Recent Advances in Organic Small-Molecule Fluorescent Probes for the Detection of Zinc Ions (Zn2+).

Zinc(II) ions (Zn2g) play crucial roles in the growth, propagation, and metabolism of animals, plants, and humans. Abnormal concentrations of Zn2+ in the environment and living organisms pose potential risks to environmental protection and human health. Therefore, it is imperative to develop rapid, reliable and in-situ detection methods for Zn2+ in both environmental and biological contexts. Furthermore, effective analytical methods are required for diagnosing diseases and understanding physiological metabolic mechanisms associated with Zn2+ concentration levels. Organic small-molecule fluorescent probes offer advantages such as fast, reliable, convenient, non-destructive detection capabilities and have significant application potential in Zn2+ detection and bioimaging; thus garnering extensive attention. Over the past two years alone, various organic small-molecule probes for Zn2+ based on different detection mechanisms and fluorophores have been rapidly developed. However, these probes still exhibit several limitations that need further resolution. In light of this context, we provide a comprehensive summary of the detection mechanisms, performance characteristics, and application scope of Zn2+ fluorescence probes since year 2022 while highlighting their advantages. We also propose solutions to address existing issues with these probes and outline future directions for their advancement. This review aims to serve as a valuable reference source offering insights into the development of advanced organic small-molecule-based fluorescence probes specifically designed for detecting Zn2+.

A Halloysite Nanotubes-based Probe for Efficient Fluorescence Detection and Adsorption Removal of Pb2+ in Water.

The detection and removal of Pb2+ is of utmost importance for environmental protection and human health due to its toxicity, persistent pollution, and bioaccumulation effects. To address the limitations associated with organic small molecule-based fluorescence probes such as poor water solubility and single functionality in detecting Pb2+, a fluorescence probe based on halloysite nanotubes was developed. This probe not only enables specific, rapid, and reliable detection of Pb2+ but also facilitates efficient removal of it from water. The development of this bifunctional fluorescent probe provides a valuable insight for designing more advanced probes targeting heavy metal ions.

Epigenetically regulated gene expression profiles reveal four molecular subtypes with prognostic and therapeutic implications in colorectal cancer.

Transcriptomic deregulation by epigenetic mechanisms plays a crucial role in the heterogeneous progression of colorectal cancer (CRC). Herein, we first demonstrated that the frequencies of the aberrancies of DNA methylation-correlated (METcor) and microRNA (miRNA)-correlated (MIRcor) genes were significantly co-regulated. Next, through integrative clustering of the expression profiles of METcor and MIRcor genes, four molecular subtypes were identified in CRC patients from The Cancer Genome Atlas and then validated in four independent datasets. More importantly, the four subtypes were well characterized and showed distinct clinical and molecular features: (i) S-I: high metabolic activity, sensitive to 5-fluorouracil-based chemotherapy and good prognosis; (ii) S-II: moderate metabolic activity, marked proliferation, frequent KRAS mutation and intermediate prognosis; (iii) S-III: moderate metabolic activity, marked proliferation, promoter DNA hypermethylation, high mutation burden, frequent BRAF and EGFR mutations, moderate levels of epithelial-mesenchymal transition (EMT) and transforming growth factor ß (TGFß) signals, immune-inflamed phenotype, sensitive to cetuximab and death protein-1 inhibitor treatment and relatively poor prognosis and (iv) S-IV: miRNA overexpression, stem/serrated/mesenchymal-like properties, hypoxia, high levels of EMT and TGFß signals, immune-excluded phenotype and poor prognosis. Overall, this study established a molecular classification based on epigenetically regulated gene expression profiles, thereby providing a better understanding of the epigenetic mechanisms underlying CRC heterogeneity.

Molecular Engineering to Achieve AIE-active Fluorophore with Near-infrared (NIR) Emission and Temperature-sensitive Property.

Near-infrared organic small molecule luminescent materials have the advantages of easy modification, high quantum efficiency, good biological affinity, and color adjustability; thus, have promising application prospects in the fields of photoelectric devices, sensitive detection, photodynamic therapy, and biomedical imaging. However, traditional organic luminescent molecules have the problems of short emission wavelength, aggregation-causing emission quenching, and low quantum yield. Herein, we successfully synthesized four D-π-A-D light-emitting molecules based on electron-withdrawing malonitrile group and different electron-donating arylamine groups. These compounds showed satisfactory solvatochromism, aggregation-induced emission, red and near-infrared fluorescence, high photoluminescence quantum efficiency and temperature response properties. This successful example of molecular engineering provides a valuable reference for the development of advanced NIR materials with AIE and temperature-sensitive properties.

