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Hydroxysafflor yellow A improved retinopathy via Nrf2/HO-1 pathway in rats

  • Zhihui Sun , Yuanyuan Wang EMAIL logo , Rui Xu , Shitong Zhang , Hongtao Yang , Jingjing Song and Tao Chang
Published/Copyright: March 24, 2022
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Open Life Sciences
From the journal Open Life Sciences Volume 17 Issue 1

Abstract

The aim of the study was to investigate the inhibitory effect of hydroxysaff yellow A (HSYA) on diabetic retinopathy (DR). For this, a total of 27 rats were randomly divided into normal control, model, and HSYA groups. The body weight, blood glucose, and blood–retinal barrier damage of the rats were observed and compared. The pathological change of retinal tissue were measured using H&E staining. The apoptosis of retinal tissue ganglion cells was detected by TUNEL. The interleukin (IL)-1β and tumor necrosis fator (TNF)-α levels were detected using enzyme-linked immunosorbent assay. The level of malondialdehyde (MDA) was detected using thiobarbituric acid method. Superoxide dismutase levels were detected using xanthine oxidase method; Nrf2 and total HO-1 protein expressions were detected using western blot assay; Bcl-2 and P53 protein expression was measured using immunohistochemical staining. The body weight and retinal damage of the HYSA group were significantly improved (p < 0.01, respectively). The apoptosis index of the HYSA group was lower than the model group (p < 0.001). The IL-1β, TNF-α, and MDA levels of the HYSA group were significantly improved in comparison with those of the model group (p < 0.01, respectively). The Nrf-2, HO-1, Bcl-2, and P53 protein expression of HYSA group was significantly improved (p < 0.001, respectively). In conclusion, HYSA can effectively alleviate the apoptosis of retinal ganglion cells in type 2 diabetic rats and improve the progression of DR.

Keywords: HYSA; Nrf2/HO-1 signaling pathway; diabetes mellitus; retinopathy

1 Introduction

Diabetic retinopathy (DR) is one of the most common microvascular diseases and also an important ocular complication in diabetic patients. The main characteristics of DR include abnormalities in various cellular functions and structures, such as the ganglion cell apoptosis, angiogenic neuroinflammatory injury, and blood–retinal barrier breakdown [1,2]. Patients with DR can experience rapid deterioration of vision, even blindness, which seriously affects the patients’ quality of life and imposes a great burden on the families and society. Currently available treatments for DR include retinal photocoagulation and vitreous surgery, which are only applicable for patients with advanced diseases. Although these approaches block the progression of the disease, a visual impairment that has occurred in patients cannot be reversed. Therefore, an early intervention and treatment in DR patients is of great clinical significance.

Safflower is a dry tubular flower of Carthamus tinctorius L., a plant of the Compositae family. It is a famous herbal medicine commonly used for improving blood circulation, removing blood stasis and treating cardiovascular and thrombotic diseases [3,4]. Hydroxy safflor yellow A (HSYA) is the most important bioactive ingredient of safflower. Pharmacological studies have shown that HSYA has significant cardiovascular and cerebrovascular protective effects owing to its vasodilatation [5], antioxidant [6], and anti-inflammatory activities [7]. HSYA inhibits the lipopolysaccharide- or hypoxia-induced expression of inflammatory factors such as tumor necrosis fator-α (TNF-α) as well as the activity of NF-κB to exert the anti-inflammatory effects [8,9,10]. However, whether HSYA affects DR in the same way remains unclear. On this basis, this study was designed to explore the effect and the underlying mechanism of HSYA on DR in type 2 diabetic rats.

2 Materials and methods

2.1 Materials

2.1.1 Animal models and grouping

Twenty-seven healthy SPF Wistar rats, weighing 300 ± 20 g, were purchased from Junke Biological Co., Ltd (Nanjing, China) and housed at room temperature (RT) (22 ± 2°C) and relative humidity of 60 ± 5% with a light–dark cycle of 12:12 h and free access to drinking water and diet. These rats were randomly divided into the normal control (NC) group (n = 9), the model group (n = 9), and the HYSA group (n = 9). All rats were adaptively fed for 7 days before inducting in the experiments.

  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.

2.1.2 Reagents

Streptozotocin (STZ) (Sigma, USA); HYSA, purity >98% (National Institutes for Food and Drug Control, China); TUNEL Apoptosis Kit (Boster Biological Technology, Wuhan, China); anti-OH-1, B lymphoblastoma-2 (Bcl-2), nuclear factor-erythroid 2-related factor-2 (Nrf2), and P53 antibodies (Abcam, UK); TNF-α and interleukin-1β (IL-1β)) enzyme-linked immunosorbent assay (ELISA) kits (Abcam, USA).

3 Methods

3.1 Modeling and drug administration

All procedures were conducted according to the methods previously described [11,12] along with results from preliminary experiments. To establish type 2 diabetes mellitus (T2DM) models, rats in the model group and the HYSA group were briefly injected with STZ in the left lower abdominal cavity (100 g/L STZ in citrate solution, pH 4.5. Injection dose was 60 mg/kg body weight), and those in the NC group were injected with the same volume of citrate solution. Blood glucose was measured from venous blood from the tails 72 h after STZ injection using a blood glucose meter. If urine glucose level was ≥ ++++, blood glucose >16.5 mmol/L, and volumes of urine and drinking water increased significantly, and T2DM model was successfully established. One week after model establishment, animals in the HYSA group were intraperitoneally injected with 50 mg/kg HSYA daily for 6 weeks (daily dose of HYSA injection in human was converted into a bioequivalent dose for rats and the experimental dosage was determined in preliminary experiments). Rats in the NC group and the model group were intraperitoneally given an equal volume of normal saline per day.

3.2 Blood glucose measurement

At the end of the experiment, the body weight of the rats was recorded. After fasting for 12 h, blood was taken from their tails and blood glucose was determined using an automatic blood glucose analyzer for animals in each group.

3.3 Specimen preparation

At the end of the experiment, after fasting for 12 h, the rats were killed by intraperitoneal injection of 1% pentobarbital sodium (50 mg/kg) and their eyeballs were dissected rapidly. One eyeball was immersed in 4% paraformaldehyde fixed solution for 24 h, and apoptosis was programmed using TUNEL assay, H&E and immunohistochemical (IHC) staining; the other eyeball was rapidly placed at −80°C to measure the levels of IL-1, TNF, and MDA, and superoxide dismutase (SOD) was used for western Blot (WB) assay.

