Startseite Downregulation of RIP3 ameliorates the left ventricular mechanics and function after myocardial infarction via modulating NF-κB/NLRP3 pathway
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Downregulation of RIP3 ameliorates the left ventricular mechanics and function after myocardial infarction via modulating NF-κB/NLRP3 pathway

  • Han Zhang , Yuan Yin , Shan Chen , Peipei Qian , Ganglin Zou , Yumei Liu , Junying Yang EMAIL logo und Haining Zhang ORCID logo EMAIL logo
Veröffentlicht/Copyright: 18. Juni 2024
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Aus der Zeitschrift Open Life Sciences Band 19 Heft 1

Abstract

Adverse cardiac mechanical remodeling is critical for the progression of heart failure following myocardial infarction (MI). We previously demonstrated the involvement of RIP3-mediated necroptosis in the loss of functional cardiomyocytes and cardiac dysfunction post-MI. Herein, we investigated the role of RIP3 in NOD-like receptor protein 3 (NLRP3)-mediated inflammation and evaluated the effects of RIP3 knockdown on myocardial mechanics and functional changes after MI. Our findings revealed that mice with MI for 4 weeks exhibited impaired left ventricular (LV) myocardial mechanics, as evidenced by a significant decrease in strain and strain rate in each segment of the LV wall during both systole and diastole. However, RIP3 knockdown ameliorated cardiac dysfunction by improving LV myocardial mechanics not only in the anterior wall but also in other remote nonischemic segments of the LV wall. Mechanistically, knockdown of RIP3 effectively inhibited the activation of the nuclear factor kappa-B (NF-κB)/NLRP3 pathway, reduced the levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18) in the heart tissues, and mitigated adverse cardiac remodeling following MI. These results suggest that downregulation of RIP3 holds promise for preventing myocardial inflammation and cardiac mechanical remodeling following MI by regulating the NF-κB/NLRP3 pathway.

Keywords: RIP3; NF-κB; NLRP3; left ventricular mechanics; myocardial infarction

1 Introduction

Despite significant advancements in the treatment of coronary artery disease, myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide [1]. Following MI, maladaptive cardiac remodeling with changes in cardiac mechanics contributes to the deterioration of cardiac performance and the progression to heart failure. Pathologically, the loss of functional cardiomyocytes due to cell death and the excessive activation of the inflammatory response after MI are major contributors to this process [2,3]. Therefore, preventing inflammation and cardiomyocyte death following MI could be an effective therapeutic strategy to ameliorate cardiac remodeling and delay the onset of heart failure.

Necroptosis, a caspase-independent programmed necrosis, is typically considered as a highly proinflammatory mode of cell death, which has been shown to play a significant role in the loss of cardiomyocytes following MI [3,4]. As a key mediator of necroptosis, RIP3 has been implicated in the pathogenesis of neurodegenerative diseases, inflammation, and post-ischemic cardiac dysfunction [5,6,7,8,9,10,11]. It has been reported that significantly higher plasma concentrations of RIP3 are observed in patients with heart failure, which is critically related to the prognosis of heart failure [12]. Our previous research showed that RIP3 is progressively upregulated in the infarct border zone of the hearts in MI mice. Knockdown of RIP3 improved the death of necrotic cardiomyocytes, reduced MI size, and significantly ameliorated MI-induced cardiac dysfunction [13]. However, the inflammatory mechanisms underlying RIP3 and the impact of RIP3 knockdown on left ventricular (LV) myocardial mechanics and function following MI are still not fully understood.

Recent studies have highlighted the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome in the ischemic heart. NLRP3 inflammasome and NLRP3 inflammasome-related proinflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-18 (IL-18) have been observed in the periphery plasma of patients with MI [14,15]. Inhibition of the NLRP3 inflammasome has been shown to reduce the inflammatory response and improve cardiac remodeling and cardiac dysfunction in animal models of acute MI [16,17,18]. Additionally, the Canakinumab Antiinflammatory Thrombosis Outcome Study trial demonstrated the efficacy of IL-1β inhibition in secondary prevention of cardiovascular events in patients with a history of MI [19], suggesting that targeting NLRP3-mediated inflammation may be a promising strategy for MI treatment.

Strain analysis using speckle tracking echocardiography (STE) has emerged as an effective tool for detecting changes of both global and regional of LV mechanics and function during cardiac remodeling in various cardiac pathologies. In comparison with the limited sensitivity of traditional echocardiographic indicators of systolic–diastolic dysfunction, STE is less angle-dependent and offers high accessibility and reproducibility among different operators [20,21]. Additionally, reduced LV myocardial deformation (strain) has been shown to correlate with the extent of MI and can serve as an independent predictor of poor prognosis in heart failure [22,23,24].

In this study, we aimed to investigate the role of RIP3 in NLRP3-mediated inflammation and evaluate the effects of RIP3 knockdown on LV mechanical and functional alterations following MI.

2 Materials and methods

2.1 Animal model and treatment

C57BL/6 male mice weighing 22–25 g were obtained from the experimental animal center of Guangdong Province in Guangzhou, China. The mice were provided with a standard diet and had unrestricted access to water. They were cared for in compliance with the Eighth Edition of the Guide for the Care and Use of Laboratory Animals (2011, published by The National Academies Press). The study was conducted in accordance with the Basic and Clinical Pharmacology and Toxicology policy for experimental and clinical studies [25].

MI was induced by permanently ligating the left anterior descending (LAD) coronary artery. Briefly, mice were anesthetized with sodium pentobarbital (50 mg/kg, intraperitoneal injection) and artificially ventilated using an animal ventilator (DH-140, Zhejiang, China). A thoracotomy was performed at the third or fourth intercostal space, and the LAD coronary artery was ligated. Mice in the sham control group underwent the same surgical procedure without ligating the LAD coronary artery.

A total of 24 mice were randomly divided into four groups, with equal numbers in each group: (i) sham group, (ii) MI group, (iii) Scramble shRNA+MI group, and (iv) RIP3 shRNA+MI group. Mice in the scramble shRNA+MI group or RIP3 shRNA+MI group received a cardiac-specific gene delivery of lentivirus carrying scramble shRNA (2 × 107 PFU) or RIP3 shRNA (2 × 107 PFU) 3 days before MI. 4 weeks after MI, mice were euthanized by inhalation of isoflurane (flow rate: 300–500 ml/min, anesthesia concentration: 1–1.5%), followed by cervical dislocation. The hearts were then harvested and processed for histological or western blotting analysis.

  1. Ethical approval: The research related to animal use has been complied with all the relevant national regulations and institutional policies for the care and use of animals, and has been approved by the Institutional Animal Care and Use Committee of Guangzhou Medical University (approval number: G2022-212).

2.2 Generation of RIP3 shRNA construct and lentiviral preparation

Following the manufacturer’s instructions, shRNA against RIP3 was inserted into the pLKO.1 lentiviral vector (Open Biosystems, Ottawa, Canada). The construct was confirmed by DNA sequence analysis. Lentivirus expressing scramble shRNA or RIP3 shRNA was prepared by co-transfecting scramble shRNA or RIP3 shRNA lentiviral plasmids with a packaging plasmid into HEK-293T cells using FuGENE6 reagent (Roche, Indianapolis, IN, USA).

2.3 In vivo cardiac-specific gene manipulation by intramyocardial injection in mice

As previously described [13], in vivo cardiac-specific gene delivery was performed. The mouse heart was quickly exposed under anesthesia at the fifth intercostal space. Lentivirus carrying scramble shRNA (2 × 107 PFU) or RIP3 shRNA (2 × 107 PFU) was delivered into the LV free wall through three separate intramyocardial injections, respectively. Knockdown of RIP3 was confirmed by western blotting.

2.4 Echocardiography

Cardiac function was assessed before and 4 weeks after MI using the Vevo 2100, a high-resolution imaging system equipped with a 25 MHz imaging transducer (Vevo 2100; VisualSonics Inc., Ontario, Canada). Two-dimensional echocardiograms were obtained from the apical four chambers and parasternal long- and short-axis views. Cardiac function parameters, including LV anterior wall in diastole and LV anterior wall in systole, were measured using the Vevo 2100. The modified biplane Simpson’s method was employed to calculate the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS). Additionally, according to the instructions, other parameters such as the ratio of E-wave velocity to A-wave velocity (E/A), isovolumetric relaxation time (IVRT) and isovolumetric contraction time (IVCT), and early diastolic mitral annulus velocity/late diastolic mitral annulus velocity (E′/A′) were also analyzed.

2.5 Speckle tracking analysis

The high frame rate 2D images of the LV short-axis views were obtained by recording three consecutive heart cycles with the Vevo 2100. The LV endocardial border was automatically traced and manually adjusted as needed using offline software (EchoPac 201, General Electric Vingmed) that divided the short-axis view of the LV into six segments (anterior wall, interventricular septum, posterior wall, inferior wall, inferior ventricular septum, and lateral wall). Strain analysis was performed on each myocardial segment to determine the peak-systolic radial strain (Srad-S), peak-systolic circumferential strain (Scir-S), systolic peak of radial strain rate (SRrad-S), systolic peak of circumferential strain rate (SRcir-S), peak value in early diastole peak (SRrad-E, SRcir-E), and late diastolic peak (SRrad-A, SRcir-A). The percentage decrease of SRrad and SRcir in each segment was calculated according to the formula:

[ ( Myocardial strain rate before myocardial infarction − Myocardial strain rate after myocardial infarction ) / Myocardial strain rate before myocardial infarction ] × 100 % .

