Biology subjects

Rezaee, S. A. R.

Publications and source records attributed to Rezaee, S. A. R..

3 recordsLinked to original sources

bioRxiv2026

PIK-75 suppresses an SREBP-centred sterol programme in PIK3CA-altered small-cell lung cancer cells, but attribution to p110α remains unresolved

Abstract: Background. Class IA PI3K isoforms are candidate therapeutic targets in small-cell lung cancer (SCLC). The transcriptional consequences of isoform-directed inhibitors in SCLC cells have not been compared genome-wide. Methods. We re-analysed GEO series GSE40564: PIK3CA-altered NCI-H69 cells treated for 24 h with vehicle, PIK-75 (p110-directed) or TGX-221 (p110{beta}-directed), three arrays per group (Affymetrix HG-U133 Plus 2.0). Differential expression used limma, with re-processing from raw files and spike-in-anchored normalisation as sensitivity analyses. Gene sets were assessed by effect size, competitive and rotation tests, and size-matched random-set nulls. Isoform dependency was examined in DepMap CRISPR screens. A PIK-75 response score was tested in 81 primary SCLCs against random-signature nulls. Results. PIK-75 reduced SREBP-controlled sterol- and lipid-synthesis genes (SQLE, HMGCS1, HMGCR, LDLR, SCD; log2 fold-change -1.1 to -1.6). Cholesterol, mTORC1, hypoxia and glycolysis gene sets fell far more than size-matched random sets. E2F-target and homologous-repair genes fell more modestly, including BRCA1 (-0.91). The response was broad: 11,645 of 17,458 genes changed at FDR < 0.05, but only 316 decreased and 20 increased significantly beyond two-fold, an asymmetry that persisted under spike-in-anchored normalisation. TGX-221 changed 358 genes, none two-fold. Its set-level effects were four- to nine-fold smaller and depended on two of three replicates. PIK-75 did not induce canonical FOXO targets, and it inhibits kinases other than p110, so the response cannot be attributed to p110 alone. In DepMap, SCLC lines depended more on PIK3CA than on PIK3CB (median Chronos -0.38 vs -0.15), as did other lineages. In patients, the response score was not associated with survival or subtype beyond what random gene signatures achieve (empirical p = 0.14 and 0.11). Conclusion. PIK-75, but not TGX-221, suppresses an SREBP-centred anabolic transcriptional programme in NCI-H69 cells. Attributing this to p110 requires confirmation with selective inhibitors or genetic perturbation.

cancer biology↗

bioRxiv2020

Host-Microbe Interactions in Manifestation of Tuberculosis: A System Biology Study in Implicated Compartments

Mycobacterium tuberculosis (Mtb) has been a dilemma for over a century. Thus the bacteria-host interactions seem to be implicated in the manifestation of the disease. Here, the behavioral activities of the Mtb and host responses were evaluated in this system biology analyses, according to the compartmental immune responses in the lung and local lymph node. Differential expression analyses were conducted between tuberculosis (TB) and the healthy group in the aforementioned compartments, to identify the hub genes and functional gene ontology (GO) terms, using KEGG, Enrichr and DAVID databases. The different phases of immune responses against Mtb occur in three compartments, lung, local lymph nodes and blood. Due to the occurrence of hypoxia within granuloma in the lung, angiogenesis was increased despite the HIF1- down-regulation via inhibition of EP300 and HDAC1. Proliferation by MYC, CDK2 and NF-{kappa}B pathways activated in the granuloma, while at the same time apoptosis was induced by P53 activation, and PI3K/Akt inhibited P53 in the lymph node. Furthermore, DNA damages suppressed by the over-expression of BRCA1, CDK1 and BCR/ABL in the lymph node, as well as FBXO6, CDK2 and CDC5A in both compartments. In the lymph node, RTK (EGFR) and calmodulin, the consequent NFAT formation and Erk/MAPK pathway down-regulated and suppressed Th1 cell activation and differentiation. Inflammation was induced in both compartments, but the antigen (Ag) presentation was suppressed through the XPO1 suppression and ubiquitination. More studies in Mtb-host interactions are needed to specify the effective mechanisms for reducing this re-emerging life-threatening disease. ImportanceTuberculosis (TB) is one of the most widespread reemerging infectious diseases in the world, which has remained a global health problem. Approximately, 10 million people are infected with Mycobacterium tuberculosis (Mtb), causing 1.2 million deaths every year. Therefore, interactions between the host and the pathogen in Mtb infection are a major challenge for the control of the disease. Typically, there are thousands of genes and ten times more interactions between any stages of the conflicts. This urged us to bring "systemic approaches" for a better understanding of such highly orchestrated systems. A holistic view of the Mtb-host interaction paves the way for a higher insight into the biology of the organism, as well as rationale solutions for the design of therapeutic agents. This study specifies the nominated disease-related genes and related signaling pathways in the pathogenesis of TB in two different compartments, lung and lymph node.

systems biology↗

bioRxiv2019

Game Theory Applications in Host-Microbe Interactions: Mycobacterium tuberculosis infection as an example

The game theory describes the interactions between two players and the pay-off from wining, losing or compromising. Mycobacterium tuberculosis (Mtb)-host interactions were used as an example for the application of the game theory to describe and predict the possibilities of victory for any players. The gene expression for eight main markers of host response and three Mtb virulence factors were assessed in broncho-alveolar lavage of TB+ and TB- patients. The game theory showed that a variety of paths exist that players can use, in response to the behaviour of the counterpart. Briefly, according to the "Nash equilibrium", Ag85B is the main virulence factor for Mtb in active phase, however it is the most immunogenic factor if the host can respond by high expression of T-bet and iNOS. In this situation, Mtb can express high levels of ESAT-6 and CFP10 and change the game to the latency, in which host responses by medium expression of T-bet and iNOS and medium level of TGF-{beta} and IDO. Consistently, The IDO expression was 134-times higher in TB+s than the TB-s, and the T-bet expression, ~200-times higher in the TB-s than the TB+s. Furthermore, Mtb-Ag85B had a strong positive association with CCR2, T-bet and iNOS, but had a negative correlation with IDO.

microbiology↗