BACKGROUND Sacubitril/valsartan (S/V) has been shown to be an effective antihypertensive drug combination. However, its therapeutic effects on blood pressure (BP), hemodynamics, and left ventricular (LV) remodeling in resistant hypertension (RHTN) remain unclear. METHODS Eighty-six patients completed this self-control study, during which olmesartan was administered within the first 8 weeks (phase 1), followed by S/V within the second 8 weeks (phase 2), with nifedipine and hydrochlorothiazide taken as background medications. Office BP, echocardiography, and hemodynamics assessment using impedance cardiography were performed at baseline and at the eighth and sixteenth weeks. RESULTS The reduction in office BP was larger in phase 2 than in phase 1 (19.59/11.66 mmHg vs. 2.88/1.15 mmHg). Furthermore, the treatment in phase 2 provided greater reductions in systemic vascular resistance index (SVRI) and thoracic blood saturation ratio (TBR), with differences between the two phases of-226.59 (-1212.80 to 509.55) dyn$s/ cm(5)/m(2) and-0.02 (-0.04 to 0.02). Switching from olmesartan to S/V also significantly reduced E/E', LV mass index, LV end-diastolic volume index, and LV end-systolic volume index (all P < 0.05). Decreases in arterial stiffness, SVRI, and TBR were correlated with changes in indicators of LV remodeling (all P < 0.05). This correlation persisted even after adjusting for confounders including changes in BP. CONCLUSIONS Switching from olmesartan to S/V effectively lowered BP and reversed ventricular remodeling in RHTN. In addition, hemodynamic improvement was also observed. Changes in hemodynamics played an important role in reversing LV remodeling of S/V, and were independent of its antihypertensive effect. (Hellenic Journal of Cardiology 2025;84:51-60) (c) 2024 Hellenic Society of Cardiology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

OBJECTIVES:To investigate the dynamic changes in serum microRNA-15b (miR-15b) and vascular endothelial growth factor (VEGF) in preterm infants with mild or moderate-to-severe bronchopulmonary dysplasia (BPD), as well as their value in assessing short-term neurodevelopment. METHODS:A retrospective analysis was conducted on the medical data of 156 preterm infants with BPD who were admitted to the neonatal intensive care unit from January 2020 to February 2023. According to the severity of BPD, they were divided into a mild group (n=88) and a moderate-to-severe group (n=68). Serum levels of miR-15b and VEGF were measured on postnatal days 1, 7, 14, and 28. Repeated measures analysis of variance was used to assess the dynamic changes in serum levels of miR-15b and VEGF. The mediating effect of VEGF between miR-15b and short-term neurological development was tested and analyzed using the stepwise regression method and the Bootstrap method. Logistic regression analysis was used to identify factors influencing adverse neurodevelopmental outcomes. RESULTS:In the mild group, there was a significant reduction in the serum level of miR-15b and a significant increase in VEGF over time (P<0.05), while in the moderate-to-severe group, there was a significant increase in miR-15b and a significant reduction in VEGF over time (P<0.05). Serum miR-15b and VEGF levels were important factors influencing neurodevelopmental outcomes, showing independent correlations (P<0.001). The mediating effect analysis indicated that miR-15b indirectly affected short-term neurodevelopment by inhibiting VEGF expression [indirect effect: -0.705 (95%CI: -1.178 to -0.372)], with the indirect effect accounting for 54.36% of the total effect. CONCLUSIONS:There are different changing trends in serum levels of miR-15b and VEGF in preterm infants with mild and moderate-to-severe BPD. miR-15b primarily influences neurodevelopment through VEGF.

