Home Medicine ADAR1 plays a protective role in proximal tubular cells under high glucose conditions by attenuating the PI3K/AKT/mTOR signaling pathway
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ADAR1 plays a protective role in proximal tubular cells under high glucose conditions by attenuating the PI3K/AKT/mTOR signaling pathway

  • Ying Wang , Jiang Chang EMAIL logo , Fa Wang , Lianying Lai , ShiXu Yang , Yueying Fu , Xingtian Ma and Chuan Yun
Published/Copyright: October 10, 2024
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Open Medicine
From the journal Open Medicine Volume 19 Issue 1

Abstract

Background

Adenosine deaminases acting on RNA 1 (ADAR1), an RNA editing enzyme, holds a role in cancer, inflammation, and immunity. However, its specific function in the nephropathy and high-glucose-induced human renal tubular epithelial cells (HK-2) injury in diabetic db/db mice is not clear.

Methods

This study explored the expression characteristics of ADAR1 in proximal renal tubular cells of diabetic db/db mice, examining its function in the mechanism of high-glucose-induced HK-2 cell injury. Furthermore, it elucidated the molecular mechanism underlying the protective effect of ADAR1, the regulation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt)/mammalian target of the rapamycin (mTOR) signaling. We observed a decrease in ADAR1 expression in proximal tubular cells of diabetic db/db mice, accompanied by an increase in the expression of inflammation-related markers (PI3K/AKT/mTOR).

Results

We constructed and validated ADAR1-overexpression plasmids and used an ADAR1 inhibitor (8-azaadenosine) to carry out cell experiments. The upregulation of ADAR1 expression alleviated high-glucose-induced endoplasmic reticulum stress, reduced HK-2 cell apoptosis, and reduced the expression of inflammation-related indicators (PI3K/AKT/mTOR).

Conclusion

Taken together, the pivotal roles of ADAR1 in the progression of proximal renal tubulopathy and the mechanism of high-glucose-induced HK-2 injury in diabetic db/db mice suggest that ADAR1 may be a potential key factor in slowing the progression of diabetic kidney disease.

Keywords: ADAR1; diabetic kidney disease; endoplasmic reticulum stress; oxidative stress

1 Introduction

Diabetic kidney disease (DKD) is a common complication in the end stage of long-term disease in diabetic patients. In the progression of DKD, the dysfunction associated with both glomerulopathy and renal tubulopathy play a pivotal role [1]. In renal tubulopathy, proximal tubular cell function is highly susceptible to diabetic disorders, which can trigger a cascade of deleterious effects including energy imbalances, oxidative stress, endoplasmic reticulum (ER) stress, and apoptosis [2]. Renal tubular epithelial cell injury is intimately linked to the development of DKD [3]. Prolonged exposure to high-glucose levels stimulates a cascade of deleterious effects, including the overproduction of reactive oxygen species, which instigates oxidative stress and triggers an inflammatory cascade. This cascade, in turn, accelerates apoptotic processes in renal tubular epithelial cells, culminating in renal tubular damage [4,5].

Adenosine deaminases acting on RNA 1 (ADAR1) is an RNA editing enzyme and it mainly catalyzes the conversion of adenosine to inosine in coding and noncoding RNA transcripts (A-to-I RNA editing). This process destabilizes double-stranded RNA (dsRNA) [6]. ADAR1 exists in two subtypes, p110 and p150. The p110 subtype is mainly expressed in the nucleus, and is associated with a number of diseases. The p150 subtype is mainly expressed in the cytoplasm, with a small amount expressed in the nucleus [7]. ADAR1 p110 and p150 subtypes differentiate from each other in molecular mass, intracellular localization, regulatory mechanisms governing, functional focus, and potential disease associations. These disparities underscore their diverse roles in the fine regulation and response to a broad spectrum of physiological and pathophysiological states within cellular environments [8]. 8-Azaadenosine blocks ADAR1 expression and inhibits thyroid cancer cell proliferation, 3D growth, invasion, and migration. In the realm of cancer investigations, ADAR1 p110 is mainly expressed in the nucleus of gastric cancer (GC) cells. It regulates β-catenin signaling and epithelial to mesenchymal transition signaling, integral to metastatic progression [9]. In non-cancer studies, ADAR1 p110 has demonstrated a role in facilitating enterovirus replication by suppressing the deaminase domain within the PKR pathway [10]. ADAR1 p150 is exclusively responsible for ADAR1 function in germinal center reactions, and the p110 isoform cannot serve the same role as p150 [11]. ADAR1 p150 is involved in antiviral and immune regulation through editing of viral dsRNA [12]. ADAR1-mediated adenosine–inosine RNA editing is an important posttranscriptional event that suppresses cellular dsRNA-mediated innate immune interferon responses and thereby functioning as a key mechanism of genetic variation associated with common inflammatory diseases [13]. The overexpression of ADAR1 inhibits the expansion of white adipose tissue in high-fat diet-induced obese mice, thereby improving metabolic phenotypes such as insulin sensitivity and glucose tolerance [14]. Research has further illuminated that a lack of ADAR1 exerts a protective effect against obesity and insulin resistance induced by high-fat diets in mice models [15]. In diabetes, it is believed that the phosphatidyl inositol 3-kinase (PI3K)/protein kinase B (PKB/Akt)/mammalian target of the rapamycin (mTOR) signaling is widely acknowledged as a fundamental pathway regulating cell proliferation, differentiation, and apoptosis [16]. In human umbilical vein endothelial cells, ADAR1 regulates cell proliferation and permeability by activating the PI3K-Akt pathway [17]. In the context of a GC study, ADAR1 has been shown to exert a regulatory influence on the activity of the mTOR signaling pathway. When ADAR1 expression is suppressed, there is a significant decrease in the phosphorylation levels of mTOR, p70S6K, and the S6 ribosomal protein [18].

The roles of ADAR1 are of remarkable significance in diabetes, autologous diseases, and cancer [7]. However, the mechanism through which ADAR1 operates in DKD is unclear. This study aimed to clarify the critical role of ADAR1 in the progression of proximal renal tubulopathy and the mechanism of high-glucose-induced HK-2 injury in diabetic db/db mice. By measuring ADAR1 expression in proximal renal tubulopathy in diabetic db/db mice, the study illuminated that ADAR1 can alleviate high-glucose-induced apoptosis, oxidative stress, and ER stress in HK-2 cells through PI3K/AKT/mTOR. This study was conducted using spontaneous type 2 diabetic db/db mice and high-glucose-induced human proximal tubular epithelial (HK-2) cells.

2 Materials and methods

2.1 Experiment animals and cells

2.1.1 Animals

Male diabetic db/db mice and db/m mice (SPF) were purchased from Cavens Laboratory Animal Co., Ltd (Changzhou, China; License key: SCXK (Su) 2021-0013). At age of 6–8 weeks, the weight reached 16–18 g. Mice breeding and experiment were both performed at Laboratory Animal Center, Hainan Medical College. All experiments strictly followed the Guide for the Care and Use of Laboratory Animals published by the US National Institute of Health and gained approval from the Ethics Committee of Hainan Medical College (HYLL-2021-296). Mice were bred in temperature-controlled (25℃) room on a 12 h light/dark schedule. The experiment was conducted for 6 weeks and the mice were divided into two groups: the db/m group (n = 5) and the db/db group (n = 5). Weight, water, and food intake of mice were measured every 6 days. Yuwell blood glucose meter was used to detect the fasting blood glucose (FBG) every 2 weeks [19]. Mice euthanasia was performed by intraperitoneal injection of pentobarbital sodium (50 mg/kg) (Tc-P8411, Merck).

2.1.2 Cells

Human renal tubular epithelial cells were purchased from Zhong Qiao Xin Zhou Biotechnology Co., Ltd, (Shanghai, China) (ZQ0313, HK-2) and cultured with specific medium for HK-2 cells, at 37℃, 5% CO2 according to the instruction. HK-2 cells were exposed to normal glucose (5.6 mmol/L) or high sugar (30 mmol/L), then added ADAR1 inhibitors (8-azaadenosine) or transfection overexpression plasmid into cells. Experimental groups were as follows: control (5.6 mmol/L normal glucose), HG (30 mmol/L glucose), HG + 8-azaadenosine (30 mmol/L glucose + 2 μM), and HG + OE-ADAR1.

2.2 Cell viability assay-cell counting kit-8 (CCK8)

About 100 µL stably transferred cell suspension was added to each hole of a 96-well plate at a density of 1 × 104 cells/well. After cultured at 37℃ in an incubator for 24 h, varied concentrations of ADAR1 inhibitor (8-azaadenosine, 1, 2, 4, 6, 8, 10, and 20 μg/mL) (HY-115686, MCE), PI3K inhibitor (LY294002, 5, 10, 15, 20, 40, 80, and 100 μM) (HY-10108, MCE), and mTOR in inhibitor (rapamycin, 5, 10, 15, 20, 40, 80, and 100 μM) (HY-10219, MCE) were added in different wells. After culturing at 37℃ for 24 h, 10 µL of CCK8 (Dojindo, Shanghai, China) reagent was added to each well. Then after culturing at 37℃ for 3 h, the absorbance of each well was measured at 450 nm using microplate reader (Rayto, China).

