Cisplatin is a clinically advanced and highly effective anticancer drug used in the treatment of a wide variety of malignancies, such as head and neck, lung, testis, ovary, breast cancer, etc. However, it has only a limited use in clinical practice due to its severe adverse effects, particularly nephrotoxicity; 20%-35% of patients develop acute kidney injury (AKI) after cisplatin administration. The nephrotoxic effect of cisplatin is cumulative and dose dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI result in impaired renal tubular function and acute renal failure, chronic kidney disease, uremia, and hypertensive nephropathy. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, apoptosis, oxidative stress, inflammation, and vascular injury in the kidneys. At present, there are no effective drugs or methods for cisplatin-induced kidney injury. Recent in vitro and in vivo studies show that numerous natural products (flavonoids, saponins, alkaloids, polysaccharide, phenylpropanoids, etc.) have specific antioxidant, anti-inflammatory, and anti-apoptotic properties that regulate the pathways associated with cisplatin-induced kidney damage. In this review we describe the molecular mechanisms of cisplatininduced nephrotoxicity and summarize recent findings in the field of natural products that undermine these mechanisms to protect against cisplatin-induced kidney damage and provide potential strategies for AKI treatment.

Endometrial cancer (EC) is the most common gynecological malignancy worldwide. However, the molecular mechanisms underlying EC progression are still largely unknown, and chemotherapeutic options for EC patients are currently very limited. In this study, we found that histone methyltransferase EZH2 and DNA methyltransferase DNMT3B were upregulated in EC samples from patients, and promoted EC cell proliferation as evidenced by assays of cell viability, cell cycle, colony formation. Mechanistically, we found that EZH2 promoted EC cell proliferation by epigenetically repressing TCF3, a direct transcriptional activator of CCKN1A (p21WAF1/Cip1), in vitro and in vivo. In addition, we found that DNMT3B specifically methylated the TCF3 promoter, repressing TCF3 expression and accelerating EC cell proliferation independently of EZH2. Importantly, elevated expression of EZH2 or DNMT3B in EC patients inversely correlated with expression of TCF3 and p21, and was associated with shorter overall survival. We show that combined treatment with GSK126 and 5-Aza-2d treatment wit synergistically inhibited methyltransferase activity of EZH2 and DNMT3B, resulting in a profound block of EC cell proliferation as well as EC tumor progression in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. These findings reveal that TCF3 functions as a tumor suppressor epigenetically silenced by EZH2 and DNMT3B in EC, and support the notion that targeting the EZH2/DNMT3B/TCF3/p21 axis may be a novel and effective therapeutic strategy for treatment of EC.

Long non-coding RNA plasmacytoma variant translocation 1 (PVT1) is a dysregulated gene in malignancy and is associated with oncogenesis. In this study, we found PVT1 RNA was an ovarian specific expressing gene, and overexpressed in multiple cancer types, including ovarian cancer (OV). Higher expression levels of PVT1 are related to shorter survival time in OV patients, especially in patients with advanced stage and grade. Recent studies indicated circular PVT1 also had an important role in cancer progression, whose roles in OV remain unclear. Knockdown of circular PVT1 significantly suppressed OV cell proliferation, migration and invasion. Bioinformatics analysis demonstrated that circular PVT1 was involved in regulating angiogenesis, osteoblast differentiation, regulation of cell growth, type B pancreatic cell proliferation, negative regulation of apoptotic process, phospholipid homeostasis, regulation of neurogenesis, definitive hemopoiesis, cell migration, regulation of glucose metabolic process, central nervous system development and type 2 immune response. Our data showed miR-149-5p targeted FOXM1, which was regulated by circular PVT1. Forkhead Box M1 (FOXM1) expression in ovarian cancer exhibited high level when compared with normal tissues, and had relation with relatively poor survival. FOXM1 promoted cell viability and reduced FOXM1 could rescue circular influence of circular PVT1-caused carcinoma induction. In conclusion, circular PVT1 increased FOXM1 level via binding to miR-149-5p and thus affected ovarian cancer cell viability and migration.

Activated hepatic stellate cells (HSCs) serve key roles in hepatic fibrosis by producing excessive extracellular matrix (ECM) components. Lipopolysaccharide (LPS) has been found to be associated with hepatic fibrogenesis through direct interactions with HSCs. Recently, the fibroblast growth factor receptor 1 (FGFR1) signalling system was identified as a key player in the process of liver fibrosis. In the present study it was evaluated whether FGFR1 mediated LPS-induced HSCs activation. In cultured cells, FGFR1 was inhibited by either siRNA silencing or by a small-molecule inhibitor in LPS-stimulated HSCs. The blockade of FGFR1 decreased LPS-induced nuclear factor-κB (NF-κB) activation, inflammatory cytokine release, fibrosis, and cell proliferation in HSCs. It was further indicated that LPS triggered FGFR1 phosphorylation via TLR4/c-Src. These findings confirmed the detrimental effect of FGFR1 activation in the pathogenesis of LPS-related HSC activation and revealed that FGFR1 may be an ideal therapeutic target for LPS-induced liver fibrosis.

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