The analysis of low-dose glucocorticoid maintenance therapy in patients with primary nephrotic syndrome suffering from COVID-19.

Objectives: This study aimed to describe the effects of low-dose (prednisolone acetate 2.5-7.5 mg/day) glucocorticoids (GCs) maintenance therapy in patients with primary nephrotic syndrome (NS) suffering from coronavirus disease 2019 (COVID-19). Methods: A single-center retrospective study of NS patients with COVID-19 infection in Zhongda Hospital Affiliated to Southeast University from 1 February 2022 to 31 March 2023 was conducted. All enrolled patients underwent renal biopsy for the pathological diagnosis and reached complete remission (CR) or near-CR before COVID-19 infection. According to the maintained therapy regimen, patients were divided into low-dose GCs group and non-GCs group. Results: A total of 125 patients were enrolled in the study. Their median age was 46.0 ± 15.6 years, and the median value of 24-h urine protein was 0.77 g. The majority of these patients received treatment for more than 6 months, with a significant portion achieving CR (29.6%) or near-CR (43.2%). The leading cause of NS was membranous nephropathy (52%). There were no significant differences in the baseline characteristics between low-dose GCs and non-GCs group. As compared to those in the non-GCs group, patients receiving low-dose GCs treatment showed less fatigue or muscle weakness, smell disorder, palpitations, decreased appetite, taste disorder, dizziness, sore throat or difficult to swallow and fever (p < 0.05). Moreover, patients in the low-dose GCs group were with higher median quality of life scores (85.0) than in the non-GCs group (p = 0.001). Further serum inflammatory factor analysis indicated that interleukin-6 (IL-6) levels in the non-GCs group were significantly higher than that in the low-dose GCs group (p < 0.05). Conclusion: Patients with NS in low-dose GCs maintenance therapy stage showed milder symptom, higher quality of life and decreased serum IL-6 levels compared to those, who were not on GCs maintenance therapy. These results suggest the beneficial effect of low-dose GCs therapy in NS patients with CR/near-CR suffering from COVID-19 infection.

Tanshinone IIA reduces pyroptosis in rats with coronary microembolization by inhibiting the TLR4/MyD88/NF-κB/NLRP3 pathway.

Pyroptosis is an inflammatory form of programmed cell death that is linked with invading intracellular pathogens. Cardiac pyroptosis has a significant role in coronary microembolization (CME), thus causing myocardial injury. Tanshinone IIA (Tan IIA) has powerful cardioprotective effects. Hence, this study aimed to identify the effect of Tan IIA on CME and its underlying mechanism. Forty Sprague-Dawley (SD) rats were randomly grouped into sham, CME, CME + low-dose Tan IIA, and CME + high-dose Tan IIA groups. Except for the sham group, polyethylene microspheres (42 µm) were injected to establish the CME model. The Tan-L and Tan-H groups received intraperitoneal Tan IIA for 7 days before CME. After CME, cardiac function, myocardial histopathology, and serum myocardial injury markers were assessed. The expression of pyroptosis-associated molecules and TLR4/MyD88/NF-κB/NLRP3 cascade was evaluated by qRT-PCR, Western blotting, ELISA, and IHC. Relative to the sham group, CME group's cardiac functions were significantly reduced, with a high level of serum myocardial injury markers, and microinfarct area. Also, the levels of caspase-1 p20, GSDMD-N, IL-18, IL-1ß, TLR4, MyD88, p-NF-κB p65, NLRP3, and ASC expression were increased. Relative to the CME group, the Tan-H and Tan-L groups had considerably improved cardiac functions, with a considerably low level of serum myocardial injury markers and microinfarct area. Tan IIA can reduce the levels of pyroptosis-associated mRNA and protein, which may be caused by inhibiting TLR4/MyD88/NF-κB/NLRP3 cascade. In conclusion, Tanshinone IIA can suppress cardiomyocyte pyroptosis probably through modulating the TLR4/MyD88/NF-κB/NLRP3 cascade, lowering cardiac dysfunction, and myocardial damage.

Development and verification of the nomogram for dilated cardiomyopathy gene diagnosis.

