A Tumor-Targeting Dual-Modal imaging probe for nitroreductase in vivo.

Nitroreductase (NTR) overexpression often occurs in tumors, highlighting the significance of effective NTR detection. Despite the utilization of various optical methods for this purpose, the absence of an efficient tumor-targeting optical probe for NTR detection remains a challenge. In this research, a novel tumor-targeting probe (Cy-Bio-NO2) is developed to perform dual-modal NTR detection using near-infrared fluorescence and photoacoustic techniques. This probe exhibits exceptional sensitivity and selectivity to NTR. Upon the reaction with NTR, Cy-Bio-NO2 demonstrates a distinct fluorescence "off-on" response at 800 nm, with an impressive detection limit of 12 ng/mL. Furthermore, the probe shows on-off photoacoustic signal with NTR. Cy-Bio-NO2 has been successfully employed for dual-modal NTR detection in living cells, specifically targeting biotin receptor-positive cancer cells for imaging purposes. Notably, this probe effectively detects tumor hypoxia through dual-modal imaging in tumor-bearing mice. The strategy of biotin incorporation markedly enhances the probe's tumor-targeting capability, facilitating its engagement in dual-modal imaging at tumor sites. This imaging capacity holds substantial promise as an accurate tool for cancer diagnosis.

Activating transcription factor 3 is a new biomarker correlation with renal clear cell carcinoma progression.

Background: Clear cell renal cell carcinoma (ccRCC) is the most invasive type of cancer, with a high risk of metastasis and recurrence. Therefore, there is an urgent need to identify novel prognostic predictors and therapeutic targets of ccRCC. Activating transcription factor 3 (ATF3), a tumor oncogene or repressor, has rarely been examined in ccRCC. In the present study, we comprehensively elucidate the prognostic value and potential functions of ATF3 in ccRCC.Methods: Several TCGA-based online databases were used to analyze ATF3 expression in ccRCC and determine ccRCC prognosis. The upstream-binding micro (mi) RNAs of ATF3 and long non-coding (lnc)RNAs were predicted using the StarBase database.Results: Analysis of several TCGA-based online databases showed that ATF3 expression is decreased in ccRCC, suggesting a significant association with the prognosis of patients with ccRCC. Furthermore, we found hsa-miR-221-3p to be potential regulatory miRNA of ATF3 in ccRCC. Prediction and analysis of the upstream lncRNAs indicated that PAXIP1-AS2 and OIP5-AS1 were the most potent upstream lncRNAs of the hsa-miR-221-3p/ATF3 axis in ccRCC. The results of the GO and KEGG analyses implied that ATF3 is likely involved in the regulation of apoptotic signaling in response to endoplasmic reticulum (ER) stress in ccRCC. Correlation analysis revealed a positive relationship between ATF3 expression and ER stress.Conclusions: Our in silico findings highlighted that ATF3 expression was low in ccRCC and negatively correlated with poor prognosis. Furthermore, PAXIP1-AS2 and the OIP5-AS1/hsa-miR-221-3p/ATF3 axis were identified as significant potential regulators of ER stress-mediated apoptosis in ccRCC.

Lonicera caerulea L. polyphenols improve short-chain fatty acid levels by reshaping the microbial structure of fermented feces in vitro.

Increasing evidence suggests that the pathogenesis of type 2 diabetes mellitus (T2DM) is closely related to the gut microbiota. Polyphenols have been shown to alleviate T2DM, but the effects of L. caerulea L. polyphenols (LPs) on the gut microbiota and metabolites remain elusive. In this study, the inhibitory effects of fermented L. caerulea L. polyphenols (FLPs) and unfermented L. caerulea L. polyphenols (ULPs) on α-amylase and α-glucosidase and the impact of LP on the gut microbiota and metabolites were investigated. Furthermore, the relationship between the two was revealed through correlation analysis. The results showed that ULP and FLP had the highest inhibitory rates against α-amylase and α-glucosidase at 4 mg ml-1, indicating a strong inhibitory ability. In addition, LP plays a regulatory role in the concentration of short-chain fatty acids (SCFAs) and tends to restore them to their normal levels. LP reversed the dysbiosis of the gut microbiota caused by T2DM, as evidenced by an increase in the abundance of bacterial genera such as Lactobacillus, Blautia, and Bacteroides and a decrease in the abundance of bacterial genera such as Escherichia-Shigella and Streptococcus. Similarly, after LP intervention, the relationships among microbial species became more complex and interconnected. In addition, the correlation between the gut microbiota and metabolites was established through correlation analysis. These further findings clarify the mechanism of action of LP against T2DM and provide a new target for T2DM interventions.

