Cdc7 and its regulator Dbf4 (Dbf4‐dependent kinase; DDK) form an essential complex due to its function in replication initiation, which is carried out by phosphorylating different residues at the ...helicase MCM during the G1/S transition. In response to replication stress, late origins are inhibited to prevent cell cycle progression until the problems are resolved. In yeast, this inhibition is partially achieved by attenuating DDK activity. In addition, evidence from yeast to human shows that Cdc7 is required for a successful DNA damage response by coordinating multiple processes dealing with replication stress (replication checkpoint, DNA damage tolerance and break‐induced replication) through mechanisms that go beyond its role in origin activation. These studies reveal the importance of getting a better understanding of the spatiotemporal regulation of DDK. Here, we will discuss how DDK operates in these processes and its putative role in controlling the activity of replication and repair factors at specific nuclease‐resistant nucleoprotein scaffolds.
Cdc7 and its regulator Dbf4 (Dbf4‐dependent kinase; DDK) is an essential complex due to its function in replication initiation. Evidence from yeast to human shows that Cdc7 is also required for a successful DNA damage response by coordinating multiple processes dealing with replication stress such as stalled fork protection, translesion synthesis (TLS), reversed fork and sister chromatid junction (SCJ) dynamics, and regulation of protein‐protein interactions at assistance nucleoprotein factories.
Due to a rising demand for proteins, food industry is considering new alternative protein sources that can be used for human food. The aim of this research was to explore the potential use of ...insects' flour as protein-rich ingredient for bakery products. Hermetia illucens, Acheta domestica and Tenebrio molitor were ground and used to replace 5% wheat flour in doughs and breads. The protein content of the insect flours ranged from 45% to 57% (d.m.) and fat content from 27% to 36% (d.m.). The inclusion of insects' flour affected the rheological properties (water absorption and stability), of dough during mixing, having less water adsorption. Breadmaking process could be carried out with all the composite flours. Breads containing A. domestica flour showed similar specific volume and texture parameters than wheat bread, but with higher content of proteins and fibers. Globally, results confirmed the usefulness of insects' flour for making breads with improved nutritional value.
This study evaluated the potential application of three different insects as protein source ingredients for bakery products. Results confirm that insects flour could be added to replace wheat flour in breads without significantly affecting dough properties and leading to breads with acceptable technological quality and improved nutritional profile.
•Mealworm, larvae of black soldier fly and cricket were ground and applied in bakery.•Nutritional composition of those insects was determined.•The insect flours were added to replace 5% wheat flour in breads.•Insect flours reduced the water adsorption of the dough.•Cricket flour led to breads with adequate volume and increased the proteins and fibers content.
It is controversial whether mitochondrial dysfunction in skeletal muscle is the cause or consequence of metabolic disorders. Herein, we demonstrate that in vivo inhibition of mitochondrial ATP ...synthase in muscle alters whole‐body lipid homeostasis. Mice with restrained mitochondrial ATP synthase activity presented intrafiber lipid droplets, dysregulation of acyl‐glycerides, and higher visceral adipose tissue deposits, poising these animals to insulin resistance. This mitochondrial energy crisis increases lactate production, prevents fatty acid β‐oxidation, and forces the catabolism of branched‐chain amino acids (BCAA) to provide acetyl‐CoA for de novo lipid synthesis. In turn, muscle accumulation of acetyl‐CoA leads to acetylation‐dependent inhibition of mitochondrial respiratory complex II enhancing oxidative phosphorylation dysfunction which results in augmented ROS production. By screening 702 FDA‐approved drugs, we identified edaravone as a potent mitochondrial antioxidant and enhancer. Edaravone administration restored ROS and lipid homeostasis in skeletal muscle and reinstated insulin sensitivity. Our results suggest that muscular mitochondrial perturbations are causative of metabolic disorders and that edaravone is a potential treatment for these diseases.
Synopsis
Lipid homeostasis in skeletal muscle is dependent on mitochondrial activity. Inhibition of ATP synthase in the muscle alters whole‐body lipid metabolism and induces insulin resistance in mice, two phenotypes that can be reverted by edavarone treatment.
Inhibition of oxidative phosphorylation (OXPHOS) in skeletal muscle promotes branched‐chain amino acids (BCAA) catabolism and de novo lipogenesis.
Accumulation of Acetyl‐CoA feeds back onto OXPHOS dysfunction by inhibiting mitochondrial respiratory complex II and increasing ROS levels.
Mice with low OXPHOS show increased lipid deposits and insulin resistance.
Edaravone rescues mitochondrial activity, and lipid and glucose homeostasis in mice with low OXPHOS.
