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Auristatin PE (PE) as an anti-microtubule agent possesses good anticancer activity. However, the poor target effect and strong side effect limit its clinical applications. Targeted delivery of PE may overcome the disadvantages associated with PE, being very conducive to continuing clinical trials of PE. Boron nitride nanotubes (BNNTs) with unique physical and chemical properties have attracted considerable attention in drug delivery. Herein, a targeted drug delivery strategy based on folate-conjugated boron nitride nanotubes (BNNTs-FA) was used to improve the efficacy of PE. It was found that PE was successfully loaded onto BNNTs-FA via π-π stacking and hydrogen bonding interactions. BNNTs-FA@PE exhibited stronger cytotoxicity to Hep G2 cells than free PE and BNNTs@PE complexes due to the increased cellular uptake of PE mediated by the FA receptor. BNNTs-FA@PE showed excellent antiproliferative activities in a dose- and time-dependent manner. Furthermore, BNNTs-FA@PE induced apoptosis of Hep G2 cells via an intrinsic mitochondria-mediated pathway by reducing the mitochondrial membrane potential, activating Caspase-9 and Caspase-3. The construction of BNNTs-FA@PE system successfully improves the target effect of PE and may be very promising for the treatment of liver cancer in the future., Competing Interests: Declaration of competing interest The authors have declared that no competing interests exist., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Auristatin PE (PE) as an anti-microtubule agent possesses good anticancer activity. However, the poor target effect and strong side effect limit the clinical application of PE. Boron nitride nanotubes (BNNTs) represent an outstanding carrier candidate providing a wise choice for liver-targeted drug delivery. A drug delivery system based on BNNTs and PE (BNNTs-PE) against liver cancer cells was designed and constructed in this study. Firstly, BNNTs were prepared and hydroxylated, subsequently, PE was loaded onto BNNTs by noncovalent conjugation and was stable at neutral pH but released at pH 4.49. It was found that BNNTs-PE demonstrates an enhanced anticancer activity against Hep G2 cells in comparison with free PE. BNNTs-PE kills cancer cells in a manner of mitochondria-mediated apoptosis pathway through reducing the mitochondrial membrane potential, activating caspase cascade. This BNNTs-PE system may be very promising for the treatment of liver cancer in the future., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Benzyl isothiocyanate (BITC) has been shown to inhibit invasion and induce apoptosis of various types of cancer. However, its role on human oral squamous cell carcinoma (OSCC) cells is still not well elucidated. In the present study, we investigated the effect of BITC on apoptosis and invasion of SCC9 cells, and its underlying mechanisms in vitro and in vivo. SCC9 cells were exposed to BITC (5 and 25 μM) for 24 and 48 h. Cell growth, apoptosis, invasion, and migration were detected in vitro by MTT, FITC-conjugated annexin V/propidium iodide staining followed by flow cytometry, Matrigel-coated semi-permeable modified Boyden, and wound-healing assay. S100A4, PUMA, and MMP-9 expressions were detected to investigate its mechanisms. Xenotransplantation experiments were used to investigate the role of BITC on tumor growth and lung metastasis. BITC inhibited cell viability and induced cell apoptosis in a dose- and time-dependent manner through upregulation of PUMA signals. BITC inhibited cell invasion and migration by downregulation of S100A4 dependent MMP-9 signals. The ip administration of BITC reduced tumor growth but not lung metastasis of SCC9 cells subcutaneously implanted in nude mice. BITC treatment activated pro-apoptotic PUMA and inhibited S100A4-dependent MMP-9 signals, resulting in the inhibition of cell growth and invasion in cultured and xenografted SCC9 cells. Thereby, BITC is a potential therapeutic approach for OSCC.

Schistosomes are causative agents of human schistosomiasis, which is endemic in tropical and subtropical areas of the world. Adult schistosomes can survive in their final hosts for several decades, and they have evolved various strategies to overcome the host immune response. Consequently, understanding the mechanisms that regulate parasitic cell survival will open avenues for developing novel strategies against schistosomiasis. Our previous study suggested that an inhibitor of apoptosis protein in Schistosoma japonicum (SjIAP) may play important roles in parasitic survival and development. Here, we demonstrated that SjIAP can negatively regulate cellular apoptosis in S. japonicum by suppressing caspase activity. Immunohistochemistry analysis indicated that SjIAP ubiquitously expressed within the worm body including the tegument. Silencing of SjIAP expression via small interfering RNA led to destruction of the tegument integrity in schistosomes. We further used co-immunoprecipitation to identify interaction partners of SjIAP and revealed the tegument protein SjTeg-20 as a putative interacting partner of SjIAP. The interaction between SjIAP and SjTeg-20 was confirmed by a yeast two-hybrid (Y2H) assay. Moreover, results of a TUNEL assay, RNA interference, scanning and transmission electron microscopy, caspase assays, transcript profiling, and protein localization of both interacting molecules provided first evidence for an essential role of SjIAP and SjTeg-20 to maintain the structural integrity of the tegument by negatively regulating apoptosis. Taken together, our findings suggest that the cooperative activities of SjIAP and SjTeg-20 belong to the strategic inventory of S. japonicum ensuring survival in the hostile environment within the vasculature of the final host., Competing Interests: The authors have declared that no competing interests exist.

