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Abstract The scarcity of suitable high-throughput screening technology for hydrogen sulfide (H2S) donors has hampered the discovery of H2S donors. In this study, a long-lived cyclometalated iridium complex was rationally designed as a mitochondria-targeted H2S probe to monitor the real-time dynamic change of H2S. By using the time-resolved emission spectroscopy (TRES) technique, an anti-interference high-throughput screening system was developed to monitor H2S in living cells with decreased false negative results. As a proof-of-concept, three natural products were identified as potential H2S donors from a natural product library using the developed TRES probe. Notably, the discovery of allicin and diallyl trisulfide demonstrated the feasibility of this screening platform, while garlic-derived allyl methyl sulfide was explored as a H2S donor candidate. The results were further validated by a commercial assay. We anticipate this high-throughput platform could facilitate the discovery of H2S donors by discriminating the endogenous interfering fluorescence from biological systems.

Abstract Breast cancer (BC) is the most frequent malignant cancer diagnosis and is a primary factor for cancer deaths in women. The clinical subtypes of BC include estrogen receptor (ER) positive, progesterone receptor (PR) positive, human epidermal growth factor receptor 2 (HER2) positive, and triple-negative BC (TNBC). Based on the stages and subtypes of BC, various treatment methods are available with variations in the rates of progression-free disease and overall survival of patients. However, the treatment of BC still faces challenges, particularly in terms of drug resistance and recurrence. The study of epigenetics has provided new ideas for treating BC. Targeting aberrant epigenetic factors with inhibitors represents a promising anticancer strategy. The KDM5 family includes four members, KDM5A, KDM5B, KDM5C, and KDMD, all of which are Jumonji C domain-containing histone H3K4me2/3 demethylases. KDM5 proteins have been extensively studied in BC, where they are involved in suppressing or promoting BC depending on their specific upstream and downstream pathways. Several KDM5 inhibitors have shown potent BC inhibitory activity in vitro and in vivo, but challenges still exist in developing KDM5 inhibitors. In this review, we introduce the subtypes of BC and their current therapeutic options, summarize KDM5 family context-specific functions in the pathobiology of BC, and discuss the outlook and pitfalls of KDM5 inhibitors in this disease.

As a commonly used metal ion, iron(II) (Fe2+) ions pose a potential threat to ecosystems and human health. Therefore, it is particularly important to develop analytical techniques for the rapid and accurate detection of Fe2+ ions. However, the development of near-infrared (NIR) luminescence probes with good photostability for Fe2+ ions remain challenging. In this work, we report a novel iridium(III) complex-based luminescence probe for the sensitive and rapid detection of Fe2+ ions in a solution based on an Fe2+-mediated reduction reaction. This probe is capable of sensitively detecting Fe2+ ions with a limit of detection (LOD) of 0.26 μM. Furthermore, this probe shows high photostability, and its luminescence remains stable under 365 nm irradiation over a time period of 30 min. To our knowledge, this is first iridium(III) complex-based NIR probe for the detection of Fe2+ ions. We believe that this work provides a new method for the detection of Fe2+ ions and has great potential for future applications in water quality testing and human monitoring.

Abstract Extracellular communication, in other words, crosstalk between cells, has a pivotal role in the survival of an organism. This communication occurs by different methods, one of which is extracellular vesicles. Exosomes, which are small lipid extracellular vesicles, have recently been discovered to have a role in signal transduction between cells inside the body. These vesicles contain important bioactive molecules including lipids, proteins, DNA, mRNA, and noncoding RNAs such as microRNAs (miRNAs). Exosomes are secreted by all cells including immune cells (macrophages, lymphocytes, granulocytes, dendritic cells, mast cells) and tumor cells. The tumor microenvironment (TME) represents a complex network that supports the growth of tumor cells. This microenvironment encompasses tumor cells themselves, the extracellular matrix, fibroblasts, endothelial cells, blood vessels, immune cells, and non-cellular components such as exosomes and cytokines. This review aims to provide insights into the latest discoveries concerning how the immune system communicates internally and with other cell types, with a specific focus on research involving exosomal miRNAs in macrophages, dendritic cells, B lymphocytes, and T lymphocytes. Additionally, we will explore the role of exosomal miRNA in the TME and the immunomodulatory effect.

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.

Proteolysis-targeting chimeras (PROTACs), a novel targeted protein degradation technology for potential clinical drug discovery, is composed of a protein-targeting ligand covalently linked to an E3 ligase ligand. Through recruiting E3 ligase to target proteins, PROTACs elicit ubiquitination and subsequent degradation of targets via the ubiquitin-proteasome system. In the past few decades, molecular docking and virtual screening have emerged as an efficient strategy in drug discovery for identifying compounds from a large database of chemical structures. For PROTACs, molecular docking accurately simulates the protein-PROTAC-E3 ternary complex, thus greatly accelerating structure-activity-relationship analysis, and improving ligand affinity and selectivity. In this review, we summarize recent efforts in the application of molecular docking and virtual screening for PROTAC drug discovery. To date, approximately nine target proteins and twelve PROTACs have been successfully developed through molecular docking and virtual screening. Finally, the potential challenges of molecular docking and virtual screening-based PROTACs are discussed.

