Objective To explore the difference in efficacy of metoprolol versus ivabradine in the treatment of postural orthostatic tachycardia syndrome(POTS)in the elderly after COVID-19 infection.Methods A total of 110 patients diagnosed with POTS at our department from Decem-ber 1,2022 to January 31,2023 were included.According to their drug regimen,they were divided into metoprolol group(62 patients)and ivabradine group(48 patients).On the 28th day of out-patient follow-up,the resting heart rate,heart rate of 10 min of standing,symptom disappearance rate,hospitalization rate,and mortality rate were compared between the two groups.Results On the 28th day of treatment,the resting heart rate and postural heart rate for 10 min were decreased in both groups when compared with the levels at initial diagnosis(P＜0.01).And there were no significant differences in the two types of heart rate between the two groups on the 28th day(71.0±7.0 vs 72.1±7.0,P=0.401;76.5±7.2 vs 77.4±7.6,P=0.573).No obvious differences were observed between the two groups in symptom disappearance rate,hospitalization rate,or mortality rate(88.7％vs 89.6％,3.2％vs2.1％,0％vs 0％,P＞0.05).Conclusion Metoprolol and ivabradine can effectively treat POTS in the elderly patients after COVID-19 infection.

Objective To explore the mechanism by which soybean isoflavone(SI)reduces calcium overload induced by cerebral ischemia-reperfusion(I/R).Methods Forty-eight SD rats were randomized into 4 groups to receive sham operation,cerebral middle artery occlusion for 2 h followed by 24 h of reperfusion(I/R model group),or injection of adeno-associated virus carrying Frizzled-2 siRNA or empty viral vector into the lateral cerebral ventricle after modeling.Western blotting was used to examine Frizzled-2 knockdown efficiency and changes in protein expressions in the Wnt/Ca2+signaling pathway.Calcium levels and pathological changes in the ischemic penumbra(IP)were measured using calcium chromogenic assay and HE staining,respectively.Another 72 SD randomly allocated for sham operation,I/R modeling,or soy isoflavones pretreatment before modeling were examined for regional cerebral blood flow using a Doppler flowmeter,and the cerebral infarct volume was assessed using TTC staining.Pathologies in the IP area were evaluated using HE and Nissl staining,and ROS level,Ca2+level,cell apoptosis,and intracellular calcium concentration were analyzed using immunofluorescence assay or flow cytometry;the protein expressions of Wnt5a,Frizzled-2,and P-CaMK II in the IP were detected with Western blotting and immunohistochemistry.Results In rats with cerebral I/R,Frizzled-2 knockdown significantly lowered calcium concentration(P<0.001)and the expression levels of Wnt5a,Frizzled-2,and P-CaMK II in the IP area.In soy isoflavones-pretreated rats,calcium concentration,ROS and MDA levels,cell apoptosis rate,cerebral infarct volume,and expression levels of Wnt/Ca2+signaling pathway-related proteins were all significantly lower while SOD level was higher than those in rats in I/R model group.Conclusion Soy isoflavones can mitigate calcium overload in rats with cerebral I/R by inhibiting the Wnt/Ca2+signaling pathway.

