GCN5 mediates DNA-PKcs crotonylation for DNA double-strand break repair and determining cancer radiosensitivity.

BACKGROUND: DNA double-strand break (DSB) induction and repair are important events for determining cell survival and the outcome of cancer radiotherapy. The DNA-dependent protein kinase (DNA-PK) complex functions at the apex of DSBs repair, and its assembly and activity are strictly regulated by post-translation modifications (PTMs)-associated interactions. However, the PTMs of the catalytic subunit DNA-PKcs and how they affect DNA-PKcs's functions are not fully understood. METHODS: Mass spectrometry analyses were performed to identify the crotonylation sites of DNA-PKcs in response to γ-ray irradiation. Co-immunoprecipitation (Co-IP), western blotting, in vitro crotonylation assays, laser microirradiation assays, in vitro DNA binding assays, in vitro DNA-PK assembly assays and IF assays were employed to confirm the crotonylation, identify the crotonylase and decrotonylase, and elucidate how crotonylation regulates the activity and function of DNA-PKcs. Subcutaneous xenografts of human HeLa GCN5 WT or HeLa GCN5 siRNA cells in BALB/c nude mice were generated and utilized to assess tumor proliferation in vivo after radiotherapy. RESULTS: Here, we reveal that K525 is an important site of DNA-PKcs for crotonylation, and whose level is sharply increased by irradiation. The histone acetyltransferase GCN5 functions as the crotonylase for K525-Kcr, while HDAC3 serves as its dedicated decrotonylase. K525 crotonylation enhances DNA binding activity of DNA-PKcs, and facilitates assembly of the DNA-PK complex. Furthermore, GCN5-mediated K525 crotonylation is indispensable for DNA-PKcs autophosphorylation and the repair of double-strand breaks in the NHEJ pathway. GCN5 suppression significantly sensitizes xenograft tumors of mice to radiotherapy. CONCLUSIONS: Our study defines K525 crotonylation of DNA-PKcs is important for the DNA-PK complex assembly and DSBs repair activity via NHEJ pathway. Targeting GCN5-mediated K525 Kcr of DNA-PKcs may be a promising therapeutic strategy for improving the outcome of cancer radiotherapy.

Posterior Intraparietal Sulcus Mediates Detection of Salient Stimuli Outside the Endogenous Focus of Attention.

Visual consciousness is shaped by the interplay between endogenous selection and exogenous capture. If stimulus saliency is aligned with a subject's attentional priorities, endogenous selection will be facilitated. In case of a misalignment, endogenous selection may be compromised as attentional capture is a strong and automatic process. We manipulated task-congruent versus -incongruent saliency in a functional magnetic resonance imaging change-detection task and analyzed brain activity patterns in the cortex surrounding the intraparietal sulcus (IPS) within the Julich-Brain probabilistic cytoarchitectonic mapping reference frame. We predicted that exogenous effects would be seen mainly in the posterior regions of the IPS (hIP4-hIP7-hIP8), whereas a conflict between endogenous and exogenous orienting would elicit activity from more anterior cytoarchitectonic areas (hIP1-hIP2-hIP3). Contrary to our hypothesis, a conflict between endogenous and exogenous orienting had an effect early in the IPS (mainly in hIP7 and hIP8). This is strong evidence for an endogenous component in hIP7/8 responses to salient stimuli beyond effects of attentional bottom-up sweep. Our results suggest that hIP7 and hIP8 are implicated in the individuation of attended locations based on saliency as well as endogenous instructions.

Humanized mouse models for inherited thrombocytopenia studies.

Inherited thrombocytopenia (IT) is a group of hereditary disorders characterized by a reduced platelet count as the main clinical manifestation, and often with abnormal platelet function, which can subsequently lead to impaired hemostasis. In the past decades, humanized mouse models (HMMs), that are mice engrafted with human cells or genes, have been widely used in different research areas including immunology, oncology, and virology. With advances of the development of immunodeficient mice, the engraftment, and reconstitution of functional human platelets in HMM permit studies of occurrence and development of platelet disorders including IT and treatment strategies. This article mainly reviews the development of humanized mice models, the construction methods, research status, and problems of using humanized mice for the in vivo study of human thrombopoiesis.

