Histidine re-sensitizes pediatric acute lymphoblastic leukemia to 6-mercaptopurine through tetrahydrofolate consumption and SIRT5-mediated desuccinylation.

Despite progressive improvements in the survival rate of pediatric B-cell lineage acute lymphoblastic leukemia (B-ALL), chemoresistance-induced disease progression and recurrence still occur with poor prognosis, thus highlighting the urgent need to eradicate drug resistance in B-ALL. The 6-mercaptopurine (6-MP) is the backbone of ALL combination chemotherapy, and resistance to it is crucially related to relapse. The present study couples chemoresistance in pediatric B-ALL with histidine metabolism deficiency. Evidence was provided that histidine supplementation significantly shifts the 6-MP dose-response in 6-MP-resistant B-ALL. It is revealed that increased tetrahydrofolate consumption via histidine catabolism partially explains the re-sensitization ability of histidine. More importantly, this work provides fresh insights into that desuccinylation mediated by SIRT5 is an indispensable and synergistic requirement for histidine combination therapy against 6-MP resistance, which is undisclosed previously and demonstrates a rational strategy to ameliorate chemoresistance and protect pediatric patients with B-ALL from disease progression or relapse.

1,5-AG suppresses pro-inflammatory polarization of macrophages and promotes the survival of B-ALL in vitro by upregulating CXCL14.

B-lineage acute lymphoblastic leukemia (B-ALL) is one of the most common malignancies in children. Despite advances in treatment, the role of the tumor microenvironment in B-ALL remains poorly understood. Among the key components of the immune microenvironment, macrophages play a critical role in the progression of the disease. However, recent research has suggested that abnormal metabolites may influence the function of macrophages, altering the immune microenvironment and promoting tumor growth. Our previous non-targeted metabolomic detection revealed that the metabolite 1,5-anhydroglucitol (1,5-AG) level in the peripheral blood of children newly diagnosed with B-ALL was significantly elevated. Except for its direct influence on leukemia cells, the effect of 1,5-AG on macrophages is still unclear. Herein, we demonstrated new potential therapeutic targets by focusing on the effect of 1,5-AG on macrophages. We used polarization-induced macrophages to determine how 1,5-AG acted on M1-like polarization and screened out the target gene CXCL14 via transcriptome sequencing. Furthermore, we constructed CXCL14 knocked-down macrophages and a macrophage-leukemia cell coculture model to validate the interaction between macrophages and leukemia cells. We discovered that 1,5-AG upregulated the CXCL14 expression, thereby inhibiting M1-like polarization. CXCL14 knockdown restored the M1-like polarization of macrophages and induced leukemia cells apoptosis in the coculture model. Our findings offer new possibilities for the genetic engineering of human macrophages to rehabilitate their immune activity against B-ALL in cancer immunotherapy.

1,5-Anhydroglucitol promotes pre-B acute lymphocytic leukemia progression by driving glycolysis and reactive oxygen species formation.

BACKGROUND: Precursor B-cell acute lymphoblastic leukemia (pre-B ALL) is the most common hematological malignancy in children. Cellular metabolic reorganization is closely related to the progression and treatment of leukemia. We found that the level of 1,5-anhydroglucitol (1,5-AG), which is structurally similar to glucose, was elevated in children with pre-B ALL. However, the effect of 1,5-AG on pre-B ALL was unclear. Here, we aimed to reveal the roles and mechanisms of 1,5-AG in pre-B ALL progression. METHODS: The peripheral blood plasma level of children with initial diagnosis of pre-B ALL and that of healthy children was measured using untargeted metabolomic analysis. Cell Counting Kit-8 assay, RNA sequencing, siRNA transfection, real-time quantitative PCR, and western blot were performed using pre-B ALL cell lines Reh and HAL-01. Cell cycle, cell apoptosis, ROS levels, and the positivity rate of CD19 were assessed using flow cytometry. Oxygen consumption rates and extracellular acidification rate were measured using XFe24 Extracellular Flux Analyzer. The lactate and nicotinamide adenine dinucleotide phosphate levels were measured using kits. The effect of 1,5-AG on pre-B ALL progression was verified using the In Vivo Imaging System in a xenotransplantation leukemia model. RESULTS: We confirmed that 1,5-AG promoted the proliferation, viability, and intracellular glycolysis of pre-B ALL cells. Mechanistically, 1,5-AG promotes glycolysis while inhibiting mitochondrial respiration by upregulating pyruvate dehydrogenase kinase 4 (PDK4). Furthermore, high levels of intracellular glycolysis promote pre-B ALL progression by activating the reactive oxygen species (ROS)-dependent mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. Conversely, N-acetylcysteine or vitamin C, an antioxidant, effectively inhibited 1,5-AG-mediated progression of leukemia cells. CONCLUSIONS: Our study reveals a previously undiscovered role of 1,5-AG in pre-B ALL, which contributes to an in-depth understanding of anaerobic glycolysis in the progression of pre-B ALL and provides new targets for the clinical treatment of pre-B ALL.