Objective To explore the mechanism by which soybean isoflavone(SI)reduces calcium overload induced by cerebral ischemia-reperfusion(I/R).Methods Forty-eight SD rats were randomized into 4 groups to receive sham operation,cerebral middle artery occlusion for 2 h followed by 24 h of reperfusion(I/R model group),or injection of adeno-associated virus carrying Frizzled-2 siRNA or empty viral vector into the lateral cerebral ventricle after modeling.Western blotting was used to examine Frizzled-2 knockdown efficiency and changes in protein expressions in the Wnt/Ca2+signaling pathway.Calcium levels and pathological changes in the ischemic penumbra(IP)were measured using calcium chromogenic assay and HE staining,respectively.Another 72 SD randomly allocated for sham operation,I/R modeling,or soy isoflavones pretreatment before modeling were examined for regional cerebral blood flow using a Doppler flowmeter,and the cerebral infarct volume was assessed using TTC staining.Pathologies in the IP area were evaluated using HE and Nissl staining,and ROS level,Ca2+level,cell apoptosis,and intracellular calcium concentration were analyzed using immunofluorescence assay or flow cytometry;the protein expressions of Wnt5a,Frizzled-2,and P-CaMK II in the IP were detected with Western blotting and immunohistochemistry.Results In rats with cerebral I/R,Frizzled-2 knockdown significantly lowered calcium concentration(P<0.001)and the expression levels of Wnt5a,Frizzled-2,and P-CaMK II in the IP area.In soy isoflavones-pretreated rats,calcium concentration,ROS and MDA levels,cell apoptosis rate,cerebral infarct volume,and expression levels of Wnt/Ca2+signaling pathway-related proteins were all significantly lower while SOD level was higher than those in rats in I/R model group.Conclusion Soy isoflavones can mitigate calcium overload in rats with cerebral I/R by inhibiting the Wnt/Ca2+signaling pathway.

Objective:To explore the trends and outcomes for heart transplantation (HT) in elderly recipients and further examine the related risk factors.Methods:Between June 2004 and December 2021, retrospective review was conducted for the relevant clinical data and age distribution of 1044 HT recipients aged ≥18 year at Fuwai Hospital. The study population was assigned into two groups of elder (≥60 year, n=877) and non-elder (<60 year, n=157). Subgroup analysis was made between recipients aged <65 year (n=107) and those aged ≥ 65 year (n=50) in elder group. Baseline demographic profiles, clinical data, in-hospital and one-year post-transplant mortality and long-term survival were compared between two groups. Then a further comparison of long-term survival was conducted among the groups of non-elder, elder aged <65 year and elder aged ≥65 year. Cox proportional risk regression and multivariate Logistic regression models were utilized for examining the relevant risk factors for cumulative survival rate and short-term mortality. Kaplan-Meier analysis was employed for plotting survival curves and Log-rank test for comparison. Multivariate Cox proportional risk regression model was utilized for examining the relevant risk factors for cumulative survival rate and multivariate Logistic regression model for analyzing the relevant risk factors for short-term mortality. After adjusting for other confounding factors, the impact of recipient age on survival post-HT was determined.Results:The number of elderly HT recipients spiked annually at our center while average age of adult recipients and average age of elderly recipients have remained relatively constant. The median follow-up period was 6.5 years. Regarding baseline data, statistically significant differences existed in ratio of males [84.7%(113/157) vs 77.5%(687/877)], hypertension history [20.4%(32/157) vs 8.9%(79/877)], smoking history [47.1%(74/157) vs 36.1%(320/877)], diabetic history [33.8%(53/157) vs 14.7%(130/877)], preoperative ICD/CRT/CRT-D implantation [28.0%(44/157) vs 18.0%(160/877)], value of creatinine [(105.3±25.3) vs (96.8±35.0) μmol/L], IMPACT score [(6.9±2.4) vs (4.2±2.9) point], serum total bilirubin [19.7(13.6, 30.3) vs 23.7(15.8, 36.8) μmol/L], mean pulmonary arterial pressure [(26.0±10.3) vs (29.7±11.0) mmHg (1 mmHg=0.133 kPa)] and ischemic duration [(274.7±105.6) vs (296.0±120.4) min] (all P<0.05). No significant inter-group difference existed in in-hospital mortality [4.5%(7/157) vs 4.7%(42/887)] or 1-year mortality [5.7%(9/157) vs 6.5%(58/887)] ( P=0.88, P=0.70); in-hospital mortality and 1-year postoperative mortality of recipients aged ≥65 years 10.0%(5/50) and 14.0%(7/50) were both higher than those aged <65 year [1.9%(2/107), 1.9%(2/107)]. The differences were both statistically significant ( P=0.02, P<0.01). Kaplan-Meier survival analysis indicated that long-term survival rate was lower in elder group than that in non-elder group and the difference was statistically significant ( P=0.046). Long-term survival rate of elders aged ≥65 year was lower than that of non-elders aged <65 year and the difference was statistically significant ( P<0.01). Regression analysis indicated that age of recipient ≥65 year, preoperative creatinine ≥133 μmol/L, preoperative total bilirubin ≥25.65 μmol/L and preoperative support of extracorporeal membrane oxygenation (ECMO) were independent risk factors for short/long-term mortality post-HT. Conclusion:Although long-term prognosis of elderly recipients is slightly worse than that of non-elderly ones, in-hospital mortality and one-year postoperative mortality are similar between two groups. For elderly recipients with fewer comorbidities and better preoperative status, they should not be excluded from HT based solely upon age. The long-term prognosis of recipients aged ≥65 year remains poor and HT decisions should be made carefully.