2.6 Histologic analysis

Mice were euthanized, and their heart tissues were collected. The heart tissue blocks were fixed in 4% paraformaldehyde, embedded in paraffin, and then sectioned. After routine dewaxing, hematoxylin and eosin staining and Masson trichrome staining were performed. The microscopic findings were recorded using appropriate objective lenses. Fibrosis in the LV was determined by measuring the area of fibrotic tissue (stained blue for collagen) over the LV area (excluding background) using ImageJ software (NIH, version 1.30, http://rsb.info.nih.gov/ij/). The researcher, who was blinded to the treatments, examined more than five fields in three different sections for each mouse.

2.7 Lactate dehydrogenase (LDH) assay

The proteins from the heart tissues were extracted using RIPA lysis buffer and then centrifuged at 3,000 rpm for 10 min. The levels of LDH in supernatant were measured using a commercially available kit (Jian Cheng Institute of Biotechnology in Nanjing, China) following the instructions provided by the manufacturer.

2.8 mRNA isolation and quantitative real-time polymerase chain reaction (RT-qPCR)

TRIzol reagent (TaKaRa Biomedical Technology, Beijing, Co., Ltd) was used to extract total RNA. An equal amount of purified RNA was then reverse-transcribed using the RNA PCR Kit following the manufacturer’s instructions. The resulting cDNAs were amplified, and real-time PCR was conducted using primers specific for alpha-smooth muscle actin (α-SMA) and collagen I (Life technology, Invitrogen, Ltd. Paisley PA4 9RF, UK). The mRNA levels of genes were normalized to the β-actin mRNA level.

2.9 Cytokine assay

The proteins from the heart tissues were extracted using RIPA lysis buffer, and the protein content was quantified by the bicinchoninic acid (BCA) protein assay (Pierce). The amount of IL-1β and IL-18 in supernatants was measured using enzyme linked immunosorbent assay (ELISA) kits (eBioScience, San Diego, California, USA) following the manufacturer’s instructions.

2.10 Western blotting analysis

The proteins were extracted from heart tissues, and the protein concentrations were determined by BCA Protein Assay Reagent Kit (Pierce). Equal amount of proteins was separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to polyvinylidene fluoride (PVDF) membranes (Roche Molecular Biochemicals, Mannheim, Germany). The membranes were blocked and subsequently probed with anti-RIP3 antibody (1:1,000, Cat# BS7363), anti-NLRP3 antibody (1:1,000, Cat# BS66103), anti-caspase 1 (p20) antibody (1:1000, Cat# BS7071), anti-β-actin antibody (1:8,000, Cat# AP0731, Bioworld Technology, St. Louis Park, MN, USA), and antibodies against p65 (1:1,000, Cat #8242) and p-p65 (Ser536) (1:1,000, Cat #3033), Cell Signaling Technology, Boston, USA). The density of the target bands was accurately quantified using the computer-aided Quantity One analysis system. β-actin was used as a loading control.

2.11 Statistical analysis

All data were expressed as mean ± standard deviation. Differences between two groups were assessed using the Student t-test performed with GraphPad Prism 8.0 software (GraphPad Software Inc). Differences between two or more groups were assessed using a one-way analysis of variance (ANOVA) followed by the Tukey post hoc test. Correlations were determined by conducting linear regression analyses. Statistical significance was defined as a P value of 0.05 or less.

3 Results

3.1 RIP3 knockdown preserved cardiac function post-MI

Lentivirus-encoded RIP3 shRNA was delivered intramyocardially to specifically target the cardiac tissue in mice. 3 days after the RIP3 knockdown, a permanent ligation of the LAD coronary artery was performed to induce MI. As shown in Figure 1, protein expression of RIP3 in heart tissue increased in MI mice compared to sham mice. The targeted shRNA against RIP3 successfully achieved a significant cardiac-specific knockdown of RIP3 protein. In contrast, scramble lentiviruses had no effect on the expression of RIP3 protein. 4 weeks after MI, the left ventricular anterior wall (LVAW) and left ventricular posterior wall (LVPW) exhibited thinning, and the left ventricular internal dimension (LVID) at both the end of diastole and the end of systole enlarged in MI mice compared to the sham-operated mice. The fractional shortening and ejection fraction (EF) of the LV were also significantly reduced in MI mice. Echocardiography analysis showed no significant difference in E/A among the sham mice, MI mice, mice with scramble shRNA and mice with RIP3 knockdown. However, both the IVRT and IVCT were prolonged, and the E′/A′ was significantly decreased in the MI mice, indicating impaired cardiac systolic and diastolic function after MI. Compared to MI mice, intramyocardial delivery of lentivirus-encoded scramble sequence had no effect on cardiac dysfunction induced by MI. However, mice with RIP3 knockdown showed significant improvements in both cardiac systolic and diastolic functions, as evidenced by increased LVEF, LVFS, as well as LVAW and LVPW. Additionally, after RIP3 knockdown, LVID was decreased, and the prolonged IVRT and IVCT, as well as decreased E′/A′ ratio, was all improved. Overall, these findings indicate that RIP3 knockdown can ameliorate the contractile and diastolic dysfunction observed 4 weeks post-MI.

Figure 1 RIP3 knockdown ameliorated cardiac dysfunction after MI. Cardiac-specific gene knockdown was performed through in vivo intramyocardial delivery of lentivirus-encoded RIP3 shRNA 3 days prior to MI. Cardiac function was assessed by echocardiograms 4 weeks after MI: (a) the expression of RIP3 was determined by western blotting after MI (one-way ANOVA, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI); (b) representative M-mode echocardiograms and transmitral flow and tissue Doppler echocardiograms; and (c)–(g) the analyzed results of cardiac function obtained from mice in each experimental group (one-way ANOVA, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI).
Figure 1

RIP3 knockdown ameliorated cardiac dysfunction after MI. Cardiac-specific gene knockdown was performed through in vivo intramyocardial delivery of lentivirus-encoded RIP3 shRNA 3 days prior to MI. Cardiac function was assessed by echocardiograms 4 weeks after MI: (a) the expression of RIP3 was determined by western blotting after MI (one-way ANOVA, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI); (b) representative M-mode echocardiograms and transmitral flow and tissue Doppler echocardiograms; and (c)–(g) the analyzed results of cardiac function obtained from mice in each experimental group (one-way ANOVA, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI).

3.2 RIP3 knockdown mitigated cardiac mechanics after MI

Speckle tracking analysis was performed to evaluate LV mechanical function after MI. Compared to sham mice, the peak value of the Srad-S, Scir-S, SRrad-S, SRcir-S, and peak value in early diastole of SRrad or SRcir (SRrad-E, SRcir-E) and late diastolic peak value of SRrad or SRcir (SRrad-A, SRcir-A) were all significantly lower in MI mice, mice delivered intramyocardially with scramble sequence, and mice with RIP3 knockdown. These decreases were observed in almost all segments (Figure 2). Notably, the anterior and lateral wall myocardium exhibited the greatest reduction in the percentage of peak-systolic radial strain and radial strain rate. None of these parameters were affected by the intramyocardial delivery of lentivirus-encoded scramble sequence compared to MI mice. However, the percentage decrease of SRrad-S, SRcir-S, SRrad-E, SRcir-E, SRrad-A, and SRcir-A in mice with RIP3 knockdown was significantly less pronounced (Figure 3).

Figure 2 RIP3 knockdown mitigated cardiac mechanics after MI: (a) LV strain was measured by speckle-tracking imaging from the midventricular short-axis view; (b) representative radial strain curves; (c) circumferential strain curves; (d) and (e) distribution of radial and circumferential strains in sham mice, MI mice, Scramble shRNA+MI mice and mice with RIP3 knockdown (Student’s t test, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI); (f) and (g) distribution of radial and circumferential systolic strain rates in sham mice, MI mice, Scramble shRNA+MI mice, and mice with RIP3 knockdown (Student’s t test, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI); (h) and (i) distribution of radial and circumferential early-diastolic strain rates in sham mice, MI mice, Scramble shRNA+MI mice, and mice with RIP3 knockdown (Student’s t test, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI); and (j) and (k) distribution of radial and circumferential late-diastolic strain rates in sham mice, MI mice, Scramble shRNA+MI mice, and mice with RIP3 knockdown (Student’s t test, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI).
Figure 2

RIP3 knockdown mitigated cardiac mechanics after MI: (a) LV strain was measured by speckle-tracking imaging from the midventricular short-axis view; (b) representative radial strain curves; (c) circumferential strain curves; (d) and (e) distribution of radial and circumferential strains in sham mice, MI mice, Scramble shRNA+MI mice and mice with RIP3 knockdown (Student’s t test, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI); (f) and (g) distribution of radial and circumferential systolic strain rates in sham mice, MI mice, Scramble shRNA+MI mice, and mice with RIP3 knockdown (Student’s t test, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI); (h) and (i) distribution of radial and circumferential early-diastolic strain rates in sham mice, MI mice, Scramble shRNA+MI mice, and mice with RIP3 knockdown (Student’s t test, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI); and (j) and (k) distribution of radial and circumferential late-diastolic strain rates in sham mice, MI mice, Scramble shRNA+MI mice, and mice with RIP3 knockdown (Student’s t test, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI).

