Lipopolysaccharide nanomedicine-based reversion of chemotherapy-induced metastatic potential of breast cancer via hampering tumoral TLR4/SIRT2 axis and IL6 secretion from tumor-associated macrophages

Article

Author: Khattab, Sherine N ; Sabra, Sally A ; Hassanin, Islam A ; Shehat, Michael G ; Abdel-Mohsen, Mohamed A ; Hussein, Ahmed A ; Mahmoud, Yosra S

Triple-negative breast cancer (TNBC) is a metastatic disease. Targeted approaches, as implementing nanoliposomes, e.g., liposomal doxorubicin (DOX), did not exhibit significantly improved survival. Therefore, we aimed at reducing the metastatic potential of TNBC through a double punch to cancer cells and tumor-associated macrophages (TAMs). Databases' analyses showed that targeting TLR4/SIRT2 axis might be a possible option. Inspired by the emergence of lipopolysaccharide (LPS) in clinical trials, we developed bioactive copolymeric nanomicelles, originating from the self-assembly of our synthesized LPS-pectin conjugate (LPS-PEC) for the delivery of DOX (DOX@LPS-PEC). Targeting TLR4 via DOX@LPS-PEC micelles enhanced cellular uptake, however, it failed to significantly improve the cytotoxic potential of DOX. Alternatively, co-targeting SIRT2 via Sirtinol at a specific ratio (DOX@LPS-PEC: Sirtinol 1:5 w/w) elevated cellular oxidative stress, improved cytotoxic potential on 2D-monolayer and 3D-spheroid models, and significantly reduced migratory potential of MDA-MB-231 cells compared to DOX@LPS-PEC alone. Finally, DOX@LPS-PEC plus Sirtinol at the same ratio exhibited an ability to hamper TAM-secreted IL6, which contribute to the metastatic potential of TNBC. In conclusion, targeting TLR4/SIRT2 axis in TNBC synergizes with the effect of chemotherapeutics, e.g. DOX, reduce the metastatic potential of TNBC cells via down-regulating TLR4 and hampering tumor-microenvironment IL6.

01 Mar 2025·Free Radical Biology and Medicine

Hyperbaric oxygen therapy attenuated limb ischemia in mice with high-fat diet by restoring Sirtuin 1 and mitochondrial function

Article

Author: Wu, Nan-Chun ; Lin, Mao-Tsun ; Niu, Ko-Chi ; Chang, Ching-Ping ; Hong, Chon-Seng ; Shih, Jhih-Yuan ; Chen, Zhih-Cherng ; Lin, You-Cheng ; Kan, Wei-Chih ; Lin, Yu-Wen ; Chang, Wei-Ting

Hyperbaric oxygen therapy (HBO) shows promise as a treatment for peripheral artery disease (PAD), particularly when complicated by metabolic syndrome and diabetes. However, its precise effects on endothelial function remain unclear. This study explored the impact of HBO on angiogenesis and apoptosis in high-fat diet (HFD)-fed mice with limb ischemia, focusing on the role of sirtuin 1 (SIRT1). After 8 weeks on a chow or HFD, mice underwent unilateral femoral artery ligation and received HBO (3 ATA, 1 h/day for 5 days). HBO improved blood flow, enhanced vascular density, and reduced apoptosis in ischemic calf muscles of HFD-fed mice. In vitro, human umbilical vein endothelial cells (HUVECs) were subjected to high-glucose and oxygen-glucose deprivation (OGD) conditions, with or without HBO. HBO restored cell proliferation, migration, and tube formation under these conditions, reduced mitochondrial dysfunction, and decreased reactive oxygen species (ROS) production. However, these benefits were reversed by treatment with sirtinol, a SIRT1 inhibitor. HBO also increased SIRT1 expression and shifted mitochondrial dynamics toward fusion. Additionally, HBO upregulated angiogenesis-related proteins (VEGF, VEGFR, and SIRT1) while downregulating apoptosis-associated proteins (Bax, caspase-3, and p53). Collectively, these findings suggest that HBO enhances angiogenesis and reduces apoptosis in both in vivo and in vitro ischemia models, primarily through SIRT1 activation.

01 Dec 2024·Molecular Biology Reports

SIRT1 activation attenuates palmitate induced apoptosis in C2C12 muscle cells

Article

Author: Razavi, Zahrasadat ; Saharkhiz, Saber ; Alipourfard, Iraj ; Taheripak, Gholamreza ; Najar, Naba ; Sabeti, Niusha

BACKGROUNDType 2 diabetes is characterized by insulin resistance, which manifests mainly in skeletal muscles. SIRT1 has been found to play a role in the insulin signaling pathway. However, the molecular underpinnings of SIRT1's function in palmitate fatty acid-induced apoptosis still need to be better understood.METHODSIn this research, skeletal muscle cells are treated with palmitate to be insulin resistant. It is approached that SIRT1 is downregulated in C2C12 muscle cells during palmitate-induced apoptosis and that activating SIRT1 mitigates this effect.RESULTSBased on these findings, palmitate-induced apoptosis suppressed mitochondrial biogenesis by lowering PGC-1 expression, while SIRT1 overexpression boosted. The SIRT1 inhibitor sirtinol, on the other hand, decreased mitochondrial biogenesis under the same conditions. This research also shows that ROS levels rise in the conditions necessary for apoptosis induction by palmitate, and ROS inhibitors can mitigate this effect. This work demonstrated that lowering ROS levels by boosting SIRT1 expression inhibited apoptotic induction in skeletal muscle cells.CONCLUSIONThis study's findings suggested that SIRT1 can improve insulin resistance in type 2 diabetes by slowing the rate of lipo-apoptosis and boosting mitochondrial biogenesis, among other benefits.

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