Background Takotsubo syndrome (TTS) primarily manifests as a cardiomyopathy induced by physical or emotional stress, remains a poorly understood condition with no established treatments. In this study, we investigated the potential of sacubitril/valsartan (sac/val) to increase the survival of TTS patients and reduce inflammation and myocardial fibrosis in experimental models. Aim This study aimed to evaluate whether sac/val could improve survival rates in TTS patients, mitigate cardiac remodeling in vivo, and explore its anti-inflammatory and antifibrotic mechanisms in vitro. Methods Clinical cases from the Chinese Takotsubo syndrome (ChiTTS) registry were analyzed to assess patient survival rates. In addition, we used isoprenaline (ISO)-induced TTS-like animal models, pre-treated with sac/val, to evaluate cardiac function and inflammatory response. Additionally, the effects of isoprenaline on cardiomyocytes and myocardial fibroblasts, as well as protection from rhBNP, were thoroughly studied. Results In TTS patients with a left ventricular ejection fraction (LVEF) ≤ 0.45, hyperglycemia, emotional stress, and inflammation were identified as independent risk factors. Moreover, the baseline characteristics of the TTS patients, heart rate, emotional triggers, female sex (%), WBC count, IL-6 concentration, PCT, ALT, AST and TG were significantly associated with decreasing left ventricular ejection fraction. In TTS patients, sac/val reduced inflammation, evidenced by lower levels of white blood cells and interleukin 6, compared to patients who did not receive sac/val by day 30. In animal models, Sac/val improved cardiac dysfunction in ISO-induced TTS-like cardiomyopathy and decreased myocardial inflammatory responses (IL-18 and Mac-3) by inhibiting the TLR4/NF-κB pathway and fibrosis through the inhibition of the TGFβ1/Smad pathway. Conclusions This study revealed that sac/val decreased inflammatory responses, myocardial edema, and fibrosis, resulting in an increased percentage of survivors in the TTS group. Similar to findings from in vivo and in vitro experiments, sac/val exerted cardioprotective effects by reducing the inflammatory response and reversing myocardial remodeling mediated by the TLR4/NF-κB and TGFβ1/Smad pathways. In conclusion, these findings highlight the anti-inflammatory and antifibrotic effects of sac/val in individuals with TTS.

Background The prevalence of obesity and its associated diseases has sharply increased, becoming a global health issue. White adipose tissue (WAT), responsible for lipid storage via hyperplasia and hypertrophy, and brown adipose tissue (BAT), which facilitates energy dissipation, have increasingly been recognized as critical regulators of weight loss. Shouhui Tongbian Capsule (SHTB) has traditionally been used for detoxification, weight loss, and lipid reduction, and clinical evidence supports its use for relieving constipation. In traditional Chinese medicine (TCM), "dissipating turbidity" is seen as a shared approach to treating both constipation and obesity. Our evidence suggests that SHTB improves obesity and metabolic disorders, but the underlying mechanisms remain unclear. Purpose This study aimed to evaluate the pharmacological effects of SHTB on obesity and to explore the underlying mechanisms involved. Methods Obese mice induced by a high-fat diet were treated with SHTB, and effects on body weight, adipose tissue, and metabolism were assessed. Active ingredients were identified through UPLC-MS, while metabolomics and RNA sequencing were performed to explore the mechanisms of SHTB in obesity, and molecular biology techniques validated its effects on energy consumption and lipolysis in adipose tissue. Finally, rescue experiments in vivo and in vitro confirmed the proposed mechanisms. Results SHTB significantly reduced body weight, body fat percentage, and WAT mass while increasing BAT weight, and enhancing energy expenditure. Metabolomics and RNA sequencing indicated activation of the G-protein coupled receptor signaling and cAMP-PKA pathway, leading to increased lipolysis in WAT and enhanced thermogenesis in BAT. H89, a PKA agonist, counteracted these effects, supporting the involvement of cAMP-PKA signaling. Conclusion SHTB may prevent obesity by promoting lipolysis and enhancing BAT thermogenesis via the cAMP-PKA pathway, offering a potential therapeutic approach for obesity management.

