Startseite TAK-242 alleviates diabetic cardiomyopathy via inhibiting pyroptosis and TLR4/CaMKII/NLRP3 pathway
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TAK-242 alleviates diabetic cardiomyopathy via inhibiting pyroptosis and TLR4/CaMKII/NLRP3 pathway

  • Xiaolong Zhao , Jing Zhang , Feng Xu , Longqi Shang , Qingquan Liu und Chunjian Shen EMAIL logo
Veröffentlicht/Copyright: 10. September 2024
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Open Life Sciences
Aus der Zeitschrift Open Life Sciences Band 19 Heft 1

Abstract

Diabetic cardiomyopathy (DCM) is identified as a progressive disease that may lead to irreparable heart failure. Toll-like receptor (TLR) signaling is believed to be implicated in the pathogenesis of DCM. This study intended to explore the potential impact of Toll-like receptor 4 (TLR4) on DCM in vitro and in vivo. Streptozotocin and HG medium were utilized to induce diabetes in animal and cell models, respectively. Selective TLR4 inhibitor TAK-242 and calcium/calmodulin-dependent protein kinase-II (CaMKII) inhibitor KN-93 were employed to explore the involvement of TLR4/CaMKII in DCM. TLR4 expression was increased in DCM hearts, while inhibition of TLR4 activation by TAK-242 improved cardiac function, attenuated heart hypertrophy, and fibrosis, as well as reduced oxidative stress and proinflammatory cytokine levels in rats, which were confirmed by Doppler echocardiography, hematoxylin and eosin staining, and Masson Trichome staining and specific enzyme-linked immunosorbent assay kits. Besides, the expression of hypertrophy-related molecules and oxidative stress damage were also inhibited by TAK-242. Furthermore, TAK-242 treatment reduced CaMKII phosphorylation accompanied by decreased expression of NOD-like pyrin domain-containing protein 3, gasdermin D (GSDMD), The N-terminal domain of Gasdermin D (GSDMD-N), apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) and Caspase-1 both in vivo and in vitro. Similar positive impacts on HG-induced pyroptosis were also observed with KN-93 treatment, and this was achieved without affecting TLR4 expression. Collectively, our work suggested that TAK-242 demonstrated substantial benefits against DCM both in vivo and in vitro, potentially attributed to the suppression of the TLR4-mediated CaMKII/NLRP3 pathway activity.

Keywords: CaMKII/NLRP3 pathway; diabetic cardiomyopathy; inflammasome; pyroptosis; TAK-242; TLR4

1 Introduction

Diabetes mellitus (DM) is a chronic condition that poses a considerable public health burden, and its global prevalence is on the rise [1]. Diabetic cardiomyopathy (DCM), first proposed by Rubler, refers to a heart muscle condition that occurs in individuals with diabetes [2]. DCM is identified as impaired cardiac function in the absence of concurrent cardiovascular conditions, including coronary heart disease, systemic hypertension, valvar disease, or other structural abnormalities in the heart [3]. Notably, the progression of DCM typically starts with impaired diastolic function of the left ventricle and cardiac hypertrophy, eventually leading to systolic dysfunction and heart failure, accompanied by cardiomyocyte loss and fibrosis accumulation in the heart [4,5]. Despite numerous studies conducted on DCM, our understanding of its pathophysiology remains incomplete.

Pyroptosis has been proven to play a significant role in the progression of DCM. Elevated glucose levels can induce cell pyroptosis [6], and inhibiting pyroptosis has shown effectiveness in alleviating DCM symptoms [7,8]. The assembly of an inflammasome complex, along with caspase-1 and IL-1β, serves as the initiation of pyroptosis [9,10]. It is well understood that inflammatory factor tumor necrosis factor-alpha (TNF-α) is involved in DCM pathogenesis on account of its role in initiating several intracellular death signaling, including pyroptosis [11]. It is reported that TNF-α forms a complex by binding to TNF receptor 1, and the complex is validated to be involved in pyroptosis initiation [12,13]. Studying pyroptosis enhances our comprehension of the mechanisms contributing to DCM progression, which reveals novel targets for advancing treatment approaches.

Toll-like receptors (TLRs) are membrane-bound receptors that play a crucial role in innate immunity and are involved in the regulation of various signal transduction pathways [14]. TLR4, in particular, has been implicated as a key mediator of inflammation in diabetes and may contribute to the development of diabetic complications [15,16]. Multiple studies have evidenced that hyperglycemia activates TLR4 and induces inflammation in DCM [17]. Suppressing TLR4-associated pathways has been proven effective in mitigating DCM [18,19]. Additionally, a previous study has shown that TLR4 mediates cell pyroptosis through various mechanisms [20]. Hence, targeting TLR4 presents a promising approach for treating DCM by effectively inhibiting pyroptosis, which could offer valuable targets for the development of innovative therapeutic interventions.

