A glycyrrhetinic acid-iridium(III) conjugate as a theranostic NIR probe for hepatocellular carcinoma with mitochondrial-targeting ability.

Hepatocellular carcinoma (HCC) is a major contributor to global mortality rates, but current treatment options have limitations. Advanced theranostics are needed to effectively integrate diagnosis and therapeutic of HCC. Glycyrrhetinic acid (GA) has abundant binding sites with glycyrrhetinic acid receptors (GA-Rs) on the surface of HCC cells and has also been reported to possess ligands with mitochondrial-targeting capability but with limited efficacy. Herein, we report a near-infrared (NIR) luminescent theranostic complex 1 through conjugating an iridium(III) complex to GA, which exhibits the desired photophysical properties and promotes mitochondrial-targeting capability. Complex 1 was selectively taken up by HepG2 liver cancer cells and was imaged within mitochondria with NIR emission. Complex 1 targeted mitochondria and opened mitochondrial permeability transition pores (MPTPs), resulting in ROS accumulation, mitochondrial damage, disruption of Bax/Bcl-2 equilibrium, and tumor cell apoptosis, resulting in significantly improved anticancer activity compared to GA. This work offers a methodology for developing multifunctional theranostic probes with amplified specificity and efficacy.

A robust luminescent assay for screening alkyladenine DNA glycosylase inhibitors to overcome DNA repair and temozolomide drug resistance.

Temozolomide (TMZ) is an anticancer agent used to treat glioblastoma, typically following radiation therapy and/or surgical resection. However, despite its effectiveness, at least 50% of patients do not respond to TMZ, which is associated with repair and/or tolerance of TMZ-induced DNA lesions. Studies have demonstrated that alkyladenine DNA glycosylase (AAG), an enzyme that triggers the base excision repair (BER) pathway by excising TMZ-induced N3-methyladenine (3meA) and N7-methylguanine lesions, is overexpressed in glioblastoma tissues compared to normal tissues. Therefore, it is essential to develop a rapid and efficient screening method for AAG inhibitors to overcome TMZ resistance in glioblastomas. Herein, we report a robust time-resolved photoluminescence platform for identifying AAG inhibitors with improved sensitivity compared to conventional steady-state spectroscopic methods. As a proof-of-concept, this assay was used to screen 1440 food and drug administration-approved drugs against AAG, resulting in the repurposing of sunitinib as a potential AAG inhibitor. Sunitinib restored glioblastoma (GBM) cancer cell sensitivity to TMZ, inhibited GBM cell proliferation and stem cell characteristics, and induced GBM cell cycle arrest. Overall, this strategy offers a new method for the rapid identification of small-molecule inhibitors of BER enzyme activities that can prevent false negatives due to a fluorescent background.

The role and prospect of lysine-specific demethylases in cancer chemoresistance.

Histone methylation plays a key function in modulating gene expression, and preserving genome integrity and epigenetic inheritance. However, aberrations of histone methylation are commonly observed in human diseases, especially cancer. Lysine methylation mediated by histone methyltransferases can be reversed by lysine demethylases (KDMs), which remove methyl marks from histone lysine residues. Currently, drug resistance is a main impediment for cancer therapy. KDMs have been found to mediate drug tolerance of many cancers via altering the metabolic profile of cancer cells, upregulating the ratio of cancer stem cells and drug-tolerant genes, and promoting the epithelial-mesenchymal transition and metastatic ability. Moreover, different cancers show distinct oncogenic addictions for KDMs. The abnormal activation or overexpression of KDMs can alter gene expression signatures to enhance cell survival and drug resistance in cancer cells. In this review, we describe the structural features and functions of KDMs, the KDMs preferences of different cancers, and the mechanisms of drug resistance resulting from KDMs. We then survey KDM inhibitors that have been used for combating drug resistance in cancer, and discuss the opportunities and challenges of KDMs as therapeutic targets for cancer drug resistance.

An optimized BRD4 inhibitor effectively eliminates NF-κB-driven triple-negative breast cancer cells.

Acetylation of NF-κB's RelA subunit at lysine-310 (AcLys310) helps to maintain constitutive NF-κB activity in cancers such as triple-negative breast cancer (TNBC). Bromodomain-containing factor BRD4 binds to acetylated RelA to promote the activity of NF-κB. Hence, interfering with the acetylated RelA-BRD4 interaction is a potential strategy for treating NF-κB-driven TNBC. Here, a new compound 13a was obtained by structural optimization and modification of our previously reported compound. In comparison with the well-known BRD4 inhibitor (+)-JQ1, 13a showed more potent anticancer activity in NF-κB-active MDA-MB-231 cells. Mechanistically, 13a antagonized the protein-protein interaction (PPI) between BRD4 and acetylated RelA, decreased levels of IL-6, IL-8, Snail, Vimentin, and ZEB1, induced cell senescence and DNA damage, and weakened the adhesion, metastasis, and invasion ability of TNBC cells. Our results provide insights into avenues for the further development of potent BRD4-acetylated RelA PPI inhibitors. Moreover, our findings highlight the effectiveness and feasibility of blocking the interaction between BRD4 and acetylated RelA against NF-κB-active cancers, and of screening antagonists of this PPI.

