Factor Binding Research Articles

Effects of digoxin in inhibiting ACE2 and SARS-CoV-2 binding for attenuating COVID-19 in human adipocytes

BACKGROUND Angiotensin-converting enzyme 2 (ACE2) has a role in SARS-CoV-2 incidence, and digoxin is a competitive inhibitor of SARS-CoV-2-ACE2 binding. This study aimed to investigate the effects of digoxin on SARS-CoV-2-ACE2 binding, proinflammatory cytokines, and prothrombotic factors in adipocytes of patients with COVID-19. METHODS This in vitro study used adipocyte cultures, which were divided into negative control, positive control (SARS-CoV-2 S1 spike protein only), SARS-CoV-2 S1 spike protein with digoxin, and SARS-CoV-2 S1 spike protein with human recombinant soluble ACE2 (hrsACE2). Data were analyzed using one-way ANOVA and Pearson correlation. RESULTS SARS-CoV-2 significantly elevated ACE2 and increased interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), tissue factor (TF), and plasminogen activator inhibitor-1 (PAI-1) compared to the negative control group (p<0.001). No SARS-CoV-2-ACE2 binding was detected in SARS-CoV-2 with digoxin and hrsACE2 groups, compared to the positive control group (0 ng/ml versus 0 ng/ml versus 36.33 [1.58] ng/ml, p<0.001). Digoxin significantly decreased IL-6 (48.94 [1.80] ng/ml versus 90.93 [4.29] ng/ml; p<0.001), TNF-α (87.65 [6.88] ng/ml versus 307.95 [57.34] ng/ml; p<0.001), TF (5.33 [0.32] ng/ml versus 6.85 [0.22] ng/ml; p<0.001), and PAI-1 levels (2.92 [0.168] ng/ml versus 4.86 [0.11] ng/ml; p<0.001), compared to positive control group. ACE2 positively correlated with IL-6 (p = 0.004, r = 0.763) and TF (p = 0.004, r = 0.768) but was not correlated with IL-1β, TNF-α, and PAI-1 levels. CONCLUSIONS This study promoted digoxin therapy to prevent cytokine storm and thromboembolism by decreasing IL-6, TNF-α, TF, and PAI-1 in adipocyte cultured models at an early stage of COVID-19.

C-repeat binding factor (CBF) identification and expression pattern to abiotic stress response in Casuarina equisetifolia and overexpression of CeCBF4 increase stress tolerance in Arabidopsis

Casuarina equisetifolia stands out as a highly valuable tree species crucial for industries and ecological restoration projects in tropical and subtropical regions, owing to its exceptional salt resistance. However, its growth is hampered in cold and drought-prone areas. Understanding the genetic basis for abiotic stress tolerance is imperative for enhancing stress-resistant breeding efforts of C. equisetifolia. However, the CBF genes are renowned for their pivotal roles in cold response and broad resilience to other adverse environments, such as drought, and high salinity. In this study, five CeCBFs were identified from the genome of C. equisetifolia. CeCBF1 and CeCBF3 belong to Clade I group, which diverged early from DREBIII members, while CeCBF2, CeCBF4, and CeCBF5 are classified into Clade II, a group innovated from Clade I. These genes lack introns in their sequences. The proteins encoded by CeCBFs feature classic AP2 domains and CBF signature sequences, localize in the nucleus and exhibit transactivation activity. Additionally, stress-related, abscisic acid, and jasmonic acid responsive elements are present on the CeCBFs promoters. Expression analysis revealed that CeCBFs were prodominantly induced by cold, drought, and salinity treatments, except for CeCBF1, which showed repression specifically under low temperature. Moreover, CeCBF1, CeCBF4, and CeCBF5 were inhibited by abscisic acid, while CeCBF1 showed reduced transcript levels in response to methyl jasmonate treatment. Furthermore, overexpression of CeCBF4 enhanced tolerance to low temperature, depriving of water, and salt by up-regulating stress-responsive genes expression and promoting proline accumulation, albeit with a trade-off in growth and productivity. Hence, CeCBFs emerge as potential regulators contributing significantly to stress tolerance mechanisms in C. equisetifolia.

