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The analysis of microRNAs (miRNAs) in exosomes is of great importance for noninvasive early disease diagnosis. However, current techniques to detect exosomal miRNAs is hampered either by laborious exosome isolation or low abundance of miRNAs in exosomes. Here, we developed a microfluidic chemiluminescence (CL) analysis method for the multiplexed detection of exosomal miR-21 and miR-155. The microfluidic device contained three parts: a snake-shaped channel for fully mixing chemiluminescent reagents, a ship-shaped channel modified with CD63 protein aptamer for capturing exosomes, and another two parallel ship-shaped channels for hybridization chain reaction (HCR) amplification and CL detection. The multiple signal amplification was realized by Y-shaped arrays, HCR amplification, and poly-HRP catalyzed CL reaction. Using this multiple signal amplification method, our microfluidic CL biosensor achieves a limit of detection of miRNAs of 0.49 fM, with a linear range of 1 fM-10 pM, which is better or comparable to previously reported biosensors. What's more, the proposed microfluidic biosensor exhibits great specificity and selectivity to the target miRNA. Moreover, the microfluidic CL strategy exhibited excellent accuracy and could significantly distinguish different cancer subtypes as well as cancer patients and healthy people. These results suggest that this simple, high sensitive, and more accurate analytical strategy by analyzing different types of exosomal miRNAs has the potential applications in cancer diagnosis and stage monitoring., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Metagenomic shotgun sequencing data can identify microbes and their proportions. But metagenomic shotgun data profiling results obtained from multiple projects using different reference databases are difficult to compare and apply meta-analysis. Our work aims to create a novel collection of human gut prokaryotic genomes, named Microbiome Collection Navigator (MBCN). 2379 human gut metagenomic samples are screened, and 16,785 metagenome-assembled genomes (MAGs) are assembled using a standardized pipeline. In addition, MAGs are combined with the representative genomes from public prokaryotic genomes collections to cluster, and pan-genomes for each cluster's genomes are constructed to build Kraken2 and Bracken databases. The databases built by MBCN are more comprehensive and accurate for profiling metagenomic reads comparing with other collections on simulated reads and virtual bio-projects. We profile 1082 human gut metagenomic samples with MBCN database and organize profiles and metadata on the web program. Meanwhile, using MBCN as a reference database, we also develop a unified, standardized, and systematic metagenomic analysis pipeline and platform, named MicrobiotaCN (http://www.microbiota.cn) and common statistical and visualization tools for microbiome research are integrated into the web program. Taken together, MBCN and MicrobiotaCN can be a valuable resource and a powerful tool that allows researchers to perform metagenomic analysis by a unified pipeline efficiently., Competing Interests: The authors have declared no competing interests., (© 2024 The Authors.)

In recent years, it has been proposed that c-mesenchymal-to-epithelial transition factor (c-Met) and histone deacetylase (HDAC) dual inhibition is a promising cancer treatment strategy. Herein, a series of c-Met/HDAC dual inhibitors were designed and synthesized given their synergistic anticancer effect in breast cancer cells. Compound 12d exhibited excellent inhibitory activity against c-Met (IC 50 = 28.92 nM) and HDAC (85.68%@1000 nM) and inhibited the proliferation of all three breast cancer cell lines. Moreover, a mechanism investigation demonstrated that 12d could simultaneously induce cell cycle arrest in the G 0 /G 1 phase and cell apoptosis in MDA-MB-231 cells, which was endorsed by c-Met and HDAC pathway blockade. It could also suppress cell invasion. Our results suggest that developing promising c-Met/HDAC dual inhibitors is a novel strategy for breast cancer therapy., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Colorectal cancer is the second most prevalent and deadly cancer worldwide. The emergence of immune checkpoint therapy has provided a revolutionary strategy for the treatment of solid tumors. However, less than 5 % of colorectal cancer patients respond to immune checkpoint therapy. Thus, it is of great scientific significance to develop "potentiators" for immune checkpoint therapy. In this study, we found that knocking down different DNMT and HDAC isoforms could increase the expression of IFNs in colorectal cancer cells, which can enhance the effectiveness of immune checkpoint therapy. Therefore, the combined inhibition of DNMT and HDAC cloud synergistically enhance the effect of immunotherapy. We found that dual DNMT and HDAC inhibitors C02S could inhibit tumor growth in immunocompetent mice but not in immunocompromised nude mice, which indicates that C02S exerts its antitumor effects through the immune system. Mechanistically, C02S could increase the expression of ERVs, which generated the intracellular levels of dsRNA in tumor cells, and then promotes the expression of IFNs through the RIG-I/MDA5-MAVS signaling pathway. Moreover, C02S increased the immune infiltration of DCs and T cells in microenvironment, and enhanced the efficacy of anti-PD-L1 therapy in MC38 and CT26 mice model. These results confirmed that C02S can activate IFNs through the RIG-I/MDA5-MAVS signaling pathway, remodel the tumor immune microenvironment and enhance the efficacy of immune checkpoint therapy, which provides new evidence and solutions for the development of "potentiator" for colorectal cancer immunotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A pico-injection-aided digital droplet detection platform is presented that integrates loop-mediated isothermal amplification (LAMP) with molecular beacons (MBs) for the ultrasensitive and quantitative identification of pathogens, leveraging the sequence-specific detection capabilities of MBs. The microfluidic device contained three distinct functional units including droplet generation, pico-injection, and droplet counting. Utilizing a pico-injector, MBs are introduced into each droplet to specifically identify LAMP amplification products, thereby overcoming issues related to temperature incompatibility. Our methodology has been validated through the quantitative detection of Escherichia coli, achieving a detection limit as low as 9 copies/μL in a model plasmid containing the malB gene and 3 CFU/μL in a spiked milk sample. The total analysis time was less than 1.5 h. The sensitivity and robustness of this platform further demonstrated the potential for rapid pathogen detection and diagnosis, particularly when integrated with cutting-edge microfluidic technologies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Triple-negative breast cancer (TNBC) is a unique breast cancer subtype characterized by a lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Since TNBC lacks ER, PR, and HER2, there are currently no drugs that specifically target TNBC. Therefore, the development of new drugs or effective treatment strategies to target TNBC has become an urgent clinical need. Research has shown that the application of histone deacetylase (HDAC) inhibitors and DNA methyltransferase (DNMT) inhibitors leads to genomic and epigenomic instability. This, in turn, triggers the activation of pattern recognition receptors (PRRs) and subsequently activates downstream interferon (IFN) signalling pathways. In this study, the bifunctional HDAC and DNMT inhibitor J208 exhibited antitumour activity in TNBC cell lines. J208 effectively induced apoptosis and cell cycle arrest at the G0/G1 phase, inhibiting cell migration and invasion in TNBC. Moreover, this bifunctional inhibitor induced the expression of endogenous retroviruses (ERVs) and elicited a viral mimicry response, which increased the intracellular levels of double-stranded RNA (dsRNA) to activate the innate immune signalling pathway in TNBC. In summary, we demonstrated that the bifunctional inhibitor J208, which is designed to inhibit HDAC and DNMT, has potent anticancer effects, providing a new research basis for reactivating antitumour immunity by triggering innate immune signalling and offering a promising strategy for TNBC treatment., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier B.V.)

