Diabetic cardiomyopathy （DCM） is one of the most common complications of diabetes mellitus and is a major threat to global health. As a key mechanism in the occurrence and progression of DCM， the inflammatory response persists throughout the entire course of the DCM. The Gaozhuo theory suggests that the basic pathogenesis of inflammatory injury in DCM is the Qi deficiency of spleen and kidney and Gaozhuo invasion， and divides the pathological process into three phases： Gaozhuo invasion， turbid heat damage to the channels， and turbid blood stasis and heat junction. Among them， the Qi deficiency of spleen and kidney and the endogenous formation of Gaozhuo represent the process of inflammatory factor formation induced by glucose metabolism disorders. Turbid heat damage to the channels refers to the process of myocardial inflammatory injury mediated by inflammatory factors， and turbid blood stasis and heat junction are the process of myocardial injury developing toward myocardial fibrosis and ventricular remodeling. As the disease continues to progress， it eventually develops into a depletion of the heart Yang， leading to the ultimate regression of heart failure. According to the theory of Gaozhuo， traditional Chinese medicine （TCM） should regulate inflammatory injury in DCM by strengthening the spleen and tonifying the kidney to address the root cause， and resolving dampness and lowering turbidity to treat the symptoms. If the turbidity has been stored for a long time and turns into heat， strengthening the spleen and tonifying the kidney， and clearing heat and resolving turbidity should be the therapy. If the turbidity， stasis， and heat are knotted in the heart and collaterals， strengthening the spleen and tonifying the kidney， and resolving stasis and lowering turbidity should be the therapy. TCM compounds and monomers can regulate the inflammatory response in DCM. TCM compounds can be divided into the categories for benefiting Qi to resolve turbidity， benefiting Qi and clearing heat to resolve turbidity， and benefiting Qi and activating blood to reduce turbidity. The compounds can inhibit upstream signals of inflammation and expression of inflammatory factors， improve the inflammatory damage to myocardium and blood vessels， myocardial fibrosis， and cardiac systole and diastole， and thus slow down the onset and progression of DCM.

Objective: To reveal the molecular biological mechanism of a rare Dc-variant individual using PacBio third-generation sequencing technology. Methods: ABO and Rh blood type identification, DAT, unexpected antibody screening and D antigen enhancement test were conducted by serological testing. The absorption-elution test was used to detect the e antigen. RHCE gene typing was performed by PCR-SSP, and the 1-10 exons of RHCE were sequenced by Sanger sequencing. The full-length sequences of RHCE, RHD and RHAG were detected by PacBio third-generation sequencing technology. Results: Serological findings: Blood type O, Dc-phenotype, DAT negative, unexpected antibody screening negative; enhanced D antigen expression; no detection of e antigen in the absorption-elution test. PCR-SSP genotyping indicated the presence of only the RHCE c allele. Sanger sequencing results: Exons 5-9 of RHCE were deleted, exon 1 had a heterozygous mutation at c. 48G/C, and exon 2 had five heterozygous mutations at c. 150C/T, c. 178C/A, c. 201A/G, c. 203A/G and c. 307C/T. Third-generation sequencing results: RHCE genotype was RHCE 02N. 08/RHCE-D(5-9)-CE; RHD genotype was RHD 01/RHD 01; RHAG genotype was RHAG 01/RHAG 01 (c. 808G>A and c. 861G>A). Conclusion: This Dc-individual carries the allele RHCE 02N. 08 and the novel allele RHCE-D(5-9)-CE. The findings of this study provide data support and a theoretical basis for elucidating the molecular mechanisms underlying RhCE deficiency phenotypes.

