Synergistic effect of chrysin and radiotherapy against triple-negative breast cancer (TNBC) cell lines

Purpose Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer, accounting for 20% of cases. Due to the lack of a molecular target, limited options are available for TNBC treatment. Radiation therapy (RT) is a treatment modality for the management of TNBC following surgery; however, it has a detrimental effect on surrounding healthy tissues/cells at a higher rate. Methods We examined the effect of RT in combination with chrysin as a possible radiosensitizing agent in an MDA-MB-231 cell line as a model of a TNBC. The growth inhibitory effects of chrysin were examined using an MTT assay. Flow cytometry was performed to evaluate apoptosis and expression of hypoxia-induced factor-1α (HIF-1α). The protein expression of p-STAT3/STAT3 and Cyclin D1 was examined using western blotting. Real-time PCR determined apoptotic-related genes (Bax, BCL2, p53). Results Treatment of MDA-MB-231 cells with chrysin in combination with RT caused synergistic antitumor effects, with an optimum combination index (CI) of 0.495. Our results indicated that chrysin synergistically potentiated RT-induced apoptosis in MDA-MB-231 compared with monotherapies (chrysin and/or RT alone). Expression of HIF-1α was decreased in the cells exposed to combinational therapy. The apoptotic effect of combinational therapy was correlated with increased Bax (pro-apoptotic gene) and p53 levels along with reduced expression of Bcl-2 (anti-apoptotic gene). Increased apoptosis was associated with reduced expression of Cyclin D1, p-STAT3. Conclusion These findings highlight the potential effect of chrysin as a radiosensitizer, indicating the synergistic anti-cancer effect of chrysin and RT in TNBC. Further investigation is warranted in this regard (AU)

Coptisine attenuates sepsis lung injury by suppressing LPS-induced lung epithelial cell inflammation and apoptosis

Objective: This study aimed to investigate the functioning and mechanism of coptisine in acute lung injury (ALI). Methods: Murine Lung Epithelial 12 (MLE-12) cells were stimulated with lipopolysaccharide (LPS) to construct an in vitro pulmonary injury model to study the functioning of coptisine in sepsis-induced ALI. The viability of MLE-12 cells was assessed by the cell counting kit-8 assay. The cytokine release of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and IL-1β was measured by enzyme-linked-immunosorbent serologic assay. The relative expression levels of TNF-α, IL-6, and IL-1β mRNA were examined by reverse transcription-quantitative polymerase chain reaction. The cell apoptosis of MLE-12 cells was determined by Annexin V/propidium iodide staining and analyzed by flow cytometry. The expressions of apoptosis-related proteins Bax and cleaved Caspase-3 were observed by Western blot analysis. The activation of nuclear factor kappa B (NF-κB) signaling pathway was discovered by the determination of phospho-p65, p65, phospho-nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα), and IκBα through Western blot analysis. Results: Coptisine treatment could significantly restore decrease in MLE-12 cell viability caused by LPS stimulation. The release of TNF-α, IL-6, and IL-1β was significantly inhibited by coptisine treatment. Coptisine treatment inhibited MLE-12 cell apoptosis induced by LPS, and also inhibited the expression levels of Bax and cleaved Caspase-3. Coptisine treatment along with LPS stimulation, significantly reduced the protein level of phospho-IκBα, increased the level of IκBα, and reduced phospho-p65–p65 ratio. Conclusion: These results indicated that coptisine attenuated sepsis lung injury by suppressing lung epithelial cell inflammation and apoptosis through NF-κB pathway. Therefore, coptisine may have potential to treat sepsis-induced ALI (AU)

Connexin 43, Bcl-2, Bax, Ki67, and E-cadherin patterns in oral squamous cell carcinoma and its relationship with GJA1 rs12197797 C/G