TransformEHR: transformer-based encoder-decoder generative model to enhance prediction of disease outcomes using electronic health records.

Deep learning transformer-based models using longitudinal electronic health records (EHRs) have shown a great success in prediction of clinical diseases or outcomes. Pretraining on a large dataset can help such models map the input space better and boost their performance on relevant tasks through finetuning with limited data. In this study, we present TransformEHR, a generative encoder-decoder model with transformer that is pretrained using a new pretraining objective-predicting all diseases and outcomes of a patient at a future visit from previous visits. TransformEHR's encoder-decoder framework, paired with the novel pretraining objective, helps it achieve the new state-of-the-art performance on multiple clinical prediction tasks. Comparing with the previous model, TransformEHR improves area under the precision-recall curve by 2% (p < 0.001) for pancreatic cancer onset and by 24% (p = 0.007) for intentional self-harm in patients with post-traumatic stress disorder. The high performance in predicting intentional self-harm shows the potential of TransformEHR in building effective clinical intervention systems. TransformEHR is also generalizable and can be easily finetuned for clinical prediction tasks with limited data.

A simple one step synthesis of magnetic-optical dual functional ZIF-8 in a sodalite phase for magnetically guided targeting bioimaging and drug delivery.

Functionalized metal-organic frameworks (MOFs) that integrate targeted tumor imaging and drug delivery are expected to significantly enhance the therapeutic efficacy of cancer. However, the complicated synthesis process has greatly limited their utilization in clinical application. Herein, a one-step simple method was used to construct novel multifunctional MOFs by co-loading doxorubicin (DOX) and Fe3O4 into the ZIF-8 with sodalite topology. DOX serves as a fluorescence imaging reagent and an anticancer drug and Fe3O4 is used as a magnetic resonance imaging and magnetic targeting anticancer reagent. The fabricated DOX/Fe3O4@ZIF-8 nanocomposite showed excellent fluorescence and magnetic resonance imaging performances in tumors. Moreover, DOX/Fe3O4@ZIF-8 can be accumulated in tumors via a magnetic targeting effect and tumor growth could be inhibited in vivo due to the release of DOX. Additionally, the apoptosis process of DOX/Fe3O4@ZIF-8 on HepG2 cells is well investigated. Overall, DOX/Fe3O4@ZIF-8 synthesized in simple one step can be used for simultaneous targeted bioimaging and cancer therapy.

Tumor-Targeting Probe for Dual-Modal Imaging of Cysteine In Vivo.

Cysteine (Cys) is a crucial biological thiol that has a vital function in preserving redox homeostasis in organisms. Studies have shown that Cys is closely related to the development of cancer. Thus, it is necessary to design an efficient method to detect Cys for an effective cancer diagnosis. In this work, a novel tumor-targeting probe (Bio-Cy-S) for dual-modal (NIR fluorescence and photoacoustic) Cys detection is designed. The probe exhibits high selectivity and sensitivity toward Cys. After reaction with Cys, both NIR fluorescence and photoacoustic signals are activated. Bio-Cy-S has been applied for the dual-modal detection of Cys levels in living cells, and it can be used to distinguish normal cells from cancer cells by different Cys levels. In addition, the probe is capable of facilitating dual-modal imaging for monitoring changes in Cys levels in tumor-bearing mice. More importantly, the excellent tumor-targeting ability of the probe greatly improves the signal-to-noise ratio of imaging. To the best of our knowledge, this is the first Cys probe to combine targeting and dual-modal imaging performance for cancer diagnosis.

Engineering Nano-Au-Based Sensor Arrays for Identification of Multiple Ni(II) Complexes in Water Samples.