BACKGROUND: Epidermal growth factor receptor (EGFR) sensitive mutation is one of the effective targets of targeted therapy for non-small cell lung cancer (NSCLC). However, due to the difficulty of obtaining some primary tissues and the economic factors in some underdeveloped areas, some patients cannot undergo traditional genetic testing. The aim of this study is to establish a machine learning (ML) model using non-invasive peripheral blood markers to explore the biomarkers closely related to EGFR mutation status in NSCLC and evaluate their potential prognostic value. METHODS: 2642 lung cancer patients who visited Jiangsu Cancer Hospital from November 2016 to May 2023 were retrospectively enrolled and finally 175 NSCLC patients with complete follow-up data were included in the study. The ML model was constructed based on peripheral blood indicators and divided into training set and test set according to the ratio of 8:2. Unsupervised learning algorithms were used for clustering blood features and mutual information method for feature selection, and an ensemble learning algorithm based on Shapley value was designed to calculate the contribution of each feature to the model prediction result. The receiver operating characteristic (ROC) curve was used to evaluate the predictive ability of the model. RESULTS: Through the feature extraction and contribution analysis of the predictive results of the interpretable ML model based on the Shapley value, the top ten indicators with the highest contribution were: pathological type, phosphorus, eosinophils, monocyte count, activated partial thromboplastin time, potassium, total bilirubin, sodium, eosinophil percentage, and total cholesterol. The area under the curve (AUC) of the model was 0.80. In addition, patients with hyponatremia and squamous cell carcinoma group had a poor prognosis (P<0.05). CONCLUSIONS The interpretable model constructed in this study provides a new approach for the prediction of EGFR mutation status in NSCLC patients, which provides a scientific basis for the diagnosis and treatment of patients who cannot undergo genetic testing.
Humans ; Carcinoma, Non-Small-Cell Lung/diagnosis* ; Machine Learning ; Lung Neoplasms/diagnosis* ; Male ; Female ; Mutation ; Middle Aged ; ErbB Receptors/genetics* ; Prognosis ; Aged ; Retrospective Studies ; Adult ; Biomarkers, Tumor/genetics*

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

Sepsis is a life-threatening organ dysfunction syndrome caused by a dysregulated host response to infection. Septic acute kidney injury (SAKI) is one of the most common complications of sepsis, and the occurrence of acute kidney injury (AKI) indicates that the patient's condition is critical with a poor prognosis. The traditional view holds that the main mechanism of SAKI is the reduction of renal blood flow, inadequate renal perfusion, inflammatory response, and microcirculatory dysfunction caused by sepsis, which subsequently leads to ischemia and necrosis of renal tubular cells. Recent research findings indicate that processes such as autophagy and other forms of programmed cell death play an increasingly important role. Autophagy is a programmed intracellular degradation process and is a form of programmed cell death. Cells degrade their cytoplasmic components via lysosomes, breaking down and recycling intracellular constituents to meet their metabolic needs, maintain intracellular homeostasis, and renew organelles. During SAKI, autophagy plays a crucial protective role through various mechanisms, including regulating inflammation and immune responses, clearing damaged organelles, and maintaining stability in the intracellular environment. In recent years, the role of autophagy in the pathogenesis and treatment of SAKI has received widespread attention. Research has confirmed that various intracellular signaling pathways and signaling molecules targeting autophagy [such as mammalian target of rapamycin (mTOR) signaling pathway, AMP-activated protein kinase (AMPK) signaling pathway, nuclear factor-κB (NF-κB) signaling pathway, and Sirtuins (SIRT), autophagy associated factor Beclin-1, and Toll-like receptor (TLR)] are involved in the development of SAKI. Due to the complex pathogenesis of SAKI, current treatment strategies include fluid management, infection control, maintenance of internal environment balance, and renal replacement therapy; however, the mortality remains high. In recent years, it has been found that autophagy plays a critical protective role in sepsis-mediated AKI. As a result, an increasing number of drugs are being developed to alleviate SAKI by regulating autophagy. This article reviews the latest advances in the role of autophagy in the pathogenesis and treatment of SAKI, with the aim of providing insights for the development of new drugs for SAKI patients.
Humans ; Acute Kidney Injury/etiology* ; Autophagy ; Sepsis/complications* ; Signal Transduction