A Dicyanoisoflurone-based Near-infrared Fluorescence Probe for Highly Sensitive Detection of Hg2.

Due to its high toxicity, long durability, easy absorption by aquatic organisms, and significant bioaccumulation, Hg2+ has caused substantial environmental damage and posed serious threats to human health. Therefore, effective detection of Hg2+ is of utmost importance. In this study, a turn-on fluorescent probe based on dicyanoisoflurone was developed for the detection of Hg2+. The probe exhibited near-infrared fluorescence signal at 660 nm upon excitation by 440 nm UV light in a mixture of CH3CN and HEPES buffer (4:1, v/v, 10 mM, pH = 7.5), with selective binding to Hg2+ in a molar ratio of 1:1. This binding event was accompanied by a visible color change from light yellow to orange. By utilizing the enhanced fluorescence signal change, this probe enables highly sensitive analysis and detection of Hg2+ with excellent selectivity (association constant = 1.63 × 104 M- 1), large Stokes shift (220 nm), high sensitivity (detection limit as low as 5.6 nM), short reaction time (30 s), and a physiological pH range of 7.5-9.5. The probe was successfully employed for detecting of Hg2+ in real water and living cells.

A near-infrared Fluorescent Probe Based on Dicyanisophorone for the Detection of Zinc Ions (Zn2+) in Water and Living Cells.

As one of the important metal ions, zinc ions (Zn2+) are widely involved in various physiological and pathological processes, and play fundamental roles in neurotransmission, cell metabolism and apoptosis. However, the convenient monitor of Zn2+ in environmental and biological samples remains challenging. In this study, a small molecule dicyanoisophorone-based schiff base incorporating with o-phenylenediamine was synthesized. It can rapidly combine with Zn2+ to emit significant near-infrared fluorescence (maximum emission wavelength: 660 nm), so it can be used as a probe to quantitatively detect Zn2+ in the range of 0-10 µM, with a detection limit as low as 4.8 nM, showing the probe has high sensitivity for Zn2+. And the probe has a fast response time to Zn2+ (less than 30 s) and a large Stoke-shift (179 nm). In addition, the high recovery rates in practical water samples, and the clear fluorescent images in living A549 cells were obtained, which are of great significance for the detection of Zn2+ in the environment and biosystem. Due to its simple operation, good selectivity and anti-interference ability, short detection time and high sensitivity, this probe has great application potential as a fast detection tool for Zn2+ in environmental water and biological samples.

Therapeutic targeting RORγ with natural product N-hydroxyapiosporamide for small cell lung cancer by reprogramming neuroendocrine fate.

Small cell lung cancer (SCLC) is an aggressive and exceptionally fatal disease. Unlike non- small cell lung cancer (NSCLC), no targetable genetic driver events have been identified in SCLC to date. Here, we investigate the function of RAR-related orphan receptor gamma (RORγ) and identified the anti-cancer activity of its natural inhibitor against SCLC and illustrate the underlying mechanism. We show that RORγ depletion affected cell growth both in 2-D cell proliferation and 3-D organoids formation. Natural marine product N-hydroxyapiosporamide (N-hydap) directly bound to RORγ and inhibited its transcriptional activity, leading to the blocking of transmission process of RORγ signaling. Gene expression profiling analysis revealed that N-hydap reprograms neuroendocrine fate via inhibiting RORγ activity in SCLC. Chromatin immunoprecipitation analysis showed that N-hydap strongly reduced RORγ occupancy and transcriptional activation-linked histone marks H3K27ac on the promoter and/or enhancer sites of neurogenesis markers gene including aurora kinase a (AURKA), delta like canonical Notch ligand 3 (DLL3) and tubulin beta 3 class III (TUBB3). Therapeutically, N-hydap exhibited a strong inhibitory effect on tumor growth and did not show significant toxicity in SCLC mice xenograft models. Taken together, RORγ could be an attractive target for SCLC and thus N-hydap can be a promising therapeutic drug candidate for SCLC by inhibiting the RORγ activation.

