Loss-of-function variants in CSDE1 have been strongly linked to neuropsychiatric disorders, yet the precise role of CSDE1 in neurogenesis remains elusive. In this study, we demonstrate that knockout of Csde1 during cortical development in mice results in impaired neural progenitor proliferation, leading to abnormal cortical lamination and embryonic lethality. Transcriptomic analysis revealed that Csde1 upregulates the transcription of genes involved in the cell cycle network. Applying a dual thymidine-labelling approach, we further revealed prolonged cell cycle durations of neuronal progenitors in Csde1-knockout mice, with a notable extension of the G1 phase. Intersection with CLIP-seq data demonstrated that Csde1 binds to the 3' untranslated region (UTR) of mRNA transcripts encoding cell cycle genes. Particularly, we uncovered that Csde1 directly binds to the 3' UTR of mRNA transcripts encoding Cdk6, a pivotal gene in regulating the transition from the G1 to S phases of the cell cycle, thereby maintaining its stability. Collectively, this study elucidates Csde1 as a novel regulator of Cdk6, sheds new light on its critical roles in orchestrating brain development, and underscores how mutations in Csde1 may contribute to the pathogenesis of neuropsychiatric disorders.
Animals ; Neurogenesis/genetics* ; Cell Cycle/genetics* ; Mice, Knockout ; Mice ; Neural Stem Cells/metabolism* ; DNA-Binding Proteins/metabolism* ; Cyclin-Dependent Kinase 6/genetics* ; Cell Proliferation ; 3' Untranslated Regions ; Cerebral Cortex/embryology* ; RNA-Binding Proteins ; Mice, Inbred C57BL

Radiation-induced thrombocytopenia (RIT) faces a perplexing challenge in the clinical treatment of cancer patients, and current therapeutic approaches are inadequate in the clinical settings. In this research, oxymatrine, a new molecule capable of healing RIT was screened out, and the underlying regulatory mechanism associated with magakaryocyte (MK) differentiation and thrombopoiesis was demonstrated. The capacity of oxymatrine to induce MK differentiation was verified in K-562 and Meg-01 cells in vitro. The ability to induce thrombopoiesis was subsequently demonstrated in Tg (cd41:enhanced green fluorescent protein (eGFP)) zebrafish and RIT model mice. In addition, we carried out network pharmacological prediction, drug affinity responsive target stability assay (DARTS) and cellular thermal shift assay (CETSA) analyses to explore the potential targets of oxymatrine. Moreover, the pathway underlying the effects of oxymatrine was determined by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, Western blot (WB), and immunofluorescence. Oxymatrine markedly promoted MK differentiation and maturation in vitro. Moreover, oxymatrine induced thrombopoiesis in Tg (cd41:eGFP) zebrafish and accelerated thrombopoiesis and platelet function recovery in RIT model mice. Mechanistically, oxymatrine directly binds to toll-like receptor 2 (TLR2) and further regulates the downstream pathway stimulator of interferon genes (STING)/nuclear factor-kappaB (NF-κB), which can be blocked by C29 and C-176, which are specific inhibitors of TLR2 and STING, respectively. Taken together, we demonstrated that oxymatrine, a novel TLR2 agonist, plays a critical role in accelerating MK differentiation and thrombopoiesis via the STING/NF-κB axis, suggesting that oxymatrine is a promising candidate for RIT therapy.

Tricuspid regurgitation(TR)is a common heart valve disease.According to the pathogenesis,TR can be divided into primary(organic)and secondary(functional)regurgitation,of which functional TR accounts for more than 90%.Patients with severe TR have poor prognosis and poor drug treatment,and surgery(valvuloplasty)is the main treatment.At present,transcatheter edge-to-edge tricuspid valve repair(T-TEER)has become an essential program of transcatheter treatment for TR,providing minimally invasive treatment for TR patients who cannot undergo surgery or are at high risk of surgery.T-TEER reduces the degree of regurgitation by clamping leaflets,and is currently in the early stage of research and development exploration and clinical validation,mainly for functional TR.T-TEER devices have also made significant progress(TriClip,PASCAL),and Chinese-made novel-designed T-TEER devices are also undergoing clinical trials(DragonFly-TTM,SQ-Kyrin-TTM,NeoBlazarTM).This paper reviews the current applications and research progress of T-TEER.

