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INTRODUCTION: Lipid metabolism disorders have been confirmed to be closely related to kidney injury caused by adriamycin (ADR) and obesity, respectively. However, it has not been explored whether lipid metabolism disorders are related to kidney injury caused by ADR aggravated by obesity, and the specific molecular mechanism needs to be further clarified. OBJECTIVES: This study was designed to examine the role of p53-fibroblast growth factor 21 (FGF21) axis in ADR-induced renal injury aggravated by high fat diet (HFD). METHODS: We engineered Fgf21 KO mice and used long-term (4â¯months) and short-term (0.5â¯months) HFD feeding, and ADR-injected mice, as well as STZ-induced type 1 diabetic mice and type 2 (db/db) diabetic mice to produce a in vivo model of nephrotoxicity. The specific effects of p53/FGF21 on regulation of lipid metabolism disorders and its downstream mediators in kidney were subsequently elucidated using a combination of functional and pathological analysis, RNA-sequencing, molecular biology and in vitro approaches. RESULTS: Long-term HFD feeding mice exhibited compromised effects of FGF21 on alleviation of renal dysfunction and lipid accumulation following ADR administration. However, these impairments were reversed by p53 inhibitor (pifithrin-α, PFT-α). PFT-α sensitized FGF21 actions in kidney tissues, while knockout of Fgf21 impaired the protective effects of PFT-α on lipid metabolism. Mechanistically, p53 impaired the renal expression of FGF recepter-1 (FGFR1) and thereby developed gradually into FGF21 resistance via inhibiting hepatocyte nuclear factor alpha (HNF4α)-mediated transcriptional activation of Fgfr1. More importantly, exogenous supplementation of FGF21 or PFT-α could not only alleviate ADR-induced lipid metabolism disorder aggravated by HFD, but also reduce lipid accumulation caused by diabetic nephropathy. CONCLUSION: Given the difficulties in developing the long-acting recombinant FGF21 analogs for therapeutic applications, sensitizing obesity-impaired FGF21 actions by suppression of p53 might be a therapeutic strategy for maintaining renal metabolic homeostasis during chemotherapy.
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INTRODUCTION: Insulin resistance (IR) is associated with multiple pathological features. Although p53- or TRIB3-orchestrated IR is extensively studied in adipose tissue and liver, the role of p53-TRIB3 axis in myocardial IR remains unknown, and more importantly target-directed therapies of myocardial IR are missing. OBJECTIVES: Considering the beneficial effects of sulforaphane (SFN) on cardiovascular health, it is of particular interest to explore whether SFN protects against myocardial IR with a focus on the regulatory role of p53-TRIB3 axis. METHODS: Mouse models including cardiac specific p53-overexpressing transgenic (p53-cTg) mice and Trib3 knockout (Trib3-KO) mice, combined with primary cardiomyocytes treated with p53 activator (nutlin-3a) and inhibitor (pifithrin-α, PFT-α), or transfected with p53-shRNA and Trib3-shRNA, followed by multiple molecular biological methodologies, were used to investigate the role of p53-TRIB3 axis in SFN actions on myocardial IR. RESULTS: Here, we report that knockdown of p53 rescued cardiac insulin-stimulated AKT phosphorylation, while up-regulation of p53 by nutlin-3a or p53-cTg mice blunted insulin sensitivity in cardiomyocytes under diabetic conditions. Diabetic attenuation of AKT-mediated cardiac insulin signaling was markedly reversed by SFN in p53-Tgfl/fl mice, but not in p53-cTg mice. Importantly, we identified TRIB3 was elevated in p53-cTg diabetic mice, and confirmed the physical interaction between p53 and TRIB3. Trib3-KO diabetic mice displayed improved insulin sensitivity in the heart. More specifically, the AMPKα-triggered CHOP phosphorylation and degradation were essential for p53 on the transcriptional regulation of Trib3. CONCLUSION: Overall, these results indicate that inhibiting the p53-TRIB3 pathway by SFN plays an unsuspected key role in the improvement of myocardial IR, which may be a promising strategy for attenuating diabetic cardiomyopathy (DCM) in diabetic patients.