019 Single-cell RNA-seq and functional analysis reveal inhibition of E2 promoter binding factor as a potential therapeutic target in Stevens-Johnson syndrome and toxic epidermal necrolysis

019 Single-cell RNA-seq and functional analysis reveal inhibition of E2 promoter binding factor as a potential therapeutic target in Stevens-Johnson syndrome and toxic epidermal necrolysis

ILF2 protein is a promising serum biomarker for early detection of gastric cancer

BackgroundOur previous small-sample study indicated that serum levels of interleukin enhancer binding factor 2 (ILF2) may have the potential for gastric cancer (GC) detection. The present study was conducted to further validate the diagnostic value of serum ILF2 protein for GC.MethodsSerum specimens and clinical data were collected from patients with GC (n = 99) or benign gastric disease (BGD) (n = 49) and healthy controls (HC) (n = 51). Serum ILF2 levels were measured using enzyme-linked immunosorbent assay. The diagnostic performance of ILF2 was evaluated using the area under the receiver operating characteristic curve (AUC). The independence and synergy of ILF2 in GC diagnosis were analyzed by modeling with conventional blood indicators.ResultsThe median serum ILF2 level was higher in the GC group (227.8ng/mL) than in the BGD group (72.0ng/mL) and the HC group (56.8ng/mL) (p < 0.001), and no significant difference across GC subgroups. The AUCs of ILF2 were 0.915 (95%CI 0.873–0.957) for GC vs. HC, 0.854 (95%CI 0.793–0.915) for GC vs. BGD, 0.885 (95%CI 0.841–0.929) for GC vs. BGD + HC, and 0.888 (95% CI 0.830–0.945) for TNM I stage GC vs. BGD + HC, outperforming conventional blood indicators (corresponding AUCs ranging from 0.641 to 0.782). ILF2 was independent of and synergistic with conventional blood indicators in GC diagnosis, and a simple diagnostic model based on ILF2 and red blood cell count improved the diagnostic performance, with positive rates of approximately 90% in various subgroups of GC.ConclusionsSerum ILF2 protein is a novel and potential serum biomarker for the detection of GC, especially for early GC.

A novel SBF1 missense mutation causes autosomal dominant Charcot–Marie–Tooth disease type 4B3

IntroductionWe present a case of autosomal dominant Charcot–Marie–Tooth disease type 4B3 (CMT4B3) in a family caused by a novel SBF1 missense mutation.MethodsTwo patients, a mother and daughter, were recruited from our hospital. Both exhibited early-onset symptoms, including distal muscle atrophy of the limbs, without cranial nerve involvement. Electromyography was performed to assess nerve amplitudes and conduction velocities. Whole-exome sequencing (WES) and Sanger sequencing were performed to identify genetic mutations.ResultsElectromyography revealed a significant decline in nerve amplitudes, while the nerve conduction velocities (NCVs) remained normal in the extremities. Sequencing identified a novel missense mutation (c.1398C &amp;gt; A, p.H466Q) in exon 13 of the SET binding factor 1 (SBF1) gene in both patients, indicating an autosomal dominant inheritance pattern.DiscussionPathogenicity and protein predictions suggest that the myotubularin-related protein 5 (MTMR5), encoded by the mutated SBF1, may possess an altered structure, resulting in disease. These findings will help expand the phenotypic and genetic spectrum of CMT4B3.

CsCBF2 contributes to cold repression of chlorophyll and carotenoid biosynthesis in albino Camellia sinensis cv. Baiye 1.

C-repeat binding factors (CBFs) play a pivotal role in regulating cold response in higher plants. Camellia sinensis cv. Baiye 1, a representative albino tea cultivar, has been identified as temperature-sensitive based on long-term observations by tea farmers. However, it remains unclear whether CsCBFs are involved in temperature-mediated albinism and seasonal greening in 'Baiye 1', and the mechanisms by which CBFs regulate cold responses in albino leaves are unknown. In this study, we demonstrate that CsCBF2 suppresses the seasonal greening of albino leaves by inhibiting chlorophyll and carotenoid biosynthesis under cold stress. In tea plantations, the accumulation of chlorophylls and carotenoids in the albino shoots of 'Baiye 1' is closely correlated with the effective accumulated temperature during its seasonal greening process. Weighted Gene Co-expression Network Analysis revealed negative associations between CsCBF expression and chlorophylls, carotenoids, as well as their biosynthetic genes REVEILLE 1 (CsRVE1) and Zeaxanthin epoxidase 1 (CsZEP1) under temperature fluctuations during seasonal greening. Cold-induced upregulation of CsCBF2 expression and decreased chlorophylls and carotenoids under controlled climate conditions. Transient suppression of CsCBF2 by antisense oligodeoxynucleotide elevated expressions of target genes, and increased chlorophylls and carotenoids. CBF-binding cis-elements were identified in CsRVE1, Protochlorophyllide oxidoreductase A (CsPORA), and CsZEP1 promoters. Luciferase assays suggested CsCBF2 binding to the CRT/DRE cis-elements and repressing expression of CsRVE1, CsPORA, and CsZEP1. These findings highlight CsCBF2 as a key transcriptional repressor involved in the seasonal greening of albino 'Baiye 1' under cold stress, by modulating cold responses and inhibiting genes associated with chlorophyll and carotenoid biosynthesis.

