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Glioblastoma (GBM) is one of the most lethal types of human brain cancer and is characterized by rapid growth, an aggressive nature and a poor prognosis. GBM is highly heterogeneous, and often involves several genetic mutations and abnormalities. Genetic disorders or low expression of phosphatase and tensin homolog (PTEN) are associated with GBM occurrence, progression and poor prognosis of patients with GBM. However, effective delivery of PTEN for expression in GBM cells within the brain remains challenging. The aim of the present study was to develop a therapeutic strategy to restore PTEN expression in GBM cells by utilizing a recombinant Newcastle disease virus (rNDV) vector expressing the human PTEN gene (rNDV-PTEN). Methods included infection of U87-MG cells with rNDV-PTEN, followed by assessments of PTEN expression, and cell proliferation, migration and apoptosis. Additionally, an orthotopic GBM mouse model was used to evaluate the in vivo efficacy of rNDV-PTEN. Infection with recombinant rNDV-PTEN treatment increased PTEN protein expression in the cytoplasm of the U87-MG cells, reduced cell proliferation and migration, and induced apoptosis by inhibiting the AKT/mTOR signaling pathway. In the orthotopic GBM mouse model, rNDV-PTEN significantly reduced tumor size and improved survival rates. Magnetic resonance imaging and in vivo imaging analyses confirmed the targeted delivery and efficacy of rNDV-PTEN. These findings highlight the usefulness of rNDV-PTEN as a promising therapeutic agent for GBM, representing a potential advancement in treatment, especially for patients with PTEN deficiency.
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OBJECTIVES: This study aimed to investigate the potential for using the phosphatase and tensin homolog (PTEN) gene as a prognostic marker in post-prostatectomy patients with castration-sensitive prostate cancer (PCa). METHODS: A total of 180 patients with castration-sensitive PCa who underwent radical prostatectomy at our institution were included in this study. PTEN expression was evaluated using immunohistochemistry, and patients were classified into two groups based on the staining intensity: PTEN-Normal and PTEN-Loss. The association between PTEN expression and biochemical recurrence was analyzed using the Cox proportional hazards model. RESULTS: Patients in the PTEN-Loss group had a higher risk of biochemical recurrence (hazard ratio, 4.642; 95% confidence interval, 2.137-10.083; p < 0.001) and a lower recurrence-free rate compared to the PTEN-Normal group (35% vs. 75%). In addition to clinicopathological factors, such as the serum prostate-specific antigen level, Gleason score, and T stage, evaluation of PTEN expression improved the prediction of biochemical recurrence after prostatectomy (area under the curve, 0.577 vs. 0.688). CONCLUSIONS: Low PTEN expression is a significant predictor of biochemical recurrence in patients with castration-sensitive PCa who have already undergone prostatectomy.
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In this letter, we comment on a recent publication by Mei et al, in the World Journal of Hepatology, investigating the hepatoprotective effects of the modified Xiaoyao San (MXS) formula in a male rat model of non-alcoholic steatohepatitis (NASH). The authors found that MXS treatment mitigated hepatic steatosis and inflammation in the NASH model, as evidenced by the reduction in lipid droplets (LDs), fibrosis markers and lipogenic factors. Interestingly, these hepatoprotective effects were associated with androgen upregulation (based on metabolomics analysis of male steroid hormone metabolites), adenosine 5'-monophosphate-activated protein kinase (AMPK) activation, and restoration of phosphatase and tensin homolog (PTEN) expression. However, the authors did not clearly discuss the relationships between MXS-induced hepatic steatosis reduction in the NASH model, and androgen upregulation, AMPK activation, and restoration of PTEN expression. This editorial emphasizes the reported mechanisms and explains how they act or interact with each other to reduce hepatic steatosis and inflammation in the NASH model. As a perspective, we propose additional mechanisms (such as autophagy/lipophagy activation in hepatocytes) for the clearance of LDs and suppression of hepatic steatosis by MXS in the NASH model. A proper understanding of the mechanisms of MXS-induced reduction of hepatic steatosis might help in the treatment of NASH and related diseases.
