The Impacts of Nirmatrelvir-Ritonavir on Myocardial Injury and Long-Term Cardiovascular Outcomes in Hospitalized Patients with COVID-19 amid the Omicron Wave of the Pandemic.

PURPOSE: Even though nirmatrelvir-ritonavir can improve the short-term morbidity and mortality in COVID-19 patients, the effects of this treatment on long-term major adverse cardiovascular events (MACEs), especially myocardial injury, remains undetermined. METHODS: This prospective cohort study identified hospitalized adult patients with COVID-19 between April 19, 2022, and June 9, 2022, amid the omicron wave of the pandemic. Matched nirmatrelvir-ritonavir-treated and non-treated cohorts were formed using the propensity score matching method. The primary outcome of this study was the incidence of MACEs (cardiovascular death, myocardial infarction, stroke, new-onset heart failure or heart failure hospitalization or ventricular arrhythmia) from 30 days to 16 months after the diagnosis of COVID-19. RESULTS: Two 949-patient cohorts with balanced baseline characteristics were formed by propensity score matching. Patients with nirmatrelvir-ritonavir, compared to those untreated, had a lower level of troponin I peak as well as the incidence of troponin I elevation. During the follow-up period, 59 patients in the nirmatrelvir-ritonavir group and 86 patients in the control group developed MACEs (P = 0.020). Regarding specific constituents of MACEs, the differences are mainly reflected in new-onset heart failure or heart failure hospitalization. COVID-19 clinical severity and troponin I peak were the independent predictors, while nirmatrelvir-ritonavir was the independent protective factor for the occurrence of MACEs in this population. CONCLUSION: Nirmatrelvir-ritonavir was effective in reducing myocardial injury as well as long-term adverse cardiovascular outcomes among hospitalized patients with COVID-19 amid the omicron wave of the pandemic.

[Lipid-lowering effect of seven traditional Chinese medicine monomers in zebrafish system].

The present study aimed to study lipid-lowering effect of seven traditional Chinese medicine monomers in zebrafish system. Zebrafish were fed with high fat diet to establish a hyperlipemia model, then fasted and bathed with seven traditional Chinese medicine monomers stigmasterol, triacontanol, chrysophanol, vanillic acid, shikimic acid, polydatin and oleanolic acid respectively. The oil red O staining was used to detect the blood lipids of zebrafish. Serum total cholesterol and triglyceride levels were detected to validate the lipid-lowering effect. The result showed that a zebrafish model of hyperlipemia could be established by feeding larvae zebrafish with high fat diet. Among the seven traditional Chinese medicine monomers, chrysophanol had lipid-lowering effect. Chrysophanol significantly reduced serum total cholesterol and triglyceride levels in adult zebrafish fed with high fat diet. Chrysophanol accelerated peristalsis frequency of zebrafish intestine and the excretion of high fat food. It is concluded that chrysophanol has lipid- lowering effect in zebrafish, and the mechanism of the effect may be due to the roles of chrysophanol in reducing lipid absorption from gastrointestinal tract and accelerating the excretion of food.

Desorption and mobilization of three strobilurin fungicides in three types of soil.

Phenamacril (JS399-19 with independent intellectual property developed by China), azoxystrobin, and kresoxim-methyl are strobilurin fungicide. Due to their broad spectrum and good control of most of known fungi, strobilurin fungicide has been widely used in agriculture management. Thus, it is important to evaluate their environmental behaviors particularly in soils and underground water. In this study, the sorption/desorption and mobility of strobilurin fungicides in three Chinese soils (Jiangxi red soil, Taihu paddy soil, and Northeast China black soil) were conducted using comprehensively analytic approaches including batch experiment and soil thin-layer chromatography. The strobilurin fungicides were hard to be adsorbed in Jiangxi red soil but had medium adsorption capability in Tanhu paddy soil and Northeast China black soil, while the desorption of three strobilurin fungicides ranked in the order of Jiangxi red soil > Taihu paddy soil > Northeast China black soil. Soil properties including soil organic matter (SOM), pH, and cationic exchange capacity (CEC) affected the adsorption/desorption of the fungicides. Azoxystrobin and kresoxim-methyl had weak mobility in the soils. JS399-19 was moderately mobile in Jiangxi red soil but was not easily moved in Taihu paddy soil and Northeast China black soil. Due to their weak mobility in soils, these strobilurin fungicides tended to remain in the soil phase but not to shift downward to underground water. As azoxystrobin and JS399-19 had a long retention period in soil, there may become persistent residues in the soil environment.