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Aims: Obese patients are highly sensitive to adriamycin (ADR)-induced cardiotoxicity. However, the potential mechanism of superimposed toxicity remains to be elucidated. Sestrin 2 (SESN2), a potential antioxidant, could attenuate stress-induced cardiomyopathy; therefore, this study aims to explore whether SESN2 enhances cardiac resistance to ADR-induced oxidative damage in high-fat diet (HFD)-induced obese mice. Results: The results revealed that obesity decreased SESN2 expression in ADR-exposed heart. And, HFD mice may predispose to ADR-induced cardiotoxicity, which was probably associated with inhibiting protein kinase B (AKT), glycogen synthase kinase-3 beta (GSK-3ß) phosphorylation and subsequently blocking nuclear localization of nuclear factor erythroid-2 related factor 2 (NRF2), ultimately resulting in cardiac oxidative damage. However, these destructive cascades and cardiac oxidative damage effects induced by HFD/sodium palmitate combined with ADR were blocked by overexpression of SESN2. Moreover, the antioxidant effect of SESN2 could be largely abolished by sh-Nrf2 or wortmannin. And sulforaphane, an NRF2 agonist, could remarkably reverse cardiac pathological and functional abnormalities caused by ADR in obese mice. Innovation and Conclusion: This study demonstrated that SESN2 might be a promising therapeutic target for improving anthracycline-related cardiotoxicity in obesity by upregulating activity of NRF2 via AKT/GSK-3ß/Src family tyrosine kinase signaling pathway. Antioxid. Redox Signal. 40, 598-615.
Subject(s)
NF-E2-Related Factor 2 , Proto-Oncogene Proteins c-akt , Animals , Humans , Mice , Antioxidants/metabolism , Cardiotoxicity , Diet, High-Fat/adverse effects , Doxorubicin/toxicity , Glycogen Synthase Kinase 3 beta/metabolism , Mice, Obese , NF-E2-Related Factor 2/metabolism , Obesity/drug therapy , Obesity/etiology , Oxidative Stress , Proto-Oncogene Proteins c-akt/metabolism , Sestrins/metabolismABSTRACT
Despite intensive studies for decades, the common mechanistic correlations among the underlying pathology of diabetes mellitus (DM), its complications, and effective clinical treatments remain poorly characterized. High-quality diets and nutrition therapy have played an indispensable role in the management of DM. More importantly, tribbles homolog 3 (TRIB3), a nutrient-sensing and glucose-responsive regulator, might be an important stress-regulatory switch, linking glucose homeostasis and insulin resistance. Therefore, this review aimed to introduce the latest research progress on the crosstalk between dietary nutrition intervention and TRIB3 in the development and treatment of DM. This study also summarized the possible mechanisms involved in the signaling pathways of TRIB3 action in DM, in order to gain an in-depth understanding of dietary nutrition intervention and TRIB3 in the pathogenesis of DM at the organism level.
Subject(s)
Diabetes Mellitus , Protein Serine-Threonine Kinases , Protein Serine-Threonine Kinases/antagonists & inhibitors , Humans , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Cell Cycle Proteins/metabolism , Insulin/metabolism , Glucose/metabolism , Diet , Repressor Proteins/metabolismABSTRACT
Quercetin is a natural flavonoid widely found in natural fruits and vegetables. Recent studies have shown that quercetin mediates multiple beneficial effects in a variety of organ damage and diseases, and is considered a healthcare supplement with health-promoting potential. Male infertility is a major health concern, and testicular damage from multiple causes is an important etiology. Previous studies have shown that quercetin has a protective effect on reproductive function. This may be related to the antioxidant, anti-inflammatory, and anti-apoptotic biological activities of quercetin. Therefore, this paper reviews the mechanisms by which quercetin exerts its pharmacological activity and its role in testicular damage induced by various etiologies. In addition, this paper compiles the application of quercetin in clinical trials, demonstrating its practical effects in regulating blood pressure and inhibiting cellular senescence in human patients. However, more in-depth experimental studies and clinical trials are needed to confirm the true value of quercetin for the prevention and protection against testicular injury.
