Citrus polymethoxyflavones degrade estrogen receptor-alpha (ERα) and combine with tamoxifen for the treatment of estrogen receptor-positive breast cancer.

Estrogen receptor-positive (ER+) breast cancer seriously endangers the women's physical and mental health worldwide and ER targeting therapy is vital. Here, we found that a citrus polymethoxyflavones (PMFs)-rich hydrolysate (C-H) and its major components (nobiletin and 3-methoxynobiletin) potently degrade ERα protein via the ubiquitin-proteasome pathway, thereby impairing the proliferation of ER+ breast cancer cells. Moreover, our study exhibited that C-H combined with tamoxifen (TAM) inhibited the cell proliferation of ER+ breast cancer in vitro. It was further confirmed that C-H decreased tumor growth of ER+ breast cancer in tumor-bearing 129 mice in vivo and improved the efficacy of tamoxifen. Our study revealed that the citrus PMFs have potential applications as pharmaceutical and healthcare products in breast cancer treatment by targeting ERα protein degradation.

Dehydrocurvularin-loaded mPEG-PLGA nanoparticles for targeted breast cancer drug delivery: preparation, characterization, in vitro, and in vivo evaluation.

Dehydrocurvularin (DCV) is a promising lead compound for anti-cancer therapy. Unfortunately, the development of DCV-based drugs has been hampered by its poor solubility and bioavailability. Herein, we prepared a DCV-loaded mPEG-PLGA nanoparticles (DCV-NPs) with improved drug properties and therapeutic efficacy. The spherical and discrete particles of DCV-NPs had a uniform diameter of 101.8 ± 0.45 nm and negative zeta potential of -22.5 ± 1.12 mV (pH = 7.4), and its entrapment efficiency (EE) and drug loading (DL) were ∼53.28 ± 1.12 and 10.23 ± 0.30%, respectively. In vitro the release of DCV-NPs lasted for more than 120 h in a sustained-release pattern, its antiproliferation efficacy towards breast cancer cell lines (MCF-7, MDA-MB-231, and 4T1) was better than that of starting drug DCV, and it could be efficiently and rapidly internalised by breast cancer cells. In vivo DCV-NPs were gradually accumulated in tumour areas of mice and significantly suppressed tumour growth. In summary, loading water-insoluble DCV onto nanoparticles has the potential to be an effective agent for breast cancer therapy with injectable property and tumour targeting capacity.

Discovery of Artemisinins as Microsomal Prostaglandins Synthase-2 Inhibitors for the Treatment of Colorectal Cancer via Chemoproteomics.

Colorectal cancer remains the second leading cause of cancer-related mortalities worldwide. While artemisinin (ART), a key active compound from the traditional Chinese medicinal herb Artemisia annua, has been recognized for its antiproliferative activity against colon cancer cells, its underlying molecular underpinnings remain elusive. Whereas promiscuity of heme-dependent alkylating of macromolecules, mainly proteins, has been seen pivotal as a universal and primary mode of action of ART in cancer cells, accumulating evidence suggests the existence of unique targets and mechanisms of actions contingent on cell or tissue specificities. Here, we employed photoaffinity probes to identify the specific targets responsible for ART's anti-colon cancer actions. Upon validation, microsomal prostaglandins synthase-2 emerged as a specific and reversible target of ART in HCT116 colorectal cancer cells, whose inhibition resulted in reduced cellular prostaglandin E2 biosynthesis and cell growth. Our discovery opens new opportunities for pharmacological treatment of colon cancer.

Recent advance of ATP citrate lyase inhibitors for the treatment of cancer and related diseases.

ATP citrate lyase (ACLY), a strategic metabolic enzyme that catalyzes the glycolytic to lipidic metabolism, has gained increasing attention as an attractive therapeutic target for hyperlipidemia, cancers and other human diseases. Despite of continual research efforts, targeting ACLY has been very challenging. In this field, most reported ACLY inhibitors are "substrate-like" analogues, which occupied with the same active pockets. Besides, some ACLY inhibitors have been disclosed through biochemical screening or high throughput virtual screening. In this review, we briefly summarized the cancer-related functions and the recent advance of ACLY inhibitors with a particular focus on the SAR studies and their modes of action. We hope to provide a timely and updated overview of ACLY and the discovery of new ACLY inhibitors.