Effects of ultrasound-guided alveolar recruitment manoeuvres compared with sustained inflation or no recruitment manoeuvres on atelectasis in laparoscopic gynaecological surgery as assessed by ultrasonography: a randomized clinical trial.

BACKGROUND: The majority of patients may experience atelectasis under general anesthesia, and the Trendelenburg position and pneumoperitoneum can aggravate atelectasis during laparoscopic surgery, which promotes postoperative pulmonary complications. Lung recruitment manoeuvres have been proven to reduce perioperative atelectasis, but it remains controversial which method is optimal. Ultrasonic imaging can be conducive to confirming the effect of lung recruitment manoeuvres. The purpose of our study was to assess the effects of ultrasound-guided alveolar recruitment manoeuvres by ultrasonography on reducing perioperative atelectasis and to check whether the effects of recruitment manoeuvres under ultrasound guidance (visual and semiquantitative) on atelectasis are superior to sustained inflation recruitment manoeuvres (classical and widely used) in laparoscopic gynaecological surgery. METHODS: In this randomized, controlled, double-blinded study, women undergoing laparoscopic gynecological surgery were enrolled. Patients were randomly assigned to receive either lung ultrasound-guided alveolar recruitment manoeuvres (UD group), sustained inflation alveolar recruitment manoeuvres (SI group), or no RMs (C group) using a computer-generated table of random numbers. Lung ultrasonography was performed at four predefined time points. The primary outcome was the difference in lung ultrasound score (LUS) among groups at the end of surgery. RESULTS: Lung ultrasound scores in the UD group were significantly lower than those in both the SI group and the C group immediately after the end of surgery (7.67 ± 1.15 versus 9.70 ± 102, difference, -2.03 [95% confidence interval, -2.77 to -1.29], P < 0.001; 7.67 ± 1.15 versus 11.73 ± 1.96, difference, -4.07 [95% confidence interval, -4.81 to -3.33], P < 0.001;, respectively). The intergroup differences were sustained until 30 min after tracheal extubation (9.33 ± 0.96 versus 11.13 ± 0.97, difference, -1.80 [95% confidence interval, -2.42 to -1.18], P < 0.001; 9.33 ± 0.96 versus 10.77 ± 1.57, difference, -1.43 [95% confidence interval, -2.05 to -0.82], P < 0.001;, respectively). The SI group had a significantly lower LUS than the C group at the end of surgery (9.70 ± 1.02 versus 11.73 ± 1.96, difference, -2.03 [95% confidence interval, -2.77 to -1.29] P < 0.001), but the benefit did not persist 30 min after tracheal extubation. CONCLUSIONS: During general anesthesia, ultrasound-guided recruitment manoeuvres can reduce perioperative aeration loss and improve oxygenation. Furthermore, these effects of ultrasound-guided recruitment manoeuvres on atelectasis are superior to sustained inflation recruitment manoeuvres. TRIAL REGISTRATION: Chictr.org.cn, ChiCTR2100042731, Registered 27 January 2021, www.chictr.org.cn .

A Novel Strategy for Regulating mRNA's Degradation via Interfering the AUF1's Binding to mRNA.

The study on the mechanism and kinetics of mRNA degradation provides a new vision for chemical intervention on protein expression. The AU enrichment element (ARE) in mRNA 3'-UTR can be recognized and bound by the ARE binding protein (AU-rich Element factor (AUF1) to recruit RNase for degradation. In the present study, we proposed a novel strategy for expression regulation that interferes with the AUF1-RNA binding. A small-molecule compound, JNJ-7706621, was found to bind AUF1 protein and inhibit mRNA degradation by screening the commercial compound library. We discovered that JNJ-7706621 could inhibit the expression of AUF1 targeted gene IL8, an essential pro-inflammatory factor, by interfering with the mRNA homeostatic state. These studies provide innovative drug design strategies to regulate mRNA homeostasis.

Cucurbitacin B inhibits the migration and invasion of breast cancer cells by altering the biomechanical properties of cells.

