The lipid side of unfolded protein response.

Although our current knowledge of the molecular crosstalk between the ER stress, the unfolded protein response (UPR), and lipid homeostasis remains limited, there is increasing evidence that dysregulation of either protein or lipid homeostasis profoundly affects the other. Most research regarding UPR signaling in human diseases has focused on the causes and consequences of disrupted protein folding. The UPR itself consists of very complex pathways that function to not only maintain protein homeostasis, but just as importantly, modulate lipid biogenesis to allow the ER to adjust and promote cell survival. Lipid dysregulation is known to activate many aspects of the UPR, but the complexity of this crosstalk remains a major research barrier. ER lipid disequilibrium and lipotoxicity are known to be important contributors to numerous human pathologies, including insulin resistance, liver disease, cardiovascular diseases, neurodegenerative diseases, and cancer. Despite their medical significance and continuous research, however, the molecular mechanisms that modulate lipid synthesis during ER stress conditions, and their impact on cell fate decisions, remain poorly understood. Here we summarize the current view on crosstalk and connections between altered lipid metabolism, ER stress, and the UPR.

Correction to "Quantum Dots Assembled with Photosynthetic Antennae on a Carbon Nanotube Platform: A Nanohybrid for the Enhancement of Light Energy Harvesting".

[This corrects the article DOI: 10.1021/acsomega.3c07673.].

Regulation of the HIF switch in human endothelial and cancer cells.

Hypoxia-inducible factors (HIFs) are transcription factors that reprogram the transcriptome for cells to survive hypoxic insults and oxidative stress. They are important during embryonic development and reprogram the cells to utilize glycolysis when the oxygen levels are extremely low. This metabolic change facilitates normal cell survival as well as cancer cell survival. The key feature in survival is the transition between acute hypoxia and chronic hypoxia, and this is regulated by the transition between HIF-1 expression and HIF-2/HIF-3 expression. This transition is observed in many human cancers and endothelial cells and referred to as the HIF Switch. Here we discuss the mechanisms involved in the HIF Switch in human endothelial and cancer cells which include mRNA and protein levels of the alpha chains of the HIFs. A major continuing effort in this field is directed towards determining the differences between normal and tumor cell utilization of this important pathway, and how this could lead to potential therapeutic approaches.

Quantum Dots Assembled with Photosynthetic Antennae on a Carbon Nanotube Platform: A Nanohybrid for the Enhancement of Light Energy Harvesting.

The construction of artificial systems for solar energy harvesting is still a challenge. There needs to be a light-harvesting antenna with a broad absorption spectrum and then the possibility to transfer harvested energy to the reaction center, converting photons into a storable form of energy. Bioinspired and bioderivative elements may help in achieving this aim. Here, we present an option for light harvesting: a nanobiohybrid of colloidal, semiconductor quantum dots (QDs) and natural photosynthetic antennae assembled on the surface of a carbon nanotube. For that, we used QDs of cadmium telluride and cyanobacterial phycobilisome rods (PBSr) or light-harvesting complex II (LHCII) of higher plants. For this nanobiohybrid, we confirmed composition and organization using infrared spectroscopy, X-ray photoelectron spectroscopy, and high-resolution confocal microscopy. Then, we proved that within such an assembly, there is a resonance energy transfer from QD to PBSr or LHCII. When such a nanobiohybrid was further combined with thylakoids, the energy was transferred to photosynthetic reaction centers and efficiently powered the photosystem I reaction center. The presented construct is proof of a general concept, combining interacting elements on a platform of a nanotube, allowing further variation within assembled elements.

Dual RNase activity of IRE1 as a target for anticancer therapies.

The unfolded protein response (UPR) is a cellular mechanism that protects cells during stress conditions in which there is an accumulation of misfolded proteins in the endoplasmic reticulum (ER). UPR activates three signaling pathways that function to alleviate stress conditions and promote cellular homeostasis and cell survival. During unmitigated stress conditions, however, UPR activation signaling changes to promote cell death through apoptosis. Interestingly, cancer cells take advantage of this pathway to facilitate survival and avoid apoptosis even during prolonged cell stress conditions. Here, we discuss different signaling pathways associated with UPR and focus specifically on one of the ER signaling pathways activated during UPR, inositol-requiring enzyme 1α (IRE1). The rationale is that the IRE1 pathway is associated with cell fate decisions and recognized as a promising target for cancer therapeutics. Here we discuss IRE1 inhibitors and how they might prove to be an effective cancer therapeutic.

The Unfolded Protein Response: A Double-Edged Sword for Brain Health.