Ca2+/calmodulin-dependent protein kinase (CaMK) family members are essential in a variety of pathophysiological functions, such as survival, proliferation, cell differentiation, and inflammatory disorders [21]. Ca2+/calmodulin-dependent protein kinase-II (CaMKII), one prominent member, acts as a multifunctional serine/threonine kinase that controls expressions of the downstream genes via activating transcription factors [22]. CaMKII is involved in initiating NOD-like pyrin domain-containing protein 3 (NLRP3) inflammasome signaling in cardiomyocytes, which triggers inflammation in non-ischemic heart disease [23]. Notably, CaMKII/NLRP3 signaling is involved in the process of pyroptosis, and targeting NLRP3 through the CaMKII/cyclic AMP response element binding protein axis has demonstrated significant alleviation symptoms in Alzheimer’s mouse models by inhibiting pyroptosis [24]. However, further research is required to elucidate the mechanistic role of CaMKII/NLRP3 in DCM.

Recent studies have highlighted the intervention methods targeting pyroptosis as a potential future direction for preventing and treating DCM [6,25], but the mechanism related to pyroptosis needs to be further studied. The previous study has reported that TLR4 activates the CaMKII Mst1/2-Rac axis by inducing calcium influx [26]. Consequently, our current investigation primarily focused on the effects and underlying mechanisms of TLR4 on HG-stimulated cardiac damage. Our findings demonstrated that inhibiting TLR4 suppressed pyroptosis, primarily through its inhibitory impact on the CaMKII/NLRP3 pathway. This study offers a new mechanistic understanding of the protective effects of TAK-242 in DCM.

2 Materials and methods

2.1 Animal model

The experiments were carried out on male Sprague Dawley (SD) rats, aged 8 weeks, weighing between 150 and 170 g. All protocols involving animal subjects adhered to the laboratory animal guidelines established by the US National Institutes of Health and received approval from the Animal Care and Use Committee of Dalian Medical University (no: CSE202301007). The experimental rats were maintained under specific pathogen-free conditions, with a conventional room setup and a 12:12-h light/dark cycle. Throughout the study, the animals were provided free access to food and water.

Male SD rats (aged 8 weeks, weighing between 150 and 170 g) were assigned at random into one of four groups following acclimatization for 1 week: control group (n = 8), DM group (n = 16), control+TAK-242 group (n = 8), and DM+TAK-242 group (n = 8). The rats in the DM and DM+TAK-242 groups were intraperitoneally administered with streptozotocin (STZ; 50 mg/kg; Sigma-Aldrich, USA) dissolved in citrate acid buffer dilution (Sigma-Aldrich, USA) for three consecutive days. Rats in the control and TAK-242 groups received the citrate buffer injection. Fasting blood glucose (FBG) levels were measured 1 week after STZ injection, and the rats with FBG levels above 16.7 mM were selected for further investigation [27]. The rats in the control+TAK-242 and DM+TAK-242 groups received daily intraperitoneal injections of TAK-242 (3 mg/kg, dissolved in DMSO) for seven consecutive days starting from 3 weeks after STZ administration. Both the control group and the DM group of rats were administered an equivalent volume of DMSO via intraperitoneal injection. Following 8 weeks of STZ injection, the DM group was further divided into two subgroups: the DM group (n = 8) and the DM+KN-93 group (n = 8). The DM+KN-93 group received intraperitoneal injections of KN-93 at a dosage of 10 mg/kg/2 days for 8 weeks, while rats in the other group received vehicle injection. Blood glucose levels were regularly monitored throughout the experiment. Following the completion of the echocardiogram (ECG), blood samples were collected, and cardiac tissues were obtained for cardiac histology and molecular biology studies. All animals were sedated utilizing 2% isoflurane administered by inhalation and underwent ECG testing to evaluate ST segment alterations. Echocardiography was performed using small-animal ultrasonography (Vinno Co., China) to assess various cardiac functions, including ejection fraction (EF), fractional shortening (FS), peak E-to-peak A ratio (E/A), and left ventricular internal dimension at systole (LVIDs).

  1. Ethical approval: The research related to animals’ use has been complied with all the relevant national regulations and institutional policies for the care and use of animals.

2.2 Histopathology

Midventricular heart samples were fixed in a solution of 4% formalin, dehydrated with alcohol, embedded in paraffin, and cut into 5 μm sections using a microtome for histological examination. Hematoxylin and eosin staining was conducted on several transverse slices of paraffin-embedded samples to visualize general tissue morphology. Additional paraffin slices were stained with Masson trichrome to assess collagen deposition [28]. The sections were analyzed under a light microscope (Olympus, Japan), and photomicrographs of the tissue sections were captured with an Olympus microscope camera.

2.3 Cell culture

H9c2 cardiomyocytes, derived from rats, were obtained from the American Type Culture Collection. The cell line was cultivated in Dulbecco’s modified Eagle’s medium (DMEM; Cytiva, America) supplemented with 10% fetal bovine serum (Kangyuan Biotechnology, China) and 1% penicillin–streptomycin. The cells were maintained in a humidified incubator at 37°C with a 5% CO2 atmosphere. Cells between passages 3 and 8 were used for subsequent experiments. To simulate the hyperglycemic (HG) state of type-1 diabetes, a high glucose solution (30 mM glucose) was utilized. The cells were separated into two groups: normoglycemic (NG, 5.5 mM glucose) and HG. TAK-242 (1 mM) and KN-93 (5 μm) were added to determine the mechanism of action. According to the experimental design, the H9c2 cardiomyocytes were categorized into five groups based on the culture media and medications employed: NG (normal glucose), HG (high glucose), NG+TAK-242, HG+TAK-242, and HG+KN-93.

