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mitochondrial engineering

Rebecca M Nisbet, Jürgen Götz
Accumulation of the peptide amyloid-β (Aβ) and the protein tau in Alzheimer's disease (AD) brains is a gradual process that involves the post-translational modification and assembly of monomeric forms into larger structures that eventually form fibrillar inclusions. This process is thought to both drive and initiate AD. However, why the axonally enriched tau in the course of AD accumulates in the somatodendritic domain is not fully understood. We discuss new data that provide a possible explanation that involves de novo protein synthesis, induced by Aβ and mediated through the kinase Fyn...
March 16, 2018: Journal of Alzheimer's Disease: JAD
Evan M Zhao, Yanfei Zhang, Justin Mehl, Helen Park, Makoto A Lalwani, Jared E Toettcher, José L Avalos
The optimization of engineered metabolic pathways requires careful control over the levels and timing of metabolic enzyme expression. Optogenetic tools are ideal for achieving such precise control, as light can be applied and removed instantly without complex media changes. Here we show that light-controlled transcription can be used to enhance the biosynthesis of valuable products in engineered Saccharomyces cerevisiae. We introduce new optogenetic circuits to shift cells from a light-induced growth phase to a darkness-induced production phase, which allows us to control fermentation with only light...
March 21, 2018: Nature
Ya-Ru Xiong, Shuai Zhao, Li-Hao Fu, Xu-Zhong Liao, Cheng-Xi Li, Yu-Si Yan, Lu-Sheng Liao, Jia-Xun Feng
High-mobility group (HMG)-box proteins are involved in chromatin organization in eukaryotes, especially in sex determination and regulation of mitochondrial DNA compaction. Although a novel HMG-box protein, PoxHmbB, had been initially identified to be required for filter paper cellulase activity by Penicillium oxalicum, the biological roles of HMG-box proteins in biomass-degrading enzyme production have not been systematically explored. The P. oxalicum mutant ∆PoxHmbB lost 34.7-86.5% of cellulase (endoglucanase, p-nitrophenyl-β-cellobiosidase, and p-nitrophenyl-β-glucopyranosidase) activities and 60...
March 6, 2018: Applied Microbiology and Biotechnology
Bärbel M Ulmer, Andrea Stoehr, Mirja L Schulze, Sajni Patel, Marjan Gucek, Ingra Mannhardt, Sandra Funcke, Elizabeth Murphy, Thomas Eschenhagen, Arne Hansen
Energy metabolism is a key aspect of cardiomyocyte biology. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a promising tool for biomedical application, but they are immature and have not undergone metabolic maturation related to early postnatal development. To assess whether cultivation of hiPSC-CMs in 3D engineered heart tissue format leads to maturation of energy metabolism, we analyzed the mitochondrial and metabolic state of 3D hiPSC-CMs and compared it with 2D culture. 3D hiPSC-CMs showed increased mitochondrial mass, DNA content, and protein abundance (proteome)...
February 26, 2018: Stem Cell Reports
Annika Zink, Josef Priller, Alessandro Prigione
Mitochondrial dysfunctions are a known pathogenetic mechanism of a number of neurological and psychiatric disorders. At the same time, mutations in genes encoding for components of the mitochondrial respiratory chain cause mitochondrial diseases, which commonly exhibit neurological symptoms. Mitochondria are therefore critical for the functionality of the human nervous system. The importance of mitochondria stems from their key roles in cellular metabolism, calcium handling, redox and protein homeostasis, and overall cellular homeostasis through their dynamic network...