Triple-negative breast cancer (TNBC) is a highly aggressive and metastasizing cancer that has the worst prognosis out of all breast cancer subtypes. The epithelial–mesenchymal transition (EMT) and cancer stem cells (CSCs) have been proposed as important mechanisms underlying TNBC metastasis. CDK9 is highly expressed in breast cancer, including TNBC, where it promotes EMT and induces cancer cell stemness. In this study, we have identified a tetrahydroisoquinoline derivative (compound 1) as a potent and selective CDK9-cyclin T1 inhibitor via virtual screening. Interestingly, by targeting the ATP binding site, compound 1 not only inhibited CDK9 activity but also disrupted the CDK9-cyclin T1 protein–protein interaction (PPI). Mechanistically, compound 1 reversed EMT and reduced the ratio of CSCs by blocking the CDK9-cyclin T1 interaction, leading to reduced TNBC cell proliferation and migration. To date, compound 1 is the first reported tetrahydroisoquinoline-based CDK9-cyclin T1 ATP-competitive inhibitor that also interferes with the interaction between CDK9 and cyclin T1. Compound 1 may serve as a promising scaffold for developing more selective and potent anti-TNBC agents. Our work also provides insight into the role of the CDK9-cyclin T1 PPI on EMT and CSCs and highlights the feasibility and significance of targeting CDK9 for the treatment of TNBC.

ABSTRACT: Diabetes has become a global concern at present, among which type 2 diabetes mellitus (T2DM) accounts for approximately 90 %–95 % of patients. T2DM is a type of metabolic disorder syndrome that results from a genetic defect, and it is based on insulin resistance and an insulin secretion disorder. The occurrence of T2DM is usually the outcome of both genetic and environmental factors and their interactions. The etiology and pathogenesis of diabetes have not been fully elucidated, and no radical therapeutic cure has been found. Patients with T2DM suffer from complications such as the development of a chronic hyperglycemic condition and even serious metabolic disorders and organ damage in the body and depression and dementia, in addition to other chronic complications. Many studies have suggested that diet is crucial in the development of diabetes and the control of blood glucose. Natural substances have the characteristics of low toxicity and few side effects and may be key to the development of diabetic health products and preventive treatments. This paper reviews the etiology, pathogenesis, risks, treatments and diets related to T2DM to summarize the types of recently available natural products, from both local and foreign sources, for lowering blood glucose at home and their application in supplementary hypoglycemic foods. The key findings and conclusions suggest that there are various known T2DM-inducing factors, including genetic and environmental factors and three types of hybrid factors.

Iridium(III) complexes are emerging as a promising tool in the area of detection and therapy due to their prominent photophysical properties, including higher photostability, tunable phosphorescence emission, long-lasting phosphorescence, and high quantum yields. In recent years, much effort has been devoted to develop novel near-infrared (NIR) iridium(III) complexes to improve signal-to-noise ratio and enhance tissue penetration. In this review, we summarize different classes of organometallic NIR iridium(III) complexes for detection and therapy, including cyclometalated ligand-enabled NIR iridium(III) complexes and NIR-dye-conjugated iridium(III) complexes. Moreover, the prospects and challenges for organometallic NIR iridium(III) complexes for targeted detection and therapy are discussed.

Enhancer of zeste homolog 2 (EZH2) is activated in breast cancer, particularly in triple-negative breast cancer (TNBC), and is critical for cell invasion. It interacts with embryonic ectoderm development (EED) in maintaining cancer stem cells (CSC) and epithelial-mesenchymal transition (EMT) properties, hence promoting CSC metastasis. Because the association of EZH2 with EED promotes the catalytic activity of EZH2, inhibiting the EED-EZH2 interaction is a potential therapeutic strategy for treating EZH2-dependent cancer. Although several EED-EZH2 protein-protein interaction (PPI) inhibitors have been developed, few target EED. Here, we identified that a cytisine derivative compound (1) potently binds EED, thus blocking the EED-EZH2 PPI. Compound 1 was found to inhibit cell proliferation and suppress the growth of 3D tumor spheres of TNBC cells. Moreover, by reversing EMT and decreasing the ratio of CSCs, the compound inhibited TNBC metastasis and invasion ability. Therefore, targeting EED to disrupt the EED-EZH2 PPI may provide a new approach for treating TNBC metastasis. To our knowledge, compound 1 is the first cytisine-based EED-EZH2 PPI inhibitor preventing metastasis in TNBC cells. This study may provide a new avenue for the development of more efficacious EED-EZH2 PPI inhibitors in TNBC treatment.

