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Identification of Key Candidate Genes and Pathways in Preterm Birth by Integrated Bioinformatical Analysis

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Identification of Key Candidate Genes and Pathways in Preterm Birth by Integrated Bioinformatical Analysis

  • Wen-Fei Zheng 1
  • Pingping Peng 1
  • Xiaoqing Yuan 1
  • Jufang Qin 1
  • Chenghong Xie 1
  • Aihua Chen 1*

*Corresponding Author: Aihua Chen,Department of Gynecology and Obstetrics, The People’s Hospital of China Three Gorges University/ The First People’s Hospital of Yichang, Hubei 443000, China

Citation: Wen-Fei Zheng, Pingping Peng, Xiaoqing Yuan , Jufang Qin , Chenghong Xie, Aihua Chen.(2021) Identification of Key Candidate Genes and Pathways in Preterm Birth by Integrated Bioinformatical Analysis J.Women Health Care and Issues 4 (2); DOI: 10.31579/2642-9756/046

Copyright: ©2021 Aihua Chen, This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: 11 March 2021 | Accepted: 04 April 2021 | Published: 09 April 2021

Keywords: preterm birth; differentially expressed genes; bioinformatics analysis

Abstract

Background: Preterm birth（PTB） is a primary cause of neonatal morbidity and mortality, the pathogenic mechanisms of PTB still remain largely unexplored. In the present study, we aimed to identify potential key genes and pathway associated with PTB by bioinformatics analysis.
Methods: The GSE46510 dataset was obtained from GEO database. Differentially expressed genes (DEGs) were identified using the limma package in R software, the functional enrichment analysis was performed, and the protein-protein interaction (PPI) network was constructed by Cytoscape software. The network topology was analyzed using MCODE.
Results: A total of 335 DEGs were identified from the dataset. The majority of up-regulated DEGs were significantly enriched in inflammatory response, while down-regulated DEGs were mainly enriched in mitotic nuclear division. The top 5 hub up regulated genes were ITGAM, IL1B, ITGAX, NFKB1, and SOCS3. Pathway analysis indicated enrichment in Cytokine-cytokine receptor interaction, signaling by Interleukins. The top 5 hub down regulated genes were CXCR4, ANAPC10, ANAPC4, UBE2V2, UBA3, Pathway analysis indicated enrichment in Ubiquitin mediated proteolysis, Phosphorylation of the APC/C.
Conclusion: Our study indicated genes and pathways in PTB by bioinformatics analysis, which may provide novel insights for unraveling pathogenesis of PTB. 
Running title: Genes and Pathways in Preterm Birth

Introduction

As one of the most common and serious complications of pregnancy, preterm birth (PTB) is defined as delivery before 37 weeks of gestation [1]. Every year, about 15 million babies are born before 37 weeks’ gestation worldwide, and such number is still increasing, with rates varying from 5% to 18% [2]. PTB is a primary cause of neonatal morbidity and mortality, causing some serious complications. In addition, PTB may lead to increased risk of adult-onset chronic diseases, placing a heavy burden on families and society [2, 3].
In the past few decades, important advances and efforts have been made in research on pregnancy and PTB. For example, the initiation of PTB is closely related to the change of inflammatory medium and its signaling pathway, such as IL-6, IL-8 and TNF-α [4,6]. Cell-free fetal DNA (cffDNA) can engage TLR-9 and induce an inflammatory response, and individuals with  high concentrations  of cffDNA are associated with increased risk for spontaneous PTB (sPTB) [7, 8] The pathogenic mechanisms of PTB still remain largely unexplored. Therefore, it is urgently necessary to identify potential target genes associated with PTB in order to prevent and predict PTB.
In the present study, we aimed to identify potential genes and miRNAs associated with PTB, and explore the underlying mechanisms in the PTB development based on the GSE46510 dataset from the Gene Expression Omnibus (GEO) database [9]. Moreover, we assessed the gene expression profiles to identify differentially expressed genes (DEGs) of individuals with an sPTB within 48 h of admission. Furthermore, functional analysis was performed, and a protein-protein interaction (PPI) network was constructed. In addition, the target miRNAs for DEGs were identified accordingly.

