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LL37-mtDNA regulates viability, apoptosis, inflammation, and autophagy in lipopolysaccharide-treated RLE-6TN cells by targeting Hsp90aa1

  • Yunlong Zuo , Run Dang , Hongyan Peng , Peidan Hu and Yiyu Yang EMAIL logo
Published/Copyright: August 28, 2024
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Open Life Sciences
From the journal Open Life Sciences Volume 19 Issue 1

Abstract

Sepsis-induced acute lung injury is associated with lung epithelial cell injury. This study analyzed the role of the antimicrobial peptide LL37 with mitochondrial DNA (LL37–mtDNA) and its potential mechanism of action in lipopolysaccharide (LPS)-treated rat type II alveolar epithelial cells (RLE-6TN cells). RLE-6TN cells were treated with LPS alone or with LL37–mtDNA, followed by transcriptome sequencing. Differentially expressed and pivotal genes were screened using bioinformatics tools. The effects of LL37–mtDNA on cell viability, inflammation, apoptosis, reactive oxygen species (ROS) production, and autophagy-related hallmark expression were evaluated in LPS-treated RLE-6TN cells. Additionally, the effects of Hsp90aa1 silencing following LL37–mtDNA treatment were investigated in vitro. LL37–mtDNA further suppressed cell viability, augmented apoptosis, promoted the release of inflammatory cytokines, increased ROS production, and elevated LC3B expression in LPS-treated RLE-6TN cells. Using transcriptome sequencing and bioinformatics, ten candidate genes were identified, of which three core genes were verified to be upregulated in the LPS + LL37–mtDNA group. Additionally, Hsp90aa1 downregulation attenuated the effects of LL37–mtDNA on LPS-treated RLE-6TN cells. Hsp90aa1 silencing possibly acted as a crucial target to counteract the effects of LL37–mtDNA on viability, apoptosis, inflammation, and autophagy activation in LPS-treated RLE-6TN cells.

Keywords: LL37; mtDNA; Hsp90aa1; autophagy; sepsis-induced acute lung injury; bioinformatics

1 Introduction

Sepsis, a severe clinical infectious disease, is characterized by an uncontrolled systemic inflammatory response syndrome. Acute lung injury is considered a common fallout with a mortality rate of up to 30–40% that has greatly affected human health [1,2]. Owing to its complicated and unclear pathogenesis, lung-protective measures are currently deemed the main clinical therapies for sepsis-induced acute lung injury [2]. Alveolar epithelial cells serve as protective hubs for the regulation of lung function [3]. Nevertheless, excessive inflammation and damage to alveolar epithelial cells due to intra- or extra-pulmonary factors are regarded as the key pathogenic mechanisms of acute lung injury [4]. Therefore, it is necessary to elucidate the mechanisms underlying lung epithelial cell injury to identify novel perspectives for the treatment of sepsis-induced acute lung injury.

Autophagy is a homeostatic cellular process that removes unnecessary or damaged components, allowing their degradation and recycling into fundamental constituents for other cellular functions [5,6]. Increasing evidence indicates that dysregulation of autophagy is implicated in the etiology of several pulmonary diseases involving epithelial cells [7]. For instance, the activation of autophagy targeting alveolar epithelial cells contributes to protection against alveolar barrier dysfunction in acute lung injury mice [8]. RAGE depletion attenuates lipopolysaccharide (LPS)-induced lung injury by directly inhibiting autophagic apoptosis in type II alveolar epithelial cells [9]. In addition, astragaloside IV mitigates idiopathic pulmonary fibrosis by facilitating the initiation of autophagy in TGF-β1 treated alveolar epithelial cells [10]. Therefore, targeting autophagy may represent a novel strategy for ameliorating lung epithelial cell injury. Thus, further in-depth exploration is necessary.

The human antimicrobial peptide LL37, which belongs to the cathelicidin family, is synthesized by neutrophils and epithelial cells [11,12]. LL37 exerts antimicrobial properties and modulates inflammatory responses and the innate immune system [12]. Moreover, LL37 can form complexes with self-DNA, which plays a crucial role in the development of therapeutic strategies against HIV infection and atopic dermatitis [13,14]. Additionally, LL37 with endogenous mitochondrial DNA (mtDNA) (LL37–mtDNA) promotes atherosclerosis progression by enhancing autophagy recognition [15]. However, the specific functions of LL37–mtDNA and its regulatory effect on autophagy, as well as the molecular mechanisms by which LL37–mtDNA regulates sepsis-induced acute lung injury remain largely unclear.