Three-dimensional culture of rat ovarian granulosa cells shows increased SPP1 and FGF7 expression through the PI3K/Akt pathway.

Ovarian granulosa cells (OGCs) play an essential role in the regulation of follicular growth and development. However, previous studies of OGCs have concentrated on traditional 2D cultures. In the present study, we used the hanging drop culture method to culture rat OGCs (rOGCs) and assessed the effects of 3D conditions on their proliferation and gene expression profiles. Compared with those grown in 2D conditions, rOGCs grown in 3D cultures showed a significantly different spatial cell distribution and cell alignment under electron microscopy. In particular, rOGCs in 3D cultures showed abundant rough and microvilli-like structures on their cell surface. Here, we showed that these cells grew slowly following 3D culture; the G0/G1-phase increased and the S- and G2/M-phases decreased. Using whole-transcriptome sequencing analysis, 501 genes were shown to have been significantly upregulated and 502 were shown to have been downregulated. Differentially expressed genes were most enriched in pathways involved in focal adhesion, MAPK, and PI3K/Akt signaling according to Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Western blotting revealed that SPP1 and FGF7 in the PI3K/Akt pathway were significantly upregulated following 3D culture. These findings improve our understanding of OGCs in real 3D environments in vivo and provide possible avenues for future research on OGCs.

Intratracheal administration of umbilical cord-derived mesenchymal stem cells attenuates hyperoxia-induced multi-organ injury via heme oxygenase-1 and JAK/STAT pathways.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is not merely a chronic lung disease, but a systemic condition with multiple organs implications predominantly associated with hyperoxia exposure. Despite advances in current management strategies, limited progress has been made in reducing the BPD-related systemic damage. Meanwhile, although the protective effects of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) or their exosomes on hyperoxia-induced lung injury have been explored by many researchers, the underlying mechanism has not been addressed in detail, and few studies have focused on the therapeutic effect on systemic multiple organ injury. AIM: To investigate whether hUC-MSC intratracheal administration could attenuate hyperoxia-induced lung, heart, and kidney injuries and the underlying regulatory mechanisms. METHODS: Neonatal rats were exposed to hyperoxia (80% O2), treated with hUC-MSCs intratracheal (iT) or intraperitoneal (iP) on postnatal day 7, and harvested on postnatal day 21. The tissue sections of the lung, heart, and kidney were analyzed morphometrically. Protein contents of the bronchoalveolar lavage fluid (BALF), myeloperoxidase (MPO) expression, and malondialdehyde (MDA) levels were examined. Pulmonary inflammatory cytokines were measured via enzyme-linked immunosorbent assay. A comparative transcriptomic analysis of differentially expressed genes (DEGs) in lung tissue was conducted via RNA-sequencing. Subsequently, we performed reverse transcription-quantitative polymerase chain reaction and western blot analysis to explore the expression of target mRNA and proteins related to inflammatory and oxidative responses. RESULTS: iT hUC-MSCs administration improved pulmonary alveolarization and angiogenesis (P < 0.01, P < 0.01, P < 0.001, and P < 0.05 for mean linear intercept, septal counts, vascular medial thickness index, and microvessel density respectively). Meanwhile, treatment with hUC-MSCs iT ame liorated right ventricular hypertrophy (for Fulton's index, P < 0.01), and relieved reduced nephrogenic zone width (P < 0.01) and glomerular diameter (P < 0.001) in kidneys. Among the beneficial effects, a reduction of BALF protein, MPO, and MDA was observed in hUC-MSCs groups (P < 0.01, P < 0.001, and P < 0.05 respectively). Increased pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin (IL)-1ß, and IL-6 expression observed in the hyperoxia group were significantly attenuated by hUC-MSCs administration (P < 0.01, P < 0.001, and P < 0.05 respectively). In addition, we observed an increase in anti-inflammatory cytokine IL-10 expression in rats that received hUC-MSCs iT compared with rats reared in hyperoxia (P < 0.05). Tran scriptomic analysis showed that the DEGs in lung tissues induced by hyperoxia were enriched in pathways related to inflammatory responses, epithelial cell proliferation, and vasculature development. hUC-MSCs administration blunted these hyperoxia-induced dysregulated genes and resulted in a shift in the gene expression pattern toward the normoxia group. hUC-MSCs increased heme oxygenase-1 (HO-1), JAK2, and STAT3 expression, and their phosphorylation in the lung, heart, and kidney (P < 0.05). Remarkably, no significant difference was observed between the iT and iP administration. CONCLUSION: iT hUC-MSCs administration ameliorates hyperoxia-induced lung, heart, and kidney injuries by activating HO-1 expression and JAK/STAT signaling. The therapeutic benefits of local iT and iP administration are equivalent.