Objective To compare the efficacy and tolerability of the novel bowel-cleansing agent TCIC-001 and the traditional polyethylene glycol (PEG) regimen for bowel preparation prior to colonoscopy. Methods Prospective inclusion of 62 patients who were scheduled to undergo colonoscopy at Zhongshan Hospital, Fudan University from July 2021 to July 2022. They were randomly divided into TCIC-001 group (n=31) and PEG group (n=31) using a random number table method. The TCIC-001 group took TCIC-001 orally, drinking water in stages, with a total liquid intake of 1 500 mL; the PEG group took PEG orally, taking it in 4 doses, with a total liquid intake of 3 000 mL. The primary endpoint indicator is the quality of intestinal hygiene evaluated by the Boston Bowel Preparation Scale (BBPS), the secondary endpoint indicators were medication adherence, medication duration, frequency of bowel movements, duration of bowel movements, and incidence of adverse events between two groups. Results No significant differences were observed in sex, age, or defecation frequency between the two groups. For efficacy, both groups achieved equivalent bowel cleanliness, with a “good preparation” rate of 93.55% and comparable BBPS score of each intestinal segment and total scores. For tolerability, the TCIC-001 group had a shorter medication duration compared to the PEG group ([48.8±25.9] min vs [82.8±28.4] min, P<0.001), a longer defecation duration ([288.6±74.0] min vs [236.5±74.3] min, P<0.001), and a lower incidence of first defecation before medication completion (9.68% vs 41.94%, P=0.004). Regarding safety, no significant differences were observed between the TCIC-001 group and the PEG group in incidences of chloride disturbances (0% vs 9.68%) and calcium disturbances (3.23% vs 6.45%), and no other adverse events. Conclusions TCIC-001 demonstrated comparable bowel-cleansing efficacy to PEG while significantly improving tolerability (reduced medication time and lower risk of premature defecation) and maintaining favorable safety.

Preeclampsia(PE)is a severe pregnancy complication that poses significant risks to maternal and fetal health,and its pathogenesis remains unclear.Recent studies have shown that lactate dehydrogenase(LDH),a key enzyme in glycolysis,plays a piv-otal role in the development and progression of PE.This article reviews the abnormal changes in the levels of LDH and its isozymes in serum and placental tissue and their impact on the pathogenesis of PE and analyzes the molecular mechanisms by which LDH subunits contribute to placental dysfunction through multiple pathways including hypoxia,inflammation,autophagy dysregulation,and cellular damage.In addition,this article discusses the role of lactate,a metabolic product of LDH activity,in the pathogenesis of PE.LDH can be used as a potential biomarker for PE,and the regulation of non-metabolic functions and metabolic reprogramming mediated by LDH provide new targets for the prevention and treatment of PE.

Objective To investigate the effect and mechanisms of celecoxib on right heart function in mice with acute high-altitude hypoxia exposure.Methods Male C57BL/6J mice(7 weeks old)were housed in a hypobaric chamber simulating an altitude of 5 800 m for 2 d to establish an animal model of acute hypobaric hypoxia.①Eighteen mice were randomly assigned to plain+saline(P+S),high-altitude hypoxia exposure+saline(H+S),and high-altitude hypoxia exposure+celecoxib(H+Cel).Body weight and routine blood indicators were measured,and cardiac ultrasound examination were performed for heart rate(HR),pulmonary artery acceleration time to ejection time ratio(AT/ET),tricuspid annular plane systolic excursion(TAPSE),tricuspid annular systolic velocity(S'),and left ventricular ejection fraction(LVEF)and fractional shortening(FS).Targeted metabolomic profiling was applied to detect the cardiac arachidonic acid(AA)metabolite levels.The contents of 12,13-dihydroxy-9Z-octadecenoic acid(12,13-diHOME)in the heart,liver,brown adipose tissue,and plasma were quantified by ELISA.② Eighteen mice were randomly assigned into plain+saline(P+S),high-altitude hypoxia exposure+saline(H+S)and high-altitude hypoxia exposure+12,13-diHOME(H+di)groups.Body weight,routine blood tests,and echocardiography were performed as above.③ Thirty-two mice were randomly divided into high-altitude hypoxia exposure+saline(H+S),high-altitude hypoxia exposure+celecoxib(H+Cel),high-altitude hypoxia exposure+soluble epoxide hydrolase inhibitor(sEHI)(H+sEHI),and high-altitude hypoxia exposure+sEHI+celecoxib(H+sEHI+Cel)groups.Body weight,routine blood tests,and echocardiography were performed as above.Cardiac and plasma contents of 12,13-diHOME and epoxyeicosatrienoic acids(EETs)were measured by ELISA.Results ① Compared to the P+S group,the H+S group exhibited significantly reduction of cardiac 12,13-diHOME level(P<0.001),increased counts of white blood cells(WBC)and neutrophils(P<0.01)and decreased TAPSE,S'and AT/ET both at resting state and under stress(P<0.01,P<0.001).Compared to the H+S group,the H+Cel group exhibited significantly increase of cardiac 12,13-diHOME level(P<0.05),reduced WBC and lymphocyte counts(P<0.01,P<0.05)and improved TAPSE and S'levels at resting state and under stress(P<0.01,P<0.001).② Compared to the H+S group,the H+di group demonstrated significantly improvement of TAPSE at basal and under stress(P<0.001)and a trend towards improved TAPSE at resting state(P=0.0532),but no obvious differences was observed in WBC and neutrophil counts between the H+di group and the H+S group.③ Compared to the H+Cel group,both the H+sEHI and H+sEHI+Cel groups exhibited significantly reduction of cardiac 12,13-diHOME level(P<0.01,P<0.05)though no statistical changes in cardiac function indicators.Compared to the H+S group,WBC counts and lymphocyte were decreased,and serum EETs level was incrased in the H+Cel group,H+sEHI group and H+sEHI+Cel group(P<0.01,P<0.001).Conclusion Celecoxib can elevate cardiac level of 12,13-diHOME and improves right heart function in mice after acute high-altitude hypoxia exposure through the CYP450-sEH metabolic pathway.

