2 crystals, were eliminated, the hysteresis of the PSCs was suppressed and the device stability under illumination or humidity stress was significantly improved. Moreover, this new surface polishing strategy can be universally applicable to other typical perovskite compositions.
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The development of highly efficient and durable water electrolysis catalysts plays an important role in the large-scale applications of hydrogen energy. In this work, protrusion-rich Cu@NiRu core@shell nanotubes are prepared by a facile wet chemistry method and used for catalyzing hydrogen evolution reaction (HER) in an alkaline environment. The protrusion-like RuNi alloy shells with accessible channels and abundant defects possess a large surface area and can optimize the surface electronic structure through the electron transfer from Ni to Ru. Moreover, the unique 1D hollow structure can effectively stabilize RuNi alloy shell through preventing the aggregation of nanoparticles. The synthesized catalyst can achieve a current density of 10 mA cm-2 in 1.0 m KOH with an overpotential of only 22 mV and show excellent stability after 5000 cycles, which is superior to most reported Ru-based catalysts. Density functional theory calculations illustrate that the weakened hydrogen adsorption on Ru sites induced by the alloying with Ni and active electron transfer between Ru and Ni/Cu are the keys to the much improved HER activity.
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BACKGROUND: Effective treatment is needed for advanced, inoperable, or chemotherapy-resistant cervical cancer patients. Immunotherapy has become a new treatment modality for cervical cancer patients, and there is an urgent need to identify additional targets for cervical cancer immunotherapy. METHODS: In this study the core gene, RGS1, which affects immune status and the FIGO stage of cervical cancer patients was identified by WGCNA analysis and differential analysis using TCGA database. 10 related genes interacting with RGS1 were identified using PPI network, and the functional and immune correlations were analyzed. Based on the expression of RGS1 and related genes, the consensus clustering method was used to divide CESC patients into two groups (group 1, high expression of RGS1; group 2, low expression of RGS1). Then, the functional enrichment analysis was used to search for the functional differences in differentially expressed genes (DEGs) between group 1 and group 2. Immune infiltration analysis was performed using ESTIMATE, CIBERSORT, and ssGSEA, and the differences in expression of immune checkpoint inhibitors (ICIs) targets were assessed between the two groups. We investigated the effect of RGS1 on the clinical relevance of CESC patients, and experimentally verified the differences in RGS1 expression between cervical cancer patient tissues and normal cervical tissues, the role of RGS1 in cell function, and the effect on tumor growth in tumor-bearing mice. RESULTS: We found that RGS1 was associated with CD4, GNAI3, RGS2, GNAO1, GNAI2, RGS20, GNAZ, GNAI1, HLA-DRA and HLA-DRB1, especially CD4 and RGS2. Functional enrichment of DEGs was associated with T cell activation. Compared with group 2, group 1 had stronger immune infiltration and higher ICI target expression. RGS1 had higher expression in cervical cancer tissues than normal tissues, especially in HPV-E6 positive cancer tissues. In cervical cancer cell lines, knockdown of RGS1 can inhibited cell proliferation, migration, invasion, and tumor growth in nude mice and promoted apoptosis. CONCLUSIONS: RGS1, as an oncogenic gene of cervical cancer, affects the immune microenvironment of patients with cervical cancer and may be a target of immunotherapy.
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Proteínas RGS , Neoplasias do Colo do Útero , Animais , Carcinogênese , Biologia Computacional , Feminino , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Humanos , Imunoterapia , Camundongos , Camundongos Nus , Proteínas RGS/genética , Proteínas RGS/metabolismo , Microambiente Tumoral , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/terapiaRESUMO
Glycolysis and the pentose phosphate pathway (PPP) are two basic metabolic pathways that are simultaneously present in yeasts. As the main pathway in most species, the glycolysis provides ATP and NADH for cell metabolism while PPP, as a complementary pathway, supplies NADPH. In this study, the performance of Kluyveromyces marxianus using glycolysis or PPP were studied through the disruption of PGI1 or ZWF1 gene, respectively. K. marxianus using glycolysis as the only pathway showed higher ethanol production ability than that of the Kluyveromyces lactis zwf1Δ mutant; K. marxianus using only PPP showed more robustness than that of Saccharomyces cerevisiae pgi1Δ mutant. Additionally, K. marxianus pgi1Δ strain accumulated much more intracellular NADPH than the wild type strain and co-utilized glucose and xylose more effectively. These findings suggest that phosphoglucose isomerase participates in the regulation of the repression of glucose on xylose utilization in K. marxianus. The NADPH/NADP+ ratio, dependent on the activity of the PPP, regulated the expression of multiple genes related to NADPH metabolism in K. marxianus (including NDE1, NDE2, GLR1, and GDP1). Since K. marxianus is considered a promising host in industrial biotechnology to produce renewable chemicals from plant biomass feedstocks, our research showed the potential of the thermotolerant K. marxianus to produce NADP(H)-dependent chemical synthesis from multiple feedstocks. KEY POINTS: ⢠The function of PGI1 and ZWF1 in K. marxianus has been analyzed in this study. ⢠K. marxianus zwf1Δ strain produced ethanol but with decreased productivity. ⢠K. marxianus pgi1Δ strain grew with glucose and accumulated NADPH. ⢠K. marxianus pgi1Δ strain released glucose repression on xylose utilization.
