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Introduction: Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, the lack of predictive biomarkers and limited understanding of response mechanisms remain a challenge. Methods: Using data from the IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with atezolizumab plus bevacizumab or with sorafenib alone into potential high and low response groups. By applying multiple statistical approaches including a Bayesian covariate prediction algorithm, we refined the signature to 10 key genes (ISS10) for clinical use while maintaining similar predictive power to the full model. We further validated ISS10 in an independent HCC cohort treated with nivolumab plus ipilimumab. Results: The study identified a significant association between the ISS and treatment response. Among patients classified as high responders, those treated with the atezolizumab plus bevacizumab combination exhibited improved overall and progression-free survival as well as better objective response rate compared to those treated with sorafenib. We also observed a significant correlation between ISS10 and response to nivolumab plus ipilimumab treatment. Analysis of immune cell subpopulations revealed distinct characteristics associated with ISS subtypes. In particular, the ISS10 high subtype displayed a more favorable immune environment with higher proportions of anti-tumor macrophages and activated T-cells, potentially explaining its better response. Conclusions: Our study suggests that ISS and ISS10 are promising predictive biomarkers for enhanced therapeutic outcomes in HCC patients undergoing combination immunotherapy. These markers are crucial for refining patient stratification and personalized treatment approaches to advance the effectiveness of standard-of-care regimens.
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BACKGROUND: Programmed cell death 6 (PDCD6) is known to be involved in apoptosis and tumorigenesis. Given the reported association with urinary cancer susceptibility through SNP analysis, we further analyzed the entire genomic structure of PDCD6. METHODS: Three VNTR regions (MS1-MS3) were identified through the analysis of the genomic structure of PDCD6. To investigate the association between these VNTR regions and urinary cancer susceptibility, genomic DNA was extracted from 413 cancer-free male controls, 267 bladder cancer patients, and 331 prostate cancer patients. Polymerase chain reaction (PCR) was performed to analyze the PDCD6-MS regions. Statistical analysis was performed to determine the association between specific genotypes and cancer risk. In addition, the effect of specific VNTRs on PDCD6 expression was also confirmed using a reporter vector. RESULTS: Among the three VNTR regions, MS1 and MS2 exhibited monomorphism, while the MS3 region represented polymorphism, with its transmission to subsequent generations through meiosis substantiating its utility as a DNA typing marker. In a case-control study, the presence of rare alleles within PDCD6-MS3 exhibited significant associations with both bladder cancer (OR = 2.37, 95% CI: 1.33-4.95, P = 0.019) and prostate cancer (OR = 2.11, 95% CI: 1.03-4.36, P = 0.038). Furthermore, through luciferase assays, we validated the impact of the MS3 region on modulating PDCD6 expression. CONCLUSIONS: This study suggests that the PDCD6-MS3 region could serve as a prognostic marker for urinary cancers, specifically bladder cancer and prostate cancer. Moreover, the subdued influence exerted by PDCD6-MS3 on the expression of PDCD6 offers another insight concerning the progression of urinary cancer.
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Background: Tagetes erecta Linn, popularly known as Marigold, has various pharmacological effects. It is used as a dietary supplement, especially for the posterior segment of the eye. However, the effect of T. erecta Linn on ocular disorders is still unknown. The purpose of this study was to investigate the effect of oral administration of ethanol extract of T. erecta Linn flower (TE) for dry eye syndrome (DED) in a murine model. Methods: Twenty-four mice were subjected to desiccation stress (DS) to induce DED and subcutaneous injection of scopolamine hydrobromide was administered 4 times a day for 21 days. TE and cyclosporine A (CsA) were administered for an additional 14 days under DS conditions. Mice were randomly divided into four groups: control, TE200, TE400, and CsA. Changes in tear production and corneal fluorescein staining were measured at baseline, after 7 days of DS, and after treatment for 7 and 14 days. Results: DS significantly decreased tear production and increased corneal fluorescein score; the parameters were significantly reversed in the TE400 (oral administration of 400 mg TE/kg body weight) group. TE markedly improved DS-induced changes including corneal epithelial detachment and lacrimal gland inflammation. The anti-inflammatory effect of TE 400 supplementation was similar to that of CsA. Conclusions: Our findings suggest that oral administration of TE may protect against DS-induced DED via stabilization of the tear film and suppression of inflammation. This study provides an experimental basis for further studies on the potential clinical use of TE in preventing DED.