A small molecule, 15b-β-hydroxy-5-N-acetylardeemin (IFB07188), was previously isolated from the fungi Aspergillus terreus. However, the toxicological features of this natural product have never been investigated. In present study, we described the anticancer activities of IFB07188. We found that IFB07188 can decrease the viability and invasive potency of multiple cancer cell lines. Further mechanistic investigation demonstrates that cell cycles are arrested at G2/M phase and the arrest is induced by deregulated cell cycle proteins. A concomitant flow cytometric analysis also shows that IFB07188 can trigger massive apoptosis in a dose-dependent manner. The proapoptotic effect of IFB07188-treated cancer cells is characterized by depolarization of mitochondria membrane potential (Δψ(m)) and positive Hochest staining. Finally, results from invasion assay suggest that IFB07188 can suppress tumor cell invasion independent of apoptosis. Collectively, these data establish that IFB07188 can effectively inhibit cancer cell growth and invasiveness, prompting its potential use in cancer chemotherapy., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Methylene blue (MB) is a widely studied agent currently under investigation for its properties relating to photodynamic therapy (PDT). Recent studies have demonstrated that MB exhibits profound phototoxicity affecting a variety of tumor cell lines. However, the mechanistic explanation for methylene-blue-mediated photodynamic therapy (MB-PDT) in the context of melanoma therapy is still obscure. In the present study, B16F1 melanoma cells were treated by MB-PDT under different conditions, and thereafter subjected to cell viability detection assays. MB-PDT could induce intense apoptotic cell death through a series of steps beginning with the photochemical generation of reactive oxygen species that activate the caspase-9/caspase-3 apoptosis pathway. Blocking activation of caspase-3 and induction of oxidative stress by caspase inhibitor and by glutathione, respectively, markedly reduced apoptotic cell death in vitro. Importantly, proteomics study defining altered protein expression in treated cells suggests the involvement of several mitochondrial proteins playing important roles in electron transfer chain, implying mitochondrial dysfunction during the treatment. Furthermore, a transplantable mouse melanoma model was utilized to estimate the effectiveness of MB-PDT in vivo. The treated mice displayed decreased tumor size and prolonged survival days, which was associated with enhanced apoptotic cell death. These results, offering solid evidence of the induction of mitochondria-related apoptosis in tumor cells, reveal new aspects of MB-PDT having potential to be a palliative treatment of melanoma.

Basic and clinical studies have demonstrated that the free radical scavenger edaravone has cytoprotective effects on acute myocardial infarction (AMI) but the underlying mechanism is not fully understood. The aim of this research is to explore the effect of edaravone on the apoptotic process involving the JAK2/STAT3 signaling pathway. AMI in rats was established by left anterior descending coronary artery ligation. Two hours after AMI model established rats were treated with edaravone, edaravone plus AG490, physiological saline, respectively. We detected antioxidant effects by reduced glutathione (GSH), glutathione S-transferase (GST), and Glutathione Peroxidase (GSHPx) Activity. The expressions of t-JAK2, p-JAK2, t-STAT3, p-STAT3 and cleaved caspase-3 were examined by western blot. The mRNA levels for Bcl-2, Bax, Fas, and FasL were measured by RT-PCR and apoptosis was assessed by TUNEL. Edaravone significantly improved hemodynamics after AMI (p < 0.05) and reduced the total infarct volumes (p < 0.05). Compared with Sham rats, the mRNA of Bax, Fas, and FasL increased in different degrees in the AMI group, however, the mRNA of Bcl-2 and the ratio of Bcl-2/Bax decreased, especially the myocardial apoptosis index significantly increased in AMI hearts (all p < 0.05). After treatment with edaravone, the mRNA levels of Bcl-2 and the ratio of Bcl-2/Bax significantly upregulated whereas Bax, Fas, FasL apparently decreased, and the protein expressions of p-JAK2 and p-STAT3 dramatically increased (p < 0.05). In addition, cotreatment with JAK2 inhibitor AG490 abolished the effects of edaravone. We conclude that edaravone attenuated myocardial apoptosis induced by AMI via JAK2/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Background. Microglial activation contributes to neuroinflammation and neuronal damage in neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases. It has been suggested that neurodegenerative disorders may be improved if neuroinflammation can be controlled. trans-cinnamaldehyde (TCA) isolated from