3.4 H&E staining

Retinal tissue was removed and fixed in 4% paraformaldehyde solution. The fixed tissue was embedded in paraffin and then sectioned. After H&E staining, the sections were observed under a microscope and the pathological damage of the retinal tissue was analyzed for animals in each group.

Huang et al. [13] pathological scoring criteria were used to evaluate the pathological score in our study. Six sections were taken from each sample, and five high power visual fields (×400) were taken from each section under a light microscope to score and analyze the pathological changes of retina. The scoring criteria of retinal medical records were normal (0 point); rod cell, and cone cell destruction (1–2 points); outer nuclear layer failure (3–4 points); Kernel layer corruption (5–6 points); and ganglion cell layer destruction (7 points).

3.5 Detection of ganglion cell apoptosis by TUNEL assay

Retinal tissue was removed and fixed in 40 g/L paraformaldehyde solution at 4°C for 24 h. After removal of the anterior segment and vitreous body, the remaining retinal tissue was embedded in paraffin, sectioned, dewaxed with xylene, and rehydrated with ethanol gradients. After washing three times with public broadcasting service (PBS), the tissue sections were placed in protein kinase K solution (1:200 ddH2O) and incubated for 20 min at RT. The sections were washed twice with ddH2O, and TdT plus fluorescein-labeled dUTP reaction solution was added, followed by incubation at 4°C overnight. Around 50 μL blocking solution was added and incubated in a humid box at 37°C for 30 min. After washing with PBS for three times, DAPI was added, and sections were mounted with 20% glycerol buffer (v/v). Each specimen was observed using light microscopy and examined under 9 microscopic fields with a digital camera (AxiocamMRc; Zeiss AG) attached to a microscope (magnification, ×200; Axioskop 2 Plus Zeiss AG) to evaluate apoptosis cell rats (nucleus of apoptotic cells was brown).

3.6 Determination of IL-1β, TNF-α, MDA, and SOD levels in the retinal tissues of animals in each group

A part of the retinal tissue was taken and homogenized. The levels of IL-1β and TNF-α were detected using ELISA and MDA with thiobarbituric acid method, and SOD by xanthine oxidase method for animals in each group.

3.7 Expression of relevant proteins by WB

A part of the retinal tissue was taken and total protein was extracted using lysis buffer. Protein concentration was determined and protein was then subjected to sodium dodecyl sulfate–polyacrylamide gel electrophoresis. The proteins were then transferred to a membrane. After washing three times with PBS, the membrane was incubated with blocking solution containing nonfat dry milk for 1 h. Then the membrane was incubated with anti-Nrf2 or OH-1 antibodies overnight at RT. The following day, the membrane was washed three times with TBS+Tween and incubated with a corresponding secondary antibody for 1 h at RT, followed by washing three times with TBST. Finally, electrochemiluminescence method was used to determine luminescent intensities. The target band was examined using ImageJ software (National Institutes of Health) for gray value analysis.

3.8 Detection of Bcl-2 and P53 protein expression in the retina by IHC staining

Paraffin sections were prepared followed by dewaxing and rehydration to water, microwave antigen retrieval in citric acid pH6.0, hydrogen peroxide blocking, and washing with PBS pH 7.2. Then, primary antibody (diluted at 1:100) was added and incubated, and after washing with PBS, the secondary antibody was added and incubated. Diaminobenzidine color development and subsequent hematoxylin counterstaining were conducted. Sections were then observed under a light microscope and images were taken. IHC positive images were semiquantitatively analyzed using the Imagepro-Plus 7.0 image analysis system (MEDIA CYBERNETICS, USA): retina on the section was chosen using 400× magnification, and the integrated optical density (IOD) of this area was measured. Area of the effective region was selected and measured for statistical analysis, and mean IOD/area or mean density was calculated. Three sections per animal and five fields per section were selected for each animal and their mean value was used for analysis.

3.9 Statistical analysis

All variables analyzed in this study were continuous ones and measurement data were presented as mean ± SD. One-way analysis of variance was used to compare the overall differences among the NC group, the model group, and the HSYA group, and the test for pairwise comparisons. All statistical analyses in this study were performed using SPSS 23.0 software (SPSS Inc., Chicago, Ill., USA) with a significance level of 0.05.

4 Results

4.1 Changes in body weight and blood glucose in animals of each group

Body weight of the rats was decreased and blood glucose was increased in the model group compared with that of the NC group (all p < 0.001), and the body weight was increased and blood glucose was decreased in animals of the HYSA group compared with that of the model group (p < 0.01, respectively, Figure 1).

Figure 1 The body weight and blood glucose of different groups. NC: normal control group; model: DR model group; HYSA: the rats were treated with 30 mg/kg HYSA every day. ***: p < 0.001, compared with the NC group; ##: p < 0.01, compared with the model group.
Figure 1

The body weight and blood glucose of different groups. NC: normal control group; model: DR model group; HYSA: the rats were treated with 30 mg/kg HYSA every day. ***: p < 0.001, compared with the NC group; ##: p < 0.01, compared with the model group.

4.2 Pathological observation of H&E staining in rat retina

In the NC group, 10 intraretinal layers were arranged neatly and the morphology of the retinal cells was normal; in the model group, retinal cells were deranged and the thickness of retina was reduced, with endocapillary proliferation, thickened basement membrane, reduced ganglion cells, and vacuolar degeneration in the nerve fiber layer. The histopathological score was significantly upregulated (p < 0.001, Figure 2), and in the HYSA group, retinal thickness was slightly thinned with no significantly increased capillary basement membrane. When compared with the model group, the histopathological score had significantly improved (p < 0.01, Figure 2). The number of ganglion cells was slightly reduced and slight vacuolar degeneration was seen in the nerve fiber layer. Retinal cells in the inner and outer nuclear layers were arranged neatly, as shown in Figure 2.