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Approximately 75% of bladder cancer cases originate as non-muscle-invasive bladder cancer (NMIBC). Despite initial diagnosis, NMIBC commonly recurs, with up to 45% advancing to muscle-invasive bladder cancer (MIBC) and metastatic disease. Treatment for high-risk NMIBC typically includes procedures like transurethral resection and, depending on recurrence risk, intravesical chemotherapy or immunotherapy such as Bacillus Calmette-Guérin (BCG). However, persistent shortages of BCG necessitate alternative first-line treatments. We aim to use a multi-gene signature in high-risk NMIBC patients to determine whether patients may benefit from immune checkpoint inhibitors (ICIs) as an alternative to BCG and to evaluate their clinical utility. The multi-gene signature obtained from the three independent NMIBC cohorts was applied to stratify the UROMOL2016 cohort (n = 476) using consensus clustering. Each subtype was distinguished by biological pathway analysis. Validation analysis using a machine learning algorithm was performed in six independent cohorts including the BRS (n = 283) cohort treated with BCG and the IMvigor210 (n = 298) clinical trials treated with PD-L1 inhibitors. Based on consensus cluster analysis, NMIBC patients in the UROMOL2016 cohort were classified into three classes exhibiting distinguished characteristics, including DNA damage repair (DDR). Survival analysis showed that the NMIBC-DDR class had the highest rates of disease progression (progression-free survival, p = 0.002 by log-rank test) in the UROMOL cohort and benefited from BCG and ICIs (respectively, p = 0.02 and p = 0.03 by log-rank test). This study suggests that the multi-gene signature may have a role in identifying high-risk NMIBC patients and improving the responsiveness of ICIs. Additionally, we propose immunotherapy as a new first-line treatment for patients with high-risk NMIBC because of the shortage of BCG supply. It is important to help more patients prioritize cancer immunotherapy.
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Mycobacterium bovis , Neoplasias não Músculo Invasivas da Bexiga , Neoplasias da Bexiga Urinária , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Vacina BCG/uso terapêutico , Imunoterapia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/terapia , Mycobacterium bovis/genéticaRESUMO
Oxidative stress contributes to the onset of chronic diseases in various organs, including muscles. Morroniside, a type of iridoid glycoside contained in Cornus officinalis, is reported to have advantages as a natural compound that prevents various diseases. However, the question of whether this phytochemical exerts any inhibitory effect against oxidative stress in muscle cells has not been well reported. Therefore, the current study aimed to evaluate whether morroniside can protect against oxidative damage induced by hydrogen peroxide (H2O2) in murine C2C12 myoblasts. Our results demonstrate that morroniside pretreatment was able to inhibit cytotoxicity while suppressing H2O2-induced DNA damage and apoptosis. Morroniside also significantly improved the antioxidant capacity in H2O2-challenged C2C12 cells by blocking the production of cellular reactive oxygen species and mitochondrial superoxide and increasing glutathione production. In addition, H2O2-induced mitochondrial damage and endoplasmic reticulum (ER) stress were effectively attenuated by morroniside pretreatment, inhibiting cytoplasmic leakage of cytochrome c and expression of ER stress-related proteins. Furthermore, morroniside neutralized H2O2-mediated calcium (Ca2+) overload in mitochondria and mitigated the expression of calpains, cytosolic Ca2+-dependent proteases. Collectively, these findings demonstrate that morroniside protected against mitochondrial impairment and Ca2+-mediated ER stress by minimizing oxidative stress, thereby inhibiting H2O2-induced cytotoxicity in C2C12 myoblasts.
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Exposure to ambient ultrafine particulate matter (UPM) causes respiratory disorders; however, the underlying molecular mechanisms remain unclear. In this study, we synthesized simulated UPM (sUPM) with controlled physicochemical properties using the spark-discharge method. Subsequently, we investigated the biological effects of sUPM using BEAS-2B human bronchial epithelial cells (HBECs) and a mouse intratracheal instillation model. High throughput RNA-sequencing and bioinformatics analyses revealed that dysregulation of the glycolytic metabolism is involved in the inhibited proliferation and survival of HBECs by sUPM treatment. Furthermore, signaling pathway and enzymatic analyses showed that the treatment of BEAS-2B cells with sUPM induces the inactivation of extracellular signal-regulated kinase (ERK) and protein kinase B (PKB, also known as AKT), resulting in the downregulation of phosphofructokinase 2 (PFK2) S483 phosphorylation, PFK enzyme activity, and aerobic glycolysis in HBECs in an oxidative stress-independent manner. Additionally, intratracheal instillation of sUPM reduced the phosphorylation of ERK, AKT, and PFK2, decreased proliferation, and increased the apoptosis of bronchial epithelial cells in mice. The findings of this study imply that UPM induces pulmonary toxicity by disrupting aerobic glycolytic metabolism in lung epithelial cells, which can provide novel insights into the toxicity mechanisms of UPM and strategies to prevent their toxic effects.
