Core Subunits Research Articles

NDUFA11 may be the disulfidptosis-related biomarker of ischemic stroke based on integrated bioinformatics, clinical samples, and experimental analyses

BackgroundProgrammed cell death plays an important role in neuronal injury and death after ischemic stroke (IS), leading to cellular glucose deficiency. Glucose deficiency can cause abnormal accumulation of cytotoxic disulfides, resulting in disulfidptosis. Ferroptosis, apoptosis, necroptosis, and autophagy inhibitors cannot inhibit this novel programmed cell death mechanism. Nevertheless, the potential mechanisms of disulfidptosis in IS remain unclear.MethodsThe GSE16561 dataset was used to screen for differentially expressed disulfidptosis-related biomarkers (DE-DRBs). A correlation between the DE-DRBs was detected. The optimal machine-learning (ML) model and predictor molecules were determined. The GSE58294 dataset was used to verify the accuracy of the optimal ML model. The DE-DRB expression was detected in the blood of patients with IS. Based on IS models, experimental analyses were performed to verify DE-DRB expression and the correlation between DE-DRBs.ResultsLeucine-rich pentatricopeptide repeat-containing (LRPPRC) and NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11 (NDUFA11) were identified as DE-DRBs. The NADH: ubiquinone oxidoreductase core subunit S1 (NDUFS1) interacted with NDUFA11 and LRPPRC. The support vector machine (SVM) model was identified as the optimal ML model. The NDUFA11 expression level in the blood of patients with IS was 20.9% compared to that in normal controls. NDUFA11 expression was downregulated in the in vitro/in vivo models of IS. The number of formed complexes of NDUFS1 and NDUFA11 decreased in the in vitro/in vivo models of IS.ConclusionThis research suggests that NDUFA11 is a specific DRB for IS and demonstrates alterations in the disulfidptosis-related protein complexes NDUFS1-NDUFA11.

The chromatin remodeler ADNP regulates neurodevelopmental disorder risk genes and neocortical neurogenesis

Although chromatin remodelers are among the most important risk genes associated with neurodevelopmental disorders (NDDs), the roles of these complexes during brain development are in many cases unclear. Here, we focused on the recently discovered ChAHP chromatin remodeling complex. The zinc finger and homeodomain transcription factor ADNP is a core subunit of this complex, and de novo ADNP mutations lead to intellectual disability and autism spectrum disorder. However, germline Adnp knockout mice were previously shown to exhibit early embryonic lethality, obscuring subsequent roles for the ChAHP complex in neurogenesis. To circumvent this early developmental arrest, we generated a conditional Adnp mutant allele. Using single-cell transcriptomics, cut&run-seq, and histological approaches, we show that during neocortical development, Adnp orchestrates the production of late-born, upper-layer neurons through a two-step process. First, Adnp is required to sustain progenitor proliferation specifically during the developmental window for upper-layer cortical neurogenesis. Accordingly, we found that Adnp recruits the ChAHP subunit Chd4 to genes associated with progenitor proliferation. Second, in postmitotic differentiated neurons, we define a network of risk genes linked to NDDs that are regulated by Adnp and Chd4. Taken together, these data demonstrate that ChAHP is critical for driving the expansion of upper-layer cortical neurons and for regulating neuronal gene expression programs, suggesting that these processes may potentially contribute to NDD etiology.

A conserved switch to less catalytically active Polycomb repressive complexes in non-dividing cells.

Polycomb repressive complex 2 (PRC2), composed of the core subunits EED, SUZ12, and either EZH1 or EZH2, is critical for maintaining cellular identity in multicellular organisms. PRC2 deposits H3K27me3, which is thought to recruit the canonical form of PRC1 (cPRC1) to promote gene repression. Here, we show that EZH1-PRC2 and cPRC1 are the primary Polycomb complexes on target genes in non-dividing, quiescent cells. Furthermore, these cells are resistant to PRC2 inhibitors. While PROTAC-mediated degradation of EZH1-PRC2 in quiescent cells does not reduce H3K27me3, it partially displaces cPRC1. Our results reveal an evolutionarily conserved switch to less catalytically active Polycomb complexes in non-dividing cells and raise concerns about using PRC2 inhibitors in cancers with significant populations of non-dividing cells.

