scholarly journals Rapamycin Ameliorates Defects in Mitochondrial Fission and Mitophagy in Glioblastoma Cells

2021 ◽  
Vol 22 (10) ◽  
pp. 5379
Author(s):  
Paola Lenzi ◽  
Rosangela Ferese ◽  
Francesca Biagioni ◽  
Federica Fulceri ◽  
Carla L. Busceti ◽  
...  
Keyword(s):  
Mtor Inhibitor ◽  
Mitochondrial Fission ◽  
Early Gene ◽  
Mtor Inhibition ◽  
Over Expression ◽  
Mitochondrial Alterations ◽  
Mitochondrial Impairment ◽  
Expression Of Genes ◽  
Autophagy Pathway ◽  
Novel Therapeutic

Glioblastoma (GBM) cells feature mitochondrial alterations, which are documented and quantified in the present study, by using ultrastructural morphometry. Mitochondrial impairment, which roughly occurs in half of the organelles, is shown to be related to mTOR overexpression and autophagy suppression. The novelty of the present study consists of detailing an mTOR-dependent mitophagy occlusion, along with suppression of mitochondrial fission. These phenomena contribute to explain the increase in altered mitochondria reported here. Administration of the mTOR inhibitor rapamycin rescues mitochondrial alterations. In detail, rapamycin induces the expression of genes promoting mitophagy (PINK1, PARKIN, ULK1, AMBRA1) and mitochondrial fission (FIS1, DRP1). This occurs along with over-expression of VPS34, an early gene placed upstream in the autophagy pathway. The topographic stoichiometry of proteins coded by these genes within mitochondria indicates that, a remarkable polarization of proteins involved in fission and mitophagy within mitochondria including LC3 takes place. Co-localization of these proteins within mitochondria, persists for weeks following rapamycin, which produces long-lasting mitochondrial plasticity. Thus, rapamycin restores mitochondrial status in GBM cells. These findings add novel evidence about mitochondria and GBM, while fostering a novel therapeutic approach to restore healthy mitochondria through mTOR inhibition.

scholarly journals NtbHLH1, a JAF13-like bHLH, interacts with NtMYB6 to enhance proanthocyanidin accumulation in Chinese Narcissus

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yuxin Fan ◽  
Jiayu Peng ◽  
Jiacheng Wu ◽  
Ping Zhou ◽  
Ruijie He ◽  
...  
Keyword(s):  
Flavonoid Biosynthesis ◽  
Transcriptional Level ◽  
Flavonoid Pathway ◽  
Regulation Of Expression ◽  
Over Expression ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Regulatory Complex ◽  
Positive Regulators ◽  
R2r3 Myb

Abstract Background Flavonoid biosynthesis in plants is primarily regulated at the transcriptional level by transcription factors modulating the expression of genes encoding enzymes in the flavonoid pathway. One of the most studied transcription factor complexes involved in this regulation consists of a MYB, bHLH and WD40. However, in Chinese Narcissus (Narcissus tazetta L. var. chinensis), a popular monocot bulb flower, the regulatory mechanism of flavonoid biosynthesis remains unclear. Results In this work, genes related to the regulatory complex, NtbHLH1 and a R2R3-MYB NtMYB6, were cloned from Chinese Narcissus. Phylogenetic analysis indicated that NtbHLH1 belongs to the JAF13 clade of bHLH IIIf subgroup, while NtMYB6 was highly homologous to positive regulators of proanthocyanidin biosynthesis. Both NtbHLH1 and NtMYB6 have highest expression levels in basal plates of Narcissus, where there is an accumulation of proanthocyanidin. Ectopic over expression of NtbHLH1 in tobacco resulted in an increase in anthocyanin accumulation in flowers, and an up-regulation of expression of the endogenous tobacco bHLH AN1 and flavonoid biosynthesis genes. In contrast, the expression level of LAR gene was significantly increased in NtMYB6-transgenic tobacco. Dual luciferase assays showed that co-infiltration of NtbHLH1 and NtMYB6 significantly activated the promoter of Chinese Narcissus DFR gene. Furthermore, a yeast two-hybrid assay confirmed that NtbHLH1 interacts with NtMYB6. Conclusions Our results suggest that NtbHLH1 may function as a regulatory partner by interacting directly with NtMYB6 to enhance proanthocyanidin accumulation in Chinese Narcissus.

scholarly journals Non-alcoholic fatty liver disease in mice with hepatocyte-specific deletion of mitochondrial fission factor