Cyclin-dependent kinase 9 (CDK9) activity is correlated with worse outcomes of triple-negative breast cancer (TNBC) patients. The heterodimer between CDK9 with cyclin T1 is essential for maintaining the active state of the kinase and targeting this protein–protein interaction (PPI) may offer promising avenues for selective CDK9 inhibition. Herein, we designed and generated a library of metal complexes bearing the 7-chloro-2-phenylquinoline CˆN ligand and tested their activity against the CDK9–cyclin T1 PPI. Complex 1 bound to CDK9 via an enthalpically-driven binding mode, leading to disruption of the CDK9–cyclin T1 interaction in vitro and in cellulo. Importantly, complex 1 showed promising anti-metastatic activity against TNBC allografts in mice and was comparably active compared to cisplatin. To our knowledge, 1 is the first CDK9–cyclin T1 PPI inhibitor with anti-metastatic activity against TNBC. Complex 1 could serve as a new platform for the future design of more efficacious kinase inhibitors against cancer, including TNBC.

Impaired wound healing is a serious complication in diabetic patients, and is associated with reduced HIF1α stability. Here, the authors design a small molecule that stabilizes HIF1α by blocking its interaction with VHL and show that it promotes wound healing in mouse models of diabetes.

Abstract Histone methylation is a key posttranslational modification of chromatin, and its dysregulation affects a wide array of nuclear activities including the maintenance of genome integrity, transcriptional regulation, and epigenetic inheritance. Variations in the pattern of histone methylation influence both physiological and pathological events. Lysine-specific demethylase 5A (KDM5A, also known as JARID1A or RBP2) is a KDM5 Jumonji histone demethylase subfamily member that erases di- and tri-methyl groups from lysine 4 of histone H3. Emerging studies indicate that KDM5A is responsible for driving multiple human diseases, particularly cancers. In this review, we summarize the roles of KDM5A in human cancers, survey the field of KDM5A inhibitors including their anticancer activity and modes of action, and the current challenges and potential opportunities of this field.

Extracellular vehicles have a natural targeting ability and immune tolerance of being usually applied in drug delivery systems; however, the purification of EVs is complicated and the production yield was quite low. We developed an artificial cellular mimetic nanovesicle (NV) with melanoma fragment membrane for the transportation with curcumin to achieve the anticancer purpose. B16F10 derived NVs were manufactured by the breakdown of cells using a series of extrusions through cut-off size filters (10 and 5 µm), and the whole procedure was easy and time-saving. To terminate the suspicion of cancer metastatic issue, B16F10 cells were treated by 30-min sonication and 1-min UVB exposure to remove genetic materials before the extrusion. B16F10 derived NV loaded with curcumin was called NV(S30U1/Cur), and the anticancer effect was evaluated by cell-based viability, immune, migration, and invasion. The results showed that NVs were manufactured by passing through 10 and 5 µm filters having an enviable production yield, and the mRNA amounts were declined within NVs produced by B16F10 cells treated with UVB in a comparison to the control group. NV(S30U1/Cur) were effectively decreased B1610 cell viability, and migratory and invasive abilities were also reduced significantly. Besides, CD8+ expression of murine primary lymphocytes was activated with CD4+ reduction by NV(S30U1/Cur) to stimulate the inherent tumor suppressive capacity in the immune system. Taken together, we established bioengineered NVs serving as novel cell mimetic nanocarriers to deliver natural compound for malignant melanoma potential immune chemotherapy. Data Availability Statement: The data used to support the findings of this study are available from the corresponding author upon requests.

Abstract Protein-protein interactions (PPIs) are central to a variety of biological processes, and their dysfunction is implicated in the pathogenesis of a range of human diseases, including cancer. Hence, the inhibition of PPIs has attracted significant attention in drug discovery. Covalent inhibitors have been reported to achieve high efficiency through forming covalent bonds with cysteine or other nucleophilic residues in the target protein. Evidence suggests that there is a reduced risk for the development of drug resistance against covalent drugs, which is a major challenge in areas such as oncology and infectious diseases. Recent improvements in structural biology and chemical reactivity have enabled the design and development of potent and selective covalent PPI inhibitors. In this review, we will highlight the design and development of therapeutic agents targeting PPIs for cancer therapy.

