Design, synthesis, and biological evaluation of N-(pyridin-3-yl)pyrimidin-4-amine analogues as novel cyclin-dependent kinase 2 inhibitors for cancer therapy.

The discovery and development of CDK2 inhibitors has currently been validated as a hot topic in cancer therapy. Herein, a series of novel N-(pyridin-3-yl)pyrimidin-4-amine derivatives were designed and synthesized as potent CDK2 inhibitors. Among them, the most promising compound 7l presented a broad antiproliferative efficacy toward diverse cancer cells MV4-11, HT-29, MCF-7, and HeLa with IC50 values of 0.83, 2.12, 3.12, and 8.61 µM, respectively, which were comparable to that of Palbociclib and AZD5438. Interestingly, these compounds were less toxic on normal embryonic kidney cells HEK293 with high selectivity index. Further mechanistic studies indicated 7l caused cell cycle arrest and apoptosis on HeLa cells in a concentration-dependent manner. Moreover, 7l manifested potent and similar CDK2/cyclin A2 nhibitory activity to AZD5438 with an IC50 of 64.42 nM. These findings revealed that 7l could serve as ahighly promisingscaffoldfor CDK2 inhibitors as potential anticancer agents and functional probes.

Lamotrigine-Induced Hemophagocytic Lymphohistiocytosis with DRESS.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory reaction syndrome caused by genetic or acquired immune dysregulation. The majority of adult HLH cases are caused by tumors, rheumatic immune disorders, and infections. However, drug-induced HLH is rarely reported. METHODS: We report a case of HLH in an adult caused by the administration of lamotrigine, to our knowledge, only nine other cases of lamotrigine-associated HLH have been reported in adult patients. RESULTS: After discontinuing lamotrigine and using steroid hormones for the HLH, the patient's condition has been brought under control. CONCLUSIONS: This case confirms that dexamethasone is also effective for drug-induced HLH. Usually, after discontinuing the relevant medications, there is no need for further maintenance treatment.

The Dawn of a New Era: Tumor-Targeting Boron Agents for Neutron Capture Therapy.

Cancer is widely recognized as one of the most devastating diseases, necessitating the development of intelligent diagnostic techniques, targeted treatments, and early prognosis evaluation to ensure effective and personalized therapy. Conventional treatments, unfortunately, suffer from limitations and an increased risk of severe complications. In light of these challenges, boron neutron capture therapy (BNCT) has emerged as a promising approach for cancer treatment with unprecedented precision to selectively eliminate tumor cells. The distinctive and promising characteristics of BNCT hold the potential to revolutionize the field of oncology. However, the clinical application and advancement of BNCT technology face significant hindrance due to the inherent flaws and limited availability of current clinical drugs, which pose substantial obstacles to the practical implementation and continued progress of BNCT. Consequently, there is an urgent need to develop efficient boron agents with higher boron content and specific tumor-targeting properties. Researchers aim to address this need by integrating tumor-targeting strategies with BNCT, with the ultimate goal of establishing BNCT as an effective, readily available, and cutting-edge treatment modality for cancer. This review delves into the recent advancements in integrating tumor-targeting strategies with BNCT, focusing on the progress made in developing boron agents specifically designed for BNCT. By exploring the current state of BNCT and emphasizing the prospects of tumor-targeting boron agents, this review provides a comprehensive overview of the advancements in BNCT and highlights its potential as a transformative treatment option for cancer.

An ESIPT-based AIE fluorescent probe to visualize mitochondrial hydrogen peroxide and its application in living cells and rheumatoid arthritis.