Diabetologia ◽  
2021 ◽  
Author(s):  
Yukina Takeichi ◽  
Takashi Miyazawa ◽  
Shohei Sakamoto ◽  
Yuki Hanada ◽  
Lixiang Wang ◽  
...  
Keyword(s):  
Er Stress ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Primary Hepatocytes ◽  
Alcoholic Fatty Liver ◽  
Expression Of Genes ◽  
Specific Deletion

Abstract Aims/hypothesis Mitochondria are highly dynamic organelles continuously undergoing fission and fusion, referred to as mitochondrial dynamics, to adapt to nutritional demands. Evidence suggests that impaired mitochondrial dynamics leads to metabolic abnormalities such as non-alcoholic steatohepatitis (NASH) phenotypes. However, how mitochondrial dynamics are involved in the development of NASH is poorly understood. This study aimed to elucidate the role of mitochondrial fission factor (MFF) in the development of NASH. Methods We created mice with hepatocyte-specific deletion of MFF (MffLiKO). MffLiKO mice fed normal chow diet (NCD) or high-fat diet (HFD) were evaluated for metabolic variables and their livers were examined by histological analysis. To elucidate the mechanism of development of NASH, we examined the expression of genes related to endoplasmic reticulum (ER) stress and lipid metabolism, and the secretion of triacylglycerol (TG) using the liver and primary hepatocytes isolated from MffLiKO and control mice. Results MffLiKO mice showed aberrant mitochondrial morphologies with no obvious NASH phenotypes during NCD, while they developed full-blown NASH phenotypes in response to HFD. Expression of genes related to ER stress was markedly upregulated in the liver from MffLiKO mice. In addition, expression of genes related to hepatic TG secretion was downregulated, with reduced hepatic TG secretion in MffLiKO mice in vivo and in primary cultures of MFF-deficient hepatocytes in vitro. Furthermore, thapsigargin-induced ER stress suppressed TG secretion in primary hepatocytes isolated from control mice. Conclusions/interpretation We demonstrated that ablation of MFF in liver provoked ER stress and reduced hepatic TG secretion in vivo and in vitro. Moreover, MffLiKO mice were more susceptible to HFD-induced NASH phenotype than control mice, partly because of ER stress-induced apoptosis of hepatocytes and suppression of TG secretion from hepatocytes. This study provides evidence for the role of mitochondrial fission in the development of NASH. Graphical abstract

scholarly journals Streptomyces roseolus, A Promising Biocontrol Agent Against Aspergillus flavus, the Main Aflatoxin B1 Producer

Toxins ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 442 ◽  
Author(s):  
Isaura Caceres ◽  
Selma Snini ◽  
Olivier Puel ◽  
Florence Mathieu
Keyword(s):  
Aspergillus Flavus ◽  
Aflatoxin B1 ◽  
Biocontrol Agent ◽  
Cyclopiazonic Acid ◽  
Over Expression ◽  
Expression Of Genes ◽  
B1 Gene ◽  
Genes Encoding ◽  
Molecular Mechanism Of Action ◽  
Potential Use

Crop contamination by aflatoxin B1 is a current problem in tropical and subtropical regions. In the future, this contamination risk may be expanded to European countries due to climate change. The development of alternative strategies to prevent mycotoxin contamination that further contribute to the substitution of phytopharmaceutical products are thus needed. For this, a promising method resides in the use of biocontrol agents. Several actinobacteria strains have demonstrated to effectively reduce the aflatoxin B1 concentration. Nevertheless, the molecular mechanism of action by which these biological agents reduce the mycotoxin concentration has not been determined. The aim of the present study was to test the potential use of Streptomyces roseolus as a biocontrol agent against aflatoxin B1 contamination. Co-cultures with Aspergillus flavus were conducted, and the molecular fungal response was investigated through analyzing the q-PCR expression of 65 genes encoding relevant fungal functions. Moreover, kojic and cyclopiazonic acid concentrations, as well as morphological fungal changes were also analyzed. The results demonstrated that reduced concentrations of aflatoxin B1 and kojic acid were respectively correlated with the down-regulation of the aflatoxin B1 gene cluster and kojR gene expression. Moreover, a fungal hypersporulated phenotype and a general over-expression of genes involved in fungal development were observed in the co-culture condition.

scholarly journals Dosage-dependent over-expression of genes in the trisomic region of Ts1Cje mouse model for Down syndrome