February 16, 2018: Journal of Molecular Biology
Claudia G Fresta, Aishik Chakraborty, Manjula B Wijesinghe, Angela M Amorini, Giacomo Lazzarino, Giuseppe Lazzarino, Barbara Tavazzi, Susan M Lunte, Filippo Caraci, Prajnaparamita Dhar, Giuseppe Caruso
Engineered nanoparticles are finding a wide spectrum of biomedical applications, including drug delivery and capacity to trigger cytotoxic phenomena, potentially useful against tumor cells. The full understanding of their biosafety and interactions with cell processes is mandatory. Using microglial (BV-2) and alveolar basal epithelial (A549) cells, in this study we determined the effects of engineered carbon nanodiamonds (ECNs) on cell viability, nitric oxide (NO) and reactive oxygen species (ROS) production, as well as on energy metabolism...
February 14, 2018: Cell Death & Disease
Miroslav Vetrík, Martin Parizek, Daniel Hadraba, Olivia Kukackova, Jiří Brus, Helena Hlídková, Lucie Komankova, Jiri Hodan, Ondrej Sedlacek, Miroslav Slouf, Lucie Bacakova, Martin Hruby
Heat-treated polyacrylonitrile (HT-PAN), also referred to as Black Orlon (BO), is a promising carbon-based material used for applications in tissue engineering and regenerative medicine. To the best of our knowledge, no such complex bone morphology-mimicking three-dimensional (3D) BO structure has been reported to date. We report that BO can be easily made into 3D cryogel scaffolds with porous structures, using succinonitrile as a porogen. The cryogels possess a porous morphology, similar to bone tissue. The prepared scaffolds showed strong osteoconductive activity, providing excellent support for the adhesion, proliferation and mitochondrial activity of human bone-derived cells...
February 13, 2018: ACS Applied Materials & Interfaces
Johannes Klose, Engin Guerlevik, Tina Trostel, Florian Kühnel, Thomas Schmidt, Martin Schneider, Alexis Ulrich
Introduction: Cholangiocarcinoma is characterized by aggressive tumor growth, high recurrence rates, and resistance against common chemotherapeutical regimes. The polyether-antibiotic Salinomycin is a promising drug in cancer therapy because of its ability to overcome apoptosis resistance of cancer cells and its selectivity against cancer stem cells. Here, we investigated the effectiveness of Salinomycin against cholangiocarcinoma in vivo, and analyzed interference of Salinomycin with autophagic flux in human cholangiocarcinoma cells...
January 9, 2018: Oncotarget
Hanumantha Rao Madala, Surendra R Punganuru, Francis Ali-Osman, Ruiwen Zhang, Kalkunte S Srivenugopal
There is great interest in repurposing disulfiram (DSF), a rapidly metabolizing nontoxic drug, for brain cancers and other cancers. To overcome the instability and low therapeutic efficacy, we engineered passively-targeted DSF-nanoparticles (DSFNPs) using biodegradable monomethoxy (polyethylene glycol) d,l-lactic-co-glycolic acid (mPEG-PLGA) matrix. The physicochemical properties, cellular uptake and the blood brain-barrier permeability of DSFNPs were investigated. The DSFNPs were highly stable with a size of ∼70 nm with a >90% entrapment...
January 9, 2018: Oncotarget
Yinghan Liu, Se Wang, Zhuang Wang, Nan Ye, Hao Fang, Degao Wang
Metal-based nanoparticles (NPs) are the most widely used engineered nanomaterials. The individual toxicities of metal-based NPs have been plentifully studied. However, the mixture toxicity of multiple NP systems (n ≥ 3) remains much less understood. Herein, the toxicity of titanium dioxide (TiO₂) nanoparticles (NPs), silicon dioxide (SiO₂) NPs and zirconium dioxide (ZrO₂) NPs to unicellular freshwater algae Scenedesmus obliquus was investigated individually and in binary and ternary combination. Results show that the ternary combination systems of TiO₂, SiO₂ and ZrO₂ NPs at a mixture concentration of 1 mg/L significantly enhanced mitochondrial membrane potential and intracellular reactive oxygen species level in the algae...