Background: To our knowledge, there is no useful and accurate prognostic biomarker or biomarkers for patientswith oral squamous cell carcinoma (OSCC), a tumor with uncertain biological behavior, and unpredictable clinical progress. The purposes of this study were: a) to determine the expresión profile of Connexin 43, Bcl-2, Bax,E-cadherin, and Ki67 in patients with OSCC; b) identify the GJCA1 rs12197797 genotypic composition.Material and Methods: A cross-sectional study using genomic DNA and biopsy samples extracted from the oralmucosa with/without OSCC, older than 18 years, both genders, attended at Facultad de Odontología, UniversidadNacional Córdoba. Immunostaining for Cx43, Bcl-2, Bax, E-cadherin, and Ki67 and genotyping GJA1 rs12197797by RFLP were performed. Odds Ratio (95% CI), Spearman Coefficient were estimated. Mann-Whitney test wasapplied to analyze immunostaining between controls/cases (p <0.05 was set for statistical significance).Results: GG (mutant) was the most frequent genotype in patients with OSCC diagnosis (53.2%) in relation toCC “healthy” genotype (p=0.00487; OR=7.33; CI95% [1.1-54.7]). And, the allele G (mutant) had a presence in75.5% of OSCC patients. However, no significant association was observed between alleles C/G and diagnosis(p=0.0565). The heterozygous genotype was the most frequent in the patients of both groups Cx43 and E-cadherinmarkers were lower in OSCCs in relation to controls. Ki67 and Bcl-2 immunolabeling were high on OSCC, andBax immunomarker was diminished in OSCC.Conclusions: We hypothesized that the oral epithelium losses Connexin 43 and E-cadherin in the membrane, whichmodifies cell differentiation. The Ki67 and Bcl2 overexpression would increase the cell density in the tissue, by promoting proliferation and decreasing apoptosis. And, this study shows evidence that patients who carry on allele G ofGJA1rs12197797 could be at risk of developing OSCC. (AU)

Probiotic mixture of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 attenuates hippocampal apoptosis induced by lipopolysaccharide in rats

In recent years, the beneficial impact of targeted gut microbiota manipulation in various neurological disorders has become more evident. Therefore, probiotics have been considered as a promising approach to modulate brain gene expression and neuronal pathways even in some neurodegenerative diseases. The purpose of this study was to determine the effect of probiotic biotherapy with combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 on the expression levels of proteins critical to neuronal apoptosis in hippocampus of lipopolysaccharide (LPS)-exposed rats. Four groups of animals (Control, LPS, Probiotic + LPS, and Probiotic) were treated with maltodextrin (placebo) or probiotic (109 CFU/ml/rat) for 2 weeks by gavage. On the 15th day, a single intraperitoneal dose of saline or LPS (1 mg/kg) was injected and 4 h later, protein assessment was performed by western blotting in hippocampal tissues. LPS significantly increased the Bax, Bax/Bcl-2 ratio, and cleaved caspase-3 expression along with decreased the Bcl-2 and procaspase-3 protein levels. However, probiotic pretreatment (L. helveticus R0052 + B. longum R0175) significantly downregulated the Bax and Bax/Bcl-2 ratio accompanied with upregulated Bcl-2 expression. Prophylactic treatment with these bacteria also attenuated LPS-induced caspase-3 activation by remarkably increasing the expression of procaspase-3 while reducing the level of cleaved caspase-3 in target tissues. Our data indicate that probiotic formulation (L. helveticus R0052 + B. longum R0175) alleviated hippocampal apoptosis induced by LPS in rats via the gut-brain axis and suggest that this probiotic could play a beneficial role in some neurodegenerative conditions

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Inhibition of microRNA-181a may suppress proliferation and invasion and promote apoptosis of cervical cancer cells through the PTEN/Akt/FOXO1 pathway

MicroRNAs (miRNAs) are endogenous, non-coding, small RNAs, which play a critical role in regulating varieties of the biological and pathologic processes. miR-181a has been reported to participate in tumorigenic progression. However, the roles of miR-181a in cervical cancer (CC) are still unknown. The aim of this research was to explore the effects and molecular mechanism of miR-181a in CC cells. In this paper, the levels of miR-181a in CC cell lines were determined by real-time PCR. We found that the levels of miR-181a were evidently enhanced in CC cell lines compared with normal cervical epithelium cells. Then, the miR-181a inhibitor was transiently transfected into HeLa and CaSKi cells using Lipofectamine 2000 reagent. Subsequently, the Cell Counting Kit-8 (CCK-8) and BrdU-ELISA results showed that down-regulation of miR-181a inhibited the cell viability and proliferation. Our data also demonstrated that miR-181a inhibitor arrested cell cycle progression of HeLa and CaSKi cells by up-regulation of p21 and p27 expressions. In addition, inhibition of miR-181a promoted apoptosis of HeLa and CaSKi cells due to increasing Bax expression and decreasing Bcl-2 expression. Ultimately, the effect of miR-181a inhibitor on the PTEN/Akt/FOXO1 signaling pathway was investigated by Western blot. From our results, down-regulation of miR-181a increased the expression of PTEN and decreased phosphorylation of Akt and FOXO1. Altogether, miR-181a might be an oncogene in CC cells. The potential mechanism was that inhibition of miR-181a might suppress proliferation and invasion and promote apoptosis of HeLa and CaSKi cells by modulating the PTEN/Akt/FOXO1 signaling pathway (AU)

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A common effect of angiotensin II and relaxin 2 on the PNT1A normal prostate epithelial cell line