A Novel Disulfidptosis-Related Risk Signature for Prognostic Prediction in Patients With Ewing Sarcoma.

Ewing sarcoma (ES) is a malignant bone tumor prevalent among children and adolescents. Disulfidptosis represents a novel form of cell death; however, the mechanism of disulfidptosis in ES remains unclear. Our aim is to explore the disulfidptosis-related prognostic signature in ES. Utilizing transcriptomic and clinical data of ES, disulfidptosis-related hub genes (DRHGs) were identified by differential gene expression analysis and Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analysis. A disulfidptosis-related risk score model (DRRS) was constructed based on these DRHGs. The performance of DRRS was assessed using survival analysis and receiver operating characteristic curve analysis. Immune cell infiltration in different risk subgroups and correlations between DRRS and antitumor reagents were also analyzed. In this study, we developed a disulfidptosis-related prognostic feature based on LRPPRC (leucine rich pentatricopeptide repeat containing), IQGAP1 (IQ motif containing GTPase activating protein 1), NDUFS1 (NADH:ubiquinone oxidoreductase core subunit S1), and TLN1 (talin 1), which may serve as a predictive and independent risk factor for ES. ES patients in the high-risk group exhibited a poorer prognosis, had a higher proportion of myeloid-derived suppressor cells (MDSCs) and M2 type of tumor-associated macrophages, and showed heightened sensitivity to some antitumor agents such as nilotinib and olaparib. This study is the first to construct a disulfidptosis-related prognostic signature that may predict the prognosis and immune response in ES patients, thereby providing a new reference for understanding the mechanisms of ES and guiding immunotherapy.

ASH2L-Mediated H3K4 Methylation and Nephrogenesis.

Many congenital anomalies of the kidney and urinary tract involve deficits in the number of nephrons, which are associated with a higher risk of hypertension and chronic kidney disease later in life. Prior work has implicated histone modifications in regulating kidney lineage-specific gene transcription and nephron endowment. Our earlier study suggested that ASH2L, a core subunit of the H3K4 methyltransferase complex, plays a role in ureteric bud morphogenesis during mammalian kidney development. However, the potential involvement of ASH2L in nephron formation remains an open question. To investigate the role of ASH2L in nephron development, we inactivated Ash2l specifically in nephron progenitor cells by crossing Six2-e(Kozak-GFPCre-Wpre-polyA)1 mice with Ash2lfl/fl mice. We utilized RNA sequencing combined with Cleavage Under Targets and Tagmentation sequencing to screen for gene and epigenomic changes, which were further verified by rescue experiments conducted on ex vivo culture explants. Inactivating ASH2L in nephron progenitor cells disrupted H3K4 trimethylation establishment at promoters of genes controlling nephron progenitor cell stemness, differentiation and cell cycle, inhibiting their progression through the cell cycle and differentiation into epithelial cell types needed to form nephrons. Inhibition of the TGF-β/SMAD signaling pathway partially rescued the dysplastic phenotype of the mutants. ASH2L-mediated H3K4 methylation was identified as a novel epigenetic regulator of kidney development. Downregulation of ASH2L expression or H3K4 trimethylation may be linked to congenital anomalies of the kidney and urinary tract.

Identifying disulfidptosis-related biomarkers in epilepsy based on integrated bioinformatics and experimental analyses.