Background. Antimicrobial resistance (AMR) poses increasing threats of mortality among neonates in low- and middle-income countries (LMICs). In response, the WHO classified antibiotics for Children into three groups: Access, Watch, and Reserve. We aimed to present data on AMR of late-onset sepsis (LOS) in preterm infants by the Access-Watch-Reserve classification and investigate risk factors of multidrug-resistant (MDR) bacteria. Methods. A prospective observational cohort study was conducted in 31 neonatal intensive care units in China (January 1, 2018, to December 31, 2022). Preterm infants (gestational age<32 weeks or birth weight<1500g) were enrolled, and followed up until discharge or death. LOS was defined as occurrence of sepsis after 3 days of life. We identified factors associated with MDR bacteria through multi-variable logistic regression analysis. Results. Among 8384 infants, 614 (7.3%) were diagnosed with LOS, of which 338 (55%) were caused by gram-negative bacteria (GNB), 181 (29.5%) by gram-positive bacteria, 95 (15.5%) by fungi. Klebsiella spp. (58.3%), Escherichia coli (13.6%), Enterobacter spp. (8.3%), Acinetobacter baumannii (8.0%) and Pseudomonas aeruginosa (5%) were top five common GNB. Amikacin listed as Access antibiotic had the lowest resistance rates ranging from 0–8.1%. Resistance rates remained high in Watch antibiotics, with ceftriaxone or ceftazidime ranging from 5.9–70.7% and meropenem ranging from 4.3–24.9%. Resistance rates of cefepime, classified as Reserve antibiotic, range from 5.9–40.3%. MDR rates ranged from 5.9–47.7%, and extensively drug-resistant rates from 0–7.6%. Antibiotic spectrum index per antibiotic day and a 10% increase in antibiotic use rate before onset of LOS were associated with MDR bacteria infections (p = 0.041, OR = 1.112, 95% CI 1.005–1.230 and p<0.001, OR = 1.383, 95% CI 1.226–1.560). Case fatality rate was higher among preterm infants with MDR bacteria than non-MDR bacteria infections (20.5% vs 11.4%, P = 0.023). Conclusions. GNB predominated in LOS, with a high resistance rate of Watch antibiotics and substantial proportion of MDR bacteria, which had higher mortality rate and were associated with excessive antibiotic exposure before onset of LOS. Conducting AMR surveillance and implementation of antimicrobial stewardship interventions are urgently needed in LMICs.

Abstract Background: Takotsubo syndrome mostly manifests as stress-induced cardiomyopathy after physical or emotional stress. However, the exact pathological mechanism of TTS remains unclear, and specific therapies are still lacking. Therefore, we investigated the potential therapeutic effect and mechanism of sacubitril/valsartan (sac/val) on preventing myocarditis and fibrosis in patients with TTS. This study detected inflammatory responses, myocardial edema, fibrosis, etc., in TTS individuals and investigated whether sac/val increased the survival of TTS patients and reversed the remodeling of TTS animal hearts in vivo and investigated the effects of anti-myocardial inflammation and fibrosis in vitro. Methods: Based on the Chinese Takotsubo syndrome (ChiTTS) registry, clinical cases were enrolled to investigate survival. Isoprenaline-induced Takotsubo-like animal models were established, and the animals were pretreated with sac/val. In addition, the effects of isoprenaline on cardiomyocyte and myocardial fibroblasts and protection from rhBNP were studied in detail. Results: In the TTS group diagnosed with an LVEF ≤ 0.45, hyperglycemia, emotional stress and inflammation were found to be independent risk factors. Moreover, the baseline characteristics of the TTS patients, heart rate, emotional triggers, female sex (%), WBC count, IL-6 concentration, PCT, ALT, AST and TG were significantly associated with decreasing left ventricular ejection fraction. Sac/val decreased inflammation, as indicated by white blood cells and interleukin-6, in TTS patients compared with that in patients not receiving sac/val on day 30. During the follow-up, the percentage of surviving patients increased significantly in the TTS group treated with sac/val compared with the group not treated with sac/val at 30 days and 1 year. In animal models, Sac/val improved cardiac dysfunction in ISO-induced TTS-like cardiomyopathy and decreased myocardial inflammatory responses (IL-18 and Mac-3) by inhibiting the TLR4/NF-κB pathway and fibrosis through the inhibition of the TGFβ1/Smad pathway. Conclusions: This study revealed that sac/val decreased inflammatory responses, myocardial edema, fibrosis, etc., resulting in an increase in the percentage of surviving TTS patients. Like in vivo and in vitro experiments, Sac/val exerted cardioprotective effects by decreasing the inflammatory response and reversing myocardial remodeling. Overall, these findings demonstrate the anti-inflammatory and antifibrotic effects of sac/val in individuals with TTS.

