Home Hyperhomocysteinemia exacerbates ischemia-reperfusion injury-induced acute kidney injury by mediating oxidative stress, DNA damage, JNK pathway, and apoptosis
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Hyperhomocysteinemia exacerbates ischemia-reperfusion injury-induced acute kidney injury by mediating oxidative stress, DNA damage, JNK pathway, and apoptosis

  • Mei Zhang , Jing Yuan , Rong Dong , Jingjing Da , Qian Li , Ying Hu , Fangfang Yu , Yan Ran , Yan Zha and Yanjun Long EMAIL logo
Published/Copyright: May 29, 2021
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Open Life Sciences
From the journal Open Life Sciences Volume 16 Issue 1

Abstract

Background

Hyperhomocysteinemia (HHcy) plays an important role in the progression of many kidney diseases; however, the relationship between HHcy and ischemia-reperfusion injury (IRI)-induced acute kidney injury (IRI-induced AKI) is far from clear. In this study, we try to investigate the effect and possible mechanisms of HHcy on IRI-induced AKI.

Methods

Twenty C57/BL6 mice were reared with a regular diet or high methionine diet for 2 weeks (to generate HHcy mice); after that, mice were subgrouped to receive sham operation or ischemia-reperfusion surgery. Twenty four hour after reperfusion, serum creatinine, blood urea nitrogen, and Malondialdehyde (MDA) were measured. H&E staining for tubular injury, western blot for γH2AX, JNK, p-JNK, and cleaved caspase 3, and TUNEL assay for tubular cell apoptosis were also performed.

Results

Our results showed that HHcy did not influence the renal function and histological structure, as well as the levels of MDA, γH2AX, JNK, p-JNK, and tubular cell apoptosis in control mice. However, in IRI-induced AKI mice, HHcy caused severer renal dysfunction and tubular injury, higher levels of oxidative stress, DNA damage, JNK pathway activation, and tubular cell apoptosis.

Conclusion

Our results demonstrated that HHcy could exacerbate IRI-induced AKI, which may be achieved through promoting oxidative stress, DNA damage, JNK pathway activation, and consequent apoptosis.

Keywords: hyperhomocysteinemia; ischemia-reperfusion injury; acute kidney injury; oxidative stress; JNK signaling pathway

1 Introduction

Acute kidney injury (AKI) is a multiphasic clinical syndrome characterized by a rapid decline in renal function. Many factors such as ischemia/reperfusion [1], sepsis [2], trauma [3], and contrast [4] can induce the development of AKI. AKI is a common problem affecting hospitalized patients, with 25–40% mortality rates in severe cases [5]. A multicenter retrospective cohort study of 659,945 hospitalized adults from a wide range of clinical settings in nine regional central hospitals across China has reported that the incidence of community-acquired AKI and hospital-acquired AKI was 2.5 and 9.1%, respectively, giving rise to an overall incidence of 11.6% [6]. AKI is associated with poor clinical outcomes and long-term health and economic consequences; therefore, research about AKI has always been one of the focuses in kidney disease.

Homocysteine (Hcy) is an intermediate product of methionine metabolism. Hyperhomocysteinemia (HHcy), defined as blood Hcy concentration >15 µmol/L, is mainly developed by dysfunction of enzymes and cofactors associated with the biosynthesis and metabolism of Hcy. Other factors such as excessive methionine intake and certain diseases can also induce the development of HHcy [7]. Evidence has demonstrated that HHcy not only has a close relationship with the development of atherosclerosis, congestive heart failure, age-related macular degeneration, Alzheimer’s disease, and cancers, but also plays important roles in the progression of many kidney diseases such as chronic kidney disease (CKD) and diabetic nephropathy (DN) [7]. For instance, in a clinical study performed by Kong et al., the authors found HHcy increases CKD risk in a middle-aged and elderly Chinese population [8]. Xu et al. found serum Hcy was significantly higher in DN patients than simple diabetic patients and concluded that serum Hcy might serve as a biomarker for DN progression [9].

Except for CKD and DN, recent evidence also indicated that HHcy has a close relationship with AKI. For instance, Prathapasinghe and colleagues found that Hcy levels were significantly elevated after ischemia-reperfusion and neutralization of Hcy with anti-Hcy antibodies not only abolished ischemia-reperfusion-induced oxidative stress and cell death, but also transiently restored renal function [10]. In our previous studies, we have demonstrated that HHcy can exacerbate Cisplatin-induced AKI [11] and accelerate AKI to CKD progression by downregulating heme oxygenase-1 expression [12]; however, the relationship between HHcy and AKI, especially ischemia-reperfusion injury (IRI)-induced AKI, is far from clear.

In the present study, we used a high methionine diet (containing 2% methionine) to feed mice for 2 weeks to generate HHcy mice. After that, the IRI-induced AKI model was established to determine whether preexisted HHcy condition can exacerbate IRI-induced AKI through mediating oxidative stress, DNA damage, c-Jun N-terminal kinase (JNK) pathway, and apoptosis.