2.4 Cell Counting Kit-8 (CCK-8) assay

H9c2 cells were seeded onto a 96-well plate with a total amount of 1 × 104 cells per well. Then, the cells were exposed to HG treatment, with or without TAK-242 (1 mM) and KN-93 (5 μM) for 48 h. The proliferation of cells was evaluated utilizing a CCK-8 Kit (Beyotime Biotechnology, China) in strict accordance with the manufacturer’s instructions. Following TAK-242 or KN-93 treatment, 10 μL of CCK-8 reagent was added, and then the cells were further incubated for 2 h at 37°C. The measurement of absorbance was taken at a wavelength of 450 nm.

2.5 Measurement of reactive oxygen species (ROS)

Intracellular ROS levels were evaluated using the 2′-7′-dichlorodihydrofluorescein diacetate (DCFH-DA) probe kit (Beyotime, China). After treating the cells with HG and/or TAK-242 for 24 h, the cells were washed three times with serum-free medium. Subsequently, the cells were incubated with DCFH-DA in the absence of light for 30 min. The fluorescence intensity was measured using a flow cytometer (ACEA, China) for quantitative analysis.

2.6 Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) staining

The TUNEL staining agents (Beyotime, China) were used to stain the cell slides or tissue sections in accordance with the manufacturer’s instructions. After staining the nuclei with 4′,6-diamidino-2-phenylindole, the sections were sealed, and a fluorescent microscope (COIC, China) was used to capture the images.

2.7 Flow cytometry

Cell apoptosis was measured by employing flow cytometry. H9c2 cells were collected and stained with Annexin V-FITC and propidium iodide. The flow cytometer (ACEA, China) was utilized to evaluate the stained cells for the dead cells population following dual labeling for 15 min at room temperature and darkness [29].

2.8 Enzyme-linked immunosorbent assay (ELISA)

The levels of IL-1β and IL-18 in the cell culture supernatants or serum were determined using ELISA kits from Elabscience Biotechnology (China). The quantification was performed following the manufacturer’s instructions and guidelines provided with the kits [30].

2.9 Reverse transcriptase qPCR

The total RNA samples were extracted from cardiac tissues as well as H9c2 cells utilizing the AG RNAex Pro Reagent (Accurate Biology, China) as per the manufacturer’s instructions, followed by reverse transcription into complementary DNA using an RT reagent kit (ABclonal, USA). SYBR Green PCR Master Mix Kit (ABclonal, USA) was utilized to quantify TLR4, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), β-major histocompatibility complex (β-MHC), CollagenI, CollagenIII, connective tissue growth factor (CTGF), and β-actin mRNA levels. The reactions were performed on a real-time PCR equipment (Bioer Technology, China) with β-actin as the internal control. The primer sequences are depicted below.

TLR4 forward 5′-CCAGAGCCGTTGGTGTATCT-3′ and reverse 5′-AGAGCATTGTCCTCCCACTC-3′.

BNP forward 5′-AGTCCTAGCCAGTCTCCAGA-3′ and reverse 5′-ATCCGGTCTATCTTGTGCCC-3′.

ANP forward 5′-GCCGGTAGAAGATGAGGTCA-3′ and reverse 5′-AGCTGGATCTTCGTAGGCTC-3′.

β-MHC forward 5′-GCAGATCATCAAGGCCAAGG-3′ and reverse 5′-AGTTGCCTCTTGAGGTCCTC-3′.

Collagen forward 5′-ATGTGCCACTCTGACTGGAA-3′ and reverse 5′-TCCATCGGTCATGCTCTCTC-3′.

CollagenIII forward 5′-CCCCTGGTTCTTCTGGACAT-3′ and reverse 5′-TGGGCCTTTGATACCTGGAG-3′.

CTGF forward 5′-GTGAGTCCTTCCAAAGCAGC-3′, reverse 5′-TAGTTGGGTCTGGGCCAAAT-3′.

β-Actin forward 5′-GGATTCCTATGTGGGCGACGA-3′ and reverse 5′-GCGTACAGGGATAGCACAGC-3′.

