Biological impact and therapeutic potential of a novel camptothecin derivative (FLQY2) in pancreatic cancer through inactivation of the PDK1/AKT/mTOR pathway.

BACKGROUND: Camptothecin (CPT), a pentacyclic alkaloid with antitumor properties, is derived from the Camptotheca acuminata. Topotecan and irinotecan (CPT derivatives) were first approved by the Food and Drug Administration for cancer treatment over 25 years ago and remain key anticancer drugs today. However, their use is often limited by clinical toxicity. Despite extensive development efforts, many of these derivatives have not succeeded clinically, particularly in their effectiveness against pancreatic cancer which remains modest. AIM OF THE STUDY: This study aimed to evaluate the therapeutic activity of FLQY2, a CPT derivative synthesized in our laboratory, against pancreatic cancer, comparing its efficacy and mechanism of action with those of established clinical drugs. METHODS: The cytotoxic effects of FLQY2 on cancer cells were assessed using an MTT assay. Patient-derived organoid (PDO) models were employed to compare the sensitivity of FLQY2 to existing clinical drugs across various cancers. The impact of FLQY2 on apoptosis and cell cycle arrest in Mia Paca-2 pancreatic cancer cells was examined through flow cytometry. Transcriptomic and proteomic analyses were conducted to explore the underlying mechanisms of FLQY2's antitumor activity. Western blotting was used to determine the levels of proteins regulated by FLQY2. Additionally, the antitumor efficacy of FLQY2 in vivo was evaluated in a pancreatic cancer xenograft model. RESULTS: FLQY2 demonstrated (1) potent cytotoxicity; (2) superior tumor-suppressive activity in PDO models compared to current clinical drugs such as gemcitabine, 5-fluorouracil, cisplatin, paclitaxel, ivosidenib, infinitinib, and lenvatinib; (3) significantly greater tumor inhibition than paclitaxel liposomes in a pancreatic cancer xenograft model; (4) robust antitumor effects, closely associated with the inhibition of the TOP I and PDK1/AKT/mTOR signaling pathways. In vitro studies revealed that FLQY2 inhibited cell proliferation, colony formation, induced apoptosis, and caused cell cycle arrest at nanomolar concentrations. Furthermore, the combination of FLQY2 and gemcitabine exhibited significant inhibitory and synergistic effects. CONCLUSION: The study confirmed the involvement of topoisomerase I and the PDK1/AKT/mTOR pathways in mediating the antitumor activity of FLQY2 in treating Mia Paca-2 pancreatic cancer. Therefore, FLQY2 has potential as a novel therapeutic option for patients with pancreatic cancer.

CAC: Confidence-Aware Co-Training for Weakly Supervised Crack Segmentation.

Automatic crack segmentation plays an essential role in maintaining the structural health of buildings and infrastructure. Despite the success in fully supervised crack segmentation, the costly pixel-level annotation restricts its application, leading to increased exploration in weakly supervised crack segmentation (WSCS). However, WSCS methods inevitably bring in noisy pseudo-labels, which results in large fluctuations. To address this problem, we propose a novel confidence-aware co-training (CAC) framework for WSCS. This framework aims to iteratively refine pseudo-labels, facilitating the learning of a more robust segmentation model. Specifically, a co-training mechanism is designed and constructs two collaborative networks to learn uncertain crack pixels, from easy to hard. Moreover, the dynamic division strategy is designed to divide the pseudo-labels based on the crack confidence score. Among them, the high-confidence pseudo-labels are utilized to optimize the initialization parameters for the collaborative network, while low-confidence pseudo-labels enrich the diversity of crack samples. Extensive experiments conducted on the Crack500, DeepCrack, and CFD datasets demonstrate that the proposed CAC significantly outperforms other WSCS methods.

Structure-Activity Relationship of FL118 Platform Position 7 Versus Position 9-Derived Compounds and Their Mechanism of Action and Antitumor Activity.