Humanized mouse models (HMMs) refer to immunodeficient mice that have been used for the investigation of human hematopoiesis and immunity for years. With engrafted human hematopoietic stem cells (HSCs), the differentiation process of HSCs and re-construction of platelets can be monitored in the mice. Until now, several strains of HMMs have been used in the studies of inherited thrombocytopenia (IT), a genetic disorder associated with low platelet count in the blood. In this study, we reviewed the development of these HMMs in IT studies, compared the different sources of HSCs transplanted into HMMs and summarize the strategies of HSC transplantation in HMMs. The Kit^−/− immunodeficient mice showed effectively long-term and stable implantation of human HSC without irradiation and higher implantation levels, and they also support multilinear differentiation of human HSC, such as platelets and red blood cells. The source and count of HSCs and the transplantation strategy may also impact the result. This study provides a basis information for HMMs used in IT and will help other investigators in this field choosing the right research plan.

A nomogram model for predicting malnutrition among older hospitalized patients with type 2 diabetes: a cross-sectional study in China.

BACKGROUND: Malnutrition remains a pervasive issue among older adults, a prevalence that is markedly higher among those diagnosed with diabetes. The primary objective of this study was to develop and validate a risk prediction model that can accurately identify instances of malnutrition among elderly hospitalized patients with type 2 diabetes mellitus (T2DM) within a Chinese demographic. METHODS: This cross-sectional study was conducted between August 2021 and August 2022, we enrolled T2DM patients aged 65 years and above from endocrinology wards. The creation of a nomogram for predicting malnutrition was based on risk factors identified through univariate and multivariate logistic regression analyses. The predictive accuracy of the model was evaluated by the receiver operating characteristic curve (ROC),the area under the ROC (AUC), the concordance index (C-index), and calibration curves. RESULTS: The study included a total of 248 older T2DM patients, with a recorded malnutrition prevalence of 26.21%. The identified critical risk factors for malnutrition in this cohort were body mass index, albumin, impairment in activities of daily living, dietary habits, and glycosylated hemoglobin. The AUC of the nomogram model reached 0.914 (95% CI: 0.877-0.951), with an optimal cutoff value of 0.392. The model demonstrated a sensitivity of 80.0% and a specificity of 88.5%. Bootstrap-based internal verification results revealed a C-index of 0.891, while the calibration curves indicated a strong correlation between the actual and predicted malnutrition risks. CONCLUSIONS: This study underscores the critical need for early detection of malnutrition in older T2DM patients. The constructed nomogram represents a practical and reliable tool for the rapid identification of malnutrition among this vulnerable population.

Potential biomarkers for inherited thrombocytopenia 2 identified by plasma proteomics.

Inherited thrombocytopenia 2 (THC2) is difficult to diagnose due to the lack of specific clinical characteristics and diagnostic methods. To identify potential plasma protein biomarkers for THC2, we collected the plasma samples from a THC2 family (9 THC2 and 15 non-THC2 members), enriched the medium and low abundant proteins using Proteominer and analyzed the protein profiles using the liquid chromatography-mass spectrometry in data independent acquisition mode. Initially, we detected 784 proteins in the plasma samples of this family and identified 27 up-regulated and 36 down-regulated in the THC2 group compared to the non-THC2 group (|log2 ratio| >1 and p-value <0.05). To improve the predictive power, top eight dysregulated proteins (B7Z2B4, LTF, HP, ERN1, IGHV1-8, A0A0X9V9C4, VH6DJ, and D3JV41) were selected by an area under the curve-based random forest process to construct a clinical model. Multivariate analysis with random forest and support vector machine showed that the prediction model provided high discrimination ability for THC2 diagnosis (AUC: 1.000 and 0.967, respectively). The potential plasma protein biomarkers will be tested in more THC2 patients and other thrombocytopenia patients to further validate their specificity and sensitivity.

EloA promotes HEL polyploidization upon PMA stimulation through enhanced ERK1/2 activity.