糖尿病心肌病(DCM)指由糖尿病引起的,不能用冠状动脉粥样硬化性心脏病、高血压心脏病、瓣膜性心脏病及其他心脏病变解释的心肌病变,其表现为舒张或收缩功能障碍,最终发展为心力衰竭,与糖尿病患者的高死亡率密切相关.DCM的发病机制复杂,尚缺少特异性治疗方法.沉默信息调节因子6(SIRT6)是新近发现的DCM的治疗靶点,其可广泛参与DNA修复、端粒维持、糖脂代谢、炎症反应等多种生理活动.本文主要综述了DCM的发病机制、治疗,并分析了SIRT6调控DCM的机制:减轻心肌纤维化和脂毒性、抗氧化应激和抗炎、调控线粒体功能,以期为DCM的治疗提供一定参考.

OBJECTIVE:There is limited data about the use of a Judkins left (JL) 3.5 guiding catheter for routine transradial right coronary artery (RCA) percutaneous coronary intervention (PCI). This study investigated the safety and efficacy of JL3.5 for RCA PCI.PATIENTS AND METHODS:Patients with acute coronary syndrome (ACS) who underwent transradial RCA PCI between November 2019 and November 2020 at the Second Hospital of Shandong University were included. The study retrospectively compared JL 3.5 vs. other routine guiding catheters (GCs), including Judkins right (JR) 4.0 and Amplatz (left). Logistic multivariable analysis was used to analyze the factors associated with transradial RCA PCI success rate, in-hospital complications, and extra support.RESULTS:The study included 311 patients: 136 in the routine GC group and 175 in the JL 3.5 group. There were no significant differences between the two groups regarding in-hospital complications, extra support technics, or success. The multivariable analyses showed that coronary chronic total occlusion (CTO) was negatively associated with intervention success (OR = 0.06, 95% CI: 0.016-0.248, p < 0.001) but positively with extra support (OR = 8.74, 95% CI: 1.518-50.293, p = 0.015). Tortuosity was associated with extra support (OR = 16.50, 95% CI: 3.324-81.589, p = 0.001). In the JL 3.5 group, the left ventricular ejection fraction (OR = 1.11, 95% CI: 1.03-1.20, p = 0.006), CTO (OR = 0.07, 95% CI: 0.008-0.515, p = 0.009), and tortuosity (OR = 0.17, 95% CI: 0.03-0.95, p = 0.043) were independently associated with intervention success.CONCLUSIONS:JL 3.5 appears to be as safe and effective as the JR 4.0 and Amplatz (left) catheters for RCA PCI. When using the JL 3.5 catheter for RCA PCI, heart function, CTO, and tortuosity should be considered.

Purpose:Significant antibiotic overuse due to prolonged antibiotic duration has not draw enough attention in developing countries with high antibiotic consumption. We aimed to describe the current status of prolonged early antibiotic duration in very-low-birth-weight (VLBW) infants in a large regional multicenter cohort in China. Patients and Methods:Institution-based prospective cohort study was conducted in all VLBW infants admitted to 16 Grade A tertiary hospitals between January 1, 2019 and December 31, 2020. Early antibiotic use was defined as antibiotic initiation within the first 3 days of life. Prolonged early antibiotic course was defined as early antibiotic initiation for more than 7 days in infants with early-onset sepsis (EOS) or more than 3 days in infants with unlikely EOS. Antibiotic use was described as days of therapy (DOT) per 1000 patient days (PD). Results:Among 1684 eligible VLBW infants, 1544 (91.7%) infants were prescribed with prolonged early antibiotic course, including 618 infants with EOS and 926 infants with unlikely EOS. The median duration of early antibiotic course was 13 (IQR 8;20) days, with 78.0% of courses >7 days and 43.6% of courses >14 days. Total early antibiotic use was 408.3DOT/1000Pd, of which prolonged antibiotic courses accounted for 98.2% of all antibiotic use days. More than three antibiotics used, escalation antibiotic therapy, antibiotics for special use and the use of third generation cephalosporins and carbapenems were significantly common in prolonged courses compared to short courses in both infants with EOS and unlikely EOS group (P<0.05). Conclusion:A large proportion of VLBW infants had excessively prolonged early antibiotic durations in the regional multicenter in China. Timely discontinuation of antibiotics in VLBW infants according to standardized guidelines and limit on the use of third-generation cephalosporins and carbapenems may be key drivers in reducing the antibiotic overuse in developing countries like ours.

