ObjectiveTo investigate the mechanism by which Feixin decoction treats hypoxic pulmonary hypertension （HPH） by regulating the peroxisome proliferator-activated receptor gamma （PPARγ）/nuclear factor-kappa B （NF-κB）/NOD-like receptor pyrin domain containing 3 （NLRP3） signaling pathway. MethodsForty-eight male SD rats were randomly allocated into normal， hypoxia， and low-， medium- and high-dose （5.85， 11.7， 23.4 g·kg^-1， respectively） Feixin decoction groups， with 8 rats in each group. Except the normal group， the remaining five groups were placed in a hypoxia chamber with an oxygen concentration of （10.0±0.5）% for 8 h per day， 28 days， and administrated with corresponding drugs during the modeling process. After 4 weeks of treatment， echocardiographic parameters ［pulmonary artery acceleration time （PAT）， pulmonary artery ejection time （PET）， right ventricular anterior wall thickness （RVAWd）， and tricuspid annular plane systolic excursion （TAPSE）］ were measured for each group. The right ventricular systolic pressure （RVSP） was measured by the right heart catheterization method， and the right ventricular hypertrophy index （RVHI） was calculated by weighing the heart. The pathological changes in pulmonary arterioles were observed by hematoxylin-eosin staining. The co-localization of α-smooth muscle actin （α-SMA） with NLRP3， N-terminal gasdermin D （N-GSDMD）， and cysteinyl aspartate-specific proteinase-1 （Caspase-1） in pulmonary arteries was detected by immunofluorescence. The protein levels of PPARγ， NF-κB， NLRP3， apoptosis-associated speck-like protein containing a CARD （ASC）， N-GSDMD， interleukin-1β （IL-1β）， interleukin-18（IL-18）， and cleaved Caspase-1 in the lung tissue was determined by Western blot. The ultrastructural changes in pulmonary artery smooth muscle cells （PASMCs） were observed by transmission electron microscopy. ResultsCompared with the normal group， the hypoxia group showed increased RVSP and RVHI （P<0.01）， decreased right heart function （P<0.01）， increased pulmonary vascular remodeling （P<0.01）， increased co-localization of α-SMA with NLRP3， N-GSDMD， and Caspase-1 in pulmonary arterioles （P<0.01）， up-regulated protein levels of NF-κB， NLRP3， ASC， N-GSDMD， IL-1β， IL-18， and cleaved Caspase-1 in the lung tissue （P<0.05， P<0.01）， a down-regulated protein level of PPARγ （P<0.05， P<0.01）， and pyroptosis in PASMCs. Compared with the hypoxia group， Feixin decoction reduced RVSP and RVHI， improved the right heart function and ameliorated pulmonary vascular remodeling （P<0.05， P<0.01）， decreased the co-localization of α-SMA with NLRP3， N-GSDMD， and Caspase-1 （P<0.05， P<0.01）， down-regulated the protein levels of NF-κB， NLRP3， ASC， N-GSDMD， IL-1β， IL-18， and cleaved Caspase-1 in the lung tissue （P<0.05， P<0.01）， up-regulated the protein level of PPARγ （P<0.05， P<0.01）， and alleviated pyroptosis in PASMCs. ConclusionFeixin decoction can ameliorate pulmonary vascular remodeling and right heart dysfunction in chronically induced HPH rats by regulating pyroptosis in PASMCs through the PPARγ/NF-κB/NLRP3 pathway.