One of the underlying mechanisms of epilepsy (EP), a brain disease characterized by recurrent seizures, is considered to be cell death. Disulfidptosis, a proposed novel cell death mechanism, is thought to play a part in the pathogenesis of epilepsy, but the exact role is unclear. The gene expression omnibus series (GSE) 33,000 and GSE63808 datasets were used to search for differentially expressed disulfidptosis-related molecules (DE-DRMs). A correlation between the DE-DRMs was discovered. Individuals with epilepsy were then used to investigate molecular clusters based on the expression of DE-DRMs. Following that, the best machine learning model which is validated by GSE143272 dataset and predictor molecules were identified. The correlation between predictive molecules and clinical traits was determined. Based on the in vitro and in vivo seizures models, experimental analyses were applied to verify the DE-DRMs expressions and the correlation between them. Nine molecules were identified as DE-DRMs: glycogen synthase 1 (GYS1), solute carrier family 3 member 2 (SLC3A2), solute carrier family 7 member 11 (SLC7A11), NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1), 3-oxoacyl-ACP synthase, mitochondrial (OXSM), leucine rich pentatricopeptide repeat containing (LRPPRC), NADH:ubiquinone oxidoreductase subunit A11 (NDUFA11), NUBP iron‑sulfur cluster assembly factor, mitochondrial (NUBPL), and NCK associated protein 1 (NCKAP1). NDUFS1 interacted with NDUFA11, NUBPL, and LRPPRC, while SLC3A2 interacted with SLC7A11. The optimal machine learning model was revealed to be the random forest (RF) model. G protein guanine nucleotide-binding protein alpha subunit q (GNAQ) was linked to sodium valproate resistance. The experimental analyses suggested an upregulated SLC7A11 expression, an increased number of formed SLC3A2 and SLC7A11 complexes, and a decreased number of formed NDUFS1 and NDUFA11 complexes. This study provides previously undocumented evidence of the relationship between disulfidptosis and EP. In addition to suggesting that SLC7A11 may be a specific DRM for EP, this research demonstrates the alterations in two disulfidptosis-related protein complexes: SLC7A11-SLC3A2 and NDUFS1-NDUFA11.

Recent advances in the structure, function and regulation of the volume-regulated anion channels and their role in immunity.

Volume-regulated anion channels (VRACs) are heteromeric complexes formed by proteins of the leucine-rich repeat-containing 8 (LRRC8) family. LRRC8A (also known as SWELL1) is the core subunit required for VRAC function, and it must combine with one or more of the other paralogues (i.e. LRRC8B-E) to form functional heteromeric channels. VRACswere discoveredin T lymphocytes over 35 years ago and are found in virtually all vertebrate cells. Initially, these anion channelswere characterized for their role in Cl- efflux during the regulatory volume decrease process triggered when cells are subjected to hypotonic challenges. However, substantial evidence suggests that VRACs also transport small molecules under isotonic conditions. These findings have expanded the research on VRACs to explore their functions beyond volume regulation. In innate immune cells, VRACs promote inflammation by modulating the transport of immunomodulatory cyclic dinucleotides, itaconate and ATP. In adaptive immune cells, VRACs suppress their function by taking up cyclic dinucleotides to activate the STING signalling pathway. In this review, we summarize the current understanding of LRRC8 proteins in immunity and discuss recent progress in their structure, function, regulation and mechanisms for channel activation and gating. Finally, we also examine potential immunotherapeutic applications of VRAC modulation.

Human umbilical mesenchymal stem cells ameliorate atrophic gastritis in aging mice by participating in mitochondrial autophagy through Ndufs8 signaling