Material and Methods
Microarray Data
The gene expression dataset of GSE46510 was obtained from GEO (http://www.ncbi.nlm.nih.gov/geo/) database, which was analyzed using Affymetrix Human Genome U133 plus 2.0 Array. There were 154 samples, which were divided into two groups as follows: women who did (n = 48) and did not have a sPTB (n = 106) within 48 h of admission. Peripheral blood was collected at hospital admission from 154 women with threatened preterm labor (TPTL) before any medical treatment.
Data Processing and Screening of Degs
The original data in CEL format were processed into expression values by the robust multi-array average (RMA) method through the Affy [10] in R software(version 1.52.0; http://bioconductor.org/packages/release/bioc/html/affy.html) . Secondly, the probe level data were transformed by R/Bioconductor platform notes package.
Identification of Degs
DEGswereidentified by Bayes methods using the limma package [11] version 3.30.3 in R software. The cut-off criteria were adjusted as P<0>1
Functional and Pathway Enrichment Analyses
The Database for Annotation, Visualization and Integrated Discovery (DAVID, version 6.8, https://david.ncifcrf.gov) provides a comprehensive set of functional annotation tools for investigators to understand biological meaning behind a large list of genes [12], including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of up-regulated and down-regulated DEGs. GO enrichment analysis, consisting of biological processes (BP), cell component (CC) and molecular function (MF), was performed by DAVID. Pathway enrichment analysis for screening of DEGs with DAVID, Reactome(Available online: http://www.reactome.org) .The cut-off criteria of GO terms and KEGG pathways enriched with DEGs were P<0>
Ppi Network Construction
The PPI network was constructed with all DEGs using an online database: STRING (version 10.5, https://string-db.org) [13]. PPI links with a combined score >0.4 were identified for constructing the PPI network. PPI network was constructed with Cytoscape software (version 3.6.0, http://cytoscape.org/) [14], and hub genes were ranked by MCODE.
Ethics
All analyses were based on the data from public database, so ethics approval and patient consent were not required.
 

Results

Identification of Degs
After integrated bioinformatical analysis, out of a collection of 19009 Genes from patients indicated dysregulation of 2% (157 up-regulated and 178 down-regulated transcripts), 37DEGs were excluded due to duplication and low expression level (Figure 1).

Figure 1:   Brief microarray results of genes

Expression levels of 19009 genes were assessed in 154 samples. Compared with women not delivered within 48h of hospital admission, 372 genes (2%) had significant changes in expression levels (fold change>1, p<0>
Hierarchical clustering revealed the DEGs expression in blood women delivered within 48h of hospital admission and not delivered samples (Figure 2).

Figure 2:   Heat Maps: Differentially expressed genes for women not delivered within 48h of hospital admission and delivered within 48h of hospital admission were hierarchically clustered. “Red” indicates high relative expression, and “green” indicates low relative expression.
 

Degs Gene Ontology and Signaling Pathway Enrichment Analysis in Preterm Birth
To investigate underlying biological associations, DEGs gene ontology analysis (GO) were performed with DAVID. As shown in Figure 3 and Table 1, in the biological process group, up-regulated genes mainly enriched in inflammatory response, myeloid dendritic cell differentiation, apoptotic process, cell adhesion, regulation of cell proliferation；Down-regulated genes mainly enriched in mitotic nuclear division, cellular response to DNA damage stimulus, cell division, regulation of cell cycle.

Figure 3:  Gene Ontology analysis and significant enriched GO terms of DEGs in preterm birth. GO analysis classified the DEGs into 3 groups (molecular function, biological process and cellular component)
 
Table 1: GO analysis of differentially expressed genes in preterm birth (P<0>
 

In the cellular component group, up-regulated genes mainly enriched in extracellular exosome, membrane, endosome, early endosome, lipid particle; Down-regulated genes mainly enriched in nucleus, nucleoplasm, nucleolus, nuclear heterochromatin, NatA complex. In the molecular function group, up-regulated genes mainly enriched in protease binding, protein binding, ATP binding, transcription factor activity, RNA polymerase II core promoter proximal region sequence-specific binding, transferase activity, transferring glycosyl groups; Down-regulated genes mainly enriched in protein binding, RNA binding, voltage-gated cation channel activity ,Rab geranylgeranyl transferase activity, nucleic acid binding. These results showed that most of the DEGs were significantly enriched in cell cycle, nucleus, protein binding. Signaling Pathway Analysis showed both up-regulated and down-regulated DEGs were mainly enriched in Immune System, Interleukins signaling pathway and Chemokine signaling pathway (Figure 4 and table 2).