Insufficient catalytic efficiency of flavonoid 6-hydroxylases in the fermentative production of scutellarin leads to the formation of at least about 18% of by-products. Here, the catalytic mechanisms of two flavonoid 6-hydroxylases, CYP82D4 and CYP706X, were investigated by molecular dynamics simulations and quantum chemical calculations. Our results show that CYP82D4 and CYP706X have almost identical energy barriers at the rate-determining step and thus similar reaction rates, while the relatively low substrate binding energy of CYP82D4 may facilitate product release, which is directly responsible for its higher catalytic efficiency. Based on the study of substrate entry and release processes, the catalytic efficiency of the L540A mutation of CYP82D4 increased by 1.37-fold, demonstrating the feasibility of theoretical calculations-guided engineering of flavonoid 6-hydroxylase. Overall, this study reveals the catalytic mechanism of flavonoid 6-hydroxylases, which may facilitate the modification and optimization of flavonoid 6-hydroxylases for efficient fermentative production of scutellarin.
Cytochrome P-450 Enzyme System/metabolism* ; Apigenin ; Glucuronates

Diabetic kidney disease is one of the complications of diabetes,which can progress to end-stage renal disease.In recent years,it has been found that miRNAs have become a research hotspot,with miRNA-21 regulating transforming growth factor β1(TGF-β1)/Smads,phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT),Wnt/β-catenin and other signaling pathways to promote the progress of diabetic kidney disease.Studies have showed that traditional Chinese medicine has a regulatory effect on the expression of miRNA-21 and can target miRNA-21 to regulate TGF-β1/Smads,phosphatase and tensin homolog/PI3K/AKT/mammalian target of rapamycin(mTOR),peroxisome proliferator activated receptors and other signal transduction pathways to trigger signal cascade reactions,which intervene in pathological processes such as fibrosis,inflammation,oxidative stress and autophagy.In this article,the role of miRNA-21 in diabetic kidney disease and the intervention of traditional Chinese medicine were summarized,in order to provide some reference for the treatment of diabetic kidney disease and the development of new drugs.

OBJECTIVE To study the impr ovement effects of Dianxianqing granule on blood-brain barrier （BBB）injury in Alzheimer’s disease （AD）model mice by regulating NLR family pyrin domain containing 3（NLRP3）inflammasome signaling pathway. METHODS Totally 125 mice were randomly divided into sham operation group （n＝25）and modeling group （n＝100） by body weight. AD model was induced by intracerebroventricular injection of β-amyloid 25-35 in model group. Sham operation group was given normal saline with same method. The 100 model mice were randomly divided into model group ，Donepezil hydrochloride tablets group （positive control 1，1.3 mg/kg，i.g.），MCC950 group [positive control 2（selective NLRP 3 inhibitor），10 mg/kg，i.p.] and Dianxianqing granule group （12.48 g/kg by crude drug ，i.g.）by body weight ，with 25 mice in each group. Second day after modeling ，administration groups were given relevant medicine ，once a day ，for consecutive 21 d. Sham operation group and model group were given intragastric administration of water and intraperitoneal injection of normal saline. At last administration，the learning and memory ability was determined by Y maze test ，and blood-brain barrier permeability was measured by Evans blue leakage assay. The expressions of NLRP 3，anti-ionized calcium-binding adapter molecule 1（IBA-1），nuclear factor kappa B （NF-κB）p65，p53 upregulated modulator of apoptosis （PUMA），occludin（ocln），zonula occluden- 1（ZO-1）and claudin-5 （cldn5） in cerebral tissue were determined. RESULTS Compared with model group ， spontaneous alternate response rate ，protein expressions of ocln ，cldn5 lnzyxyqy2003@163.com and ZO- 1 in cerebral tissue were increased significantly in administration groups （P＜0.05 or P＜0.01）；Evans blue E-mail：jiadg2003@126.com content and protein expressions of NLRP 3，IBA-1，PUMA and NF-κB p65 in cerebral tissue were decreased significantly （P＜0.05 or P＜0.01）. CONCLUSIONS Dianxianqing granule can improve BBB injury of AD model m ice by inhibiting NLRP 3 inflammasome signaling pathway.