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Poluentes Atmosféricos , Material Particulado , Humanos , Animais , Camundongos , Material Particulado/análise , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosforilação , Células Epiteliais , Glicólise , Fosfofrutoquinases/análise , Fosfofrutoquinases/metabolismo , Poluentes Atmosféricos/análiseRESUMO
Human endogenous retrovirus (HERV)-K was reportedly inserted into the human genome millions of years ago and is closely related to various diseases, including cancer and immune regulation. In our previous studies, CRISPR-Cas9-enabled knockout (KO) of the HERV-K env gene was found to potentially reduce cell proliferation, cell migration, and invasion in colorectal and ovarian cancer cell lines. The immune response involves the migration and invasion of cells and is similar to cancer; however, in certain ways, it is completely unlike cancer. Therefore, we induced HERV-K119 env gene KO in THP-1, a monocytic cell that can be differentiated into a macrophage, to investigate the role of HERV-K119 env in immune regulation. Cell migration and invasion were noted to be significantly increased in HERV-K119 env KO THP-1 cells than in MOCK, and these results were contrary to those of cancer cells. To identify the underlying mechanism of HERV-K119 env KO in THP-1 cells, transcriptome analysis and cytokine array analysis were conducted. Semaphorin7A (SEMA7A), which induces the production of cytokines in macrophages and monocytic cells and plays an important role in immune effector cell activation during an inflammatory immune response, was significantly increased in HERV-K119 env KO THP-1 cells. We also found that HERV-K119 env KO THP-1 cells expressed various macrophage-specific surface markers, suggesting that KO of HERV-K119 env triggers the differentiation of THP-1 cells from monocytic cells into macrophages. In addition, analysis of the expression of M1 and M2 macrophage markers showed that M1 macrophage marker cluster of differentiation 32 (CD32) was significantly increased in HERV-K119 env KO cells. These results suggest that HERV-K119 env is implicated in the differentiation of monocytic cells into M1 macrophages and plays important roles in the immune response.
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Retrovirus Endógenos , Feminino , Humanos , Retrovirus Endógenos/genética , Retrovirus Endógenos/metabolismo , Células THP-1 , Genes env , Linfócitos/metabolismo , Diferenciação Celular , Produtos do Gene env/genética , Produtos do Gene env/metabolismoRESUMO
Although most human endogenous retroviruses (HERVs) have been silenced and lost their ability to translocate because of accumulated mutations during evolution, they still play important roles in human biology. Several studies have demonstrated that HERVs play pathological roles in numerous human diseases, especially cancer. A few studies have revealed that long non-coding RNAs that are transcribed from HERV sequences affect cancer progression. However, there is no study on microRNAs derived from HERVs related to cancer. In this study, we identified 29 microRNAs (miRNAs) derived from HERV sequences in the human genome. In particular, we discovered that miR-4454, which is HERV-H-derived miRNA, was upregulated in non-muscle-invasive bladder cancer (NMIBC) cells. To figure out the effects of upregulated miR-4454 in NMIBC, genes whose expression was downregulated in NMIBC, as well as tumor suppressor genes, were selected as putative target genes of miR-4454. The dual-luciferase assay was used to determine the negative relationship between miR-4454 and its target genes, DNAJB4 and SASH1, and they were confirmed to be promising target genes of miR-4454. Taken together, this study suggests that the upregulation of miR-4454 derived from HERV-H in NMIBC reduces the expression of the tumor suppressor genes, DNAJB4 and SASH1, to promote NMIBC progression.