Ubiquitination Regulators Discovered by Virtual Screening for the Treatment of Cancer.

The ubiquitin-proteasome system oversees cellular protein degradation in order to regulate various critical processes, such as cell cycle control and DNA repair. Ubiquitination can serve as a marker for mutation, chemical damage, transcriptional or translational errors, and heat-induced denaturation. However, aberrant ubiquitination and degradation of tumor suppressor proteins may result in the growth and metastasis of cancer. Hence, targeting the ubiquitination cascade reaction has become a potential strategy for treating malignant diseases. Meanwhile, computer-aided methods have become widely accepted as fast and efficient techniques for early stage drug discovery. This review summarizes ubiquitination regulators that have been discovered via virtual screening and their applications for cancer treatment.

Morphine-induced RACK1-dependent autophagy in immortalized neuronal cell lines.

BACKGROUND AND PURPOSE: Autophagy is a critical cellular catabolic process in cell homoeostasis and brain function. Recent studies indicate that receptor for activated C kinase 1 (RACK1) is involved in autophagosome formation in Drosophila and mice, and that it plays an essential role in morphine-associated memory. However, the exact mechanism of the role of RACK1 in morphine-induced autophagy is not fully understood. EXPERIMENTAL APPROACH: SH-SY5Y cells were cultured and morphine, rapamycin, 3-methyladenine and RACK1 siRNA were used to evaluate the regulation of RACK1 protein in autophagy. Western blotting and immunofluorescence were used to assess protein expression. KEY RESULTS: Activation of autophagy (i.e. autophagosome accumulation and an increase in the LC3-II/LC3-I ratio) induced by morphine contributes to the maintenance of conditioned place preference (CPP) memory in mice. Moreover, morphine treatment significantly increased Beclin-1 expression and decreased the p-mTOR/mTOR and SQSTM1/p62 levels, whereas knockdown of RACK1 prevented morphine-induced autophagy in vitro. Furthermore, we found that in the mouse hippocampus, knockdown of RACK1 also markedly suppressed morphine-induced autophagy (decreased LC3-II/LC3-I ratio and increased p-mTOR/mTOR ratio). Importantly, morphine-induced autophagy in a RACK1-dependent manner. Conversely, morphine-induced RACK1 upregulation in vitro is partially inhibited by autophagy feedback. CONCLUSIONS AND IMPLICATIONS: Our findings revealed a critical role for RACK1-dependent autophagy in morphine-promoted maintenance of CPP memory in mice and supported the notion that control of RACK1-dependent autophagic pathways may become an important target for novel therapeutics for morphine-associated memory.

Synthesis of 1,2,3-Thiadiazole and Thiazole-Based Strobilurins as Potent Fungicide Candidates.

Strobilurin fungicides play a crucial role in protecting plants against different pathogens and securing food supplies. A series of 1,2,3-thiadiazole and thiazole-based strobilurins were rationally designed, synthesized, characterized, and tested against various fungi. Introduction of 1,2,3-thiadiazole greatly improved the fungicidal activity of the target molecules. Compounds 8a, 8c, 8d, and 10i exhibited a relatively broad spectrum of fungicidal activity. Compound 8a showed excellent activities against Gibberella zeae, Sclerotinia sclerotiorum, and Rhizoctonia cerealis with median effective concentrations (EC50) of 2.68, 0.44, and 0.01 µg/mL, respectively; it was much more active than positive controls enestroburin, kresoxim-methyl, and azoxystrobin with EC50 between 0.06 and 15.12 µg/mL. Comparable or better fungicidal efficacy of compound 8a compared with azoxystrobin and trifloxystrobin against Sphaerotheca fuliginea and Pseudoperonspera cubensis was validated in cucumber fields at the same application dosages. Therefore, compound 8a is a promising fungicidal candidate worthy of further development.

Impact of Cr(VI) on P removal performance in enhanced biological phosphorus removal (EBPR) system based on the anaerobic and aerobic metabolism.

Influence of Cr(VI) on P removal in enhanced biological phosphorus removal (EBPR) system was investigated with respect to the composition of poly-phosphate-accumulating organisms (PAOs) and glycogen accumulating organisms (GAOs), the transformation of poly-ß-hydroxyalkanoates (PHA) and glycogen, enzymes' activities, and the intracellular Cr. Whether EBPR system could revive after Cr(VI) shock was also explored. Results showed P removal performance was completely inhibited by Cr(VI) with the concentration more than 5 mg L(-1). PAOs were more sensitive to Cr(VI) than GAOs and the other bacteria were. PHA consumption, glycogen synthesis and adenylate kinase's activity had been inhibited by 5 mg L(-1) Cr(VI). Both adenylate kinase's activity and P removal efficiency were negatively correlated with the intracellular Cr. Recovery experiments revealed that P removal performance with 5 mg L(-1) Cr(VI) shock could revive after a 2-day recovery treatment, while systems with high level Cr(VI) (20 and 60 mg L(-1)) shock could not.