Comparative genomic profiling of CBFs pan-gene family in five yellowhorn cultivars and functional identification of Xg11_CBF11.

C-repeat binding factor (CBF) transcription factors can activate the expression of a series of cold regulation-related genes, thereby improving the cold resistance of plants. However, no detailed information is known about the biological functions of CBF proteins in yellowhorn (Xanthoceras sorbifolium). In this study, a total of 59 CBF gene family members were identified in five yellowhorn cultivars (WF18, Zhongshi 4, Jinguanxipei 2021, Zhong Guan NO.2, and XsoG11), revealing their intraspecific structural and functional diversity, with 8 core genes present in all cultivars. Phylogenetic and motif analyses highlighted conserved features and species-specific adaptations. Gene duplication events revealed that tandem duplicates are major factors involved in the expansion of this gene family in yellowhorn. Expression profiling under stress conditions demonstrated the involvement of these genes in stress responses. Of particular interest was Xg11_CBF11, which showed strong induction by low-temperature stress. Overexpression of Xg11_CBF11 in Arabidopsis thaliana was performed to validate its cold resistance function. The wild-type and T2 transgenic A. thaliana plants were subjected to low-temperature stress at 4°C for 0, 24, and 48 h, and physiological indexes related to antioxidant enzyme activity, photosynthesis, and cell membrane permeability were determined by comparative test. The results were as follows: the POD and SOD activities of transgenic lines were significantly higher than those of wild-type lines, indicating Xg11_CBF11 improved the adaptability of A. thaliana to low-temperature; The increase of relative conductivity and malondialdehyde, the decrease of chlorophyll content in transgenic lines were smaller than those of wild-type lines, indicating Xg11_CBF11 enhanced the resistance of A. thaliana to low-temperature stress. These results implied that Xg11_CBF11 has a positive regulatory effect on A. thaliana 's response to low-temperature stress.

A retrospective study of recombinant human growth hormone in the treatment of school-aged pediatric patients with idiopathic short stature.

The present study aims to investigate the clinical efficacy of recombinant human growth hormone (r-hGH) in the treatment of school-age pediatric patients with idiopathic short stature (ISS). Pediatric patients who were diagnosed with ISS and treated with r-hGH at our hospital were enrolled as research subjects. The main outcome indicators included the serum level of insulin-like growth factor-1, insulin-like growth factor binding protein-3, baseline height standard deviation scores, and posttreatment height standard deviation scores and retrospective analysis was performed. This study complies with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. A total of 42 pediatric patients with a diagnosis of ISS were enrolled in the present study (24 males and 18 females). Following treatment, the levels of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 were significantly higher than the baseline level and the difference was statistically significant. The posttreatment height standard deviation scores was significantly higher than the baseline height standard deviation scores and the difference was statistically significant. There were no significant differences between male and female participants in height standard deviation scores, either before or following treatment. This study found that r-hGH therapy may increase height in school-age pediatric patients with ISS and is therefore worthy of clinical application.