Figure 2 The pathological change of different groups in retina by H&E staining (400×). NC: normal control group; model: DR model group; HYSA: the rats were treated with 30 mg/kg HYSA every day. ***: p < 0.001, compared with NC group; ##: p < 0.01, compared to the model group.
Figure 2

The pathological change of different groups in retina by H&E staining (400×). NC: normal control group; model: DR model group; HYSA: the rats were treated with 30 mg/kg HYSA every day. ***: p < 0.001, compared with NC group; ##: p < 0.01, compared to the model group.

4.3 Apoptosis of ganglion cells by TUNEL assay

The apoptosis index of ganglion cells in the model group was significantly increased in comparison with that of the NC group (p < 0.001); and after HYSA treatment, the apoptosis index of ganglion cells in the HYSA group was significantly reduced compared with that of the model group (p < 0.01, Figure 3), indicating that HYSA could effectively improve the damaged retinal ganglion cells induced by DR.

Figure 3 The apoptosis index of different groups in retina by TUNEL assay (400 ×). NC: normal control group; model: DR model group; HYSA: the rats were treated with 30 mg/kg HYSA every day. ***: p < 0.001, compared to the NC group; ##: p < 0.01, compared with model group.
Figure 3

The apoptosis index of different groups in retina by TUNEL assay (400 ×). NC: normal control group; model: DR model group; HYSA: the rats were treated with 30 mg/kg HYSA every day. ***: p < 0.001, compared to the NC group; ##: p < 0.01, compared with model group.

4.4 Comparison of IL-1β, TNF-α, MDA, and SOD levels in retinal tissue of rats between groups

The retinal levels of IL-1β, TNF-α, and MDA were increased and that of SOD was reduced in the model group compared with those of the NC group, with statistically significant differences (p < 0.001, respectively). The retinal levels of IL-1β, TNF-α, and MDA were decreased and that of SOD was increased in the HYSA group compared with those of the model group and the differences were statistically significant (p < 0.01, respectively, Figure 4).

Figure 4 The IL-1β, TNF-α, MDA, and SOD concentrations of different groups. NC: normal control group; model: DR model group; HYSA: the rats were treated with 30 mg/kg HYSA every day. ***: p < 0.001, compared to the NC group; ##: p < 0.01, compared with model group.
Figure 4

The IL-1β, TNF-α, MDA, and SOD concentrations of different groups. NC: normal control group; model: DR model group; HYSA: the rats were treated with 30 mg/kg HYSA every day. ***: p < 0.001, compared to the NC group; ##: p < 0.01, compared with model group.

4.5 Expression of Bcl-2 and P53 proteins in rat retinal tissue

IHC analysis showed that the expression of retinal Bcl-2 protein was significantly decreased and that of P53 was significantly increased in the model group in comparison to those of the NC group (p < 0.001, respectively), and after HYSA treatment, the expression of retinal Bcl-2 protein was significantly increased and that of P53 was significantly decreased in the HYSA group in comparison to those of the model group (p < 0.001, respectively, Figure 5).

Figure 5 The Bcl-2 and P53 protein expressions of different groups by IHC assay (400×). (a) Bcl-2 protein expression of different groups by IHC assay. NC: normal control group; model: DR model group; HYSA: the rats were treated with 30 mg/kg HYSA every day. ***: p < 0.001, compared with the NC group; ##: p < 0.01, compared with the model group. (b) P53 protein expression of different groups by IHC assay. NC: normal control group; model: DR model group; HYSA: the rats were treated with 30 mg/kg HYSA every day. ***: p < 0.001, compared with the NC group; ##: p < 0.01, compared with the model group.
Figure 5

The Bcl-2 and P53 protein expressions of different groups by IHC assay (400×). (a) Bcl-2 protein expression of different groups by IHC assay. NC: normal control group; model: DR model group; HYSA: the rats were treated with 30 mg/kg HYSA every day. ***: p < 0.001, compared with the NC group; ##: p < 0.01, compared with the model group. (b) P53 protein expression of different groups by IHC assay. NC: normal control group; model: DR model group; HYSA: the rats were treated with 30 mg/kg HYSA every day. ***: p < 0.001, compared with the NC group; ##: p < 0.01, compared with the model group.

4.6 Expression of retinal Nrf-2 and HO-1 proteins in rats of each group by WB assay

WB assay showed that compared with the NC group, the expression of retinal Nrf-2 and HO-1 proteins in animals of the model group was significantly increased (p < 0.001, respectively). After HYSA intervention, the expression of retinal Nrf-2 and HO-1 proteins in the HYSA group was significantly increased (p < 0.001, respectively, Figure 6).

Figure 6 The Nrf-2 and HO-1 proteins expressions of different groups by WB assay. NC: normal control group; model: DR model group; HYSA: the rats were treated with 30 mg/kg HYSA every day. ***: p < 0.001, compared to the NC group; ##: p < 0.01, compared with the model group.
Figure 6

The Nrf-2 and HO-1 proteins expressions of different groups by WB assay. NC: normal control group; model: DR model group; HYSA: the rats were treated with 30 mg/kg HYSA every day. ***: p < 0.001, compared to the NC group; ##: p < 0.01, compared with the model group.

5 Discussion

DR is one of the common microvascular complications of diabetes, which may lead to visual loss. DR seriously affects patients’ quality of life and imposes a heavy burden on families. The pathogenesis of DR has not been completely established to date. Studies have reported that the pathogenesis of DR is closely related to diseases including vasculopathy, neuropathy, and inflammation, among which, the inflammatory response and oxidative stress mediated by Nrf-2/HO-1 signaling pathway may play an important role in this process [13]. Nrf-2 is an important transcriptional regulator that promotes the transcription and expression of various antioxidant stress-related protein genes such as catalase, heme oxygenase-1, and glutathione S-transferase to further eliminate a large number of oxidative stress products and inflammatory factors in the body, reducing the inflammatory damage of tissues and organs.