Cryo-Temperature Pretreatment Increases the Pro-Angiogenic Capacity of Three-Dimensional Mesenchymal Stem Cells via the PI3K-AKT Pathway.

To increase the potential and effectiveness of three-dimensional (3D) mesenchymal stem cells (MSCs) for clinical applications, this study explored the effects of short cryo-temperature pretreatment on MSC function. Adipose-derived MSCs (A-MSCs) were cultured via the ordinary monolayer method and 3D hanging drop spheroid method. When the cells adhered to the wall or formed a spheroid, they were subjected to hypothermic stress at 4°C for 1 h and then divided into three recovery periods at 37°C, specifically 0, 12, and 24 h. The control group was not subjected to any treatment throughout the study. Monolayer and 3D spheroid A-MSCs were analyzed via RNA sequencing after hypothermic stress at 4°C for 1 h. Subsequently, each group of cells was collected and subjected to phenotype identification via flow cytometry, and mRNA expression was detected via reverse transcription-quantitative polymerase chain reaction analysis. Western blot analysis was performed to analyze the PI3K-AKT signaling pathway in A-MSCs. The effects of A-MSCs on angiogenesis in vivo were examined using a chick chorioallantoic membrane assay. Transwell assays were performed to determine whether the culture supernatant from each group could induce the chemotaxis of human umbilical vein endothelial cells (HUVECs). Three-dimensional spheroid culture did not change the phenotype of A-MSCs. The expression of fibroblast growth factors, hepatocyte growth factors, and other angiogenesis-related factors in A-MSCs was upregulated. A-MSCs subjected to hypothermic stress promoted angiogenesis under both monolayer and 3D spheroid cultures. Moreover, the chemotaxis of HUVECs to the 3D spheroid culture supernatant increased substantially. Short cryo-temperature pretreatment could stimulate 3D spheroid A-MSCs and activate the PI3K-AKT pathway. This approach has the advantages of promoting angiogenesis and maintaining cell viability.

USP21 promotes cell proliferation by maintaining the EZH2 level in diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common category of non-Hodgkin lymphoma (NHL). However, the underlying molecular mechanism of DLBCL remains unclear. METHODS: Real-time PCR and Western blot analysis were performed to assess the expression of ubiquitin-specific peptidase 21 (USP21) or enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2). CCK8 assay and cell death staining were carried out to examine the role of USP21 in cell proliferation and cell death, respectively. RESULTS: We found that the deubiquitinase USP21 was highly expressed in the DLBCL lymphoid tissue. The expression of USP21 promoted DLBCL cell proliferation, while it had no obvious effect on cell death. In addition, we found that USP21 regulated cell proliferation via cysteine 221, the catalytic site of USP21. Furthermore, we identified that USP21 could stabilize EZH2, a protein required for germinal center formation and lymphoma formation. CONCLUSION: The deubiquitinase USP21 promotes cell proliferation by maintaining the EZH2 protein level in DLBCL.

Redox-dependent regulation of end-binding protein 1 activity by glutathionylation.

