Plants are frequently subjected to a broad spectrum of abiotic stresses including drought, salinity and extreme temperatures and have evolved both common and stress-specific responses to promote fitness and survival. Understanding the components and mechanisms that underlie both common and stress-specific responses can enable development of crop plants tolerant to different stresses. Here, we report a rice heat stress-tolerant 1 ( hst1 ) mutant with increased heat tolerance. HST1 encodes the DST transcription factor, which also regulates drought and salinity tolerance. Increased heat tolerance of hst1 was associated with suppressed expression of reactive oxygen species (ROS)-scavenging peroxidases and increased ROS levels, which reduced water loss by decreasing stomatal aperture under heat stress. In addition, increased ROS levels enhanced expression of genes encoding heat shock protein (HSPs) including HSP80, HSP74, HSP58 and small HSPs. HSPs promote stabilization of proteins and protein refolding under heat stress and accordingly mutation of HST1 also improved reproductive traits including pollen viability and seed setting under high temperature. These results broaden the negative roles of DST in abiotic stress tolerance and provide important new insights into DST-regulated tolerance to diverse abiotic stresses through both shared and stress-specific mechanisms.
Abstract Objective β‐catenin is one of the most critical oncogenes associated with many kinds of human cancers, especially in the human CRC. Innate immunity recognizes tumour derived damage‐associated molecular patterns (DAMPs) and primes the anti‐tumour adaptive responses. While the function of β‐catenin in CRC tumourigenesis is well established, its impact on innate immune evasion is largely unknown. The aim of this study is to characterize the role of β‐catenin in inhibiting RIG‐I‐like receptor (RLR)‐mediated IFN‐β signalling in colorectal cancer. Materials and Methods Immunohistochemical staining and western blotting were conducted to study the expression of β‐catenin, IRF3 and phospho‐IRF3 (p‐IRF3) in CRC samples and cell lines. Plaque assay determining virus replication was performed to assess the regulation of β‐catenin on IFN‐β signalling. The inhibition of β‐catenin on RLR‐mediated IFN‐β signalling was further studied by real‐time analyses and reporter assays in the context of lentiviral‐mediated β‐catenin stably knocking down. Lastly, co‐immunoprecipitation and nuclear fractionation assay were conducted to monitor the interaction between β‐catenin and IRF3. Results We found that high expression of β‐catenin positively correlated with the expression of IRF3 in CRC cells. Overexpression of β‐catenin increased the viral replication. Conversely knocking down of β‐catenin inhibited viral replication. Furthermore, our data demonstrated that β‐catenin could inhibit the expression of IFN‐β and interferon‐stimulated gene 56 (ISG56). Mechanistically, we found that β‐catenin interacted with IRF3 and blocked its nuclear translocation. Conclusion Our study reveals an unprecedented role of β‐catenin in enabling innate immune evasion in CRC.
Background: Brucellosis, one of the most common zoonotic diseases globally, is a serious public health problem. The complex and diverse clinical manifestations pose numerous challenges for patients when coping with brucellosis. Scarce studies have been performed in China. Objectives: This study aimed to explore the process of coping with brucellosis and different aspects of the phenomenon from the perspective of patients, and propose a conceptual framework of patients’ processes in coping with brucellosis. Methods: Qualitative study based on constructivist grounded theory methodology using in-depth interviews and focus group discussions. The data analysis included initial coding, focused coding, and theoretical coding using the constant comparative method and memo writing. Results: The conceptual framework of “compelled metamorphosing” was constructed, which conceptualized three primary types of coping strategies: “blind persistence”, “resignation to avoidance”, and “proactive pacing”. Symptoms, financial strain, information cocoon, emotional value, and family responsibility had an important impact on coping strategies and played a significant role in driving their development. Conclusions: This paper provides new insight into patients’ lives and describes the strategies patients use to cope with the challenges and problems caused by brucellosis. Compelled metamorphosing represents a basic psychosocial process. These findings can be used to develop future complex interventions and studies.