Advanced techniques for nickel (Ni(II)) removal from polluted waters have long been desired but challenged by the diversity of Ni(II) species (most in the form of complexes) which could not be readily discriminated by the traditional analytical protocols. Herein, a colorimetric sensor array is developed to address the above issue based on the shift of the UV-vis spectra of gold nanoparticles (Au NPs) after interaction with Ni(II) species. The sensor array is composed of three Au NP receptors modified by N-acetyl-l-cysteine (NAC), tributylhexadecylphosphonium bromide (THPB), and the mixture of 3-mercapto-1-propanesulfonic acid and adenosine monophosphate (MPS/AMP), to exhibit possible coordination, electrostatic attraction, and hydrophobic interaction toward different Ni(II) species. Twelve classical Ni(II) species were selected as targets to systematically demonstrate the applicability of the sensor array under various conditions. Multiple interactions with Ni(II) species were evidenced to trigger the diverse Au NP aggregation behaviors and subsequently produce a distinct colorimetric response toward each Ni(II) species. With the assistance of multivariate analysis, the Ni(II) species, either as the sole compound or as mixtures, can be unambiguously discriminated with high selectivity in simulated and real water samples. Moreover, the sensor array is very sensitive with the detection limit in the range of 4.2 to 10.5 µM for the target Ni(II) species. Principal component analysis signifies that coordination dominates the response of the sensor array toward different Ni(II) species. The accurate Ni(II) speciation provided by the sensor array is believed to assist the rational design of specific protocols for water decontamination and to shed new light on the development of convenient discrimination methods for other toxic metals of concern.

An Empirical Torsional Spring Model for the Inclined Crack in a 3D-Printed Acrylonitrile Butadiene Styrene (ABS) Cantilever Beam.

This paper presents an empirical torsional spring model for the inclined crack on a 3D-printed ABS cantilever beam. The work outlined deals mainly with our previous research about an improved torsional spring model (Khan-He model), which can represent the deep vertical (90°) crack in the structure. This study used an experimental approach to investigate the relationships between the crack angle and torsional spring stiffness. ABS cantilever beams with different crack depths (1, 1.3 and 1.6 mm) and angles (30, 45, 60, 75 and 90°) were manufactured by fused deposition modelling (FDM). The impact tests were performed to obtain the dynamic response of cracked beams. The equivalent spring stiffness was calculated based on the specimen's fundamental frequency. The results suggested that an increased crack incline angle yielded higher fundamental frequency and vibration amplitude, representing higher spring stiffness. The authors then developed an empirical spring stiffness model for inclined cracks based on the test data. These results extended the Khan-He model's application from vertical to inclined crack prediction in FDM ABS structures.

Grape Seed Extract Attenuates Demyelination in Experimental Autoimmune Encephalomyelitis Mice by Inhibiting Inflammatory Response of Immune Cells.

OBJECTIVE: To examine the anti-inflammatory effect of grape seed extract (GSE) in animal and cellular models and explore its mechanism of action. METHODS: This study determined the inhibitory effect of GSE on macrophage inflammation and Th1 and Th17 polarization in vitro. Based on the in vitro results, the effects and mechanisms of GSE on multiple sclerosis (MS)-experimental autoimmune encephalomyelitis (EAE) mice model were further explored. The C57BL/6 mice were intragastrically administered with 50 mg/kg of GSE once a day from the 3rd day to the 27th day after immunization. The activation of microglia, the polarization of Th1 and Th17 and the inflammatory factors such as tumor necrosis factor- α (TNF- α), interleukin-1 ß (IL-1 ß), IL-6, IL-12, IL-17 and interferon-γ (IFN-γ) secreted by them were detected in vitro and in vivo by flow cytometry, enzyme linked immunosorbent assay (ELISA), immunofluorescence staining and Western blot, respectively. RESULTS: GSE reduced the secretion of TNF-α, IL-1 ß and IL-6 in bone marrow-derived macrophages stimulated by lipopolysaccharide (P<0.01), inhibited the secretion of TNF-α, IL-1 ß, IL-6, IL-12, IL-17 and IFN-γ in spleen cells of EAE mice immunized for 9 days (P<0.05 or P<0.01), and reduced the differentiation of Th1 and Th17 mediated by CD3 and CD28 factors (P<0.01). GSE significantly improved the clinical symptoms of EAE mice, and inhibited spinal cord demyelination and inflammatory cell infiltration. Peripherally, GSE downregulated the expression of toll-like-receptor 4 (TLR4) and Rho-associated kinase (ROCKII, P<0.05 or P<0.01), and inhibited the secretion of inflammatory factors (P<0.01 or P<0.05). In the central nervous system, GSE inhibited the infiltration of CD45+CD11b+ and CD45+CD4+ cells, and weakened the differentiation of Th1 and Th17 (P<0.05). Moreover, it reduced the secretion of inflammatory factors (P<0.01), and prevented the activation of microglia (P<0.05). CONCLUSION: GSE had a beneficial effect on the pathogenesis and progression of EAE by inhibiting inflammatory response as a potential drug and strategy for the treatment of MS.

