Prostate-specific membrane antigen (PSMA) imaging probes are a promising tool for the diagnosis and image-guided surgery of prostate cancer (PCa). However, PSMA-specific luminescence probes for PCa detection and heterogeneity studies with high imaging contrast are lacking. Here, we report the first near-infrared (NIR) iridium(III) complex for the wash-free and specific imaging of PSMA in PCa cells and spheroids. The conjugation of a PSMA inhibitor, Lys-urea-Glu, to an iridium(III) complex synergizes the PSMA-specific affinity and biocompatibility of the inhibitor with the desirable photophysical properties of the iridium(III) complex, including NIR emission (670 nm), high photostability and a large Stokes shift. The cellular impermeability of the probe along with its strong binding affinity to PSMA enhances its specificity for PSMA, enabling the washing-free luminescent imaging of membrane PSMA with lower cytotoxicity. The probe was successfully applied for selectively visualizing PSMA-expressing cells and for the imaging of PSMA in a multicellular PCa model with good imaging penetration, indicating its potential use in complicated and heterogeneous tumor microenvironments. Furthermore, the probe showed good imaging performance in the PCa-bearing tumor mice via targeting PSMA in vivo. This work provides a novel strategy for the development of highly sensitive and specific NIR probes for PSMA in biological systems in vitro, which is of great significance for the precise diagnosis of PCa and for elucidating PCa heterogeneity.

Bromodomain-containing protein 4 (BRD4) is a reader of acetylated histones that regulates the invasion, metastasis and proliferation of cancer. Inhibition of BRD4 activity is an emerging strategy for anticancer. In this study, an iridium based-luminescent probe for screening BRD4 inhibitors in cellulo was developed. The K293 probe was designed by linking a BRD4 nuclear translocation inhibitor as a “binding unit” to an iridium complex as a luminescent “signal unit”. K293 selectively binds to BRD4 in living cancer cells. Candidate compounds compete with K293 for BRD4, resulting in a decrease in luminescence signal. The long luminescence lifetime of K293 allows its luminescence signal to be distinguished from interfering fluorescence using time-resolved techniques in order to improve sensitivity. Hence, even potential BRD4 inhibitors that are undetectable by conventional fluorescence methods can be identified. As a proof-of-concept, Azelastine, an FDA-approved histamine 1 (H1) antagonist was identified to be a potential BRD4 inhibitor using the K293 probe. Azelastine binds to BRD4 protein in the cytoplasm to prevent its translocation into the nucleus, and suppresses cancer cell growth and migration. The results demonstrated that the probe could be useful for the future drug repurposing.

Dithiocarbamate bioactive compounds are extensively used in agriculture and medicine, but traditional methods for the detection of dithiocarbamates are limited by complicated sensing systems and incompatibility with living systems. In this work, we developed an iridium(III) solvento complex (1) for the luminogenic detection of dithiocarbamates. The probe can sensitively detect a range of dithiocarbamates including sodium diethyldithiocarbamate (NDDC), sodium dimethyldithiocarbamate (SDDC) and ammonium pyrrolidinedithiocarbamate (APDC) in aqueous buffer with up to 10.3-fold luminescence enhancement and limits of detection in the submicromolar range. Moreover, the probe has the capacity to detect dithiocarbamates in water and drink samples as well as in the presence of living cells. Importantly, this probe is robust to potential interferent including other coordinative thiols and histidine. This work serves as a good starting point for developing a single molecule-based sensing system for dithiocarbamates, and opens the door for developing new imaging probe for dithiocarbamates.

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.

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 protein-protein interaction between menin and mixed lineage leukemia(MLL)plays an important role in the development of human hepatocellular carcinogenesis(HCC)and is associated with poor prognosis of HCC patients.1,2 Hence,interrupting the menin-MLL interaction is an attractive strategy in cancer treatment,particularly for liver cancer.3,4 In this study,we identified complex C1 as the first rhodium(lll)-based orally bioavailable selective inhibitor of the menin-MLL interaction for HCC.

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.

In this work, we synthesized an iridium(III) complex and studied its selective ability to interact with a specific G-quadruplex DNA sequence (GTGGGTAGGGCGGGTTGG). Results showed that the iridium(III) complex exhibits high selectivity for the G-quadruplex DNA and could be used as an efficient electrochemiluminescence (ECL) probe in a switch-on assay format for the detection of double-stranded DNA (dsDNA). To construct the assay, a hairpin-structured capture probe (CP) which was modified by thiol at its 3′ end and contained the G-quadruplex sequence at its 5′ end was firstly immobilized on a gold electrode. Upon the specific recognition of the dsDNA sequence with the corresponding CP, the hairpin structure of the CP was opened to free G-quadruplex sequence, forming the G-quadruplex structure with the assistance of K+. Then, the iridium(III) complex was able to specifically interact with the G-quadruplex to produce an obvious ECL signal that was proportional to the dsDNA concentration. Notably, this iridium(III) complex/G-quadruplex-based strategy was universal and was not limited to the analysis of DNA using specific sequences, thus opening a new avenue for the application of the G-quadruplex-selective iridium(III) complex in the field of ECL.

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.

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.