February 8, 2018: Nanomaterials
Sergio Branciamore, Grigoriy Gogoshin, Massimo Di Giulio, Andrei S Rodin
The identity/recognition of tRNAs, in the context of aminoacyl tRNA synthetases (and other molecules), is a complex phenomenon that has major implications ranging from the origins and evolution of translation machinery and genetic code to the evolution and speciation of tRNAs themselves to human mitochondrial diseases to artificial genetic code engineering. Deciphering it via laboratory experiments, however, is difficult and necessarily time- and resource-consuming. In this study, we propose a mathematically rigorous two-pronged in silico approach to identifying and classifying tRNA positions important for tRNA identity/recognition, rooted in machine learning and information-theoretic methodology...
February 8, 2018: Life
Mei Zhou, R Marc Learned, Stephen J Rossi, Alex M DePaoli, Hui Tian, Lei Ling
Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent chronic liver disease for which no approved therapies are available. Despite intensive research, the cellular mechanisms that mediate NAFLD pathogenesis and progression are poorly understood. Although obesity, diabetes, insulin resistance, and related metabolic syndrome, all consequences of a Western diet lifestyle, are well-recognized risk factors for NAFLD development, dysregulated bile acid metabolism is emerging as a novel mechanism contributing to NAFLD pathogenesis...
December 2017: Hepatology Communications
Chunhui Wu, Lianhui Wang, Yuan Tian, Xiaotian Guan, Qiuyue Liu, Shun Li, Xiang Qin, Hong Yang, Yi Yao Liu
Nanomedicine-based combination therapy has sparked a growing interest in clinical disease treatment and pharmaceutical industry. In this report, a mitochondria-targeted and near-infrared (NIR) light activable multitasking nanographene (i. e. GT/IR820/DP-CpG) had been engineered to in-situ trigger highly efficient 'triple-punch' strategy of cancer photodynamic therapy, photothermal therapy and immunotherapy. Modification of triphenylphosphonium on graphene made the vehicle specifically guide the NIR dye IR820 home to mitochondria followed by lysosomes escape in a time-dependent manner...
February 5, 2018: ACS Applied Materials & Interfaces
B R Mordhorst, S L Murphy, R M Ross, J A Benne, M S Samuel, R F Cecil, B K Redel, L D Spate, C N Murphy, K D Wells, J A Green, R S Prather
Somatic cell nuclear transfer is a valuable technique for the generation of genetically engineered animals, however the efficiency of cloning in mammalian species is low (1-3%). Differentiated somatic cells commonly used in nuclear transfer utilize the tricarboxylic acid cycle and cellular respiration for energy production. Comparatively the metabolism of somatic cells contrasts that of the cells within the early embryos which predominately use glycolysis. Early embryos (prior to implantation) are evidenced to exhibit characteristics of a Warburg Effect (WE)-like metabolism...
February 2, 2018: Molecular Reproduction and Development
Fabiao Hu, Daxia Pan, Wenyun Zheng, Ting Yan, Xiujuan He, Fuzheng Ren, Yiming Lu, Xingyuan Ma
Survivin was the smallest member of the IAP family, which was over expressed in many different cancers, and considered to be a promising hot target for cancer therapy, and our previous study demonstrated that multiple dominant negative mutants from full-length survivin could have many complex effects on cancer cells, such as cell cycle, apoptosis, and autophagy. But it was not yet known what role the two main domains played in those functions, which would be very important for the design of targeted anticancer drugs and for the interpretation of their molecular mechanisms...
December 26, 2017: Oncotarget
Jianjun Han, Weiya Z Wysham, Yan Zhong, Hui Guo, Lu Zhang, Kim M Malloy, Hallum K Dickens, Gene Huh, Douglas Lee, Liza Makowski, Chunxiao Zhou, Victoria L Bae-Jump
Obesity is a significant risk factor for ovarian cancer (OC) and associated with worse outcomes for this disease. We assessed the anti-tumorigenic effects of metformin in human OC cell lines and a genetically engineered mouse model of high grade serous OC under obese and lean conditions. Metformin potently inhibited growth in a dose-dependent manner in all four human OC cell lines through AMPK/mTOR pathways. Treatment with metformin resulted in G1 arrest, induction of apoptosis, reduction of invasion and decreased hTERT expression...