Some reports suggest that high absolute monocyte count (AMC) at diagnosis is an independent predictor of poor prognosis in acute myeloid leukemia (AML), but others disagree. Monocytic myeloid-derived suppressor cells (Mo-MDSCs) are immature monocytes. This study aimed to compare the value of monocytes and Mo-MDSCs in predicting the prognosis of AML.Peripheral blood samples from 107 newly diagnosed patients with AML and 47 healthy controls (HCs) were collected. We validated the clinical significance of AMC, monocyte count (CD14+CD45++), and Mo-MDSC count (CD14+HLA-DRlow/-CD45++) for initial induction therapy response, maintenance of treatment effects, and long-term survival.Compared with HCs, the levels of AMC, monocyte count, and Mo-MDSC count were all significantly higher among patients with AML. However, only elevated Mo-MDSC count was significantly associated with lower complete remission rate, higher relapse/refractory rate, and poorer long-term survival.Mo-MDSCs but not monocytes predict the poor prognosis of AML.Bazı yayınlara göre tanıda yüksek mutlak monosit sayısı (AMC) akut myeloid lösemi (AML) olgularında bağımsız kötü prognoz belirtecidir, ama bazı yayınlar bu sonucu desteklememektedir. Monositik myeloid süpresör hücreler (Mo-MDSCs) olgunlaşmamış monositlerdir. Bu çalışmadaki amacımız AML’de prognozu belirlemek adına monositlerin ve Mo-MDSC’lerin değerini tespit etmektir.Yüz yedi yeni tanı AML hastasından ve 47 sağlıklı kontrolden (HC) periferik kan örneği alındı. AMC, monosit sayısı (CD14+CD45++), ve Mo-MDSC sayısını (CD14+HLA-DRlow/-CD45++) indüksiyon tedavisine yanıtta, tedavi yanıtının idamesi üzerine etkisinde ve uzun dönem sağkalım için değerlendirdik.HC ile karşılaştırıldığında, AMC sayısı, monosit sayısı ve Mo-MDSC sayısı AML hastalarında anlamlı düzeyde daha yüksek saptanmıştır. Fakat, sadece Mo-MDSC sayısı daha düşük tam remisyon oranları, daha yüksek relaps/refrakterlik oranları ve uzun dönem olumsuz sağkalım süresi ile ilişkili bulundu.Monositler yerine Mo-MDSC’ler AML’de kötü prognoz için belirteçtirler.
Abstract Ovarian cancer (OCa) is the deadliest of all gynecologic cancers in the United States. Although patients with OCa respond initially to standard combinations of surgical and cytotoxic therapy, nearly 90% will develop recurrence and inevitably succumb to chemotherapy-resistant disease. Estrogen mediates its effects through the estrogen receptor α (ESR1) and estrogen receptor β (ESR2). Recent studies suggest that OCa cells and OCa stem cells express ESR2, which functions as a tumor suppressor and identified synthetic compound LY500307 as a potent ESR2 specific agonist. However, ESR2 expression decreases during tumor progression and under the selection pressure of chemotherapy; this decrease occurs via epigenetic mechanisms. The lysine-specific histone demethylase 1A (KDM1A/LSD1) is overexpressed in OCa and plays a vital role in metastasis and cancer stemness. Our group recently developed a novel KDM1A-specific inhibitor (NCD-38) based on an innovative concept of direct delivery of phenylcyclopropylamine to the KDM1A active site. We reason that agents that restore the expression and functions of ESR2 by increasing active histone marks may provide a novel therapeutic opportunity to reactivate ESR2 for suppression of OCa. The objective of this study is to test whether KDM1A inhibitor could enhance the expression and tumor suppressive functions of ESR2 and to test the combination of KDM1A inhibitor along with ESR2 agonist using in vitro and in vivo preclinical models. Our results demonstrated that combination of ESR2 agonist and KDM1A inhibitor reduces the cell viability of OCa cells synergistically. Further caspase-3/7 activity and Annexin V assays showed synergistic induction of apoptosis upon combination therapy. Matrigel invasion assays revealed reduction in cell invasion of OCa cell lines following ESR2 agonist and KDM1A inhibitor treatment. RT-qPCR analysis demonstrated that KDM1A inhibitor treatment significantly increases the expression of ESR2 and its target genes leading to increased tumor suppression. Further, co-immunoprecipitation analysis revealed that KDM1A interacts with ESR2 and Chromatin immunoprecipitation assays demonstrated that KDM1A inhibition increases the recruitment of active histone methylation mark H3K4-me2 at ESR2 0N promoter. RNA-sequencing analysis demonstrated that ESR2 agonist treatment modulates the several pathways related to cell cycle, apoptosis and DNA damage check point regulation. Finally, ESR2 agonist and KDM1A inhibitor treatment significantly reduced the in vivo tumor growth in orthotopic models. Since ESR2 agonists and KDM1A inhibitors are currently in clinical trials for other clinical indications and are well tolerated, identification of KDM1A inhibitor and ESR2 agonist combination therapy as a novel therapeutic can be readily transferred to clinical use for enhancing survival in OCa patients. Citation Format: Gangadhara Reddy R. Sareddy, Jinyou Liu, Lauren Garcia, Suryavathi Viswanadhapalli, Mei Zhou, Takayoshi Suzuki, Edward Kost, Ratna K. Vadlamudi. Enhancing estrogen receptor beta mediated tumor suppression by lysine specific demethylase 1A inhibitor for the treatment of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4052. doi:10.1158/1538-7445.AM2017-4052