P300 and CBP are two closely related histone acetyltransferases that are important transcriptional coactivators of many cellular processes. Inhibition of the transcriptional regulator p300/CBP is a promising therapeutic approach in oncology. However, there are no reported single selective p300 or CBP inhibitors to date. In this study, we designed and optimized a series of lysine acetyltransferase p300 selective inhibitors bearing a nucleoside scaffold. Most compounds showed excellent inhibitory activity against p300 with IC 50 ranging from 0.18 to 9.90 μM, except for J16, J29, J40, and J48. None of the compounds showed inhibitory activity against CBP (inhibition rate < 50 % at 10 µM). Then the cytotoxicity of the compounds against a series of cancer cells were evaluated. Compounds J31 and J32 showed excellent proliferation inhibitory activity on cancer cells T47D and H520 with desirable selectivity profile of p300 over CBP. These compounds could be promising lead compounds for the development of novel epigenetic inhibitors as antitumor agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The existing conventional treatments for breast cancer, including immune checkpoint blockade, exhibit limited effects in some cancers, particularly triple-negative breast cancer. Epigenetic alterations, specifically DNMT and HDAC alterations, are implicated in breast cancer pathogenesis. We demonstrated that DNMTs and HDACs are overexpressed and positively correlated in breast cancer. The combination of DNMT and HDAC inhibitors has shown synergistic antitumour effects, and our previously designed dual DNMT and HDAC inhibitor (termed DNMT/HDACi) 15a potently inhibits breast cancer cell proliferation, migration, and invasion and induces apoptosis in vitro and in vivo. Mechanistically, 15a induces a viral mimicry response by promoting the expression of endogenous retroviral elements in breast cancer cells, thus increasing the intracellular level of double-stranded RNA to activate the RIG-I-MAVS pathway. This in turn promotes the production of interferons and chemokines and augments the expression of interferon-stimulated genes and PD-L1. The combination of 15a and an anti-PD-L1 antibody had an additive effect in vivo. These findings indicate that this DNMT/HDACi has immunomodulatory functions and enhances the effectiveness of immune checkpoint blockade therapy. A novel dual DNMT and HDAC inhibitor induces viral mimicry, which induces the accumulation of dsRNA to activate tumoral IFN signalling and cytokine production to enhance the immune response in breast cancer., (© 2024. The Author(s).)

The clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein (Cas) (CRISPR/Cas) system enables sensitive and specific detection of biomolecules, thanks to its programmability, high fidelity, and powerful signal amplification capabilities. Herein, a universal smartphone-assisted label-free G-quadruplex (G4) DNAzyme-based chemiluminescence CRISPR/Cas12a biosensing platform (G4CLCas) is firstly described that achieves on-site, ultrasensitive visual detection of nucleic acid and non-nucleic acid targets. The G4CLCas-based sensing platform relies on Cas12a trans-cleavage activation that triggers the cleavage of the G4 DNAzyme, resulting in chemiluminescence signals off/on compared to that of the control. Chemiluminescence signals are captured as images that are quantitatively analyzed and visualized using a smartphone-assisted imaging cartridge. Under optimal conditions, G4CLCas achieves a low limit of detection (LOD) of 8.6 aM (∼5.2 copies/μL) for monkeypox virus (MPXV) DNA within the linear concentration range of 10-300 aM and can accurately quantify viral DNA in spiked samples. G4CLCas can also detect non-nucleic acid targets, whereby it achieves a low LOD value of 84.3 nM for adenosine triphosphate (ATP) within the linear concentration range of 2-2000 μM. Here, a label-free, portable, on-site CRISPR/Cas12a chemiluminescence biosensing platform based on the G4 DNAzyme substrates is proposed with potential applications in clinical detection and bioanalytical chemistry research., Competing Interests: Declaration of competing interest All authors have given approval of this manuscript. The authors declared that they have no financial or other contractual agreements that might cause conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Proteolysis-targeting chimeras (PROTACs) are essential bifunctional molecules that target proteins of interest (POIs) for degradation by cellular ubiquitination machinery. Despite significant progress made in understanding PROTACs' functions, their therapeutic potential remains largely untapped. As a result of the success of highly flexible, scalable, and low-cost mRNA therapies, as well as the advantages of the first generation of peptide PROTACs (p-PROTACs), we present for the first time an engineering mRNA PROTACs (m-PROTACs) strategy. This design combines von Hippel-Lindau (VHL) recruiting peptide encoding mRNA and POI-binding peptide encoding mRNA to form m-PROTAC and promote cellular POI degradation. We then performed proof-of-concept experiments using two m-PROTACs targeting two cancer-related proteins, estrogen receptor alpha and B-cell lymphoma-extra large protein. Our results demonstrated that m-PROTACs could successfully degrade the POIs in different cell lines and more effectively inhibit cell proliferation than the traditional p-PROTACs. Moreover, the in vivo experiment demonstrated that m-PROTAC led to significant tumor regression in the 4T1 mouse xenograft model. This finding highlights the enormous potential of m-PROTAC as a promising approach for targeted protein degradation therapy., Competing Interests: Hongyan Li is an employee in Shenzhen NeoCura Biotechnology Co., other authors have no potential relevant financial or non‐financial interests to disclose., (© 2024 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

EZH2 (enhancer of zeste homolog 2) is one of the most important histone methyltransferases (HMTs), and overexpression of EZH2 can lead to proliferation, migration and angiogenesis of tumor cells. But most of EZH2 inhibitors are only effective against some hematologic malignancies and have poor efficacy against solid tumors. Here, we report the design, synthesis, and evaluation of highly potent proteolysis targeting chimeric (PROTACs) small molecules targeting EZH2. We developed a potent and effective EZH2 degrader P4, which effectively induced EZH2 protein degradation and inhibited breast cancer cell growth. Further studies showed that P4 can significantly decrease the degree of H3K27me3 in MDA-MB-231 cell line, induce apoptosis and G 0 /G 1 phase arrest in Pfeiffer and MDA-MB-231 cell lines. Therefore, P4 is a potential anticancer molecule for breast cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

PARP inhibitors and HDAC inhibitors have been approved for the clinical treatment of malignancies, but acquired resistance of or limited effects on solid tumors with a single agent remain as challenges. Bioinformatics analyses and a combination of experiments had demonstrated the synergistic effects of PARP and HDAC inhibitors in triple-negative breast cancer. A series of novel dual PARP and HDAC inhibitors were rationally designed and synthesized, and these molecules exhibited high enzyme inhibition activity with excellent antitumor effects in vitro and in vivo. Mechanistically, dual PARP and HDAC inhibitors induced BRCAness to restore synthetic lethality and promoted cytosolic DNA accumulation, which further activates the cGAS-STING pathway and produces proinflammatory chemokines through type I IFN-mediated JAK-STAT pathway. Moreover, these inhibitors promoted neoantigen generation, upregulated antigen presentation genes and PD-L1, and enhanced antitumor immunity when combined with immune checkpoint blockade therapy. These results indicated that novel dual PARP and HDAC inhibitors have antitumor immunomodulatory functions in triple-negative breast cancer. Novel dual PARP and HDAC inhibitors induce BRCAness to restore synthetic lethality, activating tumoral IFN signaling via the cGAS-STING pathway and inducing cytokine production, promoting neoantigen generation and presentation to enhance the immune response., (© 2024. The Author(s).)