Dual-Signal Cascaded Nucleic Acid Amplification Circuit-Loaded Metal-Organic Frameworks for Accurate and Robust Imaging of Intracellular MicroRNA.

Cascaded signal amplification technologies play an important role in the sensitive detection of lowly expressed biomarkers of interests yet are constrained by severe background interference and low cellular accessibility. Herein, we constructed a metal-organic framework-encapsulating dual-signal cascaded nucleic acid sensor for precise intracellular miRNA imaging. ZIF-8 nanoparticles load and deliver FAM-labeled upstream catalytic hairpin assembly (CHA) and Cy5-modified downstream hybridization chain reaction (HCR) hairpin reactants to tumor cells, enabling visualization of the target-initiated signal amplification process for double-insurance detection of analytes. The pH-responsive ZIF-8 nanoparticles effectively protect DNA hairpins from degradation and allow the release of them in the acid tumor microenvironment. Then, intracellular target miRNAs orderly trigger cascaded nucleic acid signal amplification reaction, of which the exact progress is investigated through the analysis of the fluorescence recovering process of FAM and Cy5. In addition, DNA@ZIF-8 nanoparticles improve measurement accuracy by dual-signal colocalization imaging, effectively avoiding nonspecific false-positive signals and enabling in situ imaging of miRNAs in living cells. A dual-signal colocalization strategy allows accurate target detection in living cells, and DNA@ZIF-8 provides a promising intracellular sensing platform for signal amplification and visual monitoring.

Chemiluminescence resonance energy transfer-based multistage nucleic acid amplification circuits for MiRNA detection with low background.

Chemiluminescence resonance energy transfer (CRET)-based assays have shown great potential in biosensing due to their negligible background autofluorescence, yet are still limited by their low sensitivity and short half-life luminescence. Herein, a multistage CRET-based DNA circuit was constructed with amplified luminescence signals for accurate miRNA detection and fixed reactive oxygen species (ROS) signals for cell imaging. The DNA circuit is designed through an ingenious programmable catalytic hairpin assembly (CHA), hybridization chain reaction (HCR), and the use of DNAzyme to realize target-triggered precise regulation of distance between the donor and acceptor for CRET-mediated excitation of photosensitizers. In detail, the analyte catalyzes the hybridization of CHA reactants, which leads to the assembly of multiple HCR-mediated DNAzyme nanowires. Subsequently, DNAzymes catalyze the oxidation of luminol by H2O2, and the adjacent photosensitizer chlorin e6 (Ce6) anchored on the DNA nanostructure is stimulated by the CRET process, resulting in the amplified long-wavelength luminescence and the generation of single oxygen signals through further energy transfer to oxygen. The biomarker miRNA can be detected with great sensitivity by integrating the recognition module into a universal platform. Furthermore, the DNA circuit enables CRET-mediated intracellular miRNA imaging, by detecting singlet oxygen signals through a ROS probe. The significant amplification effect is attributed to the robust multiple recognition of the target and the guaranteed transduction of the CRET signal through programmable engineering of DNA nanostructures. The CRET-based DNA circuit achieves amplified long-wavelength luminescence for accurate miRNA detection with low background and ROS-mediated signal fixation for cell imaging, making it a promising candidate for early diagnosis and theranostics.

An Intelligent Laser-Free Photodynamic Therapy Based on Endogenous miRNA-Amplified CRET Nanoplatform.

Laser-free photodynamic therapy (PDT) is a promising noninvasive therapeutic modality for deep-seated tumor, yet is constrained by low efficiency due to the limited stimulation strategies. Herein, a novel miRNA-responsive laser-free PDT was developed through metal-organic frameworks (MOFs)-mediated chemiluminescence resonance energy transfer (CRET) nanoplatform. The photosensitizer chlorin e6 (Ce6)-loaded MOFs were functionalized with hairpin nucleic acids for sensitive responsiveness of tumor biomarker miRNA through catalytic hairpin assembly (CHA), which enabled the amplified assembly of horseradish peroxidase (HRP)-mimicking hemin/G-quadruplex DNAzyme on MOFs. Simultaneously, the on-MOF assembled DNAzymes efficiently catalyzed chemiluminescence reaction to stimulate adjacent Ce6 in the presence of luminol and H2 O2 , thus allowing the CRET-mediated Ce6 luminescence and reactive oxygen species (ROS) generation for self-illuminating PDT. The CRET nanoplatform achieved significant malignant cell apoptosis and tumor inhibition effects without external laser irradiation. It is envisioned that the miRNA-amplified CRET nanoplatform might be a selective and highly efficient antitumor nanomedicine for precise theranostic.