Inflammatory cytokines are the initiating factors for the pathways above. Studies [11,14] have shown that IL-1β, TNF-α, and other inflammatory cytokines are highly expressed in the retina of DR patients, which contributes to the inflammatory response and damage to the blood–retinal barrier and promotes the development of DR. TNF-α, among others, is mainly activated by macrophages or monocytes, and its expression is positively correlated with the destruction of blood–retinal barrier and vascular cell death. Therefore, TNF-α is believed to be the initiator for DR inflammatory response and can be used as an indicator for DR severity. IL-1β plays an important role in the pathogenesis of DR. IL-1β is highly expressed in DR patients to promote the secretion of other inflammatory factors, thereby enhancing the expression of cell adhesion molecules, calcium overload, and apoptotic pathways and the consequent DR development in diabetic patients. In addition, oxidative stress is also involved in the pathological process of DR [15]. MDA and SOD are important indicators of oxidative stress. MDA is a product of lipid peroxidation and is positively correlated with oxidative stress. Studies have shown that the level of MDA, an oxidative stress index, is significantly increased and that of SOD is significantly decreased in diabetic rats, suggesting that diabetic rats are in an oxidative stress state. Therefore, control of the inflammatory response and oxidative stress damage is one of the important approaches to manage DR.

The results of this study showed that compared with the NC group, the levels of retinal IL-1β, TNF-α, and MDA were increased and that of SOD was reduced in the model group, and the expression levels of Nrf2, HO-1, and P53 proteins were increased and that of Bcl-2 was significantly decreased in the model group, suggesting that significant inflammatory response and oxidative stress damage occurred in the retina of DR rats, which may be related to the activation of Nrf-2/HO-1 signaling pathway.

HSYA is the major bioactive component in safflower, and its antioxidant activities have been proven in recent studies [16,17]. Studies of HSYA in DR, however, are rarely reported. The results of this study showed that compared with the NC group, the body weight of the model group was significantly decreased and blood glucose level, retinal histopathology and ganglion cell apoptosis index were significantly increased in the model group; and the expression level of Bcl-2 was significantly decreased and that of P53 was significantly increased in the model group, suggesting that apoptosis of retinal cells in DR rats was significantly increased with proliferative lesions in retina. These results were consistent with the findings previously reported [18]. However, compared with the model group, the blood glucose, retinal histopathology, and ganglion cell apoptosis index of the HYSA group were significantly reduced, and the expression of Bcl-2 level was increased and that of P53 was decreased in the HYSA group, indicating that HYSA could effectively control the blood glucose level, reduce the damage of retinal barrier, and inhibit the apoptosis of retinal ganglion cells.

The Nrf2/HO-1 signaling pathway plays a crucial role in the antioxidative stress response, and nuclear translocation of Nrf2 is the key to HO-1 activation [19]. WB assay was used in this study to confirm whether HYSA induced an antioxidative stress response via the Nrf2/HO-1 pathway, and the results showed that the expression of Nrf2 and HO-1 proteins in the HYSA group was significantly increased compared with that of the model group (p < 0.01), indicating that DR induced retinal tissue damage and HYSA enhanced the expression of HO-1 protein by inducing nuclear translocation of Nrf2 to protect from oxidative damage.

6 Conclusion

HYSA can effectively inhibit the inflammatory response and oxidative stress damage of retinal cells in DR (of T2DM) and protect retinal ganglion cells. The underlying mechanism may be related to the activation of the Nrf-2/HO-1 signaling pathway.

The equal contribution in this study.

  1. Funding information: Authors state no funding involved.

  2. Conflict of interest: 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: 2021-01-18
Revised: 2021-11-10
Accepted: 2022-01-03
Published Online: 2022-03-24