Subject(s)
Flavonoids , Quercetin , Humans , Male , Quercetin/pharmacology , Quercetin/therapeutic use , Antioxidants/pharmacology , Antioxidants/therapeutic use , Blood Pressure , Cellular SenescenceABSTRACT
Doxorubicin (DOX) is a highly effective chemotherapeutic drug, but its long-term use can cause cardiotoxicity and drug resistance. Accumulating evidence demonstrates that p53 is directly involved in DOX toxicity and resistance. One of the primary causes for DOX resistance is the mutation or inactivation of p53. Moreover, because the non-specific activation of p53 caused by DOX can kill non-cancerous cells, p53 is a popular target for reducing toxicity. However, the reduction in DOX-induced cardiotoxicity (DIC) via p53 suppression is often at odds with the antitumor advantages of p53 reactivation. Therefore, in order to increase the effectiveness of DOX, there is an urgent need to explore p53-targeted anticancer strategies owing to the complex regulatory network and polymorphisms of the p53 gene. In this review, we summarize the role and potential mechanisms of p53 in DIC and resistance. Furthermore, we focus on the advances and challenges in applying dietary nutrients, natural products, and other pharmacological strategies to overcome DOX-induced chemoresistance and cardiotoxicity. Lastly, we present potential therapeutic strategies to address key issues in order to provide new ideas for increasing the clinical use of DOX and improving its anticancer benefits.
Subject(s)
Cardiotoxicity , Tumor Suppressor Protein p53 , Humans , Cardiotoxicity/etiology , Cardiotoxicity/drug therapy , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Doxorubicin/adverse effects , Apoptosis , Myocytes, Cardiac , Oxidative StressABSTRACT
Doxorubicin (DOX) has received attention due to dose-dependent cardiotoxicity through abnormal redox cycling. Native fibroblast growth factor 1 (FGF1) is known for its anti-oxidative benefits in cardiovascular diseases, but possesses a potential tumorigenic risk. Coincidentally, the anti-proliferative properties of resveratrol (RES) have attracted attention as alternatives or auxiliary therapy when combined with other chemotherapeutic drugs. Therefore, the purpose of this study is to explore the therapeutic potential and underlying mechanisms of co-treatment of RES and FGF1 in a DOX-treated model. Here, various cancer cells were applied to determine whether RES could antagonize the oncogenesis effect of FGF1. In addition, C57BL/6J mice and H9c2 cells were used to testify the therapeutic potential of a co-treatment of RES and FGF1 against DOX-induced cardiotoxicity. We found RES could reduce the growth-promoting activity of FGF1. Additionally, the co-treatment of RES and FGF1 exhibits a more powerful cardio-antioxidative capacity in a DOX-treated model. The inhibition of SIRT1/NRF2 abolished RES in combination with FGF1 on cardioprotective action. Further mechanism analysis demonstrated that SIRT1 and NRF2 might form a positive feedback loop to perform the protective effect on DOX-induced cardiotoxicity. These favorable anti-oxidative activities and reduced proliferative properties of the co-treatment of RES and FGF1 provided a promising therapy for anthracycline cardiotoxicity during chemotherapy.
Subject(s)
Cardiotoxicity , Fibroblast Growth Factor 1 , NF-E2-Related Factor 2 , Resveratrol , Sirtuin 1 , Animals , Apoptosis , Cardiotoxicity/drug therapy , Doxorubicin/toxicity , Fibroblast Growth Factor 1/pharmacology , Mice , Mice, Inbred C57BL , Myocytes, Cardiac , NF-E2-Related Factor 2/metabolism , Oxidative Stress , Resveratrol/pharmacology , Sirtuin 1/metabolismABSTRACT
Doxorubicin (DOX), an anthracycline type of chemotherapy, is an effective therapy for several types of cancer, but serious side effects, such as severe hepatotoxicity, limit its use currently. Accordingly, an effective therapeutic strategy to prevent DOX-related hepatotoxicity is urgently needed. Through the inhibition of oxidative stress, fibroblast growth factor 1 (FGF1) is an effect therapy for a variety of liver diseases, but its use is limited by an increased risk of tumorigenesis due to hyperproliferation. Resveratrol (RES), a natural product, inhibits the growth of many cancer cell lines, including liver, breast, and prostate cancer cells. Therefore, this study explored whether and how RES in combination with FGF1 can alleviate DOX-induced hepatotoxicity. The results showed that RES or FGF1 alone improved DOX-induced hepatic inflammation, apoptosis and oxidative stress, and these adverse effects were further attenuated after treatment with both RES and FGF1. Mechanistically, both in vivo and in vitro results showed that RES/FGF1 reduced oxidative stress and thereby alleviated liver injury by promoting nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) and subsequently upregulating expression of antioxidant proteins in an adenosine monophosphate-activated protein kinase (AMPK)-dependent manner. Together, our results not only demonstrate that co-treatment with RES and FGF1 significantly inhibited DOX-induced hepatic inflammation and apoptosis, but also that co-treatment with RES and FGF1 markedly suppressed DOX-induced hepatic oxidative stress, via targeting the AMPK/NRF2 pathway and subsequently ameliorating hepatic dysfunction. Thus, the combination of RES and FGF1 may provide a new therapeutic strategy for limiting DOX-induced hepatotoxicity.
