Biology subjects

Tithi, T. I.

Publications and source records attributed to Tithi, T. I..

3 recordsLinked to original sources

bioRxiv2024

Epithelial IL-2 is critical for NK cell-mediated cancer immunosurveillance in mammary glands

Interleukin 2 (IL-2) is the first identified cytokine and its interaction with receptors has been known to shape the immune responses in many lymphoid or non-lymphoid tissues for more than four decades. Active T cells are the primary cellular source for IL-2 production and epithelial cells have never been considered the major cellular source of IL-2 under physiological conditions. It is, however, tempting to speculate that epithelial cells could potentially express IL-2 that regulates the intricate interactions between epithelial cells and lymphocytes. Datamining our recently published single-cell RNAseq in the mouse mammary gland identified IL-2 expression in mammary epithelial cells, which is induced by prolactin via the STAT5 signaling pathway. Furthermore, epithelial IL-2 plays a crucial role in maintaining the physiological functions of natural killer (NK) cells within the mammary glands. IL-2 deletion in the mammary epithelial cells leads to a significant reduction in the number and function of NK cells, which in turn results in defective immunosurveillance, expansion of luminal epithelial cells, and tumor development. Interestingly, T cells in the mammary glands are not changed, indicating the specific regulation of NK cells by epithelial IL-2 production. In agreement, we also found that human epithelial cells express IL-2 and NK cells express the highest level of IL2RB among all the immune cells. Here, we provide the first evidence that epithelial cells produce IL-2, which is critical for maintaining the physiological functions of NK cells in immunosurveillance.

immunology↗

bioRxiv2023

Contrasting roles of different mismatch repair proteins in basal-like breast cancer

The mismatch repair (MMR) pathway is known as a tumor suppressive pathway and genes involved in MMR are commonly mutated in hereditary colorectal or other cancer types. However, the function of MMR genes/proteins in breast cancer progression and metastasis are largely undefined. We found that MSH2, but not MLH1, is highly enriched in basal-like breast cancer (BLBC) and that its protein expression is inversely correlated with overall survival time (OS). MSH2 expression is frequently elevated due to genomic amplification or gain-of-expression in BLBC, which results in increased MSH2 protein to pair with MSH6 (collectively referred to as MutS). Genetic deletion of MSH2 or MLH1 results in a contrasting phenotype in metastasis, with MSH2-deletion leading to reduced metastasis and MLH1-deletion to enhanced liver or lung metastasis. Mechanistically, MSH2 - but not MLH1 - binds to the promoter region of interferon receptor 1 (IFNAR1) and suppresses its expression in BLBC. Deletion of MSH2 initiates a chain of immune reactions via the upregulation of IFNAR1 expression and the activation of type 1 interferon signaling, which explains a highly immune active tumor microenvironment in tumors with MSH2-deficiency. Our study supports the contrasting functions of MSH2 and MLH1 in BLBC progression and metastasis due to the differential regulation of IFNAR1 expression, which challenges the paradigm of the MMR pathway as a universal tumor suppressive mechanism.

cancer biology↗

bioRxiv2022

An in vivo and in silico evaluation of the magical hepatoprotective potentialities of Gynura procumbens: a promising agent for combating hepatotoxicity

IntroductionLiver being the most important metabolic organ of the body performs a wide variety of vital functions. Hepatic cell injury occurs by the activation of reactive oxygen species (ROS) by CCl4, xenobiotics and other toxic substances generated through cytochrome P450 dependent step resulting from covalent bond formation with lipoproteins and nucleic acids. Observing the alarming state of hepatotoxic patients worldwide, different medicinal plants and their properties can be explored to combat against such free radical degermation of liver. This paper evaluates the antioxidant property of Gynura procumbens in both in silico and in an in vivo assay, and its hepatoprotective activity in CCl4 induced hepatotoxicity. Materials and MethodsGynura procumbens leaves were collected and extracted using 50% ethanol. Required chemicals (CCl4), standard drug (Silymarin) and blood serum analyzing kits were stocked. The in vivo tests were performed in 140 healthy Wister albino male rats under well controlled parameters dividing into 14 groups, strictly maintaining IEAC protocols. In silico molecular docking and ADMET studies were performed and the results were analyzed statistically. Results and discussionThe body weight increased significantly in CCl4 induced, G. procumbens administered hepatotoxic rats. The increase in SGPT, SGOT, ALP, creatinine, LFH, triglycerides, LDL, SOD, MDA, total cholesterol, DNA fragmentation ranges, {gamma}GT levels of CCl4 treated group was decreased by both standard drug Silymarin and G. procumbens leaf extract. On the other hand, G. procumbens increased HDL levels and displayed contrasting results in CAT level tests. Some results contradicted with the negative controlled group displaying varying efficacy between leaf extract and Silymarin. In the molecular docking analysis, G. procumbens phytoconstituents performed poorly against TGF-{beta}1 compared to the control drug Galunisertib while 26 phytoconstituents scored better than the control, bezafibrate against PPAR-. Flavonoids and phenolic compounds performed better than other constituents in providing hepatoprotective activity.

bioinformatics↗