December 19, 2017: Oncotarget
Yi Yang, Han Wu, Xiangjin Kang, Yanhui Liang, Ting Lan, Tianjie Li, Tao Tan, Jiangyun Peng, Quanjun Zhang, Geng An, Yali Liu, Qian Yu, Zhenglai Ma, Ying Lian, Boon Seng Soh, Qingfeng Chen, Ping Liu, Yaoyong Chen, Xiaofang Sun, Rong Li, Xiumei Zhen, Ping Liu, Yang Yu, Xiaoping Li, Yong Fan
Mitochondrial diseases are maternally inherited heterogeneous disorders that are primarily caused by mitochondrial DNA (mtDNA) mutations. Depending on the ratio of mutant to wild-type mtDNA, known as heteroplasmy, mitochondrial defects can result in a wide spectrum of clinical manifestations. Mitochondria-targeted endonucleases provide an alternative avenue for treating mitochondrial disorders via targeted destruction of the mutant mtDNA and induction of heteroplasmic shifting. Here, we generated mitochondrial disease patient-specific induced pluripotent stem cells (MiPSCs) that harbored a high proportion of m...
January 9, 2018: Protein & Cell
Tom P Aird, Robert W Davies, Brian P Carson
The effects of nutrition on exercise metabolism and performance remains an important topic among sports scientists, clinical, and athletic populations. Recently, fasted exercise has garnered interest as a beneficial stimulus which induces superior metabolic adaptations to fed exercise in key peripheral tissues. Conversely, pre-exercise feeding augments exercise performance compared with fasting conditions. Given these seemingly divergent effects on performance and metabolism, an appraisal of the literature is warranted...
January 6, 2018: Scandinavian Journal of Medicine & Science in Sports
Ye-Rang Yun, Hae-Won Kim, Jun-Hyeog Jang
The fibronectin type 10-peptide amphiphile (FNIII10-PA) was previously genetically engineered and showed osteogenic differentiation activity on rat bone marrow stem cells (rBMSCs). In this study, we investigated whether FNIII10-PA demonstrated cellular activity on polycaprolactone (PCL) fibers. FNIII10-PA significantly increased protein production and cell adhesion activity on PCL fibers in a dose-dependent manner. In cell proliferation results, there was no effect on cell proliferation activity by FNIII10-PA; however, FNIII10-PA induced the osteogenic differentiation of MC3T3-E1 cells via upregulation of bone sialoprotein (BSP), collagen type I (Col I), osteocalcin (OC), osteopontin (OPN), and runt-related transcription factor 2 (Runx2) mitochondrial RNA (mRNA) levels; it did not increase the alkaline phosphatase (ALP) mRNA level...
January 4, 2018: International Journal of Molecular Sciences
Arpit Bhargava, Neelam Pathak, Sriram Seshadri, Neha Bunkar, Subodh Kumar Jain, Dinesh Mishra Kumar, Nirmal Kumar Lohiya, Pradyumna Kumar Mishra
BACKGROUND: Novel bioactive plant secondary metabolites, including flavonoids, offer a spectrum of chemo-protective responses against a range of human tumor models. However, the clinical translation of these promising anti-cancer agents has been hindered largely by their poor solubility, rapid metabolism, or a combination of both, ultimately resulting in poor bioavailability upon oral administration. OBJECTIVE: To circumvent the challenges associated with herbal drug development and for effective integration into clinical setting, nano-engineering is one of the emerging pragmatic strategy which has promise to deliver therapeutic concentrations of bio-actives upon oral administration...
December 29, 2017: Anti-cancer Agents in Medicinal Chemistry
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