Interaction between Organic Compounds and Catalyst Steers the Oxidation Pathway and Mechanism in the Iron Oxide-Based Heterogeneous Fenton System.

In the past decades, extensive efforts have been devoted to the mechanistic understanding of various heterogeneous Fenton reactions. Nevertheless, controversy still remains on the oxidation mechanism/pathway toward different organic compounds in the classical iron oxide-based Fenton reaction, largely because the role of the interaction between the organic compounds and the catalyst has been scarcely considered. Here, we revisited the classic heterogeneous ferrihydrite (Fhy)/H2O2 system toward different organic compounds on the basis of a series of degradation experiments, alcohol quenching experiments, theoretical modeling, and intermediate analysis. The Fhy/H2O2 system exhibited highly selective oxidation toward the group of compounds that bear carboxyl groups, which tend to complex with the surface ≡Fe(III) sites of the Fhy catalyst. Such interaction results in a nonradical inner sphere electron transfer process, which seizes one electron from the target compound and features negligible inhibition by the radical quencher. In contrast, for the oxidation of organic compounds that could not complex with the catalyst, the traditional HO· process makes the main contribution, which proceeds via hydroxyl addition reaction and could be readily suppressed by the radical quencher. This study implies that the interaction between the organic compounds and the catalyst plays a decisive role in the oxidation pathway and mechanism of the target compounds and provides a holistic understanding on the iron oxide-based heterogeneous Fenton system.

Facile microfluidic fabrication and characterization of ethyl cellulose/PVP films with neatly arranged fibers.

Much attention and endeavor have been paid to developing biocompatible food packaging films. Here, ethyl cellulose (EC) and polyvinylpyrrolidone (PVP) were fabricated into films through a facile method, microfluidic spinning. Morphology observations showed that the fibers were neatly arranged with an average diameter of 1-4 µm. FTIR and X-ray diffraction analysis suggested the existence of good compatibility and interaction between EC and PVP. Thermogravimetric analysis demonstrated that PVP ameliorates the thermal properties; moreover, the tensile properties were improved, with tensile strength (TS) and Young's modulus up to 11.10 ± 1.04 MPa and 350.16 ± 45.46 MPa, respectively. The optimal formula was EC/PVP (2:3), of which the film displayed an enhanced TS of 4.61 ± 1.15 MPa and a modified water contact angle of 61.8 ± 4.4°, showing fine tensile and hydrophilic performance. This study provides a facile and green film fabrication method promising to be used for food wrapping.

Donor with HLA-C2 is associated with acute rejection following liver transplantation in Southern Chinese.

Apart from presenting peptides to T cells, class I HLA molecules serve as ligands for killer cell immunoglobulin-like receptor (KIRs) and regulate the response of natural killer (NK) cells. The role played by HLA and KIR in the acute rejection (AR) following liver transplantation has been controversial. In this retrospective study, we assessed the influence of class I HLA alleles, HLA matching between donor-recipient pairs, recipient KIR and donor HLA ligands on AR following liver transplantation in southern Chinese. In total, 143 recipients and 78 donors obtained from a single transplant center were included in the study cohort. Thirty-three recipients with histologically confirmed AR were observed. We found that the incidence of AR did not correlate with donor or recipient class I HLA alleles and HLA matching. Neither recipient KIR gene nor the KIR genotype was associated with AR, moreover, high-resolution genotyping of 14 functional KIR genes of recipients showed that no KIR allele was independently associated with AR. However, the frequency of HLA-C2+ donor significantly increased in AR group compared with NAR group (52.9% vs. 24.6%, p = 0.03). In the presence of HLA-C2 by the donor allograft, AR was more frequently observed in recipients with normal expressed KIR2DS4 (43.8% vs. 15.0%, p = 0.03). Donor with HLA-C2 is therefore a major determinant of AR, which can confer risk effect in liver transplantation. Our findings can provide valuable clues for better understanding pathogenesis of AR and have important clinical implications in liver transplantation for Chinese.