Grafting semi-wild tomato GZ-05 rootstocks improved cold tolerance via the signalling of melatonin and jasmonic acid

Tomato (Solanum lycopersicum) cultivation in the off-season is significantly hindered by cold stress; hence, utilising stress-resistant rootstocks in grafting is a critical solution. This study used 30 semi-wild tomato GZ-05 plants as rootstocks and Ailsa Craig (AC) tomatoes as scions. After cold stress, the scion tolerance index, leaf ion permeability, and other physiological and biological indicators were used to determine the most tolerant plants. To understand the molecular basis of GZ-05 rootstock cold stress resistance, RNA sequencing and reverse transcription polymerase chain reaction techniques were used to compare the varying genes expressed in the grafted AC/GZ-05 and self-grafted AC/AC plant scion leaves. The results indicated that genes associated with melatonin (MT) and jasmonic acid (JA) production and their signalling pathways were considerably altered. The initial MT and JA levels in the GZ-05-grafted plant scions were high, and when they were exposed to cold stress, the amount of active MT and JA in AC/GZ-05 heterologous grafts were great. Using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9, we knocked out the MT synthesis gene (SlCOMT14) and JA synthesis gene (SlLoxD) and found that GZ-05 plant cold stress tolerance decreased. External tests were conducted to evaluate the GZ-05 SlCOMT14 and SlLoxD knockout lines. Source spraying with MT and methyl jasmonate showed that knockout strain cold stress tolerance could be recovered. SlICE1, a tomato cold stress tolerance transcription factor, was silenced, resulting in decreased tolerance to MT- and JA-induced cold stress. The MT/JA-inducer of C-repeat binding factor (CBF) expression 1-CBF pathway may be the mechanism by which the semi-wild tomato GZ-05 rootstock confers cold tolerance to plants. This study has uncovered the molecular mechanism by which grafting semi-wild tomato GZ-05 rootstocks increases plant cold tolerance, thereby laying the groundwork for the utilisation of Guizhou's native semi-wild tomato germplasm resources.

Is age just a number? Intensive therapy for core binding factor acute myeloid leukemia in older adults.

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Understanding cold stress response mechanisms in plants: an overview.

Low-temperature stress significantly impacts plant growth, development, yield, and geographical distribution. However, during the long-term process of evolution, plants have evolved complicated mechanisms to resist low-temperature stress. The cold tolerance trait is regulated by multiple pathways, such as the Ca2+ signaling cascade, mitogen-activated protein kinase (MAPK) cascade, inducer of CBF expression 1 (ICE1)-C-repeat binding factor (CBF)-cold-reulated gene (COR) transcriptional cascade, reactive oxygen species (ROS) homeostasis regulation, and plant hormone signaling. However, the specific responses of these pathways to cold stress and their interactions are not fully understood. This review summarizes the response mechanisms of plants to cold stress from four aspects, including cold signal perception and transduction, ICE1-CBF-COR transcription cascade regulation, ROS homeostasis regulation and plant hormone signal regulation. It also elucidates the mechanism of cold stress perception and Ca2+ signal transduction in plants, and proposes the important roles of transcription factors (TFs), post-translational modifications (PTMs), light signals, circadian clock factors, and interaction proteins in the ICE1-CBF-COR transcription cascade. Additionally, we analyze the importance of ROS homeostasis and plant hormone signaling pathways in plant cold stress response, and explore the cross interconnections among the ICE1-CBF-COR cascade, ROS homeostasis, and plant hormone signaling. This comprehensive review enhances our understanding of the mechanism of plant cold tolerance and provides a molecular basis for genetic strategies to improve plant cold tolerance.

A seed-specific DNA-binding with One Finger transcription factor, RPBF, positively regulates galactinol synthase to maintain seed vigour in rice.

Seed vigour and longevity are intricate yet indispensable physiological traits for agricultural crops, as they play a crucial role in facilitating the successful emergence of seedlings and exert a substantial influence on crop productivity. Transcriptional regulation plays an important role in seed development, maturation, and desiccation tolerance, which are important attributes for seed vigour and longevity. Here, we have investigated the regulatory role of the seed-specific DNA binding with the One Finger (DOF) transcription factor and the RPBF (Rice P-box Binding Factor) in seed vigour. RPBF modulates the transcription of galactinol synthase and improves seed vigour. The promoter region of Galactinol synthase (GolS)-encoding genes from different species was enriched with DOF binding sites, and the expression levels of both RPBF and OsGolS were found to enhance during seed development. Furthermore, direct interaction of RPBF with OsGolS promoter has been demonstrated through multiple approaches: yeast one-hybrid (Y1H) assays, in planta promoter-GUS assays, dual luciferase assay, and in silico molecular docking. To assess functionality, Agrobacterium-mediated genetic transformation of rice was performed to generate the RNAi lines with reduced RPBF expression. In these RNAi lines, a reduction in both galactinol and raffinose content was observed. Since galactinol and raffinose are known contributors to seed vigour, the T2-transgenic lines were assessed for vigour and viability. For this, RNAi seeds were subjected to accelerated ageing by exposing them to high relative humidity and temperature, followed by scoring the germination and viability potential. Tetrazolium and seed germination assay revealed that the RNAi seeds were more sensitive to ageing compared to their wild-type and vector control counterparts. Collectively, this is the first report demonstrating that the DOF transcription factor RPBF controls the seed vigour through transcriptional regulation of galactinol synthase.