2.3 Measurement of superoxide dismutase (SOD) activity

SOD activity in HK-2 cell was measured using CuZn/Mn-SOD activity assay kit (S0103, Beyotime, China). Briefly, cell homogenate was collected using PBS buffer in ice bath and then centrifuged at 4℃. The 20 μL supernatant of the sample was added to the reagents according to the kit instructions and absorbance was read at 450 nm after 30 min incubation.

2.4 Malondialdehyde (MDA)

The level of MDA was measured using MDA assay kits (S0131S, Beyotime, China). Briefly, the cells were lysed in a lysis buffer in ice bath. Then 100 μL supernatant of the sample was added to the reagents according to the kit instructions. The mixture is then heated in boiling water bath for 15 min and centrifuged at 1,000g for 10 min. Subsequently, 200 μL of the supernatant was added to 96-well plate, after which the absorbance was read at 532 nm.

2.5 ER-Tracker Red

ER-Tracker Red Kit (C1041, Beyotime, China) was used to stain the ER according to the kit instructions. After cell treatment and incubation, the cell medium was removed and the cells were washed with PBS buffer. Then dilute the ER Tracker Red solution in a 1:1,000 ratio and obtain the ER Tracker Red working liquid. Cells were incubated in pre-warmed ER-tracker working liquid at 37℃ for 20 min. After removing ER-tracker dye solution, the cells were washed with cell medium twice, and observed using a fluorescence microscope.

2.6 TUNEL staining

Cells were fixed in 4% paraformaldehyde for 30 min, and then incubated with 0.3% Triton X-100 in PBS for 5 min at room temperature, succeeded by three washes with PBS. Labeling was achieved after applying 50 μL of labeling solution, with a 60 min incubation at 37°C in the dark. Post-PBS washing, nuclei were stained using DAPI. The apoptosis rate was subsequently quantified, and photomicrographs were captured under fluorescence microscopy to document the findings (the red fluorescent label indicates apoptotic cells).

2.7 Transfection

Overexpression plasmids of ADAR1 was constructed by Sangon Biotech Co., Ltd (Shanghai, China) (ID: 103, cloning vector: pcDNA3.1(+)). When 70–80% of cell fusion is achieved, Lipo8000TM (C0533-1.5 mL, Beyotime) was used to transfect the plasmids into HK-2 cells. After incubation for 48 h, HK-2 cells were collected to detect the efficiency of transfection by reverse transcription-polymerase chain reaction (RT-PCR).

2.8 Cell western blot assay

Protein was extracted from cells with Whole Cell Lysis Assay Kit (KeyGEN BioTECH, China) containing lysis buffer, protease inhibitors, phosphatase inhibitors, and 100 mM phenylmethylsulfonyl fluoride. BCA Protein Assay Kit (LEAGENE, China) was used to detect the protein concentration. About 30 ng of protein of each sample was then separated with 11% SDS-PAGE for immunoblot and transferred to polyvinylidene fluoride (PVDF) membrane. After 2 h of blocking in 5% skim milk at room temperature, the membranes were incubated with primary antibodies at 4℃ overnight. Primary antibodies and corresponding dilution rate are as follows: ADAR1 (1:100, sc-271854; SANTA CRUZ, USA), PI3K (1:1,000, AF6241; Affinity, China), phospho-PI3K (1:500, AF3241; Affinity, China), phospho-AKT (1:500, 80455-1-RR; Proteintech, China), AKT (1:1,000, 10176-2-AP; Proteintech, China), phospho-mTOR (1:500, 67778-1-Ig; Proteintech, China), mTOR (1:1,000, 28273-1-AP; Proteintech, China), cyclin D1 (1:1,000, 26939-1-AP; Proteintech, China), Ki-67 (1:1,000, 28074-1-AP; Proteintech, China), and β-actin (1:2,000, 20536-1-AP; Proteintech, China). Then the membranes were washed with Tris-buffered saline with Tween 20 (TBST) (T1082, Solarbio) three times and incubated with HRP-conjugated goat-anti-rabbit IgG (ZB-2301, ZSGB-Bio) or HRP-conjugated goat-anti-mouse IgG (ZB-2305, ZSGB-Bio) for 1 h at room temperature. The bands were visualized by enhanced chemiluminescence (ECL) hypersensitive luminescence solution.

2.9 Kidney tissue western blot assay

Tissue homogenate was collected, lysed with 200 μL RIPA buffer for 30 min, and then centrifuged at 12,000 rpm for 15 min. The supernatant was used to detect the protein concentration of each sample. About 30 ng of protein of each sample was then separated with 11% SDS-PAGE for immunoblot and transferred to PVDF membrane. After 2 h of blocking in 5% skim milk at room temperature, the membranes were incubated with primary antibodies at 4℃ overnight. Primary antibodies and corresponding dilution rate are as follows: ADAR1 (1:100, sc-271854; SANTA CRUZ, USA), phospho-PI3K (1:500, AF3241; Affinity, China), phospho-AKT (1:500, 80455-1-RR; Proteintech, China), and phospho-mTOR (1:500, 67778-1-Ig; Proteintech, China). Then the membranes were washed with TBST three times and incubated with HRP-conjugated goat-anti-rabbit IgG or HRP-conjugated goat-anti-mice IgG for 1 h at room temperature. The bands were visualized by ECL hypersensitive luminescence solution.

2.10 Immunohistochemistry (IHC)

After paraffin sections were deparaffinized and rehydrated, antigen retrieval was performed using EDTA antigen retrieval solution (PH8.0, ZSGB-BIO, China) in high pressure for 3 min. The cooled paraffin sections were incubated in 3% hydrogen peroxide at room temperature for 15 min and then incubated in bovine serum albumin at 37℃ for 30 min. Followed by incubating with primary antibodies: ADAR1 (1:50, sc-271854; SANTA CRUZ, USA), phospho-PI3K (1:100, AF3241; Affinity, China), phospho-AKT (1:100, 80455-1-RR; Proteintech, China), and phospho-mTOR (1:100, 67778-1-Ig; Proteintech, China) at 4℃ overnight, the paraffin sections were incubated with secondary antibody (PV6000, ZSGB-BIO, China) at 37℃ for 20 min. Immunohistochemical staining was then carried out by DAB (ZLI-9019, ZSGB-Bio), redyed by hematoxylin, and evaluated by light microscopy.

2.11 Oral glucose tolerance test (OGTT)

OGTT was performed after the mice fasted for 10 h. The dose of glucose used was 2 g/kg. Blood glucose was measured at 0, 30, 60, 90, and 120 min.

2.12 Hematoxylin and eosin (H&E) staining

Tissue samples were subjected to fixation in a 4% paraformaldehyde solution maintained at 4°C for a 24 h duration. Subsequently, paraffin embedding was performed, yielding 5 µm thick sections. These sections underwent staining procedures with 0.5% hematoxylin and 0.5% eosin solution (G1120; Solarbio) for 5 min at a temperature of 37°C.

2.13 Masson’s staining

Masson’s trichrome staining kit (BA4079B, Baso, China) was used to stain the tissue for fibrosis analysis. About 5 µm thick paraffin sections are routinely dewaxed in water and the Weigert hematoxylin A and B solutions are removed and mixed in a 1:1 ratio, which are then used to completely cover the tissue for 5 min. Sections are then stained with fuchsin acidic hematoxylin solution for 3 min, and again stained with phosphomolybdic acid solution for 5 min before being stained with aniline blue solution for 5 min. The tissue is then soaked in 0.2% acetic acid solution, routinely dehydrated and cleared, and mounted with neutral resin.

2.14 Biochemical indexes

Serum specimens were separated from the collected blood according to manufacturer’s protocols. The levels of blood creatinine (Cr) (C011-2-1, Nanjing Jiancheng Bioengineering Institute) and blood urea nitrogen (BUN) (C013-2-1, Nanjing Jiancheng Bioengineering Institute) were detected.

2.15 Determination of serum insulin

According to manufacturer’s protocol, mouse serum insulin concentration was examined using a mouse insulin ELISA kit (JYM0351Mo; Wuhan Jiyinmei Biotechnology Co., Ltd). The absorbance value was examined at 450 nm using a microplate reader.

2.16 Immunofluorescence staining

The paraffin sections were dewaxed for 30 min, repaired under high pressure, and washed three times with PBS. Permeabilize them with 0.1% Triton X-100 at 37°C for 20 min. Block the cells with goat serum at 37°C for 20 min. Add the primary antibody and incubate them at 4°C overnight in a humidified box. The antibodies used are ADAR1 (1:40, sc-271854; SANTA CRUZ, USA), phospho-PI3K (1:100, AF3241; Affinity, China), phospho-AKT (1:100, 80455-1-RR; Proteintech, China), and phospho-mTOR (1:100, 67778-1-Ig; Proteintech, China).

The next day, the samples were rewarmed and washed with PBS three times. The secondary antibody Alexa Fluor® 488 Conjugate (1:100, #ZF-0511; ZSGB-BIO) as well as Alexa Fluor® 594 Conjugate (1:100, #ZF-0513; ZSGB-BIO) was then added and incubated in the dark at 37°C for 60 min. 4',6-diamidino-2-phenylindole was added, the slide was sealed, and the samples were observed under a fluorescence microscope.

2.17 RT-PCR analysis

Total RNA was extracted by TRIzol® (Thermo Fisher Scientific, Waltham, MA, USA).

