BACKGROUND: The protective effect of mesenchymal stem cells (MSCs) on cardiac ischemia-reperfusion (I/R) injury has been widely reported. Dental pulp-derived mesenchymal stem cells (DP-MSCs) have therapeutic effects on various diseases, including diabetes and cirrhosis. This study aimed to determine the therapeutic effects of DP-MSCs on I/R injury and elucidate the underlying mechanism. METHODS: Myocardial I/R injury model mice were treated with DP-MSCs or a miR-19a-3p mimic. The infarct volume, fibrotic area, pyroptosis, inflammation level, and cardiac function were measured. Cardiomyocytes exposed to hypoxia-reoxygenation were transfected with the miR-19a-3p mimic, miR-19a-3p inhibitor, or negative control. Pyroptosis and protein expression in the interferon regulatory factor 8/mitogen-activated protein kinase (IRF-8/MAPK) pathway were measured. RESULTS: DP-MSCs protected cardiac function in cardiac I/R-injured mice and inhibited cardiomyocyte pyroptosis. The upregulation of miR-19a-3p protected cardiac function, inhibited cardiomyocyte pyroptosis, and inhibited IRF-8/MAPK signaling in cardiac I/R-injured mice. DP-MSCs inhibited cardiomyocyte pyroptosis and the IRF-8/MAPK signaling by upregulating the miR-19a-3p levels in cardiomyocytes injured by I/R. CONCLUSION DP-MSCs protected cardiac function by inhibiting cardiomyocyte pyroptosis through miR-19a-3p under I/R conditions.
Animals ; MicroRNAs/metabolism* ; Pyroptosis/genetics* ; Mesenchymal Stem Cells/metabolism* ; Myocytes, Cardiac/cytology* ; Mice ; Male ; Mice, Inbred C57BL ; Dental Pulp/cytology* ; Myocardial Reperfusion Injury/therapy* ; MAP Kinase Signaling System/physiology*

Osteoporosis is a prevalent skeletal condition characterized by reduced bone mass and strength, leading to increased fragility. Buqi-Tongluo (BQTL) decoction, a traditional Chinese medicine (TCM) prescription, has yet to be fully evaluated for its potential in treating bone diseases such as osteoporosis. To investigate the mechanism by which BQTL decoction inhibits osteoclast differentiation in vitro and validate these findings through in vivo experiments. We employed MTS assays to assess the potential proliferative or toxic effects of BQTL on bone marrow macrophages (BMMs) at various concentrations. TRAcP experiments were conducted to examine BQTL's impact on osteoclast differentiation. RT-PCR and Western blot analyses were utilized to evaluate the relative expression levels of osteoclast-specific genes and proteins under BQTL stimulation. Finally, in vivo experiments were performed using an osteoporosis model to further validate the in vitro findings. This study revealed that BQTL suppressed receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis and osteoclast resorption activity in vitro in a dose-dependent manner without observable cytotoxicity. The inhibitory effects of BQTL on osteoclast formation and function were attributed to the downregulation of NFATc1 and c-fos activity, primarily through attenuation of the MAPK, NF-κB, and Calcineurin signaling pathways. BQTL's inhibitory capacity was further examined in vivo using an ovariectomized (OVX) rat model, demonstrating a strong protective effect against bone loss. BQTL may serve as an effective therapeutic TCM for the treatment of postmenopausal osteoporosis and the alleviation of bone loss induced by estrogen deficiency and related conditions.
Animals ; NFATC Transcription Factors/genetics* ; Drugs, Chinese Herbal/pharmacology* ; Ovariectomy ; Osteoclasts/metabolism* ; Female ; Osteogenesis/drug effects* ; Rats, Sprague-Dawley ; Rats ; NF-kappa B/genetics* ; Osteoporosis/genetics* ; Signal Transduction/drug effects* ; Bone Resorption/genetics* ; Cell Differentiation/drug effects* ; Humans ; RANK Ligand/metabolism* ; Mitogen-Activated Protein Kinases/genetics* ; Transcription Factors