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Cowden syndrome (CS) is an autosomal dominant genetic disorder characterized by multiple hamartomas across various tissues and an elevated risk of several types of cancer, including breast, thyroid, and endometrial cancers. Skin findings can precede more serious malignancies, making early detection and diagnosis crucial. In this report, we detail four individual patient histories, including their initial dermatological symptoms or concerns. Due to the wide variety of their clinical presentations, this report highlights the variable level of symptom severity in the presentation of CS and how this may lead to a challenging diagnosis.
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BACKGROUND: The modified Xiaoyao San (MXS) formula is an adjuvant drug recommended by the National Health Commission of China for the treatment of liver cancer, which has the effect of preventing postoperative recurrence and metastasis of hepatocellular carcinoma and prolonging patient survival. However, the molecular mechanisms underlying that remain unclear. AIM: To investigate the role and mechanisms of MXS in ameliorating hepatic injury, steatosis and inflammation. METHODS: A choline-deficient/high-fat diet-induced rat nonalcoholic steatohepatitis (NASH) model was used to examine the effects of MXS on lipid accumulation in primary hepatocytes. Liver tissues were collected for western blotting and immunohistochemistry (IHC) assays. Lipid accumulation and hepatic fibrosis were detected using oil red staining and Sirius red staining. The serum samples were collected for biochemical assays and NMR-based metabonomics analysis. The inflammation/lipid metabolism-related signaling and regulators in liver tissues were also detected to reveal the molecular mechanisms of MXS against NASH. RESULTS: MXS showed a significant decrease in lipid accumulation and inflammatory response in hepatocytes under metabolic stress. The western blotting and IHC results indicated that MXS activated AMPK pathway but inhibited the expression of key regulators related to lipid accumulation, inflammation and hepatic fibrosis in the pathogenesis of NASH. The metabonomics analysis systemically indicated that the arachidonic acid metabolism and steroid hormone synthesis are the two main target metabolic pathways for MXS to ameliorate liver inflammation and hepatic steatosis. Mechanistically, we found that MXS protected against NASH by attenuating the sex hormone-related metabolism, especially the metabolism of male hormones. CONCLUSION: MXS ameliorates inflammation and hepatic steatosis of NASH by inhibiting the metabolism of male hormones. Targeting male hormone related metabolic pathways may be the potential therapeutic approach for NASH.
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The aberrant expression of SET8, a histone methyltransferase that mediates H4 lysine 20 mono-methylation (H4K20me1), is implicated in the pathogenesis of various tumors, however, its role in acute kidney injury (AKI) is unknown. Here we showed that SET8 and H4K20me1 were upregulated in the murine kidney with AKI induced by cisplatin, along with increased renal tubular cell injury and apoptosis and decreased expression of E-cadherin and Phosphatase and Tensin Homolog (PTEN). Suppression of SET8 by UNC0379 improved renal function, attenuated tubule damage, and restored expression of PTEN, but not E-cadherin. UNC0379 was also effective in lessening cisplatin-induced DNA damage response (DDR) as indicated by reduced expression of γ-H2AX, p53, p21, and alleviating cisplatin-impaired autophagy as shown by retained expression of Atg5, Beclin-1, and CHMP2A and enhanced levels of LC3-II in the kidney. Consistently, inhibition of SET8 with either UNC0379 or siRNA mitigated apoptosis and DDR, and restored autophagy, along with PTEN preservation in cultured renal proximal tubular epithelial cell (TKPTs) exposed to cisplatin. Further studies showed that inhibition of PTEN with Bpv or siRNA potentiated cisplatin-induced apoptosis, DDR, and hindered autophagy, and conversely, alleviated by overexpression of PTEN in TKPTs. Finally, blocking PTEN largely abolished the inhibitory effect of UNC0379 on apoptosis. Taken together, these results suggest that SET8 inhibition protects against cisplatin-induced AKI and renal cell apoptosis through a mechanism associated with the preservation of PTEN, which in turn inhibits DDR and restores autophagy.
