β-cell dysfunction is a critical determinant for both type 1 diabetes and type 2 diabetes and β-cells are shown to be highly susceptible to cellular stressors. Mesenchymal stem cells (MSCs) on the ...other hand are known to have immunomodulatory potential and preferred in clinical applications. However, there is paucity of a comparative study on these cells in relation to several cellular stressors in response to hyperglycemia and this forms the rationale for the present study. INS1 β-cells and MSCs were subjected to high-glucose treatment without and with Metformin, Lactoferrin, or TUDCA and assessed for stress signaling alterations using gene expression, protein expression, as well as functional read-outs. Compared to the untreated control cells, INS1 β-cells or MSCs treated with high glucose showed significant increase in mRNA expressions of ER stress, senescence, and proinflammation. This was accompanied by increased miR146a target genes and decreased levels of SIRT1, NRF2, and miR146a in both the cell types. Consistent with the mRNA results, protein expression levels do reflect the same alterations. Notably, the alterations are relatively less extent in MSCs compared to INS1 β-cells. Interestingly, three different agents, viz., Metformin, Lactoferrin, or TUDCA, were found to overcome the high glucose-induced cellular stresses in a concerted and inter-linked way and restored the proliferation and migration capacity in MSCs as well as normalized the glucose-stimulated insulin secretion in INS1 β-cells. While our study gives a directionality for potential supplementation of metformin/lactoferrin/TUDCA in optimization protocols of MSCs, we suggest that in vitro preconditioning of MSCs with such factors should be further explored with in-depth investigations to harness and enhance the therapeutic capacity/potential of MSCs.
Astrocyte elevated gene-1 (AEG-1) is overexpressed in various malignancies. Exostosin-1 (EXT-1), a tumor suppressor, is an intermediate for malignant tumors. Understanding the mechanism behind the ...interaction between AEG-1 and EXT-1 may provide insights into colon cancer metastasis.
AOM/DSS was used to induce tumor in BALB/c mice. Using an
-jetPEI transfection reagent, transient transfection of AEG-1 and EXT-1 siRNAs were achieved. Histological scoring, immunohistochemical staining, and gene expression studies were performed from excised tissues. Data from the Cancer Genomic Atlas and GEO databases were obtained to identify the expression status of AEG-1 and itsassociation with the survival.
In BALB/c mice, the AOM+DSS treated mice developed necrotic, inflammatory and dysplastic changes in the colon with definite clinical symptoms such as loss of goblet cells, colon shortening, and collagen deposition. Administration of AEG-1 siRNA resulted in a substantial decrease in the disease activity index. Mice treated with EXT-1 siRNA showed diffusely reduced goblet cells. In vivo investigations revealed that PTCH-1 activity was influenced by upstream gene AEG-1, which in turn may affect EXT-1 activity. Data from The Cancer Genomic Atlas and GEO databases confirmed the upregulation of AEG-1 and downregulation of EXT-1 in cancer patients.
This study revealed that AEG-1 silencing might alter EXT-1 expression indirectly through PTCH-1, influencing cell-ECM interactions, and decreasing dysplastic changes, proliferation and invasion.
Senotherapy, a promising therapeutic strategy, has drawn a lot attention recently due to its potential for combating cancer. Senotherapy refers to the targeting of senescent cells to restore tissue ...homeostasis and mitigate the deleterious effects associated with senescence. Senolytic drugs represent a promising avenue in cancer treatment, with the potential to target and modulate senescent cells to improve patient outcomes. The review highlights the intricate interplay between the senescence-associated secretory phenotype (SASP) and the tumor microenvironment, emphasizing the role of senescent cells in promoting chronic inflammation, immune evasion, and tumor-cell proliferation. It then explores the potential of senotherapy as a novel strategy for cancer therapy. This review addresses the emerging evidence on the combination of senotherapy with conventional cancer treatments, such as chemotherapy and immunotherapy.
Tumor breakthrough is driven by genetic or epigenetic variations which assist in initiation, migration, invasion and metastasis of tumors. Astrocyte elevated gene-1 (AEG-1) protein has risen recently ...as the crucial factor in malignancies and plays a potential role in diverse complex oncogenic signaling cascades. AEG-1 has multiple roles in tumor growth and development and is found to be involved in various signaling pathways of: (i) Ha-ras and PI3K/AKT; (ii) the NF-κB; (iii) the ERK or mitogen-activated protein kinase and Wnt or β-catenin and (iv) the Aurora-A kinase. Recent studies have confirmed that in all the hallmarks of cancers, AEG-1 plays a key functionality including progression, transformation, sustained angiogenesis, evading apoptosis, and invasion and metastasis. Clinical studies have supported that AEG-1 is actively intricated in tumor growth and progression which includes esophageal squamous cell, gastric, colorectal, hepatocellular, gallbladder, breast, prostate and non-small cell lung cancers, as well as renal cell carcinomas, melanoma, glioma, neuroblastoma and osteosarcoma. Existing studies have reported that AEG-1 expression has been induced by Ha-ras through intrication of PI3K/AKT signaling. Conversely, AEG-1 also activates PI3K/AKT pathway and modulates the defined subset of downstream target proteins via crosstalk between the PI3K/AKT/mTOR and Hedgehog signaling cascade which further plays a crucial role in metastasis. Thus, AEG-1 may be employed as a biomarker to discern the patients of those who are likely to get aid from AEG-1-targeted medication. AEG-1 may play as an effective target to repress tumor development, occlude metastasis, and magnify the effectiveness of treatments. In this review, we focus on the molecular mechanism of AEG-1 in the process of carcinogenesis and its involvement in regulation of crosstalk between the PI3K/AKT/mTOR and Hedgehog signaling. We also highlight the multifaceted functions, expression, clinicopathological significance and molecular inhibitors of AEG-1 in various cancer types.