Megakaryocytes (MKs) are the unique non-pathological cells that undergo polyploidization in mammals. The polyploid formation is critical for understanding the MK biology, and transcriptional regulation is involved in the differentiation and maturation of MKs. However, little is known about the functions of transcriptional elongation factors in the MK polyploidization. In this study, we investigated the role of transcription elongation factor EloA in the polyploidy formation during the MK differentiation. We found that EloA was highly expressed in the erythroleukemia cell lines HEL and K562. Knockdown of EloA in HEL cell line was shown to impair the phorbol myristate acetate (PMA) induced polyploidization process, which was used extensively to model megakaryocytic differentiation. Selective over-expression of EloA mutants with Pol II elongation activity partially restored the polyploidization. RNA-sequencing revealed that knockdown of EloA decelerated the transcription of genes enriched in the ERK1/2 cascade pathway. The phosphorylation activity of ERK1/2 decreased upon the EloA inhibition, and the polyploidization process of HEL was hindered when ERK1/2 phosphorylation was inhibited by PD0325901 or SCH772984. This study evidenced a positive role of EloA in HEL polyploidization upon PMA stimulation through enhanced ERK1/2 activity.

CRIF1 as a potential target to improve the radiosensitivity of osteosarcoma.

Resistance to ionizing radiation (IR), which is a conventional treatment for osteosarcoma that cannot be resected, undermines the efficacy of this therapy. However, the mechanism by which IR induces radioresistance in osteosarcoma is not defined. Here, we report that CR6-interacting factor-1 (CRIF1) is highly expressed in osteosarcoma and undergoes nuclear-cytoplasmic shuttling of cyclin-dependent kinase 2 (CDK2) after IR. Osteosarcoma cells lacking CRIF1 show increased sensitivity to IR, which is associated with delayed DNA damage repair, inactivated G1/S checkpoint, and mitochondrial dysfunction. CRIF1 interacts with the DNA damage checkpoint regulator CDK2, and CRIF1 and CDK2 colocalize in the nucleus after IR. Nuclear localization of CDK2 is associated with phosphorylation changes that promote DNA repair and activation of the G1/S checkpoint. CRIF1 knockdown synergized with IR in an in vivo osteosarcoma model, leading to tumor regression. Based on these findings, we identify CRIF1 as a potential therapeutic target in osteosarcoma that can increase the efficacy of radiotherapy. More broadly, our findings may provide insights into the mechanism for other types of radioresistant cancers and be exploited for therapeutic ends.

CRIF1-CDK2 Interface Inhibitors: An Unprecedented Strategy for Modulation of Cell Radiosensitivity.

Cyclin-dependent kinases (CDKs) are historic therapeutic targets implicated in tumorigenic events due to their critical involvement in the cell cycle phase. However, selectivity has proven to be a bottleneck, causing repeated failures. Previously, we reported CR6-interacting factor 1 (CRIF1), acting as a cell cycle negative regulator through interaction with CDK2. In the current report, we identified the CRIF1-CDK2 interaction interface by in silico studies and shortlisted interface inhibitors through virtual screening on CRIF1 using 40 678 drug-like compounds. These compounds were tested by cell proliferation assay, and four of these molecules were found to selectively inhibit the proliferation of osteosarcoma (OS) cell lines, but do not affect normal bone mesenchymal stem cells (BMSC). A binding study reveals significant affinities of the inhibitors on CRIF1. More importantly, treatment of the OS cells with a combination of ionizing radiation (IR) and the best-performing inhibitors remarkably increased IR inhibition potential from 19.9% to 59.6%. This occurred by selectively promoting G2/M arrest and apoptosis related to CDK2 overactivation in OS cells but not in BMSC and was supported by significant CDK2 phosphorylation modifications. Knocking down of CRIF1 by siRNA treatment showed similar effects to the interface inhibitors. Together we substantiate the identification of novel lead molecules, which may provide a new treatment to overcome selectivity issues and enhance the radiosensitivity of tumor cells, opening a conceptually novel strategy of CDK-targeting for different cancer types.

[Spectrum-effect relationship between HPLC fingerprint and free radicals scavenging in Guizhi Shaoyao Zhimu Decoction].

