RESUMO
Ferroptosis is a new programmed cell death characterized by iron-dependent lipid peroxidation. Targeting ferroptosis is considered a promising strategy for anti-cancer therapy. Recently, natural compound has gained increased attention for their advantage in cancer treatment, and the exploration of natural compounds as ferroptosis inducers offers a hopeful avenue for advancing cancer treatment modalities. Emodin is a natural anthraquinone derivative in many widely used Chinese medicinal herbs. In our previous study, we predicted that the anti-cancer effect of Emodin might related to ferroptosis by using RNA-seq in colorectal cancer (CRC). Thus, in this study, we aim to investigate the molecular mechanism underlying Emodin-mediated ferroptosis in CRC. Cell-based assays including CCK-8, colony formation, EdU, and Annexin V/PI staining were employed to assess Emodin's impact on cell proliferation and apoptosis. Furthermore, various techniques such as FerroOrange staining, C11-BODIPY 581/591 staining, iron, MDA, GSH detection assay and transmission electron microscopy were performed to examine the role of Emodin in ferroptosis. Additionally, specific NCOA4 knockdown cell lines were generated to elucidate the involvement of NCOA4 in Emodin-induced ferroptosis. Moreover, the effects of Emodin on ferroptosis were further confirmed through the application of inhibitors, including Ferrostatin-1, 3-MA, DFO, and PMA. As a results, Emodin inhibited proliferation and induced apoptosis in CRC cells. Emodin could decrease GSH content, xCT and GPX4 expression, meanwhile increasing ROS generation, MDA, and lipid peroxidation, and these effects could reverse by ferroptosis inhibitor, Ferostatin-1, iron chelator DFO, autophagy inhibitor 3-MA and NCOA4 silencing. Moreover, Emodin could inactivate NF-κb pathway, and PMA, an activator of NF-κb pathway could alleviate Emodin-induced ferroptosis in CRC cells. Xenograft mouse model also showed that Emodin suppressed tumor growth and induced ferroptosis in vivo. In conclusion, these results suggested that Emodin induced ferroptosis through NCOA4-mediated ferritinophagy by inactivating NF-κb pathway in CRC cells. These findings not only identified a novel role for Emodin in ferroptosis but also indicated that Emodin may be a valuable candidate for the development of an anti-cancer agent.
RESUMO
Iron metabolism plays an important role in maintaining cellular multiple biological functions. Dysfunction of iron homeostasis-maintaining systems was observed in many diseases, including cancer. Ribosomal L1 domain-containing 1 (RSL1D1) is an RNA-binding protein involved in multiple cellular processes, including cellular senescence, proliferation and apoptosis. However, the regulatory mechanism of RSL1D1 underlying cellular senescence and its biological process in colorectal cancer (CRC) is not clearly understood. Here, we report that RSL1D1 expression is downregulated by ubiquitin-mediated proteolysis in senescence-like CRC cells. RSL1D1, as an anti-senescence factor, is frequently upregulated in CRC, and elevated RSL1D1 prevents CRC cells from senescence-like phenotype, and correlated with poor prognosis of CRC patients. Knockdown of RSL1D1 inhibited cell proliferation, and induced cell cycle arrest and apoptosis. Notably, RSL1D1 plays important roles in regulating iron metabolism of cancer cells. In RSL1D1-knockdown cells, FTH1 expression was significantly decreased, while transferrin receptor 1 expression was increased, leading to intracellular ferrous iron accumulation, which subsequently promoted ferroptosis, indicated by the increased malondialdehyde and decreased GPX4 levels. Mechanically, RSL1D1 directly bounds with 3' untranslated region of FTH1 and subsequently promoted the mRNA stability. Moreover, RSL1D1-mediated downregulation of FTH1 was also observed in H2O2-induced senescence-like cancer cells. Taken together, these findings support RSL1D1 plays an important role in regulating intracellular iron homeostasis in CRC, and suggest that RSL1D1 could be a potential therapeutic target for cancer treatment.