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Cowden syndrome (CS) is an autosomal dominant syndrome characterized by the development of hamartomas and an increased cancer risk. Most CS patients harbor mutations in the phosphatase and tensin homolog (PTEN) gene. We herein report a 70-year-old patient with CS who presented with lower extremity weakness caused by multiple thoracic dural arteriovenous fistulas. Genetic testing revealed a truncated PTEN mutation (c.485_487delACAinsCC and p.D162Afs*5). Vascular malformations are common in CS, particularly in the extremities. However, spinal dural arteriovenous fistulas (AVFs) are extremely rare. Furthermore, in our case, the number of AVFs increased, and both lower limbs became flaccid four months after embolization. Therefore, we suggest that physicians carefully observe the changes in symptoms for prolonged periods after embolization.
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Colorectal cancer (CRC) is one of the most common malignancies worldwide. In the clinical realm, platinum-based drugs hold an important role in the chemotherapy of CRC. Nonetheless, a multitude of patients, due to tumor protein 53 (TP53) gene mutations, experience the emergence of drug resistance. This phenomenon gravely impairs the effectiveness of therapy and long-term prognosis. Gallium, a metallic element akin to iron, has been reported that has the potential to be used to develop new metal anticancer drugs. In this study, we screened and established the gallium complex K6 as a potent antitumor agent in both in vitro and in vivo. K6 exhibited superior efficacy in impeding the growth, proliferation, and viability of CRC cells carrying TP53 mutations compared to oxaliplatin. Mechanistically, K6 escalated reactive oxygen species levels and led deoxyribonucleic acid (DNA) damage. Furthermore, K6 effectively suppressed the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB)/glycogen synthase kinase 3 beta (GSK3ß) pathway, leading to the degradation of its downstream effectors myelocytomatosis (c-Myc) and Krueppel-like factor 5 (KLF5). Conversely, K6 diminished the protein expression of WW domain-containing protein 1 (WWP1) while activating phosphatase and tensin homolog (PTEN) through c-Myc degradation. This dual action further demonstrated the potential of K6 as a promising therapeutic compound for TP53-mutated CRC.
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BACKGROUND: The pathogenesis of acute lung injury (ALI) involves a severe inflammatory response, leading to significant morbidity and mortality. N6-methylation of adenosine (m6A), an abundant mRNA nucleotide modification, plays a crucial role in regulating mRNA metabolism and function. However, the precise impact of m6A modifications on the progression of ALI remains elusive. METHODS: ALI models were induced by either intraperitoneal injection of lipopolysaccharide (LPS) into C57BL/6 mice or the LPS-treated alveolar type II epithelial cells (AECII) in vitro. The viability and proliferation of AECII were assessed using CCK-8 and EdU assays. The whole-body plethysmography was used to record the general respiratory functions. M6A RNA methylation level of AECII after LPS insults was detected, and then the "writer" of m6A modifications was screened. Afterwards, we successfully identified the targets that underwent m6A methylation mediated by METTL3, a methyltransferase-like enzyme. Last, we evaluated the regulatory role of METTL3-medited m6A methylation at phosphatase and tensin homolog (Pten) in ALI, by assessing the proliferation, viability and inflammation of AECII. RESULTS: LPS induced marked damages in respiratory functions and cellular injuries of AECII. The m6A modification level in mRNA and the expression of METTL3, an m6A methyltransferase, exhibited a notable rise in both lung tissues of ALI mice and cultured AECII cells subjected to LPS treatment. METTL3 knockdown or inhibition improved the viability and proliferation of LPS-treated AECII, and also reduced the m6A modification level. In addition, the stability and translation of Pten mRNA were enhanced by METTL3-mediated m6A modification, and over-expression of PTEN reversed the protective effect of METTL3 knockdown in the LPS-treated AECII. CONCLUSIONS: The progression of ALI can be attributed to the elevated levels of METTL3 in AECII, as it promotes the stability and translation of Pten mRNA through m6A modification. This suggests that targeting METTL3 could offer a novel approach for treating ALI.