[Association of molecular genetic polymorphism of KIR-HLA systems with acute leukemia in Southern Chinese Han].

OBJECTIVE: To investigate the association of molecular genetic polymorphism of KIR-HLA systems with acute lymphoblastic leukemia (ALL) and acute myelocytic leukemia (AML) in southern Chinese Han. METHODS: A total number of 323 cases of adult ALL patients, 350 adult AML, and 745 random healthy controls were tested by KIR PCR-SSP and HLA-A, -B, -C sequence-based typing (PCR-SBT) methods. The molecular genetic polymorphisms of KIR genes and KIR gene profiles, classⅠ HLA ligands, and KIR receptor +HLA ligand combinations were compared between patient and healthy control groups. RESULTS: A total number of 32 and 33 different kinds of KIR profiles were identified in the ALL and AML patient groups. Compared with the observed frequencies of KIR profiles in healthy controls, the observed frequencies of KIR profile AA1 were significantly lower in both the ALL and AML groups (ALL group: 45.79% vs. 55.30%, Pc=0.004; AML group: 48.27% vs. 55.30%, Pc=0.030). In the ALL group, the observed frequencies of 2DL2 gene and 2DL2+HLA-C1 combination, 2DS2 gene and 2DS2+HLA-C1 combination were significantly higher than those in healthy controls (P<0.05), whereas the frequencies of 2DL3 gene, HLA-A3/A11 ligand and 3DL2+HLA-A3/A11 combination were significantly lower than those in healthy controls. However, no significant differences remained after Bonferroni correction (Pc>0.05). In AML group, the observed frequencies of both 2DS1 and 2DL5 genes were significantly higher than that in healthy controls, whereas the frequencies of HLA-C2 ligand and 2DL1+HLA-C2 combination were significantly lower than that in healthy controls(P<0.05). However, no significant difference existed after Bonferroni correction (Pc>0.05). CONCLUSION: This study revealed some potential susceptibility or protective factors related to acute leukemia in southern Chinese Han, especially the protective factor KIR profile AA1, which might provide new clues and theoretical basis for the pathogenesis of acute leukemia and individualized immunotherapy.

The Fenton Reaction in Water Assisted by Picolinic Acid: Accelerated Iron Cycling and Co-generation of a Selective Fe-Based Oxidant.

The Fenton reaction is limited by a narrow acidic pH range, the slow reduction of Fe(III), and susceptibility of the nonselective hydroxyl radical (HO•) to scavenging by water constituents. Here, we employed the biodegradable chelating agent picolinic acid (PICA) to address these concerns. Compared to the classical Fenton reaction at pH 3.0, PICA greatly accelerated the degradation of atrazine, sulfamethazine, and various substituted phenols at pH 5.0 in a reaction with autocatalytic characteristics. Although HO• served as the principal oxidant, a high-spin, end-on hydroperoxo intermediate, tentatively identified as PICA-FeIII-OOH, also exhibited reactivity toward several test compounds. Chloride release from the oxidation of 2,4,6-trichlorophenol and the positive slope of the Hammett correlation for a series of halogenated phenols were consistent with PICA-FeIII-OOH reacting as a nucleophilic oxidant. Compared to HO•, PICA-FeIII-OOH is less sensitive to potential scavengers in environmental water samples. Kinetic analysis reveals that PICA facilitates Fe(III)/Fe(II) transformation by accelerating Fe(III) reduction by H2O2. Autocatalysis is ascribed to the buildup of Fe(II) from the reduction of Fe(III) by H2O2 as well as PICA oxidation products. PICA assistance in the Fenton reaction may be beneficial to wastewater treatment because it favors iron cycling, extends the pH range, and balances oxidation universality with selectivity.

Surfactant-free preparation of mesoporous solid/hollow boehmite and bayerite microspheres via double hydrolysis of NaAlO2 and formamide from room temperature to 180 °C.