In accordance with the theory of'treating the skin diseases with the skin',skin-related Chinese medicinals are usually used for the treatment of skin diseases,which reflects the thinking mode of holistic syndrome differentiation and classification according to the manifestations in traditional Chinese medicine.With ying-yang theory as the principle of differentiation and treatment of diseases and based on the core pathogenesis of'yin-yang imbalance causing the manifestations of the skin'for the skin diseases,Chinese medical master XU AN Guo-Wei has used skin-related Chinese medicinals in the treatment of skin diseases and has given full play to their unique advantage by following the theory of'treating the skin diseases with the skin'and'balanced regulation of yin and yang'.In the clinical practice,allergic skin diseases were usually treated with Cicadae Periostracum plus Dictamni Cortex for dispelling wind and relieving itching,hypopigmentation related skin diseases were usually treated with Sojae Semen Nigrum skin plus Dictamni Cortex for dispelling wind and tonifying kidney,autoimmune skin diseases were usually treated with Moutan Cortex plus Lycii Cortex for nourishing yin,clearing heat and activating blood,and skin diseases associated with abnormal sebum secretion were usually treated with Mori Cortex plus Lycii Cortex for purging lung and nourishing kidney.Skin-related Chinese medicinals have the actions of expelling wind and promoting eruption of papules,tonifying kidney and nourishing yin.The medication method of'treating the skin diseases with the skin'will provide reference for the treatment of skin diseases.

Objective To explore the feasibility of octreotide injection for"oral administration"in children.Methods The acid resistance stability experiment was divided into experimental group(dissolve octreotide in hydrochloric acid at pH 4.0-4.5)and control group(dissolve octreotide in 0.9％NaCl at pH 7.0-7.5).BN juvenile rats were randomly assigned to the subcutaneous injection group of octreotide(12 μg·kg-1·d-1,subcutaneous injection),the oral administration group of octreotide(12 μg·kg-1·d1-1,oral administration),and the control group(0.9％NaCl)based on gender and body mass grading,with 10 rats in each group.Collect blood samples from 2 children with refractory diarrhea after subcutaneous injection and oral administration of octreotide for 1 hour,and monitor the plasma concentration.Compare the differences in plasma and gastrointestinal concentrations in rats,as well as the differences in plasma concentration in two pediatric patients.Measure the plasma concentration of octreotide using radioimmunoassay.Detection of octreotide concentration in rat intestine by immunohistochemical method.Results The concentrations of octreotide in the experimental group and control group were(810.71±1.91)and(816.55±5.60)ng·mL-1,respectively,without statistically significant difference(P＞0.05).The integrated optical density(IOD)values of octreotide in the subcutaneous injection group and oral administration group were 6.84±0.88 and 9.82±1.07;the concentrations of octreotide in peripheral blood were(26.07±12.19)and(3.53±0.76)ng·mL-1,with statistical significance(all P＜0.001).The plasma concentration of octreotide administered orally and subcutaneously in two pediatric patients were 2.52-3.30 and 22.36-31.68 ng·mL-1.Conclusion"Oral administration"of octreotide exhibits a distribution of"high gastrointestinal concentration/low plasma concentration".High gastrointestinal concentration can treat local gastrointestinal diseases in children and avoid injection pain.Oral administration of low plasma concentration is beneficial for reducing systemic adverse drug reactions in children with growth inhibition.

