A novel small-molecule activator of unfolded protein response suppresses castration-resistant prostate cancer growth.

Androgen receptor-targeted therapy improves survival in castration-resistant prostate cancer (CRPC). However, almost all patients with CRPC eventually develop secondary resistance to these drugs. Therefore, alternative therapeutic approaches for incurable metastatic CRPC are urgently needed. Unfolded protein response (UPR) is regarded as a cytoprotective mechanism that removes misfolded proteins in rapidly proliferating tumor cells. However, acute activation of the UPR directly leads to tumor cell death. This study has shown that WJ-644A, a novel small molecule activator of UPR, potently inhibited the proliferation of prostate cancer cells and caused tumor regression with a good safety profile in multiple animal models. Mechanistically, we have identified that WJ-644A induced cell methuosis and autophagy upon UPR activation. Our study not only identifies the UPR as an actionable target for CRPC treatment, but also establishes WJ-644A as a novel UPR activator that has potential therapeutic value for CRPC.

Reviews and advances in diagnostic research on Schistosoma japonicum.

Schistosomiasis is an acute and chronic parasitic disease caused by blood flukes (trematode worms) of the genus Schistosoma. Schistosoma japonicum (S. japonicum) infection has decreased significantly in prevalence and intensity of infection in China. However, this disease still remains a serious public health problem in some endemic areas of the Philippines and Indonesia. Thus, more accurate and sensitive methods are much needed for further control of this disease. Here, we review the research progress in techniques for the diagnosis of S. japonicum infection.

Regression of Castration-Resistant Prostate Cancer by a Novel Compound HG122.

Prostate cancer (PCa) is a common aggressive disease worldwide which usually progresses into incurable castration-resistant prostate cancer (CRPC) in most cases after 18-24 months treatment. Androgen receptor (AR) has been considered as a crucial factor involved in CRPC and the study of AR as a potential therapeutic target in CRPC may be helpful in disease control and life-cycle management. In this study, we identified a potent small molecule compound, HG122, that suppressed CRPC cells proliferation and metastasis, and inhibited tumor growth both in subcutaneous and orthotopic tumor model. In addition, HG122 reduced the mRNA expression of PSA and TMPRSS2 which are target genes of AR, resulting in cell growth inhibition and metastasis suppression of CRPC, without affecting the expression of AR mRNA level. Mechanically, HG122 promoted AR protein degradation through the proteasome pathway impairing the AR signaling pathway. In conclusion, HG122 overcomes enzalutamide (ENZ) resistance in CRPC both in vitro and in vivo, thus suggesting HG122 is a potential candidate for the clinical prevention and treatment of CRPC.

Development of a Recombinase Polymerase Amplification Assay for Schistosomiasis Japonica Diagnosis in the Experimental Mice and Domestic Goats.

Although the prevalence of schistosomiasis japonica has declined gradually in China, more accurate and sensitive diagnostic methods are urgently needed for the prevention and control of this disease. Molecular diagnostic methods are advantageous in terms of sensitivity and specificity, but they are time-consuming and require expensive instruments and skilled personnel, which limits their application in low-resource settings. In this study, an isothermal DNA amplification assay and recombinase polymerase amplification (RPA) combined with lateral flow dipstick (LFD) were set up. It was used to detect S. japonicum infections in experimental mice and domestic goats by amplifying a specific DNA fragment of S. japonicum. The lower limit of detection for the LFD-RPA assay was evaluated using dilutions of plasmid containing the target sequence. Cross-reactivity was evaluated using genomic DNA from eight other parasites. The effectiveness of the LFD-RPA assay was verified by assessing 36 positive plasma samples and 36 negative plasma samples from mice. The LFD-RPA assay and real-time PCR were also used to assess 48 schistosomiasis japonica-positive plasma samples and 53 negative plasma samples from goats. The LFD-RPA assay could detect 2.6 femtogram (fg) of S. japonicum target DNA (~39 fg genomic DNA of S. japonicum), only 10-fold less sensitive than real-time PCR assay. There was no cross-reactivity with DNA from the other eight parasites, such as Haemonchus contortus and Spirometra. The whole amplification process could be completed within 15 min at 39°C, and the results can be observed easily using the LFD. The sensitivity and specificity of the LFD-RPA assay were 97.22% (35/36, 95% CI, 85.47%-99.93%) and 100% (36/36, 95% CI, 90.26%-100%) in mice, and 93.75% (45/48, 95% CI, 82.80%-98.69%) and 100% (53/53, 95% CI, 93.28%-100%) in goats. By comparison, the sensitivity and specificity of real-time PCR were 100% (36/36, 95% CI, 90.26%-100%) and 100% (36/36, 95% CI, 90.26%-100%) for mice, and 97.92% (47/48, 95% CI, 88.93%-99.95%) and 100% (53/53, 95% CI, 93.28%-100%) for goats. The LFD-RPA assay exhibits high sensitivity and specificity for the diagnosis of schistosomiasis japonica, and it is an alternative method for diagnosis schistosomiasis japonica in low resource setting.