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Retrovirus Endógenos , MicroRNAs , Neoplasias não Músculo Invasivas da Bexiga , Neoplasias da Bexiga Urinária , Humanos , Retrovirus Endógenos/genética , Genoma Humano , Proteínas de Choque Térmico HSP40/genética , Proteínas de Choque Térmico HSP40/metabolismo , MicroRNAs/genética , Proteínas Supressoras de Tumor/genética , Neoplasias da Bexiga Urinária/genéticaRESUMO
Diabetic retinopathy (DR) is the leading cause of vision loss and a critical complication of diabetes with a very complex etiology. The build-up of reactive oxygen species (ROS) due to hyperglycemia is recognized as a primary risk factor for DR. Although spermidine, a naturally occurring polyamine, has been reported to have antioxidant effects, its effectiveness in DR has not yet been examined. Therefore, in this study, we investigated whether spermidine could inhibit high glucose (HG)-promoted oxidative stress in human retinal pigment epithelial (RPE) cells. The results demonstrated that spermidine notably attenuated cytotoxicity and apoptosis in HG-treated RPE ARPE-19 cells, which was related to the inhibition of mitochondrial ROS production. Under HG conditions, interleukin (IL)-1ß and IL-18's release levels were markedly increased, coupled with nuclear factor kappa B (NF-κB) signaling activation. However, spermidine counteracted the HG-induced effects. Moreover, the expression of nucleotide-binding oligomerization domain-like receptor (NLR) protein 3 (NLRP3) inflammasome multiprotein complex molecules, including TXNIP, NLRP3, ASC, and caspase-1, increased in hyperglycemic ARPE-19 cells, but spermidine reversed these molecular changes. Collectively, our findings demonstrate that spermidine can protect RPE cells from HG-caused injury by reducing ROS and NF-κB/NLRP3 inflammasome pathway activation, indicating that spermidine could be a potential therapeutic compound for DR treatment.
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Retinopatia Diabética , Inflamassomos , Humanos , Inflamassomos/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Espermidina/farmacologia , Estresse Oxidativo , Glucose/toxicidade , Células Epiteliais/metabolismo , Pigmentos da Retina/metabolismoRESUMO
BACKGROUND: The variable number of tandem repeat (VNTR) analyses are methods based on the detection of repeated sequences within the human genome. In order to perform DNA typing at the personal laboratory, it is necessary to improve the VNTR analysis. OBJECTIVE: The VNTR markers were difficult to popularize because PCR amplification was difficult due to its GC-rich and long nucleotide sequence. The aim of this study was to select the multiple VNTR markers that could only be identified by PCR amplification and electrophoresis. METHODS: We genotyped each of the 15 VNTR markers using genomic DNA from 260 unrelated individuals by PCR amplification. Differences in the fragment length of PCR products are visualized by agarose gel electrophoresis. To confirm their usefulness as a DNA fingerprint these 15 markers were simultaneously analyzed with the DNA of 213 individuals and verified the statistical significance. In addition, to investigate the usefulness of each of the 15 VNTR markers as paternity markers, Mendelian segregation by meiotic division within a family consisting of two or three generations was confirmed. RESULTS: Fifteen VNTR loci selected in this study could be easily amplified by PCR and analyzed by electrophoresis, and were newly named DTM1 ~ 15. The number of total alleles in each VNTR showed from 4 to 16, and 100 to 1600 bp in length, and their heterozygosity ranged from 0.2341 to 0.7915. In simultaneous analysis of 15 markers from 213 DNAs, the probability of chance appearing the same genotype in different individuals was less than 4.09E-12, indicating its usefulness as a DNA fingerprint. These loci were transmitted through meiosis by Mendelian inheritance in families. CONCLUSION: Fifteen VNTR markers have been found to be useful as DNA fingerprints for personal identification and kinship analysis that can be used at the personal laboratory level.