The cDNA was obtained using RevertAid First Strand cDNA Synthesis Kit (Thermo Fisher Scientific, Inc.). The primer sequences used were as follows:

ADAR1-F: 5′-CTGAGACCAAAAGAAACGCAGA-3′

ADAR1-R: 5’-GCCATTGTAATGAACAGGTGGTT-3′

GAPDH-F: 5’-TCCACCACCCTGTTGCTGTA-3′

GAPDH-R: 5’-ACCACAGTCCATGCCATCAC-3′.

mRNA levels were assessed using the PowerUp™ SYBR™ Green Master Mix (Applied Biosystems; Thermo Fisher Scientific, Inc.). Samples were denatured at 95°C for 30 s, followed by 40 cycles of 95°C for 5 s; 60°C for 40 s; 95°C for 15 s; 60 s at 60°C, 95°C for 15 s. GAPDH mRNA levels were assessed as an internal control. Relative gene expression levels were normalized using the 2−ΔΔCq method.

2.18 Statistical analysis

SPSS 22.0 was used for statistical analysis, and the data were expressed as mean ± standard deviation. Analysis of variance was used to compare the mean of samples in multiple groups, and LSD-t test was used to compare the mean of samples in pairs within groups, with the test level α = 0.05.

  1. Ethical approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Hainan Medical College (HYLL-2021-296).

3 Results

3.1 Expression characteristics of ADAR1 in proximal renal tubular cells of db/db mice with spontaneous type 2 diabetes mellitus

The FBG, body weight, food, and water intake of db/db mice with spontaneous type 2 diabetes were significantly higher than those of mice in the normal control group (Figure 1a–d). OGTT results showed that the blood glucose of db/db mice group was significantly higher than that of control group (Figure A1g). In addition, the levels of blood Cr, insulin, and BUN in db/db mice were also increased (Figure A1d–f). H&E staining showed that db/db mice group had dilation of renal tubules and a marked disorganization of tubular epithelial cells compared with the control group (Figure A1a). In the comparative analysis utilizing Masson’s staining, db/db mice had more blue-stained collagen fibers infiltrating the proximal tubule interstitium than the control (Figure A1b and c).

Figure 1 Detect the expression characteristics of ADAR1 in proximal renal tubular cells of db/db mice with spontaneous type 2 diabetes mellitus. (a) Detect FBG, (b) weight, (c) food intake, and (d) water intake of db/db mice with spontaneous type 2 diabetes mellitus and normal db/m mice. (e)–(i) IHC assays were presented for detecting the expression of (f) ADAR1, (g) p-PI3K, (h) p-AKT1, and (i) p-mTOR. (j)–(n) Western blot was presented for detecting the expression of (k) ADAR1, (l) p-PI3K, (m) p-AKT1, and (n) p-mTOR. Bar, 20 μm. *p < 0.05; **p < 0.01; ***p < 0.001.
Figure 1

Detect the expression characteristics of ADAR1 in proximal renal tubular cells of db/db mice with spontaneous type 2 diabetes mellitus. (a) Detect FBG, (b) weight, (c) food intake, and (d) water intake of db/db mice with spontaneous type 2 diabetes mellitus and normal db/m mice. (e)–(i) IHC assays were presented for detecting the expression of (f) ADAR1, (g) p-PI3K, (h) p-AKT1, and (i) p-mTOR. (j)–(n) Western blot was presented for detecting the expression of (k) ADAR1, (l) p-PI3K, (m) p-AKT1, and (n) p-mTOR. Bar, 20 μm. *p < 0.05; **p < 0.01; ***p < 0.001.

Immunohistochemical and immunofluorescence results showed that ADAR1 in the proximal renal tubular cells of mice in the normal control group was mainly expressed in the cytoplasm and that the expression of ADAR1 in the cytoplasm of cells in the mice in the model group was significantly reduced. The expression levels of P-PI3K, p-AKT, and p-mTOR in the proximal renal tubular cells of mice in the model group were significantly higher than those in the proximal renal tubular cells of mice in the normal control group (Figure 1e–i, Figure A2). Western blot results indicated that the expression of ADAR1 in the model group was significantly decreased and the expression levels of P-PI3K, p-AKT, and p-mTOR in the model group were significantly higher than those in the normal control group (Figure 1j–n). The above experiments revealed the expression characteristics of ADAR1, PI3K, Akt, and mTOR in proximal renal tubular cells of db/db mice.

3.2 ADAR1 regulates SOD and MDA

ADAR1-overexpression plasmids was constructed, RT-PCR results indicated that the ADAR1-overexpression plasmid upregulated ADAR1 mRNA expression (Figure 2a). To determine the optimal concentration of 8-azaadenosine, CCK-8 assay was performed to examine the cell viability of HK-2 cells treated with a series of concentrations of 8-azaadenosine. Our data showed that when the concentration of 8-azaadenosine reached 2 μM, distinct cytotoxicity appeared in HK-2 cells. Hence, 2 μM 8-azaadenosine was chosen as the optimal concentration (Figure 2b). CCK-8 assays showed that the ADAR1 inhibitor 8-azaadenosine (2 μM), PI3K inhibitor LY294002 (10 μM), and mTOR inhibitor rapamycin (10 μM) affected cell proliferation in a dose-dependent manner (Figure 2b–d). In the context of a high-glucose milieu, our findings unveiled a substantial decline in SOD activity accompanied by a significant rise in MDA content within HK-2 cells, indicative of heightened oxidative stress. After ADAR1 overexpression, SOD activity cells significantly increased, and MDA content significantly decreased under high-glucose conditions. However, the application of 8-azaadenosine showed a trend opposite to that of ADAR1 overexpression (Figure 2e and f). In conclusion, these data underscore the pivotal role of ADAR1 in modulating oxidative stress responses.

Figure 2 ADAR1 regulates SOD and MDA. (a) ADAR1-overexpression plasmids regulated ADAR1 mRNA expression level. The effects of different concentrations of (b) ADAR1 inhibitor 8-azaadenosine, (c) PI3K inhibitor LY294002, and (d) mTOR inhibitor rapamycin on the proliferation of HK-2 cells were screened by CCK8. (e) and (f) Detect SOD activity and MDA content under high-glucose conditions, ADAR1 inhibitor 8-azaadenosine, and ADAR1-overexpression. ***p < 0.001.
Figure 2

ADAR1 regulates SOD and MDA. (a) ADAR1-overexpression plasmids regulated ADAR1 mRNA expression level. The effects of different concentrations of (b) ADAR1 inhibitor 8-azaadenosine, (c) PI3K inhibitor LY294002, and (d) mTOR inhibitor rapamycin on the proliferation of HK-2 cells were screened by CCK8. (e) and (f) Detect SOD activity and MDA content under high-glucose conditions, ADAR1 inhibitor 8-azaadenosine, and ADAR1-overexpression. ***p < 0.001.

3.3 ADAR1 affects ER stress

Under a high-glucose environment, ADAR1 overexpression reduced the intensity of the ER fluorescent, and 8-azaadenosine enhanced the intensity of ER fluorescent, indicating high-glucose-induced ER stress (Figure 3a and b). Rapamycin reduced the intensity of ER-Tracker Red staining, indicating the amelioration of high-glucose-induced ER stress. The intensity of the ER fluorescent decreased more significantly after ADAR1overexpression, with no significant increase after ADAR1 inhibition (Figure 3c and d). Additionally, after treatment with LY294002, the expression pattern was basically the same as that after treatment with rapamycin (Figure 3e and f). ADAR1 may be closely related to the PI3K/mTOR signaling pathway in the mechanism underlying the regulation of ER stress.

Figure 3 ADAR1 affects endoplasmic reticulum stress (a) and (b) ER-tracker dye detected effect of ADAR1 on the intensity of endoplasmic reticulum stress fluorescence probe under the high-glucose environment. (c) and (d) ER-tracker dye detected effect of ADAR1 on the intensity of endoplasmic reticulum stress fluorescence probe under high-glucose environment and rapamycin treatment. (e) and (f) ER-tracker dye detected effect of ADAR1 on the intensity of endoplasmic reticulum stress fluorescence probe under high-glucose environment and LY294002 treatment. Bar, 50 μm. *p < 0.05; ***p < 0.001.
Figure 3

ADAR1 affects endoplasmic reticulum stress (a) and (b) ER-tracker dye detected effect of ADAR1 on the intensity of endoplasmic reticulum stress fluorescence probe under the high-glucose environment. (c) and (d) ER-tracker dye detected effect of ADAR1 on the intensity of endoplasmic reticulum stress fluorescence probe under high-glucose environment and rapamycin treatment. (e) and (f) ER-tracker dye detected effect of ADAR1 on the intensity of endoplasmic reticulum stress fluorescence probe under high-glucose environment and LY294002 treatment. Bar, 50 μm. *p < 0.05; ***p < 0.001.

3.4 Effect of ADAR1 on cell apoptosis and proliferation

TUNEL assay results indicated that ADAR1 overexpression reduced the ratio of red fluorescently labeled cells compared with the HG group (Figure 4a and b). Rapamycin reduced the ratio of red fluorescently labeled high-glucose-induced cells, and on this basis, the ratio of red fluorescently labeled cells also decreased after ADAR1 overexpression, but there was no significant difference compared to 8-azaadenosine (Figure 4c and d). Similar profiles emerged upon exposure to LY294002 (Figure 4e and f). Cell proliferation assay showed ADAR1 overexpression enhanced cell proliferation compared with the HG group (Figure 4g). In a high-glucose environment, rapamycin and LY294002 enhanced cell proliferation, and on this basis, cell proliferation was enhanced after ADAR1 overexpression, but there was no significant difference compared to 8-azaadenosine. ADAR1 may be closely related to the PI3K/mTOR signaling pathway in the mechanism underlying the regulation of the cell apoptosis and proliferation.