Efficient brain function requires as much as 20% of the total oxygen intake to support normal neuronal cell function. This level of oxygen usage, however, leads to the generation of free radicals, and thus can lead to oxidative stress and potentially to age-related cognitive decay and even neurodegenerative diseases. The regulation of this system requires a complex monitoring network to maintain proper oxygen homeostasis. Furthermore, the high content of mitochondria in the brain has elevated glucose demands, and thus requires a normal redox balance. Maintaining this is mediated by adaptive stress response pathways that permit cells to survive oxidative stress and to minimize cellular damage. These stress pathways rely on the proper function of the endoplasmic reticulum (ER) and the activation of the unfolded protein response (UPR), a cellular pathway responsible for normal ER function and cell survival. Interestingly, the UPR has two opposing signaling pathways, one that promotes cell survival and one that induces apoptosis. In this narrative review, we discuss the opposing roles of the UPR signaling pathways and how a better understanding of these stress pathways could potentially allow for the development of effective strategies to prevent age-related cognitive decay as well as treat neurodegenerative diseases.

HIF-1-Induced hsa-miR-429: Understanding Its Direct Targets as the Key to Developing Cancer Diagnostics and Therapies.

MicroRNAs (miRNAs) play a critical role in the regulation of mRNA stability and translation. In spite of our present knowledge on the mechanisms of mRNA regulation by miRNAs, the utilization and translation of these ncRNAs into clinical applications have been problematic. Using hsa-miR-429 as an example, we discuss the limitations encountered in the development of efficient miRNA-related therapies and diagnostic approaches. The miR-200 family members, which include hsa-miR-429, have been shown to be dysregulated in different types of cancer. Although these miR-200 family members have been shown to function in suppressing epithelial-to-mesenchymal transition, tumor metastasis, and chemoresistance, the experimental results have often been contradictory. These complications involve not only the complex networks involving these noncoding RNAs, but also the problem of identifying false positives. To overcome these limitations, a more comprehensive research strategy is needed to increase our understanding of the mechanisms underlying their biological role in mRNA regulation. Here, we provide a literature analysis of the verified hsa-miR-429 targets in various human research models. A meta-analysis of this work is presented to provide better insights into the role of hsa-miR-429 in cancer diagnosis and any potential therapeutic approach.

Time-resolved absorption measurements quantify the competition of energy and electron transfer between quantum dots and cytochrome c.

We applied transient absorption spectroscopy to study the early photodynamics in a system composed of CdTe quantum dots (QDs) and cytochrome c (Cyt c) protein. In the QDs and Cyt c mixtures, about 25 % of the excited QD electrons quickly relax (∼23 ps) to the ground state and roughly 75 % decay on slower time scale - mostly due to quenching by Cyt c. On the basis of the assumed model, we estimated the contribution of electron transfer and other mechanisms to this quenching. The primary quenching mechanism is probably energy transfer but electron transfer makes a significant contribution (∼8 %), resulting in photoreduction of Cyt c. The lifetime of one fraction of reduced Cyt c (35-90 %) is âˆ¼ 1 ms and the lifetime of the remaining fraction was longer than the âˆ¼ 50-ms time window of the experiment. We speculate that, in the former fraction, the back electron transfer from the reduced Cyt c to QDs occurs and the latter fraction of Cyt c is stably reduced.

Quantum dot clusters as self-assembled antennae with phycocyanine and phycobilisomes as energy acceptors.

In this study, we investigated an experimental and Monte-Carlo computational characterization of self-assembled antennae built using CdTe colloidal quantum dots (QDs). These clusters provide efficient excitation of phycocyanine (PC) or phycobilisomes (PBSs). PBSs are light-harvesting complexes (LHCs) of cyanobacteria, made of several PC units, organized in disks and rods. Each PC contains three separate cofactors. Therefore, we analyzed variations in multi-donor and multi-acceptor systems. The self-assembled QD clusters were formed mostly by electrostatic interactions, possibly due to the introduction of a positive charge on an originally negatively charged nanoparticle surface. Our results suggest that PC may accept energy from multiple nanoparticles localized at a distance significantly longer than the Förster radius. The excitation transfers between particular nanoparticles with possible delocalization. The maximal energy transfer efficiency was obtained for the PC/PBS : QD ratio from 1 to 20 depending on the QD size. This cannot be fully explained using computational simulations; hence, we discussed the hypothesis and explained the observations. Our self-assembled systems may be considered for possible applications in artificial light-harvesting systems because absorption spectra of QDs are different from the absorption characteristics of PC/PBS. In addition, huge clusters of QDs may effectively increase the optical cross-section of so-created nanohybrids.

Competition between Photoinduced Electron Transfer and Resonance Energy Transfer in an Example of Substituted Cytochrome c-Quantum Dot Systems.

