Home Life Sciences Association between single-nucleotide polymorphisms of NKX2.5 and congenital heart disease in Chinese population: A meta-analysis
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Association between single-nucleotide polymorphisms of NKX2.5 and congenital heart disease in Chinese population: A meta-analysis

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Published/Copyright: May 12, 2022
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Open Life Sciences
From the journal Open Life Sciences Volume 17 Issue 1

Abstract

NKX2.5 is a transcription factor that plays a key role in cardiovascular growth and development. Several independent studies have been previously conducted to investigate the association between the single-nucleotide polymorphism (SNP) 606G >C (rs3729753) in the coding region of NKX2.5 and congenital heart disease (CHD). However, the results of these studies have been inconsistent. Therefore, the present study aimed to reveal the relationship between NKX2.5 SNP 606G >C and the risk of CHD as possible in the Chinese population through meta-analysis. After retrieving related articles in PubMed, MEDLINE, EMBASE, Web of science, Cochrane, China National Knowledge Infrastructure, Wanfang DATA, and VIP database until August 2021, a total of eight studies were included in the present meta-analysis. The qualified research data were then merged into allele, dominant, recessive, heterozygous, homozygous, and additive models. Overall results of the current meta-analysis showed that 606G >C was not associated with CHD of the Chinese population in any model. In addition, subgroup analysis based on CHD type gave the same negative result. Results of sensitivity analysis showed that there was no significant correlation after the deletion of each study. Furthermore, it was noted that the results were negative and the heterogeneity was not significant. In conclusion, it was evident that NKX2-5 SNP 606G >C may not lead to the risk of CHD in Chinese population.

Keywords: congenital heart disease; NKX2.5 ; SNP; meta-analysis; case–control study
Trial registration: CRD42020185109

1 Introduction

Congenital heart disease (CHD) refers to a severe structural abnormality of the heart or intrathoracic blood vessels that occurs at birth [1]. Common types of CHD include atrial septal defect (ASD), ventricular septal defect (VSD), and patent ductus arteriosus. CHD is one of the most common types of deformities in humans [2] and also among the leading cause of neonatal death [3]. Globally, the incidence of CHD is estimated to be 9.1 per 1,000 live births [4], whereas in China, between 800,000 and 1.2 million children are born with birth defects annually, including about 220,000 cases of CHD [5].

Presently, the diagnosis of congenital fetal abnormalities mainly depends on prenatal ultrasound screening and laboratory tests [6], whereas computed tomography, magnetic resonance imaging, and echocardiography are also common imaging methods used to diagnose CHD [7]. Laboratory methods for prenatal diagnosis include cytogenetics and the biochemical examination of amniotic fluid among others. The gold standard for invasive prenatal diagnosis is classic cytogenetic analysis [8]. With the current advancement of medical technology, the survival rate of patients with CHD has also significantly increased [9]. CHD is a multifactorial disease related to both genetic and environmental factors [10]. Furthermore, the causes of birth defects have also been widely discussed, but have not yet been fully elucidated [11]. By identifying the source of the defect, the defect rate can also be reduced or eliminated [12].

The human homeobox gene NKX2.5 is the earliest discovered gene related to human heart development. It is located at the far end of chromosome 5, the 5q34–q35 region. The human homeobox gene NKX2.5 is abundantly expressed in the human fetal heart, which suggests that it plays a key role in human heart development [13]. It has been reported that deletion of NKX2.5 can cause abnormalities in the morphology of the embryonic heart, growth retardation, and embryo death in mice [14], as well as malformations in Xenopus laevis hearts [15]. Therefore, these findings further confirmed the important role of NKX2.5 in cardiac development.

Several studies have found that the NKX2.5 mutation is associated with a variety of human heart malformations [16,17,18,19,20,21,22,23,24,25]. A total of about 105 NKX2.5 mutations has been discovered that include synonymous mutations, missense mutations, insertion mutations, and deletion mutations. The evaluation of the NKX2.5 mutation can not only provide a basis for early diagnosis of CHD, but also identify the family members who may be at risk of contracting the heart disease [26]. The NKX2.5 single-nucleotide polymorphism (SNP) 63A >G (rs2277923, Glu21Glu) and 606G >C (rs3729753, Leu202Leu) are the two SNPs that have been studied more frequently in CHD.