Objective:To explore the effect of shikonin on autophagy and apoptosis of human promyelocytic leukemia cells and its possible mechanism.Methods:Human promyelocytic leukemia cells NB4 in the logarithmic growth phase were divided into control group(untreated NB4 cells),shikonin group(0.3 μmol/L shikonin treatment),740Y-P group(15 μmol/L PI3K/Akt/mTOR pathway activator 740Y-P treatment),shikonin+740Y-P group(0.3 μmol/L shikonin and 15 μmol/L 740Y-P co-treatment),after 24 hours of treatment,the cells were used for subsequent experiments.CCK-8 method was used to detect cell viability,monodansylcadaverine(MDC)staining to detect the aggregation of autophagic vesicles,flow cytometry to detect cell apoptosis,and Western blot to detect the expression of Beclinl,LC3,p62,Bax,cleaved caspase-3,Bcl-2 and PI3K/Akt/mTOR pathway related proteins.Results:Compared with the control group,the purple punctate fluorescence intensity,apoptosis rate,Beclinl,LC3-Ⅱ/LC3-Ⅰ,cleaved caspase-3,and Bax protein expression in NB4 cells were increased in the shikonin group,while OD450 value(24,48 h)and the expressions of Bcl-2 and p62 proteins were decreased(all P＜0.05).Compared with the control group,the purple punctate fluorescence intensity,apoptosis rate,Beclin1,LC3-Ⅱ/LC3-1,cleaved caspase-3,and Bax protein expression in NB4 cells were decreased,while OD450 value(24,48 h)and the expressions of Bcl-2 and p62 proteins were increased in the 740Y-P group(all P＜0.05).Compared with the shikonin group,the purple punctate fluorescence intensity,apoptosis rate,Beclinl,LC3-Ⅱ/LC3-1,cleaved caspase-3,and Bax protein expression in NB4 cells were decreased,while OD450 value(24,48 h)and the expressions of Bcl-2 and p62 proteins were increased in the shikonin+740Y-P group(all P＜0.05).Compared with the control group,the expression of PI3K/Akt/mTOR pathway related proteins p-PI3K,p-Akt,and p-mTOR in NB4 cells were significantly decreased in the shikonin group,while those in the 740Y-P group were increased(all P＜0.05).Compared with the shikonin group,the expressions of p-PI3K,p-Akt,and p-mTOR proteins in NB4 cells were significantly increased in the shikonin+740Y-P group(all P＜0.05).Conclusion:Shikonin may promote autophagy and apoptosis of NB4 cells by inhibiting PI3K/Akt/mTOR pathway.

Objective To investigate the incidence rate,clinical characteristics,and prognosis of neonatal stroke in Shenzhen,China.Methods Led by Shenzhen Children's Hospital,the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022.The incidence,clinical characteristics,treatment,and prognosis of neonatal stroke in Shenzhen were analyzed.Results The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137,1/6 060,and 1/7 704,respectively.Ischemic stroke accounted for 75％(27/36);boys accounted for 64％(23/36).Among the 36 neonates,31(86％)had disease onset within 3 days after birth,and 19(53％)had convulsion as the initial presentation.Cerebral MRI showed that 22 neonates(61％)had left cerebral infarction and 13(36％)had basal ganglia infarction.Magnetic resonance angiography was performed for 12 neonates,among whom 9(75％)had involvement of the middle cerebral artery.Electroencephalography was performed for 29 neonates,with sharp waves in 21 neonates(72％)and seizures in 10 neonates(34％).Symptomatic/supportive treatment varied across different hospitals.Neonatal Behavioral Neurological Assessment was performed for 12 neonates(33％,12/36),with a mean score of(32±4)points.The prognosis of 27 neonates was followed up to around 12 months of age,with 44％(12/27)of the neonates having a good prognosis.Conclusions Ischemic stroke is the main type of neonatal stroke,often with convulsions as the initial presentation,involvement of the middle cerebral artery,sharp waves on electroencephalography,and a relatively low neurodevelopment score.Symptomatic/supportive treatment is the main treatment method,and some neonates tend to have a poor prognosis.

