ObjectiveTo explore the role and potential mechanism of circulating glutamate in enhancing insulin sensitivity by aerobic exercise. This research may provide a novel strategy for preventing metabolic diseases through precise exercise interventions. MethodsTo investigate the effects of elevated circulating glutamate on insulin sensitivity and its potential mechanisms, 18 male C57BL/6 mice aged 6 to 8 weeks were randomly divided into 3 groups: a control group (C), a group receiving 500 mg/kg glutamate supplementation (M), and a group receiving 1 000 mg/kg glutamate supplementation (H). The intervention lasted for 12 weeks, with treatments administered 6 d per week. Following the intervention, an insulin tolerance test (ITT) and a glucose tolerance test (GTT) were conducted. Circulating glutamate levels were measured using a commercial kit, and the activity of the skeletal muscle InsR/IRS1/PI3K/AKT signaling pathway was analyzed via Western blot. To further investigate the role of circulating glutamate in enhancing insulin sensitivity through aerobic exercise, 30 male C57BL/6 mice were randomly assigned to 3 groups: a control group (CS), an exercise intervention group (ES), and an exercise combined with glutamate supplementation group (EG). The ES group underwent treadmill-based aerobic exercise, while the EG group received glutamate supplementation at a dosage of 1 000 mg/kg in addition to aerobic exercise. The intervention lasted for 10 weeks, with sessions occurring 6 d per week, and the same procedures were followed afterward. To further elucidate the mechanism by which glutamate modulates the InsR/IRS1/PI3K/AKT signaling pathway, C2C12 myotubes were initially subjected to graded glutamate treatment (0, 0.5, 1, 3, 5, 10 mmol/L) to determine the optimal concentration for cellular intervention. Subsequently, the cells were divided into 3 groups: a control group (C), a glutamate intervention group (G), and a glutamate combined with MK801 (an NMDA receptor antagonist) intervention group (GK). The G group was treated with 5 mmol/L glutamate, while the GK group received 50 μmol/L MK801 in addition to 5 mmol/L glutamate. After 24 h of intervention, the activity of the InsR/IRS1/PI3K/AKT signaling pathway was analyzed using Western blot. ResultsCompared to the mice in group C, the circulating glutamate levels, the area under curve (AUC) of ITT, and the AUC of GTT in the mice of group H were significantly increased. Additionally, the expression levels of p-InsRβ, IRS1, p-AKT, and p-mTOR proteins in skeletal muscle were significantly downregulated. Compared to the mice in group CS, the circulating glutamate levels, the AUC of ITT, and the AUC of GTT in the mice of group ES were significantly reduced. Additionally, the expression levels of p-InsRβ, IRS1, p-AKT, and p-mTOR proteins in skeletal muscle of group ES mice were significantly upregulated. There were no significant changes observed in the mice of group EG. Compared to the cells in group 0 mmol/L, the expression levels of p-InsRβ, p-IRS1, p-PI3K, and p-AKT proteins in cells of group 5 mmol/L were significantly downregulated. Compared to the cells in group C, the expression levels of p-InsRβ, p-IRS1, p-PI3K, and p-AKT proteins in the cells of group G were significantly downregulated. No significant changes were observed in the cells of group GK. ConclusionLong-term aerobic exercise can improve insulin sensitivity by lowering circulating levels of glutamate. This effect may be associated with the upregulation of the InsR/IRS1/AKT signaling pathway activity in skeletal muscle. Furthermore, glutamate can weaken the activity of the InsR/IRS1/PI3K/AKT signaling pathway in skeletal muscle, potentially by binding to NMDAR expressed in skeletal muscle.