It is not determined whether serum visfatin levels are related to the presence and severity of coronary artery disease (CAD) in non-diabetic subjects. In this study, a total of 65 consecutive non-diabetic participants who underwent coronary angiography were enrolled. Serum visfatin and fasting glucose, as well as the serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride, were measured in all participants before the procedure. The extent of coronary artery lesions was determined by Gensini score. Serum visfatin levels were significantly lower in patients with CAD compared to participants with normal coronary arteries. Inversely, the circulating levels of fasting glucose were found to be elevated in patients with CAD compared with the control subjects. Multivariable logistic regression analysis demonstrated that visfatin and impaired fasting glucose (IFG) were independently associated with the presence of CAD in non-diabetics. No significant relationship was found between serum visfatin and fasting glucose levels in IFG subjects. However, there was a negative association between visfatin concentrations and Gensini score in participants with IFG. Both circulating visfatin concentrations and IFG are independently associated with CAD in non-diabetics. Serum visfatin levels are negatively related to the angiographic severity of CAD in subjects with IFG.

Purpose Enhanced external counterpulsation (EECP) is a new non-drug treatment for coronary artery disease (CAD). However, the long-term effect of EECP on endothelial dysfunction and exercise tolerance, and the relationship between the changes in the endothelial dysfunction and exercise tolerance in the patients with coronary heart disease are still unclear. Methods A total of 240 patients with CAD were randomly divided into EECP group (n = 120) and control group (n = 120). All patients received routine treatment of CAD as the basic therapy. Patients in the EECP group received 35 1-h daily sessions of EECP during 7 consecutive weeks while the control group received the same treatment course, but the cuff inflation pressure was 0–10 mmHg. Peak systolic velocity (PSV), end diastolic velocity (EDV), resistance index (RI), and inner diameter (ID) of the right carotid artery were examined using a Color Doppler Ultrasound and used to calculate the fluid shear stress (FSS). Serum levels of human vascular endothelial cell growth factor (VEGF), vascular endothelial cell growth factor receptor 2 (VEGFR2), and human angiotensin 2 (Ang2) were determined by enzyme-linked immunosorbent assay (ELISA). Exercise load time, maximal oxygen uptake (VO2max), metabolic equivalent (METs), anaerobic threshold (AT), peak oxygen pulse (VO2max/HR) were assessed using cardiopulmonary exercise tests. Results After 1 year follow-up, the EDV, PSV, ID, and FSS were significantly increased in the EECP group (P < 0.05 and 0.01, respectively), whereas there were no significant changes in these parameters in the control group. The serum levels of VEGF and VEGFR2 were elevated in the EECP and control groups (all P < 0.05). However, the changes in VEGF and VEGFR2 were significantly higher in the EECP group than in the control group (P < 0.01). The serum level of Ang2 was decreased in the EECP group (P < 0.05) and no obvious changes in the control group. As for exercise tolerance of patients, there were significant increases in the exercise load time, VO2max, VO2max/HR, AT and METs in the EECP group (all P < 0.05) and VO2max and METs in the control group (all P < 0.05). Correlation analyses showed a significant and positive correlations of VEGF and VEGFR2 levels with the changes in FSS (all P < 0.001). The correlations were still remained even after adjustment for confounders (all Padjustment < 0.001). Linear regression displays the age, the medication of ACEI (angiotensin-converting enzyme inhibitors) or ARB (angiotensin receptor blockers), the diabetes and the changes in VEGF and VEGFR2 were positively and independently associated with the changes in METs after adjustment for confounders (all Padjustment < 0.05). Conclusion The data of our study suggested that EECP is a useful therapeutic measurement for amelioration of endothelial dysfunction and long-term elevation of exercise tolerance for patients with coronary heart disease. Clinical trial registration [http://www.chictr.org.cn/], identifier [ChiCTR1800020102].