[Growth kinetics of aquatic worms feeding on activated sludge].

The growth kinetics of aquatic worms was investigated from juvenile to decline phase for 18 weeks by cultivating with activated sludge in batch test. Results showed that the growth of aquatic worms well fit Gauss function for cultivating 18 weeks. The maximum specific growth rate, growth yield of aquatic worms and sludge reduction rate was 0.41 d(-1), 0.32 and 25.5%, respectively. When the concentration of substrate and dissolved oxygen change from low to high, the relationship between the specific growth rate with dissolved oxygen, and substrate concentration meet the Monod equation. Compared with the dissolved oxygen, the substrate concentration had greater effect on the specific growth rate of aquatic worms, and aquatic worms can live in the environment with low dissolved oxygen. Furthermore, the breath test showed the oxygen uptake rate of aquatic worms was almost 6.39, 10.10, 11.31 and 5.74 mg x (L x g x h)(-1) from juvenile to decline phase, the dissolved oxygen demand of the rapid growth and mature stage was higher than juvenile and decline phase.

[Removal of high concentration NH4(+) -N by nanochem zeolite ion exchange technology].

This paper assesses the potential of NanoChem zeolite for ammonia removal from synthetic solution and actual landfill leachate. The data from experiments in batch study were applied to Langmuir isotherm. The saturated amount of NH4(+) -N adsorbed per unit weight of NanoChem zeolite was about 364 mg x g(-1), which yield significantly 3-30 times higher ammonium adsorption capacity than nature zeolite and Microporous molecular sieves. The results of batch study showed that the contact time needed at least 20 h in order to attain exchange equilibrium; the ammonia removal capacity of NanoChem zeolite increased with the increase of initial ammonia concentration, while the ammonia removal rate decreased with the increase of initial ammonia concentration; the pH had an effect on ammonia removal efficiency as it can influence both the character of the exchanging ions and the NanoChem zeolite itself; regeneration made little change on ammonia removal efficiency, repeatability was good. In column study, the NanoChem zeolite was used for high ammonia nitrogen removal such as actual landfill leachate and the ammonia nitrogen was removed 100%.

[Concentration and risk assessment of DEHP in vegetables around plastic industrial area].

Concentration of di-(2-ethylhexyl) phthalate (DEHP)in the inner tissue of various vegetable species and their growing environment (soil and atmosphere) around plastic industrial area were investigated and determined by gas chromatography-mass spectrum (GC/MS). The results showed that concentrations of DEHP in 5 kinds of vegetable were 0.23-9.11 mg/kg, 3.82 mg/kg in average (fresh weight). Of the various vegetable species determined, the highest burden was observed in the leafy vegetables, followed by melon and root vegetables. Statistical analysis of variance showed that environment and species are the factors that significantly affect DEHP concentrations in inner vegetable tissue and soil, respectively. Atmosphere deposition is the principal pathway for the accumulation of DEHP. The ability of the plant accumulating DEHP was mainly influenced by the lipid content of the plant. Leaf with pubescence or rough surface was found to have higher DEHP than the other, when the lipid contents were similar. Evaluation of the vegetable around plastic industrial area with the acceptable daily intake (ADI) by OEHHA, concentrations of DEHP has exceeded the safety standard.

[Full-scale experiments of municipal sewage treated by symbiotic system consisting of tubifex and microbes].

A symbiotic system consisting of tubifex and microbe was formed when tubifex was incubated in the biological contact oxidation process,the tubifex attached to the outer layer of the carriers. When the density of tubifex was about 31.3 g/L, a recycling food chain between corpse of tubifex and excrement and wastewater and microbe and sludge was formed and it could reach balance. The large scale control experimental system for treating 20,000 m3 x d(-1) municipal sewage was carried out for a long time. The result showed that tubifex could improve water quality in the effluent. When the concentration in the influent of COD,NH4+ -N,TP and SS were 130-459, 14.21-27.46, 1.60-6.93, 60-466 mg x L(-1), respectively,the removal rates of COD and SS can be improved by 8.7% and 13.6%. However, tubifex can also increase the concentration of NH4+ -N in the system,but a proper operation can make the effluent concentration of NH4+ -N below 5 mg x L(-1) stably. The symbiotic system consisting of tubifex and microbe has very good phosphorus removal efficiency. The reactor has a high toleration to loading shock and it could keep the effluent quality stable.