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Lesão Pulmonar Aguda , Células Epiteliais Alveolares , Proliferação de Células , Metiltransferases , Camundongos Endogâmicos C57BL , PTEN Fosfo-Hidrolase , RNA Mensageiro , Animais , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/patologia , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/genética , Metiltransferases/metabolismo , Metiltransferases/genética , Camundongos , Proliferação de Células/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/patologia , Masculino , RNA Mensageiro/metabolismo , Sobrevivência Celular/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Metilação , Adenosina/análogos & derivados , Adenosina/metabolismo , Lipopolissacarídeos/toxicidade , Estabilidade de RNA , Células CultivadasRESUMO
Long non-coding RNAs (LncRNAs) play a substantial role in the process of cerebral ischemia-reperfusion injury (CIRI). The present work aimed to determine the probable mechanism by which LncRNA TUG1 exacerbates CIRI via the miR-340-5p/phosphatase and tensin homolog (PTEN) pathway. After developing a middle cerebral artery occlusion/reperfusion (MCAO/R) model, pcDNA-TUG1 together with miR-340-5p agomir were administrated in vivo. Furthermore, the neurologic defects in rats were assessed by a modified neurological severity score. Moreover, 2,3,5-Triphenyl-2 H-tetrazolium chloride stain-step was performed to determine the brain's infarct size. In addition, western blotting, immunohistochemistry, and qRT-PCR experiments were utilized for gauging the proteomic/genomic expression-profiles. Luciferase reporter assay validated correlations across TUG1, miR-340-5p, together with PTEN. The results indicated relatively reduced miR-340-5p levels in MCAO/R models, while upregulated TUG1 levels. The pcDNA-TUG1-treated rats indicated increasing neurological dysfunction, whereas the miR-340-5p agomir-treated rats showed improvement. Furthermore, miR-340-5p was determined to be the expected and confirmed TUG1 target. All things considered, the findings suggested that PTEN can serve as the target of miR-340-5p. In addition, TUG1 served as a miR-340-5p ceRNA, which promotes PTEN modulation. Furthermore, TUG1 overexpression decreased miR-340-5p's capacity to fend against CIRI. Conclusively, this work proved that in CIRI, targeting the TUG1/miR-340-5p/PTEN regulatory axis is a viable approach for the treatment of ischemic stroke.
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MicroRNAs , PTEN Fosfo-Hidrolase , RNA Longo não Codificante , Traumatismo por Reperfusão , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/genética , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Ratos , Masculino , Ratos Sprague-Dawley , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/patologia , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Regulação da Expressão GênicaRESUMO
BACKGROUND: Single nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes could alter miRNA expression levels or processing and, thus, may contribute to colorectal cancer (CRC) development. Therefore, this study aimed to examine whether the MIR181A1 genomic sequence possesses SNPs that can affect the expression of hsa-miR-181a-5p and, subsequently, impact its targets and associate with CRC risk. METHODS: The NCBI dbSNP database was searched for possible SNPs associated with MIR181A1. One SNP with a minor allele frequency > 5%, rs12039395 G > T was identified. In silico analyses determined the effect of the SNP on the secondary structure of the miRNA and predicted the hsa-miR-181a-5p target genes. The SNP was genotyped using allelic discrimination assay, the relative hsa-miR-181a-5p expression level was determined using quantitative real-time PCR, and immunohistochemical staining was used to detect target genes in 192 paraffin-embedded specimens collected from 160 CRC patients and 32 healthy subjects. RESULTS: The rs6505162 SNP conferred protection against CRC, and the G-allele presence provides may provide accessibility for the transcriptional machinery. Hsa-miR-181a-5p was significantly over-expressed in the CRC group compared to controls and in samples carrying the G-allele compared to those with T-allele. PTEN, identified as the only hsa-miR-181a-5p target implicated in CRC, was significantly diminished in the CRC group compared to controls and showed an inverse relationship with hsa-miR-181a-5p expression level as well as negatively associated with the G-allele presence in CRC. CONCLUSION: This study highlights that rs12039395 G > T may protect against CRC by influencing the expression of hsa-mir-181a-5p and its target gene, PTEN.