Figure 3 RIP3 knockdown lowered the percentage decrease of stain rate: (a)–(c) RIP3 knockdown decreased the percentage decrease in SRrad-S, SRrad-E, and SRrad-A (one-way ANOVA, n = 6, **P < 0.01 vs Sham, # P < 0.05 or ## P < 0.01 vs MI) and (d)–(f) RIP3 knockdown decreased the percentage decrease in SRcir-S, SRcir-E, and SRcir-A (one-way ANOVA, n = 6, **P < 0.01 vs Sham, ## P < 0.01 vs MI).
Figure 3

RIP3 knockdown lowered the percentage decrease of stain rate: (a)–(c) RIP3 knockdown decreased the percentage decrease in SRrad-S, SRrad-E, and SRrad-A (one-way ANOVA, n = 6, **P < 0.01 vs Sham, # P < 0.05 or ## P < 0.01 vs MI) and (d)–(f) RIP3 knockdown decreased the percentage decrease in SRcir-S, SRcir-E, and SRcir-A (one-way ANOVA, n = 6, **P < 0.01 vs Sham, ## P < 0.01 vs MI).

3.3 Cardiac performance was negatively correlated with the decrease percentage of strain rate

After analyzing the segmental data, a strong negative correlation between the average percentage decrease in SRrad-S and SRcir-S and LVEF in both MI mice and mice with RIP3 knockdown was observed. The correlation coefficients (r) were 0.897 and 0.862 in MI mice and 0.857 and 0.828 in mice with RIP3 knockdown, respectively. Conversely, the average percentage decrease in SRrad-S and SRcir-S positively correlated with LV end-systolic diameter (LVIDs), with correlation coefficients (r) of 0.866 and 0.881 in MI mice and 0.85 and 0.816 in mice with RIP3 knockdown, respectively (Figure 4).

Figure 4 Correlations between the average percentage decrease in strain rate and LVEF and LVIDs were examined: (a)–(d) correlations between the average percentage decrease in SRrad-S and SRcir-S and LVEF in both MI mice and mice with RIP3 knockdown and (e)–(h) correlations between the average percentage decrease in SRrad-S and SRcir-S and LVIDs in both MI mice and mice with RIP3 knockdown.
Figure 4

Correlations between the average percentage decrease in strain rate and LVEF and LVIDs were examined: (a)–(d) correlations between the average percentage decrease in SRrad-S and SRcir-S and LVEF in both MI mice and mice with RIP3 knockdown and (e)–(h) correlations between the average percentage decrease in SRrad-S and SRcir-S and LVIDs in both MI mice and mice with RIP3 knockdown.

3.4 RIP3 knockdown mitigated adverse cardiac remodeling induced by MI

Masson-Trichrome staining and RT-qPCR revealed that compared to the sham-operated mice, mice subjected to MI surgery for a duration of 4 weeks exhibited a noticeable MI scar, disordered myocardial fibers and cardiac fibrosis, along with increased expression levels of α-SMA and collagen I, the well-established fibroblast marker for the differentiation of fibroblast to myofibroblast and a marker for the accumulation of extracellular matrix proteins, which were not affected by the intramyocardial delivery of lentivirus-encoded scramble sequence. However, the knockdown of the RIP3 significantly alleviated the disturbance in myocardial fiber arrangement and reduced the mRNA levels of α-SMA and collagen I as well as the formation of fibrosis. These findings indicated that RIP3 knockdown mitigated remodeling of cardiac structure caused by MI (Figure 5a and b).

Figure 5 RIP3 knockdown ameliorated cardiac remodeling after MI. Cardiac-specific gene knockdown was performed through in vivo intramyocardial delivery of lentivirus-encoded RIP3 shRNA 3 days prior to MI. The heart was removed 4 weeks after MI: (a) representative cross-sectional images showed Masson staining; (b) analysis results for Masson staining (one-way ANOVA, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI); (c) mRNA levels of α-SMA and collagen I in the heart were determined by real-time RCR (one-way ANOVA, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI, β-actin served as a loading control); (d) LDH level in cardiac tissue was determined by LDH assay (one-way ANOVA, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI); and (e) IL-1β and IL-18 levels were determined by ELISA (one-way ANOVA, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI).
Figure 5

RIP3 knockdown ameliorated cardiac remodeling after MI. Cardiac-specific gene knockdown was performed through in vivo intramyocardial delivery of lentivirus-encoded RIP3 shRNA 3 days prior to MI. The heart was removed 4 weeks after MI: (a) representative cross-sectional images showed Masson staining; (b) analysis results for Masson staining (one-way ANOVA, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI); (c) mRNA levels of α-SMA and collagen I in the heart were determined by real-time RCR (one-way ANOVA, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI, β-actin served as a loading control); (d) LDH level in cardiac tissue was determined by LDH assay (one-way ANOVA, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI); and (e) IL-1β and IL-18 levels were determined by ELISA (one-way ANOVA, n = 6, *P < 0.05 vs sham, # P < 0.05 vs MI).

3.5 RIP3 knockdown reduced cardiac tissue inflammation post-MI

Chronic inflammation is known to play a key role in progressive adverse cardiac remodeling after MI. RIP3, a key regulator of programmed necrosis, has been reported to be linked to inflammatory cell death. We previously showed that there is progressive upregulation of RIP3 in the infarcted border zone of the hearts of MI mice, along with increased cardiomyocyte necrosis. Knockdown of RIP3 improved the death of necrotic cardiomyocytes. Herein, we confirmed myocardial necrosis, as evidenced by a significant increase in the release of LDH after MI. Moreover, we observed increased levels of IL-1β and IL-18 in the heart tissue of MI mice as compared with sham mice. In comparison with the MI mice, the levels of LDH, IL-1β, and IL-18 were not affected by the intramyocardial delivery of scramble shRNA, but were significantly decreased by knocking down of RIP3 in the heart tissue. These results indicated that the deletion of RIP3 mitigated myocardial necrosis and inflammatory myocardial injury after MI (Figure 5c and d).

3.6 RIP3 knockdown exerts anti-inflammatory effect via modulating nuclear factor kappa-B (NF-κB)/NLRP3 pathway

Given that IL-1β and IL-18 are important effector proteins of the NF-κB/NLRP3 signaling pathway, we evaluated the protein expression of the NF-κB/NLRP3 pathway. Figure 6 showed that there was a significantly increased phosphorylation of p65 in heart tissue of MI mice compared to sham mice. However, the phosphorylation level of p65 was not affected by the intramyocardial delivery of scramble shRNA, but was significantly attenuated by the deletion of RIP3 when compared to MI mice. Additionally, we observed a significant increase in the expression of NLRP3 and cleaved caspase-1 (p20) in the hearts of MI mice compared to sham mice. Once again, the expression of NLRP3 and cleaved caspase-1 (p20) was not affected by scramble shRNA, but was markedly reduced by the deletion of RIP3 in the mouse hearts.

Figure 6 RIP3 knockdown inhibited the activation of the NF-κB/NLRP3 pathway. The total protein expression and phosphorylated level of p65, and NLRP3, caspase1 p20(CASP1(p20)) in heart tissues were examined by western blotting, respectively: (a) representative blots depicting total and phosphorylated proteins and (b) the analyzed results of p-p65 level, NLRP3, and CASP1(p20) level (one-way ANOVA, n = 6, *P < 0.05 vs sham. # P < 0.05 vs MI).
Figure 6

RIP3 knockdown inhibited the activation of the NF-κB/NLRP3 pathway. The total protein expression and phosphorylated level of p65, and NLRP3, caspase1 p20(CASP1(p20)) in heart tissues were examined by western blotting, respectively: (a) representative blots depicting total and phosphorylated proteins and (b) the analyzed results of p-p65 level, NLRP3, and CASP1(p20) level (one-way ANOVA, n = 6, *P < 0.05 vs sham. # P < 0.05 vs MI).

4 Discussion

The main findings of this study are as follows: (a) mice with MI for 4 weeks exhibited impaired LV myocardial mechanics, as evidenced by a significant decrease in radial and circumferential strain and strain rates of all segments at the papillary muscle level during systole and early diastole. (b) Knockdown of RIP3 increased radial and circumferential strain and strain rates during systole and diastole and mitigated the impairment of LV myocardial mechanics and cardiac dysfunction induced by ischemic injury. (c) The percentage decrease of SRrad-S and SRcir-S showed a strong negative correlation with LVEF, while positive correlation with LVIDs both in MI mice and mice with RIP3 knockdown. (d) The decreased cardiac tissue inflammation by the deletion of RIP3 may contribute to the amelioration of LV myocardial mechanics and dysfunction post-MI.