ABSTRACT
Osteoblast dysfunction, induced by high glucose (HG), negatively impacts bone homeostasis and contributes to the pathology of diabetic osteoporosis (DOP). One of the most widely recognized mechanisms for osteoblast dysfunction is oxidative stress. Resveratrol (RES) is a bioactive antioxidant compound to combat oxidative damage. However, its role in the protection of HG-induced osteoblast dysfunction has not been clarified. Therefore, our study aimed to explore potential regulatory mechanisms of RES for attenuating HG-induced osteoblast dysfunction. Our results showed that osteoblast dysfunction under HG condition was significantly ameliorated by RES via the activation of nuclear factor erythroid 2-related factor (NRF2) to suppress oxidative stress. Furthermore, using Nrf2-shRNA and wortmannin, we identified that activation of NRF2 via RES was regulated by the AKT/glycogen synthase kinase 3ß (GSK3ß)/FYN axis.
ABSTRACT
Although it is known that the expression and activity of sirtuin 1 (SIRT1) significantly decrease in doxorubicin (DOX)-induced cardiomyopathy, the role of interaction between SIRT1 and sestrin 2 (SESN2) is largely unknown. In this study, we investigated whether SESN2 could be a crucial target of SIRT1 and the effect of their regulatory interaction and mechanism on DOX-induced cardiac injury. Here, using DOX-treated cardiomyocytes and cardiac-specific Sirt1 knockout mice models, we found SIRT1 deficiency aggravated DOX-induced cardiac structural abnormalities and dysfunction, whereas the activation of SIRT1 by resveratrol (RES) treatment or SIRT1 overexpression possessed cardiac protective effects. Further studies indicated that SIRT1 exerted these beneficial effects by markedly attenuating DOX-induced oxidative damage and apoptosis in a SESN2-dependent manner. Knockdown of Sesn2 impaired RES/SIRT1-mediated protective effects, while upregulation of SESN2 efficiently rescued DOX-induced oxidative damage and apoptosis. Most importantly, SIRT1 activation could reduce DOX-induced SESN2 ubiquitination possibly through reducing the interaction of SESN2 with mouse double minute 2 (MDM2). The recovery of SESN2 stability in DOX-impaired primary cardiomyocytes by SIRT1 was confirmed by Mdm2-siRNA transfection. Taken together, our findings indicate that disrupting the interaction between SESN2 and MDM2 by SIRT1 to reduce the ubiquitination of SESN2 is a novel regulatory mechanism for protecting hearts from DOX-induced cardiotoxicity and suggest that the activation of SIRT1-SESN2 axis has potential as a therapeutic approach to prevent DOX-induced cardiotoxicity.
Subject(s)
Cardiomyopathies , Cardiotoxicity , Animals , Apoptosis , Cardiomyopathies/metabolism , Cardiotoxicity/drug therapy , Doxorubicin/adverse effects , Mice , Myocytes, Cardiac/metabolism , Oxidative Stress , Sestrins , Sirtuin 1/genetics , Sirtuin 1/metabolismABSTRACT
A cumulative and progressively developing cardiomyopathy induced by adriamycin (ADR)-based chemotherapy is a major obstacle for its clinical application. However, there is a lack of safe and effective method to protect against ADR-induced cardiotoxicity. Here, we found that mRNA and protein levels of FGF1 were decreased in ADR-treated mice, primary cardiomyocytes and H9c2 cells, suggesting the potential effect of FGF1 to protect against ADR-induced cardiotoxicity. Then, we showed that treatment with a FGF1 variant (FGF1ΔHBS) with reduced proliferative potency significantly prevented ADR-induced cardiac dysfunction as well as ADR-associated cardiac inflammation, fibrosis, and hypertrophy. The mechanistic study revealed that apoptosis and oxidative stress, the two vital pathological factors in ADR-induced cardiotoxicity, were largely alleviated by FGF1ΔHBS treatment. Furthermore, the inhibitory effects of FGF1ΔHBS on ADR-induced apoptosis and oxidative stress were regulated by decreasing p53 activity through upregulation of Sirt1-mediated p53 deacetylation and enhancement of murine double minute 2 (MDM2)-mediated p53 ubiquitination. Upregulation of p53 expression or cardiac specific-Sirt1 knockout (Sirt1-CKO) almost completely abolished FGF1ΔHBS-induced protective effects in cardiomyocytes. Based on these findings, we suggest that FGF1ΔHBS may be a potential therapeutic agent against ADR-induced cardiotoxicity.