Background. Cardiac fibrosis (CF) is major myocardial change in diabetic cardiomyopathy (DCM). Yangxinshi as a Chinese medicine formula is used to treat cardiovascular diseases. However, the exact effective mechanism of Yangxinshi on CF is still uncertain. Hence, based on the pharmacological network, predicting the active components, potential targets and pathways of Yangxinshi on diabetic fibrosis require to be further studied. Materials and Methods. By using Cytoscape 3.6.0 Bisogenet plug-in, the active components of Yangxinshi were obtained and screened through TCMSP, and the PPI network of DCM-CF was constructed and then screened by CytoNCA plug-in. GO analysis and KEGG pathway enrichment analysis were carried out by Cluego plug-in. Combined with the results of network pharmacological analysis, cells in vitro were performed to verify the CF stimulated with high glucose or intervence with Yangxinshi, and the expressions of Cbl-b, p-smad2, and α-SMA were detected. Results. Yangxinshi might play a key role in reversing cardiac fibrosis in individuals with DCM by regulating the signal pathway of CBL and promoted the expression of Cbl-b and inhibited the expression of p-smad2 and α-SMA, verifying some predictive work via network pharmacology. Conclusion. Based on network pharmacology, this study demonstrates that the beneficial effect of Yangxinshi on CF is related to the Cbl-b/smad2 pathway, providing an idea for the therapeutic effect of Yangxinshi on cardiac fibrosis in DCM.

应激性心肌病(SC)是一种急性可逆性心力衰竭综合征,好发于绝经期女性,大多数患者在发病前遭受过心理或生理的应激刺激,临床表现与急性冠脉综合征患者相似.目前该病确切的发病机制尚未明确,可能由几个不同途径单独或协同作用导致.由于SC诊断率的逐年提升,人们对该病的认识也不断深入,本文就SC的流行病学、触发因素和易感因素、病理生理学、临床特征、诊断、治疗、预后进行综述,以提高临床对该病的认识.

Abstract Background The left ventricular ejection fraction (LVEF) plays a pivotal role in the diagnosis and prediction of ischemic heart disease (IHD). Current techniques to measure LVEF have led to some complications and are relatively expensive despite the high accuracy. Heart rate variability (HRV) is an alternative for the assessment of cardiac function and its related parameters are easily to be derived from electrocardiography. Objective This study aimed to investigate the corresponding relationship between LVEF and HRV in patients with IHD via prediction models developed by machine learning techniques and compare the accuracy of these models. Methods In this retrospective real-world study, patients with IHD admitted to Jinan 4th People’s hospital between January 2019 and December 2020 were randomly selected and divided into a derivation cohort and a validation cohort in a 7:3 ratio. LVEF were measured by color Doppler echocardiography while HRV-related parameters were derived from a 24h Holter electrocardiography recordings. Patient clinical features and HRV parameters were identified and used in the subsequent modelling process. Logistic regression, naïve Bayes, decision tree, gradient boosting, extreme gradient boosting (XGBoosting) and random forests were respectively applied to estimate the correlation between HRV and LVEF. Model performances were evaluated by the coefficient R2 (the closer the result is to 1, the better) and the accuracy (a precise prediction was defined as the accuracy ≥ 90%). Results A total of 179 patients were included in this study with 125 (mean age 67.03 ± 16.12, male 72 [53.7%]) in the derivation cohort and 54 (mean age 62.51 ± 12.97, male 19 [48.7%]) in the validation cohort. Six variables including sex, age, SDNN, SDANN, rMSSD and pNN50 were found to be correlated with LVEF. Gradient boosting and random forests outperformed other machine learning models, showing the best prediction performance (> 90%) in the prediction of both LVEF percentage (%) and LVEF stratifications (< 40%, 40–50%, > 50%). These six indicators showed different contributions in different algorithms with sex as the least important indicator. Conclusion Gradient boosting and random forests machine learning models based on HRV- and patient characteristics-related parameters provided a new method in predicting LVEF in patients with IHD, which showed a potential in the diagnosis of IHD.