To establish the spectrum-effect relationship between HPLC fingerprint and free radicals activity scavenging in Guizhi Shaoyao Zhimu Decoction( GSZD),and provide a basis for the quality evaluation and modernization of classical prescriptions. Shimadsu GL-science C18 column( 4. 6 mm×250 mm,5 µm) was used with acetonitrile-0. 1% formic acid solution as the mobile phase for gradient elution. The detective wave length was 254 nm; the column temperature was set at 32 ℃; the injection volume was 20 µL; and the flow rate was 1. 0 m L·min-1.10 batches of primary standard samples of GSZD were detected,and their HPLC fingerprint was established by using the similarity evaluation system for chromatographic fingerprint of traditional Chinese medicine( TCM). The activity of scavenging free radicals was studied by 1,1-diphenyl-2-trinitrophenylhydrazine( DPPH) method,and the spectrum-effect relationship was studied by Pearson bivariate correlation analysis. The common mode of GSZD fingerprints was established,and 26 common peaks were marked,with similarities ranging from 0. 929 to 0. 998. Eight of the chromatographic peaks were identified by using the control comparison method: gallic acid,mangiferin,paeoniflorin,glycyrrhizin,asparagus,5-O-methylvisamicin,cinnamic acid,and ammonium glycyrrhetate. Among them,the content changes of No. 14( paeoniside),20,12( mangiferin),13 and 23( cinnamic acid) common peaks were negatively correlated with free radical scavenging activity. The fingerprint showed high precision,repeatability and stability,and the common peaks were well separated,so it can be used for the quality evaluation of GSZD,and could provide reference for further studies on the material basis of GSZD.

Crif1 Promotes Adipogenic Differentiation of Bone Marrow Mesenchymal Stem Cells After Irradiation by Modulating the PKA/CREB Signaling Pathway.

Dysfunction of the hematopoietic microenvironment is the main obstacle encountered during hematopoiesis reconstruction in patients with acute hematopoietic radiation syndrome. Bone marrow mesenchymal stem cells (BM-MSCs) play a crucial supporting role in hematopoiesis by maintaining the balance between adipogenic and osteogenic differentiation. In this study, we found that irradiation decreased the colony-forming efficiency of BM-MSCs and impaired the balance between adipogenic and osteogenic differentiation. Following irradiation, BM-MCSs became strongly predisposed to adipogenesis, as evidenced by increased oil red O staining and elevated mRNA and protein levels of the adipogenic markers and transcription factors PPARγ and AP2. Overexpression of the essential adipogenesis regulator Crif1 in BM-MSCs promoted adipogenesis after irradiation exposure by upregulating adipogenesis-related genes, including C/EBPß, PPARγ, and AP2. We found that Crif1 promoted the phosphorylation of cAMP response element binding protein (CREB) through direct interaction with protein kinase A (PKA)-α. Phosphorylation of CREB was inhibited in Crif1-knockdown BM-MSCs even in the presence of a PKA agonist (db-cAMP) and could be suppressed in Crif1-overexpressing BM-MSCs by a PKAα inhibitor (H-89). These results suggest that Crif1 is an indispensable regulator of PKAα cat that modulates the PKA/CREB signaling pathway to promote adipogenic differentiation of BM-MSCs after irradiation.

Subliminal trauma reminders impact neural processing of cognitive control in adults with developmental earthquake trauma: a preliminary report.

Little is known about the effects of developmental trauma on the neural basis of cognitive control among adults who do not have posttraumatic stress disorder. To examine this question, we used functional magnetic resonance imaging to compare the effect of subliminal priming with earthquake-related images on attentional control during a Stroop task in survivors of the 2008 Wenchuan earthquake in China (survivor group, survivors were adolescents at the time of the earthquake) and in matched controls (control group). We found that the survivor group showed greater activation in the left ventral anterior cingulate cortex (vACC) and the bilateral parahippocampal gyrus during the congruent versus incongruent condition, as compared to the control group. Depressive symptoms were positively correlated with left vACC activation during the congruent condition. Moreover, psychophysiological interaction results showed that the survivor group had stronger functional connectivity between the left parahippocampal gyrus and the left vACC than the control group under the congruent-incongruent condition. These results suggested that trauma-related information was linked to abnormal activity in brain networks associated with cognitive control (e.g., vACC-parahippocampal gyrus). This may be a potential biomarker for depression following developmental trauma, and it may also provide a mechanism linking trauma reminders with depression.