2004 ◽  
Vol 13 (13) ◽  
pp. 1333-1340 ◽  
Author(s):  
Kenji Amano ◽  
Haruhiko Sago ◽  
Chiharu Uchikawa ◽  
Taishi Suzuki ◽  
Svetlana E. Kotliarova ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Over Expression ◽  
Expression Of Genes

scholarly journals Inhibiting mTOR enhanced Cardiac STAT3 Phosphorylation at Site Ser 727 and Attenuated Myocardial Ischemia Reperfusion Injury in Diabetic Rats

2021 ◽  
Author(s):  
Xiang Xie ◽  
Zhongbao Zhao ◽  
Danyong Liu ◽  
Dengwen Zhang ◽  
Yi He ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Mtor Inhibitor ◽  
Troponin I ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Diabetic Rats ◽  
H9c2 Cells ◽  
Sprague Dawley ◽  
Mtor Inhibition ◽  
Stat3 Phosphorylation

Abstract Background Reduced levels of myocardial STAT3 activity in diabetic hearts may contribute to the increased susceptibility to ischemia-reperfusion injury (I/RI). The protein mammalian target of rapamycin (mTOR) can regulate metabolism and cell processes and plays major roles in the dynamics of I/RI. However, the role of mTOR in regulation of myocardial STAT3 and thereby affect myocardial I/RI in diabetes at relatively late stages of the disease is unknown. Methods Diabetes was induced by Streptozotocin in Sprague-Dawley rats. Myocardial I/RI was achieved with coronary occlusion for 30 minutes and reperfusion for 2 hours in absence or presence of the mTOR inhibitor rapamycin. In vitro cardiomyocyte hypoxia/re-oxygenation (H/R) was established within H9C2 cells. Results In diabetic rats, the levels of troponin-I (Tn-I), lipid peroxidation products 15-F2t-Isoprostane (15-F2t-Iso) and MDA, and the expression of protein mTOR were all significantly increased,and SOD releasing, the expression of protein phosphorylation of STAT3(p-STAT3-Ser727) were both significantly decreased compared to non-diabetic rats. Myocardial I/RI significantly increased the infract size (IS) and further increased the mTOR activation and decreased p-STAT3-Ser727 compared to diabetic rats. The selective mTOR inhibitor rapamycin reversed these changes and conferred cardioprotective effect. In H9C2 cells, high glucose (HG) significantly increased lactic dehydrogenase (LDH) release, apoptosis cells, ROS release, activation of mTOR, and decreased p-STAT3-Ser727. H/R further increased cellular injury, mTOR knock-down significantly reduced H/R injury. Conclusion Myocardial mTOR was enhanced in diabetes and contributed to I/RI. mTOR inhibition attenuated myocardial I/RI through increasing p-STAT3-Ser727.

Controlling quality and amount of mitochondria by mitophagy: insights into the role of ubiquitination and deubiquitination

2016 ◽  
Vol 397 (7) ◽  
pp. 637-647 ◽  
Author(s):  
Tao Tan ◽  
Marcel Zimmermann ◽  
Andreas S. Reichert
Keyword(s):  
Mammalian Cells ◽  
Mitochondrial Fission ◽  
Baker’S Yeast ◽  
Negative Regulator ◽  
Mitochondrial Outer Membrane ◽  
Baker's Yeast ◽  
Genome Wide ◽  
A Genome ◽  
Autophagy Pathway ◽  
Quantity Control

Abstract Mitophagy is a selective autophagy pathway conserved in eukaryotes and plays an essential role in mitochondrial quality and quantity control. Mitochondrial fission and fusion cycles maintain a certain amount of healthy mitochondria and allow the isolation of damaged mitochondria for their elimination by mitophagy. Mitophagy can be classified into receptor-dependent and ubiquitin-dependent pathways. The mitochondrial outer membrane protein Atg32 is identified as the only known receptor for mitophagy in baker’s yeast, whereas mitochondrial proteins FUNDC1, NIX/BNIP3L, BNIP3 and Bcl2L13 are recognized as mitophagy receptors in mammalian cells. Earlier studies showed that ubiquitination and deubiquitination occurs in yeast, yet there is no direct evidence for an ubiquitin-dependent mitophagy pathway in this organism. In contrast, a ubiquitin-/PINK1-/Parkin-dependent mitophagy pathway was unraveled and was extensively characterized in mammals in recent years. Recently, a quantitative method termed synthetic quantitative array (SQA) technology was developed to identify modulators of mitophagy in baker’s yeast on a genome-wide level. The Ubp3-Bre5 deubiquitination complex was found as a negative regulator of mitophagy while promoting other autophagic pathways. Here we discuss how ubiquitination and deubiquitination regulates mitophagy and other selective forms of autophagy and what argues for using baker’s yeast as a model to study the ubiquitin-dependent mitophagy pathway.