The latest meta-analysis has found that there was no correlation between the NKX2.5 gene 63A >G (rs2277923, Glu21Glu) polymorphism and CHD susceptibility in Chinese and non-Chinese populations [27]. Furthermore, it has been reported that 606G >C (rs3729753, Leu202Leu) is a synonymous mutation of NKX2.5 and a large number of independent studies have also explored its relationship with CHD. However, the results are still controversial [28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45]. Therefore, the current meta-analysis was conducted because the statistical power of individual research was not enough to better assess the relationship between the NKX2.5 gene 606G >C polymorphism and the risk of Chinese CHD.

2 Methods and materials

2.1 Literature search strategy

The following keywords were used for literature search in the current study: “Homeobox Protein Nkx 2.5,” “Nkx-2.5, Homeobox Protein,” “NK2 Homeobox 5 Protein,” “Homeobox Transcription Factor Csx-Nkx2-5,” “Homeobox Transcription Factor Csx Nkx2 5,” “Homeobox Protein Csx-Nkx2.5,” “Csx-Nkx2.5, Homeobox Protein,” “Homeobox Protein Csx Nkx2.5,” “Cardiac-Specific Homeobox Protein,” “Cardiac Specific Homeobox Protein,” “Homeobox Protein, Cardiac-Specific,” “Transcription Factor Nkx-2.5,” “Nkx-2.5, Transcription Factor,” “Transcription Factor Nkx 2.5,” “Nucleotide Polymorphism, Single,” “Nucleotide Polymorphisms, Single,” “Polymorphisms, Single Nucleotide,” “Single Nucleotide Polymorphisms,” “SNPs,” “Single Nucleotide Polymorphism” to carry out an unlimited search of electronic databases of PubMed, MEDLINE, EMBASE, Web of science, Cochrane, China National Knowledge Infrastructure, Wanfang DATA, and VIP database.

The initial search was conducted on September 1, 2021, and the relevant articles were identified as well as published as of August 31, 2021. The meta-analysis was conducted and the results reported based on the preferred reporting items stated by System Review and Meta-Analysis (PRISMA).

The inclusion criteria for the present study were formulated before the literature search. Therefore, eligible studies met the following conditions: (1) Articles that have been published electronically; (2) Case–control studies of unrelated CHD patients and healthy controls; (3) Evaluation of the correlation between NKX2.5 606G >C polymorphism (rs3729753) and the risk of CHD; (4) Provided sufficient genotype data to calculate odds ratios (ORs), corresponding 95% confidence intervals (CIs) and could be able to establish various genetic models; (5) All texts are available in English or Chinese; (6) Histological or pathological confirmation of non-syndromic CHD; all clinical types, such as ASD and VSD, were included in this meta-analysis. Pedigree studies, case reports, case series, reviews, editorials, the meta-analysis, animal studies, expert opinions, and studies that consider CHD as part of any known genetic disease or multiple congenital abnormalities syndrome were also excluded in the present meta-analysis.

2.2 Data extraction

The two reviewers independently extracted the following information from the included studies: first author, year of publication, country, type of study design, types of CHD, genotype and gene frequency in patients with CHD as well as control group, and whether the NKX2.5 gene polymorphism was in accordance with Hardy–Weinberg equilibrium (HWE) in the control group.

The Newcastle-Ottawa Quality Assessment Scale, which is a classic assessment tool, was used to evaluate the quality of non-randomized studies from the perspectives of selection, comparability, exposure, and evaluate the effectiveness of all case–control studies. Two reviewers (HC and XW) independently performed data extraction and quality evaluation. Furthermore, the reviewer would write to the authors to obtain additional information or original data when necessary.

2.3 Statistical analysis

All data were analyzed using Stata software version 16.0 (Stata Corp LP, TX, USA). The statistical significance of difference was set at P-value <0.05. Furthermore, Chi-square test was used to calculate the P value of the control group HWE. The association between SNP 606G >C and susceptibility to CHD was estimated using combined ORs and 95% CIs under different genetic models. Cochran’s Q statistical test was also conducted to assess heterogeneity between various studies. If the probability value (P-value) was less than 0.1 or I 2 is greater than 50%, the random effect model was employed because of the significant heterogeneity; otherwise, the fixed-effect model was applied. Consequently, the subgroup analysis based on the type of CHD was then performed. Sensitivity analysis was performed to assess the impact of each individual study on the overall estimate, whereas Begg’s and Egger’s tests were finally used to assess potential publication bias.