Currently, the properties of LL37–mtDNA and its underlying mechanisms in sepsis-induced acute lung injury remain unclear. The novelty of this study lies in illuminating that LL37–mtDNA inhibited cell viability, augmented apoptosis, stimulated inflammatory cytokine release, and intensified autophagy in LPS-treated rat type II alveolar epithelial (RLE-6TN) cells, which were partially abolished by Hsp90aa1 knockdown.

2 Materials and methods

2.1 Cell culture, treatment, and transfection

RLE-6TN and HEK293 cells were procured from iCell (Shanghai, China). The cells were maintained in Dulbecco’s modified Eagle’s medium (DMEM; Hyclone, Logan, UT) containing 10% fetal bovine serum (Hyclone), 100 U/mL penicillin, and 100 μg/mL streptomycin (Hyclone) at 37°C with 5% CO2. RLE-6TN cells were stimulated with LPS (Sigma-Aldrich, Merck KGaA, Darmstadt, Germany) at a dose of 1 μg/mL for 6 h, followed by co-treatment with mtDNA (2 μg/mL) and antimicrobial peptide LL37 (10 μg/mL, AnaSpec, CA).

After reaching approximately 70–80% confluence, Hsp90aa1 siRNAs and negative control (si-NC) were transfected into RLE-6TN cells using Lipofectamine 3000 (Invitrogen, Carlsbad, CA). All the sequences were designed by GenePharma (Shanghai, China) and are listed in Table S1.

2.2 Preparation of mtDNA

mtDNA isolation kits (K280-50, BioVision) were used to extract and purify mtDNA from the cultivated HEK293 cells. The concentration of isolated mtDNA was determined using a spectrophotometer (Nanodrop ND-1000, Thermo Fisher Scientific, Waltham, MA, USA), and the obtained mtDNA was diluted for subsequent experiments.

2.3 Cell counting kit-8 (CCK-8) assay

RLE-6TN cells were seeded in 96-well microplates at a density of 1 × 104 cells/well and cultivated in complete DMEM in an incubator at 37°C for 24 h. After treatment, the cells were treated with 10 μL of CCK-8 reagent (Beyotime, Shanghai, China) for 2 h. The absorbance was measured at 450 nm using a microplate reader (VL0000D0, Thermo Fisher Scientific).

2.4 Cell apoptosis

RLE-6TN cells were inoculated in six-well plates at a density of 5 × 105/well at 37°C for 24 h. After different treatments, the cells were collected, centrifuged, and resuspended, and 5 μL AnnexinV-FITC/PI (Beyotime) was added for a 15 min incubation period in the dark. Finally, data were analyzed using flow cytometry (BD Biosciences, San Jose, CA).

2.5 Measurement of inflammatory cytokines and reactive oxygen species (ROS)

The culture medium from RLE-6TN cells with different treatments was harvested and centrifuged, and the obtained supernatant was transferred to new centrifuge tubes for subsequent detection. The production of inflammatory cytokines including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the supernatant was measured using specific enzyme-linked immunosorbent assay kits (Esebio, Shanghai, China). Additionally, the ROS content in the supernatant was determined using the ROS assay kit (Solarbio, Beijing, China) and a microplate reader (Thermo Fisher Scientific).

2.6 Western blotting

Total protein samples from RLE-6TN cells of each group were extracted, harvested, quantified, passed through sodium dodecyl sulfate polyacrylamide gel electrophoresis, and transferred to polyvinylidene fluoride membranes. After blocking with 5% skimmed milk for 2 h, the membranes were incubated with specific primary antibodies against LC3B (ab192890, 1:2,000; Abcam, Cambridge, UK), Dhx9 (ab183731, 1:1,000; Abcam), Hsp90aa1 (4877, 1:1,000; Cell Signalling Technology, Danvers, MA), Sf3b1 (ab172634, 1:1,000; Abcam), and GAPDH (5174, 1:1,000; Cell Signalling Technology) at 4°C overnight. Following incubation with the corresponding secondary antibody, the fluorescence signals of the membranes were detected using an imager system (Bio-Rad, Hercules, CA, USA), with GAPDH serving as an endogenous control, and quantified using ImageJ software (V1.8.0.112, NIH, Madison, WI, USA).