Subject(s)
Cardiotoxicity , Doxorubicin , Animals , Apoptosis , Cardiotoxicity/pathology , Doxorubicin/adverse effects , Fibroblast Growth Factor 1/genetics , Fibroblast Growth Factor 1/metabolism , Fibroblast Growth Factor 1/pharmacology , Mice , Myocytes, Cardiac/metabolism , Oxidative Stress , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
Fibroblast growth factor 1 (FGF1) has a critical regulatory role in the development of the cardiovascular system (CVS) and is strongly associated with the progression or treatment of cardiovascular diseases (CVDs). However, the regulatory mechanisms of FGF1 in CVS and CVDs have not yet been fully elucidated. Therefore, this review article summarized the existing literature reports on the role of FGF1 in CVS under physiological and pathological conditions. First, the expression and physiological functions of endogenous FGF1 is fully demonstrated. Then, we analyzed the role of exogenous FGF1 in normal CVS and related pathological processes. Specifically, the potential signaling pathways might be mediated by FGF1 in CVDs treatment is discussed in detail. In addition, the barriers and feasible solutions for the application of FGF1 are further analyzed. Finally, we highlight therapeutic considerations of FGF1 for CVDs in the future. Thus, this article may be as a reference to provide some ideas for the follow-up research.
Subject(s)
Cardiovascular Diseases/metabolism , Cardiovascular System/drug effects , Fibroblast Growth Factor 1/physiology , Animals , Cardiovascular Diseases/physiopathology , Cardiovascular Physiological Phenomena/drug effects , Cardiovascular System/metabolism , Fibroblast Growth Factor 1/pharmacology , HumansABSTRACT
Waste activated sludge (WAS) was disintegrated by composite ferrate solution (CFS) in this work, and the effect of CFS disintegrated sludge supernatant (CDSS), as a supplementary carbon source, on enhancement of nitrogen and phosphorus removal and sludge reduction in an AAO-CFSSDR (Anaerobic/Anoxic/Oxic combined with CFS-Sludge disintegration reactor) process was evaluated. The results showed that CDSS was easily utilizable by the denitrification bacteria due to the high content of readily biodegradable substrates. When compared with the AAO process, the operation results of AAO-CFSSDR suggested that the removal efficiencies of TN, NH4+-N and TP increased from 71.15, 79.23 and 85.52% to 85.05, 87.70 and 90.06%, respectively; and the sludge was reduced by 34.79%. The 16SrRNA high-throughput sequencing results showed that the introduction of CDSS weakened the microbial diversity but enhanced the microbial richness; and the abundance of bacteria related to the removal of nitrogen and phosphorus, increased in the AAO-CFSSDR process.