Growing evidence supports the importance of myocardial mechanic alteration in adverse cardiac remodeling post-MI [26,27,28]. However, assessing regional LV mechanics remains challenging. Conventional echocardiography is commonly used to evaluate metrics of cardiac function, such as EF and LVFS. While these metrics are valuable in assessing the overall impact of ischemic injury on global myocardial function, they do not capture regional differences in myocardial contractility. Two-dimensional speckle tracking technology, which is independent of angle and surrounding tissue movement, allows for the quantification of myocardial multi-dimensional strain and provides a more accurate reflection of myocardial mechanics. It enables a detailed assessment of both global and regional LV function in the longitudinal, circumferential, and radial directions [20,21,22,23,24]. Several studies have shown significant reductions in regional strain of ischemic LVs compared to healthy hearts. The reported strain difference between the infarcted and remote myocardium is related to infarct expansion from infarct zones to remote border zones [29,30,31,32]. Assessing segmental strain and strain rate has also been shown to be helpful in predicting adverse remodeling in ischemic cardiomyopathy and provides important prognostic clues for predicting heart failure in patients with postinfarction [33]. Using speckle tracking technology, we observed segmental wall motion abnormalities in the LV, along with thinning of the LV wall, enlarged LVID, increased cardiac fibrosis and necrosis, as well as cardiac systolic and diastolic dysfunctions in mice subjected to MI for 4 weeks. The radial and circumferential strain and strain rates during systole and diastole in all segments of the LV wall in MI mice were significantly lower, particularly in the anterior wall and lateral wall where severe injury occurred due to the occlusion of the LAD coronary artery. These results indicated that local myocardial ischemia resulting from anterior MI led to impaired regional myocardial mechanics. This impairment can potentially place an increased burden on the non-infarcted myocardium, thereby affecting the mechanics of all myocardial segments and ultimately resulting in a decrease in overall systolic and diastolic motion and function of the LV.

Myocardial inflammatory necrosis plays a key role in adverse cardiac remodeling and impaired cardiac mechanics after MI [3,4,5]. It has been reported that shortly after an acute MI, alterations in the heart’s structure are observed, which is characterized by the infarcted area undergoing necrosis, inflammation, and replacement fibrosis. These processes result in local thinning, scar formation, and increased stiffness of the ventricular wall, along with loss or paradoxical motion of myocardial segments. These alterations may potentially exacerbate the expansion of the infarct area, ultimately resulting in decreased cardiac systolic and diastolic functions [26,27,28]. We previously demonstrated that RIP3-mediated necroptosis contributes to the loss of functional cardiomyocytes and cardiac dysfunction following MI. Knockdown of RIP3 has been shown to increase the survival of ischemic cardiomyocytes, reduce the size of the infarction, and notably improve MI-induced cardiac dysfunction [13]. In the current study, we further investigated the role of inflammatory signaling pathways in the protective effect of RIP3 knockdown against MI. We found that IL-18 and IL-1β-driven inflammation were activated after MI, but this activation was significantly inhibited by RIP3 knockdown. It is well established that IL-18 and IL-1β-driven inflammation play a crucial role in the development of adverse cardiac remodeling by regulating extracellular matrix metabolism and fibroblast function [16,17]. Therefore, it is likely that both the reduction in cardiomyocyte necrosis and subsequent inflammation achieved by knocking down RIP3 in the ischemic heart contribute to the suppression of adverse cardiac remodeling and ultimately a substantial improvement in cardiac mechanics. Indeed, our findings support this hypothesis. We observed that RIP3 knockdown suppressed MI-induced upregulation of α-SMA and collagen I and alleviated the cardiac fibrosis, resulting in increased radial and circumferential strain and strain rates, not only in the ischemic anterior and lateral walls but also in other remote segments of the LV wall. The percentage decreases in SRrad-S and SRcir-S, during both systole and diastole across various segments in mice with RIP3 knockdown, were significantly lower compared to that observed in MI mice. Importantly, these percentage decreases showed a strong correlation with LVEF and LV end-systolic diameter. These findings provided further evidence that reduced cardiomyocyte necrosis and mitigated inflammatory injury through RIP3 knockdown effectively improved cardiac mechanics and cardiac dysfunction following MI. The percentage decrease in strain rate of the infarcted myocardium could be served as a crucial reference index for evaluating cardiac function.

Inflammasome activation mediated by NLRP3, a member of the nucleotide-binding oligomerization domain-like receptor (NLR) family, plays a pivotal role in inflammatory injury driven by IL-18 and IL-1β. Multiple studies have shown that various microbial or damage-associated molecular patterns could induce the activation of NLRP3 inflammasome. Once activated, NLRP3 inflammasome triggers the formation of mature caspase-1(p20) by proteolytic cleavage of caspase-1, leading to the release of active IL-1β and IL-18 from their pro-forms [34]. Growing evidence suggests that the activation of NLRP3 inflammasome is significantly involved in the pathophysiology of cardiovascular diseases, including atherosclerosis and acute MI [35]. In accordance with these results, we observed higher levels of NLRP3 and caspase-1 (p20) in the hearts of MI mice. Importantly, cardiac-specific knocking down of RIP3 resulted in a decreased expression of NLRP3 and caspase-1 (p20), along with lower levels of IL-1β and IL-18, suggesting that the suppression of the NLRP3 inflammasome by RIP3 knockdown is involved in its major anti-inflammatory action. Consistent with our results, the RIP3-mediated activation of the NLRP3 inflammasome was also observed in caspase-8-deficient dendritic cells treated with LPS and acute kidney injury [36,37]. Furthermore, we detected NF-kB activation along with the upregulation of NLRP3 and caspase-1(p20) following MI, which could be attenuated by RIP3 knockdown. Canonically, the activation of fully functional NLRP3 inflammasome requires two steps: priming and activation. Although the exact molecular mechanisms for NLRP3 activation remain incompletely understood, it has been found that the activation of NF-kB is required for the priming step to produce pro-IL-1β and optimum NLRP3, which is necessary for the subsequent activation of the NLRP3 inflammasome and the release of active IL-1β [34]. Together, these data implicated that RIP3 knockdown has the potential to inhibit myocardial inflammation after MI by targeting the NF-κB/NLRP3 inflammatory signaling pathway. Nevertheless, further studies are needed to elucidate the precise mechanisms linking RIP3 and inflammation mediated by NLRP3 inflammasome.

It is noteworthy that the activity of NF-κB can be induced or enhanced by pro-inflammatory signals and antigen receptors. Studies have demonstrated that activated IL-1β or IL-18 can enhance the activity of NF-κB. Moreover, overactivation of NF-κB can further trigger the transcription of numerous genes encoding pro-inflammatory cytokines such as tumor necrosis factor-α (TNA-α), IL-6, and IL-1β [38,39]. As a crucial mediator of the inflammatory response, the inflammatory cascade mediated by the overactivation of NF-κB has been implicated in various human diseases, including ischemic heart disease, cancer, autoimmune disorders, and viral infections [40,41,42,43,44,45]. Therefore, it is conceivable that, in addition to the RIP3-mediated NF-κB/NLRP3 signaling pathway, the activation of other inflammatory signaling may be involved in the inflammatory mechanisms underlying RIP3 in the context of MI, necessitating further investigation.

5 Conclusions

This study provides additional insight into the changes in LV mechanics following ischemic injury. We demonstrate that impaired myocardial mechanics are not confined to the ischemic segments but also affect non-ischemic segments after a 4 week MI. The degree of LV function impairment is directly correlated with the percentage decrease in myocardial strain and strain rate. The downregulation of RIP3 shows potential for preventing cardiac mechanical remodeling and heart dysfunction following MI by inhibiting inflammatory cardiac injury, possibly through regulating NF-κB/NLRP3 signaling pathway (Figure 7).

Figure 7 Scheme of downregulation of RIP3 ameliorates the LV mechanics and function after MI via modulating the NF-κB/NLRP3 pathway. The downregulation of RIP3 shows potential for preventing cardiac mechanical remodeling and heart dysfunction following MI by inhibiting inflammatory cardiac injury through regulating the NF-κB/NLRP3 signaling pathway.
Figure 7

Scheme of downregulation of RIP3 ameliorates the LV mechanics and function after MI via modulating the NF-κB/NLRP3 pathway. The downregulation of RIP3 shows potential for preventing cardiac mechanical remodeling and heart dysfunction following MI by inhibiting inflammatory cardiac injury through regulating the NF-κB/NLRP3 signaling pathway.

# Han Zhang and yuan Yin contributed equally to this work.

  1. Funding information: This work was supported by Natural Science Foundation of Guangdong Province (No. 2016A030313569 to H.N.Z), Science and Technology Program of Guangzhou (No. 201707010051 to H.N.Z), High-level University Construction Fund of Guangdong Province (06-410-2107246, 06-410-2107248, 06-410-2107262), and Undergraduate Innovation Capacity Enhancement Program (02-408-2304-13051XM).

