Search Results (318)

Glycolysis and oxidative phosphorylation are the main pathways of cellular energy production. Glucose is metabolized via glycolysis to generate pyruvate, which, under anaerobic conditions, is converted into lactate, while, under aerobic conditions, pyruvate enters mitochondria for oxidative phosphorylation to produce more energy. Accordingly, mitochondrial dysfunction disrupts the energy balance. Lactate, historically perceived as a harmful metabolic byproduct. However, emerging research indicates that lactate has diverse biological functions, encompassing energy regulation, epigenetic remodeling, and signaling activities. Notably, the 2019 study revealed the role of lactate in regulating gene expression through histone and non-histone lactylation, thereby influencing critical biological processes. Metabolic reprogramming is a key adaptive mechanism of cells responding to stresses. The Warburg effect in tumor cells exemplifies this, with glucose preferentially converted to lactate for rapid energy, accompanied by metabolic imbalances, characterized by exacerbated aerobic glycolysis, lactate accumulation, suppressed mitochondrial oxidative phosphorylation, and compromised mitochondrial function, ultimately resulting in a vicious cycle of metabolic dysregulation. As molecular bridges connecting metabolism and epigenetics, lactate and lactylation offer novel therapeutic targets for diseases like cancer and neurodegenerative diseases. This review summarizes the interplay between metabolic reprogramming and mitochondrial dysfunction, while discussing lactate and lactylation’s mechanistic in the pathogenesis of related diseases. Full article

Oncolytic virotherapy is a rapidly evolving approach to cancer treatment. Our group previously designed VV-GMCSF-Lact, a recombinant oncolytic vaccinia virus targeting solid tumors including gliomas. In this study, we used single-cell RNA sequencing to compare transcriptional responses in human glioma cells, non-malignant brain cells, and immortalized glioblastoma U87 MG cells following infection with this oncolytic virus. We found that proneural glioblastoma cells and microglia-like cells from patient-derived glioma cultures were the most susceptible to VV-GMCSF-Lact. Increased expressions of histones, translational regulators, and ribosomal proteins positively correlated with viral load at the transcript level. Furthermore, higher viral loads were accompanied by a large-scale downregulation of genes involved in mitochondrial translation, metabolism, and oxidative phosphorylation. Levels of early vaccinia virus transcripts are also positively correlated with infection intensity, suggesting that the fate of cells is determined at the early stage of infection. Full article

The ability of plants to protect themselves from stress-related damages is termed “adaptability” and the phenomenon of showing better performance in subsequent stress is termed “stress memory”. This phenomenon has been reported in various stresses such as drought, heat, salinity, cold, and heavy metal toxicity. Histone modification leading to chromatin remodeling and accumulation of phosphorylated RNA polymerase on the promoters of memory genes is a well-known mechanism of plant stress memory. Recent studies have revealed the role of non-coding RNAs (ncRNAs) and alternative splicing (AS) in memory-specific gene expression and transgenerational inheritance of stress memory. MicroRNAs (miRNAs) inhibit specific genes to enable plants to respond better in subsequent drought and heat stress, while long non-coding RNAs (lncRNAs) play roles in epigenetic regulation of memory gene expression in cold and salt stress. Small interfering RNAs (siRNAs) lead to DNA methylation during the memory response of biotic, salt, and heavy metal stress. Simultaneously, stress-responsive isoforms of tolerant genes are found to be expressed as a memory response in subsequent heat stress. This review highlights the stress-type-specific roles of ncRNAs and AS in establishing, maintaining, and transmitting stress memory, offering insights into their potential for improving crop resilience through genetic and epigenetic priming strategies. Full article