Characterization of precipitation from citrus vinegar during ageing: chemical constituents, formation mechanism and anti-proliferative effect.

Precipitation formation commonly occurs in the ageing step of fermented citrus vinegar. Hitherto, the chemical characteristics and biological properties of precipitates remain unveiled. This study focused on investigating the chemical profile, formation mechanism and biological repurposing of precipitates. Nine principal components, two flavonoid glycosides and their aglycones along with five polymethoxyflavones (PMFs), were identified from a methanol extract of precipitates. Using hydrolysis models, we demonstrated that insoluble aglycones were generated through the breakage of glycosidic bonds in flavonoid glycosides under acidic condition. Moreover, soluble bound-PMFs were destroyed by yeast-acid hybrid catalysis to release insoluble free-PMFs to form precipitates. A methanol extract of precipitates exhibited a potent anti-proliferative effect on MCF-7 cells (IC50 = 0.032 µg µL-1) via inhibiting tubulin polymerization. This study will be helpful for the food industry to aid optimizing citrus vinegar brewing and for reutilizing precipitates for functional foods and health products. Furthermore, it also provides a green strategy of PMFs enrichment from citrus using an enzyme-acid hybrid system.

Naphthoquinones from Catalpa bungei "Jinsi" as potent antiproliferation agents inducing DNA damage.

Structure-guided isolation of a CH2Cl2-soluble fraction of the heartwood of Catalpa bungei "Jinsi" provided two new naphthoquinones, 9-hydroxy-4-oxo-α-lapachone (1) and 6-hydroxy-4-oxo-α-lapachone (2), together with three undescribed ones (3-5) and six known ones (6-11). The structures were elucidated on the basis of spectroscopic methods including electronic circular dichroism calculation. The antiproliferative effects of these isolates were evaluated in human breast adenocarcinoma cells MCF7. (4R)-4,9-dihydroxy-α-lapachone (5) and (4S)-4,9-dihydroxy-α-lapachone (6) exhibited the significant activities with IC50 values of 2.19 and 2.41 µM, respectively. The structure-activity relationship of 1-11 in the antiproliferative assay was then discussed. The most potent 5 and 6 were found to induce cell arrest in G1 phage through DNA damage. The findings provided some valuable insights for the discovery and structural modification of α-lapachone as antiproliferative lead compounds against human breast adenocarcinoma cells.

Acid-improved DNAzyme-based chemiluminescence miRNA assay coupled with enzyme-free concatenated DNA circuit.

DNAzyme-based chemiluminescence assay exhibits excellent performance in bioanalysis but their operation in acid conditions remains challengeable. Herein, we constructed an acid-improved DNAzyme-based isothermal enzyme-free concatenated DNA circuit with significantly reduced background and simultaneously improved signal-to-noise ratio for miRNA detection. The chemiluminescence miRNA assay is composed of catalyzed hairpin assembly (CHA), hybridization chain reaction (HCR), and hemin/G-quadruplex DNAzyme units. The analyte initiates the self-assembly of CHA hairpins into numerous dsDNA, which triggers the subsequent autonomous cross-opening of HCR hairpins to generate long nanowires consisting of the hemin/G-quadruplex DNAzyme. The DNAzyme catalyzes the oxidation of luminol by hydrogen peroxide for the cascaded amplified chemiluminescence signal. The acid-improved property was demonstrated to be closely associated with the low catalytic activity of aggregated hemin under acidic conditions and the remained multiple amplified signal through concatenated DNA circuit. The general DNA circuit exhibited high sensitivity for miRNA-21 detection and chemiluminescence imaging under acidic conditions with a recognition hairpin. The acid-improved DNAzyme-based concatenated DNA circuit is promising to expand the application of chemiluminescence assay and provide a valuable strategy for early diagnosis and prognosis of cancer.