Changes in cellular biomechanical properties affect cell migration and invasion. The natural compound Cucurbitacin B (CuB) has potent anticancer activity; however, the mechanism underlying its inhibitory effect on breast cancer metastasis needs further study. Here, we showed that low-dose CuB inhibited adhesion and altered the viscoelasticity of breast cancer cells, thereby, reducing cell deformability. In vitro and in vivo experiments proved that CuB effectively inhibited the migration and invasion of breast cancer cells. Further studies have found that CuB downregulated the expression of F-actin/vimentin/FAK/vinculin in breast cancer cells, altering the distribution and reorganization of cytoskeletal proteins in the cells. CuB inhibited signaling by the Rho family GTPases RAC1/CDC42/RhoA downstream of integrin. These findings indicate that CuB has been proven to mediate the reorganization and distribution of cytoskeletal proteins of breast cancer cells through RAC1/CDC42/RhoA signaling, which improves the mechanical properties of cell adhesion and deformation and consequently inhibits cell migration and invasion.

Antiestrogenic Activity of the Xi-Huang Formula for Breast Cancer by Targeting the Estrogen Receptor α.

BACKGROUND/AIMS: The Xi-Huang (XH) formula has been used for breast cancer treatment in traditional Chinese medicine (TCM) since 1740. In this study, we show that, XH extract could suppress the growth of breast cancer cells in vitro and in vivo, and that it preferentially inhibits cell growth of estrogen receptor positive (ER+) breast cancer cells. Presently, little is known about the potential mechanism of XH and our studies aim to elucidate its mechanism in breast cancer treatment. METHODS: Network-based systems biology and molecular docking analyses were performed to predict explicit targets of XH and active ingredients in XH. The effects of XH on cell viability, cell cycle, apoptosis in different breast cancer cell lines were analyzed in vitro. A model of transplanted tumors on nude mice was used to study the anticancer effect in vivo. Various techniques, including western blotting, reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence, co-immunoprecipitation and immunohistochemical were utilized to assess the expression of targets of XH in vitro and in vivo. RNA sequencing (RNA-seq) was performed to study the gene targets of XH. Furthermore, we analyzed of protein-ligand binding reactions by isothermal titration calorimetry (ITC). RESULTS: Using network-based systems biology and molecular docking analyses, we predicted that the major targets of XH were ERα and HSP90. Moreover, we found that, XH mediated its anti-cancer effects by promoting the disassociation of ERα and HSP90, resulting in the degradation of ERα and blockade of transport of ERα to the nucleus. XH also caused the dissociation of ERα and other oncoproteins via binding to HSP90. Some of the active ingredients in XH share a common cyclopentane hydrogen skeleton and were predicted to target ERα based on the structural similarity. CONCLUSIONS: XH, which has been used since 1740, has antiestrogenic effects in breast cancer via the targeting of ERα.

[Purple-bluish tongue is associated with platelet counts, and the recurrence of epithelial ovarian cancer].

OBJECTIVE: To evaluate the relationship between purple-bluish tongue and platelet counts, and further to examine their associations with the recurrence of epithelial ovarian cancer. METHODS: A total of 82 epithelial ovarian cancer patients were enrolled in this study. Cluster analysis was used for grouping patients' P(RGB) (Red-R; Green-G; Blue-B; Average percentage of RGB, P(RGB)) values. Receiver operating characteristic (ROC) curve was performed for detecting the diagnostic standard of purple-bluish tongue. Χ2 test was used to assess the relationship between purple-bluish tongue and platelet counts, and the recurrence of epithelial ovarian cancer. The perioperative (preoperative) platelet level was examined with tongue image and disease recurrence. RESULTS: Tongue images were classified into two groups basing on P(RGB) values of images by cluster analysis. The numbers of cases in cluster "1" (normal color tongue) was 16 and cluster "2" (purple-bluish tongue) was 66. Two groups of P(RGB) values, classified by cluster analysis, were significantly correlated with vision-based tongue color recognition (Kappa = 0.852, P < 0.001). ROC curve showed that the ratio of P(B) to P(R) had the highest diagnostic value. The sensitivity and the specificity of the ratio of P(B) to P(R) were 95.3% and 88.9% respectively and the optimal cut-off point was 0.71. Purple-bluish tongue was significantly correlated with increased platelet counts (P < 0.001). Both the increased platelet counts (P = 0.01) and purple-bluish tongue were associated with recurrence of epithelial ovarian cancer (P < 0.001). CONCLUSION: The ratio of P(B) to P(R) greater than 0.71 could serve as an indicator for purple-bluish tongue diagnosing used in symptom pattern identification in Traditional Chinese Medicine. Purple-bluish tongue, associated with increased platelet counts, was also closely correlated with the recurrence of epithelial ovarian cancer.

