1/3 J Cardiol Clin Res 1(1): 1147.JSM Clin Cytol Pathol 1: 3

JSM Clinical Cytology and Pathology

Submitted: 16 May 2019 | Accepted: 17 May 2019 | Published: 17 May2019

*Corresponding author: Masoud Keikha, Department of Microbiology and Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran, Tel: 09386836425; Email: masoud.keykha90@gmail.com

Copyright: © 2019 Karbalaei M and Keikha M. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation: Karbalaei M, Keikha M (2019) Formulation and Evaluation of Anti-Dermatophyte Creams from Ethanol Extract of Acalypha wilkesiana Leaves. JSM Clin Cytol Pathol 1: 3.

The PI3K-Akt/mTOR Signaling Pathway Roles in Tuberculosis Pathogenesis - The First System

Biology InsightMohsen Karbalaei1 and Masoud Keikha2,3*

1Department of Microbiology and Virology, School of Medicine, Jiroft University of Medical Sciences, Iran2Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Iran

3Department of Microbiology and Virology, Mashhad University of Medical Sciences, Iran

Dear Editor,Tuberculosis (TB) is remains as major public health concern.

According to WHO reports in 2018, it estimated 10.7 million TB cases throughout the worldwide. Also there are 1.6 million died from TB and 558,000 rifampin-resistant TB (RR-TB) in 2017 [1]. Furthermore, approximately 2 billion people have contaminated with Mycobacterium tuberculosis (Mtb) without clinical symptoms as latent-TB infection (LTBI); about 5-10% of these individuals have develop to active tuberculosis during their lives [2].There are several serious challenges for control of tuberculosis including HIV/AIDS pandemic, inefficacy of BCG vaccination in adult pulmonary-TB or spread of drug-resistant TB strains which cause to failure to control of tuberculosis in recently decades [1,3].

The system biology and cellular transcriptomic information has efficient tool for acquisition of novel insights for developing diagnosis methods, treatment monitoring and development of novel therapeutic options [4]. The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K-Akt-mTOR) signaling pathway has key role in cell growth, differentiation, apoptosis, autophagy, metabolism and infectious disease particularly tuberculosis [5]. According to review of literatures, dysregulations of the PI3K-Akt/mTOR signaling pathway have shown in tuberculosis individuals [6]. For example, Ouyang et al., have shown that the PI3K-Akt/mTOR pathway is down regulation of T regulatory production via inhibition of transcription factor Forkhead O3a (Foxo1, 3a) [7]. Recently studies have suggested that down-regulation of the PI3K-Akt/mTOR pathway in tuberculosis patients can cause to changes T reg cells and play important role in development to

active tuberculosis [5,8,9]. In the present study, we accomplished system biology for analysis of the PI3K-Akt/mTOR expression changes in active-TB and latent-TB patents as well as healthy individuals.

The gene expression profiles of CD4+ T-cells of tuberculosis and healthy individuals was obtained from Gene Expression Omnibus (GEO) database (Accession number: GDS4966; GPL570 platform). Subsequently, the GEO2R analysis was performed for detection of differentially expressed genes (DEGs) from three categorized consisting active-TB, LTBI and healthy controls given that Benjamini-Hochberg FDR-adjusted p-values <0.05 [4]. Then, the AKT3, PI3K, BCL2, CDK6, CREB5, NRAS, mTOR and NF_kB expression levels are remarked according to KEGG pathway (hsa04151). Finally, the Protein-Protein Interaction Networks (PPIN) was conducted using STRING online server. According to our analysis, inflammatory cytokines, JAK-STAT signaling, MAPK signaling pathway, autophagy gene expression profiles were different among TB, LTBI and healthy donors. In heat map diagram it’s obvious to decrease in immune-related genes expression fold from healthy donors to active-tuberculosis patients. In contrast the several genes including Foxp3, CTLA-4, TIM1, JAK1, Cox11, BCL11A, TMX3, CXCL10 or PDL2 are over expressed in active-TB compared than LTBI and health group respectively. Moreover, there are significant difference (based on the adjusted p-values <0.05) in fold expretion levels of PI3K-Akt/mTOR signaling related genes such as AKT, BCL2, CDK6, CREB5, mTOR, PIK3, NRAS, NF_kB (Figure 1, Table 1).