  2. Author contributions: H.N.Z. designed the experiments. H.Z., Y.Y., and S.C. carried out the experiments. P.P.Q., G.L.Z., and Y.L. performed data curation and formal analysis. H.Z. and J.Y. prepared the manuscript with contributions from all coauthors. The authors applied the SDC approach for the sequence of the authors.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2024-03-05
Revised: 2024-05-10
Accepted: 2024-05-14
Published Online: 2024-06-18

© 2024 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  88. Interaction of ncRNAs and the PI3K/AKT/mTOR pathway: Implications for osteosarcoma
  89. Association of low attenuation area scores with pulmonary function and clinical prognosis in patients with chronic obstructive pulmonary disease
  90. Long non-coding RNAs in bone formation: Key regulators and therapeutic prospects
  91. The deubiquitinating enzyme USP35 regulates the stability of NRF2 protein
  92. Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as potential diagnostic markers for rebleeding in patients with esophagogastric variceal bleeding
  93. G protein-coupled receptor 1 participating in the mechanism of mediating gestational diabetes mellitus by phosphorylating the AKT pathway
  94. LL37-mtDNA regulates viability, apoptosis, inflammation, and autophagy in lipopolysaccharide-treated RLE-6TN cells by targeting Hsp90aa1
  95. The analgesic effect of paeoniflorin: A focused review
  96. Chemical composition’s effect on Solanum nigrum Linn.’s antioxidant capacity and erythrocyte protection: Bioactive components and molecular docking analysis
  97. Knockdown of HCK promotes HREC cell viability and inner blood–retinal barrier integrity by regulating the AMPK signaling pathway
  98. The role of rapamycin in the PINK1/Parkin signaling pathway in mitophagy in podocytes
  99. Laryngeal non-Hodgkin lymphoma: Report of four cases and review of the literature
  100. Clinical value of macrogenome next-generation sequencing on infections
  101. Overview of dendritic cells and related pathways in autoimmune uveitis
  102. TAK-242 alleviates diabetic cardiomyopathy via inhibiting pyroptosis and TLR4/CaMKII/NLRP3 pathway
  103. Hypomethylation in promoters of PGC-1α involved in exercise-driven skeletal muscular alterations in old age
  104. Profile and antimicrobial susceptibility patterns of bacteria isolated from effluents of Kolladiba and Debark hospitals
  105. The expression and clinical significance of syncytin-1 in serum exosomes of hepatocellular carcinoma patients
  106. A histomorphometric study to evaluate the therapeutic effects of biosynthesized silver nanoparticles on the kidneys infected with Plasmodium chabaudi
  107. PGRMC1 and PAQR4 are promising molecular targets for a rare subtype of ovarian cancer
  108. Analysis of MDA, SOD, TAOC, MNCV, SNCV, and TSS scores in patients with diabetes peripheral neuropathy
  109. SLIT3 deficiency promotes non-small cell lung cancer progression by modulating UBE2C/WNT signaling
  110. The relationship between TMCO1 and CALR in the pathological characteristics of prostate cancer and its effect on the metastasis of prostate cancer cells
  111. Heterogeneous nuclear ribonucleoprotein K is a potential target for enhancing the chemosensitivity of nasopharyngeal carcinoma
  112. PHB2 alleviates retinal pigment epithelium cell fibrosis by suppressing the AGE–RAGE pathway
  113. Anti-γ-aminobutyric acid-B receptor autoimmune encephalitis with syncope as the initial symptom: Case report and literature review
  114. Comparative analysis of chloroplast genome of Lonicera japonica cv. Damaohua
  115. Human umbilical cord mesenchymal stem cells regulate glutathione metabolism depending on the ERK–Nrf2–HO-1 signal pathway to repair phosphoramide mustard-induced ovarian cancer cells
  116. Electroacupuncture on GB acupoints improves osteoporosis via the estradiol–PI3K–Akt signaling pathway
  117. Renalase protects against podocyte injury by inhibiting oxidative stress and apoptosis in diabetic nephropathy
  118. Review: Dicranostigma leptopodum: A peculiar plant of Papaveraceae
  119. Combination effect of flavonoids attenuates lung cancer cell proliferation by inhibiting the STAT3 and FAK signaling pathway
  120. Renal microangiopathy and immune complex glomerulonephritis induced by anti-tumour agents: A case report
  121. Correlation analysis of AVPR1a and AVPR2 with abnormal water and sodium and potassium metabolism in rats
  122. Gastrointestinal health anti-diarrheal mixture relieves spleen deficiency-induced diarrhea through regulating gut microbiota
  123. Myriad factors and pathways influencing tumor radiotherapy resistance
  124. Exploring the effects of culture conditions on Yapsin (YPS) gene expression in Nakaseomyces glabratus
  125. Screening of prognostic core genes based on cell–cell interaction in the peripheral blood of patients with sepsis
  126. Coagulation factor II thrombin receptor as a promising biomarker in breast cancer management
  127. Ileocecal mucinous carcinoma misdiagnosed as incarcerated hernia: A case report
  128. Methyltransferase like 13 promotes malignant behaviors of bladder cancer cells through targeting PI3K/ATK signaling pathway
  129. The debate between electricity and heat, efficacy and safety of irreversible electroporation and radiofrequency ablation in the treatment of liver cancer: A meta-analysis
  130. ZAG promotes colorectal cancer cell proliferation and epithelial–mesenchymal transition by promoting lipid synthesis
  131. Baicalein inhibits NLRP3 inflammasome activation and mitigates placental inflammation and oxidative stress in gestational diabetes mellitus
  132. Impact of SWCNT-conjugated senna leaf extract on breast cancer cells: A potential apoptotic therapeutic strategy
  133. MFAP5 inhibits the malignant progression of endometrial cancer cells in vitro
  134. Major ozonated autohemotherapy promoted functional recovery following spinal cord injury in adult rats via the inhibition of oxidative stress and inflammation
  135. Axodendritic targeting of TAU and MAP2 and microtubule polarization in iPSC-derived versus SH-SY5Y-derived human neurons
  136. Differential expression of phosphoinositide 3-kinase/protein kinase B and Toll-like receptor/nuclear factor kappa B signaling pathways in experimental obesity Wistar rat model
  137. The therapeutic potential of targeting Oncostatin M and the interleukin-6 family in retinal diseases: A comprehensive review
  138. BA inhibits LPS-stimulated inflammatory response and apoptosis in human middle ear epithelial cells by regulating the Nf-Kb/Iκbα axis
  139. Role of circRMRP and circRPL27 in chronic obstructive pulmonary disease
  140. Investigating the role of hyperexpressed HCN1 in inducing myocardial infarction through activation of the NF-κB signaling pathway
  141. Characterization of phenolic compounds and evaluation of anti-diabetic potential in Cannabis sativa L. seeds: In vivo, in vitro, and in silico studies
  142. Quantitative immunohistochemistry analysis of breast Ki67 based on artificial intelligence
  143. Ecology and Environmental Science
  144. Screening of different growth conditions of Bacillus subtilis isolated from membrane-less microbial fuel cell toward antimicrobial activity profiling
  145. Degradation of a mixture of 13 polycyclic aromatic hydrocarbons by commercial effective microorganisms
  146. Evaluation of the impact of two citrus plants on the variation of Panonychus citri (Acari: Tetranychidae) and beneficial phytoseiid mites
  147. Prediction of present and future distribution areas of Juniperus drupacea Labill and determination of ethnobotany properties in Antalya Province, Türkiye
  148. Population genetics of Todarodes pacificus (Cephalopoda: Ommastrephidae) in the northwest Pacific Ocean via GBS sequencing
  149. A comparative analysis of dendrometric, macromorphological, and micromorphological characteristics of Pistacia atlantica subsp. atlantica and Pistacia terebinthus in the middle Atlas region of Morocco
  150. Macrofungal sporocarp community in the lichen Scots pine forests
  151. Assessing the proximate compositions of indigenous forage species in Yemen’s pastoral rangelands
  152. Food Science
  153. Gut microbiota changes associated with low-carbohydrate diet intervention for obesity
  154. Reexamination of Aspergillus cristatus phylogeny in dark tea: Characteristics of the mitochondrial genome
  155. Differences in the flavonoid composition of the leaves, fruits, and branches of mulberry are distinguished based on a plant metabolomics approach
  156. Investigating the impact of wet rendering (solventless method) on PUFA-rich oil from catfish (Clarias magur) viscera
  157. Non-linear associations between cardiovascular metabolic indices and metabolic-associated fatty liver disease: A cross-sectional study in the US population (2017–2020)
  158. Knockdown of USP7 alleviates atherosclerosis in ApoE-deficient mice by regulating EZH2 expression
  159. Utility of dairy microbiome as a tool for authentication and traceability
  160. Agriculture
  161. Enhancing faba bean (Vicia faba L.) productivity through establishing the area-specific fertilizer rate recommendation in southwest Ethiopia
  162. Impact of novel herbicide based on synthetic auxins and ALS inhibitor on weed control
  163. Perspectives of pteridophytes microbiome for bioremediation in agricultural applications
  164. Fertilizer application parameters for drip-irrigated peanut based on the fertilizer effect function established from a “3414” field trial
  165. Improving the productivity and profitability of maize (Zea mays L.) using optimum blended inorganic fertilization
  166. Application of leaf multispectral analyzer in comparison to hyperspectral device to assess the diversity of spectral reflectance indices in wheat genotypes
  167. Animal Sciences
  168. Knockdown of ANP32E inhibits colorectal cancer cell growth and glycolysis by regulating the AKT/mTOR pathway