Objectives:This study aimed to investigate the impact of quantitative flow ratio(QFR)-guided revascularization on outcome of elderly patients with coronary artery disease(CAD)undergoing valve surgery.Methods:We retrospectively analyzed 750 consecutive patients with angiographically confirmed CAD(≥50%stenosis)who underwent valve surgery at Zhongshan Hospital,Fudan University,between January 2016 and December 2021.According to the patients'ages,they were divided into the younger group(age<70 years old,n=532)and the elderly group(age≥70 years old,n=218).Revascularization strategies were evaluated using anatomical(angiography-based)and functional(QFR-based)criteria.Anatomical complete revascularization(CR)was defined as bypass grafting for all lesions with≥70%diameter stenosis in major coronary arteries or≥50%stenosis in the left main coronary artery.Functional CR referred bypass grafting for all lesions with QFR≤0.80.Incomplete revascularization(ICR)was defined as failure to meet CR criteria.According to the anatomical and functional definitions,the younger group and the elderly group were further divided into the incomplete revascularization subgroup and the complete revascularization subgroup respectively.Major adverse cardiovascular events(MACE),including death,myocardial infarction,repeat revascularization,and stroke,were assessed as the composite endpoint.Results:Over a follow-up of(3.7±1.8)years,the overall MACE rate was 13.3%.The younger group exhibited significantly lower MACE rates than the elderly group(10.7%vs.19.7%,P=0.001).In the younger group,anatomical ICR did not increase MACE risk(HR=1.46,95%CI:0.81-2.62,P=0.164),whereas functional ICR significantly increased MACE risk(HR=2.27,95%CI:1.24-4.15,P=0.001).In the elderly group,neither anatomical ICR(HR=1.22,95%CI:0.62-2.41,P=0.540)nor functional ICR(HR=1.52,95%CI:0.78-2.96,P=0.172)was associated with increased MACE risk.Conclusions:In patients undergoing valve surgery with CAD,functional ICR correlated with adverse outcomes in the younger group,whereas neither anatomical nor functional ICR significantly affected prognosis in elderly patients.These findings suggest that a moderately conservative revascularization strategy may be more appropriate for elderly populations.

Objectives:This study aimed to investigate the impact of quantitative flow ratio(QFR)-guided revascularization on outcome of elderly patients with coronary artery disease(CAD)undergoing valve surgery.Methods:We retrospectively analyzed 750 consecutive patients with angiographically confirmed CAD(≥50%stenosis)who underwent valve surgery at Zhongshan Hospital,Fudan University,between January 2016 and December 2021.According to the patients'ages,they were divided into the younger group(age<70 years old,n=532)and the elderly group(age≥70 years old,n=218).Revascularization strategies were evaluated using anatomical(angiography-based)and functional(QFR-based)criteria.Anatomical complete revascularization(CR)was defined as bypass grafting for all lesions with≥70%diameter stenosis in major coronary arteries or≥50%stenosis in the left main coronary artery.Functional CR referred bypass grafting for all lesions with QFR≤0.80.Incomplete revascularization(ICR)was defined as failure to meet CR criteria.According to the anatomical and functional definitions,the younger group and the elderly group were further divided into the incomplete revascularization subgroup and the complete revascularization subgroup respectively.Major adverse cardiovascular events(MACE),including death,myocardial infarction,repeat revascularization,and stroke,were assessed as the composite endpoint.Results:Over a follow-up of(3.7±1.8)years,the overall MACE rate was 13.3%.The younger group exhibited significantly lower MACE rates than the elderly group(10.7%vs.19.7%,P=0.001).In the younger group,anatomical ICR did not increase MACE risk(HR=1.46,95%CI:0.81-2.62,P=0.164),whereas functional ICR significantly increased MACE risk(HR=2.27,95%CI:1.24-4.15,P=0.001).In the elderly group,neither anatomical ICR(HR=1.22,95%CI:0.62-2.41,P=0.540)nor functional ICR(HR=1.52,95%CI:0.78-2.96,P=0.172)was associated with increased MACE risk.Conclusions:In patients undergoing valve surgery with CAD,functional ICR correlated with adverse outcomes in the younger group,whereas neither anatomical nor functional ICR significantly affected prognosis in elderly patients.These findings suggest that a moderately conservative revascularization strategy may be more appropriate for elderly populations.