Figure 4 ADAR1 affects cell apoptosis (a) and (b) TUNEL staining assessed the effect of ADAR1 on the ratio of red fluorescent-labeled cells under the high-glucose environment. (c) and (d) TUNEL staining assessed the effect of ADAR1 on the ratio of red fluorescent-labeled cells under high-glucose environment and rapamycin treatment. (e) and (f) TUNEL staining assessed the effect of ADAR1 on the ratio of red fluorescent-labeled cells under high-glucose environment and LY294002 treatment. Bar, 20 μm. (g) CCK8 assays detected cell proliferation ability of HK-2 cells with HG, ADAR1 inhibitor 8-azaadenosine, and ADAR1 overexpression. (h) CCK8 assays detected cell proliferation ability of HK-2 cells with HG, ADAR1 inhibitor 8-azaadenosine, ADAR1 overexpression, and rapamycin. (i) CCK8 assays detected cell proliferation ability of HK-2 cells with HG, ADAR1 inhibitor 8-azaadenosine, ADAR1 overexpression, and LY294002. *p < 0.05; **p < 0.01; ***p < 0.001.
Figure 4

ADAR1 affects cell apoptosis (a) and (b) TUNEL staining assessed the effect of ADAR1 on the ratio of red fluorescent-labeled cells under the high-glucose environment. (c) and (d) TUNEL staining assessed the effect of ADAR1 on the ratio of red fluorescent-labeled cells under high-glucose environment and rapamycin treatment. (e) and (f) TUNEL staining assessed the effect of ADAR1 on the ratio of red fluorescent-labeled cells under high-glucose environment and LY294002 treatment. Bar, 20 μm. (g) CCK8 assays detected cell proliferation ability of HK-2 cells with HG, ADAR1 inhibitor 8-azaadenosine, and ADAR1 overexpression. (h) CCK8 assays detected cell proliferation ability of HK-2 cells with HG, ADAR1 inhibitor 8-azaadenosine, ADAR1 overexpression, and rapamycin. (i) CCK8 assays detected cell proliferation ability of HK-2 cells with HG, ADAR1 inhibitor 8-azaadenosine, ADAR1 overexpression, and LY294002. *p < 0.05; **p < 0.01; ***p < 0.001.

3.5 Effect of ADAR1 regulation on the PI3K/AKT/mTOR signaling pathway

Compared with the control group, the expression levels of ADAR1, Ki-67, and cyclin D1 in the high-glucose group were significantly lower. Additionally, the protein expression levels of phosphorylated p-PI3K/p-AKT/p-mTOR and non-phosphorylated PI3K/AKT/mTOR increased to varying degrees. Under high-glucose conditions, ADAR1 overexpression significantly upregulated ADAR1, Ki-67, and cyclin D1 expression and decreased the protein expression of phosphorylated p-PI3K/p-AKT/p-mTOR and non-phosphorylated PI3K/AKT/mTOR. Interestingly, 8-azaadenosine enhanced the effect of high-glucose factors under high-glucose conditions (Figure 5).

Figure 5 ADAR1 affects PI3K/AKT/mTOR signaling pathway under the high-glucose environment. (a)–(j) Expressions of (b) ADAR1, (c) PI3K, (d) p-PI3K, (e) AKT1, (f) p-AKT1, (g) mTOR, (h) p-mTOR, (i) cyclin D1, and (j) Ki67 were measured by western blot in HK-2 cells or ADAR1-overexpressed HK-2 cells under the high-glucose environment. ***p < 0.001.
Figure 5

ADAR1 affects PI3K/AKT/mTOR signaling pathway under the high-glucose environment. (a)–(j) Expressions of (b) ADAR1, (c) PI3K, (d) p-PI3K, (e) AKT1, (f) p-AKT1, (g) mTOR, (h) p-mTOR, (i) cyclin D1, and (j) Ki67 were measured by western blot in HK-2 cells or ADAR1-overexpressed HK-2 cells under the high-glucose environment. ***p < 0.001.

LY294002 significantly inhibited high-glucose-induced PI3K/AKT/mTOR protein expression. The expression levels of AKT and p-PI3K were not significantly different in cells treated with LY294002 combined with 8-azaadenosine and cells treated with LY294002 alone. The expression levels of p-mTOR, p- PI3K, and PI3K/AKT were not significantly different in cells treated with LY294002 combined with ADAR1 overexpression and cells treated with LY294002 alone (Figure 6).

Figure 6 ADAR1 affects PI3K/AKT/mTOR signaling pathway under high-glucose environment and LY294002 treatment. (a)–(h) Expressions of (b) ADAR1 (c) PI3K, (d) p-PI3K, (e) AKT1, (f) p-AKT1, (g) mTOR, and (h) p-mTOR were measured by western blot in HK-2 cells or ADAR1-overexpressed HK-2 cells under high-glucose environment and LY294002 treatment. **p < 0.01; ***p < 0.001.
Figure 6

ADAR1 affects PI3K/AKT/mTOR signaling pathway under high-glucose environment and LY294002 treatment. (a)–(h) Expressions of (b) ADAR1 (c) PI3K, (d) p-PI3K, (e) AKT1, (f) p-AKT1, (g) mTOR, and (h) p-mTOR were measured by western blot in HK-2 cells or ADAR1-overexpressed HK-2 cells under high-glucose environment and LY294002 treatment. **p < 0.01; ***p < 0.001.

Rapamycin significantly inhibited high-glucose-induced mTOR and p-mTOR expression. In cells treated with rapamycin combined with 8-azaadenosine, there was no significant change in PI3K/AKT expression compared to applying rapamycin alone. Additionally, under high-glucose conditions, in cells treated with rapamycin and ADAR1 overexpression, all protein expression of phosphorylated and non-phosphorylated PI3K/AKT decreased; however, there was no significant change in mTOR and p-mTOR (Figure 7). The results further indicated that ADAR1 ameliorated high-glucose-induced oxidative stress and ER stress in HK-2 cells through the PI3K/AKT/mTOR signaling pathway.

Figure 7 ADAR1 affects PI3K/AKT/mTOR signaling pathway under high-glucose environment and rapamycin treatment. (a)–(h) Expressions of (a) ADAR1 (c) PI3K, (d) p-PI3K, (e) AKT1, (f) p-AKT1, (g) mTOR, and (h) p-mTOR were measured by western blot in HK-2 cells or ADAR1-overexpressed HK-2 cells under high-glucose environment and rapamycin treatment. ***p < 0.001.
Figure 7

ADAR1 affects PI3K/AKT/mTOR signaling pathway under high-glucose environment and rapamycin treatment. (a)–(h) Expressions of (a) ADAR1 (c) PI3K, (d) p-PI3K, (e) AKT1, (f) p-AKT1, (g) mTOR, and (h) p-mTOR were measured by western blot in HK-2 cells or ADAR1-overexpressed HK-2 cells under high-glucose environment and rapamycin treatment. ***p < 0.001.

4 Discussion

During the pathogenesis of DKD, proximal renal tubular cells undergo disturbances in their energy metabolism and aerobic processes as a consequence of hyperglycemic conditions, being prone to apoptosis, oxidative stress, and ER stress. These ultimately contribute to renal fibrosis and a decline in renal function [20]. Persistent hyperglycemic stress induces phenotypic transformation in proximal tubular cells, triggering the release of inflammatory-related factors and growth-promoting factors. This vicious cycle aggravates amplify hyperglycemia stimulation, expedites the apoptosis process in renal tubular cells, and impedes their regenerative and reparative capacities [21]. Previous studies identified ADAR1 as a novel target for cancer immunotherapy. As scholarly pursuits have progressed, the functional repertoire of ADAR1 has expanded beyond its recognized involvement in oncogenesis. ADAR1 was also found to prevent cell necrosis by inhibiting the accumulation of endogenous Z-RNA [22]. In aged cells and tissues, autophagy results in the downregulation of ADAR1, which facilitates the process of cellular senescence. Furthermore, ADAR1 knockdown has been demonstrated to induce cellular aging. Conversely, ADAR1 overexpression effectively impedes the progression of cellular aging [23]. The primary objective of our study was to delineate the expression characteristics of ADAR1 during the progression of DKD and to elucidate its functional mechanism in the context of high-glucose-induced HK-2 injury. We first characterized ADAR1 expression in proximal renal tubular cells using spontaneous type 2 diabetic mice. Second, examined the effect of ADAR1 on HK-2 cell proliferation, oxidative stress, and ER stress under a high-glucose environment. Finally, we explored the potential relationship between ADAR1 and the PI3K/AKT/mTOR signaling pathway. This study described the expression characteristics of ADAR1 in proximal renal tubular cells of diabetic db/db mice and elucidated the underlying mechanism by which ADAR1 alleviates high-glucose-induced HK-2 cell injury. Collectively, these findings revealed that ADAR1 may be a potential key factor in slowing the progression of DKD.