Objective To investigate the improvement effect of coumarin on hydrogen peroxide(H2 O2)induced oxidative damage in human ovarian granulosa cells by regulating the Kelch like ECH associated protein 1(Keap1)/nuclear factor E2 related factor 2(Nrf2)/antioxidant response element(ARE)signaling pathway.Methods The human ovarian granulosa cell line COV434 was grouped into control group(normal culture),model group(0.5 mmol·L-1 H2 O2),coumarin group(0.5 mmol·L-1 H2 O2+320 μmol·L 1 coumarin),suppressor group(0.5 mmol·L-1 H2 O2+10 μmol·L-1 Keap1/Nrf2/ARE pathway inhibitor compound 20c)and combination group(0.5 mmol·L-1 H2O2+320 μmol·L-1coumarin+10 μmol·L-1 compound 20c).Cell counting kit 8(CCK-8)method was applied to detect the optical density(OD)of COV434 cells;2',7'-dichlorodihydrofluorescein diacetate(DCFH-DA)fluorescence probe method was applied to detect intracellular reactive oxygen species(ROS);the levels of superoxide dismutase(SOD)and interleukin-18(IL-18)were detected by enzyme linked immunosorbent assay(ELISA);flow cytometry was applied to detect the apoptosis rate of COV434 cells;Western blot was applied to detect the expression of Keap1,Nrf2.Results OD values of blank group,model group,coumarin group,suppressor group and combination group were 1.53±0.20,0.91±0.10,1.35±0.14,0.56±0.05 and 1.06±0.12;the ROS levels were 1.00±0.00,2.24±0.35,1.18±0.13,3.97±0.58 and 2.09±0.20;the SOD levels were(73.43±9.76),(43.32±5.88),(71.54±8.76),(27.64±3.12)and(52.46±6.45)U·mL-1;the levels of IL-18 were(205.90±20.43),(334.56±35.68),(233.24±24.58),(456.54±47.83)and(301.13±37.64)pg·mL-1;the apoptosis rates were(5.96±0.69)％,(19.62±1.77)％,(8.89±0.97)％,(30.23±3.12)％and(17.65±1.07)％;the Keap1 protein levels were 0.95±0.10,0.66±0.08,0.93±0.09,0.31±0.04 and 0.69±0.07;the Nrf2 protein levels were 1.31±0.12,0.76±0.07,1.25±0.14,0.21±0.02 and 0.90±0.11,respectively.The differences between model group with blank group,between model group with coumarin group,suppressor group,between combination group with coumarin group,were also statistically significant(all P＜0.05).Conclusion Coumarin may improve H2 O2-induced oxidative damage in human ovarian granulosa cells by up-regulating the Keap1/Nrf2/ARE signaling pathway.

Objective Bevacizumab has been clinically used in colorectal cancer,ovarian cancer,cervical cancer,non-small cell lung cancer and other tumor diseases.Common adverse reactions during bevacizumab treatment include albuminuria,thrombosis,bleeding,gastrointestinal perforation and hypertension,among which the incidence of hypertension is as high as 19％-47％.The occurrence of hypertension affects the quality of life of patients,hinds the normal development of tumor treatment,and even induces serious cardiovascular diseases and increases the risk of death,which requires clinical attention.In this paper,the mechanism,influencing factors,prognosis and related treatment of bevacizumab associated hypertension were reviewed,so as to provide reference for clinical rational drug use.

Pathological vascular remodeling is a hallmark of various vascular diseases. Previous research has established the significance of andrographolide in maintaining gastric vascular homeostasis and its pivotal role in modulating endothelial barrier dysfunction, which leads to pathological vascular remodeling. Potassium dehydroandrographolide succinate (PDA), a derivative of andrographolide, has been clinically utilized in the treatment of inflammatory diseases precipitated by viral infections. This study investigates the potential of PDA in regulating pathological vascular remodeling. The effect of PDA on vascular remodeling was assessed through the complete ligation of the carotid artery in C57BL/6 mice. Experimental approaches, including rat aortic primary smooth muscle cell culture, flow cytometry, bromodeoxyuridine (BrdU) incorporation assay, Boyden chamber cell migration assay, spheroid sprouting assay, and Matrigel-based tube formation assay, were employed to evaluate the influence of PDA on the proliferation and motility of smooth muscle cells (SMCs). Molecular docking simulations and co-immunoprecipitation assays were conducted to examine protein interactions. The results revealed that PDA exacerbates vascular injury-induced pathological remodeling, as evidenced by enhanced neointima formation. PDA treatment significantly increased the proliferation and migration of SMCs. Further mechanistic studies disclosed that PDA upregulated myeloid differentiation factor 88 (MyD88) expression in SMCs and interacted with T-cadherin (CDH13). This interaction augmented proliferation, migration, and extracellular matrix deposition, culminating in pathological vascular remodeling. Our findings underscore the critical role of PDA in the regulation of pathological vascular remodeling, mediated through the MyD88/CDH13 signaling pathway.
Mice ; Rats ; Animals ; Myeloid Differentiation Factor 88/metabolism* ; Vascular Remodeling ; Cell Proliferation ; Vascular System Injuries/pathology* ; Carotid Artery Injuries/pathology* ; Molecular Docking Simulation ; Muscle, Smooth, Vascular ; Cell Movement ; Mice, Inbred C57BL ; Signal Transduction ; Succinates/pharmacology* ; Potassium/pharmacology* ; Cells, Cultured ; Diterpenes ; Cadherins