Nucleic acid-based therapeutics have gained increasing attention due to their ability to regulate various genetic disorders. However, the safe and effective delivery of nucleic acids to their intended cellular sites remains a challenge, primarily due to poor cell membrane permeation and low in vivo stability. Limitations associated with the commonly used nucleic acid delivering agent viral vectors such as carcinogenesis and immunogenicity have driven scientists to develop various nonviral vectors. In this study, we present a highly efficient nucleic acid delivery system based on cationic conjugated polyelectrolytes and single-strand DNA polyplexes with further application in efficient ubiquitin-regulated targeting protein degradation. These polyplexes, formed by 9TC, an aptamer sequence for estrogen receptor (ERα), and cationic PPET 3 N 2 through electrostatic and hydrophobic interactions, demonstrate improved cellular uptake efficiency as well as enhanced stability against nuclease degradation. Furthermore, by incorporation of 9TC into a proteolysis targeting chimera (PROTAC) molecule (P9TC), PPET 3 N 2 /P9TC polyplexes significantly enhance the target protein ERα degradation efficiency. Collectively, our findings suggest that PPET 3 N 2 provides a versatile, low cytotoxicity platform for safe, efficient, and simplified delivery of nucleic acids.

Introduction: Synthetic lethality (SL) provides an opportunity to leverage different genetic interactions when designing synergistic combination therapies. To further explore SL-based combination therapies for cancer treatment, it is important to identify and mechanistically characterize more SL interactions. Artificial intelligence (AI) methods have recently been proposed for SL prediction, but the results of these models are often not interpretable such that deriving the underlying mechanism can be challenging., Objectives: This study aims to develop an interpretable AI framework for SL prediction and subsequently utilize it to design SL-based synergistic combination therapies., Methods: We propose a knowledge and data dual-driven AI framework for SL prediction (KDDSL). Specifically, we use gene knowledge related to the SL mechanism to guide the construction of the model and develop a method to identify the most relevant gene knowledge for the predicted results., Results: Experimental and literature-based validation confirmed a good balance between predictive and interpretable ability when using KDDSL. Moreover, we demonstrated that KDDSL could help to discover promising drug combinations and clarify associated biological processes, such as the combination of MDM2 and CDK9 inhibitors, which exhibited significant anti-cancer effects in vitro and in vivo., Conclusion: These data underscore the potential of KDDSL to guide SL-based combination therapy design. There is a need for biomedicine-focused AI strategies to combine rational biological knowledge with developed models., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Production and hosting by Elsevier B.V.)

The Jumonji domain-containing protein demethylase 3 (JMJD3) and histone deacetylase (HADC) are related to various cancers and regard as antitumor targets for drug discovery. In this study, based on rational drug design strategy, we designed and synthesized a series of pyrimidine derivatives with hydroxamic acid as novel dual JMJD3 and HDAC inhibitors for synergistic cancer treatment. Compound A5b exhibited inhibitory potency against JMJD3 and HDAC1/6 simultaneously and favorable cytotoxicity against human cancer cells such as A549 and U937. Furthermore, mechanistic studies showed that A5b treatment in A549 cells increased the hypermethylation of histone H3K27 and hyperacetylation of H3K9, suppressed clonogenicity, migration and invasion of cancer cells. Besides, A5b induced apoptosis via the cleavage of caspase-7 and PARP, and G1 cell cycle arrest via upregulated p21 expression. All these results suggested that A5b was the first dual inhibitor against JMJD3 and HDAC and can be a potential compound for cancer therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

In terms of cancer diagnoses and cancer-related deaths worldwide, colorectal cancer (CRC) is now the third most common malignancy. The drawbacks of current screening methods are their exorbitant costs, difficult procedures, and lengthy implementation timelines. The benefits of fecal screening for CRC are ease of operation, noninvasiveness, cost-effectiveness, and superior sensitivity. As a result of its enrichment in the malignant tissues and feces of CRC patients, Fusobacterium nucleatum ( F. nucleatum ) has emerged as a crucial biomarker for the incipient detection, identification, and prognostic prediction of CRC. Here, for the first time, the whole-bacterium SELEX method was used to screen the highly specific and affinity aptamers against F. nucleatum by 13 cycles of selection. The Apt-S-5 linear correlation equation is y = 0.7363 x 2.8315 ( R 2 = 0.9864) with a limit of detection (LOD) of 851 CFU/mL. The results of the experiment using fecal samples revealed a substantial disparity between the microorganisms in the CRC patients' feces and those in the feces of healthy individuals and were consistent with those of qPCR. The aptamers may therefore offer a crucial approach to identifying F. nucleatum and hold tremendous promise for CRC diagnosis and prognostic prediction.

1,3,5-triazine derivatives, also called s-triazines, are a series of containing-nitrogen heterocyclic compounds that play an important role in anticancer drug design and development. To date, three s-triazine derivatives, including altretamine, gedatolisib, and enasidenib, have already been approved for refractory ovarian cancer, metastatic breast cancer, and leukemia therapy, respectively, demonstrating that the s-triazine core is a useful scaffold for the discovery of novel anticancer drugs. In this review, we mainly focus on s-triazines targeting topoisomerases, tyrosine kinases, phosphoinositide 3-kinases, NADP+-dependent isocitrate dehydrogenases, and cyclin-dependent kinases in diverse signaling pathways, which have been extensively studied. The medicinal chemistry of s-triazine derivatives as anticancer agents was summarized, including discovery, structure optimization, and biological applications. This review will provide a reference to inspire new and original discoveries.