Objective To evaluate the application effect of positive end-expiratory pressure(PEEP)guided by driving pressure on intraoperative oxygenation and postoperative complications in patients undergoing orthotopic liver transplantation(OLT).Methods A total of 118 patients underwent OLT from January 2020 to September 2023,89 males and 29 females,aged 18-70 years,BMI＜28 kg/m2,ASA physical status Ⅲ or Ⅳ.Patients were divided into two groups using the random number table method:drive pressure group(group D)and PEEP group(group P),59 patients in each group.Volume controlled ventilation was used during general anesthesia in two groups,I:E 1:2,VT 6 ml/kg(ideal body weight),RR 10-15 beats/minute.In group D,the PEEP titration test was started after 5 minutes of mechanical ven-tilation,gradually increasing PEEP from 2 to 10 cmH2O,selecting the PEEP that produced the lowest driv-ing pressure,and maintaining this PEEP until the end of the surgery.In group P,the PEEP was maintained at 5 cmH2O during surgery.The amount of intraoperative out put and intake,and the use of vasoactive drugs were recorded.The HR,SBP,DBP,peak airway pressure(Ppeak),airway plateau pressure(Pplat),PEEP,and blood gas analysis results were recorded 5 minutes after intubation(T1),during the anhepatic phase(T2),during the neohepatic phase(T3),and at the end of the operation(T4),and driving pres-sure,dynamic pulmonary compliance(Cdyn),oxygenation index(OI),and dead space fraction(VD/VT)were calculated.The occurrence of postoperative pulmonary complications(PPCs)within 7 days after opera-tion was recorded.Results Compared with group P,the amount of crystalloid and the usage frequencies of norepinephrine,phenylephrine,and epinephrine in group D were significantly increased(P＜0.05).Com-pared with T2,HR was significantly decreased,SBP and DBP were significantly increased at T1,T3,and T4 in the two groups(P＜0.05).Compared with T1,Ppeak,Pplat,driving pressure,and OI were signifi-cantly increased at T2-T4,and Cdyn was significantly decreased at T3 and T4 in the two groups(P＜0.05).Compared with group P,the incidence of PPCs in group D was significantly decreased(P＜0.05).There were no significant differences in other indexes between the two groups.Conclusion The driving pressure guided PEEP ventilation improves intraoperative oxygenation and reduces the incidence of PPCs in patients undergoing OLT,but the use of intraoperative vasoactive drugs increases.

Objective:This study aimed to assess left atrial function in adults across various age groups using 4-dimensional automated left atrial quantification(4D Auto LAQ)technology.The study also aimed to compare the differences in two-dimensional(2D)and four-dimensional(4D)strains of the left atrium among different age groups, with the goal of enhancing the clinical utility of 4D Auto LAQ.Methods:A total of 409 healthy volunteers were recruited for the research.Two-dimensional and four-dimensional images were obtained using a GE Vivid E95 ultrasound system with a 4Vc four-dimensional probe.The study examined variations in 2D and 4D ultrasound parameters across various age groups.Furthermore, the relationship between left atrial reservoir strain(LASr), Left atrial conduit strain(LAScd), left atrial contraction strain(LASct), and age was explored.Results:The study involved 409 volunteers, with 217 males and 192 females, who were categorized into three age groups: young(18-45 years, n=56), middle-aged(46-65 years, n=202), and elderly(>65 years, n=151).Conventional ultrasound measurements indicated changes in left atrial anterior-posterior diameter with age progression: (31.70±3.65)mm for the young group, (34.02±3.91)mm for the middle-aged group, and(35.2±4.37)mm for the elderly group( P<0.01).The 2D and 4D left atrial parameters across the age groups were as follows: LASr(2D)(%): 37.48±7.51, 30.95±8.23, 26.9±7.56( P<0.01); LA VImax(ml/m 2): 23.54±5.79, 26.33±7.6, 28.99±8.15( P<0.01); LASr(%): 31.2±17.07, 22.5±8.59, 19.49±7.47( P<0.01).Both 2D and 4D left atrial parameters exhibited significant associations with age.Specifically, the correlations between LASr(2D)(%), LAScd(2D)(%), LASr(%), LAScd(%), and age were -0.429, 0.580, -0.354, 0.298, respectively( P<0.01). Conclusions:The 4D Auto LAQ technology is efficient in assessing left atrial function across various age groups, with age playing a significant role in influencing left atrial parameters.When compared to other ultrasound parameters, both 2D and 4D left atrial strain parameters have the ability to detect differences at an early stage, making them suitable for the early screening, evaluation, and monitoring of age-related left atrial dysfunction, especially in the elderly population.