3 Results

3.1 Literature inclusion

The document retrieval and selection process was as shown in the flow chart in Figure 1. A total of 53 documents were found in the initial search. Furthermore, irrelevant or duplicated articles were excluded after reading the title and abstract, whereas 24 articles were selected for further evaluation. In addition, 16 more publications were excluded after review of the full texts because of the following reasons: Two studies had no 606G >C data, nine studies were conducted among non-Chinese, eight of these studies were unable to provide complete data to build various genetic models and complete allele data were also not obtained in the other five studies based on Chinese population.

Figure 1 Flowchart of this study [46].
Figure 1

Flowchart of this study [46].

Finally, a total of eight studies including four published in English and four in Chinese language (1,361 cases and 2,030 controls) were included in the present meta-analysis. The HWE test of each control group included in the study was consistent with HWE. Among these studies, two studies explored only one type of CHD, three studies explored only ASD and VSD, and all of the studies used the same population as a control group. The remaining studies involved multiple types of CHD, and characteristics of the included studies are shown in Table 1.

Table 1

Characteristics of the included documents

First author Year Country CHD case Control Phenotype
Genotypes Alleles Genotypes Alleles
n GG/GC/CC G/C (%) n GG/GC/CC G/C (%)
Yin, J. 2019 China 98 92/6/0 96.9/3.1 200 189/11/0 97.3/2.7 Multiple
Cao, Y.a 2016 China 107 101/6/0 97.2/2.8 487 465/22/0 97.7/2.3 ASD
Cao, Y.a 2016 China 385 367/18/0 95.3/4.7 487 465/22/0 97.7/2.3 VSD
Zhang, W. 2016 China 120 116/4/0 98.3/1.7 120 117/3/0 98.7/1.3 ASD
Cao, Y. 2015 China 70 68/2/0 98.6/1.4 136 131/5/0 98.2/1.8 Multiple
Tang, J.a 2015 China 50 48/2/0 98/2 50 47/3/0 97/3 VSD
Tang, J.a 2015 China 51 49/2/0 98/2 50 47/3/0 97/3 ASD
Zhaoa 2014 China 40 37/3/0 96.2/3.8 50 45/5/0 95/5 ASD
Zhaoa 2014 China 50 47/3/0 96.9/3.1 50 45/5/0 95/5 VSD
Zhang, W. 2009 China 230 219/11/0 97.6/2.4 130 118/12/0 97/3 Multiple
Liu, X. Y. 2009 China 160 145/15/0 95.3/4.7 200 191/9/0 97.8/2.2 VSD

a: These three studies shared identical control subjects.

3.2 Overall meta-analysis

Combined results of the 606G >C dominant model in the current study are shown in Figure 2. Furthermore, a fixed-effects model was used in the present study because heterogeneity was not significant (P = 0.884). In the heterozygous gene, allele gene, dominant gene, and additive gene models, it was found that NKX2.5 606G >C SNP was not significantly related to the occurrence of CHD. Results of various models are also indicated in Table 2. Furthermore, the recessive gene and homozygous gene models could not be analyzed in the current study because the CC data of 606G >C was zero.

Figure 2 Forest plot on association between NKX2-5 606G >C polymorphism and CHD risk (heterozygous gene model). NKX2.5 606G >C SNP was not significantly related to the occurrence of CHD.
Figure 2

Forest plot on association between NKX2-5 606G >C polymorphism and CHD risk (heterozygous gene model). NKX2.5 606G >C SNP was not significantly related to the occurrence of CHD.

Table 2

Overall analysis results of various models

Model OR 95% CI P I 2 (%)
Heterozygote 1.062 0.772–1.461 0.884 0.0
Allele 1.061 0.774–1.452 0.896 0.0
Dominant 1.062 0.772–1.461 0.884 0.0
Additive 0.941 0.684–1.295 0.884 0.0

3.3 Subgroup analysis

A subgroup analysis of existing data was performed in the present study for the NKX2.5 606G >C polymorphism and CHD risk based on the type of CHD in the study population. In multiple, VSD, and ASD subgroups (Figure 3), the current study failed to find any significant correlation between NKX2.5 606G >C polymorphism and CHD in any of the studied models (Table 3).

Figure 3 The subgroup forest plot on association between NKX2-5 606G >C polymorphism and CHD risk (heterozygous gene model). There is no significant correlation between NKX2.5 606G >C polymorphism and CHD.
Figure 3

The subgroup forest plot on association between NKX2-5 606G >C polymorphism and CHD risk (heterozygous gene model). There is no significant correlation between NKX2.5 606G >C polymorphism and CHD.