Figure 4:  Significantly enriched pathway terms of DEGs in preterm borth. DEGs functional And signaling pathway enrichment were conducted using online websites of KEGG PATHWAY，Reactomen(“Red” indicates high relative expression, and “green” indicates low relative expression).
 
Table 2: Signaling pathway enrichment analysis of differentially expressed genes function in preterm birth (P<0>
 

Ppi Network Analysis and Pathway of Hub Genes
Using String database and cytoscape software, a  total of 251 genes were filtered into PPI network, contained 251 nodes and 510 protein pairs with a PPI score of >0.4 ，as shown in (Figure 5).

Figure 5: DEGs protein–protein interaction (PIP) network complex analysis. Using the STRING online database, total of 251 DEGs (Red standing for upregulation and Blue standing for downregulation) were filtered into the DEGs PPI network complex.
 

In the PPI network, nodes stand for DEGs, while edges represent interactions between two proteins. Using MCODE plug, 36 central node genes were identified with the filtering of degree cutoff ≥2（Figure 6.

Figure 6: DEGs protein–protein interaction (PIP) network complex analysis modular analysis (36 central node genes were identified with the filtering of degree cutoff ≥2).
 

The most significant 10 (top 5 up-regulated and 5 down-regulated) node degree genes were CXCR4, ANAPC10, ANAPC4, UBE2V2, UBA3, ITGAM, IL1B, ITGAX, NFKB1, SOCS3 (Table 3).

 Table 3: Top 5 up-regulated and down-regulated nodes of the protein‑protein interaction network by MCODE
 

Further analysis showed that up-regulated hub genes were mainly associated with Immune System, Signaling by Interleukins, Chemokine signaling pathway, down-regulated hub genes were mainly associated with Ubiquitin mediated proteolysis, Class I MHC mediated antigen processing & presentation and Phosphorylation of the APC/C (Fig7 A, B and table 4).

Figure 7A: Significantly enriched pathway terms of up-regulated DEGs in preterm borth(Orange standing for KEGG Pathway and Blue standing for Reactomen Pathway)
 
Figure 7B: Significantly enriched pathway terms of down-regulated DEGs in preterm borth(Orange standing for KEGG Pathway and Blue standing for Reactomen Pathway)
 
Table 4: Signaling pathway enrichment analysis of hub expressed genes function in preterm birth (P<0>