Involvement of calcium, reactive oxygen species, and ATP in hexavalent chromium-induced damage in red blood cells.

AIM: The aim of this study was to investigate the mechanisms of Cr(6+)-induced red blood cells (RBCs) damage. METHODS: The effect of Cr(6+) exposure on RBCs was evaluated by hemolytic rate and blood gas assays. After exposure to 20 µM Cr(6+), the percentage of phosphatidylserine (PS)-exposing cells, intracellular Ca(2+), reactive oxygen species (ROS), and ATP levels were evaluated, and cell morphology was observed. RBCs were exposed to Cr(6+) in different Ringer solutions to investigate the role of changes of Ca(2+), ROS, and ATP levels in eryptosis and morphology. RESULTS: The Cr(6+)-induced damage of RBCs was dose-dependent. After a 6 h incubation with Cr(6+), RBCs exhibited significant Ca(2+) influx, ROS increase, ATP depletion, and PS exposure, but displayed no obvious change in morphology at this time point. After 24 h Cr(6+) exposure, the RBCs decreased in size, appeared to be spike-like, and had decreased forward scatter. Inhibition of Ca(2+) influx attenuated PS-exposure caused by 6 h Cr(6+) exposure, but did not prevent 24 h Cr(6+) exposure-induced morphological change in RBCs. Inhibition of rapid ATP consumption using adenine significantly ameliorated Cr(6+)-caused PS-exposure at 12 h, 24 h and 48 h, and prevented 24 h Cr(6+) incubation-induced morphological change in RBCs. CONCLUSION: Cr(6+) can lead to eryptosis. Ca(2+) influx, increased ROS levels, and rapid ATP consumption are closely related to Cr(6+)-induced RBCs damage. Ca(2+) influx plays an extremely important role in Cr(6+)-mediated toxicity.

Endolichenic Fungi: A Promising Medicinal Microbial Resource to Discover Bioactive Natural Molecules-An Update.

Lichens are some of the most unique fungi and are naturally encountered as symbiotic biological organisms that usually consist of fungal partners (mycobionts) and photosynthetic organisms (green algae and cyanobacteria). Due to their distinctive growth environments, including hot deserts, rocky coasts, Arctic tundra, toxic slag piles, etc., they produce a variety of biologically meaningful and structurally novel secondary metabolites to resist external environmental stresses. The endofungi that live in and coevolve with lichens can also generate abundant secondary metabolites with novel structures, diverse skeletons, and intriguing bioactivities due to their mutualistic symbiosis with hosts, and they have been considered as strategically significant medicinal microresources for the discovery of pharmaceutical lead compounds in the medicinal industry. They are also of great importance in the fundamental research field of natural product chemistry. In this work, we conducted a comprehensive review and systematic evaluation of the secondary metabolites of endolichenic fungi regarding their origin, distribution, structural characteristics, and biological activity, as well as recent advances in their medicinal applications, by summarizing research achievements since 2015. Moreover, the current research status and future research trends regarding their chemical components are discussed and predicted. A systematic review covering the fundamental chemical research advances and pharmaceutical potential of the secondary metabolites from endolichenic fungi is urgently required to facilitate our better understanding, and this review could also serve as a critical reference to provide valuable insights for the future research and promotion of natural products from endolichenic fungi.

Risk factors for malnutrition in patients with diabetic foot ulcer and its association with prolonged length of hospitalization.