Novel hemostatic agents based on gelatin-microbial transglutaminase mix.

Hemostasis is a major challenge in surgical procedures and traumas. Conventional hemostatic methods have limited efficacy and may cause additional tissue damage. In this study, we designed a novel hemostatic agent based on the in situ gel formation of gelatin cross-linked by a novel microbial transglutaminase (mTGase), in which the amino acid sequences differed from commercial mTGases. The new hemostatic agent showed the same biochemical crosslinking chemistry as the final stages of the blood coagulation cascade while using gelatin as a "structural" protein (rather than fibrin) and a calcium-independent mTGase as the crosslinking catalyst (rather than factor XIIIa). In rat liver hemostasis models, the hemostatic agent not only showed a similar hemostatic effect as that of SURGIFLO® (positive control), but also stronger adhesion strength and elasticity than SURGIFLO®. Therefore, this biomimetic gelatin-mTGase mix hemostatic is a novel and effective surgical sealant.

A novel synthetic small molecule YF-452 inhibits tumor growth through antiangiogenesis by suppressing VEGF receptor 2 signaling.

Tumor angiogenesis is characterized by abnormal vessel morphology, endowing tumor with highly hypoxia and unresponsive toward treatment. To date, mounting angiogenic factors have been discovered as therapeutic targets in antiangiogenic drug development. Among them, vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors exerts potent antiangiogenic activity in tumor therapy. Therefore, it may provide a valid strategy for cancer treatment through targeting the tumor angiogenesis via VEGFR2 pathway. In this study, we established a high-profile compounds library and certificated a novel compound named N-(N-pyrrolidylacetyl)-9-(4-bromobenzyl)-1,3,4,9-tetrahydro-ß-carboline (YF-452), which remarkably inhibited the migration, invasion and tube-like structure formation of human umbilical vein endothelial cells (HUVECs) with little toxicity invitro. Rat thoracic aorta ring assay indicated that YF-452 significantly blocked the formation of microvascular exvivo. In addition, YF-452 inhibited angiogenesis in chick chorioallantoic membrane (CAM) and mouse corneal micropocket assays. Moreover, YF-452 remarkably suppressed tumor growth in xenografts mice model. Furthermore, investigation of molecular mechanism revealed that YF-452 inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including extracellular signal regulated kinase (ERK), focal adhesion kinase (FAK) and Src. These results indicate that YF-452 inhibits angiogenesis and may be a potential antiangiogenic drug candidate for cancer therapy.

Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer.

Androgen receptor (AR) antagonist MDV3100 is the first therapeutic approach in treating castration-resistant prostate cancer (CRPC), but tumours frequently become drug resistant via multiple mechanisms including AR amplification and mutation. Here we identify the small molecule Ailanthone (AIL) as a potent inhibitor of both full-length AR (AR-FL) and constitutively active truncated AR splice variants (AR-Vs). AIL binds to the co-chaperone protein p23 and prevents AR's interaction with HSP90, thus resulting in the disruption of the AR-chaperone complex followed by ubiquitin/proteasome-mediated degradation of AR as well as other p23 clients including AKT and Cdk4, and downregulates AR and its target genes in PCa cell lines and orthotopic animal tumours. In addition, AIL blocks tumour growth and metastasis of CRPC. Finally, AIL possesses favourable drug-like properties such as good bioavailability, high solubility, lack of CYP inhibition and low hepatotoxicity. In general, AIL is a potential candidate for the treatment of CRPC.