Dilated cardiomyopathy (DCM) is a primary myocardial disease of unclear mechanism and poor prevention. The purpose of this study is to explore the potential molecular mechanisms and targets of DCM via bioinformatics methods and try to diagnose and prevent disease progression early. We screened 333 genes differentially expressed between DCM and normal heart samples from GSE141910, and further used Weighted correlation network analysis to identify 197 DCM-related genes. By identifying the key modules in the protein-protein interaction network and Least Absolute Shrinkage and Selection Operator regression analysis, seven hub DCM genes (CX3CR1, AGTR2, ADORA3, CXCL10, CXCL11, CXCL9, SAA1) were identified. Calculating the area under the receiver's operating curve revealed that these 7 genes have an excellent ability to diagnose and predict DCM. Based on this, we built a logistic regression model and drew a nomogram. The calibration curve showed that the actual incidence is basically the same as the predicted incidence; while the C-index values of the nomogram and the four external validation data sets are 0.95, 0.90, 0.96, and 0.737, respectively, showing excellent diagnostic and predictive ability; while the decision curve indicated the wide applicability of the nomogram is helpful for clinicians to make accurate decisions.

miR-200a-3p Attenuates Coronary Microembolization-Induced Myocardial Injury in Rats by Inhibiting TXNIP/NLRP3-Mediated Cardiomyocyte Pyroptosis.

Coronary microembolization (CME) commonly develops as a complication after percutaneous coronary intervention (PCI), and associated inflammation is a leading driver of myocardial damage. Cardiomyocyte loss in the context of ischemic myocardial disease has been linked to inflammatory pyroptotic cell death. Additionally, miR-200a-3p dysregulation has been linked to myocardial ischemia-reperfusion and many other pathological conditions. However, how miR-200a-3p impacts cardiomyocyte pyroptosis in the context of CME remains to be assessed. Herein, a rat model of CME was established via the injection of microembolic spheres into the left ventricle. When myocardial tissue samples from these rats were analyzed, miR-200a-3p levels were markedly decreased, whereas thioredoxin-interacting protein (TXNIP) levels were increased. The ability of miR-200a-3p to directly target TXNIP and to control its expression was confirmed via dual-luciferase reporter assay. Adeno-associated virus serotype 9-pre-miR-200a-3p (AAV-miR-200a-3p) construct transfection was then employed as a means of upregulating this miRNA in CME model rats. Subsequent assays, including echocardiography, enzyme-linked immunosorbent assays (ELISAs), hematoxylin-eosin (H&E) staining, hematoxylin-basic fuchsin-picric acid (HBFP) staining, TdT-mediated dUTP nick-end labeling (TUNEL) staining, immunofluorescence staining, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting revealed that miR-200a-3p overexpression inhibited cardiomyocyte pyroptosis and alleviated CME-induced myocardial injury by inhibiting the TXNIP/NOD-like receptor family pyrin domain-containing 3 (NLRP3) pathway. The ability of miR-200a-3p to protect against CME-induced myocardial injury thus highlights a novel approach to preventing or treating such myocardial damage in clinical settings.

Downregulation of miR-181a-5p alleviates oxidative stress and inflammation in coronary microembolization-induced myocardial damage by directly targeting XIAP.

BACKGROUND: Coronary microembolization (CME) is a complicated problem that commonly arises in the context of coronary angioplasty. MicroRNAs play crucial roles in cardiovascular diseases. However, the role and mechanism of miR-181a-5p in CME-induced myocardial injury remains unclear. METHODS: We established CME rat models. Cardiac function was detected by echocardiography. Haematoxylin-basic fuchsin-picric acid staining was used to measure micro-infarction size. Serum samples and cell culture supernatants were evaluated via enzyme-linked immunosorbent assay. Cellular reactive oxygen species were determined by dichloro-dihydro-fluorescein diacetate assay, and the other oxidative stress related parameters were assayed by spectrophotometry. The dual-luciferase reporter (DLR) assay and RNA pulldown were conducted to validate the association between miR-181a-5p and X-linked inhibitor of apoptosis protein (XIAP). The expression of miR-181a-5p and XIAP mRNA were determined by quantitative reverse transcription polymerase chain reaction. Proteins were evaluated via immunoblotting. The viability of the cell was evaluated via cell counting kit-8 assay. RESULTS: The miR-181a-5p level was significantly increased in CME myocardial tissues. Downregulation of miR-181a-5p improved CME-induced cardiac dysfunction and alleviated myocardial oxidative stress and inflammatory injury, whereas miR-181a-5p exhibited the opposite effects. Then, the DLR assay and RNA pulldown results revealed that miR-181a-5p directly targeting on XIAP. The XIAP level was found to be remarkably decreased after CME. XIAP overexpression attenuated CME-induced myocardial oxidative stress and inflammatory injury. Finally, in vitro rescue experiments revealed that knockdown of XIAP could abolish the protective effects of miR-181a-5p knockdown on hypoxia-induced cardiomyocyte oxidative stress and inflammatory injury. CONCLUSIONS: Downregulation of miR-181a-5p alleviates CME-induced myocardial damage by suppressing myocardial oxidative stress and inflammation through directly targeting XIAP.