2.7 Quantitative real-time polymerase chain reaction (qRT-PCR)

Total RNA was isolated from RLE-6TN cells of each group using TRIzol reagent (Invitrogen, Carlsbad, CA, USA), and the resulting RNA was reverse transcribed using the PrimeScript RT Reagent kit (TaKaRa, Otsu, Japan). The qRT-PCR analysis was conducted on the ABI7500 quantitative PCR instrument (Thermo Fisher Scientific) with the following cycling characteristics: 95°C for 30 s and 40 cycles of 95°C for 10 s and 60°C for 30 s. A comparative 2−ΔΔCt method was applied to determine changes in the relative expression of different samples, with GAPDH as the housekeeping gene. The primer sequences used were designed by Shenggong Bioengineering Company (Shanghai, China) and are listed in Table S1.

2.8 Transcriptome sequencing

Transcriptome sequencing was performed by GeneDenovo Biotechnology Co., Ltd. (Guangzhou, China). Briefly, total RNA was extracted from RLE-6TN cells of each group (three each for the LPS and LPS + LL37–mtDNA groups) using TRIzol reagent (Invitrogen). The concentration and purity of RNA were determined using NanoDrop 2000 (Thermo Fisher Scientific) and RNA integrity was detected using an Agilent 2100 Bioanalyzer (Agilent Technologies, Santa Clara, CA, USA, RIN ≥ 7.0). Subsequently, libraries were constructed and sequenced using the Illumina NovaSeq 6000 platform (Illumina, San Diego, CA, USA). The clean reads were aligned with the reference genome using hisat2.

2.9 Bioinformatics analysis

The principal component analysis (PCA) was conducted to validate the reproducibility of the transcriptome sequencing sample data. The differentially expressed genes (DEGs) were filtered with adjusted p < 0.05 and |log2fold change| > 2 as the cut-off criteria. The “ggplot2” and “Pheatmap” packages in the R software were applied to visualize the DEGs. By analyzing the intersection of DEGs with mitophagy-related genes, a Venn diagram was generated using the EVenn tool (http://www.ehbio.com/test/venn/#/).

Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genome (KEGG) analysis were conducted using “clusterProfiler” R package, and the results were depicted in the bubble plots with p < 0.05 considered significantly enriched.

The Search Tool for the Retrieval of Interacting Genes (STRING, https://www.string-db.org) was adopted to generate a protein–protein interaction (PPI) network with a confidence of 0.4 as the significance criterion. Afterward, the Molecular Complex Detection (MCODE) plugin of Cytoscape software was used for identifying key modules, and the focal genes were discovered using the degree algorithm of CytoHubba with the connectivity degree ≥10.

2.10 Statistical analysis

GraphPad Prism 9.0 (GraphPad Software Inc., San Diego, CA, USA) was used for statistical analysis with quantitative data presented as mean ± standard deviation. Student’s t-test was applied to assess differences between two sets of data, while the differences among multiple groups were compared using one-way analysis of variance in combination with Tukey’s test. Each experiment had at least three independent replicates, and significant differences were accepted when p <  0.05.

3 Results

3.1 Effects of LL37–mtDNA on LPS-treated RLE-6TN cells

We first determined the effects of LL37–mtDNA on LPS-treated RLE-6TN cells. LPS-induced release of IL-1β and TNF-α was aggravated by LL37–mtDNA treatment in RLE-6TN cells (Figure 1a). The viability of LPS-treated RLE-6TN cells decreased, and LL37–mtDNA treatment further suppressed this effect (Figure 1b). Subsequently, we found that the apoptotic cell rate increased in LPS-treated RLE-6TN cells and was more pronounced in the LL37–mtDNA + LPS group (Figure 1c). In addition, the ROS level and the protein and mRNA expression levels of LC3B were downregulated in LPS-treated RLE-6TN cells, whereas this trend was blocked by LL37–mtDNA treatment (Figure 1d–f), implying that LL37–mtDNA inhibited viability and promoted apoptosis, inflammation, and autophagy in LPS-treated RLE-6TN cells.