Mitochondrial dysfunction is a pivotal driver in the pathogenesis of acute kidney injury (AKI), chronic kidney disease (CKD), and congenital anomalies of the kidney and urinary tract (CAKUT). The kidneys, second only to the heart in mitochondrial density, rely on oxidative phosphorylation to meet the high ATP demands of solute reabsorption and filtration. Disrupted mitochondrial dynamics, such as excessive fission mediated by Drp1, exacerbate tubular apoptosis and inflammation in AKI models like ischemia–reperfusion injury. In CKD, persistent mitochondrial dysfunction drives oxidative stress, fibrosis, and metabolic reprogramming, with epigenetic mechanisms (DNA methylation, histone modifications, non-coding RNAs) regulating genes critical for mitochondrial homeostasis, such as PMPCB and TFAM. Epigenetic dysregulation also impacts mitochondrial–ER crosstalk, influencing calcium signaling and autophagy in renal pathology. Mitophagy, the selective clearance of damaged mitochondria, plays a dual role in kidney disease. While PINK1/Parkin-mediated mitophagy protects against cisplatin-induced AKI by preventing mitochondrial fragmentation and apoptosis, its dysregulation contributes to fibrosis and CKD progression. For instance, macrophage-specific loss of mitophagy regulators like MFN2 amplifies ROS production and fibrotic responses. Conversely, BNIP3/NIX-dependent mitophagy attenuates contrast-induced AKI by suppressing NLRP3 inflammasome activation. In diabetic nephropathy, impaired mitophagy correlates with declining eGFR and interstitial fibrosis, highlighting its diagnostic and therapeutic potential. Emerging therapeutic strategies target mitochondrial dysfunction through antioxidants (e.g., MitoQ, SS-31), mitophagy inducers (e.g., COPT nanoparticles), and mitochondrial transplantation, which mitigates AKI by restoring bioenergetics and modulating inflammatory pathways. Nanotechnology-enhanced drug delivery systems, such as curcumin-loaded nanoparticles, improve renal targeting and reduce oxidative stress. Epigenetic interventions, including PPAR-α agonists and KLF4 modulators, show promise in reversing metabolic reprogramming and fibrosis. These advances underscore mitochondria as central hubs in renal pathophysiology. Tailored interventions—ranging from Drp1 inhibition to mitochondrial transplantation—hold transformative potential to mitigate kidney injury and improve clinical outcomes. Additionally, dietary interventions and novel regulators such as adenogens are emerging as promising strategies to modulate mitochondrial function and attenuate kidney disease progression. Future research should address the gaps in understanding the role of mitophagy in CAKUT and optimize targeted delivery systems for precision therapies. Full article

Activation of cGAS, a cytosolic receptor recognizing double-stranded DNA, in macrophages is important in sepsis (a life-threatening condition caused by infection). The responses against sepsis induced by subcutaneous implantation of the Pseudomonas-contaminated catheters in cGAS-deficient (cGAS^−/−) mice were lower than in wild-type (WT) mice as indicated by liver enzymes, white blood cell count, cytokines, and M1-polarized macrophages in the spleens. Likewise, a lethal dose of lipopolysaccharide (LPS) induced less severe sepsis severity as determined by mortality, organ injury, cell-free DNA, and serum cytokines. Patterns of the transcriptome of lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages were clearly different between cGAS^−/− and WT cells. Gene set enrichment analysis (GSEA; a computational statistical determination of the gene set) indicated more prominent enrichment of oxidative phosphorylation (OXPHOS; the mitochondrial function) and mTORC1 pathways in LPS-activated cGAS^−/− macrophages compared with WT. Meanwhile, LPS upregulated cGAS and increased cGAMP (a cGAS inducer) only in WT macrophages along with less severe inflammation in cGAS^−/− macrophages, as indicated by supernatant cytokines, pro-inflammatory molecules (nuclear factor kappa B; NF-κB), M1 polarization (IL-1β, CD80, and CD86), and macrophage extracellular traps (METs; web-like structures composed of DNA, histones, and other proteins) through the detection of citrullinated histone 3 (CitH3) in supernatant and immunofluorescent visualization. In conclusion, less prominent pro-inflammatory responses of cGAS^−/− macrophages than WT were demonstrated in mice (catheter-induced sepsis and LPS injection model) and in vitro (transcriptomic analysis, macrophage polarization, and METs). Full article