Subject(s)
Microbiota , Sewage , Anaerobiosis , Bioreactors , Iron , Nitrogen , Phosphorus , Waste Disposal, Fluid , WastewaterABSTRACT
BACKGROUND: Cervical cancer is one of the most common cancers among females worldwide and advanced patients have extremely poor prognosis. However, adverse reactions and accumulating resistance to radiation therapy require further investigation. METHODS: The expression levels of mitogen-activated protein kinase 4 (MAPK4) mRNA were analyzed by real-time PCR and its association with overall survival was analyzed using Kaplan-Mier method. Colony formation, immunofluorescence and western blotting were used to examine the effects of MAPK4 knockout or over-expression on cervical cancer cells after radiation treatment. Drug-sensitivity of cervical cancer cells to PARP1 inhibitors, olaparib or veliparib, was analyzed by CCK-8 cell viability assays, and the 50% inhibitory concentration (IC50) was quantified using GraphPad Prism. The functional effects of MAPK4 knockout on the sensitivity of cervical cancer to radiation treatment and PARP1 inhibitors were further examined using xenograft tumor mouse models in vivo. RESULTS: Cervical cancer patients with high MAPK4 mRNA expression have lower survival rate. After radiation treatment, the colony number of MAPK4 knockout cells was markedly reduced, and the markers for DNA double-chain breakage were significantly up-regulated. In addition, MAPK4 knockout reduced protein kinase B (AKT) phosphorylation, whereas its over-expression resulted in opposite effects. In MAPK4 KO cells with irradiation treatment, inhibition of AKT phosphorylation promoted DNA double-chain breakage. Constitutive activation of AKT (CA-AKT) increased the levels of phosphorylated-AKT (p-AKT), and DNA repair-related proteins, phosphorylated-DNA-dependent protein kinase (p-DNA-PK) and RAD51 recombinase (RAD51). Furthermore, MAPK4 knockout was found to affect the sensitivity of cervical cancer cells to poly ADP-ribose polymerase 1 (PARP1) inhibitors by activating the phosphorylation of AKT. Moreover, in vivo results demonstrated that MAPK4 knockout enhanced the sensitivity of cervical cancer to radiation and PARP1 inhibitors in mouse xenograft models. CONCLUSIONS: Collectively, our data suggest that combined application of MAPK4 knockout and PARP1 inhibition can be used as therapeutic strategy in radiation treatment for advanced cervical carcinoma.
Subject(s)
Chemoradiotherapy , Gamma Rays , Gene Deletion , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , RNA Helicases/metabolism , Uterine Cervical Neoplasms/therapy , Animals , Apoptosis , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Proliferation , Female , Gene Expression Regulation, Neoplastic , Humans , Mice , Mice, Inbred BALB C , Mice, Knockout , Mice, Nude , Phosphorylation , Phthalazines/pharmacology , Piperazines/pharmacology , Prognosis , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , RNA Helicases/genetics , Radiation-Sensitizing Agents/administration & dosage , Survival Rate , Tumor Cells, Cultured , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/pathology , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Ovarian cancer is a severe gynecological malignancy. Paraneoplastic Ma antigen 5 (PNMA5) is a confirmed tumor onconeural antigen, which has been screened as a female fertility factor. PNMA5 overexpression might serve as a marker of poor prognosis in colon cancer. Our earlier study showed that PNMA5 was essential for meiosis in mouse oocytes. In this study, we investigate the role and probable mechanism of PNMA5 in the occurrence and development of epithelial ovarian cancer (EOC). METHODS: Immunochemistry and western blot analyses were used to verify PNMA5 overexpression in clinical EOC tissues and EOC cell line HO8910. A specific siRNA was used to reduce PNMA5 levels, and several proliferation and migration-related indexes were assessed. We also examined mitochondria, microfilaments, and several essential kinases. RESULTS: We found that the expression of PNMA5 in EOC tissues was significantly higher than that in benign ovarian tumors and healthy normal ovarian tissues and that this was strictly related to the FIGO stage and histological grade. PNMA5 expression in ovarian cancer cell line HO8910 was higher than that in the normal healthy ovarian cell line Moody. PNMA5 knockdown in HO8910 cells not only inhibited the proliferation, migration, invasion, cell cycle, and F-actin polymerization of HO8910 cells but also promoted early apoptosis and led to abnormal distribution and accumulation of mitochondria. PNMA5 phosphorylation was found to be positively regulated by Src activity, and PNMA5 phosphorylation promoted the downstream glycogen synthase kinase-3ß (GSK-3ß) signaling pathway. CONCLUSIONS: PNMA5 plays a pivotal role in the occurrence and development of EOC and is a potential marker of this disease.