Assuntos
Ferroptose , Células Cultivadas , Senescência Celular/genética , Ferroptose/genética , Peróxido de Hidrogênio , Ferro/metabolismo , HumanosRESUMO
BACKGROUND: The glucose-6-phosphatase catalytic subunit (G6PC) is a key enzyme that is involved in gluconeogenesis and glycogen decomposition during glycometabolism. Studies have shown that G6PC is abnormally expressed in various cancers and participates in the proliferation and metastasis of tumors. However, the role of G6PC in cervical cancer remains poorly established. METHODS: To analyze the expression of G6PC in cervical cancer tissues in patients by immunohistochemistry. Effects of G6PC deregulation on cervical cancer phenotype were determined using MTT, colony formation, transwell, and wound-healing assays. And constructed a nude mouse xenograft tumor model and CAM assay in vivo. The effect of G6PC on glycolysis in cervical cancer was also evaluated. Effect of G6PC on PI3K/AKT/mTOR pathway was detected by Western blot assay. RESULTS: In this study, G6PC expression was found to be upregulated in cervical cancer tissues, and this upregulated expression was associated with LN metastasis, clinical stage, recurrence, and disease-free survival and overall survival rates, indicating that G6PC could serve as a novel marker of early diagnosis in cervical cancer. G6PC promoted proliferation, invasion, epithelial mesenchymal transition (EMT) progression, and angiogenesis of cervical cancer cells. Mechanistically, G6PC activated PI3K/AKT/mTOR pathways. The PI3K/AKT pathway inhibitor, LY294002 could partially attenuate the effect. CONCLUSIONS: G6PC plays a key role in the progression of cervical cancer, and overexpressed G6PC is closely related to patient LN metastasis, clinical stage, recurrence and shortened survival. G6PC promoted cervical cancer proliferation, invasion, migration, EMT progression, and angiogenesis, partially through activating the PI3K/AKT pathway. G6PC, as a metabolic gene, not only plays a role in metabolism, but also participates in the development of cervical cancer. Its complex metabolic and non metabolic effects may be a potential therapeutic target and worthy of further study.
Assuntos
Carcinogênese/metabolismo , Glucose-6-Fosfatase/metabolismo , Neoplasias do Colo do Útero/metabolismo , Adulto , Idoso , Animais , Western Blotting , Carcinogênese/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Glucose-6-Fosfatase/genética , Células HeLa , Humanos , Imuno-Histoquímica , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Transplante Heterólogo , Regulação para Cima , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologiaRESUMO
BACKGROUND: This study analyzed regional corneal thickness remodeling, biomechanical properties, and visual outcomes after femtosecond laser-assisted in situ keratomileusis combined with intraoperative accelerated corneal collagen crosslinking (LASIK Xtra) for myopia. METHODS: This retrospective study analyzed 21 consecutive patients (18 women, three men; 42 eyes) who were treated with LASIK Xtra. All treatments were performed with ultraviolet-A (energy, 2.7 J/cm2; irradiance, 30 mW/cm2), using continuous (90 s) illumination. Postoperative values of corneal biometrics and visual outcomes were compared with preoperative values. Corneal thickness changes were evaluated using anterior segment optical coherence tomography. All patients were followed up for 12-month postoperatively. Preoperative and postoperative data were compared statistically using the paired t-test for normally distributed parameters and the Wilcoxon rank-sum test and Friedman analysis of variance with Bonferroni correction for non-normally distributed data. RESULTS: Uncorrected distance visual acuity (UDVA) significantly improved at 6-month after surgery (P < 0.001). The central and inner regional corneal epithelial thickness significantly increased after LASIK Xtra (P < 0.05 for all), while the peripheral corneal epithelial thickness remained stable at 12-month after surgery. There was also a statistically significant decreased in the stromal thickness at most locations (P < 0.05 for all), except in the outer superior and outer superior-temporal regions. CONCLUSIONS: LASIK Xtra provided improvement in UDVA, corneal curvature, and corneal biomechanical stability. Because the results of this retrospective study results depended on the cohort members' past information, it was inferred and confirmed that regular corneal thickness remodeling occurred after treatment.
Assuntos
Ceratomileuse Assistida por Excimer Laser In Situ , Miopia , Colágeno/uso terapêutico , Substância Própria/cirurgia , Feminino , Humanos , Ceratomileuse Assistida por Excimer Laser In Situ/métodos , Lasers de Excimer/uso terapêutico , Masculino , Miopia/cirurgia , Refração Ocular , Estudos RetrospectivosRESUMO
Intestinal Tuft cells sense luminal contents to influence the mucosal immune response against eukaryotic infection. Paneth cells secrete antimicrobial proteins as part of the mucosal protective barrier. Defects in Tuft and Paneth cells occur commonly in various gut mucosal disorders. MicroRNA-195 (miR-195) regulates the stability and translation of target mRNAs and is involved in many aspects of cell processes and pathologies. Here, we reported the posttranscriptional mechanisms by which miR-195 regulates Tuft and Paneth cell function in the small intestinal epithelium. Mucosal tissues from intestinal epithelial tissue-specific miR-195 transgenic (miR195-Tg) mice had reduced numbers of double cortin-like kinase 1 (DCLK1)-positive (Tuft) and lysozyme-positive (Paneth) cells, compared with tissues from control mice, but there were no effects on Goblet cells and enterocytes. Intestinal organoids expressing higher miR-195 levels from miR195-Tg mice also exhibited fewer Tuft and Paneth cells. Transgenic expression of miR-195 in mice failed to alter growth of the small intestinal mucosa but increased vulnerability of the gut barrier in response to lipopolysaccharide (LPS). Studies aimed at investigating the mechanism underlying regulation of Tuft cells revealed that miR-195 directly interacted with the Dclk1 mRNA via its 3'-untranslated region and inhibited DCLK1 translation. Interestingly, the RNA-binding protein HuR competed with miR-195 for binding Dclk1 mRNA and increased DCLK1 expression. These results indicate that miR-195 suppresses the function of Tuft and Paneth cells in the small intestinal epithelium and further demonstrate that increased miR-195 disrupts Tuft cell function by inhibiting DCLK1 translation via interaction with HuR.