The prostate gland is a part of the male reproductive tract which produces both angiotensin II (Ang II) and relaxin 2 (RLN2). The present study analyzes the effect of both these peptide hormones at concentration 10−8M on viability, proliferation, adhesion, migration, and invasion of normal prostate epithelial cells (PNT1A). Improved survival in two- and three-dimensional cell cultures was noted as well as visual changes in colony size and structure in Geltrex™. Stimulatory influence on cell viability of each peptide applied single was lower than in combination. Enhanced survival of PNT1A cells appears to be associated with increased BCL2/BAX messenger RNA (mRNA) expression ratio. Modulation of cell spreading and cell-extracellular matrix adhesion dynamics were also altered as an influence of tested hormone application. However, long-term Ang II and RLN2 effects may lead to an increase of normal prostate cell migration and invasion abilities. Moreover, gelatin zymography revealed that both gelatinases A and B were augmented by Ang II treatment, whereas RLN2 significantly stimulated only MMP-9 secretion. These results support the hypothesis that deregulation of locally secreted peptide hormones such as Ang II and RLN2 may take part in the development of certain cancers, including prostate cancer. Moreover, the observed ability of relaxin 2 to act as a regulator of mRNA expression levels not only LGR7 but also classic angiotensin receptors suggested that renin-angiotensin system and relaxin family peptide system are functionally linked (AU)

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BAX como factor de susceptibilidad en el cáncer colorrectal hereditario no polipósico / BAX as a suseptibility factor in hereditary non polyposis colorectal cancer

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Lack of Bax expression is associated with irinotecan-based treatment activity in advanced colorectal cancer patients

BACKGROUND: Currently, first-line chemotherapy in advanced colorectal cancer is not tailored on predictive biomarkers. Bax proapoptotic protein may correlate to chemosensitivity and differential response to irinotecan or oxaliplatin-based combinations. METHODS: Bax expression was assessed by immunohistochemistry in 49 advanced colorectal cancer patients enrolled at our institution from 2002 to 2004 within a multicenter, phase II, randomized trial of first-line UFT/leucovorin/irinotecan (TEGAFIRI) versus UFT/leucovorin/oxaliplatin (TEGAFOX). RESULTS: Bax-positive and negative samples were 49 and 51 %. Response was significantly lower in Bax positive (25 %) as compared to Bax negative (56 %) (Odds ratio = 0.26; p = 0.03). No significant difference was noted in TEGAFOX subgroup; in TEGAFIRI arm, responses were lower in Bax positive (18 %) than Bax negative (67 %) (Odds ratio = 0.11; p = 0.03). No difference in terms of progression-free and overall survival was observed according to Bax. CONCLUSION: Bax-negative colorectal cancer may identify a specific phenotype of patients with significantly higher chance to respond to doublet irinotecan-based chemotherapy (AU)

Mecanismos de acción y efectos de la proteína X (HBx) en la patogenia de la hepatitis crónica B / Effects of hepatitis B virus X protein on chronic hepatitis B pathophysiology

La infección por el virus de la hepatitis B genera frecuentemente una inflamación crónica del hígado, que evoluciona a cirrosis y hepatocarcinoma en un elevado porcentaje de pacientes. La activación persistente del sistema inmunitario origina un daño hepático continuado que estimula de forma desorganizada fenómenos de reparación y remodelado tisular. La proteína viral X (HBx) es imprescindible para la replicación del virus y, por tanto, para el mantenimiento crónico de la infección. El principal potencial oncogénico de HBx reside, por una parte, en su capacidad para integrarse al ADN celular, y por otra, en la transactivación de diversas vías de señalización implicadas en crecimiento celular, apoptosis y reparación del ADN. Además, HBx interacciona con el proteasoma y es capaz de modificar la homeostasis del calcio celular. Esta revisión analiza el papel de HBx en la progresión de la hepatitis crónica B a través de sus efectos en procesos angiogénicos, fibrogénicos y oncogénicos (AU)

The infection by hepatitis B virus often promotes chronic liver inflammation which progresses to cirrhosis and hepatocellular carcinoma in a high percentage of patients. The persistent activation of the immune system causes an incessant liver damage, which fosters a disorganized stimulation of tissue repair and remodelling phenomena. In turn, the viral protein X (HBx) is essential for virus replication and therefore for the maintenance of chronic infection. However, the important oncogenic potential of HBx seems to reside, on one hand, in its ability to integrate into cellular DNA and, additionally, in the transactivation of different cellular signaling pathways involved in cell growth regulation, apoptosis and DNA repair. HBx also interacts with proteasome subunits and notably affects mitochondrial electric potential, thus altering cellular calcium homeostasis. Finally, this review discusses the pathogenic role of HBx in the progression of chronic hepatitis B through its effects on angiogenic, fibrogenic and oncogenic processes (AU)