© 2022 Zhihui Sun et al., published by De Gruyter

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

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  36. Association between single-nucleotide polymorphisms of NKX2.5 and congenital heart disease in Chinese population: A meta-analysis
  37. Assessment of the anesthetic effect of modified pentothal sodium solution on Sprague-Dawley rats
  38. Genetic susceptibility to high myopia in Han Chinese population
  39. Potential biomarkers and molecular mechanisms in preeclampsia progression
  40. Silencing circular RNA-friend leukemia virus integration 1 restrained malignancy of CC cells and oxaliplatin resistance by disturbing dyskeratosis congenita 1
  41. Endostar plus pembrolizumab combined with a platinum-based dual chemotherapy regime for advanced pulmonary large-cell neuroendocrine carcinoma as a first-line treatment: A case report
  42. The significance of PAK4 in signaling and clinicopathology: A review
  43. Sorafenib inhibits ovarian cancer cell proliferation and mobility and induces radiosensitivity by targeting the tumor cell epithelial–mesenchymal transition
  44. Characterization of rabbit polyclonal antibody against camel recombinant nanobodies
  45. Active legumain promotes invasion and migration of neuroblastoma by regulating epithelial-mesenchymal transition
  46. Effect of cell receptors in the pathogenesis of osteoarthritis: Current insights
  47. MT-12 inhibits the proliferation of bladder cells in vitro and in vivo by enhancing autophagy through mitochondrial dysfunction
  48. Study of hsa_circRNA_000121 and hsa_circRNA_004183 in papillary thyroid microcarcinoma
  49. BuyangHuanwu Decoction attenuates cerebral vasospasm caused by subarachnoid hemorrhage in rats via PI3K/AKT/eNOS axis
  50. Effects of the interaction of Notch and TLR4 pathways on inflammation and heart function in septic heart
  51. Monosodium iodoacetate-induced subchondral bone microstructure and inflammatory changes in an animal model of osteoarthritis
  52. A rare presentation of type II Abernethy malformation and nephrotic syndrome: Case report and review
  53. Rapid death due to pulmonary epithelioid haemangioendothelioma in several weeks: A case report
  54. Hepatoprotective role of peroxisome proliferator-activated receptor-α in non-cancerous hepatic tissues following transcatheter arterial embolization
  55. Correlation between peripheral blood lymphocyte subpopulations and primary systemic lupus erythematosus
  56. A novel SLC8A1-ALK fusion in lung adenocarcinoma confers sensitivity to alectinib: A case report
  57. β-Hydroxybutyrate upregulates FGF21 expression through inhibition of histone deacetylases in hepatocytes
  58. Identification of metabolic genes for the prediction of prognosis and tumor microenvironment infiltration in early-stage non-small cell lung cancer
  59. BTBD10 inhibits glioma tumorigenesis by downregulating cyclin D1 and p-Akt
  60. Mucormycosis co-infection in COVID-19 patients: An update
  61. Metagenomic next-generation sequencing in diagnosing Pneumocystis jirovecii pneumonia: A case report
  62. Long non-coding RNA HOXB-AS1 is a prognostic marker and promotes hepatocellular carcinoma cells’ proliferation and invasion
  63. Preparation and evaluation of LA-PEG-SPION, a targeted MRI contrast agent for liver cancer
  64. Proteomic analysis of the liver regulating lipid metabolism in Chaohu ducks using two-dimensional electrophoresis
  65. Nasopharyngeal tuberculosis: A case report
  66. Characterization and evaluation of anti-Salmonella enteritidis activity of indigenous probiotic lactobacilli in mice
  67. Aberrant pulmonary immune response of obese mice to periodontal infection
  68. Bacteriospermia – A formidable player in male subfertility
  69. In silico and in vivo analysis of TIPE1 expression in diffuse large B cell lymphoma
  70. Effects of KCa channels on biological behavior of trophoblasts
  71. Interleukin-17A influences the vulnerability rather than the size of established atherosclerotic plaques in apolipoprotein E-deficient mice
  72. Multiple organ failure and death caused by Staphylococcus aureus hip infection: A case report
  73. Prognostic signature related to the immune environment of oral squamous cell carcinoma
  74. Primary and metastatic squamous cell carcinoma of the thyroid gland: Two case reports
  75. Neuroprotective effects of crocin and crocin-loaded niosomes against the paraquat-induced oxidative brain damage in rats
  76. Role of MMP-2 and CD147 in kidney fibrosis
  77. Geometric basis of action potential of skeletal muscle cells and neurons
  78. Babesia microti-induced fulminant sepsis in an immunocompromised host: A case report and the case-specific literature review
  79. Role of cerebellar cortex in associative learning and memory in guinea pigs
  80. Application of metagenomic next-generation sequencing technique for diagnosing a specific case of necrotizing meningoencephalitis caused by human herpesvirus 2
  81. Case report: Quadruple primary malignant neoplasms including esophageal, ureteral, and lung in an elderly male
  82. Long non-coding RNA NEAT1 promotes angiogenesis in hepatoma carcinoma via the miR-125a-5p/VEGF pathway
  83. Osteogenic differentiation of periodontal membrane stem cells in inflammatory environments
  84. Knockdown of SHMT2 enhances the sensitivity of gastric cancer cells to radiotherapy through the Wnt/β-catenin pathway
  85. Continuous renal replacement therapy combined with double filtration plasmapheresis in the treatment of severe lupus complicated by serious bacterial infections in children: A case report
  86. Simultaneous triple primary malignancies, including bladder cancer, lymphoma, and lung cancer, in an elderly male: A case report
  87. Preclinical immunogenicity assessment of a cell-based inactivated whole-virion H5N1 influenza vaccine
  88. One case of iodine-125 therapy – A new minimally invasive treatment of intrahepatic cholangiocarcinoma
  89. S1P promotes corneal trigeminal neuron differentiation and corneal nerve repair via upregulating nerve growth factor expression in a mouse model
  90. Early cancer detection by a targeted methylation assay of circulating tumor DNA in plasma
  91. Calcifying nanoparticles initiate the calcification process of mesenchymal stem cells in vitro through the activation of the TGF-β1/Smad signaling pathway and promote the decay of echinococcosis
  92. Evaluation of prognostic markers in patients infected with SARS-CoV-2
  93. N6-Methyladenosine-related alternative splicing events play a role in bladder cancer
  94. Characterization of the structural, oxidative, and immunological features of testis tissue from Zucker diabetic fatty rats
  95. Effects of glucose and osmotic pressure on the proliferation and cell cycle of human chorionic trophoblast cells
  96. Investigation of genotype diversity of 7,804 norovirus sequences in humans and animals of China
  97. Characteristics and karyotype analysis of a patient with turner syndrome complicated with multiple-site tumors: A case report
  98. Aggravated renal fibrosis is positively associated with the activation of HMGB1-TLR2/4 signaling in STZ-induced diabetic mice
  99. Distribution characteristics of SARS-CoV-2 IgM/IgG in false-positive results detected by chemiluminescent immunoassay
  100. SRPX2 attenuated oxygen–glucose deprivation and reperfusion-induced injury in cardiomyocytes via alleviating endoplasmic reticulum stress-induced apoptosis through targeting PI3K/Akt/mTOR axis
  101. Aquaporin-8 overexpression is involved in vascular structure and function changes in placentas of gestational diabetes mellitus patients
  102. Relationship between CRP gene polymorphisms and ischemic stroke risk: A systematic review and meta-analysis