Synergetic effects of aqueous extracts of Fuzi (Radix Aconiti Lateralis Preparata) and Tubeimu (Rhizoma Bolbostemmatis) on MDA-MB-231 and SKBR3 cells.

OBJECTIVE: To test the synergistic effects of theaqueous extract of Tubeimu (Rhizoma Bolbostemmatis) and Fuzi (Radix Aconiti Lateralis Preparata) on MDA-MB-231 and SKBR3 breast cancer cells. METHODS: A combined index was created for the effects of Tubeimu (Rhizoma Bolbostemmatis) and Fuzi (Radix Aconiti Lateralis Preparata) extracts. Cell proliferation was performed by trypan blue exclusion and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assays. Flow cytometry was used to assess cell cycle distribution and apoptosis. Cell migration was determined by wound-healing and transwell assays. Confocal microscopy was used to detect E-cadherin and actin filaments. RESULTS: The aqueous extract from Tubeimu (Rhizoma Bolbostemmatis) and Fuzi (Radix AconitiLateralis Preparata) exerted synergetic effects on the growth of MDA-MB-231 cells and G1 phase arrest. When exposed to extracts at concentrations of 62.5 :62.5 and 62.5: 31.3 µg/mL, the combination index was 0.83 and 0.74, respectively. Interestingly, 62.5: 31.3 pg/mL of combined drugs enhanced the inhibitory effect of Tubeimu (Rhizoma Bolbostemmatis) on the migration of SKBR3 cells and reduced the stimulative effect of Fuzi (Radix Aconiti Lateralis Preparata) (P < 0.01), in which cells showed an increased expression of E-cadherin and reorganization of actin filaments (P < 0.001). 62.5:62.5 µg/mL extract also synergistically induced apoptosis of MDA-MB-231 cells (P < 0.05 and P < 0.001). Acting as the main active ingredients in the extract, tubeimoside I and acetylbenzoylaconine at 10: 10 µg/ mL and 5:2.5 µg/mL also produced inhibitory effects on the proliferation and migration of cells (P < 0.01). CONCLUSION: Tubeimu (Rhizoma Bolbostemmatis) and Fuzi (Radix Aconiti Lateralis Preparata) extracts had synergic effects on MDA-MB-231 and SKBR3 cells.

Pretreatment plasma D-dimer, fibrinogen, and platelet levels significantly impact prognosis in patients with epithelial ovarian cancer independently of venous thromboembolism.

OBJECTIVE: The study aimed to evaluate the prognostic value of pretreatment plasma dimerized plasmin fragment D (D-dimer), fibrinogen, and platelet levels in epithelial ovarian cancer (EOC) after adjusting for venous thromboembolism (VTE) and to screen out the patients with the greatest risk for poor prognosis. METHODS: The study comprised 190 patients with EOC. The plasma D-dimer, fibrinogen, and platelet levels were examined before treatment and analyzed with patient clinicopathological parameters, progression-free survival (PFS), and overall survival (OS). The survival analysis was performed using the Kaplan-Meier method, and prognostic factors were assessed using the Cox proportional hazards regression model. RESULTS: The incidences of elevated plasma D-dimer levels, hyperfibrinogenemia, and thrombocytosis were 40%, 42.11%, and 45.26%, respectively. Elevated plasma D-dimer level, hyperfibrinogenemia, and thrombocytosis were associated with advanced tumor stage (P < 0.001, P = 0.013, P < 0.001). In addition, the elevated plasma D-dimer levels were associated with macroscopic postoperative residual disease (P = 0.002) and VTE events (P = 0.006). In multivariate Cox regression model, plasma D-dimer, fibrinogen, and platelet levels were identified as independent prognostic factors for OS (P = 0.039, P = 0.002, and P = 0.049). However, plasma fibrinogen and platelet levels, but not D-dimer levels, had independent prognostic value for PFS (P = 0.012 and P = 0.022). Patients with at least any 2 abnormalities of plasma D-dimer, fibrinogen, and platelet levels showed shorter PFS and OS than did patients with at most 1 abnormality of 3 parameters (P < 0.001). CONCLUSIONS: Pretreatment plasma D-dimer, fibrinogen, and platelet levels, which impact prognosis independently of VTE, were demonstrated to be potential markers to predict disease progression and surgery outcome in patients with EOC. The combined use of plasma D-dimer, fibrinogen, and platelet levels may help to identify the high-risk populations for treatment decisions.