Hepatotoxicity caused by an overdose of acetaminophen (APAP) is the leading reason for acute drug-related liver failure. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a protein that helps to regulate redox homeostasis and coordinate stress responses via binding to the Kelch-like ECH-associated protein 1 (Keap1). Targeting the Keap1-Nrf2 interaction has recently emerged as a potential strategy to alleviate liver injury caused by APAP. Here, we designed and synthesized a number of iridium (III) and rhodium (III) complexes bearing ligands with reported activity against oxidative stress, which is associated with Nrf2 transcriptional activation. The iridium (III) complex 1 bearing a bioactive ligand 2,9-dimethyl-1,10-phenanthroline and 4-chloro-2-phenylquinoline, a derivative of the bioactive ligand 2-phenylquinoline, was identified as a direct small-molecule inhibitor of the Keap1–Nrf2 protein-protein interaction. 1 could stabilize Keap1 protein, upregulate HO-1 and NQO1, and promote Nrf2 nuclear translocation in normal liver cells. Moreover, 1 reversed APAP-induced liver damage by disrupting Keap1–Nrf2 interaction and without inducing organ damage and immunotoxicity in mice. Our study demonstrates the identification of a selective and efficacious antagonist of Keap1–Nrf2 interaction possessed good cellular permeability in cellulo and ideal pharmacokinetic parameters in vivo, and, more importantly, validates the feasibility of conjugating metal complexes with bioactive ligands to generate metal-based drug leads as non-toxic Keap1–Nrf2 interaction inhibitors for treating APAP-induced acute liver injury.

Alcoholic liver disease (ALD) is a complicated disease which can lead to hepatocellular carcinoma; however, there is a lack of satisfactory therapeutics. Dehydroeburicoic acid (DEA) (1), a triterpenoid isolated from Antrodia cinnamomea, has been reported to act against ALD, but its mechanisms of action are still not clear. In this study, we report for the first time the use of DEA (1) as a dual inhibitor of the Keap1–Nrf2 protein–protein interaction (PPI) and GSK3β in an in vitro ALD cell model. DEA (1) engages Keap1 to disrupt the Keap1–Nrf2 PPI and inhibits GSK3β to restore Nrf2 activity in a Keap1-independent fashion. DEA (1) promotes Nrf2 nuclear translocation to activate downstream antioxidant genes. Importantly, DEA (1) restores the mitochondrial dysfunction induced by ethanol and generates antioxidant activity in the ALD cell model with minimal toxicity. We anticipate that DEA (1) could be a potential scaffold for the further development of clinical agents for treating ALD.

The occurrence of diseases is usually accompanied by changes in protein levels and types. These differentially expressed proteins can be used as biomarkers for the diagnosis and treatment of diseases. In recent years, luminescent iridium(III) complexes have attracted much attention in the field of protein-based disease diagnosis due to their excellent optical properties. In particular, affinity-based luminescent iridium(III) complexes have the advantage of evaluating protein information with minimal interference on their biological activities. In this review, we summarize the current advances in affinity-based luminescent iridium(III) complexes for the detection of disease-related proteins. Moreover, the future perspective for affinity-based iridium(III) complexes is discussed.

We report in this study the identification of a natural product-like antagonist (1a) of Vps34 as a potent autophagy modulator via structure-based virtual screening. Aurone derivative 1a strongly inhibited Vps34 activity in cell-free and cell-based assays. Significantly, 1a prevents autophagy in human cells induced either by starvation or by an mTOR inhibitor. In silico modeling and kinetic data revealed that 1a could function as an ATP-competitive inhibitor of Vps34. Moreover, it suppressed autophagy in vivo and without inducing heart or liver damage in mice. 1a could be utilized as a new motif for more selective and efficacious antagonists of Vps34 for the potential treatment of autophagy-related human diseases. KEY WORDS: Autophagy, Natural products, Vps34, Inhibitor, Structure-based virtual screening, Vesicle trafficking, Heart or liver damage, Aurone derivative

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.

Ochratoxin A (OTA) is a mycotoxin that is widespread throughout the world. It contaminates foods such as vegetables, fruits, and rice. It harms human health and has potential carcinogenic effects. The G-quadruplex (G4) is a tetraplexed DNA structure generated from guanine-rich DNA that has found emerging use in aptamer-based sensing systems. This review outlines the status of OTA contamination and conventional detection methods for OTA. Various G4-based methods to detect OTA developed in recent years are summarized along with their advantages and disadvantages compared to existing approaches.

Polysaccharides are considered the main active ingredient for the immune-enhancing effect of Radix Astragali, which is popularly used as medicinal food supplementary. The signal pathways involved in immune-enhancing effect remain unclear. This study is to investigate the role and regulation relation of Akt pathway with downstream kinases of TLR4 receptor in macrophages induced by Astragalus polysaccharide, RAP. The results showed that RAP induced phosphorylation of Akt, NFκB, IRF3 and MAPKs in RAW264.7 cells, and their individual inhibitors not only inhibited their inflammatory factors production and gene expression, but also suppressed the Akt phosphorylation, while Akt inhibitor exerted no effect on MAPKs, NFκB, and IRF3 phosphorylation. Taken together, these results suggested that Akt and IRF3 exerted activation role in RAP induced macrophage, and Akt exerted effect downstream of MyD88 dependent and independent pathway. This study will provide a deeper insight into the signal transduction induced by Astragalus polysaccharides.

