Transforming growth factor (TGF)-β1 mediates glycosaminoglycan (GAG) chain hyperelongation on secreted proteoglycans and these modifications are associated with increased lipid binding in the vessel wall and the development of atherosclerosis. In vascular smooth muscle cells (VSMCs), TGF-β1 regulated GAG elongation via extracellular signal-regulated kinase (ERK) and p38 as well as Smad2 linker region phosphorylation. In this study, our aim was to identify the TGF-β1 mediated signalling pathway involving reactive oxygen species (ROS) and Smad2 linker region phosphorylation that regulate the mRNA expression of GAG synthesizing enzymes, chondroitin 4-O-sulfotransferase 1 (CHST11) and chondroitin sulfate synthase 1 (CHSY1) which are the rate limiting enzymes involved in GAG chain elongation. Signalling molecules were assessed by western blotting, quantitative real-time PCR was used for analysis of gene expression and intracellular ROS level was measured by a fluorescence based assay. TGF-β1 induced ROS production in VSMCs. Nicotinamide adenine dinucleotide phosphate oxidase (Nox) inhibitors, diphenyleneiodonium (DPI) and apocynin blocked TGF-β1 mediated Smad2 linker region phosphorylation. TGF-β1 treatment increased the mRNA levels of CHST11 and CHSY1. Pharmacological inhibition of Nox blocked TGF-β1 mediated mitogen activated protein kinases (MAPKs) phosphorylation and TGF-β1 stimulated CHST11 and CHSY1 mRNA expression. These findings demonstrated that TGF-β1 mediated expression of CHST11 and CHSY1 can occur via Nox-dependent pathways and Smad2 linker region phosphorylation. KeywordsAtherosclerosis . Nox . Reactive oxygen species . Mitogen activated protein kinases . Glycosaminoglycan Abbreviations CHST11 Chondroitin 4-Ο-sulfotransferase 1 CHSY1 Chondroitin synthase 1 DPI Diphenyleneiodonium ERK Extracellular signal-regulated kinase GAG Glycosaminoglycan JNK C-Jun N-terminal kinase MAPKs Mitogen activated protein kinases. Nox Nicotinamide adenine dinucleotide phosphate oxidase ROS Reactive oxygen species TGFBR1 Transforming growth factor-β receptor type 1 TGF-β1 Transforming growth factor β1 VSMCs Vascular smooth muscle cells * Hossein Babaahmadi-Rezaei

In BAECs, ET-1 via the ETB receptor is involved in transactivation of the TβRI. The transactivation-dependent response is dependent upon de novo protein synthesis.

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Bladder cancer is one of the concerning urological malignant diseases in the world, which has a clinical need for effective targeted therapy. The development of nanotechnology-based gene delivery to bladder tumor sites is an effective strategy for targeted cancer therapy with low/no toxicity. With this view, in the present work, the mesoporous silica nanoparticles (MSNs) modified with c(RGDfK)-PLGA-PEG [c(RGDfK)-MSN NPs] were constructed for co-delivery of miR-34a and siPD-L1 within bladder cancer cells and tissues. Our findings showed that miR-34a is downregulated while PD-L1 is up-regulated in cell lines and animal studies. This nano-carrier is biocompatible in the serum environment and effectively protects miR-34a and siPD-L1 against serum degradation. However, we showed that c(RGDfK)-MSN NPs could simultaneously downregulate PD-L1 expression and up-regulate miR-34a in the T24 cells and T24 mice model and enhance anti-tumor effects both in vivo and in vitro. In conclusion, these findings presented new suggestions for improving targeted therapeutic strategies with specified molecular objectives for bladder cancer treatment.

In the following research, we specifically assessed the feasibility of a novel AS-1411-chitosan (CS)-gold nanoparticle (AuNPs) delivery system to carry methotrexate (MTX) into the cancer cells. The designed system had a spherical shape with average size of 62 ± 2.4 nm, the zeta potential of −32.1 ± 1.4 mV, and released MTX in a controlled pH- and time-dependent manner. CS-AuNPs could successfully penetrate the breast cancer cells and release the therapeutic drug, and ultimately, be accumulated by the nucleolin-AS1411 targeting mechanism within the in vivo environment. The anticancer activity of MTX was attributed to the induction of mitochondria membrane potential loss and nuclear fragmentation, which leads to apoptotic death. Moreover, the cellular internalization confirmed the high potential in the elimination of cancer cells without notable cytotoxicity on non-target cells. Therefore, it was concluded that the AS1411-CS-AuNPs with considerable in vitro and in vivo results could be utilized as a favorable system for breast cancer treatment.