  103. Effects of growth hormone on lipid metabolism and sexual development in pubertal obese male rats
  104. Cloning and identification of the CTLA-4IgV gene and functional application of vaccine in Xinjiang sheep
  105. Antitumor activity of RUNX3: Upregulation of E-cadherin and downregulation of the epithelial–mesenchymal transition in clear-cell renal cell carcinoma
  106. PHF8 promotes osteogenic differentiation of BMSCs in old rat with osteoporosis by regulating Wnt/β-catenin pathway
  107. A review of the current state of the computer-aided diagnosis (CAD) systems for breast cancer diagnosis
  108. Bilateral dacryoadenitis in adult-onset Still’s disease: A case report
  109. A novel association between Bmi-1 protein expression and the SUVmax obtained by 18F-FDG PET/CT in patients with gastric adenocarcinoma
  110. The role of erythrocytes and erythroid progenitor cells in tumors
  111. Relationship between platelet activation markers and spontaneous abortion: A meta-analysis
  112. Abnormal methylation caused by folic acid deficiency in neural tube defects
  113. Silencing TLR4 using an ultrasound-targeted microbubble destruction-based shRNA system reduces ischemia-induced seizures in hyperglycemic rats
  114. Plant Sciences
  115. Seasonal succession of bacterial communities in cultured Caulerpa lentillifera detected by high-throughput sequencing
  116. Cloning and prokaryotic expression of WRKY48 from Caragana intermedia
  117. Novel Brassica hybrids with different resistance to Leptosphaeria maculans reveal unbalanced rDNA signal patterns
  118. Application of exogenous auxin and gibberellin regulates the bolting of lettuce (Lactuca sativa L.)
  119. Phytoremediation of pollutants from wastewater: A concise review
  120. Genome-wide identification and characterization of NBS-encoding genes in the sweet potato wild ancestor Ipomoea trifida (H.B.K.)
  121. Alleviative effects of magnetic Fe3O4 nanoparticles on the physiological toxicity of 3-nitrophenol to rice (Oryza sativa L.) seedlings
  122. Selection and functional identification of Dof genes expressed in response to nitrogen in Populus simonii × Populus nigra
  123. Study on pecan seed germination influenced by seed endocarp
  124. Identification of active compounds in Ophiopogonis Radix from different geographical origins by UPLC-Q/TOF-MS combined with GC-MS approaches
  125. The entire chloroplast genome sequence of Asparagus cochinchinensis and genetic comparison to Asparagus species
  126. Genome-wide identification of MAPK family genes and their response to abiotic stresses in tea plant (Camellia sinensis)
  127. Selection and validation of reference genes for RT-qPCR analysis of different organs at various development stages in Caragana intermedia
  128. Cloning and expression analysis of SERK1 gene in Diospyros lotus
  129. Integrated metabolomic and transcriptomic profiling revealed coping mechanisms of the edible and medicinal homologous plant Plantago asiatica L. cadmium resistance
  130. A missense variant in NCF1 is associated with susceptibility to unexplained recurrent spontaneous abortion
  131. Assessment of drought tolerance indices in faba bean genotypes under different irrigation regimes
  132. The entire chloroplast genome sequence of Asparagus setaceus (Kunth) Jessop: Genome structure, gene composition, and phylogenetic analysis in Asparagaceae
  133. Food Science
  134. Dietary food additive monosodium glutamate with or without high-lipid diet induces spleen anomaly: A mechanistic approach on rat model
  135. Binge eating disorder during COVID-19
  136. Potential of honey against the onset of autoimmune diabetes and its associated nephropathy, pancreatitis, and retinopathy in type 1 diabetic animal model
  137. FTO gene expression in diet-induced obesity is downregulated by Solanum fruit supplementation
  138. Physical activity enhances fecal lactobacilli in rats chronically drinking sweetened cola beverage
  139. Supercritical CO2 extraction, chemical composition, and antioxidant effects of Coreopsis tinctoria Nutt. oleoresin
  140. Functional constituents of plant-based foods boost immunity against acute and chronic disorders
  141. Effect of selenium and methods of protein extraction on the proteomic profile of Saccharomyces yeast
  142. Microbial diversity of milk ghee in southern Gansu and its effect on the formation of ghee flavor compounds
  143. Ecology and Environmental Sciences
  144. Effects of heavy metals on bacterial community surrounding Bijiashan mining area located in northwest China
  145. Microorganism community composition analysis coupling with 15N tracer experiments reveals the nitrification rate and N2O emissions in low pH soils in Southern China
  146. Genetic diversity and population structure of Cinnamomum balansae Lecomte inferred by microsatellites
  147. Preliminary screening of microplastic contamination in different marine fish species of Taif market, Saudi Arabia
  148. Plant volatile organic compounds attractive to Lygus pratensis
  149. Effects of organic materials on soil bacterial community structure in long-term continuous cropping of tomato in greenhouse
  150. Effects of soil treated fungicide fluopimomide on tomato (Solanum lycopersicum L.) disease control and plant growth
  151. Prevalence of Yersinia pestis among rodents captured in a semi-arid tropical ecosystem of south-western Zimbabwe
  152. Effects of irrigation and nitrogen fertilization on mitigating salt-induced Na+ toxicity and sustaining sea rice growth
  153. Bioengineering and Biotechnology
  154. Poly-l-lysine-caused cell adhesion induces pyroptosis in THP-1 monocytes
  155. Development of alkaline phosphatase-scFv and its use for one-step enzyme-linked immunosorbent assay for His-tagged protein detection
  156. Development and validation of a predictive model for immune-related genes in patients with tongue squamous cell carcinoma
  157. Agriculture
  158. Effects of chemical-based fertilizer replacement with biochar-based fertilizer on albic soil nutrient content and maize yield
  159. Genome-wide identification and expression analysis of CPP-like gene family in Triticum aestivum L. under different hormone and stress conditions
  160. Agronomic and economic performance of mung bean (Vigna radiata L.) varieties in response to rates of blended NPS fertilizer in Kindo Koysha district, Southern Ethiopia
  161. Influence of furrow irrigation regime on the yield and water consumption indicators of winter wheat based on a multi-level fuzzy comprehensive evaluation
  162. Discovery of exercise-related genes and pathway analysis based on comparative genomes of Mongolian originated Abaga and Wushen horse
  163. Lessons from integrated seasonal forecast-crop modelling in Africa: A systematic review
  164. Evolution trend of soil fertility in tobacco-planting area of Chenzhou, Hunan Province, China
  165. Animal Sciences
  166. Morphological and molecular characterization of Tatera indica Hardwicke 1807 (Rodentia: Muridae) from Pothwar, Pakistan
  167. Research on meat quality of Qianhua Mutton Merino sheep and Small-tail Han sheep
  168. SI: A Scientific Memoir
  169. Suggestions on leading an academic research laboratory group
  170. My scientific genealogy and the Toronto ACDC Laboratory, 1988–2022
  171. Erratum
  172. Erratum to “Changes of immune cells in patients with hepatocellular carcinoma treated by radiofrequency ablation and hepatectomy, a pilot study”
  173. Erratum to “A two-microRNA signature predicts the progression of male thyroid cancer”
  174. Retraction
  175. Retraction of “Lidocaine has antitumor effect on hepatocellular carcinoma via the circ_DYNC1H1/miR-520a-3p/USP14 axis”
https://doi.org/10.1515/biol-2022-0030
Keywords for this article
HYSA; Nrf2/HO-1 signaling pathway; diabetes mellitus; retinopathy
Creative Commons
BY 4.0