Inhibition of ATP synthase in the muscle alters whole‐body lipid metabolism and induces insulin resistance in mice, two phenotypes that can be reverted by edavarone treatment.
Microbial oils are proposed as a suitable alternative to petroleum‐based chemistry in terms of environmental preservation. These oils have traditionally been studied using sugar‐based feedstock, ...which implies high costs, substrate limitation, and high contamination risks. In this sense, low‐cost carbon sources such as volatile fatty acids (VFAs) are envisaged as promising building blocks for lipid biosynthesis to produce oil‐based bioproducts. VFAs can be generated from a wide variety of organic wastes through anaerobic digestion and further converted into lipids by oleaginous yeasts (OYs) in a fermentation process. These microorganisms can accumulate in the form of lipid bodies, lipids of up to 60% wt/wt of their biomass. In this context, OY is a promising biotechnological tool for biofuel and bioproduct generation using low‐cost VFA media as substrates. This review covers recent advances in microbial oil production from VFAs. Production of VFAs via anaerobic digestion processes and the involved metabolic pathways are reviewed. The main challenges as well as recent approaches for lipid overproduction are also discussed.
Microbial oil are proposed as a suitable alternative to petroleum‐based chemistry in terms of environmental preservation. These oils have traditionally been studied using sugar‐based feedstock. VFAs rich digestate (VFAs) is envisaged as promising low‐cost substrate reducing process cost as well as allowing wastes valorisation.
Cellular senescence is considered a crucial process for tumour suppression, which can be facilitated by immune surveillance. However, when senescent cells persist in tissues, they can also trigger a ...plethora of tumour‐promoting effects. Here, we discuss the main hallmarks, mechanisms and roles of senescence in cancer and provide a comprehensive revision of the available tools for its detection.
Senescence refers to a cellular state featuring a stable cell‐cycle arrest triggered in response to stress. This response also involves other distinct morphological and intracellular changes including alterations in gene expression and epigenetic modifications, elevated macromolecular damage, metabolism deregulation and a complex pro‐inflammatory secretory phenotype. The initial demonstration of oncogene‐induced senescence in vitro established senescence as an important tumour‐suppressive mechanism, in addition to apoptosis. Senescence not only halts the proliferation of premalignant cells but also facilitates the clearance of affected cells through immunosurveillance. Failure to clear senescent cells owing to deficient immunosurveillance may, however, lead to a state of chronic inflammation that nurtures a pro‐tumorigenic microenvironment favouring cancer initiation, migration and metastasis. In addition, senescence is a response to post‐therapy genotoxic stress. Therefore, tracking the emergence of senescent cells becomes pivotal to detect potential pro‐tumorigenic events. Current protocols for the in vivo detection of senescence require the analysis of fixed or deep‐frozen tissues, despite a significant clinical need for real‐time bioimaging methods. Accuracy and efficiency of senescence detection are further hampered by a lack of universal and more specific senescence biomarkers. Recently, in an attempt to overcome these hurdles, an assortment of detection tools has been developed. These strategies all have significant potential for clinical utilisation and include flow cytometry combined with histo‐ or cytochemical approaches, nanoparticle‐based targeted delivery of imaging contrast agents, OFF‐ON fluorescent senoprobes, positron emission tomography senoprobes and analysis of circulating SASP factors, extracellular vesicles and cell‐free nucleic acids isolated from plasma. Here, we highlight the occurrence of senescence in neoplasia and advanced tumours, assess the impact of senescence on tumorigenesis and discuss how the ongoing development of senescence detection tools might improve early detection of multiple cancers and response to therapy in the near future.
Microalgae are regarded as a potential biomass source for biofuel purposes. With regard to bioethanol production, microalgae seem to overcome traditional substrate drawbacks. Enzymatic activities are ...responsible for carbon allocation and hence for carbohydrate profiles. Enzyme activities may be manipulated by metabolic engineering; however, this goal may also be achieved by controlling environmental conditions of the culture system. We outline the key-enzymes as well as the main operational conditions applied to microalgae growth (inorganic nutrient supplementation, irradiance and temperature) that affect carbohydrate synthesis on microalgae and cyanobacteria. Normally, harsh conditions are needed for such a goal and thus, arrested microalgae growth may occur. Potential strategies to avoid arrested growth, while enhancing carbohydrate accumulation, were also pointed out in this review.