The control of cyclin-dependent kinase 1 (CDK1) kinase activity is crucial for cell cycle progression. Cell division cycle 6 (CDC6) inhibits this activity in embryonic mitoses, and thus regulates the timing of cell division progression. The meiotic cell cycle differs greatly from the mitotic one. Metaphase II (MII)-arrested oocytes remain in prolonged M-phase state due to the high activity of CDK1 in the presence of CytoStatic Factor (CSF). The role of CDC6 in the control of CDK1 during MII and oocyte activation remains unknown. Here, we studied the role of CDC6/CDK1 interactions in Xenopus laevis cell-free extracts arrested in MII (CSF extract) and upon calcium activation leading to meiotic-to-mitotic transition. The CSF extract allows analysis of biochemical processes based on immunodepletion of selected proteins and facilitates manipulations using addition of recombinant proteins. We show by glutathione S-transferase (GST)-CDC6 pull-down that CDC6 associates with CDK1 in CSF extract and by histone H1 kinase assay that it downregulates CDK1 activity. Thus, CDC6-dependent inhibition of CDK1 is involved in the homeostasis of the MII-arrest. Upon CSF extract activation with calcium exogenous GST-CDC6 provokes accelerated transition from MII to interphase, while the depletion of endogenous CDC6 results in a slower transition to interphase. We demonstrate this by following both the phosphorylation state of CDK1 substrate cell division cycle 27 (CDC27) and histone H1 kinase assay. Importantly, increasing doses of GST-CDC6 proportionally accelerate CDK1 inactivation showing that CDC6 controls the dynamics of MII to interphase transition in a dose-dependent manner. Thus, CDC6 is a CDK1 silencer acting upon both the MII arrest and CSF extract activation by assuring the physiological activity of CDK1 during this meiotic arrest and correct timely inactivation of this kinase during the second process. Thus, we show that CDC6 controls CDK1 not only during mitotic divisions, but also in MII-arrest and the meiotic-to-mitotic transition in Xenopus laevis cell-free extracts. This study aims to bridge that gap by investigating CDC6 function using a biochemically controlled system. Full article

The DNA damage response (DDR) is crucial for maintaining genomic stability and preventing the accumulation of mutations that can lead to various diseases, including cancer. The DDR is a complex cellular regulatory network that involves DNA damage sensing, signal transduction, repair, and cell cycle arrest. Modifications in histone phosphorylation play important roles in these processes, facilitating DNA repair factor recruitment, damage signal transduction, chromatin remodeling, and cell cycle regulation. The precise regulation of histone phosphorylation is critical for the effective repair of DNA damage, genomic integrity maintenance, and the prevention of diseases such as cancer, where DNA repair mechanisms are often compromised. Thus, understanding histone phosphorylation in the DDR provides insights into DDR mechanisms and offers potential therapeutic targets for diseases associated with genomic instability, including cancers. Full article