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Kluyveromyces , Saccharomyces cerevisiae , Fermentação , Glucose , Kluyveromyces/genética , XiloseRESUMO
BACKGROUND: Hashimoto's thyroiditis is a complex autoimmune thyroid disease, the onset of which is associated with environmental exposures and specific susceptibility genes. Its incidence in females is higher than its incidence in males. Thus far, although some susceptibility loci have been elaborated, including PTPN22, FOXP3, and CD25, the aetiology and pathogenesis of Hashimoto's thyroiditis remains unclear. METHODS: Four affected members from a Chinese family with Hashimoto's thyroiditis were selected for whole-exome sequencing. Missense, nonsense, frameshift, or splicing-site variants shared by all affected members were identified after frequency filtering against public and internal exome databases. Segregation analysis was performed by Sanger sequencing among all members with available DNA. RESULTS: We identified a missense mutation in PTPN22 (NM_015967.5; c. 77A > G; p.Asn26Ser) using whole-exome sequencing. PTPN22 is a known susceptibility gene associated with increased risks of multiple autoimmune diseases. Cosegregation analysis confirmed that all patients in this family, all of whom were female, carried the mutation. All public and private databases showed that the missense mutation was extremely rare. CONCLUSIONS: We found a missense mutation in PTPN22 in a Chinese HT pedigree using whole-exome sequencing. Our study, for the first time, linked a rare variant of PTPN22 to Hashimoto's thyroiditis, providing further evidence of the disease-causing or susceptibility role of PTPN22 in autoimmune thyroid disease. Functional studies regarding the effects of this variant on thyroid autoimmunity and thyroid function are warranted.
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Povo Asiático/genética , Doença de Hashimoto/diagnóstico , Doença de Hashimoto/genética , Mutação de Sentido Incorreto/genética , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Sequenciamento do Exoma/tendênciasRESUMO
Taxus media is an important species in the family Taxaceae with high medicinal and commercial value. Overexploitation and illegal trade have led T. media to a severe threat of extinction. In addition, T. media and other Taxus species have similar morphological traits and are easily misidentified, particularly during the seedling stage. The purpose of this study is to develop a species-specific marker for T. media. Through a screening of 36 start codon targeted (SCoT) polymorphism primers, among 15 individuals of 4 Taxus species (T. media, T. chinensis, T. cuspidate and T. fuana), a clear species-specific DNA fragment (amplified by primer SCoT3) for T. media was identified. After isolation and sequencing, a DNA sequence with 530 bp was obtained. Based on this DNA fragment, a primer pair for the sequence-characterized amplified region marker was designed and named MHSF/MHSR. PCR analysis with primer pair MHSF/MHSR revealed a clear amplified band for all individuals of T. media but not for T. chinensis, T. cuspidate and T. fuana. Therefore, this marker can be used as a quick, efficient and reliable tool to identify T. media among other related Taxus species. The results of this study will lay an important foundation for the protection and management of T. media as a natural resource.