Exosomes are considered as promising biomarkers for early cancer diagnosis and prognosis. However, the majority of the research studies focused on a single type of exosomal biomarkers, which cannot comprehensively reflect the state of cancer for accurate diagnosis. To address this problem, we presented a ship-shaped microfluidic device containing a microcolumn array for simultaneous in situ detection of exosomal surface proteins and miRNAs. Exosomes were first captured in the microchannels modified with CD63 protein aptamer. Exosomal surface proteins and miRNAs were simultaneously detected in four parallel channels to avoid the interference of fluorescent signals using specific aptamers labeled by Cy5 and catalytic hairpin assembly (CHA) based signal amplification strategy. The limit of detection for multiplexed markers in exosomes was 83 exosomes per μL, which is comparable to previously reported methods. Through quantitative analysis of two disease-specific surface proteins and miRNAs derived from different cancer cells and clinical serum samples, different cancer subtypes as well as cancer patients and healthy people could be significantly distinguished. These results suggest that this simple, highly sensitive, and more accurate analytical strategy by simultaneous in situ profiling of different types of exosomal biomarkers has potential applications in cancer diagnosis and stage monitoring.

Colorectal cancer (CRC) becomes the second leading cause of cancer-related deaths in 2020. Emerging studies have indicated that microRNAs (miRNAs) play a key role in tumorigenesis and progression. The dysfunctions of miR-455-3p are observed in many cancers. However, its biological function in CRC remains to be confirmed. By sequencing serum sample, miR-455-3p was found to be up-regulated in CRC patients. RT-qPCR demonstrated that the miR-455-3p expression was both higher in the serum and tumor tissues of CRC patients. Furthermore, it indicated that miR-455-3p had the ability in promoting cell proliferation, suppressing cell apoptosis, and stimulating cell migration. In vivo experiments also showed that miR-455-3p promoted tumor growth. Additionally, H2AFZ was proved as the direct gene target of miR-455-3p by dual-luciferase assay. Taken together, miR-455-3p functioned as a tumor promoter in CRC development by regulating H2AFZ directly. Thus, it has enormous potential as a biomarker in the diagnosis of CRC.

Multiple circulating non-coding RNAs (ncRNAs) in serum may serve as vital biomarkers for use in diagnosing early-stage colorectal cancer (CRC). Herein, a universal platform for one-pot detection of CRC-related ncRNAs was developed based on branched rolling circle amplification and CRISPR-Cas12a (BRCACas). For the implementation of the method, primers incorporating ncRNA sequences of circulating CRC-associated RNAs (piRNA or miRNA) were designed that could specifically hybridize with circular probes to initiate the BRCA process. Thereafter, the generation of dendritic DNA products triggered Cas12a trans-cleavage activity to elicit a fluorescent signal. The proposed method, combining high BRCA reaction efficiency with powerful Cas12a trans-cleavage activity, provided greatly enhanced detection sensitivity, as reflected by limits of detection (LODs) for model piRNA (piR-54265) and model miRNA (miR21) of 0.76 fM and 0.87 fM, respectively. Notably, the proposed BRCACas platform, assaying two different types of CRC-associated ncRNAs in patient samples, produced consistent results with the conventional reverse transcription-quantitative PCR (RT-qPCR) method. Therefore, the one-pot, isothermal, and specific BRCACas platform provided excellent performance, thus demonstrating its promise as a rapid, adaptable, and practical diagnostic/prognostic cancer screening method., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

miRNA is considered a novel biomarker for cancer diagnosis and due to its low level in vivo, the development of new detection methods for it has become a research hotspot in recent years. Here, we firstly found that miR-625-5p was significantly upregulated in colorectal cancer tissues by means of differential expression analysis of the dbDEMC database and clinical validation. Subsequently, it was found that miR-625-5p promoted cell proliferation and migration but inhibited apoptosis through phenotypic experiments; thus, we initially identified miR-625-5p as a potential biomarker for colorectal cancer. Moreover, in order to monitor slight changes in the miR-625-5p level, we developed a novel detection method for it based on strand displacement amplification (SDA). In this system, a hairpin was designed to recognize and pair with miR-625-5p, which was used as a primer to initiate SDA, and a large number of complementary DNAs were generated via cyclic amplification, followed by the addition of SYBR Gold to achieve quantitative analysis of miR-625-5p. Moreover, this method showed a good response to miR-625-5p with a detection limit of 8.6 pM and a dynamic range of 0.01 to 200 nM, and the specificity of it was verified using a set of other miRNAs as an interference. Finally, we set up different concentrations of biologic samples for detection to verify the practicability of the method. The results of this study indicate that this detection method has great potential in clinical diagnosis.

Here, we report the first total syntheses of daphnezomine L-type alkaloids daphnezomine L methyl ester and calyciphylline K via late-stage C-N bond activation. The first synthesis of secodaphniphylline-type alkaloid caldaphnidine D was also achieved via a similar strategy. Other key transformations employed in our synthesis were a facile vicinal diol olefination and an efficient radical cyclization cascade. Biological studies indicated two synthetic compounds possess promising neuroprotective activity.

PROteolysis-TArgeting Chimeras (PROTACs) are a powerful class of drugs that selectively degrade the proteins of interest (POIs) through cellular ubiquitination mechanisms. Estrogen receptor α (ERα) plays a vital role in the pathogenesis and treatment of breast cancer. In this work, the DNA-binding domain (DBD) of ERα was selected as the target to avoid drug resistance caused by the ligand-binding domain (LBD) of ERα. The estrogen response element (ERE), a natural DNA sequence binding with DBD of ERα, was chosen as a recognized unit of PROTAC. Therefore, we designed a nucleic acid-conjugated PROTAC, ERE-PROTAC, via a click reaction, in which the ERE sequence recruits ERα and the typical small molecule VH032 recruits the von Hippel-Lindau (VHL) E3 ligase. The proposed ERE-PROTAC showed to efficiently and reversibly degrade ERα in different breast cancer cells by targeting the DBD, indicating its potential to overcome the current resistance caused by LBD mutations., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

Among the famous Daphniphyllum alkaloids family, the calyciphylline A-type subfamily has triggered particular interest from the organic synthesis community in recent years. Here, we report divergent total syntheses of three calyciphylline A-type alkaloids, namely, (-)-10-deoxydaphnipaxianine A, (+)-daphlongamine E, and (+)-calyciphylline R. Our work highlights an efficient, divergent strategy via late-stage divinyl carbinol rearrangements, including an unprecedented oxidative Nazarov electrocyclization using an unfunctionalized tertiary divinyl carbinol and an unusual allylic alcohol rearrangement. A highly efficient "donor-acceptor" platinum catalyst was used for a critical nitrile hydration step. Moreover, the power of selective amide reductions has also been showcased by novel and classic tactics.