Assuntos
Mucosa Intestinal/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , MicroRNAs/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Células CACO-2 , Linhagem Celular , Linhagem Celular Tumoral , Quinases Semelhantes a Duplacortina , Enterócitos/metabolismo , Feminino , Células Caliciformes/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Organoides/metabolismoRESUMO
BACKGROUND: This study clinically evaluated the visual outcomes after refractive surgery for myopia using femtosecond laser-assisted in situ keratomileusis (femto-LASIK) and flap-off epipolis LASIK (epi-LASIK). METHODS: In this retrospective case series study, 40 eyes of 27 patients were divided into two groups depending on the technique used for refractive surgery. Femto-LASIK and flap-off epi-LASIK flaps were created using femtosecond laser and Epi-K™ epikeratome, respectively. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity, manifest refraction, corneal asphericity, and corneal higher-order aberrations (HOAs) were assessed pre- and postoperatively. RESULTS: The improvement in logarithm of the minimum angle of resolution (logMAR) UDVA after refractive surgery was statistically significant for both groups (P < 0.001 for all groups); it was significant better in UDVA in femto-LASIK than flap-off epi-LASIK, 0.03 ± 0.06 logMAR (femto-LASIK) and 0.54 ± 0.31 logMAR (flap-off epi-LASIK), at 1 day postoperatively; 0.02 ± 0.05 logMAR (femto-LASIK) and 0.14 ± 0.13 logMAR (flap-off epi-LASIK), at 1 week postoperatively (P < 0.001 and P = 0.019). With regard to the corneal HOAs, the increment in spherical aberration (Z4,0) was greater in flap-off epi-LASIK than femto-LASIK: 0.626 ± 0.232 µm and 0.479 ± 0.139 µm in the front cornea; 0.556 ± 0.227 µm and 0.430 ± 0.137 µm in the total cornea (P = 0.016 and P = 0.017). However, the back corneal HOA changes did not have a significant effect on the total corneal HOA changes. CONCLUSION: Femto-LASIK yielded better early visual outcomes than did flap-off epi-LASIK, but there was no significant difference between the outcomes of the two procedures, 1 week postoperatively.
Assuntos
Ceratomileuse Assistida por Excimer Laser In Situ , Miopia , Humanos , Lasers de Excimer/uso terapêutico , Miopia/cirurgia , Refração Ocular , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: To evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) in patients with small hepatocellular carcinoma(sHCC) who were ineligible for surgery or ablation therapies. METHODS: From March 2011 to December 2012, 28 cases with sHCC which were ineligible or refused surgical resection, transplantation or local ablation were treated with CyberKnife SBRT. Median size of tumors was 2.1 cm (range:1.1-3.0 cm), a dose of 10-15Gy per faction was given over 3-6 consecutive days, resulting in a total dose of 35-60Gy. RESULTS: The median follow-up period was 36 months, with the response rate of complete response (CR) in 17 cases, partial response (PR) in 8 cases, stable disease (SD) in 2 cases and progressive disease (PD) in one case. Overall response rate was 89.28%. Overall survival rates in 1, 2 and 3 years were 92.86, 85.71 and 78.57%, respectively. Local control rates in 1, 2 and 3 years were 96.43, 92.86 and 89.28%, respectively. No grade ≥ 3 hepatic toxicity was observed. CONCLUSION: CyberKnife treatment was a safe and effective option for sHCC, which had shown good local control, high overall survival rates and low toxicity. CyberKnife SBRT could be served as an alternative treatment for patients with sHCC which is unsuitable for surgical treatment or local ablation.