Transcriptome-Wide N6-Methyladenosine (m6A) Profiling of Susceptible and Resistant Wheat Varieties Reveals the Involvement of Variety-Specific m6A Modification Involved in Virus-Host Interaction Pathways.

N6-methyladenosine (m6A) methylation is the most prevalent internal modification of post-transcriptional modifications in mRNA, tRNA, miRNA, and long non-coding RNA in eukaryotes. m6A methylation has been proven to be involved in plant resistance to pathogens. However, there are no reports on wheat (Triticum aestivum) m6A transcriptome-wide map and its potential biological function in wheat resistance to wheat yellow mosaic virus (WYMV). To the best of our knowledge, this study is the first to determine the transcriptome-wide m6A profile of two wheat varieties with different resistances to WYMV. By analyzing m6A-sequencing (m6A-seq) data, we identified 25,752 common m6A peaks and 30,582 common m6A genes in two groups [WYMV-infected resistant wheat variety (WRV) and WYMV-infected sensitive wheat variety (WSV)], and all these peaks were mainly enriched in 3' untranslated regions and stop codons of coding sequences. Gene Ontology analysis of m6A-seq and RNA-sequencing data revealed that genes that showed significant changes in both m6A and mRNA levels were associated with plant defense responses. Kyoto Encyclopedia of Genes and Genomes analysis revealed that these selected genes were enriched in the plant-pathogen interaction pathway. We further verified these changes in m6A and mRNA levels through gene-specific m6A real-time quantitative PCR (RT-qPCR) and normal RT-qPCR. This study highlights the role of m6A methylation in wheat resistance to WYMV, providing a solid basis for the potential functional role of m6A RNA methylation in wheat resistance to infection by RNA viruses.

Nicorandil inhibits TLR4/MyD88/NF-κB/NLRP3 signaling pathway to reduce pyroptosis in rats with myocardial infarction.

Pyroptosis is an inflammatory cell death that regulates cardiomyocyte loss after myocardial infarction. Reports indicate that nicorandil has a strong anti-inflammatory effect and protects the myocardium from myocardial infarction. However, its relationship with pyroptosis is largely unreported. Here, we investigated to influence and mechanism of action of nicorandil on cardiomyocyte pyroptosis. Forty Sprague Dawley rats were randomly assigned to sham, MI, MI + nicorandil, and MI + nicorandil + TAK242 groups (10 per group). Myocardial infarction modeling was performed through ligation of the anterior descending branch of the left coronary artery. The function of cardiac was evaluated through echocardiography, detection of myocardial adenine nucleotides, cTnI, LDH, TTC, and HE staining. Moreover, we used qRT-PCR, immunohistochemistry, and Western blotting to examine the expression of pyroptosis-related molecules and the inflammasome pathway of TLR4/MyD88/NF-κB/NLRP3. Myocardial infarction caused the activation of GSDMD, aggravated myocardial injury, and triggered cardiac dysfunction. Myocardial infarction induced pyroptotic cell death, manifested as upregulation in mRNA and protein levels associated with pyroptosis, including caspase-1 cleavage and increased expression of IL-1ß and IL-18. These changes were mitigated by nicorandil. The achieved data implicate that myocardial infarction induces pyroptosis via the TLR4/MyD88/NF-κB/NLRP3 pathway, which can be inhibited by nicorandil pretreatment. Therefore, nicorandil exerts cardioprotective effects by activating KATP channels, and at least in part through inhibition of the TLR4/MyD88/NF-κB/NLRP3 pathway to reduce myocardial infarction-induced pyroptosis. As such, it is a potential therapy for ischemic heart disease.

Puerarin pretreatment inhibits myocardial apoptosis and improves cardiac function in rats after acute myocardial infarction through the PI3K/Akt signaling pathway.