ADAR1 plays an essential role in maintaining physiological homeostasis, such as tissue cell proliferation and apoptosis [24]. The complete loss of ADAR1 activity is embryonically lethal, and ADAR1 is recognized as a negative regulator of ZBP1-mediated apoptosis [25]. Studies have also shown that the pathology effects caused by ADAR1 ZBD mutation are driven by the activation of ZBP1. Notably, the ablation of ZBP1 can effectively mitigate the pathological manifestations caused by ADAR1 modifications. However, it does not fully revert the inherent inflammatory response triggered by these ADAR1mutations [8]. ADAR1 alleviates high-fat diet-induced nonalcoholic fatty liver disease by inhibiting NLRP3 inflammasomes [26]. In this study, constructing an ADAR1-overexpression plasmid and applying an ADAR1 inhibitor (8-Aza) demonstrated that ADAR1 regulated the proliferation of HK-2 cells. Additionally, ADAR1 can regulate the levels of oxidative stress indicators such as SOD and MDA induced by high sugar, alleviating the cell apoptosis and oxidative stress induced by high sugar in HK-2 cells. Both oxidative stress and ER stress are acknowledged as integral components in the progression of DKD [27]. During the development of DKD, a sustained high-glucose stimulation results in transient ER stress in the early stage, which subsequently leads to ER stress-induced HK-2 cell damage during the later stages [28]. Interestingly, ADAR1 effectively alleviates the development of oxidative stress and ER stress, thereby underscoring its pivotal role in the progression of DKD.

In cancer research, ADAR1 has been implicated in the stabilization of the oncogene c-Myc via the AKT signaling pathway, a mechanism that fosters drug resistance in pancreatic cancer cells, specifically against BET inhibitors [29]. Knockdown of ADAR1 expression inhibits thyroid tumor proliferation and invasiveness [30]. ADAR1 emerges as a compelling biomarker for risk assessment in predicting recurrence of colorectal cancer in the remnant liver following surgical resection of liver metastases [31]. Beyond its oncological implications, the absence of the ADAR1 p150 isoform is implicated in the facilitation of autoinflammatory responses [32]. PI3K initiates a cascade of events by modifying the protein structure of AKT, subsequently activating it. This activation, in turn, orchestrates the phosphorylation-dependent regulation of proteins integral to the apoptotic machinery, thereby regulating cell proliferation, differentiation, apoptosis, and changes in the migration phenotype [33]. In the intricate cascade of apoptosis, mTOR, functioning as a downstream target of PI3K/Akt, also plays an important key role, especially in the progression of DKD [16]. In this study, we employed inhibitors of PI3K and mTOR to elucidate the mechanism underlying ADAR1’s protective effects on HK-2 cells. Although there have been related studies, the role of PI3K/AKT/mTOR signaling has not been investigated. To delve deeper into the connection between ADAR1’s impact on HG-induced HK-2 cells and the PI3K/AKT/mTOR pathway, our findings revealed elevated expression of PI3K, AKT, and mTOR in both diabetic mice and in vitro HG-stressed HK-2 cells. Notably, ADAR1 overexpression led to a substantial decrease in these proteins’ levels; conversely, inhibition of ADAR1 resulted in an increase. Furthermore, LY294002 can block the action of ADAR1, while rapamycin has no significant effect on the regulation of ADAR1. Therefore, we hypothesize that the PI3K/AKT/mTOR signaling pathway is activated in HG-induced HK-2 cells, and the upregulation of ADAR1 reduces the PI3K/AKT/mTOR signaling pathway and improves cell damage by reducing ER stress. Interestingly, 8-Aza upregulated mTOR protein expression after PI3K inhibition, and there was no significant change in mTOR expression when 8-Aza was applied together with the mTOR inhibitor rapamycin. Therefore, we believe that ADAR1 plays a role in the regulation of PI3K/AKT/mTOR pathway through multiple mechanisms, and there may be other crosstalk pathways. These hypotheses will be tested in future studies.

The two subtypes of ADAR1, p110 and p150, exhibit distinct expression across different cell types. In some cancer cell studies, the expression of ADAR1was significantly higher in the nucleus than in the cytoplasm, with predominant expression of the p110 subtype [34]. This study demonstrated a significant reduction in ADAR1 expression in the db/db mouse model and the high-glucose-induced HK-2 cell model. However, in this study, we did not delve into the expression differences and possible functional specificity of the p110 and p150 subtypes. Our study primarily focused on the expression of ADAR1 in the proximal tubules of DKD. Although we have not conducted an in-depth exploration and verification of the underlying mechanisms of renal tubular dysfunction, future research endeavors will aim to refine and expand the understanding within this field. Overall, ADAR1 upregulation can alleviate high-glucose-induced oxidative stress and ER stress in HK-2 cells by reducing PI3K/AKT/mTOR.

Taken together, these findings converge to highlight ADAR1 as a pivotal regulator with the potential to mitigate the progression of DKD. The results of in vitro and in vivo models showed that ADAR1 plays a protective role in proximal tubular cells under high-glucose conditions and could alleviate high-glucose-induced apoptosis, oxidative stress, and ER stress in HK-2 cells through PI3K/AKT/mTOR.

# Equivalent contribution author.

Acknowledgements

Not applicable.

  1. Funding information: This work has been supported by the High-level Talents Project of Hainan Natural Science Foundation of 2022 (Grant number 822RC826), Hainan Health industry scientific research project of 2021 (Grant number 21A200072), Hainan Health industry scientific research project of 2020 (Grant number 20A200012), and Youth Fund Project of Hainan Natural Science Foundation of 2021 (Grant number 821QN403).

  2. Author contributions: All authors contributed to the study conception and design. Ying Wang and Jiang Chang: conceptualization,methodology, software. Fa Wang: data curation, writing – original draft preparation. Chuan Yun: visualization, investigation. Lianying Lai: software, validation, experimentation. ShiXu Yang: writing – reviewing and editing. Yueying Fu and Xingtian Ma: experimentation. All authors read and approved the final manuscript.

  3. Conflict of interest: The authors have no relevant financial or non-financial interests to disclose.

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

Appendix

Figure A1 Detect the expression characteristics of ADAR1 in proximal renal tubular cells of db/db mice with spontaneous type 2 diabetes mellitus.(a) Immunofluorescence assays were presented for detecting the expression of (b) ADAR1, (c) p-PI3K, (d) p-AKT1, and (e) p-mTOR. Bar, 20 μm. **p < 0.01.
Figure A1

Detect the expression characteristics of ADAR1 in proximal renal tubular cells of db/db mice with spontaneous type 2 diabetes mellitus.(a) Immunofluorescence assays were presented for detecting the expression of (b) ADAR1, (c) p-PI3K, (d) p-AKT1, and (e) p-mTOR. Bar, 20 μm. **p < 0.01.

Figure A2 Detect the characteristics of db/db mice with spontaneous type 2 diabetes mellitus. Representative images of tissue stained with (a) H&E, (b) and (c) Masson’s are listed. Bar, 20 μm. (d) Cr (e) BUN levels were determined in the control and db/db mice. The result of (f) insuin (INS), (g) OGTT. **p < 0.01; ***p < 0.001.
Figure A2

Detect the characteristics of db/db mice with spontaneous type 2 diabetes mellitus. Representative images of tissue stained with (a) H&E, (b) and (c) Masson’s are listed. Bar, 20 μm. (d) Cr (e) BUN levels were determined in the control and db/db mice. The result of (f) insuin (INS), (g) OGTT. **p < 0.01; ***p < 0.001.

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Received: 2024-01-23
Revised: 2024-07-24
Accepted: 2024-08-22
Published Online: 2024-10-10