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Circular RNAs (circRNAs) are becoming new therapeutic drug targets. However, their profiles under astilbin treatment have not been reported yet. In this study, we analysed the global reprogramming of circRNA transcriptome and a regulatory network of circRNAs with their targeted genes under astilbin treatment in pulmonary fibrosis. A total of 145 circRNAs were differentially expressed in the astilbin-treated group compared with the bleomycin-treated group using RNA sequencing. In the bleomycin- and astilbin-treated groups, 29 coexpressed circRNAs were found. The maximum number of circRNAs was distributed on chromosome two, and their length varieties were mainly within 1000 bp. Four differentially expressed circRNAs (circRNA-662, 949, 394 and 986) were tested to validate the RNA sequencing data, and their targeted microRNAs and genes were analysed by qRT-PCR, Western blot, Pearson correlation coefficient, a dual-luciferase reporter system and anti-AGO2 RNA immunoprecipitation. The results showed that circRNA-662 and 949 can act as "miR-29b sponges" targeting Gli2 and STAT3 to exert their functions. Our work suggests that the transcriptome complexity at the circRNA level under astilbin treatment. These circRNAs may be potential molecular targets for drug action.
Subject(s)
Flavonols/therapeutic use , Gene Regulatory Networks/genetics , Pulmonary Fibrosis/genetics , RNA, Circular/metabolism , Animals , Bleomycin , Collagen/metabolism , Fibroblasts/drug effects , Fibroblasts/metabolism , Gene Ontology , Mice , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/metabolism , RNA, Circular/genetics , RNA-Seq , Transcriptome/geneticsABSTRACT
BACKGROUND/AIMS: High levels of cancer stem cells (CSCs) in patients with triple-negative breast cancer (TNBC) correlate with risk of poor clinical outcome and possibly contribute to chemoresistance and metastasis in patients with highly malignant TNBC. Aberrant microRNA expression is associated with the dysfunction of self-renewal and proliferation in cancer stem cells, while there is little information about the TNBC-specific microRNAs in regulating CSC ability. METHODS: Solexa deep sequencing was performed to detect the expression levels of TNBC or non-TNBC stem cells (CSCs) microRNAs. Mammosphere formation assay, qRT-PCR and the xenograft model in nude mice were performed. Bioinformatic analysis and microarray were used to select the target gene, and luciferase reporter assays were used to confirm the binding sites. RESULTS: Solexa sequencing data exhibited differential expression of 193 microRNAs between TNBC and non-TNBC stem cells. The gene ontology analysis and pathways analyses showed that genes were involved in the maintenance of stemness. MiR-4319 could suppress the self-renewal and formation of tumorspheres in TNBC CSCs through E2F2, and also inhibited tumor initiation and metastasis in vivo. Moreover, increased E2F2 could reverse the effect of miR-4319 on the self-renewal in TNBC CSCs. CONCLUSIONS: MiR-4319 suppresses the malignancy of TNBC by regulating self-renewal and tumorigenesis of stem cells and might be a remarkable prognostic factor or therapeutic target for patients with TNBC.
Subject(s)
MicroRNAs/metabolism , 3' Untranslated Regions , Animals , Antagomirs/metabolism , Base Sequence , Cell Line, Tumor , Cell Self Renewal , Cell Transformation, Neoplastic , E2F2 Transcription Factor/antagonists & inhibitors , E2F2 Transcription Factor/genetics , E2F2 Transcription Factor/metabolism , Female , Humans , Liver Neoplasms/pathology , Liver Neoplasms/secondary , Mice , Mice, Nude , MicroRNAs/antagonists & inhibitors , MicroRNAs/genetics , Neoplastic Stem Cells/cytology , Neoplastic Stem Cells/metabolism , RNA Interference , RNA, Small Interfering/metabolism , Sequence Alignment , Transplantation, Heterologous , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathologyABSTRACT
BACKGROUND/AIMS: Trastuzumab is an important treatment used for patients with Her-2-positive breast cancer, but an increasing incidence of trastuzumab resistance has been observed clinically during the past decade. Aberrant microRNA (miR) expression levels are correlated with prognosis and response to trastuzumab in breast cancer. MiR-129-5p is downregulated in trastuzumab-resistant human breast cancer cells (JIMT-1), but its potential function and underlying mechanism remain unclear. METHODS: Quantitative RT-PCR (qRT-PCR) was used to determine the expression levels of miR-129-5p and its potential target genes. The effects of miR-129-5p on cell responses to trastuzumab were analyzed by CCK-8 and flow cytometry assays in Her-2-positive breast cancer cells (SKBR-3 and JIMT-1). Bio-informatics analyses were performed to predict target genes of miR-129-5p, and luciferase assays were carried out to confirm the binding of miR-129-5p and rpS6. RESULTS: MiR-129-5p, which was downregulated and predicted to target rpS6 in trastuzumab-resistant breast cancer cells, enhanced the sensitivity of breast cancer cells to trastuzumab by reducing the expression of rpS6. Moreover, the overexpression of rpS6 reversed the sensitivity of cells to trastuzumab induced by miR-129-5p. CONCLUSIONS: MiR-129-5p sensitized Her-2-positive breast cancer to trastuzumab by downregulating rpS6. These findings provide novel insights into the common role of rpS6 and its related molecular mechanisms in mediating trastuzumab-resistance in Her-2-positive breast cancers.