Table 3

Subgroup analysis results of various models

Heterozygote Allele
OR CI P I 2 Ph OR CI P I 2 Ph
Multiple 0.886 0.483–1.626 0.696 0.0% 0.859 0.889 0.488–1.618 0.700 0.0% 0.862
ASD 1.043 0.542–2.009 0.899 0.0% 0.861 1.045 0.547–1.994 0.894 0.0% 0.871
VSD 1.190 0.753–1.883 0.323 13.9% 0.323 1.183 0.753–1.859 0.466 11.4% 0.336
Dominant Additive
Multiple 0.886 0.483–1.626 0.696 0.0% 0.859 1.129 0.615–2.072 0.696 0.0% 0.859
ASD 1.043 0.542–2.009 0.899 0.0% 0.861 0.956 0.496–1.841 0.893 0.0% 0.859
VSD 1.190 0.753–1.883 0.323 13.9% 0.323 0.841 0.532–1.331 0.319 14.6% 0.46

3.4 Sensitivity analysis

Although results of the present study showed that there was no significant heterogeneity between studies, a sensitivity analysis was still conducted to assess the impact of each study on the overall estimate. Sensitivity analysis was performed by removing one individual study at each time. For the subgroup 606G >C polymorphism, it was also found that deleting any study did not affect the overall results. Furthermore, relatively robust results were found in the sensitivity analysis of the current study.

3.5 Publication bias

Results of Begg’s and Egger’s tests in the current study which were used to detect publication bias found that there was no publication bias for NKX2.5, 606G >C (Pr > |z| = 0.350) (Figures 4 and 5).

Figure 4 Begg’s funnel plot.
Figure 4

Begg’s funnel plot.

Figure 5 Egger’s publication bias plot.
Figure 5

Egger’s publication bias plot.

4 Discussion

In most societies, the most common deaths are related to heart disease and CHD accounts for a large proportion, especially among infants as well as children [47]. Furthermore, it has been reported that genetic factors play an important role in development of CHD [48]. Prenatal diagnosis is an important means for prevention of CHD [49]. Moreover, accurate genetic counseling and prenatal examination can be provided through genetic diagnosis [50] to reduce the rate of birth defects.

The transcription factors NKX2.5, GATA 4, Myocardin, and Tbx20 play a vital role in both cardiac morphogenesis and differentiation. During development, the expression of NKX2.5 precedes the expression of other known heart-specific genes [51]. It was found that mice with the targeted disruption of the NKX2.5 gene showed cardiac developmental arrest during circulatory stage and died when still in the uterus. Its gene mutation can lead to the key determinant of cardiac morphology – circular morphogenesis does not start [14]. Furthermore, it was reported that mutation of NKX2.5 homeodomain seriously reduced the DNA binding activity, with little or no transcription activation function [52] and hence resulted in ASD, Junctional ASDs, other ventricular septal abnormalities, and mild conduction defects [53]. In embryonic, it was found that neonatal, and adult mice models, progressive and severe cardiac conduction defects as well as heart failure occurred [54,55].

To date, there has not been any functional research on 606G >C polymorphism (Leu202Leu). It locates in exon 2 of NKX2.5 gene. Although this SNP does not change the amino acid sequence and structure of the NKX2.5 domain, several studies have found that this polymorphism has no significant difference between sporadic CHD and healthy controls. However, some studies have also reached the opposite conclusion, which suggests that this polymorphism may cause CHD [28,30]. Notably, it was found that none of the studied articles provided complete genotype and allele numbers and thus it was not included in the study. Furthermore, both were published in 2018 and beyond. Therefore, the current meta-analysis was conducted to resolve the conflict and obtain a more conclusive result. Results of the current study suggested that the NKX2.5 606G >C polymorphism may not be related to the risk of CHD and this finding was in agreement with the results of the previous meta-analysis [56,57,58,59].

Although the results of the current study were consistent with the results of the previous meta-analysis, the results of the current study were more reliable and had some strengths different from other previous studies. First, considering our findings that NKX2.5 606G >C polymorphism was based on more qualified and relatively high-quality studies, the sample size of this analysis was significantly larger than the size in the previous studies (Table 4); second, to the best of our knowledge, the present meta-analysis analyzed six genetic models (heterozygous, allele, dominant, additive, recessive, and homozygous), for the time which gave a broader picture of the NKX2.5 genotype involved, rather than just the role of alleles; third, the current study further confirmed that polymorphism has no obvious relationship with CHD.