PURPOSE: The study was designed to investigate the occurrence and risk factors of malnutrition in diabetic foot ulcers (DFU) patients and examine the association between malnutrition and length of stay (LOS). METHODS: This observational study included DFU hospitalized patients in two campuses of a hospital from January 2021 to June 2023. The diagnosis standard of malnutrition was established by using the Global Leadership Initiative on Malnutrition (GLIM) criteria. Patients were followed up to ascertain the length of hospitalization, and hospital stays longer than 17 days were considered as prolonged LOS. To explore the risk factors of malnutrition and the association between malnutrition and LOS, univariate and multivariate logistic regression analyses were performed. RESULTS: Overall 219 DFU patients were enrolled, malnutrition was identified in 38.36% of patients according to GLIM criteria, and 92 patients (42%) were recognized as prolonged LOS. Logistic regression analyses showed that BMI (P <0.001), Alb (P = 0.002), HbA1c (P <0.001), ulcer infection (P <0.001), LOS (P = 0.010), and ABI (P = 0.024) were independent risk factors for malnutrition. Besides, malnutrition by GLIM criteria was closely related to prolonged LOS and malnourished DFU patients were 2.857 times (95% CI, 1.497-5.450; P = 0.001) likely to present prolonged LOS than that of normal nutrition. CONCLUSION: Malnutrition was considered to be extremely prevalent in DFU patients and was associated with approximately three times higher likelihood of prolonged LOS. Implementing and disseminating the diagnostic criteria during routine practice is crucial, given the predictive efficacy of GLIM criteria.

Light-Mediated Multilevel Flexible High-Efficiency Perovskite Resistive Switching Memory Based on Mn:CsPbCl3 Nanocrystals.

Herein, the electrical characteristics, photoelectric properties, resistive switching (RS) mechanism, and flexible storage application of Ag/PMMA&Mn:CsPbCl3/ITO (PMMA = poly(methyl methacrylate)) devices are studied by using the photoelectric material Mn:CsPbCl3 nanocrystals (NCs) embedded in PMMA as the RS layer. The devices exhibit bipolar RS behavior with low operating voltage, excellent cycling endurance (>1000 times), long retention time (≥104 s), high ON/OFF ratio (≈104), and good environmental stability. The flexible memory devices have demonstrated reliable mechanical stability of consecutive 1000 bending cycles. In addition, multilevel data storage is realized by introducing the UV light, and the adjustive resistive switching characteristics is achieved through photoelectric synergistic work. The resistive switching mechanism under the excitation of light has been studied comprehensively. This work may pave a new way for developing the next generation of high-density data storage and photoelectric memristor.

Hemodynamic changes and perinatal outcome associated with umbilical artery thrombosis: a retrospective study.

OBJECTIVE: Poor fetal and perinatal outcomes in fetuses associated with umbilical artery thrombosis (UAT), such as severe intrauterine growth restriction (IUGR) and intrauterine asphyxia have been reported by some case series. Its hemodynamic impact remains unclear. The aim of this study was to evaluate the hemodynamic changes and perinatal outcome in UAT fetuses with a relatively large sample. METHODS: We included singleton fetuses diagnosed with UAT and with at least one available Doppler evaluation before the end of pregnancy in our center from 2016 to 2023. Fetuses with structural abnormalities and with no follow-up results were excluded. Doppler waveforms from the Umbilical artery (UA), middle cerebral artery (MCA), ductus venosus (DV) and uterine artery (UtA) were routinely evaluated according to ISUOG Practice Guidelines from diagnosis. The same sample of GA-matched normal fetuses with Doppler measurements during the same period were randomly selected as control group. RESULTS: Eighty-nine singleton fetuses with UAT with at least one Doppler evaluation before the end of pregnancy were identified, 13 fetuses with no follow-up results were excluded. After comprehensive prenatal counseling, 14 cases received urgent cesarean section, the remaining 55 cases received expectant management, the median day between GA at diagnosis and end of pregnancy was 13 (5-53) days (range, 2-159). 7 (7/76, 9.2%) cases occurred stillbirth, and the incidence of IUGR and Neonatal Intensive Care Unit (NICU) admission were 18.4% (14/76) and 13.2% (10/76) respectively. 49 fetuses (49/76, 64.5%) combined with Doppler abnormalities. UA abnormalities (35/76, 46.1%) and MCA abnormalities (34/76, 44.7%) were the most changes at presentation. Compared to control group, UA-EDV was significantly increased in UAT fetuses [21.84 (15.59-26.64) vs. 16.40 (12.43-20.70) cm/s, p < 0.001], UA-PI and UA-RI significantly decreased [0.68 (0.57-0.84) vs. 0.92 (0.79-1.11), p<0.001; 0.51 (0.44-0.59) vs. 0.62 (0.55-0.68), p < 0.001, respectively]. Both the MCA-PSV and MCA-EDV were significantly higher in UAT fetuses [54.60 (48.00-61.34) vs. 44.47 (29.66-57.60) cm/s, p < 0.001; 11.19 (7.84-17.60) vs. 8.22 (5.21-12.00) cm/s, p < 0.001, respectively], this led to a lower MCA-PI and MCA-RI. Meanwhile, DV-PIV was significantly higher in UAT fetuses [0.6 (0.47-0.87) vs. 0.45 (0.37-0.55), p < 0.001], CPR and UtA-PI were no significant difference between these two groups. Multivariate logistic regression analysis showed that DV-PIV was an independent risk factor for adverse pregnancy outcomes (OR 161.922, p<0.001), the area under the ROC curve (AUC) was 0.792 (95% CI 0.668-0.917; p < 0.001). CONCLUSION: Our data showed serious adverse pregnancy consequences are combined with UAT fetuses. Hemodynamic changes in UAT fetuses showed the remaining artery for compensation and brain perfusion derangement. With a comprehensive and standardized Doppler evaluation, progression of fetal deterioration may be detailed presented.