OBJECTIVE: Experimental autoimmune myocarditis (EAM) is characterized by pronounced macrophage infiltration, cardiac necrosis, and cardiac fibrosis. Our previous studies have demonstrated that suppressed androgen receptor (AR) enables anti-inflammation to promote tissue repair by decreasing M1 macrophages and increasing M2 macrophages in an EAM model. Given that autophagy mediates inflammatory response in macrophages, we investigated whether AR inhibition executes its protective role in inflammation through the autophagy pathway in EAM. MATERIALS AND METHODS: To determine whether AR inhibition can perform its anti-inflammatory effects by upregulating autophagy, we pre-treated mice with 3-methyl adenine (3-MA), a pharmacological inhibitor of autophagy. Immunofluorescence assay and Western blot were used to detect autophagy levels and autophagy activity in five different groups. Immunofluorescence marked F4/80 and LC3 to illustrate the autophagy level in macrophages. TUNEL assays were used to detect the apoptosis level in heart tissue of five different groups. RESULTS: We demonstrated that AR inhibition resolves injury with sustained inhibition of inflammatory cytokines associated with enhanced autophagy, especially in macrophages. Increased LC3II/I expression corroborated complete autolysosome formation detected by electron microscopy and correlated with degradation of SQSTM1/p62 in the AR inhibition group by Western blot. These effects could be reversed within 3-MA, a pharmacological inhibitor of autophagy. Specifically, pharmacological inhibition of autophagy increased apoptosis and inflammation, which could be attenuated by AR inhibition. CONCLUSIONS: AR inhibition alleviates the inflammatory response and tissue apoptosis by enhancing autophagy, especially in macrophages.

Protein deglycase DJ‐1 (DJ‐1) is a multifunctional protein involved in various biological processes. However, it is unclear whether DJ‐1 influences atherosclerosis development and plaque stability. Accordingly, we evaluated the influence of DJ‐1 deletion on the progression of atherosclerosis and elucidate the underlying mechanisms. We examine the expression of DJ‐1 in atherosclerotic plaques of human and mouse models which showed that DJ‐1 expression was significantly decreased in human plaques compared with that in healthy vessels. Consistent with this, the DJ‐1 levels were persistently reduced in atherosclerotic lesions of ApoE−/− mice with the increasing time fed by western diet. Furthermore, exposure of vascular smooth muscle cells (VSMCs) to oxidized low‐density lipoprotein down‐regulated DJ‐1 in vitro. The canonical markers of plaque stability and VSMC phenotypes were evaluated in vivo and in vitro. DJ‐1 deficiency in Apoe−/− mice promoted the progression of atherosclerosis and exaggerated plaque instability. Moreover, isolated VSMCs from Apoe−/−DJ‐1−/− mice showed lower expression of contractile markers (α‐smooth muscle actin and calponin) and higher expression of synthetic indicators (osteopontin, vimentin and tropoelastin) and Kruppel‐like factor 4 (KLF4) by comparison with Apoe−/−DJ‐1+/+ mice. Furthermore, genetic inhibition of KLF4 counteracted the adverse effects of DJ‐1 deletion. Therefore, our results showed that DJ‐1 deletion caused phenotype switching of VSMCs and exacerbated atherosclerotic plaque instability in a KLF4‐dependent manner.

OBJECTIVE: SIRT6 is an NAD-dependent histone deacetylase known to regulate aging, inflammation and energy metabolism, and might play an important role in atherosclerosis. However, whether it also plays a role in coronary artery disease (CAD) remains unclear. PATIENTS AND METHODS: In this study, we detected the expression of SIRT6 in serum by Western blotting. The concentrations of SIRT6 in serum specimens from 69 patients with CAD [30 with stable angina (SA) and 39 with acute coronary syndrome (ACS)] and 16 controls were analysed using the enzyme-linked immunosorbent assay (ELISA) method. RESULTS: Western blotting analysis of the serum samples found that SIRT6 expression was decreased in the SA group (p=0.000) and ACS group (p=0.000) compared with the control group. Significantly lower levels of serum SIRT6 were observed in SA patients (18.80±9.14 ng/mL) and ACS patients (16.85±9.66 ng/mL) than in healthy controls (25.79±14.23 ng/mL). SIRT6 concentrations were positively correlated with other markers of CAD, such as high-density lipoprotein cholesterol (r=0.362, p<0.01) and age (r=0.265, p<0.05), and negatively correlated with blood glucose (r=-0.284, p<0.05). Multivariate logistic regression analysis demonstrated that lower SIRT6 levels were independently associated with the presence of CAD in men (OR=0.817, 95% CI 0.694-0.962, p=0.015). Receiver operating characteristic (ROC) curve analysis showed that lower serum SIRT6 could distinguish CAD patients (AUC, 0.726; 95% CI, 0.508-0.943; p=0.041) from controls. SIRT6 is found downregulated in blood vessels of atherosclerotic APOE-/- mice and human aorta arteries. CONCLUSIONS: We demonstrated that SA and ACS patients had lower serum concentrations of SIRT6. The decreased serum SIRT6 level was independently associated with the diagnosis of CAD. SIRT6 may play a cardioprotective role in CAD patients, and future research is required to address this issue.

