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While cancer treatment has improved dramatically, it has also encountered many critical challenges, such as disease recurrence, metastasis, and drug resistance, making new drugs with novel mechanisms an urgent clinical need. The term "drug repositioning," also known as old drugs for new uses, has emerged as one practical strategy to develop new anticancer drugs. Anesthetics have been widely used in surgical procedures to reduce the excruciating pain. Lidocaine, one of the most-used local anesthetics in clinical settings, has been found to show multi-activities, including potential in cancer treatment. Growing evidence shows that lidocaine may not only work as a chemosensitizer that sensitizes other conventional chemotherapeutics to certain resistant cancer cells, but also could suppress cancer cells growth by single use at different doses or concentrations. Lidocaine could suppress cancer cell growth in vitro and in vivo via multiple mechanisms, such as regulating epigenetic changes and promoting pro-apoptosis pathways, as well as regulating ABC transporters, metastasis, and angiogenesis, etc., providing valuable information for its further application in cancer treatment and for new drug discovery. In addition, lidocaine is now under clinical trials to treat certain types of cancer. In the current review, we summarize the research and analyze the underlying mechanisms, and address key issues in this area.The present study aimed to determine whether icariin could attenuate type 1 diabetic nephropathy (T1DN) induced by streptozotocin (STZ) after 4 weeks or not. Therefore, its therapeutic effect on diabetic kidney disease was investigated in view of reactive oxygen (ROS) and extracellular matrix (ECM) generation in human glomerular mesangial cells under high glucose. To establish the participation and the key role of GPER and Nrf2 in ECM deposition, a combination of G15 (antagonist of GPER) or siGPER and siNrf2 were performed, respectively. The results showed that T1DN can be significantly inhibited by oral icariin, evidenced by improvement of 24 h urinary volume, 24 h proteinuria, microalbuminuria, and histopathological changes of kidney. Icariin decreased the levels of intracellular superoxide anion, impeded the generation of fibronectin and increased the expression and activity of antioxidant enzymes in the human glomerular mesangial cells treated with high glucose. It acted as a GPER activator, increased dissociation of Nrf2/Keap1 complexes, combination of Keap1/p62 complexes, Nrf2 translocation to nuclear, Nrf2/ARE DNA binding activity, and ARE luciferase reporter gene activity in glomerular mesangial cells. HC-258 research buy The Nrf2 inhibitor ML385 or siNrf2 obviously abolished extracellular matrix (ECM) generation inhibited by icariin. Furthermore, icariin-induced Nrf2 activation was mainly dependent on p62-mediated Keap1 degradation, which functions as an adaptor protein during autophagy. The GPER antagonist G15 and siGPER obviously abolished the above effects by icariin. Taken together, the present study demonstrated that the therapeutic effects of icariin on type 1 diabetic nephropathy in rats via GPER mediated p62-dependent Keap1 degradation and Nrf2 activation.Ticks secrete various anti-coagulatory, anti-vasoconstrictory, anti-inflammatory, and anti-platelet aggregation factors in their saliva at the bite site during feeding to evade host immunological surveillance and responses. For the first time, we report successful isolation of exosomes (small membrane-bound extracellular signaling vesicles) from saliva and salivary glands of partially fed or unfed ixodid ticks. Our data showed a novel role of these in vivo exosomes in the inhibition of wound healing via downregulation of C-X-C motif chemokine ligand 12 (CXCL12) and upregulation of interleukin-8 (IL-8). Cryo-electron microscopy (cryo-EM) analysis revealed that tick saliva and salivary glands are composed of heterogeneous populations of in vivo exosomes with sizes ranging from 30 to 200 nm. Enriched amounts of tick CD63 ortholog protein and heat shock protein 70 (HSP70) were evident in these exosomes. Treatment of human skin keratinocytes (HaCaT cells) with exosomes derived from tick saliva/salivary glands or ISE6 cells dramatically delayed cell migration, wound healing, and repair process. Wound healing is a highly dynamic process with several individualized processes including secretion of cytokines. Cytokine array profiling followed by immunoblotting and quantitative-PCR analysis revealed that HaCaT cells treated with exosomes derived from tick saliva/salivary glands or ISE6 cells showed enhanced IL-8 levels and reduced CXCL12 loads. Inhibition of IL-8 or CXCL12 further delayed exosome-mediated cell migration, wound healing, and repair process, suggesting a skin barrier protection role for these chemokines at the tick bite site. In contrast, exogenous treatment of CXCL12 protein completely restored this delay and enhanced the repair process. Taken together, our study provides novel insights on how tick salivary exosomes secreted in saliva can delay wound healing at the bite site to facilitate successful blood feeding.Breast cancers display phenotypic and functional heterogeneity and several lines of evidence support the existence of cancer stem cells (CSCs) in certain breast cancers, a minor population of cells capable of tumor initiation and metastatic dissemination. Identifying factors that regulate the CSC phenotype is therefore important for developing strategies to treat metastatic disease. The Inhibitor of Differentiation Protein 1 (Id1) and its closely related family member Inhibitor of Differentiation 3 (Id3) (collectively termed Id) are expressed by a diversity of stem cells and are required for metastatic dissemination in experimental models of breast cancer. In this study, we show that ID1 is expressed in rare neoplastic cells within ER-negative breast cancers. To address the function of Id1 expressing cells within tumors, we developed independent murine models of Triple Negative Breast Cancer (TNBC) in which a genetic reporter permitted the prospective isolation of Id1+ cells. Id1+ cells are enriched for self-renewal in tumorsphere assays in vitro and for tumor initiation in vivo.