Oral iron is a commonly used preparation for the treatment of iron deficiency and iron-deficiency anemia in children, but its undesirable taste has become a major factor affecting clinical adherence to the medication. No studies have been conducted to evaluate the palatability of oral iron supplements. Thirteen representative oral iron supplements were selected to evaluate the palatability of oral iron supplements from different perspectives of in vivo and ex vivo by combining the electronic tongue (e-tongue) test, FaceReader facial expression analysis technology and taste interviews. E-tongue test results showed that iron dextran granlues were closest to odorless potassium chloride solution, basically free of bitterness and astringency, which was superior to the other products. FaceReader facial expression results showed that 58.7% of the subjects valued iron dextran granlues for their emotional efficacy higher than that of iron proteinsuccinylate oral solution. Among 43 participants aged ≥ 5 years, the taste preference for iron dextran granlues was 83.7%, and 83.7% of participants chose to take iron dextran granlues again. This study found that iron dextran granlues have a better taste and their flavor is more popular among children, which provides a reference for pediatric clinical use of oral iron supplementation preparations and a new idea for the evaluation of palatability of medications for children. This in vivo palatability evaluation is an investigational clinical trial that was approved by the Institutional Review Board of the Beijing Children's Hospital (No. 2021-149-Y).

ObjectiveTo investigate the effects of maltol aluminum exposure on miR-193a-3p, demethylase AlkB homolog 5 (ALKBH5), phosphatase and tensin homolog deleted on chromosome ten (PTEN) and protein kinase B (AKT), and whether miR-193a-3p is involved in aluminum-induced cognitive impairment by regulating ALKBH5/PTEN/AKT signaling pathway. Methods Specific pathogen-free male SD rats were randomly divided into control group and low-, medium- and high- dose groups according to their body weight, with eight rats in each group. Rats in the low-, medium-, and high- dose groups were intraperitoneally injected with maltol aluminum solution at concentrations of 10.00, 20.00, and 40.00 μmol/kg body weight, respectively, while the rats in control group were given an equal volume of 0.9% sodium chloride solution. Rats were injected for five days every week for three months. After injection, the novel object recognized test was used to assess the learning and memory ability of the rats. The relative expression of miR-193a-3p and B-cell lymphocytoma-2 (Bcl-2), Bcl-2 associated X protein (Bax) and cysteine aspartate protease-3 (Caspase-3) mRNA in rat hippocampus was detected using the real-time quantitative polymerase chain reaction. The relative protein expression of ALKBH5, PTEN, and AKT2 in the rat hippocampus was detected using Western blot. Results The discrimination index and the preference index of the new object recognition test of the rats in high-dose group were lower than those in control group and low-dose group (all P<0.05). The relative expression of miR-193a-3p and Bcl-2 mRNA in the hippocampus of the rats in high-dose group was lower than those in control group and low-dose group (all P<0.05). The relative mRNA expression of Bax in the high-dose group was higher than those in the control group and low-dose group (both P<0.05). The relative mRNA expression of Caspase-3 of the rats in the high-dose group was higher than that in the other three groups (both P<0.05). The relative protein expression of ALKBH5 in the hippocampus of the rats in the high-dose group was lower than that in the control group (P<0.05). The relative expression of PTEN protein was higher than those in the control group and low-dose group (both P<0.05). The relative protein expression of AKT2 was lower than those in the control group and low-dose group (both P<0.05). Conclusion Sub-chronic aluminum exposure can inhibit the expression of miR-193a-3p in the hippocampus of rats, which may disrupt the ALKBH5/PTEN/AKT pathway and affect normal neuronal homeostasis and cellular function. This pathway may play an important role in aluminum-induced cognitive impairment.