Regulation of transforming growth factor ß-mediated epithelial-mesenchymal transition of lens epithelial cells by c-Src kinase under high glucose conditions.

Recent studies have reported that high glucose (HG) conditions may contribute to the acceleration of renal cell apoptosis and renal fibrosis by inducing epithelial-mesenchymal transition (EMT) of tubular epithelial cells, in which c-Src kinase and transforming growth factor (TGF)-ß are key modulators. In the present study, the roles of c-Src kinase and TGF-ß in EMT of lens epithelial cells (LECs) under HG conditions were investigated. Results indicated human lens epithelial B3 (HLE-B3) cells under HG conditions exhibited significantly increased protein expression levels of phosphorylated c-Src (p-Src418) (P<0.05) and secreted a significantly increased amount of TGF-ß compared with HLE-B3 cells under normal glucose conditions (P<0.05). Notably the c-Src inhibitor PP1 and the activin receptor-like kinase 5 (ALK5) inhibitor SB431542 suppressed EMT of HLE-B3 cells. Results indicated that PP1 significantly inhibited the activities of c-Src and ALK5 and the secretion of TGF-ß, whereas SB431542 only significantly downregulated the protein expression levels and secretion of TGF-ß (P<0.05). Following c-Src knockdown, the protein expression levels of p-Src418, ALK5 and TGF-ß were significantly decreased, the secretion of TGF-ß was significantly suppressed (both P<0.05) and EMT was decreased in HLE-B3 cells. These results suggest that c-Src and TGF-ß may promote EMT of LECs under HG conditions, with c-Src as the upstream regulatory molecule. Thus, the signal axis of c-Src/TGF-ß in EMT of LECs may be a potential novel therapeutic target for the prevention of diabetic subcapsular cataract.

Dihydroartemisinin-induced apoptosis in human acute monocytic leukemia cells.

Dihydroartemisinin (DHA) is a derivative of artemisinin. The present study aimed to investigate whether DHA induces apoptosis in the THP-1 human acute monocytic leukemia cell line (AMoL), and to identify the relative molecular mechanisms. The results of the present study demonstrated that the viability of THP-1 cells were inhibited by DHA in a dose- and time-dependent manner, which was accompanied by morphological characteristics associated with apoptosis. After 24 h of 200 µM DHA treatment, the proportion of apoptotic cells was significantly increased compared with the untreated controls (P<0.01). In addition, DHA downregulated the levels of B-cell lymphoma (Bcl)-2, protein kinase B (Akt)1, Akt2 and Akt3 gene expression, and increased the expression of the Bcl-2-associated X protein apoptosis regulator. The protein expression of phospho-Akt and phospho-extracellular signal-regulated kinase (ERK) was also decreased, and the protein expression level of cleaved caspase-3 was increased following treatment with DHA. Therefore, DHA may induce apoptosis in the AMoL THP-1 cell line via currently unknown underlying molecular mechanisms, including the downregulation of ERK and Akt, and the activation of caspase-3.

Association between long-term prescription of aldosterone antagonist and the progression of heart failure with preserved ejection fraction in hypertensive patients.

BACKGROUND: Hypertension complicated with left ventricular hypertrophy (LVH) and diastolic dysfunction is independently related to increasing risk of subsequent incident heart failure with preserved ejection fraction (HFpEF). This study was designed to evaluate the influences of long-term aldosterone antagonist prescription in these patients. METHODS: Using a propensity score matching of 1:2 ratio, this retrospective claims database study compared spironolactone prescription (n=65) and non-spironolactone therapy (n=130) in hypertensive patients with LVH [left ventricular mass index (LVMI)>125g/m(2) for men and >110g/m(2) for women] and suspected diastolic dysfunction (E/E' ratio between 8 and 15) and without clinical signs or symptoms of heart failure. RESULTS: With a median follow-up of 7.4years, the new-onset symptomatic HFpEF occurred in 3 of 65 patients in the spironolactone group and 21 of 130 patients in the non-spironolactone group (P=0.021). Spironolactone also generated more prominent improvement in diastolic function and LVH. And multivariate logistic regression model revealed that spironolactone prescription (OR 0.177, 95% CI: 0.045-0.687, P=0.012) was associated with a reduced risk of new onset of symptomatic HFpEF, and the elevation of LVMI (OR 1.053, 95% CI: 1.011-1.097, P=0.012) or E/E' (OR 1.280, 95% CI: 1.015-1.615, P=0.037) was associated with a high risk of new onset of symptomatic HFpEF. CONCLUSIONS: Long-term aldosterone antagonist exposure was associated with protective effects in terms of the incidence of new-onset symptomatic HFpEF, LV diastolic dysfunction and LVH in hypertensive patients, which might be beneficial for the delay of HFpEF progression.