BackgroundChronic atrophic gastritis (CAG) is a chronic disease of the gastric mucosa characterized by a reduction or an absolute disappearance of the original gastric glands, possibly replaced by pseudopyloric fibrosis, intestinal metaplasia, or fibrosis. CAG develops progressively into intestinal epithelial metaplasia, dysplasia, and ultimately, gastric cancer. Epidemiological statistics have revealed a positive correlation between the incidence of CAG and age. Mesenchymal stem cells (MSCs) are a type of adult stem cells derived from mesoderm, with strong tissue repair capabilities. Therefore, the restoration of the gastric mucosa may serve as an efficacious strategy to ameliorate CAG and avert gastric cancer. However, the mechanisms by which MSCs inhibit the relentless progression of aging atrophic gastritis remain to be elucidated. This study endeavored to assess a novel approach utilizing MSCs to treat CAG and forestall carcinogenics.MethodsIn this study, we selected mice with atrophic gastritis from naturally aging mice and administered human umbilical cord-derived mesenchymal stem cells (hUMSCs) via tail vein injection to evaluate the therapeutic effects of hUMSCs on age-related chronic atrophic gastritis. Initially, we employed methods such as ELISA, immunohistochemical analysis, and TUNEL assays to detect changes in the mice post-hUMSC injection. Proteomic and bioinformatics analyses were conducted to identify differentially expressed proteins, focusing on NADH: ubiquinone oxidoreductase core subunit S8 (Ndufs8). Co-culturing hUMSCs with Ndufs8 knockout gastric mucosal epithelial cells (GMECs), we utilized flow cytometry, Western blotting, real-time quantitative PCR, and immunofluorescence to investigate the mechanisms of action of hUMSCs.ResultsWe observed that hUMSCs are capable of migrating to and repairing damaged gastric mucosa. Initially, hUMSCs significantly enhanced the secretion of gastric proteins PG-1 and G17, while concurrently reducing inflammatory cytokines. Furthermore, hUMSCs mitigated gastric fibrosis and apoptosis in mucosal cells. Proteomic and bioinformatic analyses revealed alterations in the protein network involved in mitochondrial autophagy, with Ndufs8 playing a pivotal role. Upon knocking out Ndufs8 in GMECs, we noted mitochondrial damage and reduced autophagy, leading to an aged phenotype in GMECs. Co-culturing Ndufs8-knockout GMECs with hUMSCs demonstrated that hUMSCs could ameliorate mitochondrial dysfunction and restore the cell cycle in GMECs.

Magnetic Composite Carbon from Microcrystalline Cellulose to Tackle Paracetamol Contamination: Kinetics, Mass Transfer, Equilibrium, and Thermodynamic Studies.

This study reported a one-spot preparation of magnetic composite carbon (MCC@Fe) from microcrystalline cellulose (MC). The pure cellulose was impregnated in iron (III) chloride solution and carbonized at 650 °C. The MCC@Fe composite adsorbent underwent various characterization techniques. XRD identified nanostructured Fe3O4 particles with an average crystallite size of 34.3 nm embedded in the core subunits of the material. FESEM images indicated a rough and irregular surface, with some cavities along its surface, incorporating Fe3O4 nanoparticles, while EDS analysis confirmed the presence of elements like Fe, C, and O. Notably, combining thermal and chemical treatments produces a composite with more pores and a high specific surface area (500.0 m2 g-1) compared to MC (1.5 m2/g). VSM analysis confirmed the magnetic properties (0.76 emu/g), while the Hydrophobic Index (HI) showed that MCC@Fe was hydrophobic (HI 1.395). The adsorption studies consisted of kinetic, mass transfer, equilibrium, and thermodynamics studies. Kinetic study of the adsorption of paracetamol on MCC@Fe composite proved to be rapid, and the time necessary for covering 95% of the surface (t0.95) was lower than 27 min following the fractal-like pseudo-first-order model (FPFO). Liu's isotherm proved to be the most appropriate for understanding the adsorption equilibrium. Remarkably, the maximum sorption capacity (Qmax) of paracetamol was 34.78 mg g-1 at 45 °C. The ΔH° value (+27.00 kJ/mol) and the negative ΔG° values were consistent with the physisorption mechanism and favorable process. Furthermore, the mass transfer mechanism showed that the transfer is governed by the intraparticle diffusion model, with surface diffusion being the rate-limiting step when considering the Biot number greater than 100. This research displayed a single-route production of inexpensive magnetic nano adsorbents capable of efficiently eliminating paracetamol from aqueous environments.

Protein phosphorylation and oxidative protein modification promote plant photosystem II disassembly for repair

The light-driven water-splitting reaction of photosystem II exposes its key reaction center core protein subunits to irreversible oxidative photodamage. A rapid repair cycle replaces the photodamaged core subunits in plants, but how the large antenna-core supercomplex structures of plant photosystem II disassemble for repair is not currently understood. We find a specific involvement of phosphorylation in removing the peripheral antenna from the core and monomerization of the dimeric cores. However, monomeric cores disassembled further into smaller subcomplexes even in the absence of phosphorylation as suggestive of other unknown mechanisms of disassembly. Here we show that the oxidative modifications of amino acids in core protein subunits of photosystem II are active mediators of the monomeric core disassembly. Oxidative modifications thus likely disassemble only the damaged monomeric cores, ensuring an economical photosystem disassembly process. Taken together, our results suggest phosphorylation and oxidative modification play distinct roles in photosystem II disassembly and repair.