RNA editing, an essential post-transcriptional reaction occurring in double-stranded RNA (dsRNA), generates informational diversity in the transcriptome and proteome. In mammals, the main type of RNA editing is the conversion of adenosine to inosine (A-to-I), processed by adenosine deaminases acting on the RNAs (ADARs) family, and interpreted as guanosine during nucleotide base-pairing. It has been reported that millions of nucleotide sites in human transcriptome undergo A-to-I editing events, catalyzed by the primarily responsible enzyme, ADAR1. In hematological malignancies including myeloid/lymphocytic leukemia and multiple myeloma, dysregulation of ADAR1 directly impacts the A-to-I editing states occurring in coding regions, non-coding regions, and immature miRNA precursors. Subsequently, aberrant A-to-I editing states result in altered molecular events, such as protein-coding sequence changes, intron retention, alternative splicing, and miRNA biogenesis inhibition. As a vital factor of the generation and stemness maintenance in leukemia stem cells (LSCs), disordered RNA editing drives the chaos of molecular regulatory network and ultimately promotes the cell proliferation, apoptosis inhibition and drug resistance. At present, novel drugs designed to target RNA editing(e.g., rebecsinib) are under development and have achieved outstanding results in animal experiments. Compared with traditional antitumor drugs, epigenetic antitumor drugs are expected to overcome the shackle of drug resistance and recurrence in hematological malignancies, and provide new treatment options for patients. This review summarized the recent advances in the regulation mechanism of ADAR1-mediated RNA editing events in hematologic malignancies, and further discussed the medical potential and clinical application of ADAR1.

Humans ; Transcatheter Aortic Valve Replacement ; Aortic Valve/surgery* ; Heart Valve Prosthesis Implantation ; Renal Dialysis ; Aortic Valve Stenosis/surgery* ; Treatment Outcome ; Heart Valve Prosthesis

Humans ; Transcatheter Aortic Valve Replacement ; Aortic Valve/surgery* ; Heart Valve Prosthesis Implantation ; Renal Dialysis ; Aortic Valve Stenosis/surgery* ; Treatment Outcome ; Heart Valve Prosthesis

Objective:To explore the genetic etiology and clinical phenotype of a child with Triadin knockout syndrome (TKOS), and to review the relevant literature of TKOS patients due to variants of TRDN gene. Methods:A child who was admitted to the Children′s Hospital of Xi′an Jiaotong University on March 19, 2023 due to sudden cardiac arrest 3 days earlier was selected as the study subject. Peripheral blood samples (2 to 3 mL) were collected from the child and her parents for the extraction of genomic DNA and whole exome sequencing (WES). Pathogenic variants were searched from databases such as the Genome Aggregation Database (gnomAD) and Online Mendelian Inheritance in Man (OMIM), and were assessed based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Sanger sequencing was carried out for family validation of the pathogenic variants. Using keywords such as " arrhythmias" " TRDN" and " Triadin" both in Chinese and English, relevant literature on TKOS patients due to variants of the TRDN gene was retrieved from the CNKI, Wanfang Data Knowledge Service Platform, and PubMed databases, and the time of literature retrieval was set from January 1, 2012 to December 1, 2023. This study has been approved by the Ethics Committee of the Affiliated Children′s Hospital of Xi′an Jiaotong University (No. 20230097), and informed consent was obtained from the parents of the child. Results:The child had experienced syncope and cardiac arrest after exercise. Electrocardiographic examination revealed QTc interval prolongation, T-wave inversion in precordial leads V1-V3, polymorphic ventricular premature beat (VPB), and ventricular tachycardia (VT) along with increased heart rate. WES and Sanger sequencing revealed that the child has harbored a homozygous c.463del(p.E155Kfs*20) variant of the TRDN gene, for which both of the parents were heterozygous. Based on the guidelines from the ACMG, the variant was classified as pathogenic (PVS1+ PM2+ PM3). The child was ultimately diagnosed with TKOS. In total 12 publications on TOKS cases caused by TRDN gene variants were retrieved, which involved 30 patients and 28 carriers of single heterozygous variant of the TRDN gene. Among the 30 TKOS patients, 20 had carried homozygous variants of the TRDN gene, and 10 had carried compound heterozygous variants, and all had exhibited significant clinical phenotype of arrhythmia, with most cases had experienced malignant arrhythmia induced by exercise and/or excitement during infancy or early childhood, leading to recurrent syncope and cardiac arrest. Of note, none of the 28 carriers of single heterozygous variant had abnormal clinical phenotype. Conclusion:The homozygous c.463del(p.E155Kfs20) variant of the TRDN gene probably underlay the pathogenesis of cardiac arrest in this child. Above discovery has enriched the mutational spectrum of the TRDN gene.This mutation may represent a genetic cause for cardiac arrest in children with TKOS.