The role of ß2-AR/PI3K/AKT pathway in the proliferation, migration and invasion of THLE-2 cells induced by nicotine.

Nicotine, the primary constituent of tobacco, is one of the important factors that induce the occurrence of hepatocellular carcinoma (HCC). The ß2-adrenergic receptor (ß2-AR) is implicated in the growth and advancement of tumors. However, the role of ß2-AR and its mediated cascades in nicotine-induced HCC remains unclear. This present study aims to observe the effects of nicotine on the proliferation, migration, and invasion of immortalized human liver epithelial (THLE-2) cells, as well as to explore the underlying mechanisms of action. The results of cell counting kit-8 (CCK-8) assay showed that 0.3125 µM nicotine had the ability to promote the proliferation of THLE-2 cells with a significant time-dependent manner. Therefore, THLE-2 cells were mainly selected for chronic treatment with 0.3125 µM nicotine in the later stage to cause transformation. After 30 passages of THLE-2 cells with 0.3125 µM nicotine treatment, chronic exposure to nicotine significantly enhanced the proliferation, metastasis, and invasion of cells. Besides, it also upregulated the intracellular levels of ß2-AR, phosphoinositide 3-kinase (PI3K), AKT, matrix metalloproteinase-2 (MMP-2) and Cyclin D1, as well as downregulated the expression of p53. More importantly, the ß2-AR/PI3K/AKT pathway was found to mediate the expression of MMP-2, Cyclin D1, and p53 in THLE-2 cells, playing a crucial role in their proliferation, migration, and invasion after continuous exposure to nicotine. Simply put, it demonstrated the role of ß2-AR/PI3K/AKT pathway in the transformation of THLE-2 cells induced by nicotine. This study could provide valuable insights into the relationship between nicotine and HCC. Additionally, it lays the groundwork for investigating potential anticancer treatments for liver cancer linked to tobacco consumption.

Multifunctional Microneedle Patch Based on Metal-Phenolic Network with Photothermal Antimicrobial, ROS Scavenging, Immunomodulatory, and Angiogenesis for Programmed Treatment of Diabetic Wound Healing.

In diabetic patients with skin injuries, bacterial proliferation, accumulation of reactive oxygen species (ROS) in the tissues, and impaired angiogenesis make wound healing difficult. Therefore, eliminating bacteria, removing ROS, and promoting angiogenesis are necessary for treating acute diabetic wounds. In this study, benefiting from the ability of polyphenols to form a metal-phenolic network (MPN) with metal ions, TA-Eu MPN nanoparticles (TM NPs) were synthesized. The prepared photothermal agent CuS NPs and TM NPs were then loaded onto the supporting base and needle tips of PVA/HA (PH) microneedles, respectively, to obtain PH/CuS/TM microneedles. Antibacterial experiments showed that microneedles loaded with CuS NPs could remove bacteria by the photothermal effect. In vitro experiments showed that the microneedles could effectively scavenge ROS, inhibit macrophage polarization to the M1 type, and induce polarization to the M2 type as well as have the ability to promote vascular endothelial cell migration and angiogenesis. Furthermore, in vivo experiments showed that PH/CuS/TM microneedles accelerated wound healing by inhibiting pro-inflammatory cytokines and promoting angiogenesis in a diabetic rat wound model. Therefore, PH/CuS/TM microneedles have efficient antibacterial, ROS scavenging, anti-inflammatory, immunomodulatory, and angiogenic abilities and hold promise as wound dressings for treating acute diabetic wounds.

A review on the effect of COX-2-mediated mechanisms on development and progression of gastric cancer induced by nicotine.