2.10 Western blot

To extract total proteins, rat heart tissues, as well as H9c2 cells, were lysed utilizing an ice-cold radio-immunoprecipitation lysis buffer (Absin, China). A BCA detection kit (Absin, China) was employed to quantify the concentration of isolated proteins. The proteins were separated by performing 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis and subsequently transferred onto polyvinylidene difluoride (PVDF) membranes using an electric transfer method. After the blocking step with a 5% nonfat dry milk solution for 1.5 h, the protein samples on the PVDF membrane were then incubated with the primary antibodies overnight at 4°C. This step allows the primary antibodies to specifically bind to their target proteins on the membrane for detection in subsequent steps. The following were the primary antibodies against various target proteins: TLR4 (A5258, 1:2,000, ABclonal), collagen I (14695-1-AP, 1:2,000, Proteintech), TGF-β (21898-1-AP, 1:2,500, Proteintech), α-S-adenosylmethionine (α-SAM) (14395-1-AP, 1:6,000, Proteintech), CaMKII (12666-2-AP, 1:2,000, Proteintech), p-CaMKII (AP0255, 1:4,000, ABclonal), NLRP3 (27458-1-AP, 1:1,000, Proteintech), gasdermin D (GSDMD) (20770-1-AP, 1:5,000, Proteintech), the N-terminal domain of gasdermin D (GSDMD-N) (ab215203, 1:1,000, Abcam), caspase-1 (22915-1-AP, 1:6,000, Proteintech), ASC (16087-1-AP, 1:3,000, Proteintech), and β-actin (81115-1-RR, 1:20,000, Proteintech). After conventional washing procedures, the PVDF membranes loaded with protein samples were incubated in HRP-conjugated secondary antibody (S0001, 1:3,000, Affinity) for 1.5 h at room temperature and visualized using an ECL buffer (Tanon, China). Image Lab software was applied to measure the strip absorbance values, which were normalized to the intensity of the β-actin band as the loading control [31].

2.11 Statistical analysis

Experimental data were analyzed and interpreted via utilizing GraphPad Prism 8. The results were presented in the format of mean ± standard deviation. The statistical analysis was carried out using either Student’s t-test or one-way analysis of variance by Tukey’s multiple comparison test. A p-value below 0.05 was deemed statistically significant.

3 Results

3.1 TLR4 was up-regulated in the hearts of DM rats and H9c2 cells exposed to HG

We first investigated the expression of TLR4 mRNA and protein levels in the hearts of DM rats and H9c2 cells exposed to HG. The results revealed a significant elevation of TLR4 expression in the heart tissues following STZ-induced DM, as illustrated in Figure 1a and b. Furthermore, a significant elevation in TLR4 levels was observed in H9c2 cells after HG stimulation (Figure 1c and d). TAK-242 is a specific inhibitor of TLR4. In both in vitro and in vivo experiments, the treatment of TAK-242 alone did not significantly alter the expression of TLR4, which was consistent with the previous report [32]. However, when TAK-242 was administered in conjunction with DM or HG induction, it significantly inhibited the expression of TLR4 at mRNA and protein levels (Figure 1a–d).

Figure 1 TLR4 was up-regulated in the hearts of DM rats and H9c2 cells exposed to HG. (a) TLR4 mRNA levels in the heart. (b) Protein band images and statistical analysis demonstrating TLR4 expression in the heart tissues of DM rats. (c) TLR4 mRNA levels in H9c2 cells. (d) Representative protein band pictures and statistical analysis demonstrating TLR4 expression in H9c2 cells. The in vivo experiment was repeated for eight times independently, and the in vitro for three times. *p < 0.05 versus (vs) control; # p < 0.05 vs DM.
Figure 1

TLR4 was up-regulated in the hearts of DM rats and H9c2 cells exposed to HG. (a) TLR4 mRNA levels in the heart. (b) Protein band images and statistical analysis demonstrating TLR4 expression in the heart tissues of DM rats. (c) TLR4 mRNA levels in H9c2 cells. (d) Representative protein band pictures and statistical analysis demonstrating TLR4 expression in H9c2 cells. The in vivo experiment was repeated for eight times independently, and the in vitro for three times. *p < 0.05 versus (vs) control; # p < 0.05 vs DM.

3.2 STZ-induced heart injury was ameliorated for inhibition of TLR4

DCM is one of the most prevalent consequences of diabetes, frequently resulting in substantial morbidity and mortality [33]. STZ-induced heart damage is commonly associated with the development of cardiac hypertrophy and dysfunction [34]. As depicted in Figure 2a–c, the DM group demonstrated markedly elevated FBG levels and a heightened heart weight-to-body weight (HW/BW) ratio compared to the control group, suggesting the presence of diabetes-induced cardiac hypertrophy. Treatment with TAK-242 resulted in a lower HW/BW ratio when compared to the DM group. However, no statistically significant differences were observed in FBG or BW. These findings suggested that TAK-242 therapy improved heart hypertrophy in rats with diabetes.

Figure 2 STZ-induced heart injury was ameliorated for inhibition of TLR4. FBG (a), BW (b), HW/BW (c), and morphology (d) of the rat hearts. (e) Representative photographs of heart H&E staining from various groups, as well as measurement of cardiomyocyte area. (f) qRT-PCR to detect the mRNA levels of the hypertrophic makers, including ANP, BNP, and β-MHC. (g) Echocardiographic indicator results. (h) TAK-242 effects on STZ-induced EGC alterations in rats. The in vivo experiment was repeated for eight times independently. *p < 0.05 vs control; # p < 0.05 vs DM.
Figure 2

STZ-induced heart injury was ameliorated for inhibition of TLR4. FBG (a), BW (b), HW/BW (c), and morphology (d) of the rat hearts. (e) Representative photographs of heart H&E staining from various groups, as well as measurement of cardiomyocyte area. (f) qRT-PCR to detect the mRNA levels of the hypertrophic makers, including ANP, BNP, and β-MHC. (g) Echocardiographic indicator results. (h) TAK-242 effects on STZ-induced EGC alterations in rats. The in vivo experiment was repeated for eight times independently. *p < 0.05 vs control; # p < 0.05 vs DM.