Figure 1 Effects of LL37–mtDNA in LPS-treated RLE-6TN cells. (a) The contents of Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) of each group were detected using enzyme-linked immunosorbent assay (ELISA). (b) Cell viability was detected by cell counting kit-8 (CCK-8) assay. (c) Flow cytometry was performed to detect cell apoptosis. (d) The relative reactive oxygen species (ROS) level was determined with ROS assay kit. (e) The protein expression of LC3B was detected by western blot. (f) The relative mRNA expression of LC3B was detected by quantitative real-time polymerase chain reaction (qRT-PCR). **p ＜ 0.01.
Figure 1

Effects of LL37–mtDNA in LPS-treated RLE-6TN cells. (a) The contents of Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) of each group were detected using enzyme-linked immunosorbent assay (ELISA). (b) Cell viability was detected by cell counting kit-8 (CCK-8) assay. (c) Flow cytometry was performed to detect cell apoptosis. (d) The relative reactive oxygen species (ROS) level was determined with ROS assay kit. (e) The protein expression of LC3B was detected by western blot. (f) The relative mRNA expression of LC3B was detected by quantitative real-time polymerase chain reaction (qRT-PCR). **p ＜ 0.01.

3.2 Identification of DEGs and functional enrichment analysis

The PCA showed that the reproducibility of the transcriptome sequencing sample data was modestly good (Figure S1). There were 1721 DEGs between the LPS and LPS + LL37–mtDNA treatment groups, including 1694 upregulated and 27 downregulated DEGs (Figure 2a). The heatmap shows the gene expression levels of significant DEGs in LPS- and LPS + LL37–mtDNA-treated samples (Figure 2b). The top 15 upregulated and downregulated DEGs are provided in Table S2.

Figure 2 Identification of differentially expressed genes (DEGs) and functional enrichment analysis. (a) Volcano plot highlighting DEGs (3 each for the LPS and LPS + LL37–mtDNA groups). Red, blue, and gray nodes separately indicate up-regulated, down-regulated and none significantly changed genes. (b) The heat maps of DEGs between LPS and LPS + LL37–mtDNA group. The upregulated DEGs are displayed in red, and the downregulated in blue. (c) Gene Ontology (GO) functional analysis bubble plot. Top 6 GO enrichment terms in biological process (BP), cellular component (CC), and molecular function (MF) categories of the DEGs, respectively. (d) Top ten enriched pathways of DEGs in the Kyoto Encyclopedia of Genes and Genome (KEGG) database.
Figure 2

Identification of differentially expressed genes (DEGs) and functional enrichment analysis. (a) Volcano plot highlighting DEGs (3 each for the LPS and LPS + LL37–mtDNA groups). Red, blue, and gray nodes separately indicate up-regulated, down-regulated and none significantly changed genes. (b) The heat maps of DEGs between LPS and LPS + LL37–mtDNA group. The upregulated DEGs are displayed in red, and the downregulated in blue. (c) Gene Ontology (GO) functional analysis bubble plot. Top 6 GO enrichment terms in biological process (BP), cellular component (CC), and molecular function (MF) categories of the DEGs, respectively. (d) Top ten enriched pathways of DEGs in the Kyoto Encyclopedia of Genes and Genome (KEGG) database.

To further investigate the potential functional roles of DEGs, GO and KEGG analyses were conducted. The top enriched six GO terms with the lowest p-values are shown for each item of biological process, including visual perception, positive regulation of endothelial cell proliferation, cell composition such as extracellular space and integral component of plasma membrane, and molecular function such as urea channel activity. (Figure 2c, Table S3). For KEGG analysis, the top ten pathways with the lowest p-values are presented, such as the PI3K–Akt signaling pathway (Figure 2c, Table S4).

3.3 Construction of PPI network and hub gene selection

A Venn diagram was generated between DEGs and mitophagy-associated genes, and 250 mitophagy-related DEGs were screened (Figure S2a), followed by PPI network construction using the STRING network analysis tool (Figure S2b). Subsequently, one tightly connected cluster module was obtained using the MCODE plugin (Figure 3a), and the top ten ranked hub genes were extracted using the degree algorithm in the CytoHubba plugin (Figure 3b).