2 Materials and methods

2.1 Animals experiment

Twenty 6–7 weeks male C57BL/6 mice weighing 18.0–19.2 g were purchased from Liaoning Changsheng Biotechnology Co., Ltd (Benxi, Liaoning, China). Mice were bred and maintained in the Guizhou Medical University (Guiyang, Guizhou, China). All mice were reared under the temperature of 22 ± 2°C with a humidity of 55 ± 2% and a 12/12 h light cycle. After 1 week of habituation, all mice were randomly divided into two groups: the control diet group (n = 10) and the high methionine diet group (H-Met diet, n = 10). Diets were provided ad libitum. Two weeks after grouping, blood was collected through the caudal vein, and serum Hcy level was measured by a Hcy Assay Kit (Ausa, Shenzhen, China) and point-of-care testing device provided by the Shenzhen AoSA Company (Shenzhen, China). After that, the animals of each group were randomly divided into two groups again, including the control group and IRI group (n = 5). Mice in the IRI group were anesthetized with 1.5% pentobarbital sodium (45 mg/kg, i.p.) and placed on a homeothermic station to maintain body temperature at 37.5°C. The kidneys were exposed through bilateral incision and the renal pedicles were clamped for 30 min; the clamps were then released for reperfusion. After surgery, one milliliter of warm saline (37.5°C) was intraperitoneally injected for the purpose of volume supplement. Identical procedures except for clamping of the renal pedicle were done in the mice of the control group. Twenty four hour after reperfusion, blood samples were collected from the eyeball to test serum creatinine and blood urea nitrogen (BUN). Kidney tissues were fixed in 10% neutral-buffered formalin or snap-frozen for later use.

  1. Ethical approval: The research related to animal use has been complied with all the relevant national regulations and institutional policies for the care and use of animals and was approved by the ethics committee of Guizhou Provincial People’s Hospital (ethics approval number: 2017057).

2.2 Evaluation of renal function

Serum creatinine and BUN, determined by creatinine and BUN assay kits purchased from the Bioassay system (USA), were used according to the manufacturer’s instructions to evaluate the renal function of animals.

2.3 Measurement of lipid peroxidation

Snap-frozen tissues were used to determine the lipid peroxidation levels in the kidney by measuring malondialdehyde (MDA). Briefly, 1 mL of kidney homogenate was mixed with 2 mL of trichloroacetic acid–thiobarbituric acid−HCl reagent (15% trichloroacetic acid, 0.67% thiobarbituric acid, and 0.25 N HCl) and boiled at 100°C for 15 min. After cooling, the mixture was centrifuged at 3,000 rpm for 10 min. The supernatant was collected, and the absorbance was measured at 535 nm wavelength. MDA concentration was calculated using a molar absorption coefficient of 1.56 × 105/M cm and expressed as nmol/mg protein [13].

2.4 Histopathological examination of renal tissue

4 μm paraffin-embedded sections were subjected to routine H&E staining for assessment of the histopathological changes of the kidney. The degree of tubular injury was scored according to the previously described method [11]. Briefly, under the light microscope (Leica, Wetzlar, Germany), at least ten fields in the cortex for each mouse were randomly selected to count the number of injured renal tubular including dilation, necrosis, and tubular formation by trained personnel who was blinded to the interventions. After then, a score was given to each mouse based on the percentage of damaged renal tubules to the total renal tubules: 0, less than 5%; 1, 5–25%; 2, 25–50%; 3, 50–75%; 4, over 75%.

2.5 Western blot analysis

Frozen renal cortex was lysed in the cell lysis buffer containing I and II inhibitor cocktails (Sigma, MO) for 20 min on ice. Samples were centrifuged twice, and the supernatants were obtained to measure the total protein concentration by Bradford’s method. The supernatant was then heated to 100°C with loading buffer for 5 min and separated on 8–15% SDS-PAGE gels and transferred onto PVDF membranes (Millipore, USA) following standard protocol. The PVDF membranes were incubated with primary antibodies against cleaved caspase-3 (1:1,000, Cell Signaling Technology, UK), Phospho-JNK (Thr183/Tyr185) (1:1,000, Cell Signaling Technology, UK), JNK (1:1,000, Cell Signaling Technology, UK), γH2AX (1:1,000, Abcam, USA), and GAPDH (1:1,000, Cell Signaling Technology, UK) overnight at 4°C. The membranes were washed by TBST buffer and incubated with secondary antibody for 1 h at room temperature. Target proteins were then visualized using an ECL Plus kit (Amersham, IL, USA) and analyzed using ImageJ software (National Institutes of Health, Bethesda, MD, USA).

2.6 Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay

The paraffin-embedded kidney sections were exposed to the TUNEL reaction mixture (in situ cell death detection kit, POD) according to the manufacturer’s instructions (Roche Diagnostics, Basel, Switzerland) to detect the level of renal tubular epithelial cell apoptosis. The number of apoptotic cells in 10 fields per section and five sections per kidney was counted by identifying cells with TUNEL-positive nuclei under fluorescence microscopy.

2.7 Statistical analysis

Statistical analysis was performed using SPSS19.0 (SPSS, Inc., IL, USA). Data were expressed as mean ± SD and analyzed with independent samples t-test or one-way ANOVA. P < 0.05 was considered statistically significant.

3 Results

3.1 HHcy exacerbates IRI-induced renal dysfunction and oxidative stress

After 2 weeks of diet treatment, the level of serum Hcy in the H-Met diet group was significantly higher than that of the regular diet group (35.01 ± 7.41 vs 9.15 ± 0.68, P < 0.05). Twenty four hour after reperfusion, serum creatinine and BUN levels were significantly higher in IRI mice than that of the control mice under both regular diet and H-Met diet pretreated conditions. Notably, compared with regular diet pretreatment, the H-Met diet didn’t change serum creatinine and BUN levels in control mice, but significantly increased both of them in IRI mice (Figure 1a and b).