© 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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  83. Comparison of short-segment and long-segment fixation in treatment of degenerative scoliosis and analysis of factors associated with adjacent spondylolisthesis
  84. Lycopene inhibits pyroptosis of endothelial progenitor cells induced by ox-LDL through the AMPK/mTOR/NLRP3 pathway
  85. Methylation regulation for FUNDC1 stability in childhood leukemia was up-regulated and facilitates metastasis and reduces ferroptosis of leukemia through mitochondrial damage by FBXL2
  86. Correlation of single-fiber electromyography studies and functional status in patients with amyotrophic lateral sclerosis
  87. Risk factors of postoperative airway obstruction complications in children with oral floor mass
  88. Expression levels and clinical significance of serum miR-19a/CCL20 in patients with acute cerebral infarction
  89. Physical activity and mental health trends in Korean adolescents: Analyzing the impact of the COVID-19 pandemic from 2018 to 2022
  90. Evaluating anemia in HIV-infected patients using chest CT
  91. Ponticulus posticus and skeletal malocclusion: A pilot study in a Southern Italian pre-orthodontic court
  92. Causal association of circulating immune cells and lymphoma: A Mendelian randomization study
  93. Assessment of the renal function and fibrosis indexes of conventional western medicine with Chinese medicine for dredging collaterals on treating renal fibrosis: A systematic review and meta-analysis
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  95. New target-HMGCR inhibitors for the treatment of primary sclerosing cholangitis: A drug Mendelian randomization study
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  97. Comparison of the ability of newly inflammatory markers to predict complicated appendicitis
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  99. Immune landscape of hepatocellular carcinoma: The central role of TP53-inducible glycolysis and apoptosis regulator
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  101. SHP-1 mediates cigarette smoke extract-induced epithelial–mesenchymal transformation and inflammation in 16HBE cells
  102. Acute hyper-hypoxia accelerates the development of depression in mice via the IL-6/PGC1α/MFN2 signaling pathway
  103. The GJB3 correlates with the prognosis, immune cell infiltration, and therapeutic responses in lung adenocarcinoma
  104. Physical fitness and blood parameters outcomes of breast cancer survivor in a low-intensity circuit resistance exercise program
  105. Exploring anesthetic-induced gene expression changes and immune cell dynamics in atrial tissue post-coronary artery bypass graft surgery
  106. Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism
  107. Analysis of the risk factors of the radiation-induced encephalopathy in nasopharyngeal carcinoma: A retrospective cohort study
  108. Reproductive outcomes in women with BRCA 1/2 germline mutations: A retrospective observational study and literature review
  109. Evaluation of upper airway ultrasonographic measurements in predicting difficult intubation: A cross-section of the Turkish population
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  113. Frequency and clinicopathological correlation of gastrointestinal polyps: A six-year single center experience
  114. ACSL4 mediates inflammatory bowel disease and contributes to LPS-induced intestinal epithelial cell dysfunction by activating ferroptosis and inflammation
  115. Affibody-based molecular probe 99mTc-(HE)3ZHER2:V2 for non-invasive HER2 detection in ovarian and breast cancer xenografts
  116. Effectiveness of nutritional support for clinical outcomes in gastric cancer patients: A meta-analysis of randomized controlled trials
  117. The relationship between IFN-γ, IL-10, IL-6 cytokines, and severity of the condition with serum zinc and Fe in children infected with Mycoplasma pneumoniae
  118. Paraquat disrupts the blood–brain barrier by increasing IL-6 expression and oxidative stress through the activation of PI3K/AKT signaling pathway
  119. Sleep quality associate with the increased prevalence of cognitive impairment in coronary artery disease patients: A retrospective case–control study
  120. Dioscin protects against chronic prostatitis through the TLR4/NF-κB pathway
  121. Association of polymorphisms in FBN1, MYH11, and TGF-β signaling-related genes with susceptibility of sporadic thoracic aortic aneurysm and dissection in the Zhejiang Han population
  122. Application value of multi-parameter magnetic resonance image-transrectal ultrasound cognitive fusion in prostate biopsy
  123. Laboratory variables‐based artificial neural network models for predicting fatty liver disease: A retrospective study
  124. Decreased BIRC5-206 promotes epithelial–mesenchymal transition in nasopharyngeal carcinoma through sponging miR-145-5p
  125. Sepsis induces the cardiomyocyte apoptosis and cardiac dysfunction through activation of YAP1/Serpine1/caspase-3 pathway
  126. Assessment of iron metabolism and iron deficiency in incident patients on incident continuous ambulatory peritoneal dialysis
  127. Tibial periosteum flap combined with autologous bone grafting in the treatment of Gustilo-IIIB/IIIC open tibial fractures
  128. The application of intravenous general anesthesia under nasopharyngeal airway assisted ventilation undergoing ureteroscopic holmium laser lithotripsy: A prospective, single-center, controlled trial
  129. Long intergenic noncoding RNA for IGF2BP2 stability suppresses gastric cancer cell apoptosis by inhibiting the maturation of microRNA-34a
  130. Role of FOXM1 and AURKB in regulating keratinocyte function in psoriasis
  131. Parental control attitudes over their pre-school children’s diet
  132. The role of auto-HSCT in extranodal natural killer/T cell lymphoma
  133. Significance of negative cervical cytology and positive HPV in the diagnosis of cervical lesions by colposcopy
  134. Echinacoside inhibits PASMCs calcium overload to prevent hypoxic pulmonary artery remodeling by regulating TRPC1/4/6 and calmodulin
  135. ADAR1 plays a protective role in proximal tubular cells under high glucose conditions by attenuating the PI3K/AKT/mTOR signaling pathway
  136. The risk of cancer among insulin glargine users in Lithuania: A retrospective population-based study
  137. The unusual location of primary hydatid cyst: A case series study
  138. Intraoperative changes in electrophysiological monitoring can be used to predict clinical outcomes in patients with spinal cavernous malformation
  139. Obesity and risk of placenta accreta spectrum: A meta-analysis
  140. Shikonin alleviates asthma phenotypes in mice via an airway epithelial STAT3-dependent mechanism
  141. NSUN6 and HTR7 disturbed the stability of carotid atherosclerotic plaques by regulating the immune responses of macrophages
  142. The effect of COVID-19 lockdown on admission rates in Maternity Hospital
  143. Temporal muscle thickness is not a prognostic predictor in patients with high-grade glioma, an experience at two centers in China
  144. Luteolin alleviates cerebral ischemia/reperfusion injury by regulating cell pyroptosis
  145. Therapeutic role of respiratory exercise in patients with tuberculous pleurisy
  146. Effects of CFTR-ENaC on spinal cord edema after spinal cord injury
  147. Irisin-regulated lncRNAs and their potential regulatory functions in chondrogenic differentiation of human mesenchymal stem cells
  148. DMD mutations in pediatric patients with phenotypes of Duchenne/Becker muscular dystrophy
  149. Combination of C-reactive protein and fibrinogen-to-albumin ratio as a novel predictor of all-cause mortality in heart failure patients
  150. Significant role and the underly mechanism of cullin-1 in chronic obstructive pulmonary disease
  151. Ferroptosis-related prognostic model of mantle cell lymphoma
  152. Observation of choking reaction and other related indexes in elderly painless fiberoptic bronchoscopy with transnasal high-flow humidification oxygen therapy
  153. A bibliometric analysis of Prader-Willi syndrome from 2002 to 2022
  154. The causal effects of childhood sunburn occasions on melanoma: A univariable and multivariable Mendelian randomization study
  155. Oxidative stress regulates glycogen synthase kinase-3 in lymphocytes of diabetes mellitus patients complicated with cerebral infarction
  156. Role of COX6C and NDUFB3 in septic shock and stroke
  157. Trends in disease burden of type 2 diabetes, stroke, and hypertensive heart disease attributable to high BMI in China: 1990–2019
  158. Purinergic P2X7 receptor mediates hyperoxia-induced injury in pulmonary microvascular endothelial cells via NLRP3-mediated pyroptotic pathway
  159. Investigating the role of oviductal mucosa–endometrial co-culture in modulating factors relevant to embryo implantation
  160. Analgesic effect of external oblique intercostal block in laparoscopic cholecystectomy: A retrospective study
  161. Elevated serum miR-142-5p correlates with ischemic lesions and both NSE and S100β in ischemic stroke patients
  162. Correlation between the mechanism of arteriopathy in IgA nephropathy and blood stasis syndrome: A cohort study
  163. Risk factors for progressive kyphosis after percutaneous kyphoplasty in osteoporotic vertebral compression fracture
  164. Predictive role of neuron-specific enolase and S100-β in early neurological deterioration and unfavorable prognosis in patients with ischemic stroke
  165. The potential risk factors of postoperative cognitive dysfunction for endovascular therapy in acute ischemic stroke with general anesthesia
  166. Fluoxetine inhibited RANKL-induced osteoclastic differentiation in vitro
  167. Detection of serum FOXM1 and IGF2 in patients with ARDS and their correlation with disease and prognosis
  168. Rhein promotes skin wound healing by activating the PI3K/AKT signaling pathway
  169. Differences in mortality risk by levels of physical activity among persons with disabilities in South Korea
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  173. A narrative review on adverse drug reactions of COVID-19 treatments on the kidney
  174. Emerging role and function of SPDL1 in human health and diseases
  175. Adverse reactions of piperacillin: A literature review of case reports
  176. Molecular mechanism and intervention measures of microvascular complications in diabetes
  177. Regulation of mesenchymal stem cell differentiation by autophagy
  178. Molecular landscape of borderline ovarian tumours: A systematic review
  179. Advances in synthetic lethality modalities for glioblastoma multiforme
  180. Investigating hormesis, aging, and neurodegeneration: From bench to clinics
  181. Frankincense: A neuronutrient to approach Parkinson’s disease treatment
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  183. Early detection of cardiovascular risk markers through non-invasive ultrasound methodologies in periodontitis patients
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  186. The chemoprotective hormetic effects of rosmarinic acid
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  189. Utilizing reactive oxygen species-scavenging nanoparticles for targeting oxidative stress in the treatment of ischemic stroke: A review
  190. NRXN1-related disorders, attempt to better define clinical assessment
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  193. Iron in ventricular remodeling and aneurysms post-myocardial infarction
  194. Case Reports
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  197. Successful treatment with bortezomib in combination with dexamethasone in a middle-aged male with idiopathic multicentric Castleman’s disease: A case report
  198. Complete heart block associated with hepatitis A infection in a female child with fatal outcome
  199. Elevation of D-dimer in eosinophilic gastrointestinal diseases in the absence of venous thrombosis: A case series and literature review
  200. Four years of natural progressive course: A rare case report of juvenile Xp11.2 translocations renal cell carcinoma with TFE3 gene fusion
  201. Advancing prenatal diagnosis: Echocardiographic detection of Scimitar syndrome in China – A case series
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  203. Anti-HMGCR myopathy mimicking facioscapulohumeral muscular dystrophy
  204. Recurrent opportunistic infections in a HIV-negative patient with combined C6 and NFKB1 mutations: A case report, pedigree analysis, and literature review
  205. Letter to the Editor
  206. Letter to the Editor: Total parenteral nutrition-induced Wernicke’s encephalopathy after oncologic gastrointestinal surgery
  207. Erratum
  208. Erratum to “Bladder-embedded ectopic intrauterine device with calculus”
  209. Retraction
  210. Retraction of “XRCC1 and hOGG1 polymorphisms and endometrial carcinoma: A meta-analysis”
  211. Corrigendum
  212. Corrigendum to “Investigating hormesis, aging, and neurodegeneration: From bench to clinics”
  213. Corrigendum to “Frankincense: A neuronutrient to approach Parkinson’s disease treatment”
  214. Special Issue The evolving saga of RNAs from bench to bedside - Part II
  215. Machine-learning-based prediction of a diagnostic model using autophagy-related genes based on RNA sequencing for patients with papillary thyroid carcinoma
  216. Unlocking the future of hepatocellular carcinoma treatment: A comprehensive analysis of disulfidptosis-related lncRNAs for prognosis and drug screening
  217. Elevated mRNA level indicates FSIP1 promotes EMT and gastric cancer progression by regulating fibroblasts in tumor microenvironment
  218. Special Issue Advancements in oncology: bridging clinical and experimental research - Part I
  219. Ultrasound-guided transperineal vs transrectal prostate biopsy: A meta-analysis of diagnostic accuracy and complication rates
  220. Assessment of diagnostic value of unilateral systematic biopsy combined with targeted biopsy in detecting clinically significant prostate cancer
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  222. MARK1 suppress malignant progression of hepatocellular carcinoma and improves sorafenib resistance through negatively regulating POTEE
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  224. Carboplatin combined with arsenic trioxide versus carboplatin combined with docetaxel treatment for LACC: A randomized, open-label, phase II clinical study
  225. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part I
  226. Comprehensive pan-cancer investigation of carnosine dipeptidase 1 and its prospective prognostic significance in hepatocellular carcinoma
  227. Identification of signatures associated with microsatellite instability and immune characteristics to predict the prognostic risk of colon cancer
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https://doi.org/10.1515/med-2024-1037
Keywords for this article
ADAR1; diabetic kidney disease; endoplasmic reticulum stress; oxidative stress
Creative Commons
BY 4.0