  169. Development of a detection chip for major pathogenic drug-resistant genes and drug targets in bovine respiratory system diseases
  170. Exploration of the genetic influence of MYOT and MB genes on the plumage coloration of Muscovy ducks
  171. Transcriptome analysis of adipose tissue in grazing cattle: Identifying key regulators of fat metabolism
  172. Comparison of nutritional value of the wild and cultivated spiny loaches at three growth stages
  173. Transcriptomic analysis of liver immune response in Chinese spiny frog (Quasipaa spinosa) infected with Proteus mirabilis
  174. Disruption of BCAA degradation is a critical characteristic of diabetic cardiomyopathy revealed by integrated transcriptome and metabolome analysis
  175. Plant Sciences
  176. Effect of long-term in-row branch covering on soil microorganisms in pear orchards
  177. Photosynthetic physiological characteristics, growth performance, and element concentrations reveal the calcicole–calcifuge behaviors of three Camellia species
  178. Transcriptome analysis reveals the mechanism of NaHCO3 promoting tobacco leaf maturation
  179. Bioinformatics, expression analysis, and functional verification of allene oxide synthase gene HvnAOS1 and HvnAOS2 in qingke
  180. Water, nitrogen, and phosphorus coupling improves gray jujube fruit quality and yield
  181. Improving grape fruit quality through soil conditioner: Insights from RNA-seq analysis of Cabernet Sauvignon roots
  182. Role of Embinin in the reabsorption of nucleus pulposus in lumbar disc herniation: Promotion of nucleus pulposus neovascularization and apoptosis of nucleus pulposus cells
  183. Revealing the effects of amino acid, organic acid, and phytohormones on the germination of tomato seeds under salinity stress
  184. Combined effects of nitrogen fertilizer and biochar on the growth, yield, and quality of pepper
  185. Comprehensive phytochemical and toxicological analysis of Chenopodium ambrosioides (L.) fractions
  186. Impact of “3414” fertilization on the yield and quality of greenhouse tomatoes
  187. Exploring the coupling mode of water and fertilizer for improving growth, fruit quality, and yield of the pear in the arid region
  188. Metagenomic analysis of endophytic bacteria in seed potato (Solanum tuberosum)
  189. Antibacterial, antifungal, and phytochemical properties of Salsola kali ethanolic extract
  190. Exploring the hepatoprotective properties of citronellol: In vitro and in silico studies on ethanol-induced damage in HepG2 cells
  191. Enhanced osmotic dehydration of watermelon rind using honey–sucrose solutions: A study on pre-treatment efficacy and mass transfer kinetics
  192. Effects of exogenous 2,4-epibrassinolide on photosynthetic traits of 53 cowpea varieties under NaCl stress
  193. Comparative transcriptome analysis of maize (Zea mays L.) seedlings in response to copper stress
  194. An optimization method for measuring the stomata in cassava (Manihot esculenta Crantz) under multiple abiotic stresses
  195. Fosinopril inhibits Ang II-induced VSMC proliferation, phenotype transformation, migration, and oxidative stress through the TGF-β1/Smad signaling pathway
  196. Antioxidant and antimicrobial activities of Salsola imbricata methanolic extract and its phytochemical characterization
  197. Bioengineering and Biotechnology
  198. Absorbable calcium and phosphorus bioactive membranes promote bone marrow mesenchymal stem cells osteogenic differentiation for bone regeneration
  199. New advances in protein engineering for industrial applications: Key takeaways
  200. An overview of the production and use of Bacillus thuringiensis toxin
  201. Research progress of nanoparticles in diagnosis and treatment of hepatocellular carcinoma
  202. Bioelectrochemical biosensors for water quality assessment and wastewater monitoring
  203. PEI/MMNs@LNA-542 nanoparticles alleviate ICU-acquired weakness through targeted autophagy inhibition and mitochondrial protection
  204. Unleashing of cytotoxic effects of thymoquinone-bovine serum albumin nanoparticles on A549 lung cancer cells
  205. Erratum
  206. Erratum to “Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM”
  207. Erratum to “Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation”
  208. Retraction
  209. Retraction to “MiR-223-3p regulates cell viability, migration, invasion, and apoptosis of non-small cell lung cancer cells by targeting RHOB”
  210. Retraction to “A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis”
  211. Special Issue on Advances in Neurodegenerative Disease Research and Treatment
  212. Transplantation of human neural stem cell prevents symptomatic motor behavior disability in a rat model of Parkinson’s disease
  213. Special Issue on Multi-omics
  214. Inflammasome complex genes with clinical relevance suggest potential as therapeutic targets for anti-tumor drugs in clear cell renal cell carcinoma
  215. Gastroesophageal varices in primary biliary cholangitis with anti-centromere antibody positivity: Early onset?
https://doi.org/10.1515/biol-2022-0890
Schlagwörter für diesen Artikel
RIP3; NF-κB; NLRP3; left ventricular mechanics; myocardial infarction
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Biomedical Sciences
  2. Constitutive and evoked release of ATP in adult mouse olfactory epithelium
  3. LARP1 knockdown inhibits cultured gastric carcinoma cell cycle progression and metastatic behavior
  4. PEGylated porcine–human recombinant uricase: A novel fusion protein with improved efficacy and safety for the treatment of hyperuricemia and renal complications
  5. Research progress on ocular complications caused by type 2 diabetes mellitus and the function of tears and blepharons
  6. The role and mechanism of esketamine in preventing and treating remifentanil-induced hyperalgesia based on the NMDA receptor–CaMKII pathway
  7. Brucella infection combined with Nocardia infection: A case report and literature review
  8. Detection of serum interleukin-18 level and neutrophil/lymphocyte ratio in patients with antineutrophil cytoplasmic antibody-associated vasculitis and its clinical significance
  9. Ang-1, Ang-2, and Tie2 are diagnostic biomarkers for Henoch-Schönlein purpura and pediatric-onset systemic lupus erythematous
  10. PTTG1 induces pancreatic cancer cell proliferation and promotes aerobic glycolysis by regulating c-myc
  11. Role of serum B-cell-activating factor and interleukin-17 as biomarkers in the classification of interstitial pneumonia with autoimmune features
  12. Effectiveness and safety of a mumps containing vaccine in preventing laboratory-confirmed mumps cases from 2002 to 2017: A meta-analysis
  13. Low levels of sex hormone-binding globulin predict an increased breast cancer risk and its underlying molecular mechanisms
  14. A case of Trousseau syndrome: Screening, detection and complication
  15. Application of the integrated airway humidification device enhances the humidification effect of the rabbit tracheotomy model
  16. Preparation of Cu2+/TA/HAP composite coating with anti-bacterial and osteogenic potential on 3D-printed porous Ti alloy scaffolds for orthopedic applications
  17. Aquaporin-8 promotes human dermal fibroblasts to counteract hydrogen peroxide-induced oxidative damage: A novel target for management of skin aging
  18. Current research and evidence gaps on placental development in iron deficiency anemia
  19. Single-nucleotide polymorphism rs2910829 in PDE4D is related to stroke susceptibility in Chinese populations: The results of a meta-analysis
  20. Pheochromocytoma-induced myocardial infarction: A case report
  21. Kaempferol regulates apoptosis and migration of neural stem cells to attenuate cerebral infarction by O‐GlcNAcylation of β-catenin
  22. Sirtuin 5 regulates acute myeloid leukemia cell viability and apoptosis by succinylation modification of glycine decarboxylase
  23. Apigenin 7-glucoside impedes hypoxia-induced malignant phenotypes of cervical cancer cells in a p16-dependent manner
  24. KAT2A changes the function of endometrial stromal cells via regulating the succinylation of ENO1
  25. Current state of research on copper complexes in the treatment of breast cancer
  26. Exploring antioxidant strategies in the pathogenesis of ALS
  27. Helicobacter pylori causes gastric dysbacteriosis in chronic gastritis patients
  28. IL-33/soluble ST2 axis is associated with radiation-induced cardiac injury
  29. The predictive value of serum NLR, SII, and OPNI for lymph node metastasis in breast cancer patients with internal mammary lymph nodes after thoracoscopic surgery
  30. Carrying SNP rs17506395 (T > G) in TP63 gene and CCR5Δ32 mutation associated with the occurrence of breast cancer in Burkina Faso
  31. P2X7 receptor: A receptor closely linked with sepsis-associated encephalopathy
  32. Probiotics for inflammatory bowel disease: Is there sufficient evidence?
  33. Identification of KDM4C as a gene conferring drug resistance in multiple myeloma
  34. Microbial perspective on the skin–gut axis and atopic dermatitis
  35. Thymosin α1 combined with XELOX improves immune function and reduces serum tumor markers in colorectal cancer patients after radical surgery
  36. Highly specific vaginal microbiome signature for gynecological cancers
  37. Sample size estimation for AQP4-IgG seropositive optic neuritis: Retinal damage detection by optical coherence tomography
  38. The effects of SDF-1 combined application with VEGF on femoral distraction osteogenesis in rats
  39. Fabrication and characterization of gold nanoparticles using alginate: In vitro and in vivo assessment of its administration effects with swimming exercise on diabetic rats
  40. Mitigating digestive disorders: Action mechanisms of Mediterranean herbal active compounds
  41. Distribution of CYP2D6 and CYP2C19 gene polymorphisms in Han and Uygur populations with breast cancer in Xinjiang, China