Objective To summarize the incidence of cardiac allograft vasculopathy (CAV) after heart transplantation and the effect on the long-term survival of recipients. Methods Clinical data of 1 006 heart transplant recipients were retrospectively analyzed. Of 48 CAV patients, 4 cases were not included in this analysis due to lack of imaging evidence. A total of 1 002 recipients were divided into the CAV group (n=44) and non-CAV group (n=958) according to the incidence of CAV. The incidence of CAV was summarized. Clinical data of all patients were statistically compared between two groups. Imaging diagnosis, coronary artery disease, drug treatment and complications, postoperative survival and causes of death of CAV patients were analyzed. Results Among 1 006 heart transplant recipients, 48 cases (4.77%) developed CAV. Compared with the non-CAV group, the proportion of preoperative smoking history, preoperative hypertension history, coronary artery disease and perioperative infection was significantly higher in the CAV group (all P < 0.05). Among 44 patients diagnosed with CAV by imaging examination, 24 cases were diagnosed with CAV by coronary CT angiography (CTA), 4 cases by coronary angiography (CAG), and 16 cases by coronary CTA combined with CAG. Among 44 patients, the proportion of grade Ⅰ CAV was 45% (20/44), 30% (13/44) for grade Ⅱ CAV and 25% (11/44) for grade Ⅲ CAV, respectively. All patients received long-term use of statins after operation, and 20 patients were given with antiplatelet drugs. Among 44 CAV patients, 11 patients underwent percutaneous coronary intervention, 6 cases received repeated heart transplantation, and 8 patients died. Kaplan-Meier survival analysis demonstrated that there was no significant difference in the long-term survival rate between the CAV and non-CAV groups (P > 0.05), whereas the survival rate of patients tended to decline after the diagnosis of CAV (at postoperative 6-7 years). The long-term survival rates of patients with grade Ⅰ, grade Ⅱ and grade Ⅲ CAV showed no significant difference (P > 0.05). Even for patients with grade Ⅰ CAV, the long-term survival rate tended to decline. Conclusions CAV is a common and intractable complication following heart transplantation, and the long-term survival rate of patients after the diagnosis of CAV tended to decline. Deepening understanding of CAV, prompt prevention, diagnosis and treatment should be delivered to improve the long-term survival rate of patients after heart transplantation.