Protective effect of ginsenoside Rb1 against aconitine cardiotoxicity studied by myocardial injury, action potential, and calcium signaling.

Aconitine is the main active component of Aconitum plants. Although aconitine has effects that include strengthening the heart, analgesia, anti-tumor, and immune-regulating effects, aconitine has both efficacy and toxicity, especially cardiotoxicity. Severe effects can include arrhythmia and cardiac arrest, which limits the clinical application of aconitine-containing traditional Chinese medicine. Ginsenoside Rb1(Rb1) is mainly found in plants, such as ginseng and Panax notoginseng, and has cardiovascular-protective and anti-arrhythmia effects. This study aimed to investigate the detoxifying effects of Rb1 on aconitine cardiotoxicity and the electrophysiological effect of Rb1 on aconitine-induced arrhythmia in rats. Pathological analysis, myocardial enzymatic indexes, and Western blotting were used to investigate the ameliorating effect of Rb1 on aconitine cardiotoxicity. Optical mapping was used to evaluate the effect of Rb1 on action potential and calcium signaling after aconitine-induced arrhythmia. Rb1 inhibited pathological damage caused by aconitine, decreased myocardial enzyme levels, and restored the balance of apoptotic protein expression by reducing the expression of Bax and cleaved caspase 3 and increasing the expression of Bcl-2, thereby reducing myocardial damage caused by aconitine. Rb1 also reduced the increase in heart rate caused by aconitine, accelerated action potential conduction and calcium signaling, and reduced the dispersion of action potential and calcium signal conduction. Rb1 reduced the cardiotoxicity of aconitine by attenuating aconitine-induced myocardial injury and inhibiting the aconitine-induced retardation of ventricular action potential and calcium signaling in rats.

GATA binding protein 2 mediated ankyrin repeat domain containing 26 high expression in myeloid-derived cell lines.