BACKGROUND: Treatment with chimeric antigen receptor-T (CAR-T) cells has shown promising effectiveness in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), although the process of preparing for this therapy usually takes a long time. We have recently created CD19 Fast-CAR-T (F-CAR-T) cells, which can be produced within a single day. The objective of this study was to evaluate and contrast the effectiveness and safety of CD19 F-CAR-T cells with those of CD19 conventional CAR-T cells in the management of R/R B-ALL. METHODS: A multicenter, retrospective analysis of the clinical data of 44 patients with R/R B-ALL was conducted. Overall, 23 patients were administered with innovative CD19 F-CAR-T cells (F-CAR-T group), whereas 21 patients were given CD19 conventional CAR-T cells (C-CAR-T group). We compared the rates of complete remission (CR), minimal residual disease (MRD)-negative CR, leukemia-free survival (LFS), overall survival (OS), and the incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) between the two groups. RESULTS: Compared with the C-CAR-T group, the F-CAR-T group had significantly higher CR and MRD-negative rates (95.7% and 91.3%, respectively; 71.4% and 66.7%, respectively; P = 0.036 and P = 0.044). No significant differences were observed in the 1-year or 2-year LFS or OS rates between the two groups: the 1-year and 2-year LFS for the F-CAR-T group vs.C-CAR-T group were 47.8% and 43.5% vs. 38.1% and 23.8% (P = 0.384 and P = 0.216), while the 1-year and 2-year OS rates were 65.2% and 56.5% vs. 52.4% and 47.6% (P = 0.395 and P = 0.540). Additionally, among CR patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) following CAR-T-cell therapy, there were no significant differences in the 1-year or 2-year LFS or OS rates: 57.1% and 50.0% vs. 47.8% and 34.8% (P = 0.506 and P = 0.356), 64.3% and 57.1% vs. 65.2% and 56.5% (P = 0.985 and P = 0.883), respectively. The incidence of CRS was greater in the F-CAR-T group (91.3%) than in the C-CAR-T group (66.7%) (P = 0.044). The incidence of ICANS was also greater in the F-CAR-T group (30.4%) than in the C-CAR-T group (9.5%) (P = 0.085), but no treatment-related deaths occurred in the two groups. CONCLUSION Compared with C-CAR-T-cell therapy, F-CAR-T-cell therapy has a superior remission rate but also leads to a tolerably increased incidence of CRS/ICANS. Further research is needed to explore the function of allo-HSCT as an intermediary therapy after CAR-T-cell therapy.

OBJECTIVE: To assess the efficacy of Qingda Granule (QDG) in ameliorating hypertension-induced cardiac damage and investigate the underlying mechanisms involved. METHODS: Twenty spontaneously hypertensive rats (SHRs) were used to develope a hypertension-induced cardiac damage model. Another 10 Wistar Kyoto (WKY) rats were used as normotension group. Rats were administrated intragastrically QDG [0.9 g/(kg•d)] or an equivalent volume of pure water for 8 weeks. Blood pressure, histopathological changes, cardiac function, levels of oxidative stress and inflammatory response markers were measured. Furthermore, to gain insights into the potential mechanisms underlying the protective effects of QDG against hypertension-induced cardiac injury, a network pharmacology study was conducted. Predicted results were validated by Western blot, radioimmunoassay immunohistochemistry and quantitative polymerase chain reaction, respectively. RESULTS: The administration of QDG resulted in a significant decrease in blood pressure levels in SHRs (P<0.01). Histological examinations, including hematoxylin-eosin staining and Masson trichrome staining revealed that QDG effectively attenuated hypertension-induced cardiac damage. Furthermore, echocardiography demonstrated that QDG improved hypertension-associated cardiac dysfunction. Enzyme-linked immunosorbent assay and colorimetric method indicated that QDG significantly reduced oxidative stress and inflammatory response levels in both myocardial tissue and serum (P<0.01). CONCLUSIONS Both network pharmacology and experimental investigations confirmed that QDG exerted its beneficial effects in decreasing hypertension-induced cardiac damage by regulating the angiotensin converting enzyme (ACE)/angiotensin II (Ang II)/Ang II receptor type 1 axis and ACE/Ang II/Ang II receptor type 2 axis.
Animals ; Drugs, Chinese Herbal/therapeutic use* ; Hypertension/pathology* ; Renin-Angiotensin System/drug effects* ; Rats, Inbred SHR ; Oxidative Stress/drug effects* ; Male ; Rats, Inbred WKY ; Blood Pressure/drug effects* ; Myocardium/pathology* ; Rats ; Inflammation/pathology*

The biological clock(also known as the circadian rhythm)is the fundamental reliance for all organisms on Earth to adapt and survive in the Earth's rotation environment.Circadian rhythm is the most basic regulatory mechanism of life activities,and plays a key role in maintaining normal physiological and biochemical homeostasis,disease occurrence and treatment.Recent studies have shown that the biologi-cal clock plays an important role in the development of oral tissues and in the occurrence and treatment of oral diseases.Since there is cur-rently no guiding literature on the research methods of biological clock in stomatology,researchers mainly conduct research based on pub-lished references,which has led to controversy about the research methods of biological clock in stomatology,and there are many confusions about how to rationally apply the research methods of circadia rhythms.In view of this,this expert consensus summarizes the characteristics of the biological clock and analyzes the shortcomings of the current biological clock research in stomatology,and organizes relevant experts to summarize and recommend 10 principles as a reference for the rational implementation of the biological clock in stomatology research.

