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A new diphenyl ether derivative, ethyl barceloneoate A (1), was isolated from the mangrove endophytic fungus Phoma sp. L28 (Valsaceae). Its structure was determined by comprehensive spectroscopic analyses. It displayed moderate microbial inhibitory activity against Penicillium italicum and weak activity against Fusarium graminearum, Staphylococcus aureus, and the avian pathogen Escherichia coli O78.

A novel tyroscherin derivative named pseudallecin A (

A new sesquiterpene derivative, ethyl hydroheptelidate (1), was isolated from the mangrove endophytic fungus Trichoderma harzianum R1. Its structure was elucidated by comprehensive spectroscopic analyses. This compound showed high antifungal activity against two plant pathogenic fungi, Fusarium oxysporum and Colletotrichum musae, and moderate to weak antibacterial activity against three types of avian pathogenic Escherichia coli: O8, O78, and O101.

Owing to the diversity of cancer types and the spatiotemporal heterogeneity of tumour signals, high-resolution imaging of occult malignancy is challenging. 18F-fluorodeoxyglucose positron emission tomography allows for near-universal cancer detection, yet in many clinical scenarios it is hampered by false positives. Here, we report a method for the amplification of imaging contrast in tumours via the temporal integration of the imaging signals triggered by tumour acidosis. This method exploits the catastrophic disassembly, at the acidic pH of the tumour milieu, of pH-sensitive positron-emitting neutral copolymer micelles into polycationic polymers, which are then internalized and retained by the cancer cells. Positron emission tomography imaging of the 64Cu-labelled polymers detected small occult tumours (10–20 mm3) in the brain, head, neck and breast of mice at much higher contrast than 18F-fluorodeoxyglucose, 11C-methionine and pH-insensitive 64Cu-labelled nanoparticles. We also show that the pH-sensitive probes reduce false positive detection rates in a mouse model of non-cancerous lipopolysaccharide-induced inflammation. This macromolecular strategy for integrating tumour acidosis should enable improved cancer detection, surveillance and staging. The detection of small tumours with PET is significantly enhanced by temporal integration of the imaging signals, triggered by the acidic milieu of cancers, from pH-sensitive positron-emitting polycationic polymers.

The strategy “IEMAHC” (Induction of Endophyte Metabolism by Adding Host Components) was applied to the fermentation of the endophytic fungus Epicoccum sorghinum L28 from Myoporum bontioides by introducing guaiol, an ingredient of M. bontioides, into the cultivation medium, which resulted in the purification of nine new diphenyl ethers, epicoccethers A–I (1–9). Their structures were determined by overall spectroscopic analysis. HPLC-MS analysis revealed that compounds 5–7 were products generated by induction of guaiol. Compounds 6 and 7 are the first members containing an ester moiety formed by the natural long-chain fatty acid and the hydroxyl group in the phenylmethanol unit of the diphenyl ether class. The antifungal activities of compounds 1, 2, and 4–7 against Fusarium oxysporum were 1, 1, 2, 1, 2 and 4 times as high as those of the positive control triadimefon, respectively. Compounds 4 and 5 showed 1.6 times the antifungal activities of triadimefon towards Colletotrichum musae.

To search for antifungal leads, the metabolites of an insect-derived fungus

To search for antifungal leads, the metabolites of an insect-derived fungus Fusarium lateritium ZMT01 were investigated, providing five sesquiterpenes (1–5), including new molecules microsphaeropsisins D and E (1 and 2). The evaluated antifungal activities in vitro which are higher than the positive control triadimefon include: 1 and 2 towards Fusarium oxysporum (MICs 50, 25 mg L−1; triadimefon 100 mg L−1); 1, 2, 4 and 5 towards Penicillium italicum (MICs 25, 12.5, 25, 25; triadimefon 50 mg L−1), 1, 2 and 4 towards Colletotrichum musae (MICs 25, 12.5, 25; triadimefon 80 mg L−1), 2 and 4 towards Fusarium graminearum (MICs 100, 100; triadimefon 150 mg L−1). The bioassay in vivo displayed that the banana anthracnose control effect of 2 (100 mg L−1) was also higher than that of triadimefon (Inhibition ratios 27.5 ± 2.5%, 55.3 ± 1.4%, 52.1 ± 1.3% for 2, 22.5 ± 2.1%, 47.2 ± 2.0%, 36.6 ± 2.2% for triadimefon at 4 d, 8 d and 12 d, respectively).