Background
Mammosphere formation assay has become a versatile tool to quantify the activity of putative breast cancer stem cells in non-adherent in vitro cultures. However, optimizing the suspension ...culture system is crucial to establish mammosphere cultures from primary breast tumors.
Methods
This study aimed at determining the self-renewal and sphere-forming potential of breast cancer stem-like cells derived from human primary invasive ductal carcinoma and normal breast tissue samples, and MCF-7 breast cancer cell line using an optimal suspension culture system. Mammosphere-forming efficiency of the mammospheres generated from the tissue samples and cell line were compared. We evaluated the expression of CD44
+
/CD24
−
/
low
and CD49f
+
/EpCAM
−
/
low
phenotypes in the stem-like cells by flow cytometry. CK-18, CK-19, α-SMA, and EpCAM marker expression was assessed using immunohistochemical staining.
Results
Breast epithelial cells isolated from the three samples formed two-dimensional spheroids in suspension cultures. Interestingly, mammospheres formed from patient-derived primary breast tumors were enriched in breast cancer stem-like cells with the phenotype CD44
+
/CD24
−
/
low
and exhibited a relatively more number of large spheres when compared to the normal breast stem cells. MCF-7-derived SCs were more aggressive and resulted in the formation of a significantly higher number of spheroids. The expression of CK-18/CK-19 and α-SMA/EpCAM proteins was confirmed in breast cancer tissues.
Conclusions
Thus, the use of primary tumor specimens and breast cancer cell lines as suitable models for elucidating the breast cancer stem cell activity was validated using mammosphere culture system.
beta-cell dysfunction is a critical determinant for both type 1 diabetes and type 2 diabetes and beta-cells are shown to be highly susceptible to cellular stressors. Mesenchymal stem cells (MSCs) on ...the other hand are known to have immunomodulatory potential and preferred in clinical applications. However, there is paucity of a comparative study on these cells in relation to several cellular stressors in response to hyperglycemia and this forms the rationale for the present study. INS1 beta-cells and MSCs were subjected to high-glucose treatment without and with Metformin, Lactoferrin, or TUDCA and assessed for stress signaling alterations using gene expression, protein expression, as well as functional read-outs. Compared to the untreated control cells, INS1 beta-cells or MSCs treated with high glucose showed significant increase in mRNA expressions of ER stress, senescence, and proinflammation. This was accompanied by increased miR146a target genes and decreased levels of SIRT1, NRF2, and miR146a in both the cell types. Consistent with the mRNA results, protein expression levels do reflect the same alterations. Notably, the alterations are relatively less extent in MSCs compared to INS1 beta-cells. Interestingly, three different agents, viz., Metformin, Lactoferrin, or TUDCA, were found to overcome the high glucose-induced cellular stresses in a concerted and inter-linked way and restored the proliferation and migration capacity in MSCs as well as normalized the glucose-stimulated insulin secretion in INS1 beta-cells. While our study gives a directionality for potential supplementation of metformin/lactoferrin/TUDCA in optimization protocols of MSCs, we suggest that in vitro preconditioning of MSCs with such factors should be further explored with in-depth investigations to harness and enhance the therapeutic capacity/potential of MSCs.
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•Two novel supramolecular structures of Ni(II) complexes based on dithiolate-amine binary ligand systems have been reported.•The N H···S, N H···N, C H···S type of H-bonds bestow ...stable supramolecular array.•HS study shows major H···H, N···H/H···N and S···H/H···S type of contacts in complexes.•The MTT assay and molecular docking investigation show anti-proliferative activity of Ni(2-ap)2(i-mnt).
Dithiolate-amine binary ligand systems based two novel supramolecular structures of Ni(II) coordination compounds Ni(2-ap)2(i-mnt) (1) and Ni2(i-mnt)2(tn)2n (2) where i-mnt−2: 1,1-dicyanoethylene-2,2-dithiolate, 2-ap: 2-amino pyridine, tn: 1,3-diaminopropane have been designed, synthesized and characterized by spectroscopic techniques and X-ray crystallography. In complex 1, the N2S2 coordination kernel around Ni+2 attains distorted square planar geometry (Okuniewski parameter τ/4 = 0.17) and its supramolecular array has a dominant influence of N H···N type hydrogen bonds forming significant ring geometry of graph-set-motifR428. The i-mnt−2 adopts a diverse coordination mode in 2 contrary to 1 resulting in a binuclear one-dimensional infinite polymeric chain structure of consecutive NiS4 square planar, S4 donor set τ/4 = 0 and NiN6 (octahedral) coordination kernels linked by i-mnt−2 that runs along 1 0 0 axis wherein N H···S, N H···N, C H···S type hydrogen bonds are believed to be crystal structure stabilizers. The Hirshfeld surface analyses (HS) at the molecular and atomic levels have been extensively studied to quantify all non-covalent interactions/contacts and the nature of ligand - metal interactions. The prominent N···H/H···N 28.1 % (1), 27.3 % (2A, NiS4), 20 % (2B, NiN6) and S···H/H···S contacts 10.4 % (1), 32.8 % (2A), 29 % (2B) presumably play vital role in crystal packing. The non-covalent interactions were further investigated by Molecular Electrostatic Potential (MEP) surface at PBE0-D3/def2-TZVP level and QTAIM optimizations (for 1). The MTT assay study using SW620 metastatic colon cancer cells shows a significant dose-dependent decline in cell proliferation with increasing concentration for 1 but for 2, the reverse trend is followed. A molecular docking study with the APC protein has further investigated the antiproliferative activity of 1 (MTT assay).
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