Exploring the Impact of Protein Chain Selection in Binding Energy Calculations with DFT.

Calculation of binding free energies between a protein and a ligand are highly desired for computer-aided drug design. Here we approximate the binding energies of ABL1, an enzyme which is the target for drugs used in the treatment of chronic myeloid leukaemia, with minimal models and density functional theory (DFT). Starting from the crystal structures of protein-drug complexes, we estimated the binding free energies having used all available individual molecules (protein chains) within each structure, not only a single one as commonly used, in order to see if the choice of the protein chain is important in such calculations. Differences were observed between chains in the same file. Energy decomposition analysis (EDA) revealed that the most important factors for binding were exchange, repulsion and electrostatics. The desolvation term varied dramatically between the inhibitors (between 4.2 and 92.3 kcal/mol). All functionals showed similar patterns in the EDA and in discriminating between the ligands. Non-covalent interactions (NCI) analysis was used to further explain the differences between protein chains and functionals. Overall, it is shown that small minimal models of a drug binding site can be useful to infer on the suitability of an initial crystal structure for further analysis such as EDA.

Molecular signatures of environmental adaptation mechanisms of Rhizocarpon geographicum in Horseshoe Island (west of the Antarctic Peninsula) and Türkiye

The adaptation of lichen species to different habitats and extreme conditions is due to rapid changes in expressions of the genes in their genetic backgrounds. In this study, lichen samples were collected from two different regions: from Horseshoe Island, located to the west of the Antarctic Peninsula and from the west coast of Türkiye. The nrITS gene regions of the samples were studied and the phylogenetic positions of the samples were confirmed as Rhizocarpon geographicum (L.) DC. After DNA barcoding of R. geographicum, expression differences of three below-specified stress genes were revealed. Comparative determinations of the changes in the expressions of the multiprotein binding factor-1 (MBF-1), polyketide synthase (PKS), and photosystem II D1 protein (psbA) genes due to temperature or other environmental stress change stress were performed by a real-time PCR. Specifically, under cold stress conditions such as those found on Horseshoe Island, the MBF-1 gene was highly expressed, while PKS and psbA gene expression levels were lower compared to the west coast of Türkiye. The results of this study, which is the first in its field, highlight the adaptation of Rhizocarpon geographicum specimens to those habitats and regional climate. Specimen collected from different geographical regions exhibited gene expression differences.

Sex differential effects of early maternal separation on PTSD susceptibility in adult rats accompanied by telomere shortening in the hippocampus

Early life stress (ELS) is thought to be a leading cause of mental disorders in adulthood, including PTSD. Recent studies have found that such stress has a gender and resilient specific effect on adult PTSD. This study aimed to assess emotion, and cognitive behavior, and to examine the sex differences and resilience of ELS on adult PTSD. At the same time, the expression of hippocampal telomere length and telomere repeat binding factors (TRF1 and TRF2) were detected to explore the mechanism of telomere length change. Rat offspring were separated from their dams (3 h/day or 6 h/day from PND2 ∼ PND14). Then, pups were treated with a single prolonged stress (SPS) procedure when they reached adulthood (PND80). Rats exposed early to MS and SPS showed anxiety-like and depression-like behaviors as well as impaired learning and memory. The rats exposed to MS3h showed reduced anxiety-like and depression-like behavior upon re-experiencing “secondary stress” compared to the SPS and MS6h groups. Behavioral results showed no significant gender difference. However, gender and SPS factors significantly affected telomere length and TRF1 and TRF2 gene expression in hippocampus. The SPS effect and MS*SPS interaction significantly impacted TRF1 and TRF2 protein expression. In conclusion, this study shows that MS has different effects on anxiety, depression, and cognitive memory deficits in rats experiencing “secondary stress” in adulthood and is accompanied by telomere shortening in the hippocampus. This reveals the potential impact of early MS on PTSD and provides a new perspective for further research in the field of psychological stress.