Figure 3 Identification of the hub genes. (a) One key cluster was identified by MCODE. (b) Top ten hub genes were determined by degree algorithm using CytoHubba. The deeper the red node, the higher the degree of connectivity.
Figure 3

Identification of the hub genes. (a) One key cluster was identified by MCODE. (b) Top ten hub genes were determined by degree algorithm using CytoHubba. The deeper the red node, the higher the degree of connectivity.

3.4 Quantification of key hub genes

To verify our bioinformatics analysis results, we validated the expression levels of three hub genes in RLE-6TN cells treated with LPS alone or in combination with LL37–mtDNA. Compared with LPS treatment alone, the relative mRNA expression of Hsp90aa1, Dhx9, and Sf3b1 was remarkably upregulated in the LPS + LL37–mtDNA group (Figure 4a). Consistently, the protein expression levels of these three genes were elevated in the LPS + LL37–mtDNA group (Figure 4b).

Figure 4 Quantification of hub genes. (a) QRT-PCR was applied to evaluate the expression of Hsp90aa1, Dhx9, and Sf3b1 at mRNA levels. (b) Protein levels of Hsp90aa1, Dhx9, and Sf3b1 were verified by western blot. **p ＜ 0.01 vs LPS.
Figure 4

Quantification of hub genes. (a) QRT-PCR was applied to evaluate the expression of Hsp90aa1, Dhx9, and Sf3b1 at mRNA levels. (b) Protein levels of Hsp90aa1, Dhx9, and Sf3b1 were verified by western blot. **p ＜ 0.01 vs LPS.

3.5 LL37–mtDNA facilitates inflammation, inhibits viability, promotes apoptosis, and enhances autophagy by targeting Hsp90aa1 in LPS-treated RLE-6TN cells

Next, we investigated the potential capabilities of Hsp90aa1. Hsp90aa1 was silenced in RLE-6TN cells, and the expression of Hsp90aa1 after transfection with si-Hsp90aa1-3 was the lowest compared with that in si-NC; therefore, si-Hsp90aa1-3 was selected for further experiments (Figure 5a and b). The LL37–mtDNA + si-Hsp90aa1 group exhibited lower levels of IL-1β, and TNF-α than those in the LL37–mtDNA group (Figure 5c). Hsp90aa1 silencing attenuated the inhibitory effect of LL37–mtDNA treatment on the viability of LPS-treated RLE-6TN cells (Figure 5d). The pro-apoptotic effect of LL37–mtDNA treatment was partially reversed by Hsp90aa1 knockdown in LPS-treated RLE-6TN cells (Figure 5e). Additionally, LL37–mtDNA treatment increased ROS level and LC3B expression, which was suppressed by Hsp90aa1 downregulation in LPS-treated RLE-6TN cells (Figure 5f–h). Collectively, LL37–mtDNA facilitated inflammation, restrained viability, promoted apoptosis, and enhanced autophagy by targeting Hsp90aa1 in LPS-treated RLE-6TN cells.

Figure 5 LL37–mtDNA restrains viability, promotes apoptosis and inflammation, and enhances autophagy by targeting Hsp90aa1 in LPS-treated RLE-6TN cells. (a) QRT-PCR assay was utilized to verify the knockdown efficiency of Hsp90aa1 expression. The expression of Hsp90aa1 was downregulated in the RLE-6TN cells compared to the si-NC. (b) Western blot was applied to measure the knockdown efficiency of Hsp90aa1 expression. The expression of Hsp90aa1 was downregulated in the RLE-6TN cells compared to the si-NC. (c) The levels of IL-1β, TNF-α, and ROS in the supernatant of each group were determined. (d) Viability of RLE-6TN cells after different treatments using the CCK8 assay. (e) Cell apoptosis of RLE-6TN cells in each group was analyzed by flow cytometry. (f) The ROS level in each group was examined using matched assay kits. (g) The protein level of LC3B in each group was evaluated using the Western blot. (h) The mRNA level of LC3B in each group was evaluated using qRT-PCR. **p < 0.01.
Figure 5