In this work, a series of novel 1H-indole-2-carboxylic acid derivatives targeting 14-3-3η protein were designed and synthesized for treatment of liver cancer. After structural optimization for several rounds, C11 displayed a relatively better affinity with 14-3-3η, as well as the best inhibitory activities against several typical human liver cancer cell lines, including Bel-7402, SMMC-7721, SNU-387, Hep G2 and Hep 3B cells. Compound C11 also displayed best inhibitory activity against chemotherapy-resistant Bel-7402/5-Fu cells. Besides, C11 was rather safe against hERG and possessed moderate T 1/2 and CL values in liver microsomes. In anti-proliferation, trans-well and cell apoptosis assays, C11 also showed its huge potential as a potent antitumor agent. Then, Western blot assay was conducted, following analyzed by molecular docking, the anti-proliferative mechanisms of this small-molecule inhibitor were revealed. Moreover, C11 was demonstrated to induce G 1 -S phase cell cycle arrest in liver cancer cells., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: Persistent hyperglycemia decreases the sensitivity of insulin-sensitive organs to insulin, owing to which cells fail to take up and utilize glucose, which exacerbates the progression of type 2 diabetes mellitus (T2DM). lncRNAs' abnormal expression is reported to be associated with the progression of diabetes and plays a significant role in glucose metabolism. Herein, we study the detailed mechanism underlying the functions of lncRNA EPB41L4A-AS1in T2DM., Methods: Data from GEO datasets were used to analyze the expression of EPB41L4A-AS1 between insulin resistance or type 2 diabetes patients and the healthy people. Gene expression was evaluated by qRT-PCR and western blotting. Glucose uptake was measured by Glucose Uptake Fluorometric Assay Kit. Glucose tolerance of mice was detected by Intraperitoneal glucose tolerance tests. Cell viability was assessed by CCK-8 assay. The interaction between EPB41L4A-AS1 and GCN5 was explored by RNA immunoprecipitation, RNA pull-down and RNA-FISH combined immunofluorescence. Oxygen consumption rate was tested by Seahorse XF Mito Stress Test., Results: EPB41L4A-AS1 was abnormally increased in the liver of patients with T2DM and upregulated in the muscle cells of patients with insulin resistance and in T2DM cell models. The upregulation was associated with increased TP53 expression and reduced glucose uptake. Mechanistically, through interaction with GCN5, EPB41L4A-AS1 regulated histone H3K27 crotonylation in the GLUT4 promoter region and nonhistone PGC1β acetylation, which inhibited GLUT4 transcription and suppressed glucose uptake by muscle cells. In contrast, EPB41L4A-AS1 binding to GCN5 enhanced H3K27 and H3K14 acetylation in the TXNIP promoter region, which activated transcription by promoting the recruitment of the transcriptional activator MLXIP. This enhanced GLUT4/2 endocytosis and further suppressed glucose uptake., Conclusion: Our study first showed that the EPB41L4A-AS1/GCN5 complex repressed glucose uptake via targeting GLUT4/2 and TXNIP by regulating histone and nonhistone acetylation or crotonylation. Since a weaker glucose uptake ability is one of the major clinical features of T2DM, the inhibition of EPB41L4A-AS1 expression seems to be a potentially effective strategy for drug development in T2DM treatment., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Colorectal cancer (CRC) is one of the digestive tract malignancies whose early symptoms are not obvious. This study aimed to identify novel targets for CRC therapy, especially early-stage CRC, by reanalyzing the publicly available GEO and TCGA databases. Thyroid hormone receptor interactor 13 (TRIP13) correlated with tumor progression and prognosis of patients after several rounds of analysis, including weighted gene correlation network analysis (WGCNA), and further chosen for experimental validation in cancer cell lines and patient samples. We identified that mRNA and protein levels of TRIP13 increased in CRC cells and tumor tissues with tumor progression. miR-4693-5p was significantly downregulated in CRC tumor tissues and bound to the 3' untranslated region (3'UTR) of TRIP13, downregulating TRIP13 expression. DCZ0415, a small molecule inhibitor targeting TRIP13, induced anti-tumor activity in vitro and in vivo. DCZ0415 markedly suppressed CRC cell proliferation, migration, and tumor growth, promoted cell apoptosis, and resulted in the arrest of the cell cycle. Our research suggests that TRIP13 might play a crucial role in CRC progression and could be a potential target for CRC therapy., (© 2022. The Author(s).)

Cancer is a common malignant disease with complex signaling networks, which means it is unmanageable to cancer therapy by using single classical targeted drug. Recently, dual- or multitarget drugs have emerged as a promising option for cancer therapies. Although many multifunctional compounds targeting HDAC have been validated, as far as we know, there is no molecule targeting GLP and HDAC synchronously. In the present work, we designed and synthesized a series of quinazoline-based hydroxamic acid derivatives as dual GLP and HDAC inhibitors. These hybrid compounds showed potent enzymatic inhibitory activities against GLP and HDAC1/6 with IC 50 values in the nanomolar range of less than 190 nM. Furthermore, most of our compounds displayed significant broad spectrum cytotoxic activities apart from D3 and D8 against all the tested cancer cells with IC 50 values less than 50 μM. D1, D6 and D7 showed more potent cytotoxic activities than D2, D4 and D5 in those cancer cells. Especially, compound D7 showed potent inhibitory potency activity against both GLP and HDAC1/6 with IC 50 values of 1.3, 89, 13 nM. Besides, D7 exhibited the most potent antiproliferative activity against all the tested cancer cells. Further evaluations indicated that D7 could inhibit the methylation and deacetylation of H3K9 on protein level. Moreover, D7 could induce cancer cell apoptosis, G0/G1 cell cycle arrest, and partly block migration and invasion. All these thorough evaluations warranted D7 as a promising lead compound worth further optimization and development for cancer therapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Chemokine receptor 2 (CXCR2) is the receptor of glutamic acid-leucine-arginine sequence-contained chemokines CXCs (ELR + CXCs). In recent years, CXCR2-target treatment strategy has come a long way in cancer therapy. CXCR2 antagonists could block CXCLs/CXCR2 axis, and are widely used in regulating immune cell migration, tumor metastasis, apoptosis and angiogenesis. Herein, two series of new CXCR2 small-molecule inhibitors, including 1,2,4-triazol-3-one derivatives 1-11 and pyridazinone derivatives 12-22 were designed and synthesized based on the proof-to-concept. The pyridazinone derivative 18 exhibited good CXCR2 antagonistic activity (69.4 ± 10.5 %Inh at 10 μM) and demonstrated its significant anticancer metastasis activity in MDA-MB-231 cells and remarkable anti-angiogenesis activity in HUVECs. Furthermore, noteworthy was that 18 exhibited an obvious synergistic effect with Sorafenib in anti-proliferation assay in MDA-MB-231 cells. Moreover, 18 showed a distinct reduction of the phosphorylation levels of both PI3K and AKT proteins in MDA-MB-231 cells, and also affected the expression levels of other PI3K/AKT signaling pathway-associated proteins. The molecular docking studies of 18 with CXCR2 also verified the rationality of our design strategy. All of these results revealed pyridazinone derivative 18 as a promising CXCR2 antagonist for future cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

α-Substituted peroxides have been found in natural products and are widely used as anti-malarial agents. Zn(OTf) 2 -catalyzed peroxidation of 1,3,5-triazines has been developed, accessing diversely substituted α-amino tertiary alkylperoxides with high efficiency. Mechanistic investigations and useful synthetic application of the products have also been presented., (© 2021 Wiley-VCH GmbH.)