Cytoskeletal proteins are susceptible to glutathionylation under oxidizing conditions, and oxidative damage has been implicated in several neurodegenerative diseases. End-binding protein 1 (EB1) is a master regulator of microtubule plus-end tracking proteins (+TIPs) and is critically involved in the control of microtubule dynamics and cellular processes. However, the impact of glutathionylation on EB1 functions remains unknown. Here we reveal that glutathionylation is important for controlling EB1 activity and protecting EB1 from irreversible oxidation. In vitro biochemical and cellular assays reveal that EB1 is glutathionylated. Diamide, a mild oxidizing reagent, reduces EB1 comet number and length in cells, indicating the impairment of microtubule dynamics. Three cysteine residues of EB1 are glutathionylated, with mutations of these three cysteines to serines attenuating microtubule dynamics but buffering diamide-induced decrease in microtubule dynamics. In addition, glutaredoxin 1 (Grx1) deglutathionylates EB1, and Grx1 depletion suppresses microtubule dynamics and leads to defects in cell division orientation and cell migration, suggesting a critical role of Grx1-mediated deglutathionylation in maintaining EB1 activity. Collectively, these data reveal that EB1 glutathionylation is an important protective mechanism for the regulation of microtubule dynamics and microtubule-based cellular activities.

ASK1-Mediated Phosphorylation Blocks HDAC6 Ubiquitination and Degradation to Drive the Disassembly of Photoreceptor Connecting Cilia.

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. However, the pathogenesis and molecular mechanisms underlying ROP remain elusive. Herein, using the oxygen-induced retinopathy (OIR) mouse model of ROP, we demonstrate that disassembly of photoreceptor connecting cilia is an early event in response to oxygen changes. Histone deacetylase 6 (HDAC6) is upregulated in the retina of OIR mice and accumulates in the transition zone of connecting cilia. We also show that in response to oxygen changes, apoptosis signal-regulating kinase 1 (ASK1) is activated and phosphorylates HDAC6, blocking its ubiquitination by von Hippel-Lindau and subsequent degradation by the proteasome. Moreover, depletion of HDAC6 or inhibition of the ASK1/HDAC6 axis protects mice from oxygen-change-induced pathological changes of photoreceptors. These findings reveal a critical role for ASK1/HDAC6-mediated connecting cilium disassembly in the OIR mouse model of ROP and suggest a potential value of ASK1/HDAC6-targeted agents for prevention of this disease.

The microtubule cytoskeleton acts as a sensor for stress response signaling in plants.

Stress tolerance pathways are protective mechanisms that have evolved to protect plant growth and increase production under various environmental stress conditions. Enhancing stress tolerance in crop plants has become an area of intense study with aims of increasing crop production and enhancing economic benefits. A growing number of studies suggest that in addition to playing vital roles in mechanical architecture and cell division, microtubules are also involved the adaptation to severe environmental conditions in plants. However, the mechanisms that integrate microtubule regulation, cellular metabolism and cell signaling in plant stress responses remain unclear. Recent studies suggest that microtubules act as sensors for different abiotic stresses and maintain mechanical stability by forming bundles. Characterizing the diverse roles of plant microtubules is vital to furthering our understanding of stress tolerance in plants.

Butylated hydroxytoluene induces astaxanthin and lipid production in Haematococcus pluvialis under high-light and nitrogen-deficiency conditions.

The aim of this study was to investigate the effects of butylated hydroxytoluene (BHT) on the production of astaxanthin and lipids in Haematococcus pluvialis LUGU under high-light and nitrogen-deficiency conditions. Astaxanthin and lipid contents were increased by 71.13% and 10.71%, respectively, in algal cells treated with 2 mg L-1 BHT. The maximal contents of astaxanthin and lipids were 3.17% and 46%, respectively. The levels of reactive oxygen species (ROS) in the presence of BHT were lower than in the control, and this effect involved strong activation of several antioxidases. Additionally, BHT application upregulated endogenous nitric oxide (NO) production. These results showed that this approach is useful for stimulating production of astaxanthin and lipids in H. pluvialis and that exogenous BHT induces astaxanthin and lipid production, which is responsible for the signalling molecule responses against abiotic stress conditions in H. pluvialis.

Melatonin: A Multifunctional Molecule That Triggers Defense Responses against High Light and Nitrogen Starvation Stress in Haematococcus pluvialis.