LL37–mtDNA restrains viability, promotes apoptosis and inflammation, and enhances autophagy by targeting Hsp90aa1 in LPS-treated RLE-6TN cells. (a) QRT-PCR assay was utilized to verify the knockdown efficiency of Hsp90aa1 expression. The expression of Hsp90aa1 was downregulated in the RLE-6TN cells compared to the si-NC. (b) Western blot was applied to measure the knockdown efficiency of Hsp90aa1 expression. The expression of Hsp90aa1 was downregulated in the RLE-6TN cells compared to the si-NC. (c) The levels of IL-1β, TNF-α, and ROS in the supernatant of each group were determined. (d) Viability of RLE-6TN cells after different treatments using the CCK8 assay. (e) Cell apoptosis of RLE-6TN cells in each group was analyzed by flow cytometry. (f) The ROS level in each group was examined using matched assay kits. (g) The protein level of LC3B in each group was evaluated using the Western blot. (h) The mRNA level of LC3B in each group was evaluated using qRT-PCR. **p < 0.01.

4 Discussion

Sepsis-induced acute lung injury may be attributed to the dysregulation of alveolar type II cells [16,17]. Hence, further investigation of the molecular mechanisms involved in pulmonary epithelial cell injury is of immense importance, and it may be leveraged to alleviate the development of sepsis-induced acute lung injury. In this study, combining transcriptome sequencing technology and comprehensive bioinformatics methods, we screened the top ten candidate genes between LPS alone and LPS + LL37–mtDNA treated samples. Furthermore, our results revealed that LL37–mtDNA inhibited cell viability, augmented apoptosis, facilitated inflammation, and enhanced autophagy in LPS-treated RLE-6TN cells, whereas these phenomena were partially abolished after Hsp90aa1 knockdown.

LL37 exerts a protective role against lung injury in LPS + ATP-treated alveolar epithelial cells by ameliorating the severe inflammatory response, as reflected by reduced expression levels of IL-1β and IL-18 [18]. In addition, the LL37–bacDNA complex facilitates inflammatory cytokine secretion, thus aggravating the severity of ulcerative colitis [19]. Moreover, the LL37–DNA complex greatly increases the production of IFN-α in cultured keratinocytes, indicating a link between LL37–DNA and autoinflammation in cholesteatoma [20]. In addition, LL37–mtDNA complex can deteriorate lung inflammation in septic mice with acute lung injury by impairing autophagy recognition [21]. Here, we found that LL37–mtDNA suppressed cell viability, augmented apoptosis, and promoted the production of inflammatory factors in LPS-treated RLE-6TN cells, indicating that LL37–mtDNA exacerbates alveolar epithelial cell injury.

As suggested by our KEGG analysis, the Pl3K–Akt signaling pathway was primarily enriched pathways that participated in LL37–mtDNA-treated cells. Tian et al. have found that the PI3K/Akt/HO-1 pathway is involved in the mediation of autophagy during sepsis-induced lung injury in mice [22]. Nonetheless, herein, major pathways in which overlapping DEGs are abundant were not related to apoptosis, autophagy, or ROS production. Bioinformatics tool is a viable option to predict possible pathways, which may help better understand the development of lung epithelial cell injury. However, possibly due to the small sample size and differences in transcriptome sequencing data quality, the results were easily affected, resulting in bias, we could not verify the obtained conclusions through bioinformatics; thus, more samples are necessary to further confirm the impact of LL37–mtDNA. A PPI network was constructed and three core genes, Dhx9, Hsp90aa1, and Sf3b1, were confirmed. Therefore, long noncoding RNA SH3PXD2A-AS1 interacts with Dhx9 to facilitate proliferation and cell cycle progression in non-small-cell lung carcinoma [23]. Moreover, Dhx9 is prominently linked to the prognosis of patients with lung tumors [24]. Additionally, Sf3b1 is involved in the prognosis of non-small-cell lung carcinoma [25]. In the present study, Dhx9 and Sf3b1 expression was upregulated in LPS + LL37–mtDNA-treated RLE-6TN cells, and the detailed mechanisms by which LL37–mtDNA regulates lung epithelial cell injury require further elucidation.