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Polimorfismo Genético , Plântula/genética , Taxus/genética , Marcadores Genéticos , Taxus/classificaçãoRESUMO
BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been reported to promote tumorigenesis and progression in several human malignancies. The purpose of this study was to explore the function of BDNF in lung squamous cell carcinoma (SCC) and adenocarcinoma (ADC). METHODS: The expression of BDNF was examined in 110 samples of lung SCC and ADC by immunohistochemistry. The protein level of BDNF was examined in 25 lung SCC or ADC samples and paired non-tumors by western blot. BDNF expression was also evaluated in human bronchial epithelial cells (HBE) and 4 lung cancer cell lines using western blot. Three BDNF mRNA variants containing exons IV, VI and IX were evaluated in HBE, two SCC (SK, LK2) and two ADC (A549, LTE) cell lines by RT-PCR. The expression and secretion of BDNF were also determined in cells using western blot and ELISA. Then the shRNA specific for BDNF was transfected into LK2 or A549 cells to further elucidate the BDNF knockdown on cell proliferation, apoptosis and invasion, which were confirmed by MTT, flow cytometry and transwell examinations. RESULTS: 71.8 % (79 out of 110) of lung SCC and ADC samples were detected positive BDNF, and high expression of BDNF was significantly correlated with histological type and T stage. Compared with non-tumorous counterparts, BDNF was apparently overexpressed in SCC and ADC tissues. In cell studies, the extensive expression and secretion of BDNF were demonstrated in lung cancer cells compared with HBE cells. Interestingly, the expressions of BDNF mRNA variant IV and VI were identical in all cells examined. However, more expression of BDNF mRNA variant IX was found in SK and LK2 cells. The apoptotic cells were increased, and the cell proliferation and invasion were both attenuated once the expression of BDNF was inhibited. When retreated by rhBDNF, BDNF knockdown cells showed less apoptotic or more proliferative and invasive. CONCLUSIONS: Our data show that BDNF probably facilitates the tumorigenesis of lung SCC and ADC. The expression of BDNF mRNA variant IX is probably more helpful to the upregulation of BDNF in SCC, and intervening the production of BDNF could be a possible strategy to lung cancer therapy.
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Fator Neurotrófico Derivado do Encéfalo/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Pulmonares/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Apoptose/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , Carga TumoralRESUMO
The aim of our study is to explore the involvement of PPARα and PPARγ in Ang II-induced endothelial injury. We found that Ang II significantly elevated the oxidative stress in HUVECs, causing apoptosis and cellular impairment in a time-dependent pattern. Activation of either PPARα by docosahexaenoic acid (DHA) or PPARγ by rosiglitazone protected the endothelial cells. Interestingly, a more significant effect was observed when DHA and rosiglitazone were administrated together. Moreover, we found that this protection was mediated through the PI3K/Akt pathway. Our study may help to understand the mechanism of endothelial dysfunction, contributing to the treatment of hypertension and other endothelial-related diseases.
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Angiotensina II/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Células Endoteliais , Estresse Oxidativo/efeitos dos fármacos , PPAR alfa/metabolismo , PPAR gama/metabolismo , Tiazolidinedionas/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Citoproteção/fisiologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipertensão , Fosfatidilinositol 3-Quinases/metabolismo , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rosiglitazona , Transdução de Sinais/efeitos dos fármacosRESUMO
MicroRNAs (miRNAs) are a class of small noncoding RNAs that play important roles in tumorigenesis and tumor progression through regulation of gene expression. Earlier, miR-142-3p was shown to decreased in cervical cancer cells; here; we explore the biological functional role of miR-142-3p and underlying mechanism in cervical cancer cells. We first detected the expression of miR-142-3p in six human cervical cancer cell lines and chose HeLa and SiHa cells for functional studies. By gain and loss of function experiments, we showed that overexpression of miR142-3p resulted in downregulation of Frizzled7 receptor (FZD7) and inhibited proliferation and invasion in HeLa and SiHa cells, whereas miR142-3p inhibitor-transfected cells showed reduced FZD7 expression and increased invasion capacity. In addition, we demonstrated that FZD7 was a direct target of miR-142-3p by dual luciferase assay and Western blot analysis. Overexpression of FZD7 expression was able to reverse the inhibitory effects induced by miR-142-3p. Taken together, miR-142-3p functions tumor suppressive effects in cell proliferation and invasion in cervical cancer cells, suggesting a potential therapeutic approach for cervical cancer.