Objective To investigate the effect and mechanism of Feixin Decoction(Astragali Radix,Pericae Semen,Carthami Flos,Descurainiae Semen Lepidii Semen,Paeoniae Radix Rubra,etc.)on monocrotaline-induced pulmonary arterial hypertension(PAH)rats based on peroxisome proliferator-activated receptor-γ/nuclear factor-κB(PPAR-γ/NF-κB)signaling pathway.Methods Forty-eight male SD rats were randomly divided into normal group,model group,Sildenafil group(0.025 g·kg-1)and low-,medium-and high-dose of Feixin Decoction groups(11.7,23.4,46.8 g·kg-1).PAH rat model was established by single intraperitoneal injection of monocrotaline solution(60 mg·kg-1).After 1 hour of modeling,the rats were given intragastric administration once a day for 28 days.Hemodynamic and echocardiographic parameters including right ventricular systolic pressure(RVSP),mean pulmonary artery pressure(mPAP),right ventricular hypertrophy index(RVHI),pulmonary artery acceleration time(PAAT),pulmonary artery ejection time(PET),tricuspid annular plane systolic excursion(TAPSE),right ventricular internal diameter(RVIDd)and right ventricular anterior wall thickness(RVAWT)were measured in each group.The pathological changes of pulmonary arterioles were observed by HE staining.The expression level of α-smooth muscle actin(α-SMA)in rat pulmonary artery was detected by immunofluorescence.The levels of plasma interleukin-1β(IL-1β),IL-6 and tumor necrosis factor-α(TNF-α)were detected by ELISA.The expression levels of PPAR-γ/NF-κB signaling pathway-related proteins were detected by immunohistochemistry and Western Blot.Results Compared with the normal group,the RVSP,mPAP,RVHI,RVIDd and RVAWT of the model group were significantly increased(P＜0.01).PAAT,PAAT/PET and TAPSE were significantly decreased(P＜0.01).The wall of pulmonary arterioles was significantly thickened,and the percentage of wall thickness of pulmonary arterioles to vascular diameter and the percentage of vascular wall area to total cross-sectional area of pulmonary arterioles were significantly increased(P＜0.01).The positive expression rate of α-SMA protein in pulmonary artery was significantly increased(P＜0.01).The levels of plasma IL-1β,IL-6 and TNF-α were significantly increased(P＜0.01).The positive expression rate of PPAR-γ protein in lung tissue was significantly decreased(P＜0.01),and the positive expression rate of NF-κB protein was significantly increased(P＜0.01).The protein expressions of PPAR-γ and IκB-α in lung tissue were significantly down-regulated(P＜0.01).The protein expression ratio of p-NF-κB/NF-κB was significantly increased(P＜0.01).Compared with the model group,RVSP,mPAP,RVHI,RVIDd and RVAWT in each administration group were significantly decreased(P＜0.05,P＜0.01),while PAAT,PAAT/PET and TAPSE were significantly increased(P＜0.05,P＜0.01).The thickness of the vascular wall was significantly reduced,and the percentage of the wall thickness of the pulmonary arterioles to the diameter of the blood vessels and the percentage of the vascular wall area to the total cross-sectional area of the small arteries were significantly reduced(P＜0.05,P＜0.01).The positive expression rate of α-SMA protein in pulmonary artery was significantly decreased(P＜0.05,P＜0.01).The plasma levels of IL-1β,IL-6 and TNF-α were significantly decreased(P＜0.05,P＜0.01).The positive expression rate of PPAR-γ protein in lung tissue was significantly increased(P＜0.05,P＜0.01),and the positive expression rate of NF-κB protein was significantly decreased(P＜0.05,P＜0.01).The protein expression of PPAR-γ in lung tissue was significantly up-regulated(P＜0.05,P＜0.01),and the protein expression ratio of p-NF-κB/NF-κB was significantly decreased(P＜0.01).The protein expression of IκB-α in the lung tissue of rats in the high-dose group of Feixin Decoction was significantly up-regulated(P＜0.01).Conclusion Feixin Decoction can improve pulmonary artery pressure,right ventricular dysfunction and pulmonary vascular remodeling in PAH rats induced by monocrotaline.The mechanism may be related to the regulation of PPAR-γ/NF-κB signaling pathway to inhibit inflammatory response.

