Melatonin is present in virtually all organisms from bacteria to mammals, and it exhibits a broad spectrum of biological functions, including synchronization of circadian rhythms and oncostatic activity. Several functions of melatonin are mediated by its membrane receptors, but others are receptor-independent. For the latter, melatonin is required to penetrate membrane and enters intracellular compartments. However, the mechanism by which melatonin enters cells remains debatable. In this study, it was identified that melatonin and its sulfation metabolites were the substrates of oligopeptide transporter (PEPT) 1/2 and organic anion transporter (OAT) 3, respectively. The docking analysis showed that the binding of melatonin to PEPT1/2 was attributed to their low binding energy and suitable binding conformation in which melatonin was embedded in the active site of PEPT1/2 and fitted well with the cavity in three-dimensional space. PEPT1/2 transporters play a pivotal role in melatonin uptake in cells. Melatonin's membrane transportation via PEPT1/2 renders its oncostatic effect in malignant cells. For the first time, PEPT1/2 were identified to localize in the mitochondrial membrane of human cancer cell lines of PC3 and U118. PEPT1/2 facilitated the transportation of melatonin into mitochondria. Melatonin accumulation in mitochondria induced apoptosis of PC3 and U118 cells. Thus, PEPT1/2 can potentially be used as a cancer cell-targeted melatonin delivery system to improve the therapeutic effects of melatonin in cancer treatment.

Resveratrol, a natural phytoalexin, exhibits a remarkable range of biological activities, such as anticancer, cardioprotective, neuroprotective and antioxidant properties. However, the therapeutic application of resveratrol was encumbered for its low bioavailability. Therefore, many researchers focused on designing and synthesizing the derivatives of resveratrol to enhance the bioavailability and the pharmacological activity of resveratrol. During the past decades, a large number of natural and synthetic resveratrol derivatives were extensively studied, and the methoxylated, hydroxylated and halogenated derivatives of resveratrol received particular more attention for their beneficial bioactivity. So, in this review, we will summarize the chemical structure and the therapeutic versatility of resveratrol derivatives, and thus provide the related structure activity relationship reference for their practical applications.

Twelve new and 10 known protostane triterpenoids were isolated from the rhizome of Alisma orientale. Their structures were elucidated based on physical data analyses, including UV, HRESIMS, NMR experiments ((1)H, (13)C NMR, (1)H-(1)H COSY, HSQC, HMBC, and NOESY), and induced electronic circular dichroism. New compounds 1-12 were classified as protostanes (1-10), 29-norprotostane (11), and 24-norprotostane (12) by structure analyses. Furthermore, the inhibitory effects on human carboxylesterases (hCE-1, hCE-2) of compounds 1-22 were evaluated. Compounds 2, 6, 9, and 11 showed moderate inhibitory activities and were selective toward hCE-2 enzymes, with IC50 values of 8.68, 4.72, 4.58, and 2.02 μM, respectively. The inhibition kinetics of compound 11 toward hCE-2 were established, and the Ki value was determined as 1.76 μM using a mixed inhibition model. The interaction of bioactive compound 11 with hCE-2 was shown using molecular docking.

STAT3 is the most ubiquitous member of the STAT family and involved in many biological processes, such as cell proliferation, differentiation, and apoptosis. Mounting evidence has revealed that STAT3 is aberrantly activated in many malignant tumors and plays a critical role in cancer progression. STAT3 is usually regarded as an effective molecular target for cancer treatment, and abolishing the STAT3 activity may diminish tumor growth and metastasis. Recent studies have shown that negative regulators of STAT3 signaling such as PIAS, SOCS, and PTP, can effectively retard tumor progression. However, PIAS, SOCS, and PTP have also been reported to correlate with tumor malignancy, and their biological function in tumorigenesis and antitumor therapy are somewhat controversial. In this review, we summarize actual knowledge on the negative regulators of STAT3 in tumors, and focus on the potential role of PIAS, SOCS, and PTP in cancer treatment. Furthermore, we also outline the STAT3 inhibitors that have entered clinical trials. Targeting STAT3 seems to be a promising strategy in cancer therapy.

Gamabufotalin (CS-6), a main active compound isolated from Chinese medicine Chansu, has been shown to strongly inhibit cancer cell growth and inflammatory response. However, its effects on angiogenesis have not been known yet. Here, we sought to determine the biological effects of CS-6 on signaling mechanisms during angiogenesis. Our present results fully demonstrate that CS-6 could significantly inhibit VEGF triggered HUVECs proliferation, migration, invasion and tubulogenesis in vitro and blocked vascularization in Matrigel plugs impregnated in C57/BL6 mice as well as reduced vessel density in human lung tumor xenograft implanted in nude mice. Computer simulations revealed that CS-6 interacted with the ATP-binding sites of VEGFR-2 using molecular docking. Furthermore, western blot analysis indicated that CS-6 inhibited VEGF-induced phosphorylation of VEGFR-2 kinase and suppressed the activity of VEGFR-2-mediated signaling cascades. Therefore, our studies demonstrated that CS-6 inhibited angiogenesis by inhibiting the activation of VEGFR-2 signaling pathways and CS-6 could be a potential candidate in angiogenesis-related disease therapy.