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Neoplasias Colorretais , Predisposição Genética para Doença , MicroRNAs , PTEN Fosfo-Hidrolase , Polimorfismo de Nucleotídeo Único , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Colorretais/genética , PTEN Fosfo-Hidrolase/genética , Feminino , Masculino , Pessoa de Meia-Idade , Estudos de Casos e Controles , Idoso , Regulação Neoplásica da Expressão GênicaRESUMO
The intracellular distribution of phosphatase and tensin homolog (PTEN) is closely related to directed cell migration. In single cells, PTEN accumulates at the rear of the cell before and during directed migration; however, the spatiotemporal distribution of PTEN in confluent cell monolayers, particularly before directed migration, remains unclear. In this study, we wounded a cell in confluent fetal rat skin keratinocytes (FRSKs) and examined the dynamics of PTEN in the cells adjacent to the wounded cell. In contrast to single-cell migration, we found that PTEN translocated to the nucleus before the beginning of directed migration. This nuclear translocation of PTEN did not occur in disconnected cells, and it was also suppressed by importin-ß inhibitor and actin inhibitor. When the nuclear localization of PTEN was inhibited by an importin-ß inhibitor, cell elongation in the direction of migration was also significantly inhibited. Our results indicate that PTEN translocation is induced by the disruption of cell-cell adhesion and requires the involvement of importin-ß and actin cytoskeleton signaling. In addition, phosphatidylinositol 3,4,5-triphosphate (PIP3) may regulate PTEN distribution through its localized accumulation at the cell edge. Our findings suggest that the translocation of PTEN is crucial for directed cell migration and for responding to mechanical environmental changes in confluent cell monolayers.
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The complement system is an evolutionarily conserved arm of innate immunity, which forms one of the first lines of host response to pathogens and assists in the clearance of debris. A deficiency in key activators/amplifiers of the cascade results in recurrent infection, whereas a deficiency in regulating the cascade predisposes to accelerated organ failure, as observed in colitis and transplant rejection. Given that there are over 60 proteins in this system, it has become an attractive target for immunotherapeutics, many of which are United States Food and Drug Administration-approved or in multiple phase 2/3 clinical trials. Moreover, there have been key advances in the last few years in the understanding of how the complement system operates locally in tissues, independent of its activities in circulation. In this review, we will put into perspective the abovementioned discoveries to optimally modulate the spatiotemporal nature of complement activation and regulation at mucosal surfaces.
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Ativação do Complemento , Proteínas do Sistema Complemento , Imunidade nas Mucosas , Humanos , Animais , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Imunomodulação , Imunidade InataRESUMO
BACKGROUND: This study was designed to investigate the mechanism by which miR-30a-5p mediates cardiomyocyte apoptosis after acute myocardial infarction (AMI) induced by hypoxia/reoxygenation (H/R). METHODS: Differentially expressed miRNAs were analyzed by RNA high-throughput sequencing in acute myocardial infarction (ST-elevation myocardial infarction) patients versus healthy individuals (controls). The H/R model was used to assess the regulatory mechanism of miRNAs in AMI. Lentivirus-associated vectors were used to overexpress or knock down miR-30a-5p in cellular models. The pathological mechanisms of miR-30a-5p regulating the development of acute myocardial infarction were serially explored by qPCR, bioinformatics, target gene prediction, dual luciferase, enzyme-linked immunosorbent assays (ELISAs) and Western blotting. RESULTS: The results showed that the expression of miR-30a-5p was significantly increased in AMI patients and H9C2 cells. Hypoxia decreased cardiomyocyte survival over time, and reoxygenation further reduced cell survival. Bax and Phosphatase and tensin homolog (PTEN)were suppressed, while Bcl-2 was upregulated. Additionally, miR-30a-5p specifically targeted the PTEN gene. According to the GO and KEGG analyses, miR-30a-5p may participate in apoptosis by interacting with PTEN. The miR-30a-5p mimic decreased the expression of apoptosis-related proteins and the levels of the proinflammatory markers IL-1ß, IL-6, and TNF-α by activating the PTEN/PI3K/Akt signaling pathway. Conversely, anti-miR-30a-5p treatment attenuated these effects. Additionally, silencing PTEN and anti-miR-30a-5p had opposite effects on H/R-induced cell apoptosis. CONCLUSIONS: miR-30a-5p plays a crucial role in cardiomyocyte apoptosis after hypoxia-induced acute myocardial infarction. Our findings provide translational evidence that miR-30a-5p is a novel potential therapeutic target for AMI.