To further confirm the effect of TLR4 suppression on heart enlargement caused by STZ injection, heart size was measured (Figure 2d). Furthermore, myocyte area, as determined by H&E staining, revealed that TLR4 suppression played a critical role in reducing STZ-induced cardiac injury (Figure 2e). Additionally, mRNA levels of cardiac hypertrophy markers (ANP, BNP, and β-MHC) were significantly elevated in the DM group compared to the control group. TLR4 suppression with TAK-242 effectively prevented these elevations in comparison to the DM group (Figure 2f).

Moreover, cardiac function was measured utilizing the echocardiography. The results indicated that diabetes led to a notable decrease in EF, FS, and the E/A ratio, along with an increase in LVIDs compared to the control group. However, TLR4 inhibition with TAK-242 significantly improved EF, FS, and E/A ratio, while reducing LVIDs (Figure 2g). The ECG data in Figure 2h depicted that the DM group had a considerably higher ST-segment elevation compared to the control group. TAK-242 therapy clearly ameliorated the ECG abnormalities, demonstrating the protective effect of TLR4 inhibition.

3.3 TAK-242 attenuated fibrosis in DCM

In the context of STZ-induced DCM, DM rats exhibited higher levels of fibrosis when compared to the control group. Notably, TAK-242 treatment showed a reduction in the extent of fibrotic tissues (Figure 3a). Cardiac tissues from DM rats indicated a significant upregulation of Collagen I, Collagen III, and CTGF compared to the control. However, when comparing DM+TAK-242 to DM alone, there was a considerable downregulation of these genes (Figure 3b). Similarly, increased levels of Collagen I, α-SAM, and TGF-β proteins were observed following STZ induction, which subsequently decreased upon TAK-242 treatment (Figure 3c). These findings suggested that the attenuation of cardiac damage by TAK-242 was associated with the suppression of fibrosis.

Figure 3 TAK-242 attenuated fibrosis in DCM. (a) Representative images of Masson trichromatic staining, as well as a quantitative analysis of the fibrotic area ratio. (b) Relative mRNA expression levels of Collagen I, III, and CTGF. (c) Quantification of collagen I, α-SMA, and TGF-β protein levels was demonstrated using Western blot. The in vivo experiment was repeated for eight times independently. *p < 0.05 vs control and # p < 0.05 vs DM.
Figure 3

TAK-242 attenuated fibrosis in DCM. (a) Representative images of Masson trichromatic staining, as well as a quantitative analysis of the fibrotic area ratio. (b) Relative mRNA expression levels of Collagen I, III, and CTGF. (c) Quantification of collagen I, α-SMA, and TGF-β protein levels was demonstrated using Western blot. The in vivo experiment was repeated for eight times independently. *p < 0.05 vs control and # p < 0.05 vs DM.

3.4 TAK-242 inhibited HG-induced ROS generation in vitro

To examine the potential antioxidative impact of TAK-242 therapy in vitro, DCFH-DA fluorescence was utilized to monitor ROS formation in H9c2 cells. Subsequently, confocal microscopy and flow cytometry were then employed to measure intracellular ROS levels. Our results showed that HG treatment significantly augmented ROS production in H9c2 cells. However, pretreatment with TAK-242 exhibited a remarkable reduction in HG-induced ROS production in H9c2 cells (Figure 4a and b).

Figure 4 TAK-242 inhibited HG-induced ROS generation in vitro. DCFH-DA staining (a), flow cytometry (b) were employed to access the intracellular ROS levels. The in vitro experiment was repeated for three times independently. *p < 0.05 vs NG; # p < 0.05 vs HG.
Figure 4

TAK-242 inhibited HG-induced ROS generation in vitro. DCFH-DA staining (a), flow cytometry (b) were employed to access the intracellular ROS levels. The in vitro experiment was repeated for three times independently. *p < 0.05 vs NG; # p < 0.05 vs HG.

3.5 TAK-242 inhibited CaMKII phosphorylation and cardiomyocytes pyroptosis in DM rats

In the DM group, there was an elevated p-CaMKII/CaMKII ratio and increased expression of pyroptosis-related proteins, including NLRP3, GSDMD, GSDMD-N, caspase 1, and ASC compared to the control group. However, TAK-242 administration resulted in a reduction of the p-CaMKII/CaMKII ratio and decreased expression of NLRP3, GSDMD, GSDMD-N, caspase 1, and ASC when compared to the DM group (Figure 5a). The DM group displayed significantly elevated concentrations of IL-1β and IL-18 in the serum compared to the control group. However, TAK-242 administration considerably lowered the serum levels of these cytokines (Figure 5b). Furthermore, the experimental results revealed a minimal presence of TUNEL-positive cells in the control group. In contrast, the DM group exhibited a significant rise in the number of TUNEL-positive cells compared to the control group. Interestingly, the DM+TAK-242 group demonstrated a reduction in TUNEL-positive cells when compared to the DM group (Figure 5c).