Figure 1 HHcy exacerbates IRI-induced renal dysfunction. (a) The level of serum creatinine in mice. (b) The level of blood urea nitrogen (BUN) in mice. Data are expressed as mean ± SD, n = 5. *P < 0.05 vs the control group under same diet; # P < 0.05 vs the IRI group pretreated with regular diet. H-met diet: High methionine diet.
Figure 1

HHcy exacerbates IRI-induced renal dysfunction. (a) The level of serum creatinine in mice. (b) The level of blood urea nitrogen (BUN) in mice. Data are expressed as mean ± SD, n = 5. *P < 0.05 vs the control group under same diet; # P < 0.05 vs the IRI group pretreated with regular diet. H-met diet: High methionine diet.

To determine the influence of HHcy on oxidative stress, the level of MDA (an indicator of lipid peroxidation) was measured. As shown in Figure 2, the MDA level was significantly increased in IRI mice compared with the control mice; particularly, H-Met diet-pretreated IRI mice had the highest MDA level among mice. Our results indicate that preexisted HHcy condition can exacerbate IRI-induced renal dysfunction and oxidative stress.

Figure 2 HHcy exacerbates IRI-induced oxidative stress. Data are expressed as mean ± SD, n = 5. *P < 0.05 vs the control group under same diet. # P < 0.05 vs the IRI group pretreated with regular diet. MDA: Malondialdehyde; H-met diet: High methionine diet.
Figure 2

HHcy exacerbates IRI-induced oxidative stress. Data are expressed as mean ± SD, n = 5. *P < 0.05 vs the control group under same diet. # P < 0.05 vs the IRI group pretreated with regular diet. MDA: Malondialdehyde; H-met diet: High methionine diet.

3.2 HHcy exacerbates IRI-induced tubular injury and DNA damage

Twenty four hours after reperfusion, tubular injuries such as necrosis, dilatation, and cell swelling were observed in IRI mice under both regular diet and H-Met diet pretreated conditions. Notably, the degree of renal tubular injury was significantly severer in the H-Met diet pretreated IRI mice than regular diet pretreated IRI mice (Figure 3a and b), suggesting that preexisted HHcy condition can exacerbate IRI-induced tubular injury.

Figure 3 HHcy exacerbates IRI-induced tubular injury and DNA damage. (a) Representative figures of H&E staining show the tubular injury at 24 h after reperfusion. (b) Quantification assessment of tubular injury on the basis of H&E staining. (c) Representative western blot figures of γH2AX. (d) Graphic representation of relative expression of γH2AX normalized to GADPH. Data are expressed as mean ± SD, n = 5. *P < 0.05 vs the control group under same diet. # P < 0.05 vs the IRI group pretreated with regular diet. H-met diet: High methionine diet.
Figure 3

HHcy exacerbates IRI-induced tubular injury and DNA damage. (a) Representative figures of H&E staining show the tubular injury at 24 h after reperfusion. (b) Quantification assessment of tubular injury on the basis of H&E staining. (c) Representative western blot figures of γH2AX. (d) Graphic representation of relative expression of γH2AX normalized to GADPH. Data are expressed as mean ± SD, n = 5. *P < 0.05 vs the control group under same diet. # P < 0.05 vs the IRI group pretreated with regular diet. H-met diet: High methionine diet.

To determine the HHcy’s influence on the DNA damage, western blot analysis was performed to confirm the expression of γH2AX. As shown in Figure 3c and d, γH2AX was significantly increased in IRI mice, especially in H-Met diet pretreated IRI mice, indicating that preexisted HHcy condition can exacerbate IRI-induced DNA damage.

3.3 HHcy promotes the activation of JNK pathway in IRI-induced AKI mice

To determine the potential influence of HHcy on the JNK pathway, western blot analysis was performed to examine the expression of JNK and p-JNK. As shown in Figure 4a and b, JNK pathway activation manifested as increased expression of p-JNK was noticed in IRI mice, particularly in H-Met diet pretreated IRI mice. Our results suggest that preexisted HHcy condition can promote the activation of the JNK pathway caused by IRI.

Figure 4 HHcy promotes IRI-induced JNK pathway activation. (a) Representative western blot figures of JNK and p-JNK. (b) Graphic representation of the ratio of p-JNK/JNK. Data are expressed as mean ± SD, n = 5. *P < 0.05 vs the control group under same diet. # P < 0.05 vs the IRI group pretreated with regular diet. H-met diet: High methionine diet.
Figure 4

HHcy promotes IRI-induced JNK pathway activation. (a) Representative western blot figures of JNK and p-JNK. (b) Graphic representation of the ratio of p-JNK/JNK. Data are expressed as mean ± SD, n = 5. *P < 0.05 vs the control group under same diet. # P < 0.05 vs the IRI group pretreated with regular diet. H-met diet: High methionine diet.

3.4 HHcy exacerbates IRI-induced renal tubular epithelial cell apoptosis

To determine the potential effect of HHcy on the renal tubular epithelial cell apoptosis, TUNEL assay was performed. As shown in Figure 5a and b, only very few apoptotic cells were detected in control animals under both regular diet and H-Met diet pretreated conditions, while more tubular apoptotic cells were noticed in the H-Met diet pretreated IRI mice than regular diet pretreated IRI mice. Determination of cleaved caspase-3 by western blotting further confirmed that severer apoptosis was existed in the H-Met diet pretreated IRI mice (Figure 5c and d). Our results suggest that preexisted HHcy condition can exacerbate IRI-induced renal tubular epithelial cell apoptosis.