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Impressões Digitais de DNA , Repetições Minissatélites , Humanos , Impressões Digitais de DNA/métodos , Repetições Minissatélites/genética , Reação em Cadeia da Polimerase , Paternidade , DNARESUMO
Bladder cancer is the most common urological malignancy worldwide, and its high recurrence rate leads to poor survival outcomes. The effect of anticancer drug treatment varies significantly depending on individual patients and the extent of drug resistance. In this study, we developed a validation system based on an organ-on-a-chip integrated with artificial intelligence technologies to predict resistance to anticancer drugs in bladder cancer. As a proof-of-concept, we utilized the gemcitabine-resistant bladder cancer cell line T24 with four distinct levels of drug resistance (parental, early, intermediate, and late). These cells were co-cultured with endothelial cells in a 3D microfluidic chip. A dataset comprising 2,674 cell images from the chips was analyzed using a convolutional neural network (CNN) to distinguish the extent of drug resistance among the four cell groups. The CNN achieved 95.2% accuracy upon employing data augmentation and a step decay learning rate with an initial value of 0.001. The average diagnostic sensitivity and specificity were 90.5% and 96.8%, respectively, and all area under the curve (AUC) values were over 0.988. Our proposed method demonstrated excellent performance in accurately identifying the extent of drug resistance, which can assist in the prediction of drug responses and in determining the appropriate treatment for bladder cancer patients.
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CLPTM1L (Cleft Lip and Palate Transmembrane Protein 1-Like) has previously been implicated in tumorigenesis and drug resistance in cancer. However, the genetic link between CLPTM1L and bladder cancer remains uncertain. In this study, we investigated the genetic association of variable number of tandem repeats (VNTR; minisatellites, MS) regions within CLPTM1L with bladder cancer. We identified four CLPTM1L-MS regions (MS1~MS4) located in intron regions. To evaluate the VNTR polymorphic alleles, we analyzed 441 cancer-free controls and 181 bladder cancer patients. Our analysis revealed a higher frequency of specific repeat sizes within the MS2 region in bladder cancer cases compared to controls. Notably, 25 and 27 repeats were exclusively present in the bladder cancer group. Moreover, rare alleles within the medium-length repeat range (25-29 repeats) were associated with an elevated bladder cancer risk (odds ratio [OR] = 5.78, 95% confidence interval [CI]: 1.49-22.47, p = 0.004). We confirmed that all MS regions followed Mendelian inheritance, and demonstrated that MS2 alleles increased CLPTM1L promoter activity in the UM-UC3 bladder cancer cells through a luciferase assay. Our findings propose the utility of CLPTM1L-MS regions as DNA typing markers, particularly highlighting the potential of middle-length rare alleles within CLPTM1L-MS2 as predictive markers for bladder cancer risk.
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Neoplasias da Bexiga Urinária , Humanos , Alelos , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Bexiga Urinária , Neoplasias da Bexiga Urinária/genéticaRESUMO
Chemotherapy resistance is an obstacle to cancer therapy and is considered a major cause of recurrence. Thus, understanding the mechanisms of chemoresistance is critical to improving the prognosis of patients. Here, we have established a stepwise gemcitabine-resistant T24 bladder cancer cell line to understand the molecular mechanisms of chemoresistance within cancer cells. The characteristics of the stepwise chemoresistance cell line were divided into 4 phases (parental, early, intermediate, and late phases). These four phase cells showed increasingly aggressive phenotypes in vitro and in vivo experiments with increasing phases and revealed the molecular properties of the biological process from parent cells to phased gemcitabine-resistant cell line (GRC). Taken together, through the analysis of gene expression profile data, we have characterized gene set of each phase indicating the response to anticancer drug treatment. Specifically, we identified a multigene signature (23 genes including GATA3, APOBEC3G, NT5E, MYC, STC1, FOXD1, SMAD9) and developed a chemoresistance score consisting of that could predict eventual responsiveness to gemcitabine treatment. Our data will contribute to predicting chemoresistance and improving the prognosis of bladder cancer patients.
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Contrary to many reports that antiplatelet agents inhibit cancer growth and metastasis, new solid tumors have been reported in patients receiving long-term antiplatelet therapy. We investigated the effects of these agents directly on cancer cells in the absence of platelets to mimic the effects of long-term therapy. When four antiplatelet agents (aspirin, clopidogrel, prasugrel, and ticagrelor) were administered to colon cancer cells, cancer cell proliferation was inhibited similarly to a previous study. However, surprisingly, when cells were treated with a purinergic P2Y12 inhibitor (purinergic antiplatelet agent), the motility of the cancer cells was significantly increased. Therefore, gene expression profiles were identified to investigate the effect of P2Y12 inhibitors on cell mobility, and Serpin family 1 (SERPINE1) was identified as a common gene associated with cell migration and cell death in three groups. Antiplatelet treatment increased the level of SERPINE1 in cancer cells and also promoted the secretion of SERPINE1 into the medium. Increased SERPINE1 was found to induce MMP1 and, thus, increase cell motility. In addition, an increase in SERPINE1 was confirmed using the serum of patients who received these antiplatelet drugs. With these results, we propose that SERPINE1 could be used as a new target gene to prevent the onset and metastasis of cancer in patients with long-term antiplatelet therapy.