In this work, a series of novel substituted polycyclic pyridone derivatives were designed and synthesized as potent anti-influenza agents. The cytopathic effect (CPE) assay and cytotoxicity assay indicated that all of the compounds possessed potent anti-influenza virus activity and relatively low cytotoxicity; some of them inhibited the replication of influenza A virus (IAV) at picomolar concentrations. Further studies revealed that, at a concentration of 3 nM, three compounds ( 10a , 10d , and 10g ) could significantly reduce the M2 RNA amounts and M2 protein expression of IAV and inhibit the activity of RNA-dependent RNA polymerase (RdRp). Among them, ( R )-12-(5 H -dibenzo[ a , d ][7]annulen-5-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1 H -[1,4]oxazino[3,4- c ]pyrido[2,1- f ][1,2,4]triazine-6,8-dione ( 10a ) was found to be a promising anti-influenza drug candidate with good human liver microsomal stability, as well as with better selectivity index and oral bioavailability than Baloxavir.

In this work, two series of cyclic amine-containing benzimidazole carboxamide derivatives were designed and synthesized as potent anticancer agents. PARP1/2 inhibitory activity assays indicated that most of the compounds showed significant activity. The in vitro antiproliferative activity of these compounds was investigated against four human cancer cell lines (MDA-MB-436, MDA-MB-231, MCF-7 and CAPAN-1), and several compounds exhibited strong cytotoxicity to tumor cells. Among them, 2-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide (17d) was found to be effective PARP1/2 inhibitors (IC 50  = 4.30 and 1.58 nM, respectively). In addition, 17d possessed obvious selective antineoplastic activity and noteworthy microsomal metabolic stability. What's more, further studies revealed that 17d was endowed with an excellent ADME profile. These combined results indicated that 17d could be a promising candidate for the treatment of cancer., (Copyright © 2021. Published by Elsevier Inc.)

Colorectal cancer (CRC) is a frequently occurring digestive system cancer and postoperative tumor metastasis and recurrence are the main reasons for the failure of CRC treatment. The aim of this study was to identifying and validating key genes associated with metastatic recurrence of CRC. RNA expression of three datasets (GSE17538, GSE32323, and GSE29623) was used for biomarker discovery. We identified integrin-binding sialoprotein (IBSP) as a candidate biomarker which was validated in three clinical cohorts (GSE41258, GSE21510, and GSE39582) and our clinical specimens. The results suggested that IBSP expression significantly increased at mRNA and protein levels among CRC cases, which was associated with metastatic recurrence, metastasis, high risk of recurrence, and poor survival in CRC. Consistent results were obtained in CRC cells. The relative level of serum IBSP evidently increased among CRC patients relative to normal controls, and downregulated after operation. As suggested by gene set enrichment analysis (GSEA), the IBSP level was associated with cell-matrix adhesion in CRC. Functional experiments in vitro showed that IBSP promoted the growth and aggressiveness of CRC, and the potential mechanism by which IBSP promoted carcinogenesis of CRC was the abnormal activation of Fyn/β-catenin signaling pathway. To sum up, findings in the present work indicate that IBSP can serve as the candidate biomarker for the diagnosis, treatment, and prognosis of CRC., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Metal coordination-driven composite systems have excellent stability and pH-responsive ability, making them suitable for specific drug delivery in physiological conditions. In this study, an anionic conjugated polymer PPEIDA with a poly(p-phenylene ethynylene) backbone and iminodiacetic acid (IDA) side chains is used as a drug carrier to construct a class of pH-responsive nanoparticles, PPEIDA-Cu-DOX conjugated polymer nanoparticles (CPNs), by taking advantage of the metal coordination interaction of Cu 2+ with PPEIDA and the drug doxorubicin (DOX). PPEIDA-Cu-DOX CPNs have high drug loading and encapsulation efficiency (EE), calculated to be 54.30 ± 1.10 and 95.80 ± 0.84%, respectively. Due to the good spectral overlap, Förster resonance energy transfer (FRET) takes place between PPEIDA and the drug DOX, which enables the observation of the loading and the release of DOX from CPNs in an acidic environment by monitoring fluorescence emission changes. Therefore, PPEIDA-Cu-DOX CPNs can also be used in real-time cell imaging to monitor drug release in addition to delivering DOX targeting tumor cells. Compared with free DOX, PPEIDA-Cu-DOX CPNs show a similar inhibition to tumor cells and lower toxicity to normal cells. Our results demonstrate the feasibility and potential of constructing pH-responsive CPNs via metal-ligand coordination interactions for cancer treatment.

Acquired resistance leads to the failure of EGFR TKIs in NSCLC treatment. A novel series of hydroxamic acid-containing 4-aminoquinazoline derivatives as irreversible ErbB/HDAC multitargeted inhibitors for NSCLC therapy had been designed and synthesized, which displayed weak anti-proliferative activity in several EGFR wild-type cancer cell lines (NCI-H838, SK-BR-3, A549, A431) yet retained moderate activity to EGFR T790M resistance mutation harboring NCI-H1975 cells. The mechanistic studies revealed that the representative compound 11e was able to inhibit the phosphorylation of EGFR, up-regulate hyperacetylation of histone H3 and even reduce the expression of EGFR and Akt in NCI-H1975 cells. In further assays, compound 11e also showed moderate anti-proliferative activity in other EGFR T790M harboring tumor cell lines (NCI-H820, Ba/F3&#95;EGFR&#95;Del19-T790M-C797S) and low toxicities in normal cell lines (HL-7702, FHC). This selectivity of designed multitargeted compounds could serve as a potential strategy to circumvent multiple mechanisms of acquired resistance to EGFR-targeted therapy without severe toxicities and side effects resulting from broad inhibition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Glucose performs many essential functions associated with metabolic processes in the living system, and is closely related to many diseases such as diabetes and hypoglycemia. Most of the existing glucose concentration detection methods require complex instruments, which undoubtedly limit its widespread use. Here, we have designed a glucose colorimetric detection system composed of glucose, glucose oxidase (GOD), manganese dioxide nanosheets (MnO 2 NSs) and 3,3',5,5'-tetramethylbenzidine (TMB) to achieve colorimetric detection with the naked eye. Compared with the single-color change of the colorimetric method in previous studies, multiple-color changes have been realized. MnO 2 NSs, as a kind of nanomaterial imitating oxidase, can directly oxidize TMB to oxTMB. Because oxTMB showed a dark yellow color when strongly oxidized and light blue when weakly oxidized, this feature can achieve multiple-color changes rather than a single-color change, which is helpful for colorimetric observation with the naked eye. Finally, we successfully used MnO 2 NSs for colorimetric detection of glucose and realized multiple-color changes, making it easier to achieve colorimetric observation with the naked eye. The linear detection range is 0-4000 μM and limit of detection is 5.0 μM. This is not only useful for glucose, but also has an important significance for other experiments considering colorimetric experiments with the naked eye.