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Apoptose , Hipóxia Celular , MicroRNAs , Miócitos Cardíacos , PTEN Fosfo-Hidrolase , Transdução de Sinais , Animais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Estudos de Casos e Controles , Linhagem Celular , Regulação da Expressão Gênica , MicroRNAs/genética , MicroRNAs/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/enzimologia , Miócitos Cardíacos/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/enzimologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/genéticaRESUMO
Exposure to glyphosate-based herbicides (GBH) and consumption of cafeteria (CAF) diet, which are widespread in Western society, seem to be associated with endometrial hyperplasia (EH). Here, we aimed to evaluate the effects of a subchronic low dose of GBH added to the CAF diet on the rat uterus. Female Wistar rats were fed from postnatal day (PND)21 until PND240 with chow (control) or CAF diet. Since PND140, rats also received GBH (2 mg of glyphosate/kg/day) or water through food, yielding four experimental groups: control, CAF, GBH, and CAF+GBH. On PND240, CAF and CAF+GBH animals showed an increased adiposity index. With respect to the control group, no changes in the serum levels of 17ß-estradiol and progesterone were found. However, progesterone levels were higher in the CAF+GBH group than in the CAF and GBH groups. In the uterus, both studied factors alone and in combination induced morphological and molecular changes associated with EH. Furthermore, the addition of GBH provoked an increased thickness of subepithelial stroma in rats fed with the CAF diet. As a consequence of GBH exposure, CAF+GBH rats exhibited an increased density of abnormal gland area, considered preneoplastic lesions, as well as a reduced PTEN and p27 expression, both tumor suppressor molecules that inhibit cell proliferation, with respect to control rats. These results indicate that the addition of GBH exacerbates the CAF effects on uterine lesions and that the PTEN/p27 signaling pathway seems to be involved. Further studies focusing on the interaction between unhealthy diets and environmental chemicals should be encouraged to better understand uterine pathologies.
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Glicina , Glifosato , Herbicidas , Ratos Wistar , Útero , Animais , Feminino , Útero/efeitos dos fármacos , Útero/patologia , Útero/metabolismo , Herbicidas/toxicidade , Glicina/análogos & derivados , Ratos , Hiperplasia Endometrial/induzido quimicamente , Hiperplasia Endometrial/patologia , Hiperplasia Endometrial/metabolismo , Progesterona/sangue , Dieta , Estradiol/sangue , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/genéticaRESUMO
PURPOSE: Vitexin can cooperate with hyperbaric oxygen to sensitize the radiotherapy of glioma by inhibiting the hypoxia-inducible factor (HIF)-1α. However, whether vitexin has a direct radiosensitization and how it affects the HIF-1α expression remain unclear. This study investigated these issues. METHODS: The SU3 cells-inoculated nude mice were divided into control, radiation, and vitexinâ¯+ radiation groups. The vitexinâ¯+ radiation-treated mice were intraperitoneally injected with 75â¯mg/kg vitexin daily for 21 days. On the 3rd, 10th, and 17th days during the vitexin treatment, the radiation-treated mice were locally irradiated with 10â¯Gy, respectively. In vitro, the microRNA (miR)-17-5p or miR-130b-3p mimics-transfected SU3 cells were used to examine the effects of vitexin plus radiation on expression of miR-17-5p- or miR-130b-3p-induced radioresistance-related pathway proteins. The effects of vitexin on miR-17-5p and miR-130b-3p expression in SU3 cells were also evaluated. RESULTS: Compared with the radiation group, the tumor volume, tumor weight, and expression of HIF-1α, vascular endothelial growth factor, and glucose transporter-1/3 proteins, miR-17-5p, and miR-130b-3p in tumor tissues in the vitexinâ¯+ radiation group decreased, whereas the expression of phosphatase and tensin homolog (PTEN) protein increased. After treatment of miR-17-5p or miR-130b-3p mimics-transfected SU3 cells with vitexin plus radiation, the PTEN protein expression also increased, the HIF-1α protein expression decreased correspondingly. Moreover, vitexin decreased the miR-17-5p and miR-130b-3p expression in SU3 cells. CONCLUSION: Vitexin can enhance the radiosensitivity of glioma, and its mechanism may partly be related to the attenuation of HIF-1α pathway after lowering the inhibitory effect of miR-17-5p and miR-130b-3p on PTEN.