Objective: To discuss the correlation between growth status and eating behaviors in children with attention deficit and hyperactivity disorder (ADHD), providing reference data for management and dietary behavior guidance among ADHD children. Methods: A total of 703 children aged 4-13 years old were collected from the ADHD patients from Children s Health Department of Children s Hospital of Nanjing Medical University from June to September, 2019. The demographic characteristics and information regarding children’s eating behaviors were collected by self-designed questionnaire and Chinese version of the parent-completed Children’s Eating Behavior Questionnaire(CEBQ). The correlation physical growth with dietary behaviors among the ADHD children were analyzed. Results: Food avoidant behaviors, including satiety responsiveness, slowness in eating and emotional undereating in ADHD children with thinness scored significantly higher than that of children with short stature, overweight and obesity(F=17.57, 29.32, 4.07, P<0.01), while food approach behaviors, including food responsiveness, enjoyment of food, desire to drink and emotional overeating scored higher in obese children, compared to other three groups(F=24.54, 47.44, 2.96,5.85, P<0.05). Multiple linear regression analysis showed that, after adjusting for the confounders, satiety responsiveness, slowness in eating were still negatively associated with BMI-Z score of the ADHD children(B=-0.05, -0.07, P<0.01). Food responsiveness, enjoyment of food and emotional overeating had a positive association with the BMI-Z score(B=0.04, 0.09, 0.05, P<0.05). Conclusion Emotional eating and high food responsiveness in ADHD children are associated with the overweight and obesity, while long eating time and high satiety responsiveness is associated with underweight among ADHD children. For clinical doctors and parents, problematic eating behaviors among ADHD children should be concerned regarding its negative effects on growth and development, besides core symptoms of ADHD.

Objective:To investigate the effect of licochalcone A on osteoarthritis in rats and its relationship with p38-MAPK inflammatory signaling pathway.Methods:A total of 160 male Wistar rats were randomly divided into blank non-intervention, blank intervention, arthritis non- intervention and arthritis intervention groups with 40 rats in each group. Rats in the arthritis groups were subjected to unilateral anterior cruciate ligament transection, while rats in the blank groups were only subjected to skin incision and suture. Rats in the intervention groups were treated by intra-articular injection of 1 mL 10 μmol/L licochalcone A for 8 successive weeks. Eight weeks later, the cartilage of rats in each group was stained with safranin, and osteoarthritis soft tissue was scored according to Osteoarthritis Research Society International guideline under the optical microscope. The cartilage was cultured in low glucose cell culture medium supplemented with 5% fetal bovine serum for 48 hours. The contents of nitric oxide, prostaglandin E 2, sulfated glycosaminoglycan and collagen II in the medium were determined by the chemiluminescence reaction method. The expression levels of p38, phosphorylated p38 (p-p38) and matrix metalloproteinase in cartilage tissue were detected by western blot assay. Results:The progress of osteoarthritis in rats treated with licochalcone A was slow. The Osteoarthritis Research Society International score in the arthritis intervention group was significantly lower than that in the arthritis non-intervention group [(3.8 ± 1.7) points vs. (9.7 ± 1.2) points, P = 0.0064]. The contents of nitric oxide, prostaglandin E 2, sulfated glycosaminoglycan, and collagen II in the arthritis intervention group were (77.84 ± 17.65) μmol/mg and (6.78 ± 1.76) ng/mg, (89.78 ± 9.76) μg/mg, and (1.78 ± 0.76) μg/mg, respectively, which were significantly lower than those in the arthritis non-intervention group [(107.56 ± 18.74) μmol/mg, (10.756 ± 1.87) ng/mg, (125.75 ± 8.87) μg/mg, (3.76 ± 0.88) μg/mg, (NO: P = 0.002; PGE 2: P < 0.001; sGAG: P < 0.001; Collagen II: P < 0.001). Western blot assay results revealed that the relative expression of p38, p-p38, p-p38 to total p38 ratio, matrix metalloproteinase in the arthritis intervention group were (3 454 ± 421), (2 072 ± 175), (0.65 ± 0.14 )and (1 776 ± 765), respectively, which were significantly lower than those in the arthritis non-intervention group (5 322 ± 323), (4 257 ± 184), (0.89 ± 0.11), (3 865 ± 874)( p38: P < 0.001; p-p38: P < 0.001; p-p38/p38: P = 0.002; MMP: P = 0.001). Conclusion:Licochalcone A can delay the progression of osteoarthritis in rats with osteoarthritis through inhibiting inflammatory reaction and cartilage matrix degradation, and p38-MAPK signaling pathway may be involved in the regulation process.