Melatonin (MLT), a ubiquitously distributed small molecule, functions in plant responses to various biotic and abiotic stresses. However, the interactions between melatonin and other important molecules in Haematococcus pluvialis response stresses are largely unknown. In the present study, exogenous melatonin improved H. pluvialis resistance to nitrogen starvation and high light. We concluded that exogenous melatonin treatment prevented the reactive oxygen species (ROS) burst and limited cell damage induced by abiotic stress through activation of antioxidant enzymes and antioxidants. Astaxanthin, a major antioxidant in H. pluvialis cells, exhibited a 2.25-fold increase in content after treatment with melatonin. The maximal astaxanthin content was 32.4 mg g-1. The functional roles of the nitric oxide (NO)-mediated mitogen activated protein kinase (MAPK) signaling pathway and cyclic adenosine monophosphate (cAMP) signaling pathway induced by melatonin were also evaluated. The results clearly indicate that cAMP signaling pathways are positively associated with microalgal astaxanthin biosynthesis. Additionally, the NO-dependent MAPK signaling cascade is activated in response to astaxanthin accumulation induced by melatonin, confirming that MAPK is a target of NO action in physiological processes. This work is the first to use H. pluvialis as in vivo model and documents the influence of melatonin on the physiological response to abiotic stress in this microalgae.

Melatonin enhances lipid production in Monoraphidium sp. QLY-1 under nitrogen deficiency conditions via a multi-level mechanism.

In this study, melatonin (MT) promoted lipid accumulation in Monoraphidium sp. QLY-1 under nitrogen deficiency conditions. The lipid accumulation increased 1.22- and 1.36-fold compared with a nitrogen-starved medium and a normal BG-11 medium, respectively. The maximum lipid content was 51.38%. The reactive oxygen species (ROS) level in the presence of melatonin was lower than that in the control group, likely because of the high antioxidant activities. The application of melatonin upregulated the gibberellin acid (GA) production and rbcL and accD expression levels but downregulated the abscisic acid (ABA) content and pepc expression levels. These findings demonstrated that exogenous melatonin could further improve the lipid production in Monoraphidium sp. QLY-1 by regulating antioxidant systems, signalling molecules, and lipid biosynthesis-related gene expression under nitrogen deficiency conditions.

miR-181a Participates in Contextual Fear Memory Formation Via Activating mTOR Signaling Pathway.

Long-term memory formation has been proven to require gene expression and new protein synthesis. MicroRNAs (miRNAs), as an endogenous small non-coding RNAs, inhibit the expression of their mRNA targets, through which involve in new memory formation. In this study, elevated miR-181a levels were found to be responsible for hippocampal contextual fear memory consolidation. Using a luciferase reporter assay, we indicated that miR-181a targets 2 upstream molecules of mTOR pathway, namely, PRKAA1 and REDD1. Upregulated miR-181a can downregulate the PRKAA1 and REDD1 protein levels and promote mTOR activity to facilitate hippocampal fear memory consolidation. These results indicate that miR-181a is involved in hippocampal contextual fear memory by activating the mTOR signaling pathway. This work provides a novel evidence for the role of miRNAs in memory formation and demonstrates the implication of mTOR signaling pathway in miRNA processing in the adult brain.

JIP1 and JIP3 cooperate to mediate TrkB anterograde axonal transport by activating kinesin-1.

Long-range anterograde axonal transport of TrkB is important for neurons to exert appropriate BDNF responses. TrkB anterograde axonal delivery is mediated by kinesin-1, which associates with TrkB via the adaptor protein JIP3 or the Slp1/Rab27B/CRMP-2 protein complex. However, little is known about the activation mechanisms of TrkB-loaded kinesin-1. Here, we show that JIP1 mediates TrkB anterograde axonal transport using JIP1 knockout mice, sciatic nerve ligation analysis and live imaging. Next, we proved that JIP1 and JIP3 cooperate to mediate TrkB anterograde axonal transport. Finally, microtubule-binding and microfluidic chamber assays revealed that JIP1 and JIP3 cooperate to relieve kinesin-1 autoinhibition, which depends on the binding of JIP1 to kinesin-1 heavy chain (KHC) and light chain (KLC) and the binding of JIP3 to KLC and is essential for TrkB anterograde axonal transport and BDNF-induced TrkB retrograde signal. These findings could deepen our understanding of the regulation mechanism underlying TrkB anterograde axonal transport and provide a novel kinesin-1 autoinhibition-relieving model.

A strategy for promoting lipid production in green microalgae Monoraphidium sp. QLY-1 by combined melatonin and photoinduction.