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  38. Genetic susceptibility to high myopia in Han Chinese population
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  45. Active legumain promotes invasion and migration of neuroblastoma by regulating epithelial-mesenchymal transition
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  47. MT-12 inhibits the proliferation of bladder cells in vitro and in vivo by enhancing autophagy through mitochondrial dysfunction
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  49. BuyangHuanwu Decoction attenuates cerebral vasospasm caused by subarachnoid hemorrhage in rats via PI3K/AKT/eNOS axis
  50. Effects of the interaction of Notch and TLR4 pathways on inflammation and heart function in septic heart
  51. Monosodium iodoacetate-induced subchondral bone microstructure and inflammatory changes in an animal model of osteoarthritis
  52. A rare presentation of type II Abernethy malformation and nephrotic syndrome: Case report and review
  53. Rapid death due to pulmonary epithelioid haemangioendothelioma in several weeks: A case report
  54. Hepatoprotective role of peroxisome proliferator-activated receptor-α in non-cancerous hepatic tissues following transcatheter arterial embolization
  55. Correlation between peripheral blood lymphocyte subpopulations and primary systemic lupus erythematosus
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  57. β-Hydroxybutyrate upregulates FGF21 expression through inhibition of histone deacetylases in hepatocytes
  58. Identification of metabolic genes for the prediction of prognosis and tumor microenvironment infiltration in early-stage non-small cell lung cancer
  59. BTBD10 inhibits glioma tumorigenesis by downregulating cyclin D1 and p-Akt
  60. Mucormycosis co-infection in COVID-19 patients: An update
  61. Metagenomic next-generation sequencing in diagnosing Pneumocystis jirovecii pneumonia: A case report
  62. Long non-coding RNA HOXB-AS1 is a prognostic marker and promotes hepatocellular carcinoma cells’ proliferation and invasion
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  64. Proteomic analysis of the liver regulating lipid metabolism in Chaohu ducks using two-dimensional electrophoresis
  65. Nasopharyngeal tuberculosis: A case report
  66. Characterization and evaluation of anti-Salmonella enteritidis activity of indigenous probiotic lactobacilli in mice
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  68. Bacteriospermia – A formidable player in male subfertility
  69. In silico and in vivo analysis of TIPE1 expression in diffuse large B cell lymphoma
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  71. Interleukin-17A influences the vulnerability rather than the size of established atherosclerotic plaques in apolipoprotein E-deficient mice
  72. Multiple organ failure and death caused by Staphylococcus aureus hip infection: A case report
  73. Prognostic signature related to the immune environment of oral squamous cell carcinoma
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  75. Neuroprotective effects of crocin and crocin-loaded niosomes against the paraquat-induced oxidative brain damage in rats
  76. Role of MMP-2 and CD147 in kidney fibrosis
  77. Geometric basis of action potential of skeletal muscle cells and neurons
  78. Babesia microti-induced fulminant sepsis in an immunocompromised host: A case report and the case-specific literature review
  79. Role of cerebellar cortex in associative learning and memory in guinea pigs
  80. Application of metagenomic next-generation sequencing technique for diagnosing a specific case of necrotizing meningoencephalitis caused by human herpesvirus 2
  81. Case report: Quadruple primary malignant neoplasms including esophageal, ureteral, and lung in an elderly male
  82. Long non-coding RNA NEAT1 promotes angiogenesis in hepatoma carcinoma via the miR-125a-5p/VEGF pathway
  83. Osteogenic differentiation of periodontal membrane stem cells in inflammatory environments
  84. Knockdown of SHMT2 enhances the sensitivity of gastric cancer cells to radiotherapy through the Wnt/β-catenin pathway
  85. Continuous renal replacement therapy combined with double filtration plasmapheresis in the treatment of severe lupus complicated by serious bacterial infections in children: A case report
  86. Simultaneous triple primary malignancies, including bladder cancer, lymphoma, and lung cancer, in an elderly male: A case report
  87. Preclinical immunogenicity assessment of a cell-based inactivated whole-virion H5N1 influenza vaccine
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  89. S1P promotes corneal trigeminal neuron differentiation and corneal nerve repair via upregulating nerve growth factor expression in a mouse model
  90. Early cancer detection by a targeted methylation assay of circulating tumor DNA in plasma
  91. Calcifying nanoparticles initiate the calcification process of mesenchymal stem cells in vitro through the activation of the TGF-β1/Smad signaling pathway and promote the decay of echinococcosis
  92. Evaluation of prognostic markers in patients infected with SARS-CoV-2
  93. N6-Methyladenosine-related alternative splicing events play a role in bladder cancer
  94. Characterization of the structural, oxidative, and immunological features of testis tissue from Zucker diabetic fatty rats
  95. Effects of glucose and osmotic pressure on the proliferation and cell cycle of human chorionic trophoblast cells
  96. Investigation of genotype diversity of 7,804 norovirus sequences in humans and animals of China
  97. Characteristics and karyotype analysis of a patient with turner syndrome complicated with multiple-site tumors: A case report
  98. Aggravated renal fibrosis is positively associated with the activation of HMGB1-TLR2/4 signaling in STZ-induced diabetic mice
  99. Distribution characteristics of SARS-CoV-2 IgM/IgG in false-positive results detected by chemiluminescent immunoassay
  100. SRPX2 attenuated oxygen–glucose deprivation and reperfusion-induced injury in cardiomyocytes via alleviating endoplasmic reticulum stress-induced apoptosis through targeting PI3K/Akt/mTOR axis
  101. Aquaporin-8 overexpression is involved in vascular structure and function changes in placentas of gestational diabetes mellitus patients
  102. Relationship between CRP gene polymorphisms and ischemic stroke risk: A systematic review and meta-analysis
  103. Effects of growth hormone on lipid metabolism and sexual development in pubertal obese male rats
  104. Cloning and identification of the CTLA-4IgV gene and functional application of vaccine in Xinjiang sheep
  105. Antitumor activity of RUNX3: Upregulation of E-cadherin and downregulation of the epithelial–mesenchymal transition in clear-cell renal cell carcinoma
  106. PHF8 promotes osteogenic differentiation of BMSCs in old rat with osteoporosis by regulating Wnt/β-catenin pathway
  107. A review of the current state of the computer-aided diagnosis (CAD) systems for breast cancer diagnosis
  108. Bilateral dacryoadenitis in adult-onset Still’s disease: A case report