Figure 5 HHcy exacerbates IRI-induced renal tubular epithelial cell apoptosis. (a) Representative immunofluorescence figures show apoptotic cell death detected by TUNEL staining at 24 h after reperfusion. (b) Quantitative determination of apoptotic tubular cells. The number of apoptotic cells was counted in 10 fields per section and five sections per kidney. (c) Representative western blot figures of cleaved caspase-3. (d) Graphic representation of cleaved caspase-3 normalized to GADPH. Data are expressed as the mean ± SD, n = 5. *P < 0.05 vs the control group under same diet. # P < 0.05 vs the IRI group pretreated with regular diet. H-met diet: High methionine diet.
Figure 5

HHcy exacerbates IRI-induced renal tubular epithelial cell apoptosis. (a) Representative immunofluorescence figures show apoptotic cell death detected by TUNEL staining at 24 h after reperfusion. (b) Quantitative determination of apoptotic tubular cells. The number of apoptotic cells was counted in 10 fields per section and five sections per kidney. (c) Representative western blot figures of cleaved caspase-3. (d) Graphic representation of cleaved caspase-3 normalized to GADPH. Data are expressed as the mean ± SD, n = 5. *P < 0.05 vs the control group under same diet. # P < 0.05 vs the IRI group pretreated with regular diet. H-met diet: High methionine diet.

4 Discussion

In the present study, we used high methionine diet to generate HHcy mice; after that, the IRI-induced AKI model was employed to explore the effect and potential mechanisms of HHcy on IRI-induced AKI. Our results showed that the preexisted HHcy condition exerts very little influence on normal mice, but significantly exacerbates the renal damage, characterized by a decline in renal function and increase of tubular injury of IRI-induced AKI mice, which may be related to its potential in mediating oxidative stress, DNA damage, JNK pathway, and apoptosis.

In humans, two metabolism pathways, including remethylation and transsulfuration, are mainly involved in the metabolism of Hcy. It has been reported that up to 70% of plasma Hcy is removed from the kidney, mainly through transsulfuration [14]. Therefore, kidney injury can increase plasma Hcy concentration; in return, increased Hcy may be harmful to the kidney. In a study performed by Ye et al., the authors found that CKD patients with HHcy had higher incidence of renal damage than patients with normohomocysteinemia [15]. Liu and colleagues retrospectively analyzed 7,240 hypertensive patients and found that patients who developed HHcy had a higher long-term rate of renal function decline compared with patients who didn’t develop HHcy [16]. In an animal study, authors found renal dysfunction appeared in cystathionine β-synthase-deficient HHcy mice compared with wild-type mice [17]. In the present study, we noticed that HHcy almost doesn’t influence the renal function and tubular structure of control mice, which was consistent with the observations of Li et al. [18]. We speculate that the detrimental role of Hcy may not appear because of the moderate concentration and short action time of Hcy. While, on the other hand, our results showed that HHcy could exacerbate the renal damage of IRI-induced AKI mice.

Renal tubular epithelial cells account for about 70% of renal parenchymal cells in the kidney and are vulnerable to ischemia, hypoxia, nephrotoxin, and immune inflammation during acute renal injury because of their nature of high oxygen consumption. In the present study, significant renal damage, including tubular epithelial cell apoptosis and necrosis, was noticed in the IRI-induced AKI mice, consistent with previous studies [19,20]. Notably, the renal damage was severer in the H-Met diet pretreated IRI mice than regular diet pretreated IRI mice. To determine the potential mechanisms of this phenomenon, we further focused on the changes of oxidative stress, DNA damage, and the JNK pathway because they are closely related to tubular epithelial cell apoptosis.

As we know, oxidative stress is a well-known hallmark of IRI-induced AKI, which is believed to be one of the critical factors causing kidney injury during ischemia-reperfusion [21]. DNA damage, a deleterious event that occurs in the genome, may be induced under many conditions such as oxidative stress or free radical insult, irradiation, and UV exposure [22]. Increasing evidence indicated that oxidative stress and DNA damage occur in kidney tissues following ischemia-reperfusion [13,20]. In response to DNA damage, several pathways such as NF-κB and JNK pathways may be activated to maintain genome homeostasis [23]. Besides, endoplasmic reticulum stress, induced by oxidative stress, hypoxia, or energy deprivation, also existed in IRI-induced AKI, which can trigger the activation of the JNK pathway [5]. In the present study, our results showed that the expression of MDA, γH2AX, and p-JNK, as well as the number of apoptotic tubular epithelial cells, was significantly higher in the H-Met diet pretreated IRI mice than regular diet pretreated IRI mice. We speculate that HHcy might exhibit its detrimental role in IRI-induced AKI mice by promoting oxidative stress, which causes DNA damage and triggers apoptosis through activation of the JNK pathway. Considering the detrimental role of HHcy, close attention should be paid to it in patients vulnerable to IRI-induced AKI.

However, this study has limitations. The most noticeable one is that this in vivo study is not sufficient to make a definite conclusion. In the future, activation or inhibition experiments focused on oxidative stress, DNA damage, or JNK pathway are warranted to further explore the relationship between HHcy and IRI-induced AKI.

5 Conclusion

Our results demonstrated that preexisted HHcy condition could exacerbate IRI-induced AKI, which may be achieved through promoting oxidative stress, DNA damage, JNK pathway activation, and consequent apoptosis.

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  1. Funding information: This research was funded by grants from the National Natural Science Foundation of China (81760125), the Science & Technology Foundation of Guizhou Province (QKHJC[2016]1087), the Special Fund for Basic Scientific Research Operating of Central Public Welfare Research Institutes, the Chinese Academy of Medical Sciences (2019PT320003), and Guizhou high-level innovative talents program [QKHPTRC(2018)5636].