Optimizing methods for the study of intravascular lipid metabolism in zebrafish.

The zebrafish (Danio rerio) is a useful vertebrate model for use in cardiovascular drug discovery. The present study aimed to construct optimized methods for the study of intravascular lipid metabolism of zebrafish. The lipophilic dye, Oil Red O, was used to stain fasting zebrafish one to eight days post-fertilization (dpf) and to stain 7-dpf zebrafish incubated in a breeding system containing 0.1% egg yolk as a high-fat diet (HFD) for 48 h. Three-dpf zebrafish were kept in CholEsteryl boron-dipyrromethene (BODIPY) 542/563 C11 water for 24 h which indicated the efficiency of CholEsteryl BODIPY 542/563 C11 intravascular cholesterol staining. Subsequently, 7-dpf zebrafish were incubated in water containing the fluorescent probe CholEsteryl BODIPY 542/563 C11 and fed a high-cholesterol diet (HCD) for 10 d. Two groups of 7-dpf zebrafish were incubated in regular breeding water and fed with a regular or HCD containing CholEsteryl BODIPY 542/563 C11 for 10 d. Finally, blood lipids of adult zebrafish fed with regular or HFD for seven weeks were measured. Oil Red O was not detected in the blood vessels of 7-8-dpf zebrafish. Increased intravascular lipid levels were detected in 7-dpf zebrafish incubated in 0.1% egg yolk, indicated by Oil Red O staining. Intravascular cholesterol was efficiently stained in 3-dpf zebrafish incubated in breeding water containing CholEsteryl BODIPY 542/563 C11; however, this method was inappropriate for the calculation of intravascular fluorescence intensity in zebrafish >7­dpf. In spite of this, intra-aortic fluorescence intensity of zebrafish fed a HCD containing CholEsteryl BODIPY 542/563 C11 was significantly higher (P<0.05) than that of those fed a regular diet containing CholEsteryl BODIPY 542/563 C11. The serum total cholesterol and triglyceride levels of adult zebrafish fed a HFD were markedly increased compared to those of the control group (P<0.05). In conclusion, the use of Oil Red O staining and CholEsteryl BODIPY 542/563 C11 may have applications in zebrafish intravascular lipid metabolism research and screens for novel lipid-regulating drugs.

An application of embryonic skin cells to repair diabetic skin wound: a wound reparation trail.

Cell therapy has shown its power to promote diabetic chronic wound healing. However, problems of scar formation and loss of appendages have not yet been solved. Our study aims to explore the potential of using embryonic skin cells (ESkCs) to repair diabetic wounds. Circular wound was created on the back of the diabetic mice, and ESkCs stained with CM-DIL were transplanted into the wound. Wound area was recorded at the day 4, 7, 11, and 14 after transplantation. The tissue samples were obtained at week 1, 2, and 3, and the tissue sections were stained by transforming growth factor ß1 (TGF-ß1), TGF-ß3, vascular endothelial growth factor (VEGF), and CD31. The new skin formed on the wound of the diabetic mice with ESkC treatment at week 1 but not on the wounds of the non-treatment group. The histological scores of diabetic group with ESkC treatment were significantly better than the non-treatment group (P < 0.05). The fluorescence examination of CM-DIL and CD31 staining indicated that the ESkCs participated in the tissue regeneration, hair follicles formation, and angiogenesis. The expression of TGF-ß1 and VEGF in ESkC-treated groups was noticeable in week 1 but disappeared in week 2. TGF-ß3 was not expressed at week 1 but expressed markedly around hair follicles in week 2 in ESkC-treated groups. Our study demonstrated that ESkCs are capable of developing new skin with appendage restoration to repair the diabetic wounds.

The evaluation of rapid cooling as an anesthetic method for the zebrafish.