As a chronic inflammatory disease, rheumatoid arthritis (RA) can cause progressive damage to joints and various organs. Hydrogen peroxide plays a significant role in the pathogenesis and progression of RA and thus serves as a biomarker for diagnosing this disease. Although fluorescent probes have emerged as promising tools for detecting H2O2, most available ones suffer from the aggregation-caused quenching (ACQ) effect, short-wavelength emission, low sensitivity, and poor water solubility. Herein, a new type of "turn-on" AIE probe based on excited state intramolecular proton transfer (ESIPT) was developed, with phenylboronic acid pinacol ester-appended quinolinium as the H2O2 recognition site, which is in the quenched state due to the twisted intramolecular charge transfer (TICT) effect. The probe HTQ-R exhibits good water solubility, high sensitivity, a low detection limit (210 nM), rapid response ability, and good biocompatibility towards hydrogen peroxide, and has shown the ability to accurately target mitochondria. Furthermore, HTQ-R was successfully used to detect exogenous and endogenous hydrogen peroxide in living cells, which enabled real-time monitoring of H2O2 in RA mice, demonstrating its potential significance in the diagnosis and treatment of RA.

Ligand-based discovery of coronavirus main protease inhibitors using MACAW molecular embeddings.

Ligand-based drug design methods are thought to require large experimental datasets to become useful for virtual screening. In this work, we propose a computational strategy to design novel inhibitors of coronavirus main protease, Mpro. The pipeline integrates publicly available screening and binding affinity data in a two-stage machine-learning model using the recent MACAW embeddings. Once trained, the model can be deployed to rapidly screen large libraries of molecules in silico. Several hundred thousand compounds were virtually screened and 10 of them were selected for experimental testing. From these 10 compounds, 8 showed a clear inhibitory effect on recombinant Mpro, with half-maximal inhibitory concentration values (IC50) in the range 0.18-18.82 µM. Cellular assays were also conducted to evaluate cytotoxic, haemolytic, and antiviral properties. A promising lead compound against coronavirus Mpro was identified with dose-dependent inhibition of virus infectivity and minimal toxicity on human MRC-5 cells.

Synthesis and biological evaluation of novel 5-substituted/unsubstituted triazolothiadiazines as tubulin depolymerizing and vascular disrupting agents with promising antitumor activity.

A novel series of 5-substituted/unsubstituted [1,2,4]triazolo[3,4-b][1,3,4] thiadiazine compounds has been achieved successfully through chemoselective reduction of the C = N bond, based on our prior work. Initial biological evaluation illustrated that the most active derivative 7j exhibited significant cell growth inhibitory activity toward MCF-7, A549, HCT116, and A2780 with the IC50 values of 0.75, 0.94, 2.90, and 4.15 µM, respectively. Most importantly, all the representative analogs did not demonstrate obvious cytotoxic activity against the non-tumoural cell line HEK-293 (IC50 > 100 µM). The mechanism study revealed that 7j caused the G2 /M phase arrest, induced cell apoptosis in HeLa cells in a concentration-dependent manner, and also showed potent tubulin polymerization inhibitory effect. Meanwhile, 7j exerted significant antivascular activity in the wound-healing and tube formation assays. These observations indicate that 5-unsubstituted 6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine scaffold might be considered as a potential lead for antitubulin inhibitors to develop highly efficient anticancer agents with potent selectivity over normal human cells.

Distinct roles of pH and organic ligands in the dissolution of goethite by cysteine.

Electron shuttles such cysteine play an important role in Fe cycle and its availability in soils, while the roles of pH and organic ligands in this process are poorly understood. Herein, the reductive dissolution process of goethite by cysteine were explored in the presence of organic ligands. Our results showed that cysteine exhibited a strong reactivity towards goethite - a typical iron minerals in paddy soils with a rate constant ranging from 0.01 to 0.1 hr-1. However, a large portion of Fe(II) appeared to be "structural species" retained on the surface. The decline of pH was favorable to generate more Fe(II) ions and enhancing tendency of Fe(II) release to solution. The decline of generation of Fe(II) by increasing pH was likely to be caused by a lower redox potential and the nature of cysteine pH-dependent adsorption towards goethite. Interestingly, the co-existence of oxalate and citrate ligands also enhanced the rate constant of Fe(II) release from 0.09 to 0.15 hr-1; nevertheless, they negligibly affected the overall generation of Fe(II) in opposition to the pH effect. Further spectroscopic evidence demonstrated that two molecules of cysteine could form disulfide bonds (S-S) to generate cystine through oxidative dehydration, and subsequently, inducing electron transfer from cysteine to the structural Fe(III) on goethite; meanwhile, those organic ligands act as Fe(II) "strippers". The findings of this work provide new insights into the understanding of the different roles of pH and organic ligands on the generation and release of Fe induced by electron shuttles in soils.