Subject(s)
Antineoplastic Agents, Immunological/pharmacology , Breast Neoplasms/drug therapy , Drug Resistance, Neoplasm , MicroRNAs/genetics , Receptor, ErbB-2/analysis , Ribosomal Protein S6/genetics , Trastuzumab/pharmacology , Antineoplastic Agents, Immunological/therapeutic use , Breast/drug effects , Breast/metabolism , Breast/pathology , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , Down-Regulation , Female , Gene Expression Regulation, Neoplastic , Humans , Trastuzumab/therapeutic useABSTRACT
Breast cancer is one of the most common malignancies and bone is the commonest site of distant metastases. Evidences indicate that adequate supply of vitamin D will decrease the morbidity and mortality of breast cancer. However, the main role of vitamin D deficiency in breast cancer bone metastases remains unclear. In this study, the relationship between vitamin D and breast cancer bone metastases were evaluated. Results showed that 1,25(OH)2D3 can not only inhibit the proliferation, migration and invasion of breast cancer cell TM40D in vitro, but also attenuate the breast cancer cell TM40D-induced bone destruction in vivo, whose underlying mechanism was at least partially through decreasing the number of the osteoclasts. To our knowledge, this is the first to use 1-alpha-hydroxylase [1α(OH)ase] knockout mice which characterized vitamin D deficiency to establish the breast cancer bone metastases model. Based on this model, we also found that vitamin D deficiency will accelerate the osteolytic lesions, and 1,25(OH)2D3 supplement will restrain osteolytic lesions. Therefore, these findings suggest that vitamin D has the potential capacity to be a therapeutic agent for the breast cancer bone metastases.
Subject(s)
Bone Neoplasms/secondary , Bone and Bones/pathology , Calcitriol/deficiency , Mammary Neoplasms, Animal/pathology , 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/metabolism , Animals , Bone Neoplasms/diagnostic imaging , Bone Neoplasms/pathology , Bone Remodeling , Bone and Bones/diagnostic imaging , Cell Line, Tumor , Cell Movement , Cell Proliferation , Disease Models, Animal , Female , Mice , Neoplasm Invasiveness , Osteolysis/complications , Osteolysis/pathology , Tartrate-Resistant Acid Phosphatase/metabolism , X-Ray MicrotomographyABSTRACT
OBJECTIVE: To study clinical efficacy of surgery after the DCF induction chemotherapy in T2-3 laryngeal carcinoma and hypopharyngeal carcinoma. METHOD: To analyze clinical data about 102 cases of T2-3 laryngeal carcinoma and hypopharyngeal carcinoma retrospectively, 62 cases were divided into experimental group and 40 cases in control group, the experimental group completed three cycles of the DCF induction chemotherapy, then the efficacy was evaluated, surgery were carried out in the end, the control group received operation directly. In two groups, tumor response rates, toxicities, positive surgical margin rates and survival rate differences were observed and compared. RESULT: Tumor response rate was 61.3% in experimental group, the laryngeal carcinoma rate was significantly lower than that in hypopharyngeal (44.4% VS 84.6%, P < 0.05). Compared to its control, there were no significant differences about the positive surgical margin rate, the median survival time, 3-year and 5-year survival rate of laryngeal carcinoma(P > 0.05). The foci edges of 0. 3 cm and 0. 5 cm positive margin rate of hypopharyngeal carcinoma in experimental group were significantly lower than in its control (P < 0.05), but among the 1 cm edge' positive rate, the median survival time, 3-year and 5-year survival rate no significant differences were found (P > 0.05). During induction chemotherapy in the experimental group, no serious adverse reactions were found. CONCLUSION: Induction chemotherapy of DCF regimen can not only narrow T2-3 laryngeal carcinoma and hypopharyngeal carcinoma' area, but also ensure an adequate safety margin.