  42. VSP-2 attenuates secretion of inflammatory cytokines induced by LPS in BV2 cells by mediating the PPARγ/NF-κB signaling pathway
  43. Factors influencing spontaneous hypothermia after emergency trauma and the construction of a predictive model
  44. Long-term administration of morphine specifically alters the level of protein expression in different brain regions and affects the redox state
  45. Application of metagenomic next-generation sequencing technology in the etiological diagnosis of peritoneal dialysis-associated peritonitis
  46. Clinical diagnosis, prevention, and treatment of neurodyspepsia syndrome using intelligent medicine
  47. Case report: Successful bronchoscopic interventional treatment of endobronchial leiomyomas
  48. Preliminary investigation into the genetic etiology of short stature in children through whole exon sequencing of the core family
  49. Cystic adenomyoma of the uterus: Case report and literature review
  50. Mesoporous silica nanoparticles as a drug delivery mechanism
  51. Dynamic changes in autophagy activity in different degrees of pulmonary fibrosis in mice
  52. Vitamin D deficiency and inflammatory markers in type 2 diabetes: Big data insights
  53. Lactate-induced IGF1R protein lactylation promotes proliferation and metabolic reprogramming of lung cancer cells
  54. Meta-analysis on the efficacy of allogeneic hematopoietic stem cell transplantation to treat malignant lymphoma
  55. Mitochondrial DNA drives neuroinflammation through the cGAS-IFN signaling pathway in the spinal cord of neuropathic pain mice
  56. Application value of artificial intelligence algorithm-based magnetic resonance multi-sequence imaging in staging diagnosis of cervical cancer
  57. Embedded monitoring system and teaching of artificial intelligence online drug component recognition
  58. Investigation into the association of FNDC1 and ADAMTS12 gene expression with plumage coloration in Muscovy ducks
  59. Yak meat content in feed and its impact on the growth of rats
  60. A rare case of Richter transformation with breast involvement: A case report and literature review
  61. First report of Nocardia wallacei infection in an immunocompetent patient in Zhejiang province
  62. Rhodococcus equi and Brucella pulmonary mass in immunocompetent: A case report and literature review
  63. Downregulation of RIP3 ameliorates the left ventricular mechanics and function after myocardial infarction via modulating NF-κB/NLRP3 pathway
  64. Evaluation of the role of some non-enzymatic antioxidants among Iraqi patients with non-alcoholic fatty liver disease
  65. The role of Phafin proteins in cell signaling pathways and diseases
  66. Ten-year anemia as initial manifestation of Castleman disease in the abdominal cavity: A case report
  67. Coexistence of hereditary spherocytosis with SPTB P.Trp1150 gene variant and Gilbert syndrome: A case report and literature review
  68. Utilization of convolutional neural networks to analyze microscopic images for high-throughput screening of mesenchymal stem cells
  69. Exploratory evaluation supported by experimental and modeling approaches of Inula viscosa root extract as a potent corrosion inhibitor for mild steel in a 1 M HCl solution
  70. Imaging manifestations of ductal adenoma of the breast: A case report
  71. Gut microbiota and sleep: Interaction mechanisms and therapeutic prospects
  72. Isomangiferin promotes the migration and osteogenic differentiation of rat bone marrow mesenchymal stem cells
  73. Prognostic value and microenvironmental crosstalk of exosome-related signatures in human epidermal growth factor receptor 2 positive breast cancer
  74. Circular RNAs as potential biomarkers for male severe sepsis
  75. Knockdown of Stanniocalcin-1 inhibits growth and glycolysis in oral squamous cell carcinoma cells
  76. The expression and biological role of complement C1s in esophageal squamous cell carcinoma
  77. A novel GNAS mutation in pseudohypoparathyroidism type 1a with articular flexion deformity: A case report
  78. Predictive value of serum magnesium levels for prognosis in patients with non-small cell lung cancer undergoing EGFR-TKI therapy
  79. HSPB1 alleviates acute-on-chronic liver failure via the P53/Bax pathway
  80. IgG4-related disease complicated by PLA2R-associated membranous nephropathy: A case report
  81. Baculovirus-mediated endostatin and angiostatin activation of autophagy through the AMPK/AKT/mTOR pathway inhibits angiogenesis in hepatocellular carcinoma
  82. Metformin mitigates osteoarthritis progression by modulating the PI3K/AKT/mTOR signaling pathway and enhancing chondrocyte autophagy
  83. Evaluation of the activity of antimicrobial peptides against bacterial vaginosis
  84. Atypical presentation of γ/δ mycosis fungoides with an unusual phenotype and SOCS1 mutation
  85. Analysis of the microecological mechanism of diabetic kidney disease based on the theory of “gut–kidney axis”: A systematic review
  86. Omega-3 fatty acids prevent gestational diabetes mellitus via modulation of lipid metabolism
  87. Refractory hypertension complicated with Turner syndrome: A case report
  88. Interaction of ncRNAs and the PI3K/AKT/mTOR pathway: Implications for osteosarcoma
  89. Association of low attenuation area scores with pulmonary function and clinical prognosis in patients with chronic obstructive pulmonary disease
  90. Long non-coding RNAs in bone formation: Key regulators and therapeutic prospects
  91. The deubiquitinating enzyme USP35 regulates the stability of NRF2 protein
  92. Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as potential diagnostic markers for rebleeding in patients with esophagogastric variceal bleeding
  93. G protein-coupled receptor 1 participating in the mechanism of mediating gestational diabetes mellitus by phosphorylating the AKT pathway
  94. LL37-mtDNA regulates viability, apoptosis, inflammation, and autophagy in lipopolysaccharide-treated RLE-6TN cells by targeting Hsp90aa1
  95. The analgesic effect of paeoniflorin: A focused review
  96. Chemical composition’s effect on Solanum nigrum Linn.’s antioxidant capacity and erythrocyte protection: Bioactive components and molecular docking analysis
  97. Knockdown of HCK promotes HREC cell viability and inner blood–retinal barrier integrity by regulating the AMPK signaling pathway
  98. The role of rapamycin in the PINK1/Parkin signaling pathway in mitophagy in podocytes
  99. Laryngeal non-Hodgkin lymphoma: Report of four cases and review of the literature
  100. Clinical value of macrogenome next-generation sequencing on infections
  101. Overview of dendritic cells and related pathways in autoimmune uveitis
  102. TAK-242 alleviates diabetic cardiomyopathy via inhibiting pyroptosis and TLR4/CaMKII/NLRP3 pathway
  103. Hypomethylation in promoters of PGC-1α involved in exercise-driven skeletal muscular alterations in old age
  104. Profile and antimicrobial susceptibility patterns of bacteria isolated from effluents of Kolladiba and Debark hospitals
  105. The expression and clinical significance of syncytin-1 in serum exosomes of hepatocellular carcinoma patients
  106. A histomorphometric study to evaluate the therapeutic effects of biosynthesized silver nanoparticles on the kidneys infected with Plasmodium chabaudi
  107. PGRMC1 and PAQR4 are promising molecular targets for a rare subtype of ovarian cancer
  108. Analysis of MDA, SOD, TAOC, MNCV, SNCV, and TSS scores in patients with diabetes peripheral neuropathy
  109. SLIT3 deficiency promotes non-small cell lung cancer progression by modulating UBE2C/WNT signaling
  110. The relationship between TMCO1 and CALR in the pathological characteristics of prostate cancer and its effect on the metastasis of prostate cancer cells
  111. Heterogeneous nuclear ribonucleoprotein K is a potential target for enhancing the chemosensitivity of nasopharyngeal carcinoma
  112. PHB2 alleviates retinal pigment epithelium cell fibrosis by suppressing the AGE–RAGE pathway
  113. Anti-γ-aminobutyric acid-B receptor autoimmune encephalitis with syncope as the initial symptom: Case report and literature review
  114. Comparative analysis of chloroplast genome of Lonicera japonica cv. Damaohua
  115. Human umbilical cord mesenchymal stem cells regulate glutathione metabolism depending on the ERK–Nrf2–HO-1 signal pathway to repair phosphoramide mustard-induced ovarian cancer cells
  116. Electroacupuncture on GB acupoints improves osteoporosis via the estradiol–PI3K–Akt signaling pathway
  117. Renalase protects against podocyte injury by inhibiting oxidative stress and apoptosis in diabetic nephropathy
  118. Review: Dicranostigma leptopodum: A peculiar plant of Papaveraceae
  119. Combination effect of flavonoids attenuates lung cancer cell proliferation by inhibiting the STAT3 and FAK signaling pathway
  120. Renal microangiopathy and immune complex glomerulonephritis induced by anti-tumour agents: A case report
  121. Correlation analysis of AVPR1a and AVPR2 with abnormal water and sodium and potassium metabolism in rats
  122. Gastrointestinal health anti-diarrheal mixture relieves spleen deficiency-induced diarrhea through regulating gut microbiota
  123. Myriad factors and pathways influencing tumor radiotherapy resistance
  124. Exploring the effects of culture conditions on Yapsin (YPS) gene expression in Nakaseomyces glabratus
  125. Screening of prognostic core genes based on cell–cell interaction in the peripheral blood of patients with sepsis
  126. Coagulation factor II thrombin receptor as a promising biomarker in breast cancer management
  127. Ileocecal mucinous carcinoma misdiagnosed as incarcerated hernia: A case report
  128. Methyltransferase like 13 promotes malignant behaviors of bladder cancer cells through targeting PI3K/ATK signaling pathway