COVID-19 pneumonia: CT findings of 122 patients and differentiation from influenza pneumonia.

OBJECTIVES: To investigate the clinical and chest CT characteristics of COVID-19 pneumonia and explore the radiological differences between COVID-19 and influenza. MATERIALS AND METHODS: A total of 122 patients (61 men and 61 women, 48 ± 15 years) confirmed with COVID-19 and 48 patients (23 men and 25 women, 47 ± 19 years) confirmed with influenza were enrolled in the study. Thin-section CT was performed. The clinical data and the chest CT findings were recorded. RESULTS: The most common symptoms of COVID-19 were fever (74%) and cough (63%), and 102 patients (83%) had Wuhan contact. Pneumonia in 50 patients with COVID-19 (45%) distributed in the peripheral regions of the lung, while it showed mixed distribution in 26 patients (74%) with influenza (p = 0.022). The most common CT features of the COVID-19 group were pure ground-glass opacities (GGO, 36%), GGO with consolidation (51%), rounded opacities (35%), linear opacities (64%), bronchiolar wall thickening (49%), and interlobular septal thickening (66%). Compared with the influenza group, the COVID-19 group was more likely to have rounded opacities (35% vs. 17%, p = 0.048) and interlobular septal thickening (66% vs. 43%, p = 0.014), but less likely to have nodules (28% vs. 71%, p < 0.001), tree-in-bud sign (9% vs. 40%, p < 0.001), and pleural effusion (6% vs. 31%, p < 0.001). CONCLUSIONS: There are significant differences in the CT manifestations of patients with COVID-19 and influenza. Presence of rounded opacities and interlobular septal thickening, with the absence of nodules and tree-in-bud sign, and with the typical peripheral distribution, may help us differentiate COVID-19 from influenza. KEY POINTS: • Typical CT features of COVID-19 include pure ground-glass opacities (GGO), GGO with consolidation, rounded opacities, bronchiolar wall thickening, interlobular septal thickening, and a peripheral distribution. • Presence of rounded opacities and interlobular septal thickening, with the absence of nodules and tree-in-bud sign, and with the typical peripheral distribution, may help us differentiate COVID-19 from influenza.

A novel "AIE + ESIPT" near-infrared nanoprobe for the imaging of γ-glutamyl transpeptidase in living cells and the application in precision medicine.

γ-Glutamyl transpeptidase (GGT) has been reported as a biomarker of hepatocellular carcinoma (HCC), and its imaging is of great benefit for early detection in precise medicine as well as intraoperative navigation. Herein, we have designed and synthesized a novel near-infrared fluorescent probe coupled aggregation-induced emission (AIE) and excited-state intramolecular proton transfer (ESIPT) effect for the detection of GGT. Thanks to conjugated glutamate acid, this probe could be dispersed in aqueous solution and showed barely any fluorescence emission. Through a GGT-mediated enzymatic reaction, the aggregation state of the probe in aqueous solution was changed and an intramolecular hydrogen bond was formed, resulting in an enhanced fluorescence emission. An excellent linear relationship was observed and the concentration of GGT measured was in the range of 10-90 U L-1 with a limit of detection calculated at 2.9 U L-1. Its feasibility has been confirmed by detecting GGT in HepG2 cells with high specificity and long-term sustainability, satisfying clinical need. Moreover, this nanoprobe showed great potential for precise medicine guided surgery by realizing fluorescence imaging in human liver tumour tissue and distinguishing it from normal tissue. Thus, we supposed that our AIE coupled ESIPT fluorescent nanoprobe has great potential in the early detection of HCC, the selective fluorescence imaging of GGT positive cells during surgery and application in precision medicine.

Gold nanoclusters as a near-infrared fluorometric nanothermometer for living cells.