OCIAD1 and prohibitins regulate the stability of the TIM23 protein translocase

Mitochondrial proteins are transported and sorted to the matrix or inner mitochondrial membrane by the presequence translocase TIM23. In yeast, this essential and highly conserved machinery is composed of the core subunits Tim23 and Tim17. The architecture, assembly, and regulation of the human TIM23 complex are poorly characterized. The human genome encodes two paralogs, TIMM17A and TIMM17B. Here, we describe an unexpected role of the ovarian cancer immunoreactive antigen domain-containing protein 1 (OCIAD1) and the prohibitin complex in the biogenesis of human TIM23. Prohibitins were required to stabilize both the TIMM17A- and TIMM17B-containing variants of the translocase. Interestingly, OCIAD1 assembled with the prohibitin complex to protect the TIMM17A variant from degradation by the YME1L protease. The expression of OCIAD1 was in turn regulated by the status of the TIM23 complex. We postulate that OCIAD1 together with prohibitins constitute a regulatory axis that differentially regulates variants of humanTIM23.

CDTL contributes to breast cancer progression through regulating redox homeostasis via affecting the function of system xc.

Ferroptosis is a new type of cell death caused by redox imbalance mediated by iron-dependent lipid peroxidation, which is intimately linked to human disease. Circular RNA, characterized by covalently closed loop structure, has attracted much attention due to its involvement in various biological functions. However, little is known about the role of circRNA in ferroptosis. In this study, we identified cDTL (a circular RNA derived from DTL gene) as a ferroptosis-related circRNA. cDTL expression was remarkably elevated by ferroptotic stress. Knockdown of cDTL significantly inhibited breast cancer cell growth both in vitro and in vivo through promoting ferroptosis. Mechanistically, cDTL directly bound to NRF2 and BCLAF1 in the nucleus and cytoplasm, respectively, resulting in transcriptional activation and mRNA stability of SLC7A11 (the core subunit of system Xc-), thereby repressing ferroptosis via activating GSH/GPX4 axis. Moreover, cDTL was identified as a direct transcriptional target of Myc, a well-known protooncogene that is highly activated in breast cancer. More importantly, cDTL was overexpressed in human breast cancer tissues, which was associated with dismal progression-free survival and poor differentiation. In conclusion, our data suggest that cDTL is a novel regulator of ferroptosis, targeting cDTL may be a potential therapeutic strategy for breast cancer.

METTL14 Promotes Lipopolysaccharide-Induced Myocardial Damage via m6A-Dependent Stabilization of TRPM7 mRNA.

Sepsis-induced myocardial injury (SIMI) is a vital pathological component of severe sepsis and septic shock. As a prevalent internal mRNA modification in eukaryotic cells, N6-methyladenosine (m6A) modification is implicated in sepsis and immune disorders. Methyltransferase-like 14 (METTL14), a core subunit of the methyltransferase complex that catalyzes messenger RNA m6A modification, is involved in the regulation of human cardiomyocyte cell line (AC16) injury. This study aimed to explore the role and mechanism of METTL14 in lipopolysaccharide (LPS) -induced myocardial injury.Cell viability and apoptosis were analyzed via 3- (4,5-Dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT), flow cytometry, and TdT-mediated dUTP nick-end labeling (TUNEL) assay. The Tumor necrosis factor alpha (TNF-α) and Interleukin-1beta (IL-1β) levels were analyzed via Enzyme linked immunosorbent assay (ELISA). Caspase-3 activity, reactive oxygen species activity, malondialdehyde level, and glutathione level were assessed using special assay kits. The levels of transient receptor potential melastatin 7 (TRPM7) and METTL14 mRNA were determined via Real-time quantitative polymerase chain reaction (RT-qPCR). Meanwhile, the protein levels of TRPM7, METTL14, phospho-p65 (p-p65), total p65 (p65), p-IκBα, and total IκBα (IκBα) were examined via western blot assay.LPS treatment repressed AC16 cell viability and induced cell apoptosis, inflammatory response, oxidative stress, and ferroptosis in vitro. METTL14 and TRPM7 were upregulated in LPS-treated AC16 cells. At the molecular level, METTL14 could increase the stability of TRPM7 mRNA via m6A methylation. Moreover, METTL14 deficiency could abolish LPS-triggered AC16 cell injury and ferroptosis via TRPM7 regulation.METTL14 knockdown reversed LPS-caused myocardial cell damage mainly by regulating the stability of TRPM7 mRNA, providing a novel therapeutic target for septic cardiomyopathy treatment.