Table 4

Characteristics of previous meta-studies

Author Year Case number Control number Result
Wang, Z. 2013 748 630 Negative
Xie, X. 2016 1330 1167 Negative
Chen, L. T. 2018 978 937 Negative
Gonzalez-Castro 2021 890 953 Negative

In previous meta-analyses, scholars also analyzed the association of the other two NKX2.5 SNPs (rs2277923 and rs703752) with CHD, with varied results. The etiology of CHD is complex and is associated with environmental and genetic factors. Different geographic regions, living environments, and dietary structures can lead to differences in the frequency of gene polymorphism distribution and hence genetic susceptibility, whereas the lack of data on environmental effects on genes and gene interactions limits the analysis of interactions. The literature included in each meta-analysis are different and these may have contributed to the inconsistent results.

This study had some limitations: first, the number of studies that studied the relationship between NKX2.5 gene polymorphisms and risk of CHD was limited, especially the number of studies that include genotype and allele results and only some studies the data could be integrated. Second, this meta-analysis was only based on the Chinese population. There was only one non-Chinese study that could provide enough data to establish various genetic models and hence the role of this polymorphism in other ethnic groups could not be known. Third, all the studies included in the present meta-analysis were published in English or Chinese and hence some qualified articles in published in other languages might have been missed out. Fourth, the sample size was relatively small. In addition, all the included studies were in a retrospective study design. Therefore, there is need for other large-scale and well-designed studies to further confirm results of the present study. Fifth, it was impossible to obtain some basic data for comparison, such as the ratio of men to women, and age, among others which prevents further analysis.

5 Conclusion

In conclusion, the current meta-analysis shows that NKX2.5 606G >C polymorphism has no significant correlation with pathogenesis of Chinese CHD. However, considering that the current results are based on a limited number of case–control studies and are limited to studies in Chinese populations, there is need to draw more credible conclusions in a multicenter, larger sample, high-quality case–control study. Furthermore, homeobox transcription factor NKX2.5 is a key regulator of cardiac gene expression, cardiac development, and it is also the most studied cardiac development gene. Therefore, although results of the current meta-analysis were negative, there is need for more research on the role of this gene and its polymorphism in the pathogenesis of CHD.

  1. Funding information: This study was financially supported by Major Scientific and Technological Projects for collaborative prevention and control of birth defects in Hunan Province (2019SK1010).

  2. Author contributions: H.C. wrote the manuscript. H.C. and Xin W. participated in the search strategy development. Xi W. and M.W. assisted in acquisition, analysis, or interpretation of data for the current work. Y.W. and T.L. prepared figures and tables. X.F. contributed to study the concept and design. All authors contributed to critical manuscript revision. The authors applied the FLAE approach for the sequence of authors.

  3. Conflict of interest: Authors state no conflict of interest.

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

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Received: 2021-12-15
Revised: 2022-02-18
Accepted: 2022-03-03
Published Online: 2022-05-12

© 2022 Huan Chen et al., published by De Gruyter

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

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https://doi.org/10.1515/biol-2022-0058
Keywords for this article
congenital heart disease; NKX2.5; SNP; meta-analysis; case–control study
Creative Commons
BY 4.0

Articles in the same Issue

  1. Biomedical Sciences
  2. Effects of direct oral anticoagulants dabigatran and rivaroxaban on the blood coagulation function in rabbits
  3. The mother of all battles: Viruses vs humans. Can humans avoid extinction in 50–100 years?
  4. Knockdown of G1P3 inhibits cell proliferation and enhances the cytotoxicity of dexamethasone in acute lymphoblastic leukemia
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  6. Association study of CLDN14 variations in patients with kidney stones
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  8. Regulation of miR-30b in cancer development, apoptosis, and drug resistance
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  16. Effect of dietary pattern on pregnant women with gestational diabetes mellitus and its clinical significance
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  20. Nutrition intervention in the management of novel coronavirus pneumonia patients
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  22. Bmi-1 directly upregulates glucose transporter 1 in human gastric adenocarcinoma
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  24. Hydroxysafflor yellow A improved retinopathy via Nrf2/HO-1 pathway in rats
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  34. Expression of Zeb1 in the differentiation of mouse embryonic stem cell
  35. Study on the genetic damage caused by cadmium sulfide quantum dots in human lymphocytes
  36. Association between single-nucleotide polymorphisms of NKX2.5 and congenital heart disease in Chinese population: A meta-analysis
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  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”
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