An analysis of acid-labile subunit (ALS) levels in children with short stature born with normal weight.

The acid-labile subunit (ALS) is a protein best known for its function in stabilising the insulin like growth factor-1/2-insulin-like growth factor-1 binding protein 3/5 (IGF-1/2-IGFBP3/5) binary complex by creating the ternary complex and in consequence regulating the biological activity of IGF-1. The aim of the study was to assess ALS concentrations in a chosen population of children with short stature taking into account their clinical diagnosis. A total of 109 prepubertal children were involved in the study - 85 children in the study group and 24 in controls. In all the children IGF-1, IGFBP3, and ALS were measured. The study group was divided according to diagnosis into groups: growth hormone deficiency (GHD), constitutional delay of growth and puberty (CDGP), idiopathic short stature (ISS), and familial short stature (FSS). In the control group the ALS concentration ranged from 4.81 to 13.66 μg/mL. In the whole study group the ALS concentration ranged from 2.73 to 15.81 μg/mL. The difference between both groups was statistically significant (p < 0.0001, R = 0.39). A strong, statistically significant correlation between ALS levels and age was observed, but only in the study group (p < 0.0001, r = 0.59). The ALS standard deviation score (SDS) was not significantly different between the control and CDGP children (p = 0.0644). The ALS concentration was significantly lower in children with short stature. There was, however, no difference between the subgroups of the study group. There was no significant difference in ALS SDS between the control group and children with constitutional delay of growth and development. The usefulness of ALS in routine short stature diagnostics is uncertain, but it might play a role in the diagnosis of children with ISS and CDGP in the future.

Oxct1 regulates cardiomyocyte PANoptosis in acute myocardial infarction via succinylating Tfam

Abstract Background Myocardial ischemia leads to various forms of programmed cell death in cardiomyocytes, resulting in acute myocardial infarction (AMI) and the development of heart failure in the long term. PANoptosis is a unique cell death regulatory mechanism orchestrated by the PANoptosome complex, which regulates and intersects multiple forms of programmed cell death. Oxct1 has been demonstrated to play crucial roles in tumors, pressure-overloaded hearts, and cardiac endothelial cells. However, whether Oxct1 is involved in the regulation of PANoptosis and correlated mechanisms during AMI remains unclear. Purpose To elucidate the role of Oxct1 in cardiomyocytes during AMI and uncover the potential mechanisms. Methods The myocardial infarction model induced by anterior descending branch ligation and the primary cardiomyocytes hypoxia model were employed in our experiments. Small interfering RNA (siRNA) and adenovirus were constructed to knock down and overexpress Oxct1 for altering its expression in cardiomyocytes in vitro. Cardiomyocyte-specific knockout mice were constructed to alter Oxct1 expression in vivo. PANoptosis characteristic measurement, including Z-DNA binding protein 1(Zbp1), pyroptosis markers, apoptosis markers, necroptosis markers, ROS, and mitochondrial morphology, were performed to verify the ability of Oxct1 to regulate the PANoptosis of cardiomyocytes. Cardiac morphological, structural, and functional changes were measured to assess the effect of Oxct1 on AMI. RNA sequencing was performed to identify downstream pathways. Immunoprecipitation +Mass spectrometry and co-immunoprecipitation were performed to identify the specific binding factors of Oxct1. Results We found that the expression of Oxct1 was significantly elevated after AMI. Besides, gain- and loss-of-function experiments were constructed both in vitro and in vivo. Functionally, Oxct1 knockdown significantly enhanced cardiomyocyte vitality, reduced ROS production and mtDNA cytoplasmic release in hypoxic cardiomyocytes. In vivo, Oxct1cko mice manifested reduced infarct size, improved cardiac function and alleviated cardiac fibrosis by mitigating PANoptosis. However, Oxct1 overexpression resulted in the opposite effects. Afterwards, RNA-seq analysis results showed that cytosolic DNA-sensing pathway was significantly enriched in Oxct1 knockdown cardiomyocytes. Mechanistically, Oxct1 could bind to mitochondrial transcription factor A(Tfam) and increased its succinylation, promoting Tfam degradation. Downregulation of Tfam resulted in ROS production and mtDNA damage, while mtDNA released into cytoplasm could activate Zbp1 and induce cascade reaction of PANoptosis. Conclusion This study demonstrates that Oxct1 promotes Tfam degradation through succinylation, exacerbating ROS production, mtDNA damage and cytoplasmic release, ultimately leading to cardiomyocyte PANoptosis in AMI.