Tripartite interactions of PKA catalytic subunit and C-terminal domains of cardiac Ca2+ channel may modulate its β-adrenergic regulation

BackgroundThe β-adrenergic augmentation of cardiac contraction, by increasing the conductivity of L-type voltage-gated CaV1.2 channels, is of great physiological and pathophysiological importance. Stimulation of β-adrenergic receptors (βAR) activates protein kinase A (PKA) through separation of regulatory (PKAR) from catalytic (PKAC) subunits. Free PKAC phosphorylates the inhibitory protein Rad, leading to increased Ca2+ influx. In cardiomyocytes, the core subunit of CaV1.2, CaV1.2α1, exists in two forms: full-length or truncated (lacking the distal C-terminus (dCT)). Signaling efficiency is believed to emanate from protein interactions within multimolecular complexes, such as anchoring PKA (via PKAR) to CaV1.2α1 by A-kinase anchoring proteins (AKAPs). However, AKAPs are inessential for βAR regulation of CaV1.2 in heterologous models, and their role in cardiomyocytes also remains unclear.ResultsWe show that PKAC interacts with CaV1.2α1 in heart and a heterologous model, independently of Rad, PKAR, or AKAPs. Studies with peptide array assays and purified recombinant proteins demonstrate direct binding of PKAC to two domains in CaV1.2α1-CT: the proximal and distal C-terminal regulatory domains (PCRD and DCRD), which also interact with each other. Data indicate both partial competition and possible simultaneous interaction of PCRD and DCRD with PKAC. The βAR regulation of CaV1.2α1 lacking dCT (which harbors DCRD) was preserved, but subtly altered, in a heterologous model, the Xenopus oocyte.ConclusionsWe discover direct interactions between PKAC and two domains in CaV1.2α1. We propose that these tripartite interactions, if present in vivo, may participate in organizing the multimolecular signaling complex and fine-tuning the βAR effect in cardiomyocytes.

Histone-binding protein RBBP4 is necessary to promote neurogenesis in the developing mouse neocortical progenitors.

Chromatin regulation plays a crucial role in neocortical neurogenesis, and mutations in chromatin modifiers are linked to neurodevelopmental disorders. RBBP4 is a core subunit of several chromatin-modifying complexes; however, its functional role and genome-wide occupancy profile in the neocortical primordium are unknown. To address this, we performed RBBP4 knockdown using CRISPR/Cas9 on neocortical progenitors derived from mice of both sexes at embryonic age 12.5 during deep-layer neurogenesis. Our study demonstrates that downregulation of RBBP4 in the E12.5 neocortical progenitors reduced neuronal output, specifically affecting CTIP2-expressing neurons. We demonstrate that RBBP4 plays an essential role in regulating neocortical progenitor proliferation. However, overexpression of RBBP4 alone was not sufficient to regulate neuronal fate.Genome-wide occupancy analysis revealed that RBBP4 primarily binds to distal regulatory elements, and neuron differentiation is a significant GO biological pathway of RBBP4-bound genes. Interestingly, we found that RBBP4 binds to Cdon, a receptor protein in the Shh signaling pathway, and knockdown of Cdon phenocopies RBBP4 knockdown resulting in a significant reduction in neurogenesis, particularly CTIP2-expressing neurons. CDON overexpression could rescue the phenotype caused upon loss of RBBP4 in the neocortex, thereby suggesting the functional link between RBBP4 and its target gene CDON. Our results shed light on the cellular role of RBBP4 and identify CDON as a novel regulator of deep-layer neurogenesis in the neocortical progenitors. Our findings are significant in the context of understanding how dysregulated chromatin regulation impacts cellular mechanisms in neurodevelopmental disorders.Significance Statement Chromatin modifier RBBP4 regulates chromatin structure and, thereby, gene expression. It is expressed in the dorsal telencephalon progenitors during deep-layer neurogenesis. In this study, we unveil a novel role for RBBP4 in regulating deep-layer neurogenesis in the neocortical progenitors. Our research underscores RBBP4's critical role in governing progenitor proliferation and neuronal subtype specification in the neocortex while identifying its genome-wide binding occupancy profile. Moreover, we identify Cdon as a novel binding target of RBBP4, also involved in regulating deep-layer neurogenesis. These findings illuminate the mechanisms by which chromatin modifiers influence neocortical development, offering insights into how mutations in chromatin modifiers could impact cortical development and contribute to neurodevelopmental disorders.