BACKGROUND: Thrombocytopenia 2, an autosomal dominant inherited disease characterized by moderate thrombocytopenia, predisposition to myeloid malignancies and normal platelet size and function, can be caused by 5'-untranslated region (UTR) point mutations in ankyrin repeat domain containing 26 (ANKRD26). Runt related transcription factor 1 (RUNX1) and friend leukemia integration 1 (FLI1) have been identified as negative regulators of ANKRD26. However, the positive regulators of ANKRD26 are still unknown. AIM: To prove the positive regulatory effect of GATA binding protein 2 (GATA2) on ANKRD26 transcription. METHODS: Human induced pluripotent stem cells derived from bone marrow (hiPSC-BM) and urothelium (hiPSC-U) were used to examine the ANKRD26 expression pattern in the early stage of differentiation. Then, transcriptome sequencing of these iPSCs and three public transcription factor (TF) databases (Cistrome DB, animal TFDB and ENCODE) were used to identify potential TF candidates for ANKRD26. Furthermore, overexpression and dual-luciferase reporter experiments were used to verify the regulatory effect of the candidate TFs on ANKRD26. Moreover, using the GENT2 platform, we analyzed the relationship between ANKRD26 expression and overall survival in cancer patients. RESULTS: In hiPSC-BMs and hiPSC-Us, we found that the transcription levels of ANKRD26 varied in the absence of RUNX1 and FLI1. We sequenced hiPSC-BM and hiPSC-U and identified 68 candidate TFs for ANKRD26. Together with three public TF databases, we found that GATA2 was the only candidate gene that could positively regulate ANKRD26. Using dual-luciferase reporter experiments, we showed that GATA2 directly binds to the 5'-UTR of ANKRD26 and promotes its transcription. There are two identified binding sites of GATA2 that are located 2 kb upstream of the TSS of ANKRD26. In addition, we discovered that high ANKRD26 expression is always related to a more favorable prognosis in breast and lung cancer patients. CONCLUSION: We first discovered that the transcription factor GATA2 plays a positive role in ANKRD26 transcription and identified its precise binding sites at the promoter region, and we revealed the importance of ANKRD26 in many tissue-derived cancers.

Associated congenital anomalies and genetic anomalies in fetuses with isolated and non-isolated aberrant right subclavian artery.

OBJECTIVE: This study's aim was to determine the prevalence of chromosomal anomalies in fetuses with isolated and non-isolated aberrant right subclavian artery (ARSA) and to evaluate its association with other congenital anomalies. METHODS: From September 2018 to October 2021, 668 ARSA cases were diagnosed by prenatal ultrasound in our hospital; cases with missed visits and a lack of chromosomal findings were excluded and 363 cases were eligible for enrollment. General information, ultrasound presentation, chromosomal findings and pregnancy outcomes were retrospectively analyzed. RESULTS: Among the 363 cases, 296 were isolated, and 67 were associated with structural abnormalities or soft marker abnormalities. The proportion of fetuses with chromosomal abnormalities in the isolated ARSA group was significantly lower than that in the non-isolated ARSA group (p < .001). In the non-isolated ARSA group, 22 cases were combined with other soft marker abnormalities and 45 cases were combined with structural abnormalities. The most frequent structural abnormality coexisting with ARSA was cardiac malformations (38.81%). CONCLUSION: The most common combined malformation in ARSA is intracardiac malformation. Isolated ARSA has a low risk of chromosomal abnormalities, so invasive chromosomal testing is not recommended. Non-isolated ARSA has a high incidence of chromosomal abnormalities, so early karyotyping should be recommended.

Inhibition of integrin receptors reduces extracellular matrix levels, ameliorating benign prostate hyperplasia.

Although a high prevalence of benign prostate hyperplasia (BPH) has been documented, the risk factors are poorly understood. Metabolic syndrome increases the risk of BPH. Succinylation, a type of posttranslational modification, mostly targets metabolic processes. The level of succinylation was investigated in 4 BPH patients and 4 healthy controls. Additionally, 176 patients with BPH were analyzed by using pan-antisuccinyllysine antibody blotting. TMT-labeling proteomic and sc-RNAseq Cellchat analyses were employed to identify key signaling factors involved in the development of BPH. In vivo and in vitro experiments were used to confirm the role of integrin receptors. The global succinylation level in BPH was higher than that in the healthy prostate. Positive correlations of prostate volume with IHC score sand urodynamics testing were found in large clinical cohorts. The extracellular matrix (ECM), metabolic processes and immune signaling were involved in succinylation in BPH, as indicated by using TMT-labeling proteomic analysis, and this finding was also confirmed by sc-RNAseq CellChat analysis. The proteins upregulated in SIRT5 knockout WPMY-1 cells were also enriched in the extracellular matrix and metabolic processes. More importantly, integrin receptor inhibition in a mouse model of BPH significantly ameliorated prostate hyperplasia. High levels of succinylation modifications were found in BPH, and succinylated proteins influenced the activation of the ECM. Inhibition of ECM signaling further ameliorated prostate hyperplasia in mice.