MiR-221-5p_R-4 regulates internalized trehalose-induced autophagy by targeting NRBF2 in porcine granulosa cells

Trehalose, as a food and feed additive, can regulate physiological and pathological processes by activating autophagy, yet the molecular mechanism of trehalose dominated a rise in autophagy has not been elucidated. This study investigated the mechanisms of trehalose-induced autophagy in porcine granulosa cells (PGCs). Trehalose was internalized into PGCs by endocytosis and caused a temporary change of the lysosome pH, ultimately inducing autophagy. Furthermore, miRNA-seq analysis of PGCs indicated that trehalose upregulated the expression of miR-221-5p_R-4, which can target nuclear receptor binding factor 2 (NRBF2) to induce autophagy of PGCs. In summary, this study reveals that miR-221-5p_R-4 targeting NRBF2 was involved in the autophagy of PGCs challenged by trehalose, which was taken up by PGCs through endocytosis.

Human Satellite 3 DNA encodes megabase-scale transcription factor binding platforms.

Eukaryotic genomes are frequently littered with large arrays of tandem repeats, called satellite DNA, which underlie the constitutive heterochromatin often found around centromeric regions. While some satellite DNA types have well-established roles in centromere biology, other abundant satellite DNAs have poorly characterized functions. For example, Human Satellite 3 (HSat3), which makes up roughly 2% of the human genome, forms enormous arrays up to tens of megabases, but these arrays play no known roles in centromere function and were almost fully excluded from genome assemblies until recently. As a result, these massive genomic regions have remained relatively understudied, and the potential functional roles of HSat3 have remained largely unknown. To address this, we performed a systematic screen for novel HSat3 binding factors. Our work revealed HSat3 arrays contain high densities of transcription factor (TF) motifs that are bound by factors related to multiple, highly conserved signaling pathways. Unexpectedly, the most enriched TFs in HSat3 belong to the Hippo pathway transcription effector family TEAD. We found that TEAD recruits the co-activator YAP to HSat3 regions in a cell-state specific manner. Using RNA polymerase-I reporter assays, targeted repression of HSat3, inducible degradation of YAP, and super-resolution microscopy, we show that HSat3 arrays can localize YAP/TEAD inside the nucleolus, where YAP regulates RNA Polymerase-I activity. Beyond revealing a direct relationship between the Hippo pathway and ribosomal DNA regulation, this work demonstrates that satellite DNA can encode multiple transcription factor binding motifs, defining a new role for these enormous genomic elements.

Influence of aroma binding factors of coffee matrix on characteristic aroma in a model system

The stability of coffee's characteristic aroma was investigated during half an hour incubation of coffee brew, revealing that thiols, including 2-furfurylthiol (2-FFT), 2-methyl-3-furanthiol (2M3F), and methanethiol (MET), experienced reductions to 3.3%, 34.4%, and 25.5%, respectively. To identify the dominant components responsible for the reduction of aromas, the effects of coffee lipids, hydroxyhydroquinone, melanoidin of varying molecular sizes, and carbohydrates on selected characteristic aroma compounds were evaluated in a mimic coffee model. It was proposed that higher amounts of lipids generally led to a reduction in coffee aromas, particularly those with a positive oil-water partition coefficient. Among potential aroma-binding precursors, hydroxyhydroquinone, a thermal degradation product of chlorogenic acid, exhibited the highest correlation with the loss of 2-FFT and 2M3F. In contrast, the reduction of aromas such as MET, 2,3-butanedione, 2,5-dimethylpyrazine, dimethyl trisulfide, and difurfuryl disulfide was significantly negatively correlated with melanoidin, especially low molecular weight melanoidin (<3 kD). The binding reaction between hydroxyhydroquinone and 2-furfurylthiol was further investigated in brewed coffee, demonstrating that quinones, the oxidation products of hydroxyhydroquinone, exhibited a higher reactivity, directly reacting with 2-furfurylthiol, which was the primary reactant for 2-furfurylthiol.