Figure 5 TAK-242 inhibited CaMKII phosphorylation and cardiomyocytes pyroptosis in DM rats. (a) Western blot representative images and quantitative analysis of p-CaMKII/CaMKII, NLRP3, GSDMD, GSDMD-N, Caspase 1, and ASC levels. (b) TAK-242 effects on IL-1β and IL-18 levels in rat serum. (c) Illustration of TUNEL staining and examination of positive cells. The in vivo experiment was repeated for eight times independently. *p < 0.05 vs control and # p < 0.05 vs DM.
Figure 5

TAK-242 inhibited CaMKII phosphorylation and cardiomyocytes pyroptosis in DM rats. (a) Western blot representative images and quantitative analysis of p-CaMKII/CaMKII, NLRP3, GSDMD, GSDMD-N, Caspase 1, and ASC levels. (b) TAK-242 effects on IL-1β and IL-18 levels in rat serum. (c) Illustration of TUNEL staining and examination of positive cells. The in vivo experiment was repeated for eight times independently. *p < 0.05 vs control and # p < 0.05 vs DM.

3.6 KN-93 inhibited the expression of pyroptosis-related proteins in DM rats

KN-93, a selective CaMKII inhibitor, was utilized to investigate the involvement of CaMKII in pyroptosis-related signaling. KN-93 treatment significantly decreased the p-CaMKII/CaMKII ratio as well as the protein levels of NLRP3, GSDMD, GSDMD-N, Caspase 1, and ASC when compared to the DM group. However, the intervention did not impact TLR4 expression (Figure 6a). In addition, the levels of pro-inflammatory variables such as IL-1β and IL-18 in blood were considerably lower in the DM+KN-93 group compared to the DM group (Figure 6b).

Figure 6 KN-93 inhibited the expression of pyroptosis-related proteins in DM rats. (a) Western blot representative images and quantitative analysis of TLR4, p-CaMKII/CaMKII, NLRP3, GSDMD, GSDMD-N, caspase 1, and ASC levels. (b) KN-93 effects on cardiac inflammatory cytokines in serum. The in vivo experiment was repeated for eight times independently. *p < 0.05 vs control and # p < 0.05 vs DM.
Figure 6

KN-93 inhibited the expression of pyroptosis-related proteins in DM rats. (a) Western blot representative images and quantitative analysis of TLR4, p-CaMKII/CaMKII, NLRP3, GSDMD, GSDMD-N, caspase 1, and ASC levels. (b) KN-93 effects on cardiac inflammatory cytokines in serum. The in vivo experiment was repeated for eight times independently. *p < 0.05 vs control and # p < 0.05 vs DM.

3.7 TAK-242 suppressed HG-induced pyroptosis in H9c2 cells

To further study the inhibitory effect of TAK-242 on HG-induced pyroptosis in H9c2 cells, the p-CaMKII/CaMKII ratio and the expression levels of NLRP3, GSDMD, GSDMD-N, Caspase 1, and ASC were measured. The results demonstrated a significant elevation of these proteins in response to HG stimulation. However, TAK-242 treatment effectively reduced the production of these key proteins, thereby inhibiting pyroptosis in H9c2 cells (Figure 7a). Moreover, HG stimulation led to a substantial increase in the production of IL-1β and IL-18 in the culture medium. However, treatment with TAK-242 effectively inhibited this rise in IL-1β and IL-18 levels (Figure 7b). In addition, incubation with HG substantially induced pyroptosis in H9c2 cells, as evidenced by an increase in TUNEL-positive cells. Conversely, TAK-242 treatment led to a decrease in TUNEL-positive cells (Figure 7c). Flow cytometry results further supported these findings, revealing an increased rate of pyroptosis in H9c2 cells following the HG challenge, which was ameliorated by TAK-242 treatment (Figure 7d). These findings suggest that TAK-242, by suppressing TLR4, attenuates HG-induced cardiomyocyte damage.

Figure 7 TAK-242 suppressed HG-induced pyroptosis in H9c2 cells. (a) The expression of pyroptosis pathway proteins was accessed using Western blot. (b) ELISA kits were used to detect the effect of TAK-242 on the levels of IL-1β and IL-18 in the supernatant of H9c2 cell culture media. (c) TUNEL staining assay representative images. (d) The proportion of dead cells was determined by flow cytometry. The in vitro experiment was repeated for three times independently. *p < 0.05 against NG and # p < 0.05 vs HG.
Figure 7

TAK-242 suppressed HG-induced pyroptosis in H9c2 cells. (a) The expression of pyroptosis pathway proteins was accessed using Western blot. (b) ELISA kits were used to detect the effect of TAK-242 on the levels of IL-1β and IL-18 in the supernatant of H9c2 cell culture media. (c) TUNEL staining assay representative images. (d) The proportion of dead cells was determined by flow cytometry. The in vitro experiment was repeated for three times independently. *p < 0.05 against NG and # p < 0.05 vs HG.