The transformation from solid boehmite microspheres to hollow bayerite microspheres at room temperature (25 °C) was successfully realized via the double hydrolysis of NaAlO2 and formamide (FA) solution. Effects of reaction time, temperature and FA dos on the transformation process were studied in detail. The results show that hollow boehmite microspheres were obtained via increasing the temperature above 120 °C and the FA dos above 12 mL; amorphous alumina hydrate, solid boehmite and hollow bayerite microspheres were also obtained at 25 °C for 1 h, 2 h and 24 h reactions, respectively; solid bayerite microspheres were obtained by decreasing the FA dos below 4 mL at 25 °C. Because of the slow change of pH from 12.9 to 8.7, simultaneous dissolution and regeneration for different aluminum hydroxide were the key factors for forming hollow boehmite/bayerite microspheres. The Al yield for boehmite microspheres reached 41.4% at 25 °C for a 2 h reaction; when increasing the temperature to 180 °C, the Al yield for hollow boehmite microspheres with higher crystallinity increased to 82.7%. Moreover, the solid/hollow boehmite microspheres with high surface areas showed outstanding adsorption capacities of 751.9 mg/g and 694.4 mg/g, respectively, for Congo red. This significant transformation of structure and morphology provides an effective strategy for preparing mono-phase hydrated alumina with excellent adsorption performance.

Singlet oxygen mediated iron-based Fenton-like catalysis under nanoconfinement.

For several decades, the iron-based Fenton-like catalysis has been believed to be mediated by hydroxyl radicals or high-valent iron-oxo species, while only sporadic evidence supported the generation of singlet oxygen (1O2) in the Haber-Weiss cycle. Herein, we report an unprecedented singlet oxygen mediated Fenton-like process catalyzed by ∼2-nm Fe2O3 nanoparticles distributed inside multiwalled carbon nanotubes with inner diameter of ∼7 nm. Unlike the traditional Fenton-like processes, this delicately designed system was shown to selectively oxidize the organic dyes that could be adsorbed with oxidation rates linearly proportional to the adsorption affinity. It also exhibited remarkably higher degradation activity (22.5 times faster) toward a model pollutant methylene blue than its nonconfined analog. Strikingly, the unforeseen stability at pH value up to 9.0 greatly expands the use of Fenton-like catalysts in alkaline conditions. This work represents a fundamental breakthrough toward the design and understanding of the Fenton-like system under nanoconfinement, might cause implications in other fields, especially in biological systems.

Overexpression of long non coding RNA CA3-AS1 suppresses proliferation, invasion and promotes apoptosis via miRNA-93/PTEN axis in colorectal cancer.

AIMS: In previous studies, dysregulated lncRNAs in colorectal cancer were screened using RNA-sequencing by Atsushi Yamada. In these dysregulated lncRNAs, a long non coding RNA named CA3-AS1 attracted our attention due to its high conservation and fold change, which was downregulated in colorectal cancer. In this study, we aimed to investigate the function and mechanism of lncRNA CA3-AS1 in colorectal cancer. METHODS: RT-PCR was used to detect CA3-AS1, miR-93, PTEN mRNA expression. Apoptosis, proliferation, and invasion were examined by western blotting, CCK8, transwell assay to evaluate the function of RPL34-AS1. RESULTS: We found that lncRNA CA3-AS1 mainly located in cytoplasm, and overexpression of lncRNA CA3-AS1 inhibits cell proliferation, invasion and promotes cell apoptosis. Our results revealed that miR-93 could directly bind to CA3-AS1, and verified the oncogenic role of miR-93. Furthermore, we found that miR-93 played its role through regulating PTEN, the tumor-suppressor gene, which was inversely correlated with miR-93. CONCLUSION: Based on the investigation, lncRNA CA3-AS1 inhibited the proliferation, invasion and apoptosis, which could be blocked by overexpression of miR-93. In summary, our study demonstrated that CA3-AS1/miR-93/PTEN axis may play an important role in the regulation of colorectal cancer progression, which provides new insights for clinical treatment.

MicroRNA-135a Inhibits Nasopharyngeal Carcinoma Cell Proliferation Through Targeting Interleukin-17.