As zebrafish became a popular research system in contemporary biomedical research, effective anesthesia, which had low toxicity and high efficacy, was needed. The objective of this article was to evaluate the anesthetic effect of rapid cooling for embryo and larvae zebrafish with ice slush (ice and water admixture). The time to stage 5 anesthesia and maintaining for more than 5 s were detected and compared to MS-222 anesthesia. Besides, the time of recovery from anesthesia, mortality, and the survivability were measured and compared with MS-222 anesthesia. The results showed that anesthesia was generally achieved within 10 s for rapid cooling, which was more rapid than MS-222. The survivability assay demonstrated that rapid cooling was suitable for embryo and larvae zebrafish (1-14 days) and could be used for repeated anesthesia. The most important advantage was that this anesthesia could persist for 10 min and had no mortality. These findings suggested that rapid cooling provided advantages of improved safety, rapid anesthesia, and potentially low mortality rates and could be an effective anesthetic method for scientific research.

Efficacy and safety of drug-eluting stent implantation for the treatment of in-stent restenosis occurring within bare-metal stent and drug-eluting stent.

OBJECTIVE: Although drug-eluting stent (DES) implantation is the primary treatment modality for bare-metal stent (BMS) in-stent restenosis (ISR), little is known about the efficacy and safety profile of DES in the treatment of DES-ISR. The goal of this study was to compare the clinical outcomes following DES treatment for BMS-ISR and DES-ISR. METHODS: Rates of major adverse cardiac events (MACE) were compared in 97 consecutive patients who underwent DES implantation for the treatment of ISR (56 BMS-ISR and 41 DES-ISR) from January 2004 to December 2008. RESULTS: Baseline clinical and procedural characteristics were comparable, except that the DES used in the BMS-ISR group was longer and had a larger diameter. The length of follow-up was (28.60+/-1.96) and (20.34+/-1.54) months for the BMS-ISR and DES-ISR groups, respectively. One patient (1.8%) experienced non-cardiac mortality and one (1.8%) had target-vessel revascularization (TVR) in the BMS-ISR group. In the DES-ISR group, three patients (7.3%) died of sudden death with a documented acute ST-segment elevation myocardial infarction, and three suffered TVR (7.3%). Kaplan-Meier analysis indicated that cumulative survival probability and MACE-free probability were both significantly lower for the DES-ISR group (log rank test P=0.047 and P=0.005, respectively). In Cox regression analysis, DES-ISR remained an independent predictor for future MACE occurrence after adjustment for other factors (compared with BMS-ISR, risk ratio (RR)=8.743, 95% confidence interval (CI) 1.54-49.54, P=0.014). Switching to a different type of DES to treat DES-ISR did not improve the prognosis. CONCLUSION: DES-ISR patients had a poorer prognosis than BMS-ISR patients after DES therapy.

Role of activated endocannabinoid system in regulation of cellular cholesterol metabolism in macrophages.

AIMS: Evidence from recent studies suggests that the endocannabinoid system participates in the regulation of lipid metabolism and body composition. We hypothesize that the system is activated by oxidized low-density lipoprotein (oxLDL) and regulates cellular cholesterol metabolism in macrophages. METHODS AND RESULTS: Primary peritoneal macrophages isolated from Sprague-Dawley rats and RAW264.7 mice macrophages were cultured. A liquid chromatography/mass spectrometry (LC/MS) system was used to measure the endocannabinoid anandamide (AEA), 2-arachidonoylglycerol (2-AG), and cellular cholesterol levels in macrophages. The regulatory mechanisms of cellular cholesterol metabolism were also investigated by molecular biology methods. The results showed that the endocannabinoid system in macrophages was activated by oxLDL through elevation of the AEA and 2-AG levels and the up-regulation of the cannabinoid CB1 and CB2 receptor expression. Win55,212-2, a synthetic cannabinoid, promotes cellular cholesterol accumulation in macrophages, which was associated with an increase in the expression of CD36 and a decrease in the expression of ATP-binding cassette protein A1 (ABCA1) as mediated by an up-regulated peroxisome proliferator-activated receptor gamma (PPARgamma). AM251, a selective cannabinoid CB1 receptor antagonist, impaired the abilities of Win55,212-2-treated macrophages to accumulate cholesterol by down-regulating CD36 receptor expression and up-regulating ABCA1 expression. CONCLUSION: We have demonstrated, for the first time, that the endocannabinoid system in macrophages is activated by oxLDL and that the activated endocannabinoid system promotes cellular cholesterol accumulation in macrophages. The results also indicate that selectively blocking the CB1 receptor can reduce oxLDL accumulation in macrophages, which might represent a promising therapeutic strategy for atherosclerosis.