scholarly journals Role of BET Inhibitors in Triple Negative Breast Cancers

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 784 ◽  
Author(s):  
Durga Khandekar ◽  
Venkataswarup Tiriveedhi
Keyword(s):  
Triple Negative ◽  
Preliminary Evidence ◽  
Special Focus ◽  
Solid Organ ◽  
Breast Cancers ◽  
Over Expression ◽  
Expression Of Genes ◽  
Cancer Models ◽  
Bet Inhibitors

Bromodomain and extraterminal domain (BET) proteins have evolved as key multifunctional super-regulators that control gene expression. These proteins have been shown to upregulate transcriptional machinery leading to over expression of genes involved in cell proliferation and carcinogenesis. Based on favorable preclinical evidence of BET inhibitors in various cancer models; currently, 26 clinical trials are underway in various stages of study on various hematological and solid organ cancers. Unfortunately, preliminary evidence for these clinical studies does not support the application of BET inhibitors as monotherapy in cancer treatment. Furthermore, the combinatorial efficiency of BET inhibitors with other chemo-and immunotherapeutic agents remain elusive. In this review, we will provide a concise summary of the molecular basis and preliminary clinical outcomes of BET inhibitors in cancer therapy, with special focus on triple negative breast cancer.

scholarly journals INCREASE IN HSP25 EXTENDS LIFESPAN AND IMPROVES RESPONSE TO TAU TOXICITY THROUGH A CELL, NON-AUTONOMOUS MECHANISM

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S730-S730
Author(s):  
Karl Rodriguez
Keyword(s):  
Stress Response ◽  
Protein Aggregation ◽  
Cell Types ◽  
Over Expression ◽  
C Elegans ◽  
Expression Of Genes ◽  
Stress Response Pathway ◽  
A Cell ◽  
Cytotoxic Proteins ◽  
Improve Health

Abstract The accrual of aggregation-prone cytotoxic proteins underlies neural pathologies seen in aging, Alzheimer’s disease and other dementias. Recent evidence indicates that heat shock protein 25kDa (HSP25) interacts with tau. To demonstrate a causal role for HSP25 in these pathologies, we overexpressed HSP25 protein in worms. This manipulation led to an increase in life span. Moreover, the longevity-effect was associated with increased expression of genes downstream of the SKN-1/Nrf2 stress-response transcription factor. HSP25 over-expression also reduces aggregate pathology and extends lifespan in a C. elegans neuronal-specific, aggregate-prone tau model . We propose that over-expression of HSP25 could provide protection from protein aggregation induced neurodegeneration. However, it is not yet clear whether this HSP25 effect could be efficaciously provided exogenously by other cell types. Thus, we will test whether increased peripheral HSP25 will reduce protein aggregation and stimulate a global Skn-1 stress-response pathway, reduce toxicity in neurons, and improve health outcomes.

scholarly journals MYC as a Multifaceted Regulator of Tumor Microenvironment Leading to Metastasis

2020 ◽  
Vol 21 (20) ◽  
pp. 7710
Author(s):  
Erna Marija Meškytė ◽  
Sabiha Keskas ◽  
Yari Ciribilli
Keyword(s):  
Tumor Microenvironment ◽  
Treatment Strategies ◽  
Invasion And Migration ◽  
Over Expression ◽  
Novel Studies ◽  
Expression Of Genes ◽  
Promote Tumor Growth ◽  
Infiltrating Cells ◽  
Metastasis Development ◽  
And Migration

The Myc family of oncogenes is deregulated in many types of cancer, and their over-expression is often correlated with poor prognosis. The Myc family members are transcription factors that can coordinate the expression of thousands of genes. Among them, c-Myc (MYC) is the gene most strongly associated with cancer, and it is the focus of this review. It regulates the expression of genes involved in cell proliferation, growth, differentiation, self-renewal, survival, metabolism, protein synthesis, and apoptosis. More recently, novel studies have shown that MYC plays a role not only in tumor initiation and growth but also has a broader spectrum of functions in tumor progression. MYC contributes to angiogenesis, immune evasion, invasion, and migration, which all lead to distant metastasis. Moreover, MYC is able to promote tumor growth and aggressiveness by recruiting stromal and tumor-infiltrating cells. In this review, we will dissect all of these novel functions and their involvement in the crosstalk between tumor and host, which have demonstrated that MYC is undoubtedly the master regulator of the tumor microenvironment. In sum, a better understanding of MYC’s role in the tumor microenvironment and metastasis development is crucial in proposing novel and effective cancer treatment strategies.

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