Chemoproteomic profiling reveals celastrol as a potential modulator of cholesterol signaling.

We report a quantitative chemoproteomic approach that utilizes a clickable photoreactive probe for global profiling of celastrol targets, which may significantly improve the current understanding of celastrol's mode of action.

Stereoselective O-Glycosylation of Glycals with Arylboronic Acids Using Air as the Oxygen Source.

An open-air palladium-catalyzed O-glycosylation was developed using glycals and arylboronic acids with base additives at ambient conditions. The novel approach enabled facile access to various O-glycosides in high yields, with exclusive 1,4-cis-stereoselectivity tolerating reactive hydroxyl/amino groups. Mechanistic studies indicated that chemo-/stereoselectivity arose from the coordination between palladium and phenols generated in situ by oxidizing arylboronic acids, followed by an intramolecular attack. Isotope-labeling experiments revealed that the oxygen of O-glycosidic bonds came from O2.

Xylariaopyrones E-I, five new α-pyrone derivatives from the endophytic fungus Xylariales sp. (HM-1).

Five new α-pyrones, xylariaopyrones E-I (1-5), along with three known analogues (6-8) were isolated from the cultivation broth of the endophytic fungus Xylariales sp. (HM-1). The structures of the new compounds including their absolute configurations were elucidated by comprehensive spectroscopic methods and quantum ECD calculations. Xylariaopyrone E (1) is the first example of α-pyrone derivative with a novel [3, 2, 0] bridge ring system via a ketal function group in the side chain. In bioactivity assays, xylariaopyrones E-G (1-3) showed moderate inhibiting activities against Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa with MIC values from 25.4 to 64.5 µg/mL, whereras xylariaopyrone G (3) exhibited significant inhibition of monoamine oxidase B with an IC50 value of 15.6 µmol/L. Xylariaopyrone H (4) and the known compound 7 showed moderate toxicity against brine shrimp larvae with inhibition rates of 42.8% and 44.5%, respectively.

Review of 10,11-Dehydrocurvularin: Synthesis, Structural Diversity, Bioactivities and Mechanisms.

10,11-Dehydrocurvularin is a natural benzenediol lactone (BDL) with a 12-membered macrolide fused to a resorcinol ring produced as a secondary metabolite by many fungi. In this review, we summarized the pieces of literature regarding biosynthesis, chemical synthesis, biological activities, and assumed work mechanisms of 10,11-dehydrocurvularin, which presented a potential for agricultural and pharmaceutical uses.

An updated patent review of protein arginine N-methyltransferase inhibitors (2019-2022).

Protein arginine methyltransferases (PRMTs), enzymes catalyzing the methylation of target proteins, play an essential role in maintaining functional homeostasis in normal physiology. Aberrant expressions and enhanced enzymatic activities of PRMTs have been closely associated with pathological states such as cancer, inflammatory, immune, metabolic, and neurodegenerative diseases. Therefore, the development of inhibitors targeting PRMTs has attracted a great deal of attention in both pharmaceutical industries and academic community. This review focuses on the small-molecule inhibitors targeting PRMTs in cancer therapy in the patents published since 2019. The recent clinical development is also discussed here. In recent years, the discovery of small-molecule PRMT inhibitors, especially PRMT5 inhibitors has become a rapidly expanding research area for cancer therapy. Although a number of potent PRMT inhibitors with different chemical scaffolds have been developed and nine of them have entered into clinical trials, their scaffolds are relatively less diverse. Sub-type selectivity should be considered in drug discovery as nonselective inhibition of PRMTs may cause undesirable pharmacological effects. Hence, the development of new effective inhibitors with isoform-specific and tumor-biased distributions remains an important area for further studies.

10,11-dehydrocurvularin exerts antitumor effect against human breast cancer by suppressing STAT3 activation.