  109. A novel association between Bmi-1 protein expression and the SUVmax obtained by 18F-FDG PET/CT in patients with gastric adenocarcinoma
  110. The role of erythrocytes and erythroid progenitor cells in tumors
  111. Relationship between platelet activation markers and spontaneous abortion: A meta-analysis
  112. Abnormal methylation caused by folic acid deficiency in neural tube defects
  113. Silencing TLR4 using an ultrasound-targeted microbubble destruction-based shRNA system reduces ischemia-induced seizures in hyperglycemic rats
  114. Plant Sciences
  115. Seasonal succession of bacterial communities in cultured Caulerpa lentillifera detected by high-throughput sequencing
  116. Cloning and prokaryotic expression of WRKY48 from Caragana intermedia
  117. Novel Brassica hybrids with different resistance to Leptosphaeria maculans reveal unbalanced rDNA signal patterns
  118. Application of exogenous auxin and gibberellin regulates the bolting of lettuce (Lactuca sativa L.)
  119. Phytoremediation of pollutants from wastewater: A concise review
  120. Genome-wide identification and characterization of NBS-encoding genes in the sweet potato wild ancestor Ipomoea trifida (H.B.K.)
  121. Alleviative effects of magnetic Fe3O4 nanoparticles on the physiological toxicity of 3-nitrophenol to rice (Oryza sativa L.) seedlings
  122. Selection and functional identification of Dof genes expressed in response to nitrogen in Populus simonii × Populus nigra
  123. Study on pecan seed germination influenced by seed endocarp
  124. Identification of active compounds in Ophiopogonis Radix from different geographical origins by UPLC-Q/TOF-MS combined with GC-MS approaches
  125. The entire chloroplast genome sequence of Asparagus cochinchinensis and genetic comparison to Asparagus species
  126. Genome-wide identification of MAPK family genes and their response to abiotic stresses in tea plant (Camellia sinensis)
  127. Selection and validation of reference genes for RT-qPCR analysis of different organs at various development stages in Caragana intermedia
  128. Cloning and expression analysis of SERK1 gene in Diospyros lotus
  129. Integrated metabolomic and transcriptomic profiling revealed coping mechanisms of the edible and medicinal homologous plant Plantago asiatica L. cadmium resistance
  130. A missense variant in NCF1 is associated with susceptibility to unexplained recurrent spontaneous abortion
  131. Assessment of drought tolerance indices in faba bean genotypes under different irrigation regimes
  132. The entire chloroplast genome sequence of Asparagus setaceus (Kunth) Jessop: Genome structure, gene composition, and phylogenetic analysis in Asparagaceae
  133. Food Science
  134. Dietary food additive monosodium glutamate with or without high-lipid diet induces spleen anomaly: A mechanistic approach on rat model
  135. Binge eating disorder during COVID-19
  136. Potential of honey against the onset of autoimmune diabetes and its associated nephropathy, pancreatitis, and retinopathy in type 1 diabetic animal model
  137. FTO gene expression in diet-induced obesity is downregulated by Solanum fruit supplementation
  138. Physical activity enhances fecal lactobacilli in rats chronically drinking sweetened cola beverage
  139. Supercritical CO2 extraction, chemical composition, and antioxidant effects of Coreopsis tinctoria Nutt. oleoresin
  140. Functional constituents of plant-based foods boost immunity against acute and chronic disorders
  141. Effect of selenium and methods of protein extraction on the proteomic profile of Saccharomyces yeast
  142. Microbial diversity of milk ghee in southern Gansu and its effect on the formation of ghee flavor compounds
  143. Ecology and Environmental Sciences
  144. Effects of heavy metals on bacterial community surrounding Bijiashan mining area located in northwest China
  145. Microorganism community composition analysis coupling with 15N tracer experiments reveals the nitrification rate and N2O emissions in low pH soils in Southern China
  146. Genetic diversity and population structure of Cinnamomum balansae Lecomte inferred by microsatellites
  147. Preliminary screening of microplastic contamination in different marine fish species of Taif market, Saudi Arabia
  148. Plant volatile organic compounds attractive to Lygus pratensis
  149. Effects of organic materials on soil bacterial community structure in long-term continuous cropping of tomato in greenhouse
  150. Effects of soil treated fungicide fluopimomide on tomato (Solanum lycopersicum L.) disease control and plant growth
  151. Prevalence of Yersinia pestis among rodents captured in a semi-arid tropical ecosystem of south-western Zimbabwe
  152. Effects of irrigation and nitrogen fertilization on mitigating salt-induced Na+ toxicity and sustaining sea rice growth
  153. Bioengineering and Biotechnology
  154. Poly-l-lysine-caused cell adhesion induces pyroptosis in THP-1 monocytes
  155. Development of alkaline phosphatase-scFv and its use for one-step enzyme-linked immunosorbent assay for His-tagged protein detection
  156. Development and validation of a predictive model for immune-related genes in patients with tongue squamous cell carcinoma
  157. Agriculture
  158. Effects of chemical-based fertilizer replacement with biochar-based fertilizer on albic soil nutrient content and maize yield
  159. Genome-wide identification and expression analysis of CPP-like gene family in Triticum aestivum L. under different hormone and stress conditions
  160. Agronomic and economic performance of mung bean (Vigna radiata L.) varieties in response to rates of blended NPS fertilizer in Kindo Koysha district, Southern Ethiopia
  161. Influence of furrow irrigation regime on the yield and water consumption indicators of winter wheat based on a multi-level fuzzy comprehensive evaluation
  162. Discovery of exercise-related genes and pathway analysis based on comparative genomes of Mongolian originated Abaga and Wushen horse
  163. Lessons from integrated seasonal forecast-crop modelling in Africa: A systematic review
  164. Evolution trend of soil fertility in tobacco-planting area of Chenzhou, Hunan Province, China
  165. Animal Sciences
  166. Morphological and molecular characterization of Tatera indica Hardwicke 1807 (Rodentia: Muridae) from Pothwar, Pakistan
  167. Research on meat quality of Qianhua Mutton Merino sheep and Small-tail Han sheep
  168. SI: A Scientific Memoir
  169. Suggestions on leading an academic research laboratory group
  170. My scientific genealogy and the Toronto ACDC Laboratory, 1988–2022
  171. Erratum
  172. Erratum to “Changes of immune cells in patients with hepatocellular carcinoma treated by radiofrequency ablation and hepatectomy, a pilot study”
  173. Erratum to “A two-microRNA signature predicts the progression of male thyroid cancer”
  174. Retraction
  175. Retraction of “Lidocaine has antitumor effect on hepatocellular carcinoma via the circ_DYNC1H1/miR-520a-3p/USP14 axis”
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