Chinese tongue sole (Cynoglossus semilaevis) is an important mariculture fish in China, and female individuals present a growth advantage. However, genetic females (ZW) can sex reverse to phenotypic males, designated pseudomales. The pseudomale shows abnormal spermatogenesis and produces only Z sperm. Histone is pivotal in spermatogenesis, and post-translational modification could regulate its function. A comparison of testis phosphorylated and ubiquitinated proteins revealed 8 and 12 differentially phosphorylated and ubiquitinated histones in the testes of male and pseudomale Chinese tongue soles, respectively, but there was no difference in the translation level of these proteins. We selected four histone genes, h1.1-like, h1.2-like, h3, and h3.3-like, for further analysis. The expression levels of the h1.1-like, h3, and h3.3-like genes reached their highest levels at 2 years post-hatching (yph), and the expression level of h1.2-like reached its highest level at 1.5 years post-hatching (1.5 yph), indicating that its role began during the late stage of gonadal development. Promoter activity verification revealed that the promoters of the h1.1-like, h1.2-like, h3, and h3.3-like genes were located approximately upstream 2000 bp and six histone-related transcription factor sites were predicted. YY1A, YY1B, C-JUN, and JUNB may have negative regulatory effects on h1.1-like, h1.2-like, h3, and h3.3-like; AR and ETS-2 may have positive regulatory effects on h3 and h3.3-like. The ISH results revealed that h1.1-like, h1.2-like, h3, and h3.3-like mRNAs were located mainly in the sperm cells in the testes and the oocytes at various stages in the ovaries. After siRNA knockdown, the expression of dmrt1 in testis cell lines and the expression of tesk1 and neurl3 in males was downregulated, suggesting that the h1.1-like, h1.2-like, h3, and h3.3-like genes may have a negative regulatory role in spermatogenesis. The regulatory role in female fish remains to be explored. Mass spectrometry analysis revealed that histones have an important role in chromosome remodeling. These results provide a genetic basis for the molecular mechanism of gonadal development and spermatogenesis in Chinese tongue sole. Full article

Background/Objectives: Incomptine A (IA) has cytotoxic activity in non-Hodgkin lymphoma (NHL) cancer cell lines. Its effects on U-937 cells include induction of apoptosis, production of reactive oxygen species, and inhibition of glycolytic enzymes. We examined the altered protein levels present in the lymph nodes of an in vivo mouse model. Methods: We induced an in vivo model with Balb/c mice with U-937 cells and treated it with IA or methotrexate, as well as healthy mice. We determined expressed proteins by TMT based on the LC-MS/MS method (Data are available via ProteomeXchange with identifier PXD060392) and a molecular docking study targeting 15 deregulated proteins. We developed analyses through the KEGG, Reactome, and Gene Ontology databases. Results: A total of 2717 proteins from the axillary and inguinal lymph nodes were analyzed and compared with healthy mice. Of 412 differentially expressed proteins, 132 were overexpressed (FC ≥ 1.5) and 117 were underexpressed (FC ≤ 0.67). This altered expression was associated with 20 significantly enriched processes, including chromatin remodeling, transcription, translation, metabolic and energetic processes, oxidative phosphorylation, glycolysis/gluconeogenesis, cell proliferation, cytoskeletal organization, and with cell death with necroptosis. Conclusions: We confirmed the previously observed dose-dependent effect of IA as a secondary metabolite with important potential as an anticancer agent for the treatment of NHL, showing that the type of drug or the anatomical location influences the response to treatment. The IA promises to be a likely safer and more effective treatment to improve outcomes, reduce toxicities, and improve survival in patients with NHL, initially targeting histones and transcription factors that will affect cell death proteins. Full article

Plants are subjected to various stresses during the growth process, including biotic stresses, as well as abiotic stresses such as temperature, drought, salt, and heavy metals. To cope with these biotic and abiotic adversities, plants have evolved complex regulatory mechanisms during their long-term environmental adaptations. In a suddenly changing environment, protein modifiers target other proteins to induce post-translational modification (PTM) in order to maintain cell homeostasis and protein biological activity in plants. PTMs modulate the activity of enzymes and transcription factors in their respective metabolic pathways, enabling plants to produce essential compounds for their survival under stress conditions. Examples of post-translational mechanisms include phosphorylation, ubiquitination, glycosylation, acetylation, protein–protein interactions, and targeted protein degradation. Furthermore, the role of histone modifications in regulating secondary metabolism deserves attention due to its potential impact on heritability and its contribution to stress tolerance. Understanding the epigenetic aspect of these modifications can provide valuable insights into the mechanisms underlying stress response. In this context, also examining PTMs that impact the biosynthesis of secondary metabolites is meaningful. Secondary metabolites encompass a wide range of compounds such as flavonoids, alkaloids, and terpenoids. These secondary metabolites play a crucial role in plant defense against herbivores, pathogens, and oxidative stress. In this context, it is imperative to understand the contribution of secondary metabolism to plant tolerance to abiotic stresses and how this understanding can be leveraged to improve long-term survival. While many studies have focused on the transcriptional regulation of these metabolites, there is a growing interest in understanding various changes in PTMs, such as acetylation, glycosylation, and phosphorylation, that are able to modulate plants’ response to environmental conditions. In conclusion, a comprehensive exploration of post-translational mechanisms in secondary metabolism can enhance our understanding of plant responses to abiotic stress. This knowledge holds promise for future applications in genetic improvement and breeding strategies aimed at increasing plant resilience to environmental challenges. Full article