The role of peritumoral electroacupuncture in regulating cuproptosis for sensitization of chemotherapy efficacy in mice with triple-negative breast cancer

To explore the enhanced sensitization effect of peritumoral electroacupuncture (PEA) on doxorubicin (DOX) chemotherapy in mice with triple-negative breast cancer (TNBC). Eighteen female Balb/c mice were randomly divided into the model, DOX, and EA+DOX groups, with 6 mice in each group. TNBC cells were injected into the mammary fat pad of mice to establish the breast cancer-bearing mice model. Mice of the DOX and EA+DOX groups were injected intraperitoneally with DOX solution at 4 mg/kg once a week for 4 weeks. For mice of the EA+DOX group, 4 filiform needles were inserted surrounding tumor tissues, followed by giving the mice with EA (1 mA, 2 Hz/100 Hz) stimulation for 3 min, once a week for 4 weeks. During the intervention, the tumor volume was measured every two days, and at the end of intervention, the weight of the tumor tissue was measured. The expression of Ki67 and proliferating cell nuclear antigen (PCNA) in tumor tissues was detected by immunohistochemistry. The protein expression levels of iron redox protein 1 (FDX1), lipoic acid synthase (LIAS), aconitase 2 (ACO2) and NADH：ubiquinone oxidoreductase core subunit V1 (NDUFV1), dihydrolipoamide S-acetyltransferase(DLAT), dihydrolipoyl succinyltransferase(DLST) in tumor tissues were detected by Western blot. The content of copper ions, pyruvic acid and α-ketoglutaric acid, succinic acid in tumor tissues was detected by copper ion kit, and the content of reactive oxygen species (ROS) in tumor tissues of mice was detected by fluorescence method. Compared with the model group, the tumor volume and weight, the expression levels of Ki67 and PCNA in tumor tissues were decreased (P<0.05, P<0.01) in the DOX and EA+DOX groups. The improvement of the above indicators was more significant in the EA+DOX group than that in the DOX group (P<0.05, P<0.01). Compared with the model and DOX groups, the contents of ROS, copper ions, pyruvic acid and α-ketoglutaric acid were increased (P<0.05, P<0.01), while the contents of succinic acid, and the expressions of FDX1, LIAS, ACO2 and NDUFV1, DLAT, DLST proteins were decreased (P<0.01) in the EA+DOX group. The combination of PEA and DOX can effectively control the growth rate of tumors in mice with TNBC, which may contribute to its function in enhancing the chemotherapy efficacy of DOX on TNBC by promoting cuproptosis.

The serine palmitoyltransferase core subunit StLcb2 regulates sphingolipid metabolism and promotes Setosphaeria turcica pathogenicity by modulating appressorium development

The fungal pathogen Setosphaeria turcica (S. turcica) causes northern corn leaf blight (NCLB), resulting in significant yield and economic losses in maize. To elucidate the metabolic pathways essential for its pathogenicity, we investigated the metabolome of S. turcica during appressorium development, a critical stage for host infection. Our analysis indicated a substantial enrichment of sphingosine and related compounds during this phase. The application of chemical inhibitors to disrupt sphingolipid metabolism confirmed their pivotal role in appressorium formation and pathogenicity. Additionally, silencing of the serine palmitoyl transferase (Spt) core subunit gene StLCB2 led to significant alterations in fungal morphology and growth, accompanied by changes in cell membrane integrity, surface hydrophobicity, melanin, and sphingosine synthesis. These findings underscore the importance of sphingolipids in the pathogenicity of S. turcica and suggest that targeting specific components of the sphingolipid pathway could aid in developing novel fungicides or genetically engineered maize varieties with increased resistance to NCLB.