BACKGROUND: Puerarin demonstrates a protective effect in many cardiovascular diseases. However, the role of puerarin in acute myocardial infarction (AMI)-induced injury and the exact molecular mechanisms are not fully understood. OBJECTIVES: To investigate whether puerarin pretreatment improves cardiac function and to study the mechanism of action of puerarin. MATERIAL AND METHODS: Thirty rats were grouped into sham group, AMI group and AMI+puerarin (PUE) group at random (n = 10 per group). Except for the sham group, a model of AMI was established via left anterior descending artery ligation. The PUE group received puerarin 120 mg/(kg × day) for 7 days before the operation. Echocardiography was used for evaluation of cardiac function in rats and TUNEL staining for measuring myocardial apoptosis. The expression levels of p-PI3K, t-Akt, p-Akt, Bax, Bcl-2, and cleaved caspase-3 proteins were measured with western blot. RESULTS: Compared to the sham group, the AMI group demonstrated poor cardiac function and decreased p-PI3K, p-Akt and Bcl-2 proteins levels, while Bax, cleaved caspase-3, and myocardial apoptosis levels increased. Compared with the AMI group, the PUE group showed significant improvement in cardiac function and increased protein expression of p-PI3K, p-Akt and Bcl-2, while Bax and cleaved caspase-3 levels decreased and myocardial apoptosis was attenuated. CONCLUSIONS: Puerarin pretreatment in AMI can effectively improve cardiac function by inhibiting myocardial apoptosis. The molecular mechanism of this protective effect may be mediated by activating the PI3K/Akt pathway in cardiomyocytes.

Breviscapine Pretreatment Inhibits Myocardial Inflammation and Apoptosis in Rats After Coronary Microembolization by Activating the PI3K/Akt/GSK-3ß Signaling Pathway.

PURPOSE: Coronary microembolization (CME) can cause myocardial inflammation, apoptosis and progressive cardiac dysfunction. On the other hand, breviscapine exerts a significant cardioprotective effect in many cardiac diseases although its role and the potential mechanisms in CME remain unclear. Therefore, the present study aimed to ascertain whether pretreatment with breviscapine could improve CME-induced myocardial injury by alleviating myocardial inflammation and apoptosis. The possible underlying mechanisms were also explored. METHODS: In this study, 48 Sprague-Dawley (SD) rats were randomly assigned to the CME, CME + breviscapine (CME + BE), CME + breviscapine + LY294002 (CME + BE + LY) and sham groups (12 rats per group). In addition, the CME model was successfully established by injecting 42 µm inert plastic microspheres into the left ventricle of rats. Rats in the CME + BE and CME + BE + LY groups received 40 mg/kg/d of breviscapine for 7 days before inducing CME. Moreover, rats in the CME + BE + LY group were intraperitoneally injected with the phosphoinositide 3-kinase (PI3K) specific inhibitor, LY294002 (10 mg/kg) 30 minutes before CME modeling. 12 h after surgery, the study measured cardiac function, the serum levels of markers of myocardial injury, myocardial inflammation-associated mRNAs and proteins, myocardial apoptosis-associated mRNAs and proteins and conducted myocardial histopathology. RESULTS: The findings demonstrated that pretreatment with breviscapine alleviated myocardial injury following CME by improving cardiac dysfunction, decreasing the serum levels of markers of myocardial injury, reducing the size of myocardial microinfarct and lowering the cardiomyocyte apoptotic index. More importantly, pretreatment with breviscapine resulted to a decrease in the levels of inflammatory and pro-apoptotic mRNAs and proteins in myocardial tissues and there was an increase in the levels of anti-apoptotic mRNAs and proteins. However, these protective effects were eliminated when breviscapine was combined with LY294002. CONCLUSION: The findings from this study indicated that breviscapine may inhibit myocardial inflammation and apoptosis by regulating the PI3K/protein kinase B (Akt)/glycogen synthase kinase-3ß (GSK-3ß) pathway, thereby ameliorating CME-induced cardiac dysfunction and reducing myocardial injury.

Puerarin pretreatment attenuates cardiomyocyte apoptosis induced by coronary microembolization in rats by activating the PI3K/Akt/GSK-3ß signaling pathway.

Coronary microembolization (CME) is associated with cardiomyocyte apoptosis and cardiac dysfunction. Puerarin confers protection against multiple cardiovascular diseases, but its effects and specific mechanisms on CME are not fully known. Hence, our study investigated whether puerarin pretreatment could alleviate cardiomyocyte apoptosis and improve cardiac function following CME. The molecular mechanism associated was also explored. A total of 48 Sprague-Dawley rats were randomly divided into CME, CME + Puerarin (CME + Pue), sham, and sham + Puerarin (sham + Pue) groups (with 12 rats per group). A CME model was established in CME and CME + Pue groups by injecting 42 µm microspheres into the left ventricle of rats. Rats in the CME + Pue and sham + Pue groups were intraperitoneally injected with puerarin at 120 mg/kg daily for 7 days before operation. Cardiac function, myocardial histopathology, and cardiomyocyte apoptosis index were determined via cardiac ultrasound, hematoxylin-eosin (H&E) and hematoxylin-basic fuchsin-picric acid (HBFP) stainings, and TdT-mediated dUTP nick-end labeling (TUNEL) staining, respectively. Western blotting was used to measure protein expression related to the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase-3ß (GSK-3ß) pathway. We found that, puerarin significantly ameliorated cardiac dysfunction after CME, attenuated myocardial infarct size, and reduced myocardial apoptotic index. Besides, puerarin inhibited cardiomyocyte apoptosis, as revealed by decreased Bax and cleaved caspase-3, and up-regulated Bcl-2 and PI3K/Akt/GSK-3ß pathway related proteins. Collectively, puerarin can inhibit cardiomyocyte apoptosis and thus attenuate myocardial injury caused by CME. Mechanistically, these effects may be achieved through activation of the PI3K/Akt/GSK-3ß pathway.