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Apigenina , Glioma , Subunidade alfa do Fator 1 Induzível por Hipóxia , Camundongos Nus , MicroRNAs , PTEN Fosfo-Hidrolase , Tolerância a Radiação , Animais , MicroRNAs/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Apigenina/farmacologia , Apigenina/uso terapêutico , PTEN Fosfo-Hidrolase/genética , Camundongos , Glioma/radioterapia , Glioma/patologia , Glioma/genética , Glioma/tratamento farmacológico , Tolerância a Radiação/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Transdução de Sinais/efeitos dos fármacos , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamento farmacológico , Radiossensibilizantes/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB CRESUMO
Dehydroepiandrosterone (DHEA) is frequently integrated as an adjuvant in over a quarter of controlled ovarian hyperstimulation (COH) protocols, despite the ongoing debate regarding its impact. This study aimed to evaluate the efficacy and mechanism of action of DHEA on ovarian follicular development and ovarian response in rats with varying ovarian reserves. The study involved 75 rats categorized into 15 distinct groups. The ovarian tissues of rats in both the normal ovarian reserve group and the premature ovarian insufficiency (POI) group, induced by 4-vinylcyclohexene diepoxide (VCD) injection, were subjected to histomorphological and biochemical analyses following the administration of DHEA, either alone or in combination with COH. Follicle counting was performed on histological sections obtained from various tissues. Serum concentrations of anti-Müllerian hormone (AMH) and the quantification of specific proteins in ovarian tissue, including phosphatase and tensin homolog of chromosome 10 (PTEN), phosphoinositide 3-kinase (PI3K), phosphorylated protein kinase B (pAKT), cyclooxygenase 2 (COX-2), caspase-3, as well as assessments of total antioxidant status and total oxidant status, were conducted employing the ELISA method. The impact of DHEA exhibited variability based on ovarian reserve. In the POI model, DHEA augmented follicular development and ovarian response to the COH protocol by upregulating the PTEN/PI3K/AKT signaling pathway, mitigating apoptosis, inflammation, and oxidative stress, contrary to its effects in the normal ovarian reserve group. In conclusion, it has been determined that DHEA may exert beneficial effects on ovarian stimulation response by enhancing the initiation of primordial follicles and supporting antral follicle populations.