Rivaroxaban is one of the new oral anticoagulants (NOAC) for preventing stroke and systemic embolism in patients with non-valvular atrial fibrillation. It has clear pharmacokinetic parameters, stable plasma concentration, less drug-drug interaction and higher compliance of patients. However, the discrepancy of pharmacokinetics between individuals and drug-induced hemorrhage events frequently occur clinically, therefore the association of gene polymorphism with drug metabolism has become a research hotspot. This article reviews the research progress on pharmacokinetic characteristics of rivaroxaban and its relationship with gene polymorphism, to provide a reference for the individualized rational use of rivaroxaban.

Objective:To explore the related factors influencing the length of hospital stay(LOS) of pregnant women with heart disease (PWHD) after cesarean section.Methods:A total of 306 patients with PWHD who underwent cesarean section from January 2012 to March 2019 were collected. Among them, 203 patients had not undergone heart surgery (uncorrected group) and 103 patients who had undergone heart surgery (corrected group) during the same period. Demographic, perioperative and postoperative data were recorded. Predictors associated with postoperative LOS were determined using univariate and multivariate linear regression analysis models.Results:(1) The median LOS after cesarean section in the uncorrected group was 6 days (5-8 days). The results of univariate linear regression analysis showed that 38 parameters had significant impact on LOS ( P<0.05). The results of multivariate linear regression analysis showed that 5 parameters were independent risk factors for prolonged LOS in the uncorrected group; among them, the median LOS in uncorrected group with hypertensive disorders of pregnancy was 3 days longer than that in patients with PWHD alone [7 days (5-8 days) vs 4 days (4-5 days), β=0.195, P=0.001]; the median LOS in uncorrected group with high serum creatinine was 3 days longer than normal patients [7 days (5-13 days) vs 4 days (4-5 days), β=0.145, P=0.015]; the LOS of patients who chose general anesthesia was 2 days longer than that of patients who chose spinal anesthesia [6 days (4-8 days) vs 4 days (4-5 days), β=0.154, P=0.007]; the LOS of patients with postoperative pulmonary infection was 4 days longer than that of patients without pulmonary infection [8 days (5-15 days) vs 4 days (4-5 days), β=0.269, P<0.01]; the LOS of patients who admitted to ICU after surgery was 2 days longer than that not admitted patients [6 days (5-8 days) vs 4 days (4-5 days), β=0.268, P<0.01]. (2) The median LOS after cesarean section in corrected group was 4 days (4-5 days). The results of univariate linear regression analysis showed that 8 parameters had significant impact on the LOS (all P<0.05). The results of multivariate linear regression analysis showed that 2 parameters, which were American Society of Anesthesiologists (ASA) grade ( β=0.198, P=0.028) and intraoperative blood loss ( β=0.285, P=0.003), were the independent risk factors for prolonged LOS in corrected group. Conclusion:Preoperative with hypertensive disorders of pregnancy, preoperative creatinine increase, intraoperative general anesthesia, postoperative pulmonary infection, and postoperative admission to ICU are independent predictors of prolonged LOS in uncorrected patients with PWHD; ASA classification and intraoperative bleeding are independent predictor of prolonged postoperative LOS in patients with corrected PWHD.