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Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Receptores Frizzled/genética , MicroRNAs/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Apoptose , Biomarcadores Tumorais/metabolismo , Western Blotting , Feminino , Receptores Frizzled/metabolismo , Humanos , Invasividade Neoplásica , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/metabolismoRESUMO
BACKGROUND: Adenocarcinomas with a micropapillary component (MPC) have been described as an unusual morphological variant in various organs. However, few reports have described MPCs in gastric carcinomas, and the clinicopathological features of MPC are unclear. METHODS: Immunohistochemistry was used to detect the expression of epithelial membrane antigen, CK7, CK20, p53, epidermal growth factor receptor, ß-catenin, c-erbB-2, and Ki-67. Correlation of the MPC to tumor stage, lymph node metastasis, and lymphovascular invasion was performed using Fisher's exact test. Kaplan-Meier estimates were used to analyze overall survival. RESULTS: Immunohistochemical staining demonstrated that micropapillary and conventional gastric carcinomas showed similar positivity rates for all markers. However, aberrant expression of E-cadherin was detected in the tumors with MPCs without immunoreactivity in the stroma face. Epithelial membrane antigen showed the characteristic inside-out staining pattern of MPCs. Lymphatic invasion (P = 0.003), venous invasion (P = 0.017), lymph node metastasis (P = 0.014), and tumor stage (P = 0.022) were significantly increased in patients with MPCs when compared with conventional adenocarcinomas. MPC subtype II had a significantly higher frequency of lymph node metastasis than subtype I (P = 0.014). However, the proportion of MPC was not associated with lymph node metastases (P = 0.136). Overall survival of patients with an MPC was significantly shorter than that of patients with conventional adenocarcinomas (P = 0.031). In addition, overall survival was significantly lower in patients with a subtype II MPC growth pattern than in those with subtype I MPC in gastric carcinomas (P = 0.040). CONCLUSION: Gastric adenocarcinomas with MPC appear to be an aggressive variant associated with a poor prognosis. MPCs occurring in gastric adenocarcinomas should be included in surgical pathology reports, even if the proportion of MPC in the lesions is very low in the lesion.
Assuntos
Adenocarcinoma Papilar/mortalidade , Adenocarcinoma/patologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma Papilar/metabolismo , Adenocarcinoma Papilar/patologia , Idoso , Caderinas/metabolismo , Receptores ErbB/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfonodos/patologia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/metabolismoRESUMO
Angiotensin II (Ang II) plays important roles in ageing-related disorders through its type 1 receptor (AT1 R). However, the role and underlying mechanisms of AT1R in ageing-related vascular degeneration are not well understood. In this study, 40 ageing rats were randomly divided into two groups: ageing group which received no treatment (ageing control), and valsartan group which took valsartan (selective AT1R blocker) daily for 6 months. 20 young rats were used as adult control. The aorta structure were analysed by histological staining and electron microscopy. Bcl-2/Bax expression in aorta was analysed by immunohistochemical staining, RT-PCR and Western blotting. The expressions of AT1 R, AT2 R and mitogen-activated protein kinases (MAPKs) were detected. Significant structural degeneration of aorta in the ageing rats was observed, and the degeneration was remarkably ameliorated by long-term administration of valsartan. With ageing, the expression of AT1R was elevated, the ratio of Bcl-2/Bax was decreased and meanwhile, an important subgroup of MAPKs, extracellular signal-regulated kinase (ERK) activity was elevated. However, these changes in ageing rats could be reversed to some extent by valsartan. In vitro experiments observed consistent results as in vivo study. Furthermore, ERK inhibitor could also acquire partial effects as valsartan without affecting AT1R expression. The results indicated that AT1R involved in the ageing-related degeneration of aorta and AT1R-mediated ERK activity was an important mechanism underlying the process.