  2. Conflict of interest: The authors state no conflict of interest.

  3. 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: 2020-11-09
Revised: 2021-04-01
Accepted: 2021-04-22
Published Online: 2021-05-29

© 2021 Mei Zhang et al., published by De Gruyter

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

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  34. lncRNA myocardial infarction-associated transcript (MIAT) knockdown alleviates LPS-induced chondrocytes inflammatory injury via regulating miR-488-3p/sex determining region Y-related HMG-box 11 (SOX11) axis
  35. Identification of circRNA circ-CSPP1 as a potent driver of colorectal cancer by directly targeting the miR-431/LASP1 axis
  36. Hyperhomocysteinemia exacerbates ischemia-reperfusion injury-induced acute kidney injury by mediating oxidative stress, DNA damage, JNK pathway, and apoptosis
  37. Potential prognostic markers and significant lncRNA–mRNA co-expression pairs in laryngeal squamous cell carcinoma
  38. Gamma irradiation-mediated inactivation of enveloped viruses with conservation of genome integrity: Potential application for SARS-CoV-2 inactivated vaccine development
  39. ADHFE1 is a correlative factor of patient survival in cancer
  40. The association of transcription factor Prox1 with the proliferation, migration, and invasion of lung cancer
  41. Is there a relationship between the prevalence of autoimmune thyroid disease and diabetic kidney disease?
  42. Immunoregulatory function of Dictyophora echinovolvata spore polysaccharides in immunocompromised mice induced by cyclophosphamide
  43. T cell epitopes of SARS-CoV-2 spike protein and conserved surface protein of Plasmodium malariae share sequence homology
  44. Anti-obesity effect and mechanism of mesenchymal stem cells influence on obese mice
  45. Long noncoding RNA HULC contributes to paclitaxel resistance in ovarian cancer via miR-137/ITGB8 axis
  46. Glucocorticoids protect HEI-OC1 cells from tunicamycin-induced cell damage via inhibiting endoplasmic reticulum stress
  47. Prognostic value of the neutrophil-to-lymphocyte ratio in acute organophosphorus pesticide poisoning
  48. Gastroprotective effects of diosgenin against HCl/ethanol-induced gastric mucosal injury through suppression of NF-κβ and myeloperoxidase activities
  49. Silencing of LINC00707 suppresses cell proliferation, migration, and invasion of osteosarcoma cells by modulating miR-338-3p/AHSA1 axis
  50. Successful extracorporeal membrane oxygenation resuscitation of patient with cardiogenic shock induced by phaeochromocytoma crisis mimicking hyperthyroidism: A case report
  51. Effects of miR-185-5p on replication of hepatitis C virus
  52. Lidocaine has antitumor effect on hepatocellular carcinoma via the circ_DYNC1H1/miR-520a-3p/USP14 axis
  53. Primary localized cutaneous nodular amyloidosis presenting as lymphatic malformation: A case report
  54. Multimodal magnetic resonance imaging analysis in the characteristics of Wilson’s disease: A case report and literature review
  55. Therapeutic potential of anticoagulant therapy in association with cytokine storm inhibition in severe cases of COVID-19: A case report
  56. Neoadjuvant immunotherapy combined with chemotherapy for locally advanced squamous cell lung carcinoma: A case report and literature review
  57. Rufinamide (RUF) suppresses inflammation and maintains the integrity of the blood–brain barrier during kainic acid-induced brain damage
  58. Inhibition of ADAM10 ameliorates doxorubicin-induced cardiac remodeling by suppressing N-cadherin cleavage
  59. Invasive ductal carcinoma and small lymphocytic lymphoma/chronic lymphocytic leukemia manifesting as a collision breast tumor: A case report and literature review
  60. Clonal diversity of the B cell receptor repertoire in patients with coronary in-stent restenosis and type 2 diabetes
  61. CTLA-4 promotes lymphoma progression through tumor stem cell enrichment and immunosuppression
  62. WDR74 promotes proliferation and metastasis in colorectal cancer cells through regulating the Wnt/β-catenin signaling pathway
  63. Down-regulation of IGHG1 enhances Protoporphyrin IX accumulation and inhibits hemin biosynthesis in colorectal cancer by suppressing the MEK-FECH axis
  64. Curcumin suppresses the progression of gastric cancer by regulating circ_0056618/miR-194-5p axis
  65. Scutellarin-induced A549 cell apoptosis depends on activation of the transforming growth factor-β1/smad2/ROS/caspase-3 pathway
  66. lncRNA NEAT1 regulates CYP1A2 and influences steroid-induced necrosis
  67. A two-microRNA signature predicts the progression of male thyroid cancer
  68. Isolation of microglia from retinas of chronic ocular hypertensive rats
  69. Changes of immune cells in patients with hepatocellular carcinoma treated by radiofrequency ablation and hepatectomy, a pilot study
  70. Calcineurin Aβ gene knockdown inhibits transient outward potassium current ion channel remodeling in hypertrophic ventricular myocyte
  71. Aberrant expression of PI3K/AKT signaling is involved in apoptosis resistance of hepatocellular carcinoma
  72. Clinical significance of activated Wnt/β-catenin signaling in apoptosis inhibition of oral cancer
  73. circ_CHFR regulates ox-LDL-mediated cell proliferation, apoptosis, and EndoMT by miR-15a-5p/EGFR axis in human brain microvessel endothelial cells
  74. Resveratrol pretreatment mitigates LPS-induced acute lung injury by regulating conventional dendritic cells’ maturation and function
  75. Ubiquitin-conjugating enzyme E2T promotes tumor stem cell characteristics and migration of cervical cancer cells by regulating the GRP78/FAK pathway
  76. Carriage of HLA-DRB1*11 and 1*12 alleles and risk factors in patients with breast cancer in Burkina Faso
  77. Protective effect of Lactobacillus-containing probiotics on intestinal mucosa of rats experiencing traumatic hemorrhagic shock
  78. Glucocorticoids induce osteonecrosis of the femoral head through the Hippo signaling pathway
  79. Endothelial cell-derived SSAO can increase MLC20 phosphorylation in VSMCs
  80. Downregulation of STOX1 is a novel prognostic biomarker for glioma patients
  81. miR-378a-3p regulates glioma cell chemosensitivity to cisplatin through IGF1R
  82. The molecular mechanisms underlying arecoline-induced cardiac fibrosis in rats
  83. TGF-β1-overexpressing mesenchymal stem cells reciprocally regulate Th17/Treg cells by regulating the expression of IFN-γ
  84. The influence of MTHFR genetic polymorphisms on methotrexate therapy in pediatric acute lymphoblastic leukemia
  85. Red blood cell distribution width-standard deviation but not red blood cell distribution width-coefficient of variation as a potential index for the diagnosis of iron-deficiency anemia in mid-pregnancy women
  86. Small cell neuroendocrine carcinoma expressing alpha fetoprotein in the endometrium