Objective:To verify the accuracy of the International Warfarin Pharmacogenetics Consortium(IWPC)model, identify the effects of genetic and clinical factors on steady-state doses of Warfarin, and establish a Warfarin dose prediction model for the Han-Chinese population aged 75 years and over under the guidance of pharmacogenetics.Methods:A total of 544 Han-Chinese patients receiving Warfarin therapy for atrial fibrillation were divided into two groups: those aged 75 years and over(n=164)and those aged below 75 years(n=380). Data for the whole population and the two age groups were each substituted into the IWPC prediction model for accuracy verification.Demographic and clinical characteristics of 164 patients aged 75 years and over were recorded, and the genotypes of CYP2 C9 and VKORC1- G1639 A were detected by polymerase chain reaction.A new pharmacogenetic-guided dosing algorithm for the elderly was obtained by stepwise multiple linear regression.The accuracy of the new model was compared with that of the IWPC model. Results:The predictive accuracy of IWPC for steady-state dosing of warfarin was 35.47% in all subjects, 33.75% in 164 subjects aged below 75 years, and only 28.70% in subjects aged 75 years and over, respectively.In 164 subjects aged 75 years and over, three genotypes of *1/*1, *1/*3 and *1/*2 were detected in CYP2 C9 polymorphism, and the CYP2 C9*1/*1 genotype was the most common one, with a frequency of 87.80%(144/164), followed by the CYP2 C9*1/*3 genotype, at 11.59%(19/164). GG, GA and AA genotypes were detected in VKORC1 polymorphism, among which the AA genotype accounted for 82.32%(135/164)and the GG genotype accounted for only 1.83%(3/164). The steady state dose for Warfarin in patients with the wild-type CYP2 C9*1/*1 was higher than in those with the heterozygote CYP2 C9*1/*3 and *1/*2(3.18±0.86 mg/d vs.2.27±0.51 mg/d, t=5.637, P<0.05). Patients with a mutant homozygotic AA genotype of VKORC1 required lower maintenance doses than those with the heterozygotic GA and GG genotypes(2.96±0.66 mg/d vs. 3.59±1.43 mg/d, t=-2.092, P<0.05). The steady-state dose for Warfarin in subjects carrying CYP2 C9 (*1/*2 or *3)and VKORC1 (GA and GG)was(2.00±0.63)mg/d, lower than in those carrying other genotype combinations( P<0.05). We established a new Warfarin dosing algorithm for elderly subjects aged 75 years and over containing height, creatinine, amiodarone usage, CYP2 C9 and VKORC1 mutants, and the accuracy of the new model was 56.0%, which could explain 56.0% of individual variability, and the accuracy was higher than that of the IWPC algorithm(56.0% vs. 45.8%, P<0.05). Conclusions:Polymorphisms of CYP2 C9 and VKORC1 clearly affect the steady-state dose for Warfarin in the elderly Han-Chinese population aged 75 years and over.A combination of pharmacogenomics with clinical factors can better guide warfarin medication in Han-Chinese people aged 75 years and over.

Objective:To study the correlation between the Rivaroxaban concentration and bleeding events in patients with nonvalvular atrial fibrillation(NVAF).Methods:This was a retrospective study.According to the inclusion and exclusion criteria, 369 patients with NVAF taking Rivaroxaban admitted to Beijing Hospital or Tianjin Medical University General Hospital from January 2018 to June 2019 were enrolled.Clinical data including sex, height, weight, liver and kidney function, drug valley concentrations and peak concentrations, doses, CHADS2 scores and bleeding events after 6 months of medication were recorded.Results:The average drug valley concentration was (44.92±38.39) mg/L, the average drug peak concentration was (226.96±139.34) mg/L, and the average CHADS2 score was (2.8±1.2). Among the 369 patients, 22 had bleeding events.The peak drug concentration and valley drug concentration were similar between those with or without bleeding events( P=0.324 and 0.960, respectively). With the increase of age, the peak drug concentration and valley drug concentration were significantly elevated(all P<0.001). In addition, compared with those without bleeding events, patients with bleeding events had a significantly higher average valley concentration( P=0.009), valley/dose ratio( P=0.001), peak/dose ratio( P=0.028)and similar peak drug concentration( P=0.360). Conclusions:Age affects the peak and valley drug concentration of Rivaroxaban, especially for the elderly, who should be given appropriately reduced doses.Monitoring the peak and valley drug concentration is of great significance for patients at high-risk for bleeding.