3.8 Inhibition of CaMKII relieved pyroptosis levels of H9c2 cells induced by HG

To confirm whether TLR4 exerted its effects via CaMKII-mediated pyroptosis, H9c2 cells were exposed to KN-93. Preliminary tests were conducted to assess the impact of TAK-242 and KN-93 on cell viability. The application of 1 mM TAK242 or 5 μM KN-93 did not result in a significant impact on cell viability. Therefore, we used 1 mM TAK242 or 5 μM KN-93 in the later experiments. In addition, we found that HG significantly reduced cell viability, while TAK-242 and KN-93 significantly alleviated HG-induced cell death (Figure S1).

The group given both HG and KN-93 exhibited a reduction in the enhanced levels of pyroptosis-related proteins induced by HG, while TLR4 expression remained unaffected (Figure 8a). Additionally, the ELISA analysis revealed that KN-93 significantly decreased the concentrations of IL-1β and IL-18 in the H9c2 cell culture supernatants (Figure 8b). These findings indicated that inhibiting CaMKII activation was beneficial for mitigating cell damage to some extent in vitro.

Figure 8 Inhibition of CaMKII relieved the pyroptosis levels of H9c2 cells induced by HG. (a) Western blot representative images and quantitative analysis of TLR4, p-CaMKII/CaMKII, NLRP3, GSDMD, GSDMD-N, caspase 1, and ASC levels. (b) ELISA was used to measure IL-1β and IL-18 levels in H9c2 cell culture supernatants. The in vitro experiment was repeated for three times independently. *p < 0.05 vs NG and # p < 0.05 vs HG.
Figure 8

Inhibition of CaMKII relieved the pyroptosis levels of H9c2 cells induced by HG. (a) Western blot representative images and quantitative analysis of TLR4, p-CaMKII/CaMKII, NLRP3, GSDMD, GSDMD-N, caspase 1, and ASC levels. (b) ELISA was used to measure IL-1β and IL-18 levels in H9c2 cell culture supernatants. The in vitro experiment was repeated for three times independently. *p < 0.05 vs NG and # p < 0.05 vs HG.

4 Discussion

Our research illustrated that targeting TLR4 possessed therapeutic potential in alleviating heart injury associated with DCM. TAK-242 treatment was effective in reducing fibrosis in DCM and inhibiting ROS production induced by HG. Furthermore, TAK-242 was able to inhibit CaMKII phosphorylation, NLRP3 expression, and pyroptosis both in vivo and in vitro. These results indicated that focusing on TLR4 and the downstream CaMKII/NLRP3-mediated pyroptosis pathway could be a promising treatment approach for DCM.

Inhibition of TLR4 could be a potential treatment target for DCM [18,19]. The previous study has shown that GTS-21 exhibited cardioprotective effects by mitigating the TLR4/NF-κB pathway in rats with STZ-induced DCM [35]. Nicotinamide mononucleotide prevented CD36-mediated lipid accumulation and CD36-TLR4 interaction, thereby reducing inflammation, fibrosis, cardiac dysfunction, and whole-body insulin resistance [36]. Our study revealed that the expression of TLR4 was elevated in the left ventricular myocardium of DCM rats. Furthermore, to evaluate the role of TLR4 in DCM, we employed TAK-242, a well-known TLR4 inhibitor, to investigate whether inhibiting TLR4 could slow disease progression. Our findings provided additional evidence that hyperglycemia contributed to hypertrophy, fibrosis, oxidative stress, pyroptosis in cardiomyocytes, and eventually leading to cardiac failure. Treatment with TAK-242 reversed cardiac hypertrophy in rats, as indicated by reduced HW/BW ratio, decreased cross-sectional area of cardiomyocytes, and downregulation of hypertrophy-related genes, such as ANP, BNP, and β-MHC. Notably, no significant change was observed in blood glucose levels or body weight between the DM+TAK-242 group and the DM group, indicating that the preventive effects of TAK-242 on DCM were not dependent on metabolic regulation.

Diabetes-induced cardiomyopathy is characterized by myocardial fibrosis as its hallmark pathology [37,38]. Previous research demonstrated that suppression of TLR4 protected experimental rats from left ventricular dysfunction and cardiac fibrosis following myocardial infarction [39]. We observed significant impairments in diastolic function, as evidenced by reduced E/A ratio, and systolic dysfunction, indicated by reduced EF and FS, in the DM group compared to the control group in our current study. Besides, treatment with TAK-242 effectively restored these functional parameters. Moreover, the inhibition of TLR4 by TAK-242 led to a significant decrease in cardiac fibrosis by downregulating the expression of the TGF-β signaling pathway. This resulted in reduced levels of fibrotic markers, including α-SMA and collagen I, in the hearts of diabetic rats. Moreover, arrhythmia, defined by elevated ST segment, is a common consequence of DCM [40,41]. Remarkably, TAK-242 treatment effectively decreased diabetic-induced ST-segment elevation, indicating its protective impact on myocardial cells.

