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Although tetraarsenic hexoxide is known to exert an anti-tumor effect by inducing apoptosis in various cancer cells, its effect on other forms of regulated cell death remains unclear. Here, we show that tetraarsenic hexoxide induces the pyroptotic cell death through activation of mitochondrial reactive oxygen species (ROS)-mediated caspase-3/gasdermin E (GSDME) pathway, thereby suppressing tumor growth and metastasis of triple-negative breast cancer (TNBC) cells. Interestingly, tetraarsenic hexoxide-treated TNBC cells exhibited specific pyroptotic characteristics, including cell swelling, balloon-like bubbling, and LDH releases through pore formation in the plasma membrane, eventually suppressing tumor formation and lung metastasis of TNBC cells. Mechanistically, tetraarsenic hexoxide markedly enhanced the production of mitochondrial ROS by inhibiting phosphorylation of mitochondrial STAT3, subsequently inducing caspase-3-dependent cleavage of GSDME, which consequently promoted pyroptotic cell death in TNBC cells. Collectively, our findings highlight tetraarsenic hexoxide-induced pyroptosis as a new therapeutic strategy that may inhibit cancer progression of TNBC cells.

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p300/CBP-associated factor (PCAF), a histone acetyltransferase, is involved in many cellular processes such as differentiation, proliferation, apoptosis, and reaction to cell damage by modulating the activities of several genes and proteins through the acetylation of either the histones or transcription factors. Here, we examined a pathogenic role of PCAF and its potential as a novel therapeutic target in the progression of renal tubulointerstitial fibrosis induced by non-diabetic unilateral ureteral obstruction (UUO) in male C57BL/6 mice. Administration of garcinol, a PCAF inhibitor, reversed a UUO-induced increase in the renal expression of total PCAF and histone 3 lysine 9 acetylation and reduced positive areas of trichrome and α-smooth muscle actin and collagen content. Treatment with garcinol also decreased mRNA levels of transforming growth factor-β, matrix metalloproteinase (MMP)-2, MMP-9, and fibronectin. Furthermore, garcinol suppressed nuclear factor-κB (NF-κB) and pro-inflammatory cytokines such as tumor necrosis factor-α and IL-6, whereas it preserved the nuclear expression of nuclear factor erythroid-derived 2-like factor 2 (Nrf2) and levels of Nrf2-dependent antioxidants including heme oxygense-1, catalase, superoxide dismutase 1, and NAD(P)H:quinone oxidoreductase 1. These results suggest that the inhibition of inordinately enhanced PCAF could mitigate renal fibrosis by redressing aberrant balance between inflammatory signaling and antioxidant response through the modulation of NF-κB and Nrf2.

Ginkgetin, a biflavone from Ginkgo biloba leaves, was previously reported to be a phospholipase A 2 inhibitor and this compound showed the potent antiarthritic activity in rat adjuvant-induced arthritis as well as analgesic activity. This investigation was carried out to find effects on cyclooxygenase-2 (COX-2) in vitro effect. Ginkgetin inhibits COX-2 dependent phases of prostaglandin D 2 (PGD 2 ) generation in bone marrow-derived mast cells (BMMC) in a concentration-dependent manner with IC 50 values of 0.75 m mM. Western blotting probed with specific anti-COX-2 antibodies showed that the decrease in quantity of the PGD 2 product was accompanied by a decrease in the COX-2 protein level. In addition, this compound consistently inhibited the production of leukotriene C 4 (LTC 4 ) in a dose dependent manner, with an IC 50 value of 0.33 m mM. These results demonstrate that ginkgetin has a dual cyclooxygenase-2/5-lipoxygenase inhibitory activity. Furthermore, this compound also inhibited degranulation reaction in a dose dependent manner, with an IC 50 value of 6.52 m mM. Therefore, this compound might provide a basis for novel anti-inflammatory agents.

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IntroductionAfter embryo implantation and decidualization, a critical step in placental development is the formation of the placental labyrinth (LA), which enables nutrient and gas exchange between the embryonic vasculature and the maternal blood supply. 1-5 LA formation is associated with substantial tissue remodeling and cell differentiation, as well as ingrowth of the embryonic vasculature through the chorion to a point of immediate proximity with the maternal blood supply. During this process, chorionic trophoblasts (CHs) differentiate into 2 perivascular cell populations that form distinct bilaminar envelopes of syncytiotrophoblasts in immediate contact with the fetal vascular endothelium. 6 Multiple transcription factors, growth factors, adhesion molecules, and gap junction molecules are known to influence the formation of the LA. 7 Interestingly, few if any proteolytic enzymes have so far been proven essential for LA formation although tissue remodeling is considered an integral part of this morphogenetic process. Several of the matrix metalloproteinases (MMPs), cathepsins, and serine proteinases are expressed in the placenta during development, however to date none have proven indispensable for development of the LA and in turn development of the embryo to term. [8][9][10][11][12] Among the 6 known membrane-type MMP (MT-MMP) molecules in the mouse, MT1-MMP and MT3-MMP possess pericellular collagenase activity and are required for both prenatal and postnatal remodeling of the major fibrillar collagen types, cell surface receptors, and signaling molecules. [13][14][15] Ablation of MT1-MMP deprives cells of the ability to migrate through and process several both permanent and provisional extracellular matrices, and in vivo leads to severe defects in postnatal remodeling of connective tissues. [16][17][18][19] Moreover, MT1-MMP is required in the stromal compartment for efficient dissemination of malignant epithelial cells in mouse mammary carcinoma. 20 MT1-MMP deficiency is partially mitigated by the activity of the molecular relative, MT3-MMP, which shares at least some overlapping substrate specificity with MT1-MMP. Accordingly, incremental loss of alleles encoding each molecule markedly exacerbates the cellular matrix remodeling deficit in a gene dosage dependent manner, and double deficiency results in severe developmental deficits and perinatal death, but importantly, not preterm loss of embryos. 15 As expected from these observations, MT1-MMP and MT3-MMP are frequently coexpressed in the same tissue compartments. The placental LA however is devoid of MT3-MMP expression but displays conspicuous expression of another MT-MMP family member, MT2-MMP. 11,21 So far, the function of MT2-MMP has been determined biochemically and in cell-based assays. Under these conditions, MT2-MMP displays the ability to process basement membrane components and fibrillar collagen matrices whereas its role in vivo has remained unexplored. 22,23 Here we demonstrate that MT2-MMP deficiency in the mouse is compatible with develop...