Objective To monitor heart-related parameters of hypoxic pulmonary hypertension(PH)mouse models induced by hypoxia alone and hypoxia combined with vascular endothelial growth factor receptor inhibitor SU5416 using echocardiography,and to construct the prediction equation of right ventricular systolic pressure(RVSP).Twenty-four C57BL/6J male mice were randomly divided into simple hypoxia group(group A),hypoxia combined with SU5416 group(group B),control group(group C),each group 8 mice.Hypoxic PH models were constructed with hypoxia alone and hypoxia combined with SU5416 in group A and group B,respectively.Echocardiography was performed before and during modeling(2,3,4 weeks after interventions),and the relevant parameters were obtained.RVSP was measured using right heart catheterization after the last echocardiography.The changes of ultrasonic parameters were observed,the correlations of ultrasonic parameters 4 weeks after intervention with RVSP were observed,and linear equations for predicting RVSP were established.Results With time going,during modeling,pulmonary artery diameter(PAD),PAD/aorta diameter(AOD)and right ventricle anterior wall thickness(RVAWT)increased,while heart rate,pulmonary artery acceleration time(PAAT),PAAT/pulmonary artery ejection time(PAET)and tricuspid annular plane systolic excursion(TAPSE)decreased in group A and B(all P＜0.05).Three and 4 weeks after interventions,PAET,PAAT/PAET and TAPSE in group B decreased compared with those in group A(all P＜0.05).Four weeks after interventions,RVSP in group A and B were highly correlated with PAD/AOD,RVAWT,PAAT,PAAT/PAET and TAPSE(all P＜0.05).The linear regression equations of PAAT/PAET and TAPSE for predicting RVSP in simple hypoxic PH mice models included RVSP=-161.7 ×(PAAT/PAET)+63.85,as well as RVSP=-36.53 ×TAPSE+71.55,while of predicting RVSP in hypoxia combined with VEGFR-2 inhibitor PH mouse models were as follows:RVSP=-266.4 ×(PAAT/PAET)+91.59,RVSP=-69.14 × TAPSE+116.5.Conclusion Four weeks after inerventions,the phenotypes of hypoxic PH mouse models induced by hypoxia alone and hypoxia combined with SU5416 became obvious.Prediction equations of RVSP established based on PAAT/PAET and TAPSE obtained with echocardiography could provide references for relevant research.

Pulmonary hypertension(PH)is a progressive pulmonary vascular disease that can lead to right heart failure and death.In recent years,the incidence of PH has been increasing year by year and there is a lack of effective treatment.TCM can play an important synergistic role in the treatment of PH.Pulmonary vascular remodeling is a core pathological feature of PH,which is closely related to the physiological structure and pathological changes of the collaterals.Based on the collateral disease theory,this article described the key pathogenesis of PH in TCM and Western medicine,including the lesions of the pulmonary and cardiovascular complexes and pulmonary vascular remodeling,analyzed the physiology of the"collateral-vessel"in PH,sorting out the pathological correlation,and explored TCM targeting pulmonary vascular remodeling in the identification and treatment of PH,so as to provide a new way of thinking for the clinical treatment of PH.

Objective: To investigate the clinical features and gene variation characteristics of children with dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) gene associated spinal muscular atrophy with lower extremity predominant (SMALED) 1. Methods: The clinical data of 4 SMALED1 children admitted to Peking University First Hospital from December 2018 to May 2021, who were found to have pathogenic variation of DYNC1H1 gene through genetic testing, except for other genes known to be related to motor retardation, were retrospectively summarized to analyze the phenotype and genotype characteristics. Results: There were 3 males and 1 female. The age of onset was 1 year, 1 day, 1 day and 4 months, respectively. The age of diagnosis was 4 years and 10 months, 9 months, 5 years and 9 months, and 3 years and 1 month, respectively. The clinical manifestations were muscle weakness and muscular atrophy of lower limbs, 2 cases with foot deformity, 1 case with early non progressive joint contracture, 1 case with hip dislocation and 1 case with mental retardation. De novo heterozygous missense variations in DYNC1H1 gene were found in all 4 children. According to the rating of American College of medical genetics and genomics, they were all possible pathogenic and pathogenic variations, with p.R598C, p.P776L, p.Y1109D variations had been reported, and p.I1086R variation had not been reported. Conclusions: For those with unexplained lower limb muscle weakness, muscle atrophy, joint contracture and foot deformity, upper limb motor ability related retention, with or without mental retardation, as well as the motor ability progresses slowly, it is necessary to consider the possibility of SMALED1 and the detection of DYNC1H1 gene when necessary.
Female ; Male ; Humans ; Intellectual Disability ; Retrospective Studies ; Muscular Atrophy, Spinal/genetics* ; Lower Extremity ; Muscle Weakness ; Muscular Atrophy ; Contracture ; Cytoplasmic Dyneins/genetics*