Background and Purpose
Mitochondrial encephalomyopathy, lactic acidosis and stroke‐like episodes (MELAS) syndrome is a genetically heterogeneous disorder caused by mitochondrial DNA mutations. There ...are no disease‐modifying therapies, and treatment remains mainly supportive. It has been shown previously that patients with MELAS syndrome have significantly increased cerebrospinal fluid (CSF) glutamate and significantly decreased CSF glutamine levels compared to controls. Glutamine has many metabolic fates in neurons and astrocytes, and the glutamate–glutamine cycle couples with many metabolic pathways depending on cellular requirements. The aim was to compare CSF glutamate and glutamine levels before and after dietary glutamine supplementation. It is postulated that high‐dose oral glutamine supplementation could reduce the increase in glutamate levels.
Method
This open‐label, single‐cohort study determined the safety and changes in glutamate and glutamine levels in CSF after 12 weeks of oral glutamine supplementation.
Results
Nine adult patients with MELAS syndrome (66.7% females, mean age 35.8 ± 3.2 years) were included. After glutamine supplementation, CSF glutamate levels were significantly reduced (9.77 ± 1.21 vs. 18.48 ± 1.34 μmol/l, p < 0.001) and CSF glutamine levels were significantly increased (433.66 ± 15.31 vs. 336.31 ± 12.92 μmol/l, p = 0.002). A side effect observed in four of nine patients was a mild sensation of satiety. One patient developed mild and transient elevation of transaminases, and another patient was admitted for an epileptic status without stroke‐like episode.
Discussion
This study demonstrates that high‐dose oral glutamine supplementation significantly reduces CSF glutamate and increases CSF glutamine levels in patients with MELAS syndrome. These findings may have potential therapeutic implications in these patients.
Trial Registration Information
ClinicalTrials.gov Identifier: NCT04948138. Initial release 24 June 2021, first patient enrolled 1 July 2021. https://clinicaltrials.gov/ct2/show/NCT04948138.
High‐dose oral glutamine supplementation for 12 weeks significantly reduces cerebrospinal fluid (CSF) glutamate and increases CSF glutamine levels in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke‐like episodes (MELAS) syndrome. This decrease in CSF glutamate levels could reduce glutamate‐mediated excitotoxicity. These findings may have potential therapeutic implications in patients with MELAS syndrome.
The link between nutrition and health has focused on the strategy of diet-based programs to deal with various physiological threats, such as cardiovascular disease, oxidative stress, and diabetes. ...Therefore, the consumption of fruits and vegetables as a safeguard for human health is increasingly important. Among fruits, the intake of persimmon is of great interest because several studies have associated its consumption with health benefits due to its high content of bioactive compounds, fiber, minerals, and vitamins. However, during digestion, some changes take place in persimmon nutritional compounds that condition their subsequent use by the human body. In vitro studies indicate different rates of recovery and bioaccessibility depending on the bioactive compound and the matrix in which they are found. In vivo studies show that the pharmacological application of persimmon or its functional components, such as proanthocyanidins, can help to prevent hyperlipidemia and hyperglycemia. Thus, persimmon and persimmon derived products have the potential to be a fruit recommended for diet therapy. This review aims to compile an updated review of the benefits of persimmon and its derived products, focusing on the in vitro and in vivo digestibility of the main nutrients and bioactive compounds.
Chromatin organization is disrupted genome-wide during DNA replication. On newly synthesized DNA, nucleosomes are assembled from new naive histones and old modified histones. It remains unknown ...whether the landscape of histone post-translational modifications (PTMs) is faithfully copied during DNA replication or the epigenome is perturbed. Here we develop chromatin occupancy after replication (ChOR-seq) to determine histone PTM occupancy immediately after DNA replication and across the cell cycle. We show that H3K4me3, H3K36me3, H3K79me3, and H3K27me3 positional information is reproduced with high accuracy on newly synthesized DNA through histone recycling. Quantitative ChOR-seq reveals that de novo methylation to restore H3K4me3 and H3K27me3 levels occurs across the cell cycle with mark- and locus-specific kinetics. Collectively, this demonstrates that accurate parental histone recycling preserves positional information and allows PTM transmission to daughter cells while modification of new histones gives rise to complex epigenome fluctuations across the cell cycle that could underlie cell-to-cell heterogeneity.
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•ChOR-seq determines histone PTM occupancy on newly replicated DNA•Histone PTM positional information is preserved through parental histone recycling•Parental H3K27me3 domains are stable and inherited to daughter cells•Restoration of histone PTM levels follows mark- and locus-specific kinetics
Histone modifications are a core component of the epigenome. Reverón-Gómez et al. develop ChOR-seq to profile histone modifications after DNA replication and find that the genomic localization of modified parental histones is preserved on daughter strands while new histone modification to restore pre-replication levels follows mark- and locus-specific kinetics.
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