Enzyme-linked immunosorbent assay is a widely used analytical technique for detecting and quantifying disease-specific protein biomarkers. Despite recent progresses in disease-specific protein biomarkers detection with microfluidic chips, many devices still suffer from the limited mass transport of target molecules, and consequently low detection efficiency or long incubation time. In this work, we present a novel strategy to significantly enhance the sensing efficiency of a chip-based biosensor by exploiting micro-streaming in an acoustofluidic device, which boosts intermolecular interactions and a hybridization chain reaction to increase the fluorescent signals. This device was made of a microfluidic chip that contains an array of PDMS micropillars in a ship-shaped microchannel. And the inner surface of the channel was functionalized with capture aptamers that bind with thrombin, chosen as a model target molecule. An ultrasonic transducer underneath the chip operating at 150 kHz generates circular micro-streaming flows around the pillars that significantly improves the binding efficiency of thrombin with capture aptamers by 1) increasing the retention time and 2) enhancing mass transport via local convection versus diffusion. The effects of ultrasound parameters, such as operating frequencies and voltages, on the distribution and magnitude of flows were optimized to obtain a better performance of the sensor chip. Under the optimized conditions, the detection limit was increased by one order of magnitude. Although this work has focused on the detection of thrombin as a model molecule, this streaming-enhanced, microstructure-based sensing strategy can be applied to detect a wide range of molecules or even cells., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: We explored specific expression profiles of BGN and COL11A1 genes and studied their biological functions in CRC using bioinformatics tools., Patients and Methods: A total of 68 pairs of cancer and non-cancerous tissues from CRC patients were enrolled in this study. Methods we used in this articles including: qRT-PCR, Western blot analysis, ELISA, GO and KEGG regulatory network analysis, tumor infiltration, luciferase reporter-based protein and etc., Results: According to The Cancer Genome Atlas (TCGA) data, BGN and COL11A1 expression levels were significantly higher in CRC patient samples than in samples from healthy controls. Moreover, levels were much higher in late-stage CRC than in early-stage disease, warranting evaluation of these genes as CRC prognostic biomarkers. Subsequently, qRT-PCR, Western blot analysis, and ELISA results obtained from analyses of CRC cells, tissues, and patient sera aligned with TCGA results. GO and KEGG regulatory network analysis revealed BGN- and COL11A1- associated genes that were functionally related to extracellular matrix (ECM) receptor pathway activation, with transcription factor genes RELA and NFKB1 positively associated with BGN expression and CEBPZ and SIRT1 with COL11A1 expression. Meanwhile, BGN and COL11A1 expression were separately and significantly correlated to tumor infiltration by six immune cell types. Additionally, kinase genes PLK1 and LYN appeared to be downstream targets of differentially expressed BGN and COL11A1 , respectively. In addition, the expression of PLK1 mRNA was down-regulated while BGN was down-regulated. Finally, BGN effects on CRC cell proliferation, cycle, apoptosis, invasion, and migration were studied using molecular biological methods, including luciferase reporter-based protein analysis, qRT-PCR, and Western blot results, which revealed that miR-6828-5p may regulate BGN expression., Conclusion: We speculate that the use of BGN and COL11A1 as CRC biomarkers would improve CRC staging, while also providing several novel targets for use in the development of more effective CRC treatments., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Chen et al.)

Multi-microRNA (miRNA) detection would greatly facilitate early diagnosis of colorectal cancer (CRC). Here a convenient cascade isothermal amplification approach incorporating a G-quadruplex molecular beacon (G4MB) was established for achieving one-pot detection of multiple CRC miRNAs (miRNA-21, miRNA-92a, miRNA-31); this strategy incorporated a Bsu DNA polymerase (Bsu pol)-induced strand-displacement reaction and a Lambda exonuclease (λexo)-aided recycling reaction. In the presence of target miRNA, the G-rich stem structure was opened and became available for hybridization with the primer to initiate synthesis of Bsu pol-catalyzed double-stranded DNA (dsDNA) that displaced the miRNA target and released it, allowing it to participate in subsequent amplification cycles. Meanwhile, the dsDNA was gradually digested into fragments by λexo from the 5' phosphorylated end, releasing the newly synthesized DNA strand for participation in subsequent cycles that led to amplification of the fluorescent signal. This approach provided a low limit of detection (LOD) of zeptomolar-level, 85.8 zM, 77.6 zM, 78.9 zM for miRNA-21, miRNA-92a, miRNA-31, respectively. It could distinguish the mismatched targets and achieved three miRNA targets detection run in parallel in one-pot within 2 h. Thus, this fast, simple, and convenient strategy holds great promise as a clinical application for the detection of multiple miRNAs in clinical CRC samples., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Nuclear paraspeckles assembly transcript 1 (NEAT1) is a well-known long noncoding RNA (lncRNA) with various functions in different physiological and pathological processes. Notably, aberrant NEAT1 expression is implicated in the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease (AD). However, the molecular mechanism of NEAT1 in AD remains poorly understood. In this study, we investigated that NEAT1 regulated microtubules (MTs) polymerization via FZD3/GSK3β/p-tau pathway. Downregulation of NEAT1 inhibited Frizzled Class Receptor 3 (FZD3) transcription activity by suppressing H3K27 acetylation (H3K27Ac) at the FZD3 promoter. Our data also demonstrated that P300, an important histone acetyltransferases (HAT), recruited by NEAT1 to bind to FZD3 promoter and mediated its transcription via regulating histone acetylation. In addition, according to immunofluorescence staining of MTs, metformin, a medicine for the treatment of diabetes mellitus, rescued the reduced length of neurites detected in NEAT1 silencing cells. We suspected that metformin may play a neuroprotective role in early AD by increasing NEAT1 expression and through FZD3/GSK3β/p-tau pathway. Collectively, NEAT1 regulates microtubule stabilization via FZD3/GSK3β/P-tau pathway and influences FZD3 transcription activity in the epigenetic way.