BACKGROUND/AIMS: The objective of this study was to investigate the potential role of IL-17 in the development of nasopharyngeal carcinoma (NPC) and to screen microRNAs (miRNAs) that potentially target IL-17 in NPC cells. METHODS: Blood was collected from NPC patients and normal subjects, and plasma IL-17 concentration was quantified by enzyme-linked immunosorbent assay. An immortalized normal human nasopharyngeal epithelial cell line, NP69, was treated with or without human IL-17 (15 ng/mL) for various times, and expression of IL-1ß, IL-6, IL-12, and TNF-α mRNA was assessed by real-time reverse transcription PCR. The candidate miRNAs that potentially target IL-17 were predicted by a bioinformatics strategy. The selected miR-135a mimic was transfected into primary NPC cells, and cell proliferation was assessed by MTT assay. RESULTS: The concentration of plasma IL-17 was significantly higher in the NPC patients (92.5 ± 7.3 pg/mL) than in the control subjects (56.8 ± 2.9 pg/mL). In response to IL-17 treatment, the mRNA expression of IL-1ß and IL-6 was significantly upregulated and reached a peak at 12 h, followed by a slight decrease at 24 h, while the mRNA expression of IL-12 and TNF-α was significantly upregulated at 12 h and remained high even at 48 h after exposure to IL-17. Moreover, miR-135a specifically targets IL-17 and was dramatically downregulated in NPC cells compared with NP69 cells. Transfection of exogenous miR-135a mimic resulted in significant suppression of IL-17 secretion and subsequent inhibition of NPC cell proliferation. CONCLUSIONS: Blood IL-17 was significantly higher in NPC patients compared with normal subjects. Expression of miR-135a in the cancer cells isolated from nasopharyngeal tumors was significantly lower than that in NP69 cells, and suppression of IL-17 by miR-135a mimic resulted in significant inhibition of NPC cell proliferation. These findings suggested that downregulation of miR-135a may contribute to the development of NPC via the mechanism of IL-17 stimulation of proinflammatory cytokine expression.

Actein enhances TRAIL effects on suppressing gastric cancer progression by activating p53/Caspase-3 signaling.

Actein (ACT), isolated from the rthizomes of Cimicifuga foetida, is a triterpene glycoside, showing inhibitory role in breast cancer cells. However, the effects of ACT treatment on gastric cancer have little been known. Thus, the study is conducted to explore the in vitro and in vivo role of ACT in gastric cancer. And the interactions between ACT and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) were investigated in gastric cancer cells. A synergistic effect of ACT and TRAIL combination on apoptosis induction in gastric cancer cells was observed. The cancer cells were insensitive to TRAIL single therapy. However, gastric cancer cells receiving ACT were sensitive to TRAIL-triggered apoptotic response by enhancing Caspases cleavage, due to elevation of decoy receptor 1 and 2 (DcR1 and DcR2) dependent on p53. Bcl-2 family members of Bcl-2 and Mcl-1, belonging to anti-apoptosis, were decreased, whereas Bad and Bak, as pro-apoptotic members, were increased for ACT and TRAIL combined treatment. Additionally, the mouse xenograft model suggested that ACT and TRAIL in combination markedly inhibited gastric cancer growth in comparison to ACT or TRAIL monotherapy without toxicity. The present study revealed a dramatically therapeutic strategy for promoting TRAIL-induced anti-cancer effects on gastric cancer cells via ACT combination.

Significant Improvement of Metabolic Characteristics and Bioactivities of Clopidogrel and Analogs by Selective Deuteration.

In the search for prodrug analogs of clopidogrel with improved metabolic characteristics and antiplatelet bioactivity, a group of clopidogrel and vicagrel analogs selectively deuterated at the benzylic methyl ester group were synthesized, characterized, and evaluated. The compounds included clopidogrel-d3 (8), 2-oxoclopidogrel-d3 (9), vicagrel-d3 (10a), and 12 vicagrel-d3 analogs (10b-10m) with different alkyl groups in the thiophene ester moiety. The D3C-O bond length in 10a was shown by X-ray single crystal diffraction to be shorter than the H3C-O bond length in clopidogrel, consistent with the slower rate of hydrolysis of 8 than of clopidogrel in rat whole blood in vitro. A study of the ability of the compounds to inhibit ADP-induced platelet aggregation in fresh rat whole blood collected 2 h after oral dosing of rats with the compounds (7.8 µmol/kg) showed that deuteration increased the activity of clopidogrel and that increasing the size of the alkyl group in the thiophene ester moiety reduced activity. A preliminary pharmacokinetic study comparing 10a with vicagrel administered simultaneously as single oral doses (72 µmol/kg of each drug) to male Wistar rats showed 10a generated more of its active metabolite than vicagrel. These results suggest that 10a is a potentially superior antiplatelet agent with improved metabolic characteristics and bioactivity, and less dose-related toxicity.