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Cicloexenos , Desidroepiandrosterona , PTEN Fosfo-Hidrolase , Fosfatidilinositol 3-Quinases , Insuficiência Ovariana Primária , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Compostos de Vinila , Animais , Feminino , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Cicloexenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Desidroepiandrosterona/farmacologia , Desidroepiandrosterona/administração & dosagem , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Ovário/efeitos dos fármacos , Ovário/metabolismo , Reserva Ovariana/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismoRESUMO
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive disease that can metastasize to distant organs such as the lung and liver. However, the exact mechanisms underlying PDAC metastasis remain unclear. Tumor-associated macrophages (TAMs) have been shown to play a critical role in cancer initiation, progression, outgrowth, and metastasis, likely through their interaction with cancer cells via extracellular vesicles known as exosomes. However, the precise mechanisms of this interaction are not fully understood. METHODS: In this study, we obtained TAMs from PDAC patients and isolated exosomes from their culture medium. We characterized these exosomes and analyzed their miRNA expression profiles using Multiplex miRNA assays with FirePlex particle technology. Additionally, we conducted in vitro co-culture experiments between PDAC cells and conditioned media or exosomes from TAMs to investigate the crosstalk between these cells via exosomes. Furthermore, we evaluated the in vivo lung metastasis of PDAC cells treated with TAM-derived exosomes in athymic nude mice. RESULTS: TAMs from PDAC patients promoted the invasiveness and migratory potential of PDAC cells, partially through the effects of TAM-derived exosomes. Specifically, we identified two microRNAs, miR-202-5p and miR-142-5p, which were transferred from TAM-derived exosomes to PDAC cells, resulting in the suppression of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and promoting their invasiveness and migratory potential. We also found that distal metastasis was increased in PDAC cells treated with TAM-derived exosomes, partially through miR-202-5p and miR-142-5p. CONCLUSIONS: Exosomal transfer of miR-202-5p and miR-142-5p plays a significant role in conferring invasiveness and migratory potential to PDAC cells. Targeting exosome communication may represent a promising new therapeutic strategy for reducing cancer metastasis of PDACs.
Assuntos
Carcinoma Ductal Pancreático , MicroRNAs , Neoplasias Pancreáticas , Humanos , Animais , Camundongos , MicroRNAs/genética , Camundongos Nus , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/genética , Macrófagos , Linhagem Celular TumoralRESUMO
Angiogenesis is a complex process that involves the expansion of the pre-existing vascular plexus to enhance oxygen and nutrient delivery and is stimulated by various factors, including hypoxia. Since the process of angiogenesis requires a lot of energy, mitochondria play an important role in regulating and promoting this phenomenon. Besides their roles as an oxidative metabolism base, mitochondria are potential bioenergetics organelles to maintain cellular homeostasis via sensing alteration in oxygen levels. Under hypoxic conditions, mitochondria can regulate angiogenesis through different factors. It has been indicated that unidirectional and bidirectional exchange of mitochondria or their related byproducts between the cells is orchestrated via different intercellular mechanisms such as tunneling nanotubes, extracellular vesicles, and gap junctions to maintain the cell homeostasis. Even though, the transfer of mitochondria is one possible mechanism by which cells can promote and regulate the process of angiogenesis under reperfusion/ischemia injury. Despite the existence of a close relationship between mitochondrial donation and angiogenic response in different cell types, the precise molecular mechanisms associated with this phenomenon remain unclear. Here, we aimed to highlight the possible role of mitochondria concerning angiogenesis, especially the role of mitochondrial transport and the possible relation of this transfer with autophagy, the housekeeping phenomenon of cells, and angiogenesis.
Assuntos
Mitocôndrias , Humanos , Metabolismo Energético , Hipóxia/metabolismo , Mitocôndrias/metabolismo , Oxigênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo , AnimaisRESUMO
Rheumatoid arthritis (RA) is a chronic, progressive, systemic autoimmune disease. Among them, abnormal proliferation, migration and vascularization of fibroblast-like synoviocytes (FLS) are the main pathological basis of persistent synovitis and bone destruction in RA. In the current study, we attempted to find effective molecular mechanisms for the treatment of RA by investigating RA-FLS. Firstly, the study was conducted to identify the potential target gene PTEN and its related signaling pathway through bioinformatics analysis. Subsequently, the target gene PTEN overexpression was regulated by cell transfection. The expression of FOXO signaling factors and autophagy-related proteins were detected by western blotting assay. Cell proliferation was measured by CCK-8 and EdU assays. Inflammation level was detected by ELISA. Cell migration and invasion were detected using wound healing assay and transwell chamber assay, respectively. Cell apoptosis was detected using flow cytometry. The results showed that overexpression of PTEN activated FOXO1 signaling in RA-FLS, and regulated autophagy, proliferation, invasion, migration, and the levels of pro-inflammatory factors in the disease. In conclusion, PTEN might provide an effective therapeutic strategy for rheumatoid arthritis by mediating the FOXO1 signaling pathway.