Recent Advances in Organic Small-Molecule Fluorescent Probes Based on Dicyanoisophorone Derivatives.

Fluorescent probe technology holds great promise in the fields of environmental monitoring and clinical diagnosis due to its inherent advantages, including easy operation, reliable detection signals, fast analysis speed, and in situ imaging capabilities. In recent years, a wide range of fluorescent probes based on diverse fluorophores have been developed for the analysis and detection of various analytes, yielding significant achievement. Among these fluorophores, the dicyanoisophorone-based fluorophores have garnered significant attention. Dicyanoisoporone exhibits minimal fluorescence, yet possesses a robust electron-withdrawing capability, rendering it suitable for constructing of D-π-A structured fluorophores. Leveraging the intramolecular charge transfer (ICT) effect, such fluorophores exhibit near-infrared (NIR) fluorescence emission with a large Stokes shift, thereby offering remarkable advantages in the design and development of NIR fluorescence probes. This review article primarily focus on small-molecule dicyanoisoporone-based probes from the past two years, elucidating their design strategies, detection performances, and applications. Additionally, we summarize current challenges while predicting future directions to provide valuable references for developing novel and advanced fluorescence probes based on dicyanoisoporone derivatives.

A versatile fluorescent probe for the ratiometric detection of hydrazine (N2H4) in water, soil, plant, and food samples.

Hydrazine (N2H4) is a crucial chemical raw material extensively utilized in chemical production. However, due to its volatility, water solubility, and high toxicity, both the gaseous form and aqueous solution of N2H4 pose significant environmental risks by causing severe pollution that can adversely impact plants, microorganisms, and human health. Therefore, accurate detection of N2H4 in the environment is imperative for safeguarding public health. In this study, we synthesized a ratiometric fluorescent probe (BCaz-Cy2) based on Carbazole and Hemicyanine groups. This probe exhibits simple synthesis procedure, rapid response time, high sensitivity and selectivity as well as remarkable detection signals. It enables effective detection of N2H4 in various matrices such as water, food, soil and plant samples thereby significantly expanding the scope of applications for N2H4 probes.

A ratiometric fluorescent probe for selective detection of hypochlorite (ClO-) and gallium (III) (Ga3+) ions in environmental and food samples.

Hypochlorite (ClO-) and gallium (Ⅲ) ions (Ga3+) have extensive applications in various human industries and daily activities. However, their inherent toxicity poses significant risks to environmental preservation and human well-being. Hence, the development of reliable and handy detection tools for ClO- and Ga3+ in the environment and food is crucial. In this study, a ratiometric fluorescent probe was prepared based on benzothiazolaldehyde and pyridine-2-carboxylic acid hydrazide, which exhibited exceptional performance characteristics for the selective detection of ClO- and Ga3+. These features include high specificity, low detection limits (0.28 µM for ClO-, 0.13 µM for Ga3+), mild pH conditions (pH 4-11 for ClO-, pH 6-11 for Ga3+), fast response time (within 30 s), as well as versatile applicability across different matrices such as water, soil, food, and plant samples. Additionally, this probe can be used with a smartphone color recognition app. The probe offers a convenient and effective tool for the detection of ClO- and Ga3+, demonstrating its potential application value in environmental monitoring and food safety.

Network Pharmacology Based Elucidation of Molecular Mechanisms of Laoke Formula for Treatment of Advanced Non-Small Cell Lung Cancer.