  87. Superoxide dismutase and the sigma1 receptor as key elements of the antioxidant system in human gastrointestinal tract cancers
  88. Molecular characterization and phylogenetic studies of Echinococcus granulosus and Taenia multiceps coenurus cysts in slaughtered sheep in Saudi Arabia
  89. ITGB5 mutation discovered in a Chinese family with blepharophimosis-ptosis-epicanthus inversus syndrome
  90. ACTB and GAPDH appear at multiple SDS-PAGE positions, thus not suitable as reference genes for determining protein loading in techniques like Western blotting
  91. Facilitation of mouse skin-derived precursor growth and yield by optimizing plating density
  92. 3,4-Dihydroxyphenylethanol ameliorates lipopolysaccharide-induced septic cardiac injury in a murine model
  93. Downregulation of PITX2 inhibits the proliferation and migration of liver cancer cells and induces cell apoptosis
  94. Expression of CDK9 in endometrial cancer tissues and its effect on the proliferation of HEC-1B
  95. Novel predictor of the occurrence of DKA in T1DM patients without infection: A combination of neutrophil/lymphocyte ratio and white blood cells
  96. Investigation of molecular regulation mechanism under the pathophysiology of subarachnoid hemorrhage
  97. miR-25-3p protects renal tubular epithelial cells from apoptosis induced by renal IRI by targeting DKK3
  98. Bioengineering and Biotechnology
  99. Green fabrication of Co and Co3O4 nanoparticles and their biomedical applications: A review
  100. Agriculture
  101. Effects of inorganic and organic selenium sources on the growth performance of broilers in China: A meta-analysis
  102. Crop-livestock integration practices, knowledge, and attitudes among smallholder farmers: Hedging against climate change-induced shocks in semi-arid Zimbabwe
  103. Food Science and Nutrition
  104. Effect of food processing on the antioxidant activity of flavones from Polygonatum odoratum (Mill.) Druce
  105. Vitamin D and iodine status was associated with the risk and complication of type 2 diabetes mellitus in China
  106. Diversity of microbiota in Slovak summer ewes’ cheese “Bryndza”
  107. Comparison between voltammetric detection methods for abalone-flavoring liquid
  108. Composition of low-molecular-weight glutenin subunits in common wheat (Triticum aestivum L.) and their effects on the rheological properties of dough
  109. Application of culture, PCR, and PacBio sequencing for determination of microbial composition of milk from subclinical mastitis dairy cows of smallholder farms
  110. Investigating microplastics and potentially toxic elements contamination in canned Tuna, Salmon, and Sardine fishes from Taif markets, KSA
  111. From bench to bar side: Evaluating the red wine storage lesion
  112. Establishment of an iodine model for prevention of iodine-excess-induced thyroid dysfunction in pregnant women
  113. Plant Sciences
  114. Characterization of GMPP from Dendrobium huoshanense yielding GDP-D-mannose
  115. Comparative analysis of the SPL gene family in five Rosaceae species: Fragaria vesca, Malus domestica, Prunus persica, Rubus occidentalis, and Pyrus pyrifolia
  116. Identification of leaf rust resistance genes Lr34 and Lr46 in common wheat (Triticum aestivum L. ssp. aestivum) lines of different origin using multiplex PCR
  117. Investigation of bioactivities of Taxus chinensis, Taxus cuspidata, and Taxus × media by gas chromatography-mass spectrometry
  118. Morphological structures and histochemistry of roots and shoots in Myricaria laxiflora (Tamaricaceae)
  119. Transcriptome analysis of resistance mechanism to potato wart disease
  120. In silico analysis of glycosyltransferase 2 family genes in duckweed (Spirodela polyrhiza) and its role in salt stress tolerance
  121. Comparative study on growth traits and ions regulation of zoysiagrasses under varied salinity treatments
  122. Role of MS1 homolog Ntms1 gene of tobacco infertility
  123. Biological characteristics and fungicide sensitivity of Pyricularia variabilis
  124. In silico/computational analysis of mevalonate pyrophosphate decarboxylase gene families in Campanulids
  125. Identification of novel drought-responsive miRNA regulatory network of drought stress response in common vetch (Vicia sativa)
  126. How photoautotrophy, photomixotrophy, and ventilation affect the stomata and fluorescence emission of pistachios rootstock?
  127. Apoplastic histochemical features of plant root walls that may facilitate ion uptake and retention
  128. Ecology and Environmental Sciences
  129. The impact of sewage sludge on the fungal communities in the rhizosphere and roots of barley and on barley yield
  130. Domestication of wild animals may provide a springboard for rapid variation of coronavirus
  131. Response of benthic invertebrate assemblages to seasonal and habitat condition in the Wewe River, Ashanti region (Ghana)
  132. Molecular record for the first authentication of Isaria cicadae from Vietnam
  133. Twig biomass allocation of Betula platyphylla in different habitats in Wudalianchi Volcano, northeast China
  134. Animal Sciences
  135. Supplementation of probiotics in water beneficial growth performance, carcass traits, immune function, and antioxidant capacity in broiler chickens
  136. Predators of the giant pine scale, Marchalina hellenica (Gennadius 1883; Hemiptera: Marchalinidae), out of its natural range in Turkey
  137. Honey in wound healing: An updated review
  138. NONMMUT140591.1 may serve as a ceRNA to regulate Gata5 in UT-B knockout-induced cardiac conduction block
  139. Radiotherapy for the treatment of pulmonary hydatidosis in sheep
  140. Retraction
  141. Retraction of “Long non-coding RNA TUG1 knockdown hinders the tumorigenesis of multiple myeloma by regulating microRNA-34a-5p/NOTCH1 signaling pathway”
  142. Special Issue on Reuse of Agro-Industrial By-Products
  143. An effect of positional isomerism of benzoic acid derivatives on antibacterial activity against Escherichia coli
  144. Special Issue on Computing and Artificial Techniques for Life Science Applications - Part II
  145. Relationship of Gensini score with retinal vessel diameter and arteriovenous ratio in senile CHD
  146. Effects of different enantiomers of amlodipine on lipid profiles and vasomotor factors in atherosclerotic rabbits
  147. Establishment of the New Zealand white rabbit animal model of fatty keratopathy associated with corneal neovascularization
  148. lncRNA MALAT1/miR-143 axis is a potential biomarker for in-stent restenosis and is involved in the multiplication of vascular smooth muscle cells
https://doi.org/10.1515/biol-2021-0054
Keywords for this article
hyperhomocysteinemia; ischemia-reperfusion injury; acute kidney injury; oxidative stress; JNK signaling pathway
Creative Commons
BY 4.0