Objective To explore the diagnostic value of brain cord blood flow ultrasound combined with glucose metabolism indexes in the patients with preeclampsia(PE)complicated with fetal growth restriction(FGR).Methods This study was a prospective cohort case-control study.A total of 198 PE patients admitted to the hospital from January 2017 to January 2022 were collected and divided into group A(PE patients com-plicated with FGR,101 cases)and group B(PE patients without FGR,97 cases)according to whether they were complicated with FGR.45 pregnant women with healthy prenatal examination in the hospital were se-lected as group C,and the differences of brain cord blood flow ultrasound indexes and glucose metabolism inde-xes among the three groups and the efficiency for diagnosing PE complicated with FGR were analyzed.Results Fast-ing blood glucose and fasting insulin levels in group A,group B and group C were gradually decreased(P＜0.05).The peak systolic flow velocity/peak diastolic flow velocity(S/D),resistance index(RI)and pulsatility index(PI)of middle cerebral artery(MCA)of fetus in group A,group B and group C increased gradually(P＜0.05).The levels of umbilical artery(UA)of fetus in group A,group B and group C decreased gradually(P＜0.05).The area under the curve of fasting insulin,fasting blood glucose,S/D,RI and PI of MCA,S/D,RI,PI of UA and the combined detection were 0.782,0.748,0.765,0.836,0.805,0.758,0.811,0.795 and 0.895,respectively.The diagnostic efficiency of combined detection was higher than that of single diagnosis(Z=4.327,4.862,4.551,3.400,3.946,4.679,3.742,4.102,P＜0.05).Conclusion The combined detection of glucose metabolism indexes and brain cord blood flow ultrasound indexes is of great value in the differential diagnosis of patients with PE complicated with FGR,and has good clinical application value.

[Abstract] [Objective] To evaluate the immunogenicity of red blood cell blood group antigens in the population of Xi'an. [Methods] Data on blood group antigens of voluntary blood donors from the Shaanxi Province Blood Center and unexpected antibody detection results from clinically submitted cases between January 2019 and May 2024 were analyzed. The Giblett blood group antigen immunogenicity calculation formula was used to calculate the immunogenicity of blood group antigens based on the frequency of unexpected antibodies and the probability of antigen-negative patients receiving antigen-positive red blood cells. The relative immunogenicity of each blood group antigen was obtained by multiplying the immunogenicity of the K antigen (0.095). [Results] A total of 30 921 individuals were included for red blood cell blood group antigen analysis, with 511 cases of unexpected antibody identification. The ranking of red blood cell blood group antigen immunogenicity for the overall population was: Wr^a>E>Di^b>Fy^a>K>C>e>c>Di^a>Jk^a>M>Le^a>Jk^b>Le^b>Fy^b>S, while for males, it was: Di^b>Wr^a>E>K>Fy^a>C>e>c>M>Di^a>Jk^a>Fy^b>Le^a>Le^b>Jk^b>S. [Conclusion] Based on the immunogenicity ranking from strong to weak of red blood cell antigens in the population of Xi'an, this study provides theoretical support for the expansion and matching of antigens, and technical support for achieving precise red blood cell transfusions to improve transfusion efficacy and safety.