Articles in the same Issue

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  2. EDNRB inhibits the growth and migration of prostate cancer cells by activating the cGMP-PKG pathway
  3. STK11 (LKB1) mutation suppresses ferroptosis in lung adenocarcinoma by facilitating monounsaturated fatty acid synthesis
  4. Association of SOX6 gene polymorphisms with Kashin-Beck disease risk in the Chinese Han population
  5. The pyroptosis-related signature predicts prognosis and influences the tumor immune microenvironment in dedifferentiated liposarcoma
  6. METTL3 attenuates ferroptosis sensitivity in lung cancer via modulating TFRC
  7. Identification and validation of molecular subtypes and prognostic signature for stage I and stage II gastric cancer based on neutrophil extracellular traps
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  9. Correlation between ABCB1 and OLIG2 polymorphisms and the severity and prognosis of patients with cerebral infarction
  10. Study on the radiotherapy effect and serum neutral granulocyte lymphocyte ratio and inflammatory factor expression of nasopharyngeal carcinoma
  11. Transcriptome analysis of effects of Tecrl deficiency on cardiometabolic and calcium regulation in cardiac tissue
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  18. Downregulation of carbonic anhydrase IX expression in mouse xenograft nasopharyngeal carcinoma model via doxorubicin nanobubble combined with ultrasound
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  20. miR-335-3p improves type II diabetes mellitus by IGF-1 regulating macrophage polarization
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  23. Comprehensive analysis based on the disulfidptosis-related genes identifies hub genes and immune infiltration for pancreatic adenocarcinoma
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  27. Downregulation of lncRNA XLOC_032768 in diabetic patients predicts the occurrence of diabetic nephropathy
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  29. Effectiveness of ginkgo diterpene lactone meglumine on cognitive function in patients with acute ischemic stroke
  30. The construction of a novel prognostic prediction model for glioma based on GWAS-identified prognostic-related risk loci
  31. Evaluating the impact of childhood BMI on the risk of coronavirus disease 2019: A Mendelian randomization study
  32. Lactate dehydrogenase to albumin ratio is associated with in-hospital mortality in patients with acute heart failure: Data from the MIMIC-III database
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  34. Efficacy of etonogestrel subcutaneous implants versus the levonorgestrel-releasing intrauterine system in the conservative treatment of adenomyosis
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  43. Secreted frizzled-related protein 5 protects against renal fibrosis by inhibiting Wnt/β-catenin pathway
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  45. Overexpression of miR-532-5p restrains oxidative stress response of chondrocytes in nontraumatic osteonecrosis of the femoral head by inhibiting ABL1
  46. Autologous liver transplantation for unresectable hepatobiliary malignancies in enhanced recovery after surgery model
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  49. No genetic causality between obesity and benign paroxysmal vertigo: A two-sample Mendelian randomization study
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  81. The H2Valdien derivatives regulate the epithelial–mesenchymal transition of hepatoma carcinoma cells through the Hedgehog signaling pathway
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  83. Comparison of short-segment and long-segment fixation in treatment of degenerative scoliosis and analysis of factors associated with adjacent spondylolisthesis
  84. Lycopene inhibits pyroptosis of endothelial progenitor cells induced by ox-LDL through the AMPK/mTOR/NLRP3 pathway
  85. Methylation regulation for FUNDC1 stability in childhood leukemia was up-regulated and facilitates metastasis and reduces ferroptosis of leukemia through mitochondrial damage by FBXL2
  86. Correlation of single-fiber electromyography studies and functional status in patients with amyotrophic lateral sclerosis
  87. Risk factors of postoperative airway obstruction complications in children with oral floor mass
  88. Expression levels and clinical significance of serum miR-19a/CCL20 in patients with acute cerebral infarction
  89. Physical activity and mental health trends in Korean adolescents: Analyzing the impact of the COVID-19 pandemic from 2018 to 2022
  90. Evaluating anemia in HIV-infected patients using chest CT
  91. Ponticulus posticus and skeletal malocclusion: A pilot study in a Southern Italian pre-orthodontic court
  92. Causal association of circulating immune cells and lymphoma: A Mendelian randomization study
  93. Assessment of the renal function and fibrosis indexes of conventional western medicine with Chinese medicine for dredging collaterals on treating renal fibrosis: A systematic review and meta-analysis
  94. Comprehensive landscape of integrator complex subunits and their association with prognosis and tumor microenvironment in gastric cancer
  95. New target-HMGCR inhibitors for the treatment of primary sclerosing cholangitis: A drug Mendelian randomization study
  96. Population pharmacokinetics of meropenem in critically ill patients
  97. Comparison of the ability of newly inflammatory markers to predict complicated appendicitis
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  100. Serum SIRT3 levels in epilepsy patients and its association with clinical outcomes and severity: A prospective observational study
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  104. Physical fitness and blood parameters outcomes of breast cancer survivor in a low-intensity circuit resistance exercise program
  105. Exploring anesthetic-induced gene expression changes and immune cell dynamics in atrial tissue post-coronary artery bypass graft surgery
  106. Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism
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  108. Reproductive outcomes in women with BRCA 1/2 germline mutations: A retrospective observational study and literature review
  109. Evaluation of upper airway ultrasonographic measurements in predicting difficult intubation: A cross-section of the Turkish population
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  114. ACSL4 mediates inflammatory bowel disease and contributes to LPS-induced intestinal epithelial cell dysfunction by activating ferroptosis and inflammation
  115. Affibody-based molecular probe 99mTc-(HE)3ZHER2:V2 for non-invasive HER2 detection in ovarian and breast cancer xenografts
  116. Effectiveness of nutritional support for clinical outcomes in gastric cancer patients: A meta-analysis of randomized controlled trials
  117. The relationship between IFN-γ, IL-10, IL-6 cytokines, and severity of the condition with serum zinc and Fe in children infected with Mycoplasma pneumoniae
  118. Paraquat disrupts the blood–brain barrier by increasing IL-6 expression and oxidative stress through the activation of PI3K/AKT signaling pathway
  119. Sleep quality associate with the increased prevalence of cognitive impairment in coronary artery disease patients: A retrospective case–control study
  120. Dioscin protects against chronic prostatitis through the TLR4/NF-κB pathway
  121. Association of polymorphisms in FBN1, MYH11, and TGF-β signaling-related genes with susceptibility of sporadic thoracic aortic aneurysm and dissection in the Zhejiang Han population
  122. Application value of multi-parameter magnetic resonance image-transrectal ultrasound cognitive fusion in prostate biopsy
  123. Laboratory variables‐based artificial neural network models for predicting fatty liver disease: A retrospective study
  124. Decreased BIRC5-206 promotes epithelial–mesenchymal transition in nasopharyngeal carcinoma through sponging miR-145-5p
  125. Sepsis induces the cardiomyocyte apoptosis and cardiac dysfunction through activation of YAP1/Serpine1/caspase-3 pathway
  126. Assessment of iron metabolism and iron deficiency in incident patients on incident continuous ambulatory peritoneal dialysis
  127. Tibial periosteum flap combined with autologous bone grafting in the treatment of Gustilo-IIIB/IIIC open tibial fractures
  128. The application of intravenous general anesthesia under nasopharyngeal airway assisted ventilation undergoing ureteroscopic holmium laser lithotripsy: A prospective, single-center, controlled trial
  129. Long intergenic noncoding RNA for IGF2BP2 stability suppresses gastric cancer cell apoptosis by inhibiting the maturation of microRNA-34a
  130. Role of FOXM1 and AURKB in regulating keratinocyte function in psoriasis
  131. Parental control attitudes over their pre-school children’s diet
  132. The role of auto-HSCT in extranodal natural killer/T cell lymphoma
  133. Significance of negative cervical cytology and positive HPV in the diagnosis of cervical lesions by colposcopy
  134. Echinacoside inhibits PASMCs calcium overload to prevent hypoxic pulmonary artery remodeling by regulating TRPC1/4/6 and calmodulin
  135. ADAR1 plays a protective role in proximal tubular cells under high glucose conditions by attenuating the PI3K/AKT/mTOR signaling pathway
  136. The risk of cancer among insulin glargine users in Lithuania: A retrospective population-based study