Colloidal quantum dots (QDs) are nanoparticles that are able to photoreduce redox proteins by electron transfer (ET). QDs are also able to transfer energy by resonance energy transfer (RET). Here, we address the question of the competition between these two routes of QDs' excitation quenching, using cadmium telluride QDs and cytochrome c (CytC) or its metal-substituted derivatives. We used both oxidized and reduced versions of native CytC, as well as fluorescent, nonreducible Zn(II)CytC, Sn(II)CytC, and metal-free porphyrin CytC. We found that all of the CytC versions quench QD fluorescence, although the interaction may be described differently in terms of static and dynamic quenching. QDs may be quenchers of fluorescent CytC derivatives, with significant differences in effectiveness depending on QD size. SnCytC and porphyrin CytC increased the rate of Fe(III)CytC photoreduction, and Fe(II)CytC slightly decreased the rate and ZnCytC presence significantly decreased the rate and final level of reduced FeCytC. These might be partially explained by the tendency to form a stable complex between protein and QDs, which promoted RET and collisional quenching. Our findings show that there is a net preference for photoinduced ET over other ways of energy transfer, at least partially, due to a lack of donors, regenerating a hole at QDs and leading to irreversibility of ET events. There may also be a common part of pathways leading to photoinduced ET and RET. The nature of synergistic action observed in some cases allows the hypothesis that RET may be an additional way to power up the ET.

Intracellular partners of fibroblast growth factors 1 and 2 - implications for functions.

Fibroblast growth factors 1 and 2 (FGF1 and FGF2) are mainly considered as ligands of surface receptors through which they regulate a broad spectrum of biological processes. They are secreted in non-canonical way and, unlike other growth factors, they are able to translocate from the endosome to the cell interior. These unique features, as well as the role of the intracellular pool of FGF1 and FGF2, are far from being fully understood. An increasing number of reports address this problem, focusing on the intracellular interactions of FGF1 and 2. Here, we summarize the current state of knowledge of the FGF1 and FGF2 binding partners inside the cell and the possible role of these interactions. The partner proteins are grouped according to their function, including proteins involved in secretion, cell signaling, nucleocytoplasmic transport, binding and processing of nucleic acids, ATP binding, and cytoskeleton assembly. An in-depth analysis of the network of these binding partners could indicate novel, non-classical functions of FGF1 and FGF2 and uncover an additional level of a fine control of the well-known FGF-regulated cellular processes.

Nanoparticles as energy donors and acceptors in bionanohybrid systems.

The bionanohybrids are the junctions of at least two objects of different origin: abiotic and biotic. The abiotic part is a nanoparticle (often a fluorescent quantum dot), the biotical one may be a protein (especially fluorescent one or redox-active one), nucleic acid, carbohydrate as well as a simple organic molecule. When such a junction undergoes illumination, the energy transfer between the partners is possible. The nanoparticles, depending on their characteristics, may be donors, acceptors or mediators of the energy transfer. In most cases, the mechanism of the transfer is the Förster resonance energy transfer (FRET) or the electron transfer (ET). Here, we reviewed the newest achievements in the field with special attention paid to those bionanohybrids which allow FRET or ET. Such nanohybrids are important not only for exploration of the mechanism of the partner interaction but mainly for working out nanobiodevices for biosensing and nanotools for modern therapies.

Comparison of α-Helix and ß-Sheet Structure Adaptation to a Quantum Dot Geometry: Toward the Identification of an Optimal Motif for a Protein Nanoparticle Cover.

While quantum dots (QDs) are useful as fluorescent labels, their application in biosciences is limited due to the stability and hydrophobicity of their surface. In this study, we tested two types of proteins for use as a cover for spherical QDs, composed of cadmium selenide. Pumilio homology domain (Puf), which is mostly α-helical, and leucine-rich repeat (LRR) domain, which is rich in ß-sheets, were selected to determine if there is a preference for one of these secondary structure types for nanoparticle covers. The protein sequences were optimized to improve their interaction with the surface of QDs. The solubilization of the apoproteins and their assembly with nanoparticles required the application of a detergent, which was removed in subsequent steps. Finally, only the Puf-based cover was successful enough as a QD hydrophilic cover. We showed that a single polypeptide dimer of Puf, PufPuf, can form a cover. We characterized the size and fluorescent properties of the obtained QD:protein assemblies. We showed that the secondary structure of the Puf proteins was not destroyed upon contact with the QDs. We demonstrated that these assemblies do not promote the formation of reactive oxygen species during illumination of the nanoparticles. The data represent advances in the effort to obtain a stable biocompatible cover for QDs.