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  34. lncRNA myocardial infarction-associated transcript (MIAT) knockdown alleviates LPS-induced chondrocytes inflammatory injury via regulating miR-488-3p/sex determining region Y-related HMG-box 11 (SOX11) axis
  35. Identification of circRNA circ-CSPP1 as a potent driver of colorectal cancer by directly targeting the miR-431/LASP1 axis
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  40. The association of transcription factor Prox1 with the proliferation, migration, and invasion of lung cancer
  41. Is there a relationship between the prevalence of autoimmune thyroid disease and diabetic kidney disease?
  42. Immunoregulatory function of Dictyophora echinovolvata spore polysaccharides in immunocompromised mice induced by cyclophosphamide
  43. T cell epitopes of SARS-CoV-2 spike protein and conserved surface protein of Plasmodium malariae share sequence homology
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  45. Long noncoding RNA HULC contributes to paclitaxel resistance in ovarian cancer via miR-137/ITGB8 axis
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  49. Silencing of LINC00707 suppresses cell proliferation, migration, and invasion of osteosarcoma cells by modulating miR-338-3p/AHSA1 axis
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  52. Lidocaine has antitumor effect on hepatocellular carcinoma via the circ_DYNC1H1/miR-520a-3p/USP14 axis
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  54. Multimodal magnetic resonance imaging analysis in the characteristics of Wilson’s disease: A case report and literature review
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  62. WDR74 promotes proliferation and metastasis in colorectal cancer cells through regulating the Wnt/β-catenin signaling pathway
  63. Down-regulation of IGHG1 enhances Protoporphyrin IX accumulation and inhibits hemin biosynthesis in colorectal cancer by suppressing the MEK-FECH axis
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  66. lncRNA NEAT1 regulates CYP1A2 and influences steroid-induced necrosis
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  69. Changes of immune cells in patients with hepatocellular carcinoma treated by radiofrequency ablation and hepatectomy, a pilot study
  70. Calcineurin Aβ gene knockdown inhibits transient outward potassium current ion channel remodeling in hypertrophic ventricular myocyte
  71. Aberrant expression of PI3K/AKT signaling is involved in apoptosis resistance of hepatocellular carcinoma
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  76. Carriage of HLA-DRB1*11 and 1*12 alleles and risk factors in patients with breast cancer in Burkina Faso
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  79. Endothelial cell-derived SSAO can increase MLC20 phosphorylation in VSMCs
  80. Downregulation of STOX1 is a novel prognostic biomarker for glioma patients
  81. miR-378a-3p regulates glioma cell chemosensitivity to cisplatin through IGF1R
  82. The molecular mechanisms underlying arecoline-induced cardiac fibrosis in rats
  83. TGF-β1-overexpressing mesenchymal stem cells reciprocally regulate Th17/Treg cells by regulating the expression of IFN-γ
  84. The influence of MTHFR genetic polymorphisms on methotrexate therapy in pediatric acute lymphoblastic leukemia
  85. Red blood cell distribution width-standard deviation but not red blood cell distribution width-coefficient of variation as a potential index for the diagnosis of iron-deficiency anemia in mid-pregnancy women
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  88. Molecular characterization and phylogenetic studies of Echinococcus granulosus and Taenia multiceps coenurus cysts in slaughtered sheep in Saudi Arabia
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  91. Facilitation of mouse skin-derived precursor growth and yield by optimizing plating density
  92. 3,4-Dihydroxyphenylethanol ameliorates lipopolysaccharide-induced septic cardiac injury in a murine model
  93. Downregulation of PITX2 inhibits the proliferation and migration of liver cancer cells and induces cell apoptosis
  94. Expression of CDK9 in endometrial cancer tissues and its effect on the proliferation of HEC-1B
  95. Novel predictor of the occurrence of DKA in T1DM patients without infection: A combination of neutrophil/lymphocyte ratio and white blood cells
  96. Investigation of molecular regulation mechanism under the pathophysiology of subarachnoid hemorrhage
  97. miR-25-3p protects renal tubular epithelial cells from apoptosis induced by renal IRI by targeting DKK3
  98. Bioengineering and Biotechnology
  99. Green fabrication of Co and Co3O4 nanoparticles and their biomedical applications: A review
  100. Agriculture
  101. Effects of inorganic and organic selenium sources on the growth performance of broilers in China: A meta-analysis