Assuntos
Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/radioterapia , Radiocirurgia , Adulto , Idoso , Biomarcadores Tumorais , Carcinoma Hepatocelular/diagnóstico por imagem , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Radiocirurgia/métodos , Dosagem Radioterapêutica , Análise de Sobrevida , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Carga TumoralRESUMO
Emerging evidence has demonstrated that the high expression of HBXIP has been correlated with many cancers. With evaluation of the functional role of HBXIP in non-small-cell lung cancer, the primary aim of this study is to investigate the correlation between HBXIP expression and the prognosis of non-small-cell lung cancer patients. The protein levels of HBXIP were detected using western blotting in non-small-cell lung cancer cells. Cell proliferation and migration assays were measured to evaluate the function of HBXIP in non-small-cell lung cancer cells. A total of 120 non-small-cell lung cancer patients with strict follow-up and 60 adjacent non-tumor lung tissues were selected for immunohistochemical staining of the HBXIP protein. The localization of the HBXIP protein was detected in A549 non-small-cell lung cancer cells using immunofluorescence staining. The correlation between HBXIP expression and the clinicopathological features of non-small-cell lung cancer patients was analyzed by a chi-squared and Fisher's exact test. The overall survival rates of all of the non-small-cell lung cancer patients were calculated using the Kaplan-Meier method, and univariate and multivariate analyses were performed using the Cox proportional hazards regression model. In function, we showed that suppression of HBXIP decreased A549 cell proliferation and migration. HBXIP protein showed a mainly cytoplasmic staining pattern in non-small-cell lung cancer using immunohistochemical staining in paraffin-embedded non-small-cell lung cancer tissues and immunofluorescence staining in A549 cells. The HBXIP protein had strong positive staining in the non-small-cell lung cancer tissues, which was significantly higher than the percentage of adjacent non-tumor tissues. The overexpression of HBXIP was closely correlated with histological grade, clinical stage, lymph node metastasis, and lower overall survival rates of patients with non-small-cell lung cancer. Moreover, multivariate analysis suggested that HBXIP emerged as a significant independent prognostic factor along with clinical stage in patients with non-small-cell lung cancer. In conclusion, a high level of expression of HBXIP is associated with the progression of non-small-cell lung cancer and may be a useful biomarker for poor prognostic evaluation and a potential molecular therapy target for patients with non-small-cell lung cancer.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Proliferação de Células/genética , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Adulto , Idoso , Biomarcadores Tumorais/biossíntese , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular/genética , Progressão da Doença , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Mortalin is a member of the heat shock protein 70 family, which is involved in multiple cellular processes and may play key roles in promoting carcinogenesis. This study attempted to identify the clinical consequences of Mortalin overexpression and its roles in the prognostic evaluation of non-small cell lung cancer. A total of 120 non-small cell lung cancer samples paired with the adjacent non-tumor tissue samples and 10 normal lung tissues were selected for immunohistochemical staining for Mortalin. The localization of Mortalin was detected in A549 non-small cell lung cancer cells using immunofluorescence staining. The correlations between Mortalin overexpression and the clinical features of non-small cell lung cancers were evaluated using the chi-square test. The survival analysis was calculated via the Kaplan-Meier method and the Cox proportional hazard models. Our studies suggested that Mortalin exhibited a primarily cytoplasmic staining pattern in the non-small cell lung cancers. The rate of strongly positive Mortalin expression was higher in the non-small cell lung cancer samples than in the adjacent non-tumor samples or in normal lung tissues. Mortalin overexpression was significantly correlated with high histological grades, advanced stages, lymph node metastases, and lower disease-free survival and overall survival rates of the patients with non-small cell lung cancer. The survival analysis demonstrated that Mortalin overexpression was a significant independent prognostic factor in non-small cell lung cancer, especially for patients with early stage of non-small cell lung cancer. In conclusion, Mortalin is up-regulated in non-small cell lung cancer, and it may be a potential biomarker of prognostic evaluation and a molecular therapeutic target for patients with early stage of non-small cell lung cancer.
Assuntos
Biomarcadores Tumorais/biossíntese , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas de Choque Térmico HSP70/biossíntese , Prognóstico , Células A549 , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas de Choque Térmico HSP70/genética , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Emerging evidence demonstrated that hepatitis B virus X-interacting protein (HBXIP) has broad roles in cancers. However, high-level expression of HBXIP has been correlated with human malignancies, suggesting roles in carcinogenesis and tumor progression. The aim of the study is to investigate the role and mechanism of HBXIP oncogene and the correlation to the clinicopathological status in cervical cancers. METHODS: A total of 107 cervical cancer patients with strict follow-up, 105 cervical intraepithelial neoplasia (CIN) and 31 normal cervical epithelia samples were selected for immunohistochemical (IHC) staining of HBXIP protein. Additionally, the cervical cancer cell line of SiHa was included in this study. The relationship between HBXIP expression and clinicopathological characteristics were analyzed to verify the clinical value of HBXIP protein expression in patient prognosis, and survival rates were calculated using the Kaplan-Meier