Background At present, the relationship between thyrotropin (TSH) and free thyroxine (FT4) in relation to postmenstrual age (PMA) in preterm infants is still unclear, and there is no reliable standard thyroid hormone reference ranges, resulting in different diagnostic criteria for congenital hypothyroidism been used by different newborn screening programs and different countries. Objectives To investigate the relationship between TSH/FT4 and PMA in very preterm infants (VPIs) born with gestational age (GA) <32 weeks and to derive thyroid function reference charts based on PMA. Methods A prospective cohort study was performed on VPIs born with GA<32 weeks and born in or transferred to the 27 neonatal intensive care units from January 1, 2019 to December 31, 2019. Serial TSH and FT4 values were measured at the end of each week during the first month after birth and also at PMA36 weeks, PMA40 weeks and at discharge, respectively. The 2.5th, 5th, 50th, 95th, and 97.5th percentiles of TSH and FT4 of different PMA groups were calculated to draw the percentile charts based on PMA. Results 1,093 preterm infants were included in this study. The percentile charts of TSH and FT4 levels based on PMA were drawn respectively, and the result indicated that the percentile charts of TSH values were gradually increased initially and then decreased with increasing PMA. The 97.5th percentile chart reached the peak at PMA30 weeks (17.38μIU/ml), and then decreased gradually, reaching the same level as full-term infants (9.07μIU/ml) at PMA38–40 weeks. The 2.5th percentile chart of FT4 was at its lowest point at PMA26–27 weeks (5.23pmol/L), then increased slowly with PMA and reached the same level as full-term infants at PMA38–40 weeks (10.87pmol/L). At PMA36 weeks, the reference intervals of the 2.5th to 97.5th percentiles of TSH and FT4 were 1.18–12.3μIU/ml and 8.59–25.98pmol/L, respectively. Conclusion The percentile charts of TSH and FT4 in VPIs showed characteristic change with PMA. The results prompt that age-related cutoffs, instead of a single reference range, might be more useful to explain the thyroid function of VPIs. And repeated screening is necessary for preterm infants.

Saxagliptin (SAX) can protect against tissue damage caused by diabetic nephropathy. However, whether this compound can restore kidney function, and its specific mechanism of action remain unclear. The present study explored the therapeutic effects and mechanisms of SAX. Male Wistar rats (8 weeks old) were randomly divided into the following groups: A control group (n=10); a group with streptozocin-induced diabetes mellitus (DM) treated with saline (n=20); and a group with streptozocin-induced DM treated with SAX (n=20). Following 20 weeks of treatment, renal function and the extent of renal damage were assessed based on histological staining using hematoxylin and eosin, periodic acid-Schiff and Masson's trichrome staining. The experimental results indicated that Streptozocin induction of DM led to thicker basement membranes in mesangial cells and a more abundant extracellular matrix. These changes were ameliorated following treatment with SAX. The data demonstrated that renal tissue and renal cell apoptosis were ameliorated significantly following treatment with SAX. Furthermore, the expression levels of the apoptotic genes poly (ADP-ribose) polymerase-1 (PARP-1) and caspase 3 were significantly decreased following treatment with SAX. Therefore, SAX may reduce the extent of renal apoptosis and pathological outcomes in diabetic nephropathy by downregulating the expression of caspase 3 and PARP-1 in the death receptor pathway of apoptosis.