Aberrant activation of signal transducer and activator of transcription 3 (STAT3) plays a critical role in many types of cancers. As a result, STAT3 has been identified as a potential target for cancer therapy. In this study we identified 10,11-dehydrocurvularin (DCV), a natural-product macrolide derived from marine fungus, as a selective STAT3 inhibitor. We showed that DCV (2-8 µM) dose-dependently inhibited the proliferation, migration and invasion of human breast cancer cell lines MDA-MB-231 and MDA-MB-468, and induced cell apoptosis. In the two breast cancer cell lines, DCV selectively inhibited the phosphorylation of STAT3 Tyr-705, but did not affect the upstream components JAK1 and JAK2, as well as dephosphorylation of STAT3. Furthermore, DCV treatment strongly inhibited IFN-γ-induced STAT3 phosphorylation but had no significant effect on IFN-γ-induced STAT1 and STAT5 phosphorylation in the two breast cancer cell lines. We demonstrated that the α, ß-unsaturated carbonyl moiety of DCV was essential for STAT3 inactivation. Cellular thermal shift assay (CETSA) further revealed the direct engagement of DCV with STAT3. In nude mice bearing breast cancer cell line MDA-MB-231 xenografts, treatment with DCV (30 mg·kg-1·d-1, ip, for 14 days) markedly suppressed the tumor growth via inhibition of STAT3 activation without observed toxicity. Our results demonstrate that DCV acts as a selective STAT3 inhibitor for breast cancer intervention.

Selective profiling of steviol-catalyzing UDP-glycosyltransferases with a metabolically synthesized probe.

Selective profiling of steviol-catalyzing UDP-glycosyltransferases in plants was accomplished with a probe metabolically synthesized from two substrate-derived components comprising an alkynylated sugar receptor (steviol) module and a diazirine-modified sugar donor (UDP-glucose) module, thereby illustrating a facile approach for harnessing biosynthetic enzymes of natural glycosides in plants for synthetic biology.

Molecular Imaging and In Situ Quantitative Profiling of Fatty Acid Synthase with a Chemical Probe.

Cancer cells rely on fatty acid synthase (FASN), a key enzyme for de novo biosynthesis of long chain fatty acids, to sustain their proliferative potential and drive invasion. Unfortunately, conventional FASN assays are technically inadequate for discerning otherwise elusive FASN activity in complex biological milieux, which has hindered progress in the functional study of FASN and development of its inhibitors. Here, we describe a chemical probe with unprecedented selectivity and sensitivity for the labeling of active FASN in living cells, thus demonstrating a new analytical modality for visualizing endogenous FASN activity and exploring opportunities for drug discovery.

Dehydrocurvularin is a potent antineoplastic agent irreversibly blocking ATP-citrate lyase: evidence from chemoproteomics.

Natural-product macrolide 10,11-dehydrocurvularin (DCV) was revealed to be a potent irreversible inhibitor of ATP-citrate lyase (ACLY) via classical chemoproteomic profiling, which mechanistically illuminates the anti-cancer mode of action of DCV and its analogues.

High cell density culture of baker's yeast FX-2 based on pH-stat coupling with respiratory quotient.

The high cell density culture of baker's yeast FX-2 was investigated in a 50 L(A) automatic bioreactor. Herein, it was found firstly that the Crabtree effect clearly existed in batch fermentation with higher glucose content, then the critical initial glucose content range (≤2.00 g L-1 ) was reasonably ascertained to effectively avoid Crabtree effect. In the next fed-batch fermentations with different strategies, the second strategy (maintain ethanol concentration lower than 0.10% and pH around 4.80) was confirmed to be more beneficial to yeast growth than the first strategy (keep reducing sugar not more than 2.00 g L-1 and control steady Carbon/Nitrogen ratio 3.05:1.00). After that, one optimal control strategy (maintain pH around 4.80 and keep respiratory quotient in the range of 0.90-1.00) was constructed to further enhance cell yield. Under an optimal control strategy, four schemes with the aim of achieving pH-stat were compared, and yeast extract instead of other alkaline materials was selected as a better regulator. As a result, 148.37 g L-1 dry cell weight, 38.25 × 108 mL-1 living cells, and 8.24 g L-1  h-1 productivity were harvested, which respectively elevated 23.74%, 135.38%, and 24.47% compared to that obtained under the traditional scheme (regulate pH with ammonia); meanwhile, the maximum oxygen uptake rate and carbon dioxide excretion rate were both more than 250.00 mmol L-1  min-1 .