The study unveils a novel discovery suggesting that the inhibition of the CaMKII/NLRP3 axis shows promise in suppressing pyroptosis and mitigating myocardial damage in DCM. The significant role of CaMK family members, particularly CaMKII, in disease pathogenesis and their involvement in essential cellular processes make them compelling targets for therapeutic interventions [21]. In this study, we investigated the inhibitory effect of TLR4 on CaMKII protein and delved into the underlying mechanisms. Targeting the CaMKII/NLRP3 axis has been proven to mitigate sepsis-induced cardiac injury by reducing pyroptosis [42]. TLR4 signaling has been proven to be linked to CaMKII activation, with TLR4 acting as an upstream molecule in the CaMKII signaling pathway [43]. In our experimental model of DCM induced by STZ, inhibiting TLR4 improved cardiac dysfunction and reduced the expression of pyroptosis-related proteins in myocardial tissue. Additionally, TAK-242 treatment effectively reduced the degree of cardiomyocyte pyroptosis caused by HG in vitro. Importantly, TAK-242-mediated suppression of TLR4 led to a reduction in p-CaMKII expression, whereas KN-93 treatment had no effect on TLR4 expression. These results provide evidence that TLR4 functions as an upstream regulator of CaMKII activity in heart damage induced by HG. Hence, our findings revealed that TAK-242 inhibited CaMKII activity, thereby preventing CaMKII-mediated cardiomyocyte pyroptosis.

The prior investigation has presented evidence implicating the NLRP3 inflammasome, which comprises NLRP3, pro-caspase 1, and apoptosis-associated speck-like protein with a CARD domain (ASC), as an inflammatory mediator in the development of DCM [44]. Following NLRP3 inflammasome activation, active caspase-1 enhances its activity in maturing the progenitors of the inflammatory cytokines IL-1β and IL-18 [45,46]. Blocking TLR4 signaling has been confirmed to decrease NLRP3 expression via decreasing the expression of nuclear factor-kappa B (NF-κB) in HG-induced cardiac cells [47]. In our study, we discovered that HG dramatically stimulated the creation and activation of NLRP3 inflammasomes, which boosted the production of mature IL-1β and IL-18 in vitro and in vivo. TAK-242 effectively reversed the pyroptosis-related alterations in NLRP3, caspase 1, IL-1β, and IL-18 in diabetic rats and HG-exposed H9c2, thereby mitigating myocardial damage.

Furthermore, TAK242 was reported to reduce ROS accumulation in H9c2 cells [48], hence decreasing HG-induced cell damage. It is worth noting that there is a close relationship between ROS generation and the pyroptosis process. Intracellular oxidative stress and increased ROS generation promote pyroptosis via the NLRP3 inflammasome [49]. The interplay between ROS and pyroptosis aggravates the inflammation, which leads to significant cell damage. However, this investigation does not provide evidence regarding the specific mechanism by which ROS influences cardiac pyroptosis. Future work is needed to investigate the role of ROS in modulating cardiomyocyte pyroptosis.

This study has several limitations that should be acknowledged. First, ethical considerations prevented the assessment of TLR4 expression in the left ventricular tissue of diabetic patients. Thus, the direct relevance of our findings to human DCM remains to be determined. Second, our study primarily utilized TAK-242 to confirm its effect and did not employ genetically modified rats specifically targeting TLR4. Future studies should consider addressing these limitations to further investigate the mechanisms underlying DCM and identify potential therapeutic interventions.

5 Conclusion

In summary, this study demonstrated the significance of TLR4 in STZ-induced cardiac injury and explored the impact and underlying mechanism of TAK-242 on DCM in vitro and in vivo.

Notably, this research provides novel evidence demonstrating that TAK-242, a specific TLR4 inhibitor, effectively alleviates cardiomyocyte pyroptosis by inhibiting active CaMKII and subsequently restricting the activation of pyroptosis-related proteins. These findings imply that modulating TLR4 to target the CaMKII/NLRP3 signaling pathway could be a possible treatment option for DCM.

# The authors contributed equally to the paper.

Acknowledgements

The authors are grateful for the reviewer’s valuable comments that improved the manuscript.

  1. Funding information: This study was supported by the Health Commission of Shenyang.

  2. Author contributions: Chunjian Shen designed the study. Xiaolong Zhao and Jing Zhang wrote the manuscript. Xiaolong Zhao, Jing Zhang, and Feng Xu performed the experiments. Xiaolong Zhao, Qingquan Liu, and Longqi Shang analyzed the data. Xiaolong Zhao prepared the figures. Chunjian Shen revised the manuscript. All authors reviewed the manuscript.

  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: 2024-04-24
Revised: 2024-07-19
Accepted: 2024-08-12
Published Online: 2024-09-10

© 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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  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-2022-0957
Schlagwörter für diesen Artikel
CaMKII/NLRP3 pathway; diabetic cardiomyopathy; inflammasome; pyroptosis; TAK-242; TLR4
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Biomedical Sciences
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  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
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  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
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  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
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  22. Sirtuin 5 regulates acute myeloid leukemia cell viability and apoptosis by succinylation modification of glycine decarboxylase
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  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
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  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
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  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
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  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
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  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
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  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
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  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 27.9.2025 von https://www.degruyterbrill.com/document/doi/10.1515/biol-2022-0957/html
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