  102. Crop-livestock integration practices, knowledge, and attitudes among smallholder farmers: Hedging against climate change-induced shocks in semi-arid Zimbabwe
  103. Food Science and Nutrition
  104. Effect of food processing on the antioxidant activity of flavones from Polygonatum odoratum (Mill.) Druce
  105. Vitamin D and iodine status was associated with the risk and complication of type 2 diabetes mellitus in China
  106. Diversity of microbiota in Slovak summer ewes’ cheese “Bryndza”
  107. Comparison between voltammetric detection methods for abalone-flavoring liquid
  108. Composition of low-molecular-weight glutenin subunits in common wheat (Triticum aestivum L.) and their effects on the rheological properties of dough
  109. Application of culture, PCR, and PacBio sequencing for determination of microbial composition of milk from subclinical mastitis dairy cows of smallholder farms
  110. Investigating microplastics and potentially toxic elements contamination in canned Tuna, Salmon, and Sardine fishes from Taif markets, KSA
  111. From bench to bar side: Evaluating the red wine storage lesion
  112. Establishment of an iodine model for prevention of iodine-excess-induced thyroid dysfunction in pregnant women
  113. Plant Sciences
  114. Characterization of GMPP from Dendrobium huoshanense yielding GDP-D-mannose
  115. Comparative analysis of the SPL gene family in five Rosaceae species: Fragaria vesca, Malus domestica, Prunus persica, Rubus occidentalis, and Pyrus pyrifolia
  116. Identification of leaf rust resistance genes Lr34 and Lr46 in common wheat (Triticum aestivum L. ssp. aestivum) lines of different origin using multiplex PCR
  117. Investigation of bioactivities of Taxus chinensis, Taxus cuspidata, and Taxus × media by gas chromatography-mass spectrometry
  118. Morphological structures and histochemistry of roots and shoots in Myricaria laxiflora (Tamaricaceae)
  119. Transcriptome analysis of resistance mechanism to potato wart disease
  120. In silico analysis of glycosyltransferase 2 family genes in duckweed (Spirodela polyrhiza) and its role in salt stress tolerance
  121. Comparative study on growth traits and ions regulation of zoysiagrasses under varied salinity treatments
  122. Role of MS1 homolog Ntms1 gene of tobacco infertility
  123. Biological characteristics and fungicide sensitivity of Pyricularia variabilis
  124. In silico/computational analysis of mevalonate pyrophosphate decarboxylase gene families in Campanulids
  125. Identification of novel drought-responsive miRNA regulatory network of drought stress response in common vetch (Vicia sativa)
  126. How photoautotrophy, photomixotrophy, and ventilation affect the stomata and fluorescence emission of pistachios rootstock?
  127. Apoplastic histochemical features of plant root walls that may facilitate ion uptake and retention
  128. Ecology and Environmental Sciences
  129. The impact of sewage sludge on the fungal communities in the rhizosphere and roots of barley and on barley yield
  130. Domestication of wild animals may provide a springboard for rapid variation of coronavirus
  131. Response of benthic invertebrate assemblages to seasonal and habitat condition in the Wewe River, Ashanti region (Ghana)
  132. Molecular record for the first authentication of Isaria cicadae from Vietnam
  133. Twig biomass allocation of Betula platyphylla in different habitats in Wudalianchi Volcano, northeast China
  134. Animal Sciences
  135. Supplementation of probiotics in water beneficial growth performance, carcass traits, immune function, and antioxidant capacity in broiler chickens
  136. Predators of the giant pine scale, Marchalina hellenica (Gennadius 1883; Hemiptera: Marchalinidae), out of its natural range in Turkey
  137. Honey in wound healing: An updated review
  138. NONMMUT140591.1 may serve as a ceRNA to regulate Gata5 in UT-B knockout-induced cardiac conduction block
  139. Radiotherapy for the treatment of pulmonary hydatidosis in sheep
  140. Retraction
  141. Retraction of “Long non-coding RNA TUG1 knockdown hinders the tumorigenesis of multiple myeloma by regulating microRNA-34a-5p/NOTCH1 signaling pathway”
  142. Special Issue on Reuse of Agro-Industrial By-Products
  143. An effect of positional isomerism of benzoic acid derivatives on antibacterial activity against Escherichia coli
  144. Special Issue on Computing and Artificial Techniques for Life Science Applications - Part II
  145. Relationship of Gensini score with retinal vessel diameter and arteriovenous ratio in senile CHD
  146. Effects of different enantiomers of amlodipine on lipid profiles and vasomotor factors in atherosclerotic rabbits
  147. Establishment of the New Zealand white rabbit animal model of fatty keratopathy associated with corneal neovascularization
  148. lncRNA MALAT1/miR-143 axis is a potential biomarker for in-stent restenosis and is involved in the multiplication of vascular smooth muscle cells
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