method. RESULTS: HBXIP protein showed a mainly cytoplasmic staining pattern in cervical cancers by using IHC staining in paraffin embedded cervical cancer tissues and IF staining in SiHa cervical cancer cells. The strongly positive rate of HBXIP protein expression was significantly higher in cervical SCCs and CINs than in normal cervical epithelia. HBXIP protein over-expression was significantly correlated with the clinical stage, differentiation, lymph node metastasis, HPV infection, the over-expression of P63 and overall survival rates in cervical cancer. All of these data defined that HBXIP was involved in the progression of the cervical cancer. However, the detailed mechanism need to the further study. CONCLUSIONS: HBXIP over-expression appears to associate with cervical cancer progression, and may potentially be used as a cervical cancer biomarker for the early diagnosis, prognostic evaluation and therapeutic target for cervical cancer.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Biomarcadores Tumorais/biossíntese , Carcinoma de Células Escamosas/metabolismo , Displasia do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/metabolismo , Adulto , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Microscopia Confocal , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Displasia do Colo do Útero/patologia , Displasia do Colo do Útero/virologiaRESUMO
BACKGROUND: T-lymphoma invasion and metastasis-inducing protein 1 (Tiam1) has been implicated in tumor occurrence and progression. Recent studies have shown that high expression levels of Tiam1 protein appear to be associated with the progression of numerous human tumors. This study attempted to explore the role of Tiam1 protein in tumor progression and the prognostic evaluation of breast cancer. METHODS: The localization of the Tiam1 protein was determined in the MDA-MB-231 breast cancer cell line using immunofluorescence (IF) staining. In addition, a total of 283 breast tissue samples, including 153 breast cancer tissues, 67 ductal carcinoma in situ (DCIS) and 63 adjacent non-tumor breast tissues, were analyzed by immunohistochemical (IHC) staining of the Tiam1 protein. The correlation between Tiam1 expression and clinicopathological characteristics was evaluated by Chi-square test and Fisher's exact tests. Disease-free survival (DFS) and 10-year overall survival (OS) rates were calculated by the Kaplan-Meier method. Additionally, univariate and multivariate analyses were performed by the Cox proportional hazards regression models. RESULTS: Tiam1 protein showed a mainly cytoplasmic staining pattern in breast cancer cells; however, nuclear staining was also observed. Tiam1 protein expression was significantly higher in breast cancers (42.5 %, 65/153) and DCIS (40.3 %, 27/67) than in adjacent non-tumor tissues (12.7 %, 8/63). In addition, Tiam1 associated with tumor stage and Ki-67 expression, but negatively correlated with receptor tyrosine-protein kinase erbB-2 (Her2) expression. Moreover, survival analyses showed that DFS and 10-year OS rates were significantly lower in breast cancer patients with high Tiam1 expression than those with low Tiam1 expression. Univariate analysis suggested that molecular types, clinical stage, Her2 expression levels and Tiam1 expression levels were also significantly associated with DFS and 10-year OS rates of breast cancer patients. Furthermore, multivariate analysis suggested that Tiam1 expression is a significant independent prognostic factor along with tumor stage in patients with breast cancer. CONCLUSIONS: Tiam1 expression is frequently up-regulated in breast cancer. Tiam1 expression correlated with clinicopathological parameters, suggesting that it may be a useful prognostic biomarker and potential therapeutic target for patients with breast cancer.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/genética , Adulto , Idoso , Biomarcadores Tumorais , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/mortalidade , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células TRESUMO
Ezrin, a member of the ezrin/radixin/moesin (ERM) protein family, plays an important role in tumor metastasis. Accumulating studies demonstrated that a high expression level of human ezrin has been correlated with numerous human malignancies. This study was aimed to explore the clinicopathological significance of ezrin protein expression in pancreatic ductal adenocarcinomas (PDAC), and to further identify its role as a potential biomarker and therapeutic target of PDAC. Immunohistochemical (IHC) staining of ezrin protein was performed on 106 PDAC tissue samples and 37 adjacent and 21 normal pancreatic tissue samples. Additionally, localization of ezrin protein in Panc-1 PDAC cell line was observed using immunofluorescence (IF) staining. The correlation between ezrin overexpression and the clinicopathological features of PDAC was evaluated using Chi-square test, and differences in survival curves were analyzed using log-rank tests. In results, ezrin protein is widely distributed in the cytoplasm and membrane of PDAC cells by IHC and IF staining, but some cases showed a cell membrane staining pattern. The positive rate of ezrin protein expression was 82.1% (87/106) in PDAC, which was significantly higher than it in either adjacent pancreatic tissues (37.8%, 14/37) or normal pancreatic tissues (19.0%, 4/21). Overexpression of ezrin was closely related with larger tumor size, positive lymph node metastasis and advanced clinical stage. However, it was not correlated with patient age, gender, differentiation, Ki-67 expression index, and pancreas calcification point. Survival analysis showed that patients with ezrin high expression level had significantly lower overall survival rate than that with ezrin low expression level. Importantly, further analysis using a Cox proportional hazard regression model revealed that high ezrin expression emerged as a significant independent hazard factor for overall survival rates of patients with PDAC along with lymph node metastasis and TNM stage. In conclusion, ezrin protein played an important role in the progression of PDAC, and the overexpression of ezrin protein might be a useful prognostic marker of PDAC.
Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Proteínas do Citoesqueleto/metabolismo , Pâncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/secundário , Progressão da Doença , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pâncreas/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Taxa de Sobrevida , Neoplasias PancreáticasRESUMO
ß-Lapachone is a natural product that can promote ROS generation and ultimately triggers tumor cells death by inducing DNA damage. Recent studies have indicated that the targeting of ferroptosis or iron metabolism is a feasible strategy for treating cancer. In this study, bulk RNA-seq analysis suggested that ß-Lapachone might induce ferroptosis in CRC cells. We further tested this hypothesis using a xenograft model of human colorectal cancer as an animal model and in SW620 and DLD-1 of CRC cell lines. Western blot was used to determine the key proteins of ferroptosis (SLC7A11, GPX4), autophagy (LC3B, P62, ATG7), ferritinophagy (NCOA4, FTH1, TFRC), and JNK pathway (p-JNK, JNK, p-c-Jun, c-Jun). The levels of MDA, GSH/GSSG, lipid ROS, and intracellular ferrous iron were determined after ß-Lapachone treatment, and inhibitors of various pathways, including NAC, Ferrostatin-1, DFO, 3-MA, and SP600125 were utilized to explore the molecular mechanism underlying ß-Lapachone-mediated ferroptosis. As the result, we identified that ß-Lapachone inhibited cell proliferation and induced apoptosis, autophagy, and ROS generation. In addition, ß-Lapachone induced ferroptosis as demonstrated by intra-cellular iron overload, increased levels of lipid ROS and MDA. Mechanistically, JNK signaling pathway was involved in ß-Lapachone-induced xCT/GPX4-mediated ferroptosis and NCOA4-mediated ferritinophagy in CRC cells. In vivo experiments in nude mice demonstrated that ß-Lapachone significantly inhibited CRC growth and induced ferroptosis and NCOA4-mediated ferritinophagy. These findings not only identify a novel role for ß-Lapachone in ferroptosis but also indicate that ß-Lapachone may be a valuable candidate for the research and development of anti-cancer therapeutic agents.
Assuntos
Neoplasias Colorretais , Ferroptose , Naftoquinonas , Animais , Camundongos , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos Nus , Espécies Reativas de Oxigênio , Autofagia , Fatores de Transcrição , Ferro , Neoplasias Colorretais/tratamento farmacológico , Lipídeos , Coativadores de Receptor NuclearRESUMO
PURPOSE: The purpose of this study was to evaluate the efficacy and safety of red ginseng oil (RXGIN) in men with lower urinary tract symptoms. MATERIALS AND METHODS: Men aged between 40 and 75 years with a total International Prostate Symptom Score (IPSS) of 8 to 19 points were recruited from April 2020 to December 2020. Subjects were randomly assigned to either the RXGIN group or the control group in a 1:1 ratio and received either RXGIN or placebo daily for 12 weeks. For the primary outcome, changes in IPSS scores at 6 and 12 weeks from baseline were analyzed. The secondary outcomes were changes in International Index of Erectile Function (IIEF), maximum urinary flow rate, and post-void residual volume at weeks 6 and 12 compared to baseline. Urine analysis and blood tests were additionally performed for safety assessment. RESULTS: A total of 88 subjects (RXGIN group, 46; control group, 42) completed the study. The total IPSS and IPSS subscores (residual urine sensation, frequency, intermittency, urgency, weak stream, straining, nocturia, and quality of life) were significantly improved in the RXGIN group compared to the control group at weeks 6 and 12. Total IIEF and sexual desire were significantly improved in the RXGIN group at week 6 and week 12, respectively, but there were no significant changes in the level of serum testosterone or dihydrotestosterone. The serum prostate-specific antigen showed significant decrease at weeks 12. No serious adverse events leading to discontinuation of the study drug were observed in the RXGIN group. CONCLUSIONS: Red ginseng oil (RXGIN) appears to be safe and effective in improving lower urinary tract symptoms in men and may also improve some aspects of sexual function.
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BACKGROUND: The DEK protein is related to chromatin reconstruction and gene transcription, and plays an important role in cell apoptosis. High expression levels of the human DEK gene have been correlated with numerous human malignancies. This study explores the roles of DEK in tumor progression and as a prognostic determinant of colorectal cancer. METHODS: Colorectal cancer specimens from 109 patients with strict follow-up, and colorectal adenomas from 52 patients were selected for analysis of DEK protein by immunohistochemistry. The correlations between DEK over expression and the clinicopathological features of colorectal cancers were evaluated by Chi-square test and Fisher's exact tests. The survival rates were calculated by the Kaplan-Meier method, and the relationship between prognostic factors and patient survival was also analyzed by the Cox proportional hazard models. RESULTS: DEK protein showed a nuclear immunohistochemical staining pattern in colorectal cancers. The strongly positive rate of DEK protein was 48.62% (53/109) in colorectal cancers, which was significantly higher than that in either adjacent normal colon mucosa (9.17%, 10/109) or colorectal adenomas (13.46%, 7/52). DEK over expression in colorectal cancers was positively correlated with tumor size, grade, lymph node metastasis, serosal invasion, late stage, and disease-free survival- and 5-year survival rates. Further analysis showed that patients with late stage colorectal cancer and high DEK expression had worse survival rates than those with low DEK expression. Moreover, multivariate analysis showed high DEK expression, serosal invasion, and late stage are significant independent risk factors for mortality in colorectal cancer. CONCLUSIONS: DEK plays an important role in the progression of colorectal cancers and it is an independent poor prognostic factor of colorectal cancers.