Smoking is a documented risk factor for cancer, e.g., gastric cancer. Nicotine, the principal tobacco alkaloid, would exert its role of contribution to gastric cancer development and progression through nicotinic acetylcholine receptors (nAChRs) and ß-adrenergic receptors (ß-ARs), which then promote cancer cell proliferation, migration and invasion. As a key isoenzyme in conversion of arachidonic acid to prostaglandins, cyclooxygenase-2 (COX-2) has been demonstrated to have a wide range of effects in carcinogenesis and tumor development. At present, many studies have reported the effect of nicotine on gastric cancer by binding to nAChR, as well as indirectly stimulating ß-AR to mediate COX-2-related pathways. This review summarizes these studies, and also proposes more potential COX-2-mediated mechanisms. These events might contribute to the growth and progression of gastric cancer exposed to nicotine through tobacco smoke or cigarette substitutes. Also, this review article has therefore the potential not only to make a significant contribution to the treatment and prognosis of gastric cancer for smokers but also to the clinical application of COX-2 antagonists. In addition, this work also discusses the considerable challenges of this field with special reference to the future perspective of COX-2-mediated mechanisms in development and progression of gastric cancer induced by nicotine.

The role of α7-nAChR-mediated PI3K/AKT pathway in lung cancer induced by nicotine.

Nicotine enters the environment mainly through human activity, as well as natural sources. This review article examines the increasing evidence implicating nicotine in the initiation and progression of lung cancer. Moreover, it primarily focuses on elucidating the activation mechanism of phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB, also known as AKT) signaling pathway, regulated by α7 subtype nicotinic acetylcholine receptor (α7-nAChR), in relation to the proliferation, invasion, and metastasis of lung cancer cells induced by nicotine, as well as nicotine-mediated anti-apoptotic effects. This process involves PI3K/AKT phosphorylated-B-cell lymphoma-2 (Bcl-2) family proteins, PI3K/AKT/mammalian target of rapamycin (mTOR), PI3K/AKT/nuclear factor-κB (NF-κB), hepatocyte growth factor (HGF)/cellular-mesenchymal epithelial transition factor (c-Met)-induced PI3K/AKT and PI3K/AKT activated-hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathways. In addition, we also deliberated on the related challenges and upcoming prospects within this field. These lay the foundation for further study on nicotine, lung tumorigenesis, and PI3K/AKT related molecular mechanisms. This work has the potential to significantly contribute to the treatment and prognosis of gastric cancer in smokers. Besides, the crucial significance of PI3K/AKT signaling pathway in multiple molecular pathways also suggests that its target antagonists may inhibit the development and progression of lung cancer, providing a possible new perspective for solving the problem of nicotine-promoted lung cancer. The emerging knowledge about the carcinogenic mechanisms of nicotine action should be considered during the environmental assessment of tobacco and other nicotine-containing products.

The role of PICT1 in RPL11/Mdm2/p53 pathway-regulated inhibition of cell growth induced by topoisomerase IIα inhibitor against cervical cancer cell line.

Our previous work showed that a podophyllum derivative (D-3F), named 4-N-(2-Amino-3-fluoropyridine) -4-deoxidation-4'-demethylepipofophyllotoxin, inhibits the activity of topoisomerase II (TOPO II) and then results in DNA damage. Also, D-3F increases the expression of p53 to induce cervical cancer HeLa cell apoptosis by enhancing its stability, due to the translocation of RPL11 to interact with Mdm2 and then consequently causing the blockage of the Mdm2-p53 feedback loop. In present study, we further explored the detailed mechanism of the antitumor activity of D-3F against cervical cancer cell line. Firstly, the decreased level of protein interacting with carboxyl terminus 1 (PICT1) in cervical cancer cell lines (HeLa and SiHa) treated with D-3F, exerted its potent inhibitory effect on cellular proliferation, which was dependent on the inhibition of TOPO IIα activity induced by D-3F in vitro. In addition, the downregulation of PICT1 was required to enhancement of p53 stability, resulted from its promoting the nucleoplasmic translocation of RPL11 to bind to Mdm2 following D-3F treatment. Altogether, it demonstrated that the reduction of PICT1 level in HeLa cell line, as well as SiHa exposed to D-3F, a TOPO IIα inhibitor, may play an essential role in the regulation of RPL11/Mdm2/p53 pathway to induce cell apoptosis. Besides, it suggested the potential of this podophyllum derivative (D-3F) as an alternative agent for therapy in cervical cancer.