The authors describe the syntheses and application of glutathione-capped gold nanoclusters (AuNCs) with thermoresponsive properties. The AuNCs have excitation/emission maxima at 430/610 nm and the bright redfluorescence changes along with the temperature in the range from 0 to 90 °C which covers the normal temperature range of living cells. In the range of physiological temperatures (35-42 °C), the temperature resolution is 0.73 °C. The AuNCs display excellent colloidal stability and biocompatibility. They were used for fluorometric temperature detection and imaging of hepatic stellate cells. With such attractive features, the AuNCs are quite promising luminescence nanothermometers. Graphical abstract Schematic presentation of the fluorescence of glutathione-capped gold nanoclusters (AuNCs) as nanothermometers in living cells. The AuNCs have excitation/emission maxima at 430/610 nm and the red fluorescence changes with temperature in a wide range of 0 to 90 °C which covers the normal temperature of living cells.

Applications of Nanoparticles Probes for Prostate Cancer Imaging and Therapy.

Prostate cancer (PCa) is the most common type of cancer in men with high morbidity and mortality. However, the current treatment with drugs often leads to chemotherapy resistance. It is known that the multi-disciplines research on molecular imaging is very helpful for early diagnosing, staging, restaging and precise treatment of PCa. In the past decades, the tumor-specific targeted drugs were developed for the clinic to treat prostate cancer. Among them, the emerging nanotechnology has brought about many exciting novel diagnosis and treatments systems for PCa. Nanotechnology can greatly enhance the treatment activity of PCa and provide novel theranostics platform by utilizing the unique physical/chemical properties, targeting strategy, or by loading with imaging/therapeutic agents. Herein, this chapter focuses on state-of-art advances in imaging and diagnosing PCa with nanomaterials and highlights the approaches used for functionalization of the targeted biomolecules, and in the treatment for various aspects of PCa with multifunctional nanoparticles, nanoplatforms and nanodelivery system.

A ratiometric upconversion nanoprobe for fluorometric turn-on detection of sulfite and bisulfite.

A nanoprobe is described for the ratiometric fluorometric determination of sulfite ions. Upconversion nanoparticles (UCNPs) of the type ß-NaYF4:Yb(III),Er(III),Tm(III) were covalently modified with the molecular probe HIAN which is a hydroxynaphthalimide fluorophore modified with a (cationic) indolinium moiety. Under excitation at 980 nm, the green emission of the UCNPs (peaking at 543 nm) is almost totally quenched, while the NIR emission (peaking at 802 nm) remains unaffected. In the presence of sulfite or bisulfite (hydrogen sulfite), the green fluorescence is restored and can be visually observed. A ratiometric method was worked out by measurement of the ratio of the green and NIR emissions. The analytical range extends from 10 to 250 µM, the limit of detection is 0.14 µM, and the assay can be performed within 40 s. Graphical abstract Based on the use of a molecular probe for sulfite and hydrogen sulfite, and by exploiting an inner filter effect (IFE), an assay for sulfite/hydrogen sulfite was developed by using upconversion nanoparticles (UCNPs). Addition reaction of sulfite/bisulfite with the material results in weakened IFE and enhanced green fluorescence of the UCNPs at excitation/emission wavelengths of 980/543 nm.

Smart Self-Assembled Organic Nanoprobe for Protein-Specific Detection: Design, Synthesis, Application, and Mechanism Studies.

Specific detection or imaging protein has high potential to contribute greatly to medical diagnosis, biological research, and therapeutic applications. The level of human serum albumin (HSA) in blood is related to a variety of diseases and thus serves as an important biomarker for fast clinical diagnosis. Here we report the use of aggregation-induced emission (AIE) based supramolecular assembly to design biomolecular responsive smart organic nanomaterials for detection protein HSA. The designed nanoprobes were aggregates of small molecules and silent in fluorescence, but in the presence of HSA they disassembled and produced a clear turn-on fluorescent signal. Of a small library of nanoprobes constructed for HSA detection, structure-optical signaling and screening studies revealed that nanoprobe 7 is the most efficient one. Mechanism studies showed that nanoprobe 7 was bonded with Site I of HSA through the multiple noncovalent interactions. The resultant restriction of intramolecular rotation of nanoprobe 7 in the hydrophobic cavity of HSA induced fluorescent emission, which was validated by competitive binding assays and molecular docking. More importantly, nanoprobe 7 was successfully applied to recognize and quantify HSA in human serum samples. This study demonstrates nanoprobe 7 is a promising tool for clinical real and fast detection of HSA and thus may find many applications, and the molecular assembly based on AIE also opens a new avenue for designing smart nanomaterials for the sensitive and selective detection for varied analytes.