Objective: To investigate the efficacy of chitinase-3-like protein 1 (CHI3L1) and Golgi protein 73 (GP73) in the diagnosis of cirrhosis and the dynamic changes of CHI3L1 and GP73 after HCV clearance in patients with chronic hepatitis C (CHC) treated with direct-acting antiviral drugs (DAAs). The comparison of continuous variables of normal distribution were statistically analyzed by ANOVA and t-test. The comparison of continuous variables of non-normal distribution were statistically analyzed by rank sum test. The categorical variables were statistically analyzed by Fisher's exact test and χ(2) test. Correlation analysis was performed using Spearman correlation analysis. Methods: Data of 105 patients with CHC diagnosed from January 2017 to December 2019 were collected. The receiver operating characteristic curve (ROC curve) was plotted to study the efficacy of serum CHI3L1 and GP73 for the diagnosis of cirrhosis. Friedman test was used to compare CHI3L1 and GP73 change characteristics. Results: The areas under the ROC curve for CHI3L1 and GP73 in the diagnosis of cirrhosis at baseline were 0.939 and 0.839, respectively. Serum levels of CHI3L1 and GP73 in the DAAs group decreased significantly at the end of treatment compared with baseline [123.79 (60.25, 178.80) ng/ml vs. 118.20 (47.68, 151.36) ng/ml, P = 0.001; 105.73 (85.05, 130.69) ng/ml vs. 95.52 (69.52, 118.97) ng/ml, P = 0.001]. Serum CHI3L1 and GP73 in the pegylated interferon combined with ribavirin (PR) group were significantly lower at the end of 24 weeks of treatment than the baseline [89.15 (39.15, 149.74) ng/ml vs. 69.98 (20.52, 71.96) ng/ml, P < 0.05; 85.07 (60.07, 121) ng/ml vs. 54.17 (29.17, 78.65) ng/ml, P < 0.05]. Conclusion: CHI3L1 and GP73 are sensitive serological markers that can be used to monitor the fibrosis prognosis in CHC patients during treatment and after obtaining a sustained virological response. Serum CHI3L1 and GP73 levels in the DAAs group decreased earlier than those in the PR group, and the serum CHI3L1 levels in the untreated group increased compared with the baseline at about two years of follow-up.
Humans ; Hepatitis C, Chronic/drug therapy* ; Antiviral Agents/therapeutic use* ; Membrane Proteins/metabolism* ; Liver Cirrhosis/diagnosis* ; Fibrosis ; Biomarkers

【Objective】 To explore the relationship between the storage time of leukodepleted red blood cells and transfusion adverse reactions by analyzing the occurrence of transfusion adverse reactions of patients after leukodepleted red blood cells transfusion from four hospitals. 【Methods】 By using the electronic medical record management system, the collection and transfusion dates of leukodepleted red blood cells from four hospitals in Enshi Prefecture from 2018 to 2022, as well as the information on transfusion adverse reactions, were retrieved. 【Results】 From 2018 to 2022, a total of 697 61 bags of leukodepleted red blood cells were transfused in four hospitals, resulting in 166 cases of transfusion adverse reactions, among which 93 were allergic reactions, 63 were non hemolytic febrile reactions, and 10 were others, with a total incidence rate of transfusion adverse reactions at 0.24%. The average storage time of leukodepleted red blood cells with and without transfusion adverse reactions was (20.25±6.31) and (19.88±5.50) days, respectively. With a storage time of 7 days as the threshold, the incidence of transfusion adverse reactions was the lowest for a storage time of 15~21 days. The incidence of transfusion adverse reactions of leukodepleted red blood cells in two groups (with storage days ≤21 days and >21 days) was not statistically significant(P>0.05). 【Conclusion】 Allergic reactions were the main type of transfusion adverse reaction caused by leukodepleted red blood cells, and the incidence of transfusion adverse reactions decreased and then increased with the prolongation of the storage time of leukodepleted red blood cells. There was no significant difference in the incidence of transfusion adverse reactions with leukodepleted red blood cells stored for ≤ 21 days and >21 days.