Molecular mechanisms of MAZ targeting up-regulation of NDUFS3 expression to promote malignant progression in melanoma

Myc-associated Zinc-finger Protein (MAZ) has been implicated in the malignant progression of various tumors. However, its expression and functional relationship of MAZ in melanoma have not been previously investigated. This study confirms elevated expression of MAZ in melanoma, correlating with poor patient prognosis. Furthermore, our findings demonstrate that MAZ enhances melanoma progression by promoting proliferation, migration and invasion. It is worth noting that we found that MAZ can target and regulate the transcription of NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3), a core subunit of mitochondrial complex I, to enhance mitochondrial metabolism and thus promote malignant progression of melanoma. Predictive modeling indicates that the co-expression of MAZ and NDUFS3 could serve as a potential prognostic marker for melanoma patients.

Ginsenoside-Enriched Extract from Black Ginseng Anti-Fatigue Effects by Improving Antioxidant Capacity and Mitochondrial Function.

In this study, we investigated the anti-fatigue effects of black ginseng ginsenosides using exercise performance tests, serum analyses, and gene expression profiling. No significant differences in dietary intake or body weight were observed between groups. The low-dose black ginseng (LBG) group showed no significant improvements in swimming and rotating rod tests. In contrast, the medium (MBG)- and high-dose (HBG) groups showed notable increases in swimming time and significant improvements in the rotating rod test. All treatment groups exhibited longer running times, particularly the HBG group. Serum analysis revealed increased muscle and hepatic glycogen, catalase, and lactate dehydrogenase levels in the MBG and HBG groups, whereas lactate, lipid peroxide, and superoxide dismutase levels were decreased. Additionally, gene expression analysis showed significant upregulation of key antioxidant and mitochondrial function genes, including those encoding cationic amino acid transporter 2, stearoyl-CoA desaturase-2, nuclear respiratory factor 1, nuclear factor erythroid 2-related factor 2, mitochondrial transcription factor A, cytochrome c oxidase II, and NADH-ubiquinone oxidoreductase core subunit 1, particularly in the HBG group, indicating enhanced antioxidant capacity and improved mitochondrial function. These findings suggested that black ginseng ginsenosides effectively mitigated fatigue.

AtDGCR14L contributes to salt-stress tolerance via regulating pre-mRNA splicing in Arabidopsis.

In plants, pre-mRNA alternative splicing has been demonstrated to be a crucial tier that regulates gene expression in response to salt stress. However, the underlying mechanisms remain elusive. Here, we studied the roles of DIGEORGE-SYNDROME CRITICAL REGION 14-like (AtDGCR14L) in regulating pre-mRNA splicing and salt stress tolerance. We discovered that Arabidopsis AtDGCR14L is required for maintaining plant salt stress tolerance and the constitutively spliced and active isoforms of important stress- and/or abscisic acid (ABA)-responsive genes. We also identified the interaction between AtDGCR14L and splicing factor U1-70k, which needs a highly conserved three amino acid (TWG) motif in DGCR14. Different from wild-type AtDGCR14L, the overexpression of the TWG-substituted AtDGCR14L mutant did not change salt stress tolerance or pre-mRNA splicing of stress/ABA-responsive genes. Additionally, SWITCH3A (SWI3A) is a core subunit of the SWI/SUCROSE NONFERMENTING (SWI/SNF) chromatin-remodeling complexes. We found that SWI3A, whose splicing depends on AtDGCR14L, actively enhances salt stress tolerance. These results revealed that AtDGCR14L may play an essential role in crosstalk between plant salt-stress response and pre-mRNA splicing mechanisms. We also unveiled the potential role of SWI3A in controlling salt stress tolerance. The TWG motif in the intrinsically disordered region of AtDGCR14L is highly conserved and crucial for DGCR14 functions.