Current treatment options for glioblastoma (GBM) are poor, the mortality rates are very high and therapy resistance is a major clinical problem. Standard treatment consists of surgical resection, external beam radiation therapy, adjuvant chemotherapy with temozolomide (TMZ), and tumor treating fields. Nonetheless, despite a heavy investment in therapy, all patients eventually succumb to their disease. Recent studies suggest that estrogen receptor beta (ERβ) may function as a tumor suppressor in GBM. However, the mechanism(s) by which ERβ contributes to chemo- and radiation therapy response remains unknown. The objective of this study is to examine whether ERβ sensitizes GBM to chemo- and radiation therapy and to understand the mechanistic insights of ERβ mediated tumor suppression in GBM.Methods: To study the functions of endogenous ERβ in GBM cells, we have utilized multiple ERβ overexpressing GBM model (GBM- ERβ) cells using lentiviral transduction. As a second model we have also generated ERβ knockout (ERβKO) cells using CRISPR/Cas9 system, and as a third model we used lentiviral-ERβshRNA transfected primary GBM cells (ERβKD). We then examined the effect of TMZ and radiation on the expression of ERβ using qRT-PCR. The effect of TMZ and radiation on ERβ overexpression and knockout models was examined using MTT cell viability assays. Mechanistic studies were conducted using RNA-seq, HR reporter gene assays, confocal microscopy, western blot, and qRT-PCR analysis. The in vivo role of ERβ on chemo sensitivity of TMZ was studied using orthotopic models of GBM and mouse survival was determined using Kaplan-Meier survival curves.Results: Cell viability and survival assays using multiple established and primary GBM cells demonstrated that ERβ sensitizes GBM cells to DNA damaging agents including TMZ and radiation therapy. qRT-PCR analysis demonstrated that ERβ expression was decreased following chemo- and radiation treatment. Combination analysis of RNA-seq studies using ERβ overexpression, and ERKO models, revealed an alteration in the number of genes involved in DNA recombination and repair, ATM signaling, and cell cycle check point control. Mechanistic studies showed that ERβ plays a significant role in homologous recombination (HR) mediated repair; and ERβ reduced expression and activation of ATM upon DNA damage. Generation of optimal γH2AX foci following TMZ treatment is dependent on the status of ERβ. More importantly, GBM cells expressing ERβ had increased survival when compared to control GBM cells in orthotopic GBM models. ERβ overexpression further enhanced the survival of mice to TMZ therapy in both TMZ sensitive and TMZ resistant GBM models.Conclusion: Our results provided evidence that ERβ is required for optimal chemo- and radiation- induced DNA damage response in GBM cells.Citation Format: Uday P. Pratap, Gangadhara Reddy Sareddy, Mengxing Li, Yiliao Luo, Mei Zhou, Suryavathi Viswanadhapalli, Rajeshwar Rao Tekmal, Andrew Brenner, Ratna K. Vadlamudi. Estrogen receptor beta signaling sensitizes glioblastoma cells to chemo and radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1712.
Abstract Background: Glioblastoma (GBM) is a recurrent, chemoresistant, malignant brain tumor. Hypoxia is a major factor contributing to resistance in GBM which develops due to aggressive tumor growth and chronic anti-angiogenic therapy. Thus, under limited oxygen supply it is unlikely that the high energy consuming pathways are solely able to provide the energy requirement of GBM cells. Thus, based on our metabolomics data stated below we hypothesize that GBM cells adapt to chronic hypoxia utilizing alternate metabolic pathways such as peroxisomal fatty acid oxidation (FAO). Here we have explored the role of Acyl coenzyme A oxidase (ACOX-1), a rate limiting enzyme for peroxisomal FAO in the metabolic adaptations to hypoxia and as a potential drug target. Methods: U251 CRISPR dox inducible ACOX1 (KO) cells and patient derived primary GBM were grown under normoxic and hypoxic conditions (2%O2, 5%CO2, 70% humidity). Metabolic analysis was done using UHPLC-MS and LCMS analysis. RNAseq was done using TopHat2 (genome alignment), HTSeq, and DEseq to study the differential gene expression at cut-off of 2-fold change, and p<0.05. GSEA was used to interpret biological pathways. NCr/SCID (Severe Combined Immunodeficiency) mice (n=5) inoculated with U251 ACOX1 knockout cells expressing luciferase were used and treated with anti-angiogenic agent pazopanib at 30 mg/kg, 5 days a week. The U251 luciferase-labeled tumors were imaged starting weekly for tumor volumes using the IVIS (In Vivo Imaging System) Lumina. Results: In patient derived primary GBM cell lines alterations in metabolites in chronic hypoxia compared to normoxia, such as decrease in citric acid cycle metabolites, increase in glycolytic metabolites, and dysfunctional mitochondrial metabolites. In RNA seq downregulation of genes PCK1, SCD, SREBF1, and PIPOX (p<1x108) involved in PPAR and lipid metabolism pathways in hypoxia versus normoxia were noted. Inhibition of ACOX-1 displayed increased survival in mice administered (p=6.7E-04) with pazopanib compared to the U251 parental control group. Conclusion: There is metabolomic reprogramming in ACOX-1 KO cells channeled predominantly through FAO as seen through the downregulation of genes downstream of the PPAR signaling pathway, mediated through SREBF1 the master regulator of lipid metabolism. Thus, these genes could be future targets for therapy in combination with anti-angiogenic therapies that aggravate hypoxia in GBM. Citation Format: Ayon Bhattacharya, Laura Caflisch, Henriette Balinda, Alessia Lodi, Mei Zhou, Mengxing Li, Jennifer Chiou, Renu Pandey, Gangadhara R. Sareddy, Stefano Tiziani, Yidong Chen, Ratna K. Vadlamudi, Andrew J. Brenner. Metabolic adaptations of glioblastoma in hypoxia is mediated by acox-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4422.
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