the stem bark of Cinnamomum cassia possesses potent anti-inflammatory capability; we thus tested whether TCA presents neuroprotective effects on improving neuronal survival by inhibiting neuroinflammatory responses in BV2 microglial cells. Results. To determine the molecular mechanism behind TCA-mediated neuroprotective effects, we assessed the effects of TCA on lipopolysaccharide- (LPS-) induced proinflammatory responses in BV2 microglial cells. While LPS potently induced the production and expression upregulation of proinflammatory mediators, including NO, iNOS, COX-2, IL-1β, and TNF-α, TCA pretreatment significantly inhibited LPS-induced production of NO and expression of iNOS, COX-2, and IL-1β and recovered the morphological changes in BV2 cells. TCA markedly attenuated microglial activation and neuroinflammation by blocking nuclear factor kappa B (NF-κB) signaling pathway. With the aid of microglia and neuron coculture system, we showed that TCA greatly reduced LPS-elicited neuronal death and exerted neuroprotective effects. Conclusions. Our results suggest that TCA, a natural product, has the potential of being used as a therapeutic agent against neuroinflammation for ameliorating neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • 14-3-3 protein and ubiquitin C (UBC) interact with an inhibitor of apoptosis protein in Schistosoma japonicum. • Inhibition of Schistosoma japonicum 14-3-3 and UBC lead to tegument destruction in parasites. • 14-3-3 and UBC might play important roles in maintaining tegument integrity in S. japonicum. Abstract Schistosomiasis, caused by trematodes of the genus Schistosoma , remains an important public health issue. Adult schistosomes can survive in the definitive host for several decades, although they are subject to the host immune response. Consequently, understanding the mechanism underlying worm survival in the definitive hosts could aid in developing novel strategies against schistosomiasis. We previously found that an inhibitor of apoptosis in Schistosoma japonicum (SjIAP) could negatively regulate apoptosis by inhibiting caspase activity, which plays a critical role in maintaining tegument integrity. The current study aimed to further analyze the mechanism related to SjIAP governing worm tegument integrity; therefore, we used a yeast two-hybrid screen and identified a series of putative interacting partners of SjIAP, including 14-3-3 (Sj14-3-3) and ubiquitin C (SjUBC). Quantitative real time PCR (qRT-PCR) analysis indicated that transcript profiles of Sj14-3 - 3 and SjUBC increased together with worm development in definitive hosts, which corresponds to those of SjIAP in S. japonicum. Immunohistochemical analysis showed Sj14-3-3 and SjUBC were located in the tegument of adult parasites while they were also ubiquitously distributed in the bodies of worms. Silencing of Sj14-3 - 3 / SjUBC expression led to increased caspase activity and induced worm death. Inhibition of Sj14-3-3 or SjUBC resulted in significant morphological alterations in the schistosome tegument. Overall, our findings indicated that Sj14-3-3 and SjUBC interacting with SjIAP may belong to another strategy of S. japonicum to maintain the tegument integrity. [ABSTRACT FROM AUTHOR]

Melanoma, the type of skin cancer considered as most malignant, and known to be linked with a high incidence as well as high mortality rate. Although the dysregulation of ASF1B and miR-767-3p expression is involved in the progression of various cancers, their biological function in melanoma remains unclear. Real-time qPCR was the primary source for determining the levels of ASF1B and miR-767-3p in melanoma. For the validation of association among miR-767-3p and ASF1B, luciferase activity assay was used. Quantification of cell apoptosis, proliferation, migration and viability in melanoma cells were carried out by flow cytometry, BrdU, transwell assays, and CCK-8, respectively. Further evaluation of tumor growth was achieved by xenograft in vivo. Results showed an increased expression of ASF1B while declined expression of miR-767-3p in melanoma. ASF1B knockdown repressed cell migration, viability, proliferation, and tumor growth whereas boosted apoptosis in A375 as well as in A875 melanoma cells. Moreover, miR-767-3p attenuated the migration and proliferation of melanoma cells and encouraged cell apoptosis by reducing ASF1B levels. In this study, miR-767-3p was shown to inhibit ASF1B which will attenuate melanoma tumorigenesis, and by this it can be a potential new effective biomarker for the treatment of melanoma. • ASF1B is identified as the miR-767-3p downstream effector. • ASF1B was obviously increased in melanoma. • ASF1B knockdown inhibited tumor growth of melanoma in vivo. • ASF1B accelerated the progression of melanoma cells. [ABSTRACT FROM AUTHOR]