As a kind of food supplementary, polysaccharide-rich tonic herbs become more and more popular. However, little is known regarding the interaction between known active molecules with these polysaccharides. This study aims to investigate effects of luteolin on RAW264.7 cells induced by Astragalus polysaccharide RAP in comparison with lipopolysaccharide (LPS). The results showed that luteolin suppressed inflammatory meditors in LPS-induced RAW264.7 cells. While in the RAP-induced RAW264.7 cells, luteolin only decreased the NO production and iNOS gene expression, but only inhibit IL-6 at high concentration, and was ineffective in term of TNF-α. The results of western blot analysis suggested that luteolin only inhibited the phosphorylation of NF-κB p65 and Akt, but not MAPKs and IRF3 in RAP-induced RAW264.7 cells. Taken together, lutelion exerted less inhibitory effect on macrophage induced by RAP than by LPS. This study demonstrated the luteolin-containing foods may not strongly interfere the immunoregulation effect of polysaccharide RAP.

Abstract A sensitive turn-on luminescent sensor for H2O2 based on the silver nanoparticle (AgNP)-mediated quenching of an luminescent Ir(III) complex (Ir-1) has been designed. In the absence of H2O2, the luminescence intensity of Ir-1 can be quenched by AgNPs via non-radiative energy transfer. However, H2O2 can oxidize AgNPs to soluble Ag+ cations, which restores the luminescence of Ir-1. The sensing platform displayed a sensitive response to H2O2 in the range of 0−17 μM, with a detection limit of 0.3 μM. Importantly, the probe was successfully applied to monitor intracellular H2O2 in living cells, and it also showed high selectivity for H2O2 over other interfering substances.

Abstract A novel luminescent turn-on detection method for Hg(II) was developed. The method was based on the silver nanoparticle (AgNP)-mediated quenching of Ir(III) complex 1. The addition of Hg(II) ions causes the luminescence of complex 1 to be recovered due to the oxidation of AgNPs by Hg(II) ions to form Ag(I) and Ag/Hg amalgam. The luminescence intensity of 1 increased in accord with an increased Hg(II) concentration ranging from 0 nM to 180 nM, with the detection limit of 5 nM. This approach offers an innovative method for the quantification of Hg(II).

An amendment to this paper has been published and can be accessed via the original article.

Purpose: The purpose of this study was to determine if an Astragalus polysaccharide (RAP) can protect immune cells from the toxic side effects of paclitaxel (Taxol), a powerful anti-tumor drug whose equally powerful side effects limit its clinical use.Methods: We hypothesized that RAP can reduce the toxic effects induced by Taxol. To test this hypothesis, we conducted a series of studies in vivo and in vitro. First, we confirmed RAP’s effects in vivo utilizing BALB/c mice inoculated with 4T1 mouse breast cancer cells as the tumor model. Mice were treated with RAP and/or Taxol, and the differences in the life spans were recorded. Second, a co-culture cell model was used to study the protective effect of RAP on cells vis-a-vis Taxol. The cell cycle and apoptosis of RAW 264.7 cells that were treated with RAP with/without Taxol were checked by flow cytometry and Hoechst staining. Proteins involved in the cell cycle and apoptosis were also tested by Western blot to reveal the probable mechanism.Results: RAP prolonged the life span of tumor-bearing mice treated with Taxol. The in vitro experiments showed that Taxol suppressed the proliferation of RAW 264.7 cells while RAP protected the RAW 264.7 cells from Taxol-induced suppression. The protection is selective because RAP had no effect on 4T1 cells. Furthermore, Taxol clearly led to cell cycle arrest mainly at the G2/M phase and generated cytotoxicity against RAW 264.7 cells, while RAP blocked cell cycle arrest and protected cells from apoptosis. Taxol up-regulated the protein levels of P-H2A, PARP, Chk1, p53, and p21 and down-regulated Bcl-Xl and Mcl-1, and RAP reversed the expression of all these proteins.Conclusion: These results suggested that RAP can protect immune cells from Taxol-induced toxicity, by changing the cell cycle and apoptosis.

In this study, we report the use of a cyclometalated luminescent iridium(III) complex for the visualization of thiols. The detection of glutathione (GSH) by complex 1 is achieved through the reduction of its phendione N^N donor, which influences the metal-to-ligand charge-transfer (MLCT) of the complex. Complex 1 produced a maximum threefold luminescence enhancement at 587 nm in response to GSH. The linear detection range of 1 for GSH is between 0.2 and 2 M equivalents of GSH, with a detection limit of 1.67 μM. Complex 1 also displays good selectivity for thiols over other amino acids.

A one-pot, two-step approach to prepare 2-tetrahydrofuran and -pyran substituted 1,3-dicarbonyl compounds by PhI=NTs-mediated amination/Brønsted base-catalyzed cross dehydrogenative coupling (CDC) reaction of the cyclic ether and 1,3-dicarbonyl derivative under mild conditions is reported. The reaction is compatible with a variety of cyclic ethers and 1,3-dicarbonyl compounds, affording the corresponding coupled products in moderate to good yields of up to 80% over two steps.