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Neoplasias do Colo , Inibidores da Agregação Plaquetária , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Humanos , Metaloproteinase 1 da Matriz , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , TiclopidinaRESUMO
Platycodin D (PD) is a triterpenoid saponin, a major bioactive constituent of the roots of Platycodon grandiflorum, which is well known for possessing various pharmacological properties. However, the anti-cancer mechanism of PD in bladder cancer cells remains poorly understood. In the current study, we investigated the effect of PD on the growth of human bladder urothelial carcinoma cells. PD treatment significantly reduced the cell survival of bladder cancer cells associated with induction of apoptosis and DNA damage. PD inhibited the expression of inhibitor of apoptosis family members, activated caspases, and induced cleavage of poly (ADP-ribose) polymerase. PD also increased the release of cytochrome c into the cytoplasm by disrupting the mitochondrial membrane potential while upregulating the expression ratio of Bax to Bcl-2. The PD-mediated anti-proliferative effect was significantly inhibited by pre-treatment with a pancaspase inhibitor, but not by an inhibitor of necroptosis. Moreover, PD suppressed the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway, and the apoptosis-inducing effect of PD was further enhanced by a PI3K inhibitor. In addition, PD increased the accumulation of reactive oxygen species (ROS), whereas N-acetyl cysteine (NAC), an ROS inhibitor, significantly attenuated the growth inhibition and inactivation of the PI3K/Akt/mTOR signaling caused by PD. Furthermore, NAC significantly suppressed apoptosis, DNA damage, and decreased cell viability induced by PD treatment. Collectively, our findings indicated that PD blocked the growth of bladder urothelial carcinoma cells by inducing ROS-mediated inactivation of the PI3K/Akt/mTOR signaling.
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Carcinoma de Células de Transição , Saponinas , Triterpenos , Neoplasias da Bexiga Urinária , Apoptose , Humanos , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinase/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Saponinas/farmacologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Triterpenos/farmacologia , Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologiaRESUMO
Fisetin is a kind of bioactive flavonol, widely present in various fruits such as strawberries and apples, and is known to act as a potent free radical scavenger. However, the mechanism of action related to the antioxidant activity of this compound in human retinal pigment epithelial (RPE) cells is not precisely known. In this study, we aimed to investigate whether fisetin could attenuate oxidative stress-induced cytotoxicity on human RPE ARPE-19 cells. To mimic oxidative stress, ARPE-19 cells were treated with hydrogen peroxide (H2O2), and fisetin significantly inhibited H2O2-induced loss of cell viability and increase of intracellular reactive oxygen species (ROS) production. Fisetin also markedly attenuated DNA damage and apoptosis in H2O2-treated ARPE-19 cells. Moreover, mitochondrial dysfunction in H2O2-treated cells was alleviated in the presence of fisetin as indicated by preservation of mitochondrial membrane potential, increase of Bcl-2/Bax expression ratio, and suppression of cytochrome c release into the cytoplasm. In addition, fisetin enhanced phosphorylation and nuclear translocation of nuclear factor erythroid 2 related factor 2 (Nrf2), which was associated with increased expression and activity of heme oxygenase-1 (HO-1). However, the HO-1 inhibitor, zinc protoporphyrin, significantly reversed the protective effect of fisetin against H2O2-mediated ARPE-19 cell injury. Therefore, our results suggest that Nrf2-mediated activation of antioxidant enzyme HO-1 may play an important role in the ROS scavenging activity of fisetin in RPE cells, contributing to the amelioration of oxidative stress-induced ocular disorders.