  137. The unusual location of primary hydatid cyst: A case series study
  138. Intraoperative changes in electrophysiological monitoring can be used to predict clinical outcomes in patients with spinal cavernous malformation
  139. Obesity and risk of placenta accreta spectrum: A meta-analysis
  140. Shikonin alleviates asthma phenotypes in mice via an airway epithelial STAT3-dependent mechanism
  141. NSUN6 and HTR7 disturbed the stability of carotid atherosclerotic plaques by regulating the immune responses of macrophages
  142. The effect of COVID-19 lockdown on admission rates in Maternity Hospital
  143. Temporal muscle thickness is not a prognostic predictor in patients with high-grade glioma, an experience at two centers in China
  144. Luteolin alleviates cerebral ischemia/reperfusion injury by regulating cell pyroptosis
  145. Therapeutic role of respiratory exercise in patients with tuberculous pleurisy
  146. Effects of CFTR-ENaC on spinal cord edema after spinal cord injury
  147. Irisin-regulated lncRNAs and their potential regulatory functions in chondrogenic differentiation of human mesenchymal stem cells
  148. DMD mutations in pediatric patients with phenotypes of Duchenne/Becker muscular dystrophy
  149. Combination of C-reactive protein and fibrinogen-to-albumin ratio as a novel predictor of all-cause mortality in heart failure patients
  150. Significant role and the underly mechanism of cullin-1 in chronic obstructive pulmonary disease
  151. Ferroptosis-related prognostic model of mantle cell lymphoma
  152. Observation of choking reaction and other related indexes in elderly painless fiberoptic bronchoscopy with transnasal high-flow humidification oxygen therapy
  153. A bibliometric analysis of Prader-Willi syndrome from 2002 to 2022
  154. The causal effects of childhood sunburn occasions on melanoma: A univariable and multivariable Mendelian randomization study
  155. Oxidative stress regulates glycogen synthase kinase-3 in lymphocytes of diabetes mellitus patients complicated with cerebral infarction
  156. Role of COX6C and NDUFB3 in septic shock and stroke
  157. Trends in disease burden of type 2 diabetes, stroke, and hypertensive heart disease attributable to high BMI in China: 1990–2019
  158. Purinergic P2X7 receptor mediates hyperoxia-induced injury in pulmonary microvascular endothelial cells via NLRP3-mediated pyroptotic pathway
  159. Investigating the role of oviductal mucosa–endometrial co-culture in modulating factors relevant to embryo implantation
  160. Analgesic effect of external oblique intercostal block in laparoscopic cholecystectomy: A retrospective study
  161. Elevated serum miR-142-5p correlates with ischemic lesions and both NSE and S100β in ischemic stroke patients
  162. Correlation between the mechanism of arteriopathy in IgA nephropathy and blood stasis syndrome: A cohort study
  163. Risk factors for progressive kyphosis after percutaneous kyphoplasty in osteoporotic vertebral compression fracture
  164. Predictive role of neuron-specific enolase and S100-β in early neurological deterioration and unfavorable prognosis in patients with ischemic stroke
  165. The potential risk factors of postoperative cognitive dysfunction for endovascular therapy in acute ischemic stroke with general anesthesia
  166. Fluoxetine inhibited RANKL-induced osteoclastic differentiation in vitro
  167. Detection of serum FOXM1 and IGF2 in patients with ARDS and their correlation with disease and prognosis
  168. Rhein promotes skin wound healing by activating the PI3K/AKT signaling pathway
  169. Differences in mortality risk by levels of physical activity among persons with disabilities in South Korea
  170. Review Articles
  171. Cutaneous signs of selected cardiovascular disorders: A narrative review
  172. XRCC1 and hOGG1 polymorphisms and endometrial carcinoma: A meta-analysis
  173. A narrative review on adverse drug reactions of COVID-19 treatments on the kidney
  174. Emerging role and function of SPDL1 in human health and diseases
  175. Adverse reactions of piperacillin: A literature review of case reports
  176. Molecular mechanism and intervention measures of microvascular complications in diabetes
  177. Regulation of mesenchymal stem cell differentiation by autophagy
  178. Molecular landscape of borderline ovarian tumours: A systematic review
  179. Advances in synthetic lethality modalities for glioblastoma multiforme
  180. Investigating hormesis, aging, and neurodegeneration: From bench to clinics
  181. Frankincense: A neuronutrient to approach Parkinson’s disease treatment
  182. Sox9: A potential regulator of cancer stem cells in osteosarcoma
  183. Early detection of cardiovascular risk markers through non-invasive ultrasound methodologies in periodontitis patients
  184. Advanced neuroimaging and criminal interrogation in lie detection
  185. Maternal factors for neural tube defects in offspring: An umbrella review
  186. The chemoprotective hormetic effects of rosmarinic acid
  187. CBD’s potential impact on Parkinson’s disease: An updated overview
  188. Progress in cytokine research for ARDS: A comprehensive review
  189. Utilizing reactive oxygen species-scavenging nanoparticles for targeting oxidative stress in the treatment of ischemic stroke: A review
  190. NRXN1-related disorders, attempt to better define clinical assessment
  191. Lidocaine infusion for the treatment of complex regional pain syndrome: Case series and literature review
  192. Trends and future directions of autophagy in osteosarcoma: A bibliometric analysis
  193. Iron in ventricular remodeling and aneurysms post-myocardial infarction
  194. Case Reports
  195. Sirolimus potentiated angioedema: A case report and review of the literature
  196. Identification of mixed anaerobic infections after inguinal hernia repair based on metagenomic next-generation sequencing: A case report
  197. Successful treatment with bortezomib in combination with dexamethasone in a middle-aged male with idiopathic multicentric Castleman’s disease: A case report
  198. Complete heart block associated with hepatitis A infection in a female child with fatal outcome
  199. Elevation of D-dimer in eosinophilic gastrointestinal diseases in the absence of venous thrombosis: A case series and literature review
  200. Four years of natural progressive course: A rare case report of juvenile Xp11.2 translocations renal cell carcinoma with TFE3 gene fusion
  201. Advancing prenatal diagnosis: Echocardiographic detection of Scimitar syndrome in China – A case series
  202. Outcomes and complications of hemodialysis in patients with renal cancer following bilateral nephrectomy
  203. Anti-HMGCR myopathy mimicking facioscapulohumeral muscular dystrophy
  204. Recurrent opportunistic infections in a HIV-negative patient with combined C6 and NFKB1 mutations: A case report, pedigree analysis, and literature review
  205. Letter to the Editor
  206. Letter to the Editor: Total parenteral nutrition-induced Wernicke’s encephalopathy after oncologic gastrointestinal surgery
  207. Erratum
  208. Erratum to “Bladder-embedded ectopic intrauterine device with calculus”
  209. Retraction
  210. Retraction of “XRCC1 and hOGG1 polymorphisms and endometrial carcinoma: A meta-analysis”
  211. Corrigendum
  212. Corrigendum to “Investigating hormesis, aging, and neurodegeneration: From bench to clinics”
  213. Corrigendum to “Frankincense: A neuronutrient to approach Parkinson’s disease treatment”
  214. Special Issue The evolving saga of RNAs from bench to bedside - Part II
  215. Machine-learning-based prediction of a diagnostic model using autophagy-related genes based on RNA sequencing for patients with papillary thyroid carcinoma
  216. Unlocking the future of hepatocellular carcinoma treatment: A comprehensive analysis of disulfidptosis-related lncRNAs for prognosis and drug screening
  217. Elevated mRNA level indicates FSIP1 promotes EMT and gastric cancer progression by regulating fibroblasts in tumor microenvironment
  218. Special Issue Advancements in oncology: bridging clinical and experimental research - Part I
  219. Ultrasound-guided transperineal vs transrectal prostate biopsy: A meta-analysis of diagnostic accuracy and complication rates
  220. Assessment of diagnostic value of unilateral systematic biopsy combined with targeted biopsy in detecting clinically significant prostate cancer
  221. SENP7 inhibits glioblastoma metastasis and invasion by dissociating SUMO2/3 binding to specific target proteins
  222. MARK1 suppress malignant progression of hepatocellular carcinoma and improves sorafenib resistance through negatively regulating POTEE
  223. Analysis of postoperative complications in bladder cancer patients
  224. Carboplatin combined with arsenic trioxide versus carboplatin combined with docetaxel treatment for LACC: A randomized, open-label, phase II clinical study
  225. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part I
  226. Comprehensive pan-cancer investigation of carnosine dipeptidase 1 and its prospective prognostic significance in hepatocellular carcinoma
  227. Identification of signatures associated with microsatellite instability and immune characteristics to predict the prognostic risk of colon cancer
  228. Single-cell analysis identified key macrophage subpopulations associated with atherosclerosis
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