Lycorine is a novel inhibitor of the growth and metastasis of hormone-refractory prostate cancer.

Lycorine, a natural alkaloid extracted from the Amaryllidaceae plant family, has been reported to exhibit a wide range of physiological effects, including the potential effect against cancer. However, the anti-prostate cancer (PCa) efficacy of Lycorine remains unrevealed. In this context, we figured out Lycorine's anti-proliferative and anti-migratory properties for PCa treatment. Lycorine inhibited proliferation of various PCa cell lines, induced cell apoptosis and cell death. Here we showed that Lycorine decreased proliferation, migration, invasion, survival and EMT of prostate cancer cell lines. Subcutaneous and orthotopic xenotransplantations by ectopic implantation of the human hormone-refractory PC-3M-luc cells were used to confirm in vivo anticancer effects of Lycorine. Lycorine inhibited both growth and metastasis in multiple organs (liver, lung, kidney, spleen and bone) in vivo and improved mice survival. Lycorine prevented EGF-induced JAK/STAT signaling. Importantly, anti-cancer effects of Lycorine were dependent on STAT expression. We suggest that Lycorine is a potential therapeutic in prostate cancer.

Dioscin, a natural steroid saponin, shows remarkable protective effect against acetaminophen-induced liver damage in vitro and in vivo.

The aim of the study was to investigate the protective effect of dioscin against APAP-induced hepatotoxicity. In the in vitro tests, HepG2 cells were given APAP pretreatment with or without dioscin. In the in vivo experiments, mice were orally administrated dioscin for five days and then given APAP. Some biochemical and morphology parameters were assayed and the possible mechanism was investigated. Dioscin improved AST release, mitochondrial dysfunction, apoptosis and necrosis of HepG2 cells induced by APAP. Following administration of dioscin, APAP-induced hepatotoxicity in mice was significantly attenuated. Furthermore, the liver cell apoptosis and necrosis, and hepatic mitochondrial edema were also prevented. Fifteen differentially expressed proteins were found by using proteomics, and six of them, Suox, Krt18, Rgn, Prdx1, MDH and PNP were validated. These proteins may be involved in the hepatoprotective effect of dioscin and might cooperate with the levels of Ca(2+) in mitochondria, decreased expression of ATP2A2, and decreased mitochondrial cardiolipin. In addition, dioscin inhibited APAP-induced activation and expression of CYP2E1, up-regulated the expression of Bcl-2 and Bid, and inhibited the expression of Bax, Bak and p53. Dioscin showed a remarkable protective effect against APAP-induced hepatotoxicity by adjusting mitochondrial function. These results indicated that dioscin has the capability on the treatment of liver injury.

Mechanism investigation of dioscin against CCl4-induced acute liver damage in mice.

The mechanisms of the ameliorating effects of dioscin against CCl(4) induced acute liver damage are investigated in this study. Dioscin significantly inhibited (p<0.01) the increases of serum ALT and AST activities compared with the CCl(4)-treated animals. The hepatic lipid peroxidation formation and, concentrations of TNF-α and IL-6 were also decreased. Liver histopathologic studies and a DNA laddering assay indicated that dioscin protected hepatocytes against CCl(4)-induced apoptosis and necrosis. Furthermore, dioscin decreased the protein expressions of Fas/FasL, increased Bcl-2/Bax ratio, inhibited the release of cytochrome c from mitochondrion to cytosol and attenuated CCl(4)-induced caspase-3 and -8 activities. The expressions of ICAM-1, vimentin, prohibitin, HGF, c-MET and GSTA1 were also regulated by dioscin and iNOS was also involved in the effects of this agent. These protective effects against CCl(4) induced acute liver damage might be through inhibiting lipid peroxidation, inflammatory cytokines, necrosis and apoptosis, and dioscin shows promise for development toward the treatment of acute chemically mediated liver injury.