Notably, Hsp90aa1 is an isoform of the molecular chaperone Hsp90 which significantly regulates signal transduction, proliferation, cell cycle, apoptosis, and tumor progression [26,27]. Hsp90aa1 is downregulated in the blood and human osteoarthritic cartilage and is negatively associated with the risk of osteoarthritis [28]. Conversely, Hsp90aa1 is overexpressed in patients with lung cancer, and downregulation of Hsp90aa1 promotes cell apoptosis and inhibits proliferative ability by inhibiting the AKT1/ERK pathway [29]. Additionally, Hsp90aa1 was significantly elevated in the lung tissues of an idiopathic pulmonary fibrosis rat model and is considered a novel system biomarker [30]. Consistently, we demonstrated that the expression of Hsp90aa1 was increased in RLE-6TN cells co-treated with LPS and LL37–mtDNA. In addition, downregulation of Hsp90aa1 ameliorated the effects of LL37–mtDNA treatment on viability, apoptosis, and inflammatory cytokine release in LPS-treated RLE-6TN cells, suggesting that Hsp90aa1 silencing may be an attractive therapeutic target for lung epithelial cell injury.

The exact role of autophagy in the pathophysiology of LPS-induced acute lung injury remains somewhat controversial. Autophagy possibly exerts protective effects in LPS-induced inflammatory lung injury [31]. lncRNA-SNHG14 is participated in alveolar type II epithelial cell injury induced by LPS through controlling the occurrence of autophagy [32]. Ketamine facilitates autophagy in alveolar type II epithelial cells after LPS treatment and in a sepsis-induced acute lung injury mouse model by regulating AMPK/mTOR pathway activation [33]. Isorhamnetin can also protect type II alveolar epithelial cells against LPS-induced injury by activating autophagy via the inhibition of the mTOR pathway [34]. Inositol enhances autophagy activation by ameliorating LPS-treated alveolar epithelial cell inflammation, which is attributed to the regulation of the HIF-1 α-SLUG axis [35]. Conversely, long-term or ineffective autophagy may harm the lung epithelial cells and exacerbate lung damage [36]. Through the suppression of the PI3K/Akt/mTOR pathway, aspirin activates autophagy, thereby promoting pulmonary fibrosis [37]. In the present study, we found that LL37–mtDNA treatment contributed to enhanced autophagy activation, as reflected by the partially reversal of LC3B reduction triggered by LPS in RLE-6TN cells after using LL37–mtDNA. Nonetheless, these phenomena were further suppressed by Hsp90aa1 downregulation. These data imply that LL37–mtDNA may enhance autophagy by modulating Hsp90aa1 expression in a sepsis-induced acute lung injury cell model.

However, this study had some limitations. We preliminarily explored the effects of LL37–mtDNA on lung epithelial cell injury but investigated only one lung epithelial cell line. Furthermore, the impact of LL37–mtDNA lacked animal experiments and clinical verification. In addition, more specific molecular mechanisms and interactions with LL37–mtDNA should be elucidated.

In summary, ten hub genes were extracted by combining transcriptome sequencing technology and comprehensive bioinformatics analysis, among which three core genes were confirmed to be upregulated after co-treatment with LPS and LL37–mtDNA. Our data illustrated that LL37–mtDNA reduced cell viability, augmented apoptosis, stimulated inflammatory cytokine release, and intensified autophagy in LPS-treated RLE-6TN cells, while these changes were partially counteracted by Hsp90aa1 silencing. Overall, the findings of this study suggested that Hsp90aa1 knockdown is a potential novel candidate target for ameliorating lung epithelial cell injury, which may further novel insights into the etiopathogenesis of sepsis-induced acute lung injury.

tel: +86-18902268806

  1. Funding information: Guangzhou Medical Health Science and Technology Project (No. 2150160-03).

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and consented to its submission to the journal, reviewed all the results, and approved the final version of the manuscript. Yunlong Zuo designed the experiments and carried them out. Run Dang, Hongyan Peng, Peidan Hu, and Yiyu Yang carried the experiments out. Yunlong Zuo and Yiyu Yang prepared the manuscript with contributions from all co-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: 2024-05-08
Revised: 2024-07-03
Accepted: 2024-07-19
Published Online: 2024-08-28

© 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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  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”
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https://doi.org/10.1515/biol-2022-0943
Keywords for this article
LL37; mtDNA; Hsp90aa1; autophagy; sepsis-induced acute lung injury; bioinformatics
Creative Commons
BY 4.0

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  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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