Melatonin (MLT), produced by the pineal gland and other tissues, is known for its anti-inflammatory effects, particularly in regulating inflammatory markers and cytokines in intestinal cells. Our study aimed to investigate how MLT influences the expression of inflammatory genes through histone modification in canine ileum epithelial cells (cIECs). In our experiment, cIECs were cultured and divided into a control group (CON) and an MLT-treatment group. MLT did not significantly affect cell growth or death in cIECs compared to the CON. However, MLT treatment led to an upregulation of CD40, ZAP70, and IL7R and a downregulation of LCK, RPL37, TNFRSF13B, CD4, CD40LG, BLNK, and CIITA at the mRNA expression level. Moreover, MLT significantly altered the NF-kappa B signaling pathway by upregulating genes, such as CD40, ZAP70, TICAM1, VCAMI, GADD45B, IRAK1, TRADD, RELA, RIPK1, and RELB, and downregulating PRKCB, LY96, CD40LG, ILIB, BLNK, and TNFRSF11A. Using ChIP-qPCR, we discovered that MLT treatment enhanced histone acetylation marks H3K9ac, H3K18ac, H3K27ac, and methylation marks H3K4me1 and H3K4me3 at the ZAP70 and CD40 gene loci (p < 0.05). Additionally, the enrichment of RNA polymerase II and phosphorylated Ser5 pol-II at these loci was increased in MLT-treated cells (p < 0.05), indicating heightened transcriptional activity. In conclusion, our findings suggest that MLT mitigates inflammation in cIECs by modulating the transcription of ZAP70 and CD40 through histone modifications, offering potential therapeutic insights for inflammatory bowel diseases. Full article

In the field of medicinal chemistry, the introduction of silylated groups is an important strategy to alter the activity, selectivity, and pharmacokinetics of compounds based on the diverse traits of silicon, including atomic size, electronegativity, and hydrophobicity. The hydroxy group on C-9 or C-9 and C-10 of hydroxystearic acids have been functionalized as t-butyl dimethyl silyl ether. The target compounds have been fully characterized and tested for in vitro cytotoxicity in tumor cells HT29, HCT116, CaCo2, HeLa, MCF7, U2OS, and Jurkat J6 and normal I407 cells. In particular, the silyl derivative of (R)-9-hydroxystearic acid was more active in colon cancer cells. Analyses of cell proliferation, oxidative cell status, histones post-translational modifications, protein phosphorylation, gene expression, and DNA damage were performed to obtain information on the antitumor properties of the new molecules in comparison with the unmodified (R)-9-hydroxystearic acid’s previously studied effects. Our results suggest that the incorporation of a silyl functionality may be a useful tool for the structural development of new pharmaceutically active compounds against colon cancer. Full article