The JAK2/STAT3 signaling pathway plays a critical role in tumorigenesis, and has been suggested as a potential molecular target for anti-melanoma therapeutics. However, few JAK2 inhibitors were being tested for melanoma therapy. In this study, eight amentoflavone analogues were evaluated for their activity against human malignant melanoma cells. The most potent analogue, compound 1, inhibited the phosphorylation of JAK2 and STAT3 in human melanoma cells, but had no discernible effect on total JAK2 and STAT3 levels. A cellular thermal shift assay was performed to identify that JAK2 is engaged by 1 in cell lysates. Moreover, compound 1 showed higher antiproliferative activity against human melanoma A375 cells compared to a panel of cancer and normal cell lines. Compound 1 also activated caspase-3 and cleaved PARP, which are markers of apoptosis, and suppressed the anti-apoptotic Bcl-2 level. Finally, compound 1 induced apoptosis in 80% of treated melanoma cells. To our knowledge, compound 1 is the first amentoflavone-based JAK2 inhibitor to be investigated for use as an anti-melanoma agent.

Due to role of the Keap1−Nrf2 protein−protein interaction (PPI) in protecting cells from oxidative stress, the development of small molecule inhibitors that inhibit this interaction has arisen as a viable approach to combat maladies caused by oxidative stress, such as cancers, neurodegenerative disease and diabetes. To obtain specific and genuine Keap1−Nrf2 inhibitors, many efforts have been made towards developing new screening approaches. However, there is no inhibitor for this target entering the clinic for the treatment of human diseases. New strategies to identify novel bioactive compounds from large molecular databases and accelerate the developmental process of the clinical application of Keap1−Nrf2 protein−protein interaction inhibitors are greatly needed. In this review, we have summarized virtual screening and other methods for discovering new lead compounds against the Keap1−Nrf2 protein−protein interaction. We also discuss the advantages and limitations of different strategies, and the potential of this PPI as a drug target in disease therapy.

Targeting apoptosis is a principal strategy in the design of anticancer drugs. In recent years, non-platinum-based scaffolds have been exploited as viable candidates for the exploitation of anticancer agents with potentially lower toxicity than the widely used cisplatin analogues. This review highlights the latest advances in developing iridium(III) complexes as anticancer agents that act particularly via targeting apoptotic cell death in cancer cells.

Platinum-based drugs have revolutionized cancer care, but are unfortunately associated with various adverse effects. Meanwhile, natural product scaffolds exhibit multifarious bioactivities and serve as an attractive resource for cancer therapy development. Thus, the conjugation of natural product scaffolds to metal complexes becomes an attractive strategy to reduce the severe side effects arising from the use of metal bearing drugs. This review aims to highlight the recent examples of natural product-conjugated metal complexes as cancer therapies with enhanced selectivity and efficacy. We discuss the mechanisms and features of different conjugate complexes and present an outlook and perspective for the future of this field.

Lysine-specific demethylase 1A (LSD1, also named KDM1A) is a demethylase that can remove methyl groups from histones H3K4me1/2 and H3K9me1/2. It is aberrantly expressed in many cancers, where it impedes differentiation and contributes to cancer cell proliferation, cell metastasis and invasiveness, and is associated with inferior prognosis. Pharmacological inhibition of LSD1 has been reported to significantly attenuate tumor progression in vitro and in vivo in a range of solid tumors and acute myeloid leukemia. This review will present the structural aspects of LSD1, its role in carcinogenesis, a comparison of currently available approaches for screening LSD1 inhibitors, a classification of LSD1 inhibitors, and its potential as a drug target in cancer therapy.

We report herein the use of an exonuclease III and G-quadruplex probe to construct a G-quadruplex-based luminescence detection platform for Hg2+. Unlike common DNA-based Hg2+ detection methods, when using the dsDNA probe to monitor the hairpin formation, the intercalation of the dsDNA probe may be influenced by the distortion of dsDNA. This ‘mix-and-detect’ methodology utilized the G-quadruplex probe as the signal transducer and is simple, rapid, convenient to use and can detect down to 20 nM of Hg2+.

Polysaccharides, which exert immunoregulatory effects, are becoming more and more popular as food supplements; however, certain components of ordinary foods could be reducing the polysaccharides beneficial effects. Quercetin, a flavonoid found in common fruits and vegetables, is one such component. This study investigated the effects of quercetin on Astragalus polysaccharide RAP induced-macrophage activation. The results show quercetin decreases the NO production and iNOS gene expression in RAW264.7 cells, and it inhibits the production of cytokines in RAW264.7 cells and peritoneal macrophages. Western blot analysis results suggest that quercetin inhibits the phosphorylation of Akt/mTORC1, MAPKs, and TBK1, but has no effect on NF-κB in RAP-induced RAW264.7 cells. Taken together, the results show that quercetin partly inhibits macrophage activation by the Astragalus polysaccharide RAP. This study demonstrates that quercetin-containing foods may interfere with the immune-enhancing effects of Astragalus polysaccharide RAP to a certain extent.