Discussion

These several decades, a lots of work has been done about preterm birth and recent prematurity rates seem to be on the decline is considered [15]. The prevention of preterm birth is a public health priority because of the potential to reduce infant and childhood morbidity and mortality related to this condition [16]. We need to recognize that PTB is caused by multiple factors, such as microbial-induced inflammation, decidual hemorrhage and vascular disease, disruption of maternal-fetal tolerance, decline in progesterone action, cell-free fetal DNA and so on [17]. It is critically important to understand the molecular mechanism of these factors.
In the current study, the dataset (GSE46510) were downloaded from GEO database to identify DEGs between sPTB and not sPTB samples using bioinformatics analysis. A total of 335 DEGs, including 157 up- and 178 down-regulated DEGs, were identified. These differentially expressed genes were classified into three groups by GO terms using online website (DAVID).  Functional and signaling pathway enrichment were conducted using DAVID and Reactomen, both of up and down regulated genes were mostly enriched in Immune System and Interleukin- signaling. After that, protein–protein interaction (PPI) network complex was developed using String and Cytoscape, 180 nodes/DEGs were identified with 518 edges, the most significant module was filtered using MCODE plug, 36 central node genes were identified and most of the corresponding genes were associated with Immune System, Signaling by Interleukins, Ubiquitin mediated proteolysis.
Through integrated bioinformatical analysis, we have identified 36 hub genes, ITGAM, IL1β， ITGAX, NFKB1, SOCS3 ,CXCR4, ANAPC10, ANAPC4, UBE2V2, UBA3, were listed at the top of the most changed genes, and their biological functions are involved in cell adhesion, inflammatory response and proteasome-mediated ubiquitin-dependent protein catabolic process. ITGAM and ITGAX encode the integrin alpha M and X chain, respectively. ITAGM and ITGAX also known as CD11B and CD11c, they play an important role in the adherence of neutrophils and monocytes to stimulated endothelium cells, and in the phagocytosis of complement coated particles. Gervasi et al [18] showed that preterm labour was associated with a significant increase in the expression of CD11b, CD15 and CD66b on neutrophils and CD11b and CD15 on monocytes, CD11a and b mediate binding to ICAM-1, which was up-regulated in endothelium of human cervix and myometrium during labour [19]. Once leukocytes emigrate to the myometrium and cervix, chemotaxis of more neutrophils and monocytes is mediated by their own increased expression of IL-8 and MCP-1, respectively [20]. Pro-inflammatory cytokines (such as IL-1, IL-6, IL-8 and TNF-α) can directly trigger the transition from a uterine quiescent state to a subsequent unscheduled activation of the uterus [21,23].
During labor, the IL1β level is increased due to the influx of leukocytes into intrauterine tissues, which can enhance the contractile potential of myometrial smooth muscle[24 ,25].In addition, it has been demonstrated that IL-1βcan increase prostaglandin production and MMP9 expression via NF-kappa B signaling pathway [26 ,27], which are known to induce cervical ripening and myometrial contractions[28 29]. There is higher expression of the subunit of NF-κB in membranes, cervix and myometrium [30,31]. NF-κB can be activated by pro- inflammatory cytokines such as TNF and IL1β, and microbial or viral components that activate toll-like receptors (TLRs) [32].
Suppressor of cytokine signaling 3 (SOCS3) is a member of SOCS family, induced by various cytokines, including IL6, IL10, and interferon (IFN)-gamma [33]. Inflammatory mediators might enter the circulation and activate placental macrophages, leading to IL-1βrelease and subsequent SOCS activation as a feedback/response mechanism , play a role in the interaction of endothelial cells of the villous placenta with neighboring cells, participate in  Placental inflammation [34].
Activation of NF-κB involves the phosphorylation of the NFKBIA protein, NFKBIA will be ubiquitinated and subsequently degraded by proteasomes [32]. Ubiquitin like modifier activating enzyme 3(UBA3) encodes a member of the E1 ubiquitin-activating enzyme family, regulates cell division, signaling and embryogenesis. Ubiquitin-conjugating enzyme E2 variant proteins (UBE2V2), is a distinct subfamily within the E2 protein family, the protein encoded by this gene shares homology with ubiquitin-conjugating enzyme E2 variant 1. Both genes are down-regulated in premature births, and they may play a role in influencing NFKB pathway by reducing ubiquitination.
The anaphase-promoting complex (APC/C) is a multimeric RING E3 ubiquitin ligase, which is composed with many different subunits (APC1-8, APC9-11, and CDC26) and plays a crucial role in coordinating mitosis progression through targeting numerous regulators for destruction by the 26S proteasome[35, 36]. It helps during ubiquitination of free polyubiquitin chain that leads to MAP3K7 activation that in turn, leads to the activation of NFκB via its  respective activation pathways [37]. Anaphase promoting complex subunit 4(ANAPC4/APC4) and 10(ANAPC10/APC10), are subunit of the anaphase-promoting complex (APC), APC10 is the core subunit, plays a critical role in facilitating the activity of the APC to function as an E3 protein ubiquitin ligase [38].In the present study, ANAPC10, ANAPC4, UBE2V2, UBA3 down-regulated expression, play a role in preterm by influencing ubiquitination and proteasome degradation.
Cytokines are the major inducible products of immune system cells. CXCR4 encodes a CXC chemokine receptor specific for stromal cell-derived factor-1. CXCR4 is activated by NFKB, regulates decidual leukocyte recruitment during labor [39 ,40]. Study confirmed that CXCR4 was up regulated in labor and is related to inflammatory response[41], it is contrary to the results of this study. In this study, CXCR4 was down regulated. This is an interesting thing, more research is needed in the future.