Non-invasive High-Frequency Oscillatory Ventilation as Initial Respiratory Support for Preterm Infants With Respiratory Distress Syndrome.

Objectives: The aim of this study was to investigate the safety and feasibility of nHFOV as initial respiratory support in preterm infants with RDS. Methods: This study retrospectively analyzed the clinical data of 244 premature infants with RDS who were treated in our hospital from January 2016 to January 2019 and divided into the nHFOV group (n = 115) and the BiPAP group (n = 129) based on the initial respiratory support method. Results: Respiratory outcomes showed that the rate of NIV failure during the first 72 hours of life in the nHFOV group was significantly lower than that in the BiPAP group. The time of NIV in the nHFOV group was significantly shorter than that in the BiPAP group. The time of supplemental oxygen in the nHFOV group was significantly shorter than that in the BiPAP group. The incidence of air leakage syndrome in the nHFOV group was significantly lower than that in the BiPAP group, and the length of hospital stay of the nHFOV group was also significantly shorter than that in the BiPAP group. Although the rate of infants diagnosed with BPD was similar between the two groups, the rate of severe BPD in the nHFOV group was significantly lower than that in the BiPAP group. Conclusion: This study showed that nHFOV as initial respiratory support for preterm infants with RDS was feasible and safe compared to BiPAP. Furthermore, nHFOV can reduce the need for IMV and reduce the incidence of severe BPD and air leak syndrome.

An Endostatin-lentivirus (ES-LV)-EPC gene therapy agent for suppression of neovascularization in oxygen-induced retinopathy rat model.

BACKGROUND: Transplantation of gene transfected endothelial progenitor cells (EPCs) has provided novel methods for tumor neovascularization therapy but not for ocular disease therapy. This study aimed to investigate the efficacy of endostatin transfected EPCs in retinal neovascularization therapy. RESULTS: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) showed the high expression of endostatin in endostatin-lentivirus-EPCs. The neovascularization leakage area and the number of preretinal neovascular cell nuclei were significantly decreased in the endostatin-lentivirus and endostatin-lentivirus-EPC groups, and the effects of these two treatments on inhibiting retinal neovascularization were almost the same. These two groups also showed the greater retinal distribution of endostatin. Intravitreal injections of endostatin-lentivirus-EPCs inhibited retinal neovascularization, vascular endothelial growth factor (VEGF) and CD31 expression, and increased endostatin expression in vivo. Endostatin-lentivirus-EPCs targeted and prevented pathologic retinal neovascularization. CONCLUSIONS: Gene-combined EPCs represent a potential new therapeutic agent for the treatment of neovascular eye diseases.

Hierarchically porous carbons as supports for fuel cell electrocatalysts with atomically dispersed Fe-N x moieties.

The development of high-performance non-platinum group metal (non-PGM) catalysts for the oxygen reduction reaction (ORR) is still of significance in promoting the commercialization of proton exchange membrane fuel cells (PEMFCs). In this work, a "hierarchically porous carbon (HPC)-supporting" approach was developed to synthesize highly ORR active Fe-phenanthroline (Fe-phen) derived Fe-N x -C catalysts. Compared to commercial carbon black supports, utilizing HPCs as carbon supports can not only prevent the formation of inactive iron nanoparticles during pyrolysis but also optimize the porous morphology of the catalysts, which eventually increases the amount of reactant-accessible and atomically dispersed Fe-N x active sites. The prepared catalyst therefore exhibits a remarkable ORR activity in both half-cells (half-wave potential of 0.80 V in 0.5 M H2SO4) and H2-air PEMFCs (442 mA cm-2 at a working voltage of 0.6 V), making it among the best non-PGM catalysts for PEMFCs.