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BACKGROUND: Despite the availability of several treatments for non-muscle-invasive bladder cancer (NMIBC), many patients are still not responsive to treatments, and the disease progresses. A new prognostic classifier can differentiate between treatment response and progression, and it could be used as a very important tool in patient decision-making regarding treatment options. In this study, we focused on the activation of Yes-associated protein 1 (YAP1), which is known to play a pivotal role in tumour progression and serves as a factor contributing to the mechanism of resistance to various relevant therapeutic agents. We further evaluated its potential as a novel prognostic agent. METHODS: We identified YAP1-associated gene signatures based on UC3-siYAP1 cells (n=8) and NMIBC cohort (n=460). Cross-validation was performed using 5 independent bladder cancer patient cohorts (n=1006). We also experimentally validated the changes of gene expression levels representing each subgroup. FINDINGS: The 976-gene signature based on YAP1-activation redefined three subgroups and had the benefits of Bacillus Calmette-Guérin (BCG) treatment in patients with NMIBC (hazard ratio 3.32, 95% CI 1.29-8.56, p = 0.01). The integrated analysis revealed that YAP1 activation was associated with the characterization of patients with high-risk NMIBC and the response to immunotherapy. INTERPRETATION: This study suggests that YAP1 activation has an important prognostic effect on bladder cancer progression and might be useful in the selection of immunotherapy. FUNDING: A funding list that contributed to this research can be found in the Acknowledgements section.
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Neoplasias da Bexiga Urinária , Adjuvantes Imunológicos , Vacina BCG , Humanos , Fatores Imunológicos/uso terapêutico , Imunoterapia , Invasividade Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Prognóstico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/terapia , Proteínas de Sinalização YAPRESUMO
The tumor microenvironment (TME) plays a critical role in tumorigenesis and is comprised of different components, including tumor cells, stromal cells, and immune cells. Among them, the relationship between each mediator involved in the construction of the TME can be understood by focusing on the secreting or expressing factors from each cells. Therefore, understanding the various interactions between each cellular component of the TME is necessary for precise therapeutic approaches. In carcinoma, stromal cells are well known to influence extracellular matrix (ECM) formation and tumor progression through multiple mediators. Immune cells respond to tumor cells by causing cytotoxicity or inflammatory responses. However, they are involved in tumor escape through immunoregulatory mechanisms. In general, anti-cancer therapy has mainly been focused on cancer cells themselves or the interactions between cancer cells and specific cell components. However, cancer cells directly or indirectly influence other TME partners, and members such as stromal cells and immune cells also participate in TME organization through their mutual communication. In this review, we summarized the relationship between stromal cells and immune cells in the TME and discussed the positive and negative relationships from the point of view of tumor development for use in research applications and therapeutic strategies.
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Fibroblastos Associados a Câncer , Neoplasias , Fibroblastos Associados a Câncer/patologia , Humanos , Células Estromais/patologia , Evasão Tumoral , Microambiente TumoralRESUMO
Subsequently to the publication of the above article, an interested reader drew to the authors' attention that certain of the data panels featured in Figs. 1B, 4A, 6A and 8A, showing DAPI or NAC staining of the cells, appeared to contain overlapping data. The authors have consulted their original data, and realize that errors were made during the compilation of these figures; consequently, they have repeated the affected experiments. The revised versions of Figs. 1, 4, 6 and 8, featuring replacement data for Figs. 1B, 4A, 6A and 8A, are shown on the subsequent pages. The authors regret the errors that were made during the preparation of the published figures, and confirm that these errors did not affect the conclusions reported in the study. The authors are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish a Corrigendum, and all the authors agree to this Corrigendum. Furthermore, they apologize to the readership for any inconvenience caused. [the original article was published in Oncology Reports 36: 205214, 2016; DOI: 10.3892/or.2016.4812].
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It is well-known that some species of lizard have an exceptional ability known as caudal autotomy (voluntary self-amputation of the tail) as an anti-predation mechanism. After amputation occurs, they can regenerate their new tails in a few days. The new tail section is generally shorter than the original one and is composed of cartilage rather than vertebrae bone. In addition, the skin of the regenerated tail distinctly differs from its original appearance. We performed a proteomics analysis for extracts derived from regenerating lizard tail tissues after amputation and found that endoplasmin (ENPL) was the main factor among proteins up-regulated in expression during regeneration. Thus, we performed further experiments to determine whether ENPL could induce chondrogenesis of tonsil-derived mesenchymal stem cells (T-MSCs). In this study, we found that chondrogenic differentiation was associated with an increase of ENPL expression by ER stress. We also found that ENPL was involved in chondrogenic differentiation of T-MSCs by suppressing extracellular signal-regulated kinase (ERK) phosphorylation. [BMB Reports 2022; 55(5): 226-231].