Microalgae lipids are potential candidates for the production of renewable biodiesel. The combination of plant hormones and two-step cultivation regulates lipid production in microalgae. A strategy for promoting lipid accumulation in Monoraphidium sp. QLY-1 by combining exogenous melatonin (MT) and photoinduction was developed. The effects of melatonin on the lipid content, reactive oxygen species (ROS), and activities of three key fatty acid biosynthetic enzyme in Monoraphidium sp. QLY-1 were investigated. The lipid content increased by 1.32-fold under 1µM melatonin treatment. The maximum lipid content achieved was 49.6%. However, the protein and carbohydrate contents decreased rapidly from 57.21% to 47.96% and from 53.4% to 37.71%, respectively. Biochemical and physiological analyses suggested that the ROS and lipid biosynthesis-related enzyme activities correlated with increased lipid accumulation under photo-melatonin induction conditions.

JIP3 regulates neuronal radial migration by mediating TrkB axonal anterograde transport in the developing cerebral cortex.

Radial migration is essential for the precise lamination and the coordinated function of the cerebral cortex. However, the molecular mechanisms for neuronal radial migration are not clear. Here, we report that c-Jun NH2-terminal kinase (JNK)-interacting protein-3 (JIP3) is highly expressed in the brain of embryonic mice and essential for radial migration. Knocking down JIP3 by in utero electroporation specifically perturbs the radial migration of cortical neurons but has no effect on neurogenesis and neuronal differentiation. Furthermore, we illustrate that JIP3 knockdown delays but does not block the migration of cortical neurons by investigating the distribution of neurons with JIP3 knocked down in the embryo and postnatal mouse. Finally, we find that JIP3 regulates cortical neuronal migration by mediating TrkB axonal anterograde transport during brain development. These findings deepen our understanding of the regulation of neuronal development by JIP3 and provide us a novel view on the regulating mechanisms of neuronal radial migration.

HDAC7 Ubiquitination by the E3 Ligase CBX4 Is Involved in Contextual Fear Conditioning Memory Formation.

Histone acetylation, an epigenetic modification, plays an important role in long-term memory formation. Recently, histone deacetylase (HDAC) inhibitors were demonstrated to promote memory formation, which raises the intriguing possibility that they may be used to rescue memory deficits. However, additional research is necessary to clarify the roles of individual HDACs in memory. In this study, we demonstrated that HDAC7, within the dorsal hippocampus of C57BL6J mice, had a late and persistent decrease after contextual fear conditioning (CFC) training (4-24 h), which was involved in long-term CFC memory formation. We also showed that HDAC7 decreased via ubiquitin-dependent degradation. CBX4 was one of the HDAC7 E3 ligases involved in this process. Nur77, as one of the target genes of HDAC7, increased 6-24 h after CFC training and, accordingly, modulated the formation of CFC memory. Finally, HDAC7 was involved in the formation of other hippocampal-dependent memories, including the Morris water maze and object location test. The current findings facilitate an understanding of the molecular and cellular mechanisms of HDAC7 in the regulation of hippocampal-dependent memory.SIGNIFICANCE STATEMENT The current findings demonstrated the effects of histone deacetylase 7 (HDAC7) on hippocampal-dependent memories. Moreover, we determined the mechanism of decreased HDAC7 in contextual fear conditioning (CFC) through ubiquitin-dependent protein degradation. We also verified that CBX4 was one of the HDAC7 E3 ligases. Finally, we demonstrated that Nur77, as one of the important targets for HDAC7, was involved in CFC memory formation. All of these proteins, including HDAC7, CBX4, and Nur77, could be potential therapeutic targets for preventing memory deficits in aging and neurological diseases.

Effect of fulvic acid induction on the physiology, metabolism, and lipid biosynthesis-related gene transcription of Monoraphidium sp. FXY-10.

Fulvic acid (FA) triggers lipid accumulation in Monoraphidium sp. FXY-10, which can produce biofuels. Therefore, the metabolism shift and gene expression changes influenced by fulvic acid should be investigated. In this study, lipid and protein contents increased rapidly from 44.6% to 54.3% and from 31.4% to 39.7% under FA treatment, respectively. By contrast, carbohydrate content sharply declined from 49.5% to 32.5%. The correlation between lipid content and gene expression was also analyzed. Results revealed that accD, ME, and GPAT genes were significantly correlated with lipid accumulation. These genes could likely influence lipid accumulation and could be selected as modification candidates. These results demonstrated that FA significantly increased microalgal lipid accumulation by changing the intracellular reactive oxygen species, gene expression, and enzyme activities of acetyl-CoA carboxylase, malic enzyme, and phosphoenolpyruvate carboxylase.