Melanogenesis is a complex physiological mechanism involving various paracrine factors. Skin cells such as keratinocytes, fibroblasts, and melanocytes communicate with one another through secreted regulators, thereby regulating the melanocytes’ bio-functions. The stem cell factor (SCF) is a paracrine factor produced by fibroblasts, and its receptor, c-kit, is expressed on melanocytes. Binding of SCF to c-kit activates autophosphorylation and tyrosine kinase to switch on its signal transmission. SCF inhibition does not suppress fibroblast proliferation in MTT assay, and SCF silencing induced mRNA expressions of paracrine factor genes, HGF, NRG-1, and CRH in qPCR results. Following UVB stimulation, gene expressions of HGF, NRG, and CRH were higher than homeostasis; in particular, HGF exhibited the highest correlation with SCF variations. We detected fibroblasts regulated SCF in an autocrine-dependent manner, and the conditioned medium obtained from fibroblast culture was applied to treat melanocytes. Melanogenesis-related genes, tyrosinase and pmel17, were upregulated under conditioned mediums with SCF silencing and exposed to UVB treatments. Melanin quantities in the melanocytes had clearly increased in the pigment content assay. In conclusion, SCF silencing causes variations in both fibroblast paracrine factors and melanocyte melanogenesis, and the differences in gene expressions were observed following UVB exposure.

Cinnamomum osmophloeum Kanehira belongs to the Lauraceae family of Taiwan’s endemic plants. In this study, C. osmophloeum Kanehira extract has shown inhibition of tyrosinase activity on B16-F10 cellular system first. Whether extracts inhibited mushroom tyrosinase activity was tested, and a considerable inhibition of mushroom tyrosinase activity by in vitro assays was presented. Animal experiments of C. osmophloeum Kanehira were carried out by observing animal wound repair, and the extracts had greater wound healing power than the vehicle control group (petroleum jelly with 8% DMSO, w/v). In addition, the antioxidant capacity of C. osmophloeum Kanehira extracts in vitro was evaluated. We measured C. osmophloeum Kanehira extract’s free radical scavenging capability, metal chelating, and reduction power, such as biochemical activity analysis. The results showed that a high concentration of C. osmophloeum Kanehira extract had a significant scavenging capability of free radical, a minor effect of chelating ability, and moderate reducing power. Further exploration of the possible physiological mechanisms and the ingredient components of skincare product for skin-whitening, wound repair, or antioxidative agents are to be done.

Sanhuang Tablet (SHT) is a Chinese patented drug commonly used for the treatment of inflammations of the respiratory tract, gastrointestinal tract, and skin. It contains a special medicinal composition including the single compound berberine hydrochloride, extracts of Scutellariae Radix and Rhei Radix et Rhizoma, as well as the powder of Rhei Radix et Rhizoma. Despite advances in analytical techniques, quantitative evaluation of a Chinese patented drug like SHT remains a challenge due to the complexity of its chemical profile. In this study, ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was used to simultaneously quantify 29 non-sugar small molecule components of SHT (11 flavonoids, two isoflavonoids, one flavanone, five anthraquinones, two dianthranones, five alkaloids, two organic acids and one stilbene). Three major saccharide components, namely fructose, glucose, and sucrose, were also quantitatively determined using high performance liquid chromatography-charged aerosol detector (HPLC-CAD) on an Asahipak NH2P-50 4E amino column. The established methods were validated in terms of linearity, sensitivity, precision, accuracy, and stability, and then successfully applied to analyze 27 batches of commercial SHT products. A total of up to 57.61% (w/w) of SHT could be quantified, in which the contents of the determined non-saccharide small molecules varied from 5.91% to 16.83% (w/w) and three saccharides accounted for 4.41% to 48.05% (w/w). The results showed that the quality of the commercial products was inconsistent, and only four of those met Chinese Pharmacopoeia criteria.