Rat dental pulp stem cells (DPSCs) can be used to elucidate mesenchymal stem cell (MSC) applications in regenerative medicine. However, information on rat DPSCs during long-term passage, which could lead to replicative senescence, is limited. In this study, we investigated the phenotypic changes in DPSCs after 3–26 passages (3P–26P). The results show that cell morphology and nuclear size increase proportionally with passage number. The phosphorylated histone H2A.X (γ-H2A.X) positive cells (indicating DNA damage) increased significantly earlier than the 4-Hydroxynonenal (4-HNE) stained cells (indicating an abundance of intracellular reactive oxygen species). Compared to the cells subjected to 3P and 5P, the cells subjected to 15P showed reduced proliferation despite being positive for Ki67. Furthermore, cell growth was completely arrested after 26P. The senescence markers, senescence-associated β-galactosidase (SA-β-gal) and p16, exhibited similar expression patterns that were not correlated with those of p21 and urokinase-type plasminogen activator receptor (uPAR). Nearly all cells expressed SA-β-gal and p16 after 26P, whereas only half expressed p21 and uPAR. These results will contribute to understanding the characteristics of DPSCs toward replicative senescence, which are applicable to elucidate mechanisms related to regenerative medicine and stem cell aging. Full article

Background/Objectives: We analyzed the relationship between synapsis, recombination, and transcription during the spermatogenesis of the grasshopper Eyprepocnemis plorans carrying B chromosomes (type B1). Methods: The progression of synapsis was interpreted according to the dynamics of the cohesin subunit SMC3 axes. DNA double-strand breaks were revealed by RAD51 immunolabeling, while transcriptional activity was determined by the presence of RNA polymerase II phosphorylated at serine 2 (pRNApol II) immunolabeling. The two repressive epigenetic modifications, histone H3 methylated at lysine 9 (H3K9me3) and histone H2AX phosphorylated at serine 139 (γ-H2AX), were employed to reveal transcriptional inactivity. Results: During prophase I, spermatocytes with one B1 chromosome showed overall transcription except in the regions occupied by both the X and the B1 chromosomes. This transcriptional inactivity was accompanied by the accumulation of repressive epigenetic modifications. When two B1 chromosomes were present, they could appear as a fully synapsed monochiasmatic bivalent, showing intense H3K9me3 labeling and absence of pRNApol II, while γ-H2AX labeling was similar to that shown by the autosomes. Conclusions: According to our results, B1 transcriptional inactivation was triggered in spermatogonia, long before the beginning of meiosis, and was accompanied by H3K9me3 heterochromatinization that was maintained throughout spermatogenesis. Moreover, when two B1 were present, the transcriptional inactivation did not preclude synapsis and recombination achievement by these chromosomes. Full article

This study investigates the potential of 4-hexylresorcinol (4HR) as a novel antidiabetic agent by assessing its effects on blood glucose levels, Glut4 expression, AMPK phosphorylation, and Histone H3 acetylation (Ac-H3) in the liver. In vitro experiments utilized Huh7 and HepG2 cells treated with varying concentrations of 4HR. Glut4, p-AMPK, and Ac-H3 expression levels were quantified via Western blotting. Additionally, GAPDH activity and glucose uptake were evaluated. In vivo experiments employed streptozotocin (STZ)-induced diabetic rats, with or without 4HR treatment, monitoring blood glucose, body weight, and hepatic levels of Glut4, p-AMPK, and Ac-H3. In vitro, 4HR treatment increased GAPDH activity and glucose uptake. Elevated Glut4, p-AMPK, and Ac-H3 levels were observed 8 h after 4HR administration. Inhibition of p-AMPK using compound C reduced 4HR-mediated Glut4 expression. In STZ-induced diabetic rats, 4HR significantly upregulated Glut4, p-AMPK, and Ac-H3 expression in the liver. Periodic 4HR injections mitigated weight loss and lowered blood glucose levels in STZ-injected animals. Histological analysis revealed increased glycogen storage in hepatocytes of the 4HR-treated group. Overall, 4HR enhanced Glut4 expression through upregulation of AMPK activity and histone H3 acetylation in vitro and in vivo, improving hepatic glucose homeostasis and suggesting potential as a candidate for diabetes treatment. Full article