A self-assembled fluorescent organic nanoprobe and its application for sulfite detection in food samples and living systems.

Sulfur dioxide (SO2) is a widely distributed air pollutant, and humans can easily be exposed to sulfite by inhaling SO2, thus inducing respiratory responses and diseases. Hence, to develop a rapid, sensitive and selective method for detection of sulfites is of great importance. Herein, we designed and synthesized a novel tetraphenyl imidazole compound TIBM with aggregation-induced emission enhancement (AIEE). TIBM can self-assemble into well-organized nanoparticles and is reported as an excellent probe for detection of sulfite with high selectivity and sensitivity. The nanoprobe performed very well for the detection of sulfite with an ultrafast detection time (15 s) and an ultralow detection limit (7.4 nM), which is superior to most of the reported probes. Moreover, the nanoprobe was successfully used to detect sulfite in food samples with a favorable accuracy. In addition, we developed paper-based devices for point-of-care detection of sulfite with naked eyes. Furthermore, due to its high water solubility, cell membrane permeability and good biocompatibility, the nanoproboe was further applied to detect sulfite in living systems. This study may offer some helpful insights for designing other AIE-based fluorescent nanosensors for various analytes.

Small Molecule-Photoactive Yellow Protein Labeling Technology in Live Cell Imaging.

Characterization of the chemical environment, movement, trafficking and interactions of proteins in live cells is essential to understanding their functions. Labeling protein with functional molecules is a widely used approach in protein research to elucidate the protein location and functions both in vitro and in live cells or in vivo. A peptide or a protein tag fused to the protein of interest and provides the opportunities for an attachment of small molecule probes or other fluorophore to image the dynamics of protein localization. Here we reviewed the recent development of no-wash small molecular probes for photoactive yellow protein (PYP-tag), by the means of utilizing a quenching mechanism based on the intramolecular interactions, or an environmental-sensitive fluorophore. Several fluorogenic probes have been developed, with fast labeling kinetics and cell permeability. This technology allows quick live-cell imaging of cell-surface and intracellular proteins without a wash-out procedure.

Evaluation of a dansyl-based amino acid DNSBA as an imaging probe for apoptosis detection.

Imaging agents that enable direct detection of apoptosis are highly desirable in the field of monitoring chemotherapeutic response as well as early diagnosis and disease monitoring. Previous work demonstrated that the dansyled amino acid DNSBA is used to specifically and selectively detect apoptotic cancer cells at the both early and late stages, but the mechanism remains unclear. In this work, we evaluated DNSBA as a tool for monitoring cell apoptosis in CNE1 tumor cell models both in vitro and ex vivo after its in vivo administration, which was confirmed by other assays. The ability of DNSBA to detect multiple pathways and different stages of apoptosis leading to cell death may be advantageous in the evaluation of cancer treatment indicative of a positive therapeutic outcome. The uptake change of molecular probes DNSBA in CNE1 cells represented the changes of apoptotic rate in a caspase-dependent manner. However, the accumulation of DNSBA in apoptotic cells did not increase with the enhanced membrane permeability. Furthermore, ex vivo study demonstrated DNSBA has a similar pattern as the TUNEL-positive cells. In conclusion, DNSBA cellular imaging is useful for the early assessment of treatment-induced apoptosis, and thus may act as a substitute for Annexin V for assessing treatment response.

Dual-Modality Noninvasive Mapping of Sentinel Lymph Node by Photoacoustic and Near-Infrared Fluorescent Imaging Using Dye-Loaded Mesoporous Silica Nanoparticles.