Common reference methods for COVID-19 variant diagnosis include viral sequencing and PCR-based methods. However, sequencing is tedious, expensive, and time-consuming, while PCR-based methods have high risk of insensitive detection in variant-prone regions and are susceptible to potential background signal interference in biological samples. Here, we report a loop-mediated interference reduction isothermal nucleic acid amplification (LM-IR-INA) strategy for highly sensitive single-base mutation detection in viral variants. This strategy exploits the advantages of nicking endonuclease-mediated isothermal amplification, luminescent iridium(III) probes, and time-resolved emission spectroscopy (TRES). Using the LM-IR-INA strategy, we established a luminescence platform for diagnosing COVID-19 D796Y single-base substitution detection with a detection limit of 2.01 × 105 copies/μL in a linear range of 6.01 × 105 to 3.76 × 108 copies/μL and an excellent specificity with a variant/wild-type ratio of significantly less than 0.0625%. The developed TRES-based method was also successfully applied to detect D796Y single-base substitution sequence in complicated biological samples, including throat and blood, and was a superior to steady-state technique. LM-IR-INA was also demonstrated for detecting the single-base substitution D614G as well as the multiple-base mutation H69/V70del without mutual interference, indicating that this approach has the potential to be used as a universal viral variant detection strategy.

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.

In hypoxia and hyperglycemia, SET7/9 plays an important role in controlling HIF-1α methylation and regulating the transcription of HIF-1α target genes, which are responsible for angiogenesis and wound healing. Here, we report the Ir(III) complex Set7_1a bearing acetonitrile (ACN) ligands as a SET7/9 methyltransferase inhibitor and HIF-1α stabilizer. Interestingly, Set7_1a could engage SET7/9 and strongly inhibit SET7/9 activity, especially after preincubation with homocysteine (Hcy), which is elevated in diabetes. We hypothesize that Set7_1a exchanges ACN subunits for Hcy to disrupt the interaction between SET7/9 and SAM/SAH, which are structurally related to Hcy. Inhibition of SET7/9 methyltransferase activity by Set7_1a led to reduced HIF-1α methylation at the lysine 32 residue, causing increased HIF-1α level and recruitment of HIF-1α target genes that promote angiogenesis, such as VEGF, GLUT1, and EPO, in hypoxia and hyperglycemia. Significantly, Set7_1a improved wound healing in a type 2 diabetic mouse model by activating HIF-1α signaling and downstream proangiogenic factors. To our knowledge, this is the first Hcy-targeting iridium compound shown to be a SET7/9 antagonist that can accelerate diabetic wound healing. More importantly, this study opens a therapeutic avenue for the treatment of diabetic wounds by the inhibition of SET7/9 lysine methyltransferase activity.

Boron trifluoride (BF3) is a potential environmental pollutant, and excess exposure to it may cause human dis-eases. However, the sensitive, rapid and accurate detection of BF3 for on-site purposes is still a challenge. In this work, we developed the first NIR iridium(III)-based probe with dual emission and a Stokes shift of 370 nm for self-calibrated and luminogenic detection of BF3. This probe exhibited a strong luminescence enhancement at around 650 nm to BF3 (0-100 mu M) with almost no change in luminescence at 475 nm, displaying a 220-fold I-650 (nm)/I(475nm )enhancement at 100 mu M of BF3 with a detection limit of 0.35 mu M. Moreover, the probe showed a fast response time of less than 5 s to BF3 along with an obvious color change under UV irradiation for visual detection. Importantly, the desirable photophysical properties of the iridium(III)-based probe can be harnessed for time-resolved detection of BF3 in the presence of the fluorescence background. The applicability of the probe was further verified in an organic solvent waste-spiked system and on a glass pane. This work will provide a solid basis for the development of sensitive and on-site BF3 sensing toolkits for environmental monitoring.

Herein, an Ir(III) complex-doped coordination polymer network (Ir(III)@GMP-Eu3+) is fabricated for the first time for the ratiometric luminescent detection of the anthrax biomarker 2,6-dipicolinic acid (DPA) through the analysis of time-resolved emission spectra (TRES). The linear detection range is from 10 nM to 5 μM with a detection limit of 3.3 nM in aqueous solution. Attributed to the long lifetime of Ir(III)@GMP-Eu3+, the developed sensor exhibits an excellent DPA monitoring ability in a high-background solution through TRES.

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.

>While the function of DNA in biology is for storage of genetic information, chemists have developed methods to obtain DNA sequences with catalytic and molecular recognition functions. Thus, DNA is a highly attractive molecule for developing biosensors. DNA probes are known for their detection of complementary DNA and RNA. In addition,

MicroRNAs are potential biomarkers for human cancers and other diseases due to their roles as post-transcriptional regulators for gene expression. However, the detection of miRNAs by conventional methods such as RT-qPCR, in situ hybridization, northern blot-based platforms, and next-generation sequencing is complicated by short length, low abundance, high sequence homology, and susceptibility to degradation of miRNAs. In this study, we developed a nicking endonuclease-mediated interference reduction rolling circle amplification (NEM-IR-RCA) strategy for the ultrasensitive and highly specific detection of miRNA-21. This method exploits the advantages of the optical properties of long-lived iridium(III) probes, in conjunction with time-resolved emission spectroscopy (TRES) and exponential rolling circle amplification (E-RCA). Under the NEM-IR-RCA-based signal enhancement processes, the limit of detection of miRNA-21 was down to 0.0095 fM with a linear range from 0.05 to 100 fM, which is comparable with the conventional RT-qPCR. Unlike RT-qPCR, the strategy was performed at a lower and constant temperature without heating/cooling cycles and reverse transcription. The strategy could clearly discriminate between matched and mismatched targets, demonstrating high specificity. Moreover, the potential application of this method was demonstrated in cancer cells and mouse serum samples, showing good agreement with RT-qPCR results. Apart from miRNA-21 detection, this platform could be also adapted for detecting other miRNAs, such as let-7a and miRNA-22, indicating its excellent potential for biomedical research and clinical diagnostics.