Egg ovalbumin (OVA) as a macromolecular carrier has the potential to improve the solubility and stability of insolubility bioactive molecules, however, their binding behavior and the mechanism is still ambiguous. In this work, the curcumin was selected as the target to study the interaction and binding mechanism between curcumin and OVA by thermodynamic titration technique in combination with molecular dynamic simulation. The results suggested that the binding included two steps: first, curcumin molecule entered into the hydrophobic pocket of OVA by hydrophobic interaction; and second the interaction was enhanced via hydrogen bonds, resulting in static fluorescence quenching and secondary structural change of OVA. This study provided further evidence in support of the proposed mechanism of the polyphenol-protein binding by the “Hands-gloves” model. Furthermore, when the OVA was as a carrier, the solubility of curcumin has been increased ~370 times to 32.73 μg/mL compared to that of free curcumin at pH 7.0. The photostability was enhanced significantly indicating that it is an efficient way to improve the stability of curcumin in contributing to its application in nutritional supplements or functional foods.

Programmed death–ligand 1 (PD-L1) expression on tumor cells is essential for T cell impairment, and PD-L1 blockade therapy has shown unprecedented durable responses in several clinical studies. Although higher expression of PD-L1 on tumor cells is associated with a better immune response after Ab blockade, some PD-L1–negative patients also respond to this therapy. In the current study, we explored whether PD-L1 on tumor or host cells was essential for anti–PD-L1–mediated therapy in 2 different murine tumor models. Using real-time imaging in whole tumor tissues, we found that anti–PD-L1 Ab accumulates in tumor tissues, regardless of the status of PD-L1 expression on tumor cells. We further observed that, while PD-L1 on tumor cells was largely dispensable for the response to checkpoint blockade, PD-L1 in host myeloid cells was essential for this response. Additionally, PD-L1 signaling in defined antigen-presenting cells (APCs) negatively regulated and inhibited T cell activation. PD-L1 blockade inside tumors was not sufficient to mediate regression, as limiting T cell trafficking reduced the efficacy of the blockade. Together, these findings demonstrate that PD-L1 expressed in APCs, rather than on tumor cells, plays an essential role in checkpoint blockade therapy, providing an insight into the mechanisms of this therapy.

Owing to the diversity of cancer types and the spatiotemporal heterogeneity of tumour signals, high-resolution imaging of occult malignancy is challenging.

Chemical modification is a useful method to change the properties of enzymes. Laccase is a phenol oxidase belonging to a multicopper protein, which catalyzes the oxidation of many phenolics. DeniLite IIS, a commercial laccase preparation from the Novozymes China Company, was purified by ammonium sulfate fractional precipitation. Succinic anhydride (SA) was used as a modifier for the chemical modification of the purified laccase. The effects of modification were characterized using the 6-trinitrobenzene sulfonic acid method, ultraviolet spectroscopy, and fluorescence spectroscopy. The pH stability, thermal stability, and the phenolics removal efficiency for the native and modified laccases were compared. The results showed that the average amino modification yield of the modified laccase was 85% and the modified laccase had a blue shifted ultraviolet peak and fluorescence emission peak as well as a decrease in the ultraviolet absorbance and an increase in the fluorescence intensity. Although chemical modification with SA did not change the optimum temperature for the catalysis of the laccase, it caused the optimum pH of the catalysts to shift from 4.5 to 5.5 and the enzymatic activity increased by 60%. Compared with the native laccase, the modified laccase exhibited remarkably higher pH stability and thermal stability and its catalysis efficiency (kcat) and substrate affinity (kcat/Km) increased by 53% and 122%, respectively. The phenolics removal efficiency (o-, m-, p-dihydroxybenzene) of the modified laccase increased by 48%, 57%, and 18%, respectively. These results indicate that the modified laccase with higher stability and higher efficiency is suitable for application in industrial production and for the treatment of phenolics-polluted water.