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Biomarcadores Tumorais/análise , Proteínas Cromossômicas não Histona/biossíntese , Neoplasias Colorretais/metabolismo , Proteínas Oncogênicas/biossíntese , Adulto , Idoso , Proteínas Cromossômicas não Histona/análise , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteínas Oncogênicas/análise , Proteínas de Ligação a Poli-ADP-Ribose , Prognóstico , Modelos de Riscos Proporcionais , Regulação para CimaRESUMO
A novel urolithiasis treatment in which a chelating solution encapsulated in poly(lactic-co-glycolic acid); PLGA-based microcapsules was delivered magnetically to specific urolithiasis sites and then subjected to ultrasound (US) to release the chelating solution and dissolve the stones. Using a double-droplet microfluidics method, a hexametaphosphate (HMP) chelating solution was encapsulated in an Fe3O4 nanoparticle (Fe3O4 NP)-loaded PLGA polymer shell with a thickness of <15 µm, forming homogenous microcapsules of 319 ± 14 µm in size. The obtained microcapsules (HMP/Fe3O4@PLGA) exhibited efficient magnetic mobility and US-responsive solution release. Moreover, in a Ψ-shaped flow chip, selective delivery of HMP from the microcapsules was achieved with high magnetic delivery efficiency (>90%), and an effective removal efficacy (>95%, 7 repeat cycles) of artificial calcium oxalate (5 mm in size) via a chelating effect. Eventually, the potential removal of urolithiasis in the body was verified using a PDMS-based kidney urinary flow-imitating chip with a human kidney stone (CaOx 100%, 5-7 mm in size) located in the minor calyx under an artificial urine counter flow (0.5 mL min-1). In the end, more than 50% of the stone, even in surgically tricky regions, was removed by 10 repeated treatments. Therefore, the selective approach of stone-dissolution capsules will help to develop alternative urolithiasis treatments to conventional surgical and systemic dissolution approaches.
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Polímeros , Urolitíase , Humanos , Cápsulas , Rim , Fenômenos MagnéticosRESUMO
Background: To evaluate the efficacy and safety of Cervi Parvum Cornu, Angelicae Gigantis Radix and Glycyrrhizae Radix complex (CAG) in men with moderate lower urinary tract symptoms (LUTS). Materials and methods: From November 2020 to January 2022, participants with International Prostate Symptom Score (IPSS) of 12-19 in two centers were recruited and randomize into three groups: a CAG 500 mg/day group (CAG 500), a CAG 1000 mg/day group (CAG 1000), and a placebo group (PG). They were treated for 12 weeks. The primary endpoint was change of IPSS at the end of study from baseline. Secondary end points included change of prostate specific antigen (PSA), testosterone, dihydrotestosterone (DHT), maximum urinary flow rate (Q max), post-void residual volume (PVR), International Index of Erectile Function (IIEF), and drug safety. Results: A total of 103 patients were able to finish the study according to the study protocol. Total IPSS and sub-scores (residual urine sensation, frequency, weak stream, hesistancy, nocturia, and quality of life) in CAG 500 and CAG 1000 were significantly improved at the 12th week compared to those of the PG. Changes of serum PSA, DHT, and testosterone levels at the 12th week from baseline did not show significant differences among the three groups. Q max and PVR changes did not show significant differences among the three groups either. Total IIEF and sub-scores (erectile function, orgasmic function, sexual desire, intercourse satisfaction) in CAG 1000 were significantly improved at 12th week compared to those in PG. No significant adverse events were found. Conclusions: CAG is well tolerated in patients with moderate LUTS. Treatment with CAG for 12 weeks has a therapeutic effect on moderate LUTS.