OBJECTIVE: To explore the specific pharmacological molecular mechanisms of Laoke Formula (LK) on treating advanced non-small cell lung cancer (NSCLC) based on clinical application, network pharmacology and experimental validation. METHODS: Kaplan-Meier method and Cox regression analysis were used to evaluate the survival benefit of Chinese medicine (CM) treatment in 296 patients with NSCLC in Tianjin Medical University Cancer Institute and Hospital from January 2011 to December 2015. The compounds of LK were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and the corresponding targets were performed from Swiss Target Prediction. NSCLC-related targets were obtained from Therapeutic Target Database and Comparative Toxicogenomics Database. Key compounds and targets were identified from the compound-target-disease network and protein-protein interaction (PPI) network analysis, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis were used to predict the potential signaling pathways involved in the treatment of advanced NSCLC with LK. The binding affinities between key ingredients and targets were further verified using molecular docking. Finally, A549 cell proliferation and migration assay were used to evaluate the antitumor activity of LK. Western blot was used to further verify the expression of key target proteins related to the predicted pathways. RESULTS: Kaplan-Meier survival analysis showed that the overall survival of the CM group was longer than that of the non-CM group (36 months vs. 26 months), and COX regression analysis showed that LK treatment was an independent favorable prognostic factor (P=0.027). Next, 97 components and 86 potential targets were included in the network pharmacology, KEGG and GO analyses, and the results indicated that LK was associated with proliferation and apoptosis. Moreover, molecular docking revealed a good binding affinity between the key ingredients and targets. In vitro, A549 cell proliferation and migration assay showed that the biological inhibition effect was more obvious with the increase of LK concentration (P<0.05). And decreased expressions of nuclear factor κB1 (NF-κB1), epidermal growth factor receptor (EGFR) and AKT serine/threonine kinase 1 (AKT1) and increased expression of p53 (P<0.05) indicated the inhibitory effect of LK on NSCLC by Western blot. CONCLUSION: LK inhibits NSCLC by inhibiting EGFR/phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, NFκB signaling pathway and inducing apoptosis, which provides evidence for the therapeutic mechanism of LK to increase overall survival in NSCLC patients.

Cationic fructan-based pH and intestinal flora dual stimulation nanoparticle with berberine for targeted therapy of IBD.

Inflammatory bowel disease (IBD) can cause intestinal microbial imbalance and aggravate intestinal inflammation. Mixed fructan is more easily fermented by colonic microorganisms and can be used as colonic drug delivery materials. Here, we constructed a mixed fructan based nanoparticle with dual targeted stimulation of pH and intestinal flora to effectively deliver berberine for the treatment of ulcerative colitis (UC). The complex of fructan based nanoparticle and berberine (BBRNPs) significantly ameliorated the inflammatory response of sodium dextran sulfate (DSS)-induced colitis in mice by inhibiting the activation of NF-κB/STAT-3 pathway and increasing tight junction protein expression in vivo. Importantly, BBRNPs improved the responsiveness of colitis microbiome and effectively regulated the relative homeostasis of harmful flora Enterobacteriaceae and Escherichia-shigolla, and beneficial flora Ruminococcaceae and Akkermansiaceae. This study provides a promising strategy for the effective treatment of UC and expands the application of branched fructan in pharmaceutics.

Gekko-sulfated glycopeptide inhibits tumor angiogenesis by targeting basic fibroblast growth factor.

Basic fibroblast growth factor (bFGF) is a therapeutic target of anti-angiogenesis. Here, we report that a novel sulfated glycopeptide derived from Gekko swinhonis Guenther (GSPP), an anticancer drug in traditional Chinese medicine, inhibits tumor angiogenesis by targeting bFGF. GSPP significantly decreased the production of bFGF in hepatoma cells by suppressing early growth response-1. GSPP inhibited the release of bFGF from extracellular matrix by blocking heparanase enzymatic activity. Moreover, GSPP competitively inhibited bFGF binding to heparin/heparan sulfate via direct binding to bFGF. Importantly, GSPP abrogated the bFGF-stimulated proliferation and migration of endothelial cells, whereas it had no inhibitory effect on endothelial cells in the absence of bFGF. Further study revealed that GSPP prevented bFGF-induced neovascularization and inhibited tumor angiogenesis and tumor growth in a xenograft mouse model. These results demonstrate that GSPP inhibits tumor angiogenesis by blocking bFGF production, release from the extracellular matrix, and binding to its low affinity receptor, heparin/heparan sulfate.