Objectives: Traditional cancer chemotherapy is normally associated with systemic toxicity due to the lack of tumor-targeting specificity. Recent efforts have therefore focused on targeted therapy to reduce such systemic toxicity. We have recently developed a pair of 18/19F-labeled theranostic small-molecule drug conjugates (18/19F-T-SMDCs) for prostate cancer precision theranostics, which consists of a prostate-specific membrane antigen (PSMA) specific ligand for prostate cancer targeting, a cytotoxic drug (DM1, with high antimitotic cytotoxicity at subnanomolar range) for chemotherapy, and an 18F imaging unit via a lysine-PEG trifunctional linker for PET imaging or a nonradioactive 19F unit for therapy in order to overcome the dosage gap between diagnostic and therapeutic agents. The18/19F-T-SMDCs have been demonstrated to retain the PSMA binding affinity, exhibit high cell uptake in PSMA-positive cells, display an appreciable level of internalization in a time-dependent manner, and be capable of specifically imaging PSMA-expressing cancer xenografts in mice. Here we evaluated the in vitro cytotoxicity and in vivo therapeutic potency of the18/19F-T-SMDCs. Methods: The in vitro cytotoxicity of 19F-T-SMDC was measured by crystal violet cell growth assay in PSMA-positive LNCaP cells and PSMA-negative PC-3 cells. The DM1 free drug was included in the assay as an internal positive standard to compare the toxicity of 19F-T-SMDC in these two cell lines. In vivo treatment study was performed in SCID mice bearing PSMA-positive PC3-PIP subcutaneous tumors to evaluate both imaging and therapeutic performance of 18/19F-T-SMDCs (DM1). The treatment started when the average tumor volumes were in the range of 100 - 200 mm3 (length × width × height × 0.523), with intravenous injection of 15 or 40 nmol 19F-T-SMDC in 10% ethanol solution per mouse (n = 8) for three times a week for total four injections. The control group of mice received 10% ethanol solution plus 0.075 nmol 19F-T-SMDC (DM1) following the same injection schedule (n = 3). PET imaging with 18F-T-SMDC (DM1) was conducted before (Day 0: 18F-T-SMDC only) and during the 1st-dose treatment (Day 1: coinjection of 18/19F-T-SMDC) for both 15 and 40 nmol groups (n = 3). Besides the PET imaging with 18F-T-SMDC, concurrent FDG PET imaging was also conducted in the 15 nmol group mice (n = 3) before and post treatment (week 4) to monitor the treatment responses. Results: The PSMA-positive LNCaP cells exhibited higher toxicity from 19F-T-SMDC (DM1) than PSMA-negative PC-3 cells. In comparison to free DM1 drug, the 19F-T-SMDC (DM1) was less toxic in both LNCaP and PC-3 cells. The reduced toxicity of the T-SMDC is desirable to alleviate the acute side effects of the drug (DM1) to normal tissues. For treatment study, 19F-T-SMDC (DM1) showed controllable acute toxicity, with the body weight loss all within 15%. While the 40-nmol group showed a greater body weight loss than the 15-nmol group, both groups started their body weight recovery from Day 18. In contrast, the control group showed no body weight loss until Day 10 when the tumor burden became severe. The average tumor sizes of both high- and low-dose treatment groups stopped increasing by Day 7. After then, all tumors started shrinking over the course of the treatment. Meanwhile, the control group was observed with fast and continuous tumor growth. Although the increased dose did not benefit the tumor reduction, the high-dose treatment group exhibited delayed tumor recurrence compared to the low-dose group. Conclusions: The 18/19F-T-SMDCs retain PSMA binding affinity, exhibit PSMA-dependent toxicity, and are capable of specifically imaging PSMA-positive cancer xenografts in mice. They also show effective therapeutic performance in in vivo tumor treatment study, and can be served as a promising strategy for prostate cancer precision theranostics Citation Format: Bing Guan, Yunkou Wu, Jingyue Yang, Yahong Xiong, Jer-Tsong Hsieh, Guiyang Hao, Xiankai Sun. Development of paired small-molecule drug conjugates for prostate cancer precision theranostics [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B066.