Hydrogen sulfide (H 2 S), a well-known signaling molecule, exerts significant regulatory effects on the cardiovascular and nervous systems. Therefore, monitoring the metabolism of H 2 S offers a potential mechanism to detect various diseases. In addition, biotin is significantly used as a targeting group to detect cancer cells exclusively. In this work, a biotin-guided benzoxadizole-based fluorescent probe, NP-biotin, was developed for H 2 S detection and evaluated in normal liver cell (LO2) and liver cancer cell (HepG2) lines. Results reveal that NP-biotin can detect cellular H 2 S with high sensitivity and selectivity. Moreover, NP-biotin has been confirmed to possess the ability to target cancer cells under the guidance of the biotin group., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Successful discrimination of complex biological samples by sensor array remains a challenging problem. Herein, a three-unit fluorescence sensor array was fabricated using fluorescent molecules, which interact with proteins and generate rich response signals, to realize the discrimination of urinary proteins. As a proof of concept, six urinary proteins were selected as analytes. Results showed 100% accuracy in differentiation and quantitative discrimination of every single protein and their complex mixtures. Moreover, protein profiles of urine samples from healthy people and patients with different urinary diseases, including tubular injury (TI), diabetic nephropathy (DN), and nephropathy (Nep), were well distinguished.

A cationic conjugated polyelectrolyte PPET3-N2 was used as a photosensitizer for photocatalytic oxidation of organic sulfides, including thioanisole, ethyl phenyl sulfide, 4-methylphenyl methyl sulfide, etc., to form sulfoxides with good yields and high selectivity. Oxidation reactions were performed in both batch and microfluidic reactors, where the microfluidic reactor can significantly promote the conversion of photocatalytic oxidation reaction to over 98% in about 8 min. Further studies of the photocatalytic oxidation of the antitumor drug ricobendazole in the microfluidic reactor demonstrate the potential application of the polymer material in organic reactions given its high selectivity, good efficiency, and operation convenience.

Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) using conventional organic matrices for detection of small molecules has some limitations, such as heterogeneous analyte/matrix co-crystals, as well as interference of matrices in the low-molecular-weight range. In this work, a zeolite framework nanomaterial, TS-1, was applied as a MALDI matrix for the analysis of small molecules by MALDI-MS for the first time. To improve the signal intensity and reproducibility, TS-1 was modified with polydopamine (TS-1@PDA). Using TS-1@PDA as a matrix, organic substances in the low-molecular-weight region such as amino acids, nucleosides, peptides, oligosaccharides, and fatty acids can be detected by MALDI-MS in positive ion mode. Compared with traditional organic matrices like 2,5-dihydroxybenzoic acid (2,5-DHB) and α-cyano-4-hydroxycinnamic acid (CHCA), TS-1@PDA has the advantages including the formation of uniform sample spots, small background interference at low molecular weight, and better salt tolerance. Furthermore, this matrix was employed for the analysis of endogenous glucose in urine samples, and the level of glucose was quantified with a linear range of 0-10 mM ( R 2 > 0.98). The results demonstrated that TS-1@PDA has the potential to be used as an effective MALDI matrix for the analysis of small molecules in biological samples with excellent reproducibility and moderate sensitivity., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Small molecule JAK inhibitors have been demonstrated efficacy in rheumatoid arthritis, inflammatory bowel disease, and psoriasis with the approval of several drugs. Aiming to develop potent JAK1/2 inhibitors, two series of triazolo [1,5-a] pyridine derivatives were designed and synthesized by various strategies. The pharmacological results identified the optimized compounds J-4 and J-6, which exerted high potency against JAK1/2, and selectivity over JAK3 in enzyme assays. Furthermore, J-4 and J-6 effectively suppressed proliferation of JAK1/2 high-expression BaF3 cells accompanied with acceptable metabolic stability in liver microsomes. Therefore, J-4 and J-6 might serve as promising JAK1/2 inhibitors for further investigation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Ltd.)

Polybrominated diphenyl ether-47 (BDE-47) is a congener of polybrominated diphenyl ethers (PBDEs) and relates to different health risks. However, in vivo study of the association between BDE-47 and breast cancer was scarce. In this study, we performed in vivo exposure of BDE-47 to breast cancer nude mice and conducted mass spectrometry-based metabolomics and lipidomics analysis to investigate the metabolic changes in mice. Results showed that the tumor sizes were positively associated with the dosage of BDE-47. Metabolomics and lipidomics profiling analysis indicated that BDE-47 induced significant alterations of metabolic pathways in livers, including glutathione metabolism, ascorbate and aldarate metabolism, and lipids metabolism, etc. The upregulations of phosphatidylcholines (PCs) and phosphatidylethanolamines (PEs) suggested the membrane remodeling, and the downregulations of Lyso-PCs and Lyso-PEs might be associated with the tumor growth. Targeted metabolomics analysis revealed that BDE-47 inhibited fatty acid β-oxidation (FAO) and induced incomplete FAO. The inhibition of FAO and downregulation of PPARγ would contribute to inflammation, which could promote tumor growth. In addition, BDE-47 elevated the expression of the cytokines TNFRSF12A, TNF-α, IL-1β and IL-6, and lowered the cytokines SOCS3 and the nuclear receptor PPARα. The changes of cytokines and receptor may contribute to the tumor growth of mice., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Pokemon, a transcriptional repressor, inhibits the transcription of tumor suppressor genes and promotes tumor formation by affecting chromatin recombination or binding directly to the tumor suppressor genes. In this study, the mechanism behind the Pokemon regulation of liver cancer cell metabolism was evaluated using liquid chromatography-mass spectrometry (LC-MS)-based metabolomics. Pokemon-overexpressing HL7702 cells were obtained by lipofection. The cells were collected at different time points after transfection and their intracellular metabolites were analyzed using an LC-MS-based metabolomic method. Based on the results of a multivariate statistical analysis, candidate metabolites with significant differences were selected, and 36 of them were confirmed by database and MS/MS analysis. These metabolites were primarily involved in lipid synthesis by KEGG database searches. Further analysis indicated that both the acetyl-coenzyme carboxylase and the fatty acid synthase were activated in the lipid synthesis pathway. The results show that Pokemon can affect cell metabolism by activating the lipid synthesis pathways in cells.

Introduction : The global incidence of hepatocellular carcinoma (HCC) is not expected to decline significantly over the next 30 years. And although the latest gene sequencing studies have established its genetic map, the potentially targetable drivers of HCC are, so far, difficult to identify. To date, only seven drugs have been approved by the FDA for unresectable HCC treatment; thus, effective therapeutic breakthroughs are still needed urgently. Areas covered : In this review, the authors discuss both genetic and epigenetic alterations in HCC and introduce the current progress with some of the representative molecular targeting inhibitors, listing some of the approved drugs for the targets of HCC. The structure-activity relationship of molecules (e.g. thalidomide, bortezomil) used for HCC is also discussed. Expert opinion : Effective therapeutic targets and effective drugs for HCC treatment are an urgent unmet need. Better understanding and characterization of genetic and epigenetic alterations, which are important to hepatocarcinogenesis, may help to understand the molecular pathogenesis of HCC, as well as provide novel therapeutic lead compounds for HCC treatment.