Based on the signaling network analysis, there are several PI3K-Akt/mTOR signaling related genes in central nodes of PPIN (such as mTOR, AKTs, CREB5, RICTOR, PIK3, MITF, NRAS or IKZF3) which are surrounded by various genes that regulated vital cell process including apoptosis, autophagy, cell-growth, p53 signaling pathway, NF_kB related genes (Figure 2).

Overall, according to present study, it’s obvious different expression profiles of the PI3K-Akt/mTOR signaling pathway in three groups of active-TB, LTBI and healthy individuals. Autophagy related genes (ATG), inflammatory cytokines, NF_kB pathway or MAPK signaling pathway are down-regulated from healthy donors to LTBI and active-TB patients. In contrast, apoptosis related genes, cell growth, P53 signaling pathway and cell proliferation were over-expressed in active-TB compared that LTBI and health individuals. The present study was the first document for explain of the PI3K-Akt/mTOR signaling pathway roles in different stages of tuberculosis disease.

Letter to the Editor © Karbalaei1 M and Keikha M, 2019

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Figure 1 The different expression of the AKT, BCL2, CDK6,CREB5, mTOR, PIK3, NRAS, NF_kB as seperate diagrams from Ato H respectively.

Figure 2 The PPIN conduceted for the PI3K-Akt/mTOR sign aling pathway related genes..

3/3JSM Clin Cytol Pathol 1: 3

In summary, or funding imply that expression amounts of the PI3K-Akt/mTOR signaling pathway is changed during tuberculosis pathogenesis; the PI3K-Akt/mTOR signaling pathway is influenced cell process particularly introduction of T regulatory cells via FOXO1. Previous reports are suggested that T reg cells are over expressed in active-TB patients who suppressed Th1 response. Therefore, expression of the PI3K-Akt/mTOR signaling pathway is important for determination of tuberculosis outcomes and monitoring of tuberculosis progression in LTBI cases.

Ethical ConsiderationsThe Ethics Committee of Mashhad University of Medical

Sciences was approved the study.

References1. World Health Organization, Editor. Global tuberculosis report 2018.

World Health Organization; 2018.

2. Evans TG, Schrager L, Thole J. Status of vaccine research and development of vaccines for tuberculosis. Vaccine. 2016; 34: 2911-2914.

3. Farmer PE. Better and safer treatment for multidrug-resistant tuberculosis. Lancet. 2018; 392: 798-800.

4. Wang C, Yang S, Sun G, Tang X, Lu S, Neyrolles O, et al. Comparative miRNA expression profiles in individuals with latent and active tuberculosis. PLos One. 2011; 6: e25832.

5. Zhang X, Huang T, Wu Y, Peng W, Xie H, Pan M, et al. Inhibition of the PI3K-Akt-mTOR signaling pathway in T lymphocytes in patients with active tuberculosis. Int J Infect Dis. 2017; 59: 110-117.

6. Singh P, Subbian S. Harnessing the mTOR pathway for tuberculosis treatment. Front Microbiol. 2018; 9: 70.

7. Ouyang W, Beckett O, Ma Q, Paik JH, DePinho RA, Li MO, et al. Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. Nat Immunol. 2010; 11: 618.

8. Keikha M, Shabani M, Navid S, Sadegh EB, Karbalaei ZB. What is the role of” T reg Cells” in tuberculosis pathogenesis?. Indian J Tuberc. 2018; 65: 360-361.

9. Sharma PK, Saha PK, Singh A, Sharma SK, Ghosh B, Mitra DK. FoxP3+ regulatory T cells suppress effector T-cell function at pathologic site in miliary tuberculosis. Am J Respir Crit Care Med. 2009; 179: 1061-1070.

Table 1: Different expression amounts of the PI3K-Akt/mTOR signaling genes in three groups of active-TB, latent-TB and health group.

Genes Active-TB LTBI Health group

AKT 9.74 10.13 10.8

BCL2 2.52 3.55 3.31

CDK6 9.85 9.56 9.48

CREB5 9.08 8.03 8.13

mTOR 8.71 8.83 8.76

PIK3 4.41 4.48 4.66

NRAS 14.91 14.81 14.81

NF_kB 10.05 10.21 10.23

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