There are several limitations in our analysis. First, all the predicted results need to be confirmed by experimental data. Second, there are fewer  samples of PTB. Third, we only chose genes, while transcription regulator (TF) and miRNA were not predicted. In future studies, large-scale samples are required to validate the expressions of above-mentioned DEGs. Moreover, future investigations should focus on the interactions of DEGs, regulatory associations between TFs, miRNAs and DEGs, and possible pathways underlying these gene alterations.
 

Conclusions

Using bioinformatical analysis, we have identified commonly changed 335 DEGs (including 157 up- and 178 down-regulated DEGs), and finally found 10 mostly changed hub genes, which significant enriched in several pathways, mainly associated with inflammatory response, ubiquitination and proteasome degradation. These findings significantly improve the understanding of the cause and underlying molecular events in preterm birth, and the candidate genes and pathways could be used as therapeutic targets.
Conflicts Of Interest
The author(s) declare(s) that they have no conflicts of interest related to the subject matter or materials discussed in this article
Funding
No

Abbreviations:
PTB: preterm birth

PPI: protein-protein interaction

DEG: Differentially expressed genes

IL-6: interleukin 6

IL-8: interleukin 8

TNF-α: tumour necrosis factor alpha-like 

 IL1B: interleukin 1 beta

TLR-9: toll-like receptors 9

GEO: Gene Expression Omnibus

GO: Gene Ontology

KEGG:  Kyoto Encyclopedia of Genes and Genomes

CXCR4: C-X-C motif chemokine receptor 4

ANAPC10: Anaphase promoting complex subunit 10

ANAPC4: Anaphase promoting complex subunit 4

UBE2V2: Ubiquitin-conjugating enzyme E2 variant proteins

 UBA3: Ubiquitin like modifier activating enzyme 3

ITGAM: integrin subunit alpha M

ITGAX: integrin subunit alpha X

NFKB1: nuclear factor kappa B subunit 1

SOCS3: Suppressor of cytokine signaling 3

APC: anaphase-promoting complex

TF: transcription regulator

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We would like to thank the Journal of Thoracic Disease and Cardiothoracic Surgery because of the services they provided us for our articles. The peer-review process was done in a very excellent time manner, and the opinions of the reviewers helped us to improve our manuscript further. The editorial office had an outstanding correspondence with us and guided us in many ways. During a hard time of the pandemic that is affecting every one of us tremendously, the editorial office helped us make everything easier for publishing scientific work. Hope for a more scientific relationship with your Journal.

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Layla Shojaie

The peer-review process which consisted high quality queries on the paper. I did answer six reviewers’ questions and comments before the paper was accepted. The support from the editorial office is excellent.

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Sing-yung Wu

Journal of Neuroscience and Neurological Surgery. I had the experience of publishing a research article recently. The whole process was simple from submission to publication. The reviewers made specific and valuable recommendations and corrections that improved the quality of my publication. I strongly recommend this Journal.

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Orlando Villarreal

Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.

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Katarzyna Byczkowska

Thank you most sincerely, with regard to the support you have given in relation to the reviewing process and the processing of my article entitled "Large Cell Neuroendocrine Carcinoma of The Prostate Gland: A Review and Update" for publication in your esteemed Journal, Journal of Cancer Research and Cellular Therapeutics". The editorial team has been very supportive.

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Anthony Kodzo-Grey Venyo

Testimony of Journal of Clinical Otorhinolaryngology: work with your Reviews has been a educational and constructive experience. The editorial office were very helpful and supportive. It was a pleasure to contribute to your Journal.

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Pedro Marques Gomes

Dr. Bernard Terkimbi Utoo, I am happy to publish my scientific work in Journal of Women Health Care and Issues (JWHCI). The manuscript submission was seamless and peer review process was top notch. I was amazed that 4 reviewers worked on the manuscript which made it a highly technical, standard and excellent quality paper. I appreciate the format and consideration for the APC as well as the speed of publication. It is my pleasure to continue with this scientific relationship with the esteem JWHCI.

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Bernard Terkimbi Utoo

This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.

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Prof Sherif W Mansour

Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.

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Hao Jiang

As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.