  129. The debate between electricity and heat, efficacy and safety of irreversible electroporation and radiofrequency ablation in the treatment of liver cancer: A meta-analysis
  130. ZAG promotes colorectal cancer cell proliferation and epithelial–mesenchymal transition by promoting lipid synthesis
  131. Baicalein inhibits NLRP3 inflammasome activation and mitigates placental inflammation and oxidative stress in gestational diabetes mellitus
  132. Impact of SWCNT-conjugated senna leaf extract on breast cancer cells: A potential apoptotic therapeutic strategy
  133. MFAP5 inhibits the malignant progression of endometrial cancer cells in vitro
  134. Major ozonated autohemotherapy promoted functional recovery following spinal cord injury in adult rats via the inhibition of oxidative stress and inflammation
  135. Axodendritic targeting of TAU and MAP2 and microtubule polarization in iPSC-derived versus SH-SY5Y-derived human neurons
  136. Differential expression of phosphoinositide 3-kinase/protein kinase B and Toll-like receptor/nuclear factor kappa B signaling pathways in experimental obesity Wistar rat model
  137. The therapeutic potential of targeting Oncostatin M and the interleukin-6 family in retinal diseases: A comprehensive review
  138. BA inhibits LPS-stimulated inflammatory response and apoptosis in human middle ear epithelial cells by regulating the Nf-Kb/Iκbα axis
  139. Role of circRMRP and circRPL27 in chronic obstructive pulmonary disease
  140. Investigating the role of hyperexpressed HCN1 in inducing myocardial infarction through activation of the NF-κB signaling pathway
  141. Characterization of phenolic compounds and evaluation of anti-diabetic potential in Cannabis sativa L. seeds: In vivo, in vitro, and in silico studies
  142. Quantitative immunohistochemistry analysis of breast Ki67 based on artificial intelligence
  143. Ecology and Environmental Science
  144. Screening of different growth conditions of Bacillus subtilis isolated from membrane-less microbial fuel cell toward antimicrobial activity profiling
  145. Degradation of a mixture of 13 polycyclic aromatic hydrocarbons by commercial effective microorganisms
  146. Evaluation of the impact of two citrus plants on the variation of Panonychus citri (Acari: Tetranychidae) and beneficial phytoseiid mites
  147. Prediction of present and future distribution areas of Juniperus drupacea Labill and determination of ethnobotany properties in Antalya Province, Türkiye
  148. Population genetics of Todarodes pacificus (Cephalopoda: Ommastrephidae) in the northwest Pacific Ocean via GBS sequencing
  149. A comparative analysis of dendrometric, macromorphological, and micromorphological characteristics of Pistacia atlantica subsp. atlantica and Pistacia terebinthus in the middle Atlas region of Morocco
  150. Macrofungal sporocarp community in the lichen Scots pine forests
  151. Assessing the proximate compositions of indigenous forage species in Yemen’s pastoral rangelands
  152. Food Science
  153. Gut microbiota changes associated with low-carbohydrate diet intervention for obesity
  154. Reexamination of Aspergillus cristatus phylogeny in dark tea: Characteristics of the mitochondrial genome
  155. Differences in the flavonoid composition of the leaves, fruits, and branches of mulberry are distinguished based on a plant metabolomics approach
  156. Investigating the impact of wet rendering (solventless method) on PUFA-rich oil from catfish (Clarias magur) viscera
  157. Non-linear associations between cardiovascular metabolic indices and metabolic-associated fatty liver disease: A cross-sectional study in the US population (2017–2020)
  158. Knockdown of USP7 alleviates atherosclerosis in ApoE-deficient mice by regulating EZH2 expression
  159. Utility of dairy microbiome as a tool for authentication and traceability
  160. Agriculture
  161. Enhancing faba bean (Vicia faba L.) productivity through establishing the area-specific fertilizer rate recommendation in southwest Ethiopia
  162. Impact of novel herbicide based on synthetic auxins and ALS inhibitor on weed control
  163. Perspectives of pteridophytes microbiome for bioremediation in agricultural applications
  164. Fertilizer application parameters for drip-irrigated peanut based on the fertilizer effect function established from a “3414” field trial
  165. Improving the productivity and profitability of maize (Zea mays L.) using optimum blended inorganic fertilization
  166. Application of leaf multispectral analyzer in comparison to hyperspectral device to assess the diversity of spectral reflectance indices in wheat genotypes
  167. Animal Sciences
  168. Knockdown of ANP32E inhibits colorectal cancer cell growth and glycolysis by regulating the AKT/mTOR pathway
  169. Development of a detection chip for major pathogenic drug-resistant genes and drug targets in bovine respiratory system diseases
  170. Exploration of the genetic influence of MYOT and MB genes on the plumage coloration of Muscovy ducks
  171. Transcriptome analysis of adipose tissue in grazing cattle: Identifying key regulators of fat metabolism
  172. Comparison of nutritional value of the wild and cultivated spiny loaches at three growth stages
  173. Transcriptomic analysis of liver immune response in Chinese spiny frog (Quasipaa spinosa) infected with Proteus mirabilis
  174. Disruption of BCAA degradation is a critical characteristic of diabetic cardiomyopathy revealed by integrated transcriptome and metabolome analysis
  175. Plant Sciences
  176. Effect of long-term in-row branch covering on soil microorganisms in pear orchards
  177. Photosynthetic physiological characteristics, growth performance, and element concentrations reveal the calcicole–calcifuge behaviors of three Camellia species
  178. Transcriptome analysis reveals the mechanism of NaHCO3 promoting tobacco leaf maturation
  179. Bioinformatics, expression analysis, and functional verification of allene oxide synthase gene HvnAOS1 and HvnAOS2 in qingke
  180. Water, nitrogen, and phosphorus coupling improves gray jujube fruit quality and yield
  181. Improving grape fruit quality through soil conditioner: Insights from RNA-seq analysis of Cabernet Sauvignon roots
  182. Role of Embinin in the reabsorption of nucleus pulposus in lumbar disc herniation: Promotion of nucleus pulposus neovascularization and apoptosis of nucleus pulposus cells
  183. Revealing the effects of amino acid, organic acid, and phytohormones on the germination of tomato seeds under salinity stress
  184. Combined effects of nitrogen fertilizer and biochar on the growth, yield, and quality of pepper
  185. Comprehensive phytochemical and toxicological analysis of Chenopodium ambrosioides (L.) fractions
  186. Impact of “3414” fertilization on the yield and quality of greenhouse tomatoes
  187. Exploring the coupling mode of water and fertilizer for improving growth, fruit quality, and yield of the pear in the arid region
  188. Metagenomic analysis of endophytic bacteria in seed potato (Solanum tuberosum)
  189. Antibacterial, antifungal, and phytochemical properties of Salsola kali ethanolic extract
  190. Exploring the hepatoprotective properties of citronellol: In vitro and in silico studies on ethanol-induced damage in HepG2 cells
  191. Enhanced osmotic dehydration of watermelon rind using honey–sucrose solutions: A study on pre-treatment efficacy and mass transfer kinetics
  192. Effects of exogenous 2,4-epibrassinolide on photosynthetic traits of 53 cowpea varieties under NaCl stress
  193. Comparative transcriptome analysis of maize (Zea mays L.) seedlings in response to copper stress
  194. An optimization method for measuring the stomata in cassava (Manihot esculenta Crantz) under multiple abiotic stresses
  195. Fosinopril inhibits Ang II-induced VSMC proliferation, phenotype transformation, migration, and oxidative stress through the TGF-β1/Smad signaling pathway
  196. Antioxidant and antimicrobial activities of Salsola imbricata methanolic extract and its phytochemical characterization
  197. Bioengineering and Biotechnology
  198. Absorbable calcium and phosphorus bioactive membranes promote bone marrow mesenchymal stem cells osteogenic differentiation for bone regeneration
  199. New advances in protein engineering for industrial applications: Key takeaways
  200. An overview of the production and use of Bacillus thuringiensis toxin
  201. Research progress of nanoparticles in diagnosis and treatment of hepatocellular carcinoma
  202. Bioelectrochemical biosensors for water quality assessment and wastewater monitoring
  203. PEI/MMNs@LNA-542 nanoparticles alleviate ICU-acquired weakness through targeted autophagy inhibition and mitochondrial protection
  204. Unleashing of cytotoxic effects of thymoquinone-bovine serum albumin nanoparticles on A549 lung cancer cells
  205. Erratum
  206. Erratum to “Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM”
  207. Erratum to “Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation”
  208. Retraction
  209. Retraction to “MiR-223-3p regulates cell viability, migration, invasion, and apoptosis of non-small cell lung cancer cells by targeting RHOB”
  210. Retraction to “A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis”
  211. Special Issue on Advances in Neurodegenerative Disease Research and Treatment
  212. Transplantation of human neural stem cell prevents symptomatic motor behavior disability in a rat model of Parkinson’s disease
  213. Special Issue on Multi-omics
  214. Inflammasome complex genes with clinical relevance suggest potential as therapeutic targets for anti-tumor drugs in clear cell renal cell carcinoma
  215. Gastroesophageal varices in primary biliary cholangitis with anti-centromere antibody positivity: Early onset?
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Heruntergeladen am 26.9.2025 von https://www.degruyterbrill.com/document/doi/10.1515/biol-2022-0890/html
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