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PURPOSE: To evaluated the efficacy and safety of gelatinized Maca (Lepidium meyenii) for eugonadal patients with late onset hypogonadism symptoms (LOH). MATERIALS AND METHODS: Participants were instructed to receive 1,000 mg of Maca or placebo, two pills at a time, three times per day for 12 weeks before food intake. To evaluate the efficacy of the drug, Aging Males' Symptoms scale (AMS), Androgen Deficiency in the Aging Males (ADAM), International Prostate Symptom Score (IPSS), and International Index of Erectile Function (IIEF) questionnaires, serologic tests (total testosterone and free testosterone, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglyceride), body weight, and waist circumference were assessed at 4 and 12 weeks after treatment. RESULTS: A total of 80 participants were enrolled and randomly assigned to Maca treated group (n=41) or the placebo group (n=39). AMS, IIEF, and IPSS were significantly (p<0.05) improved in Maca treated group than in the placebo group. ADAM positive rate was also significantly (p<0.0001) decreased in Maca treated group. CONCLUSIONS: Maca may be considered an effective and safe treatment for eugonadal patients with late onset hypogonadism symptoms.
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BACKGROUND: Sparc/osteonectin, cwcv and kazal-like domain proteoglycan 1 (SPOCK1) has been reported to function as an oncogene in a variety of cancer types. Increasing evidence suggests that SPOCK1 contributes to the metastatic cascade, including invasion, epithelial-mesenchymal transition (EMT) and micro-metastasis formation. As yet, however, the underlying mechanism is not clearly understood. Here, we evaluated the expression and clinicopathological significance of SPOCK1 in primary pancreatic cancer (PC) specimens and explored the mechanisms underlying SPOCK1-mediated PC cell growth and metastasis. METHODS: The clinical relevance of SPOCK1 was evaluated in 81 patients with PC. The effect of SPOCK1 on proliferation, cell cycle progression, EMT and metastasis was examined in vitro and in vivo. The molecular mechanisms involved in SPOCK1-mediated regulation of NF-κB-dependent EMT were assessed in PC cell lines. RESULTS: We found that SPOCK1 expression was increased in PC tissues and was associated with lymph node metastasis. Silencing or exogenous overexpression of SPOCK1 markedly altered the proliferation of PC cells through cell cycle transition. Overexpression of SPOCK1 promoted PC cell migration and invasion by regulating EMT progression. Moreover, we found that SPOCK1 contributes to EMT and metastasis by activating the NF-κB signalling pathway via direct interaction with IκBα. After NF-κB pathway inhibition by BAY11-7082, we found that PC cell motility and EMT induced by SPOCK1 were reversed. CONCLUSION: From our data we conclude that SPOCK1 promotes PC metastasis via NF-κB-dependent EMT by interacting with IκBα. This newly identified mechanism may provide novel clues for the (targeted) treatment of PC patients.
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Transição Epitelial-Mesenquimal , Inibidor de NF-kappaB alfa , Neoplasias Pancreáticas , Proteoglicanas , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Metástase Neoplásica , Osteonectina/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteoglicanas/genética , Proteoglicanas/metabolismoRESUMO
OBJECTIVE: To investigate the effectiveness of lateral condyle sliding osteotomy (LCSO) in total knee arthroplasty (TKA) for the treatment of lateral femoral bowing deformity. METHODS: The clinical data of 17 patients with lateral femoral bowing deformity treated by LCSO during TKA between July 2018 and July 2020 was retrospectively analysed. There were 3 males and 14 females, with an average of 63.2 years (range, 58-68 years). The etiology of lateral femoral bowing deformity included 12 cases of femoral developmental deformity and 5 cases of femoral fracture malunion. Kellgren-Lawrence classification of knee osteoarthritis was 4 cases of grade â ¢ and 13 cases of grade â £. The preoperative hip-knee shaft was 9.5°-12.5° (mean, 10.94°). The disease duration was 3-25 years (mean, 15.1 years). The mechanical lateral distal femur angle (mLDFA), hip-knee-ankle angle (HKA), and mechanical axis deviation (MAD) of the distal femur were measured before operation and at last follow-up to evaluate the correction of extra-articular deformities in the joints and the recovery of mechanical force lines of the lower extremities. The knee society score (KSS) knee score and function score, visual analogue scale (VAS) score, knee joint range of motion (ROM) were used to evaluate effectiveness. The knee varus/valgus stress test and osteotomy healing by X-ray films were performed to evaluate the joint stability and the safety of LCSO. RESULTS: All incisions of the patients healed by first intention after operation, and there was no early postoperative complication such as infection of the incision and deep vein thrombosis of the lower extremities. All 17 patients were followed up 12-36 months, with an average of 23.9 months. The osteotomy slices all achieved bony healing, and the healing time was 2-5 months, with an average of 3.1 months. After operation, the knee varus/valgus stress tests were negative, and there was no relaxation and rupture of the lateral collateral ligament, instability of the knee joint, loosening, revision and infection of the prosthesis occurred. At last follow-up, mLDFA, HKA, MAD, knee ROM, VAS score, KSS knee score and function score significantly improved when compared with preoperative ones ( P<0.05). CONCLUSION: LCSO is effective and safe in TKA with lateral femoral bowing deformity. Extra-articular deformities are corrected intra-articularly. The mechanical force line and joint balance of the lower extremities can be restored simultaneously in an operation.