Objective:To explore the levels of regulatory T cells(Tregs)and cytokines IL-35,TGF-β and IL-10 in peripheral blood of hemophilia A(HA)patients with F Ⅷ inhibitor and their clinical significance.Methods:43 HA patients admitted to the Hematology Department of the Affiliated Hospital of North China University of Science and Technology from October 2019 to December 2020 were selected,including 6 cases with F Ⅷ inhibitor and 37 cases without FⅧ inhibitor.In addition,20 healthy males who underwent physical examinations were selected as healthy controls.Flow cytometry was used to detect the levels of CD4+CD25+CD127-Tregs in peripheral blood of the HA patients and healthy controls,and ELISA assay was used to detect the expression levels of IL-35,TGF-β and IL-10 in serum,and their differences between different groups were compared.Results:Compared with the healthy control group,the level of Tregs in HA patients was decreased,and the level of Tregs in the FⅧ inhibitor positive group was the lowest,the difference was statistically significant(P＜0.05).There was no significant difference in the expression level of Tregs in HA patients of different severity levels.The serum IL-35,TGF-β,and IL-10 levels in both FⅧ inhibitor negative and positive groups were significantly lower than those in healthy control group,and those in FⅧ inhibitor positive group were significantly lower than those in FⅧ inhibitor negative group(all P＜0.05).Conclusion:The decrease of Tregs,IL-35,TGF-β,and IL-10 levels in HA patients may be related to the formation of FⅧ inhibitors.

Objective: To evaluate and compare the short-term efficacy of domestic mechanical-locked (Clip2Edge) and elastic self-locked (ValveClip) transcranial mitral valve edge-to-edge interventional repair (TEER) devices in the treatment of functional mitral regurgitant valves. Methods: In this retrospective non-randomized comparative study, patients underwent TEER procedure in Fuwai Yunnan Cardiovascular Disease Hospital from May 2022 to April 2023 for heart failure combined with moderate to severe or severe functional mitral valve were divided into Clip2Edge and ValveClip groups based on the TEER system used. Baseline, perioperative, and postoperative 30 d follow-up data were collected and compared between the two groups. The primary outcome was the success rate on the 30 d post operation, while secondary outcomes included immediate postoperative technical success rate and the incidence of all-cause mortality on the 30 d post operation, readmission rate of acute heart failure, cerebral infarction, severe bleeding, and other serious adverse events rates. Results: A total of 60 patients were enrolled, 34 patients were in the Clip2Edge group and 26 in the ValveClip group, mean age was (63.8±9.3) years, and 24 patients (40%) were female. There were no significant differences in baseline data of age, cardiac function, comorbidities, mitral regurgitation 4+(19(73%) vs. 29(85%)), the end-diastolic volume of left ventricle ((220.8±91.2) ml vs. (210.8±71.7) ml) between the two groups (all P>0.05). The technical success rate immediately after the procedure was 100%. There were no readmission of acute heart failure, death, cerebral infarction, severe bleeding, and other serious adverse events up to the 30 d follow-up. Device success rate was similar between the ValveClip group (24 cases (100%)) and the Clip2Edge group (27 cases (96%)) (P>0.05). Conclusion: Both types of novel domestic TEER devices are safe and feasible in treating patients with functional mitral regurgitation.
Humans ; Female ; Middle Aged ; Aged ; Male ; Mitral Valve Insufficiency/etiology* ; Retrospective Studies ; East Asian People ; Heart Valve Prosthesis Implantation ; Treatment Outcome ; China ; Heart Failure/etiology* ; Cardiac Catheterization

Humans ; Mitral Valve/surgery* ; Cardiac Surgical Procedures ; Mitral Valve Insufficiency/surgery* ; Heart Valve Prosthesis Implantation ; Cardiac Catheterization ; Treatment Outcome