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Dr Shiming Tang

Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.

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Raed Mualem

International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.

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Andreas Filippaios

Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.

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Dr Suramya Dhamija

Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.

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Bruno Chauffert

I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!

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Baheci Selen

"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".

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Jesus Simal-Gandara

I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.

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Douglas Miyazaki

We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.

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Dr Griffith

I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.

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Dr Tong Ming Liu

I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.

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Husain Taha Radhi

I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.

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S Munshi

Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.

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Tania Munoz

“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.

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George Varvatsoulias

Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.

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Rui Tao

Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.

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Khurram Arshad

Clinical Cardiology and Cardiovascular Interventions, we deeply appreciate the interest shown in our work and its publication. It has been a true pleasure to collaborate with you. The peer review process, as well as the support provided by the editorial office, have been exceptional, and the quality of the journal is very high, which was a determining factor in our decision to publish with you.

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Gomez Barriga Maria Dolores

The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews journal clinically in the future time.

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Lin Shaw Chin

Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.

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Maria Dolores Gomez Barriga

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, I hope this message finds you well. I want to express my utmost gratitude for your excellent work and for the dedication and speed in the publication process of my article titled "Navigating Innovation: Qualitative Insights on Using Technology for Health Education in Acute Coronary Syndrome Patients." I am very satisfied with the peer review process, the support from the editorial office, and the quality of the journal. I hope we can maintain our scientific relationship in the long term.

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Dr Maria Dolores Gomez Barriga

Dear Monica Gissare, - Editorial Coordinator of Nutrition and Food Processing. ¨My testimony with you is truly professional, with a positive response regarding the follow-up of the article and its review, you took into account my qualities and the importance of the topic¨.

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Dr Maria Regina Penchyna Nieto

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, The review process for the article “The Handling of Anti-aggregants and Anticoagulants in the Oncologic Heart Patient Submitted to Surgery” was extremely rigorous and detailed. From the initial submission to the final acceptance, the editorial team at the “Journal of Clinical Cardiology and Cardiovascular Interventions” demonstrated a high level of professionalism and dedication. The reviewers provided constructive and detailed feedback, which was essential for improving the quality of our work. Communication was always clear and efficient, ensuring that all our questions were promptly addressed. The quality of the “Journal of Clinical Cardiology and Cardiovascular Interventions” is undeniable. It is a peer-reviewed, open-access publication dedicated exclusively to disseminating high-quality research in the field of clinical cardiology and cardiovascular interventions. The journal's impact factor is currently under evaluation, and it is indexed in reputable databases, which further reinforces its credibility and relevance in the scientific field. I highly recommend this journal to researchers looking for a reputable platform to publish their studies.

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Dr Marcelo Flavio Gomes Jardim Filho

Dear Editorial Coordinator of the Journal of Nutrition and Food Processing! "I would like to thank the Journal of Nutrition and Food Processing for including and publishing my article. The peer review process was very quick, movement and precise. The Editorial Board has done an extremely conscientious job with much help, valuable comments and advices. I find the journal very valuable from a professional point of view, thank you very much for allowing me to be part of it and I would like to participate in the future!”

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Zsuzsanna Bene

Dealing with The Journal of Neurology and Neurological Surgery was very smooth and comprehensive. The office staff took time to address my needs and the response from editors and the office was prompt and fair. I certainly hope to publish with this journal again.Their professionalism is apparent and more than satisfactory. Susan Weiner

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Dr Susan Weiner

My Testimonial Covering as fellowing: Lin-Show Chin. The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews.

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Lin-Show Chin

My experience publishing in Psychology and Mental Health Care was exceptional. The peer review process was rigorous and constructive, with reviewers providing valuable insights that helped enhance the quality of our work. The editorial team was highly supportive and responsive, making the submission process smooth and efficient. The journal's commitment to high standards and academic rigor makes it a respected platform for quality research. I am grateful for the opportunity to publish in such a reputable journal.

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Sonila Qirko

My experience publishing in International Journal of Clinical Case Reports and Reviews was exceptional. I Come forth to Provide a Testimonial Covering the Peer Review Process and the editorial office for the Professional and Impartial Evaluation of the Manuscript.

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Luiz Sellmann