The imaging of sentinel lymph nodes (SLNs), the first defense against primary tumor metastasis, has been considered as an important strategy for noninvasive tracking tumor metastasis in clinics. In this study, we developed an imaging contrast system based on fluorescent dye-loaded mesoporous silica nanoparticles (MSNPs) that integrate near-infrared (NIR) fluorescent and photoacoustic (PA) imaging modalities for efficient SLN mapping. By balancing the ratio of dye and nanoparticles for simultaneous optimization of dual-modality imaging (NIR and PA), the dye encapsulated MSNP platform was set up to generate both a moderate NIR emission and PA signals simultaneously. Moreover, the underlying mechanisms of the relevance between optical and PA properties were discovered. Subsequently, dual-modality imaging was achieved to visualize tumor draining SLNs up to 2 weeks in a 4T1 tumor metastatic model. Obvious differences in uptake rate and contrast between metastatic and normal SLNs were observed both in vivo and ex vivo. Based on all these imaging data, it was demonstrated that the dye-loaded MSNPs allow detection of regional lymph nodes in vivo with time-domain NIR fluorescent and PA imaging methods efficiently.

A novel excited-state intramolecular proton transfer (ESIPT) dye with unique near-IR keto emission and its application in detection of hydrogen sulfide.

A new ESIPT dye of benzothiazole with a conjugative electron acceptor was discovered and synthesized. Due to its unique NIR keto emission and a large Stokes shift, it was used to develop a fluorescent probe for sensitive and selective detection of hydrogen sulfide.

A peptide-based pH-sensitive antibacterial hydrogel for healing drug-resistant biofilm-infected diabetic wounds.

Diabetic foot ulcers are a significant complication affecting roughly 15% of diabetic patients. These chronic wounds can be incredibly burdensome, leading to high treatment costs, potential amputations, and additional health complications. Microbiological studies reveal that bacterial infections are the primary culprit behind delayed wound healing. To solve the problem of infection at the wound site, the most fundamental thing is to kill the pathogenic bacteria. Herein, a neoteric strategy to construct novel antibacterial hydrogel COA-T3 that combined photosensitizers (PSs) and antimicrobial peptides (AMPs) via covalent coupling was proposed. Hydrogel COA-T3 composed of quaternized chitosan (QCS) and oxidized dextran (OD) was constructed for co-delivery of the photosensitizer TPI-PN and the antimicrobial peptide HHC10. In vitro and in vivo experiments demonstrated remarkable effectiveness of COA-T3 against drug-resistant bacteria. Furthermore, the hydrogel significantly promoted healing of diabetic infected wounds. This enhanced antibacterial activity is attributed to the pH-sensitive release of both PSs and AMPs within the hydrogel. Additionally, COA-T3 exhibits excellent biocompatibility, making it a promising candidate for wound dressing materials. These findings indicated that the COA-T3 hydrogel is a promising wound dressing material for promoting the healing of diabetic foot ulcers by providing an environment conducive to improved wound healing in diabetic patients.

High-fidelity imaging of a tumour-associated lysosomal enzyme with an acceptor engineering-boosted near-infrared fluorescent probe.

To facilitate the understanding of the dynamic distribution and activity of lysosomal enzymes, it is highly desirable to develop high-fidelity near-infrared (NIR) activatable fluorescent probes. Here, we propose a general acceptor engineering strategy to construct NIR probes with lysosome-targeting capability. Upon isosteric replacement and additional functionalization, the ß-gal-activatable probe OELyso-Gal exhibited excellent lysosome-targeting capability and favorable responsive performance to the enzyme of interest. Notably, the steric hindrance effect from acceptor engineering is modest, which renders the probe unprecedented affinity to enzymes. Upon the introduction of acceptor engineering, the lysosome-targeting probe became more sensitive to ß-gal in cells and tissues, boosting the discrimination of high ß-gal-expressing ovarian cancer tumours from low ß-gal-expressing tissues. Furthermore, the superiority of OELyso-Gal was validated in real-time visualization of ovarian cancer in tumour-bearing mice. This elegant acceptor engineering strategy provides inspirational insights into the development of customized fluorescent probes for monitoring disease-associated biomarkers within subcellular organelles.