Assuntos
Envelhecimento , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Aorta/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Tetrazóis/farmacologia , Valina/análogos & derivados , Angiotensina II/metabolismo , Animais , Aorta/lesões , Aorta/patologia , Western Blotting , Células Cultivadas , Endotélio Vascular/patologia , MAP Quinases Reguladas por Sinal Extracelular/genética , Técnicas Imunoenzimáticas , Masculino , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Receptor Tipo 1 de Angiotensina/química , Receptor Tipo 1 de Angiotensina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Valina/farmacologia , ValsartanaRESUMO
Background: Single nucleotide polymorphisms (SNPs) in DNA repair genes can impair protein function and hinder DNA repair, leading to genetic instability and increased cancer risk. The Excision Repair Cross-Complementation (ERCC) family plays a crucial role in nucleotide excision repair, yet their comprehensive multi-omics characterization and roles in tumor prognosis and immune microenvironment remain unexplored. Methods and materials: We performed bioinformatics analysis using publicly available data from 33 cancer types to investigate associations between ERCC gene expression, patient prognosis, and clinical features. We also validated the role of ERCC2 in bladder cancer through in vitro assays, including CCK-8, colony formation, wound healing, and Transwell assays. Results: By utilizing the most recent database, we have conducted an analysis that reveals associations between variations in ERCC expression across multiple cancer types and both patient prognosis and the tumor microenvironment. To ensure the reliability of our findings, we applied the Benjamini-Hochberg procedure to adjust for multiple testing. After correction, we identified that ERCC expression levels remained significantly correlated with patient prognosis in various cancer types (p < 0.05). In addition, according to the results of drug sensitivity studies of anticancer drugs, there is a large correlation between ERCC expression and the sensitivity of different anticancer drugs. Finally, in vitro cell behavioral assays determined that knockdown of ERCC2 gene expression significantly inhibited the proliferation, migration and invasion of bladder cancer cells. Conclusion: Through in-depth exploration of ERCC differential expression and its correlation with immune-related indicators, the unique microenvironment of tumors, and patient prognosis, we verified the potential role of ERCC2 in the process of bladder cancer genesis and progression. Therefore, we believe that the ERCC family of genes is expected to be a new option for cancer treatment and deserves to be further explored in the future.
Assuntos
Biologia Computacional , Microambiente Tumoral , Neoplasias da Bexiga Urinária , Proteína Grupo D do Xeroderma Pigmentoso , Humanos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologia , Proteína Grupo D do Xeroderma Pigmentoso/genética , Biologia Computacional/métodos , Prognóstico , Linhagem Celular Tumoral , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Regulação Neoplásica da Expressão Gênica , Proteínas de Ligação a DNA/genética , Biomarcadores Tumorais/genética , Polimorfismo de Nucleotídeo Único , Proliferação de Células/genética , Reparo do DNARESUMO
Background: In recent years, despite several surgical techniques having been applied, the early incontinence rate after radical prostatectomy (RP) remains high. In this study, we reconstructed an internal urethral sphincter (IUS) with anterior bladder neck tube (ABNT) to improve early return of continence and find a more effective technique for early urinary incontinence after RP. Methods: In this study, 96 previous patients who did not receive an ABNT between October 2018 and May 2020 were compared as historical controls (the control group). A total of 210 consecutive patients underwent robotic or laparoscopic RP with ABNT between May 2020 and February 2023 (the ABNT group). The inclusion criteria included Eastern Cooperative Oncology Group (ECOG) score 0-1 and localized prostate cancer (clinical stages cT1-3, cN0, cM0). The exclusion criteria included patients with diabetes, neurologic diseases, previous pelvic operations, symptoms of urinary incontinence, prior radiation, focal therapy, or androgen deprivation therapy for prostate cancer. ABNT was reconducted with a U-shaped flap from the anterior wall of the bladder neck, and was then anastomosed with the urethra. In the control group, the bladder outlet was directly anastomosed with the urethra. Continence, as defined if 0 pads were used per day and International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) score ≤6, was assessed at 1, 4, 8, 12, and 24 weeks after catheter removal. At 2 weeks after catheter removal, urethral pressure profilometry (UPP) and upright urethrography were performed to evaluate the function of ABNT in the ABNT group. Results: More patients in the ABNT group were continent than those in the control group at 1 week (85.2% vs. 22.9%, P<0.001), 4 weeks (91.4% vs. 27.1%, P<0.001), 8 weeks (95.2% vs. 40.6%, P<0.001), 12 weeks (100% vs. 71.9%, P<0.001), and at 24 weeks (100% vs. 87.5%, P<0.001) after catheter removal. Stricture was presented in 5.2% and 2.1% (P=0.34) in the ABNT group and control group, respectively. UPP showed that a functional IUS was reconstructed with ABNT. Upright urethrography showed that the ABNT was filled with contrast medium in the urination period and with no contrast medium during the storage period and interruption of urination. Conclusions: The ABNT technique significantly improved early return of continence in comparison with the no ABNT technique, especially the immediate continence. The ABNT technique reconstructed the functional IUS with acceptable urethral stricture. The limitations of the present study include that the comparison was conducted retrospectively with a historical cohort and lack of randomization, and the single center setting. A prospective, randomized, and multicenter evaluation is expected.