Dendrobium officinale extract shows potent anti-fatigue effects; however, the active substance responsible for these effects remains undetermined. A glucomannan with a huge molecular size of 730 kDa, called DOP, was identified as the unique authentication marker of this expensive herb. DOP exhibited immunomodulating effects on macrophages and lymphocytes in our previous study. Clinical reports also showed that people with fatigue syndrome have a disturbed immune system. Because DOP is the unique and dominant component of D. officinale, we hypothesize that DOP may also have anti-fatigue activity. The present study aims to evaluate the anti-fatigue activity of DOP on BALB/c mice, with Rhodiola rosea extract as a positive control. DOP and Rhodiola rosea extract were orally administered at doses of 50 mg/kg and 100 mg/kg, respectively, for four weeks, and the anti-fatigue activity of DOP on BALB/c mice was evaluated using the weight-loaded swimming test. The contents of lactic dehydrogenase (LDH), creatine phosphokinase (CK), triglyceride (TG), blood urea nitrogen (BUN), superoxide dismutase (SOD), malondialdehyde (MDA), lactic acid (LD), and glutathione peroxidase (GSH-Px) in serum, glycogen of liver and gastrocnemius muscle were also determined. Their effects on variability of T cells and B cells were determined by using tetrazolium compound (MTS) method. The weight-loaded swimming exercise caused fatigue syndrome, mainly including the decreases of serum SOD/GSH-Px and gastrocnemius glycogen, as well as the increases of LDH, BUN, MDA, CK, TG, and LD in serum. All of these indicators of fatigue were inhibited to a certain extent by both DOP and Rhodiola rosea extract; however, the effects of DOP were much stronger than those of Rhodiola rosea extract. Compared to the positive control, mice dosed with DOP showed increases in endurance, body weight, and food intake. Furthermore, DOP-feeding mice significantly increased the cell variability of T lymphocytes and B lymphocytes, compared with that of mice in control group. This study indicates that the unique and dominant polysaccharide DOP of D. officinale has stronger anti-fatigue activity than Rhodiola rosea extract. As such, DOP has promising potential for pharmaceutical development into health products to reduce fatigue.

A novel iridium(III) complex-based chemosensor bearing the 5,6-bis(salicylideneimino)-1,10-phenanthroline ligand receptor was developed, which exhibited a highly sensitive and selective color change from colorless to yellow and a visible turn-off luminescence response upon the addition of Cu(II) ions. The interactions of this iridium(III) complex with Cu2+ ions and thirteen other cations have been investigated by UV-Vis absorption titration, emission titration, and 1H NMR titration.

In this study, we applied structure-based virtual screening techniques to identify natural product or natural product-like inhibitors of iNOS. The iNOS inhibitory activity of the hit compounds was characterized using cellular assays and an in vivo zebrafish larvae model. The natural product-like compound 1 inhibited NO production in LPS-stimulated Raw264.7 macrophages, without exerting cytotoxic effects on the cells. Significantly, compound 1 was able to reverse MPTP-induced locomotion deficiency and neurotoxicity in an in vivo zebrafish larval model. Hence, compound 1 could be considered as a scaffold for the further development of iNOS inhibitors for potential anti-inflammatory or anti-neurodegenerative applications.

A cell permeable cyclometalated iridium(III) complex has been developed as a phosphorescent probe for cell imaging. The iridium(III) solvato complex [Ir(phq)2(H2O]2)] preferentially stains the cytoplasm of both live and dead cells with a bright luminescence.

We report herein the G-quadruplex-selective property of a luminescent cyclometallated iridium(III) complex for the detection of adenosine-5'-triphosphate (ATP) in aqueous solution. The ATP-binding aptamer was employed as the ATP recognition unit, while the iridium(III) complex was used to monitor the formation of the G-quadruplex structure induced by ATP. The sensitivity and fold enhancement of the assay were higher than those of the previously reported assay using the organic dye crystal violet as a fluorescent probe. This label-free luminescent switch-on assay exhibits high sensitivity and selectivity towards ATP with a limit of detection of 2.5 µM.

We report herein a novel luminescent iridium(III) complex with two hydrophobic carbon chains as a non-reaction based chemosensor for the detection of Hg(2+) ions in aqueous solution (

Aberrant Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is crucial to the development of gastric cancer. In this study, we examined the role of STAT3 in the expression and methylation of its targets in gastric cancer patients. Results from RNA sequencing identified an inverse correlation between the expression of STAT3 and GATA6 in 23 pairs of gastric cancer patient samples. We discovered that the expression of GATA6 is epigenetically silenced through promoter methylation in gastric cancer cell lines. Interestingly, the inhibition of STAT3 using a novel STAT3 inhibitor restored the expression of GATA6 and its targets, trefoil factors 1 and 2 (TFF1/2). Moreover, disruption of STAT3 binding to GATA6 promoter by small hairpin RNA restored GATA6 expression in AGS cells. A clinically significant correlation was also observed between the expression of GATA6 and TFF1/2 among tissue samples from 60 gastric cancer patients. Finally, bisulfite pyrosequencing revealed GATA6 methylation in 65% (39/60) of the patients, and those with higher GATA6 methylation tended to have shorter overall survival. In conclusion, we demonstrated that aberrant JAK/STAT signaling suppresses TFF1/2 partially through the epigenetic silencing of GATA6. Therapeutic intervention of STAT3 in reversing the epigenetic status of GATA6 could benefit the treatment of gastric cancer and is worthy of further investigation.