Structurally, FL118 is a camptothecin analogue and possesses exceptional antitumor efficacy against human cancer through a novel mechanism of action (MOA). In this report, we have synthesized and characterized 24 FL118 Position 7-substituted and 24 FL118 Position 9-substituted derivatives. The top compounds were further characterized for their MOA in colorectal cancer (CRC) models using CRC patient-derived xenograft (PDX) models and pancreatic cancer PDX models to evaluate their antitumor activities. Four FL118 Position 7-substituted derivatives showed significantly better antitumor efficacy than the FL118 Position 9-substituted derivatives. The four identified compounds also appeared to have better antitumor activity than their parental platform FL118. Interestingly, RNA-Seq analyses indicated that three of the four compounds exerted antitumor effects via an MOA similar to FL118, which provided an intriguing opportunity for follow-up studies. Extended in vivo studies revealed that FL77-6 (7-(4-ethylphenyl)-FL118), FL77-9 (7-(4-methoxylphenyl)-FL118), and FL77-24 (7-(3, 5-dimethoxyphenyl)-FL118) exhibit potential for further development toward clinical trials.

HAZMAT Vehicle Reidentification in Road Tunnels Based on the Fusion of Appearance and Spatiotemporal Information.

Vehicles transporting hazardous material (HAZMAT) pose a severe threat to highway safety, especially in road tunnels. Vehicle reidentification is essential for identifying and warning abnormal states of HAZMAT vehicles in road tunnels. However, there is still no public dataset for benchmarking this task. To this end, this work releases a real-world tunnel HAZMAT vehicle reidentification dataset, VisInt-THV-ReID, including 10,048 images with 865 HAZMAT vehicles and their spatiotemporal information. A method based on multimodal information fusion is proposed to realize vehicle reidentification by fusing vehicle appearance and spatiotemporal information. We design a spatiotemporal similarity determination method for vehicles based on the spatiotemporal law of vehicles in tunnels. Compared with other reidentification methods based on multimodal information fusion, i.e., PROVID, Visual + ST, and Siamese-CNN, experimental results show that our approach significantly improves the vehicle reidentification recognition precision.

Design, synthesis and biological evaluation of novel phenylfuran-bisamide derivatives as P-glycoprotein inhibitors against multidrug resistance in MCF-7/ADR cell.

The co-administration of anticancer drugs and P-glycoprotein (P-gp) inhibitors was a treatment strategy to surmount multidrug resistance (MDR) in anticancer chemotherapy. In this study, novel phenylfuran-bisamide derivatives were designed as P-gp inhibitors based on target-based drug design, and 31 novel compounds were synthesized and screened on MCF-7/ADR cells. The result of bioassay revealed that compound y12d exhibited low cytotoxicity and promising MDR reversal activity (IC50 = 0.0320 µM, reversal fold = 1163.0), 3.64-fold better than third-generation P-gp inhibitor tariquidar (IC50 = 0.1165 µM, reversal fold = 319.3). The results of Western blot and rhodamine 123 accumulation verified that compound y12d exhibited excellent MDR reversal activity by inhibiting the efflux function of P-gp but not expression. Furthermore, molecular docking showed that compound y12d bound to target P-gp by forming the double H-bond interactions with residue Gln 725. These results suggest that compound y12d might be a potential MDR reveal agent acting as a P-gp inhibitor in clinical therapeutics, and provide insight into design strategy and skeleton optimization for the development of P-gp inhibitors.

Insight into catalytic activation of bisulfite for lomefloxacin degradation by simple composite of calcinated red mud.

Antibiotic was detected in many environments, and it had posed a serious threat to human health. The advanced oxidation process has been considered an effective way to treat antibiotics. In this work, using industrial waste red mud (RM) as raw material, a series of modified RM (MRM-T; T donates the calcination temperature) was obtained via a facile calcination method and applied to activate sodium bisulfite (NaHSO3) for the lomefloxacin (LOM) degradation. Among all MRM-T, MRM-700 exhibited superior catalytic activity, and approximately 89% of LOM (10 mg/L) was degraded at 30 min through the activation of NaHSO3 ([NaHSO3] = 0.5 g/L) by MRM-700 ([MRM-700] = 0.9 g/L). Moreover, the kinetic constant of LOM removal in the MRM-700/NaHSO3 system (0.082 min-1) was 16.4 times higher than that of the RM-raw/NaHSO3 system (0.005 min-1). The as-synthesized product of MRM-700 was characterized by N2 adsorption-desorption isotherms, X-ray diffraction (XRD), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and Raman spectra. The result indicated that the catalyst possessed excellent pore structure, high specific area, and abundant Fe3+ sites, and the lattice of Fe2O3 was doped after calcination, both of which were favorable for the activation of NaHSO3. The quenching experiment proved that •SO4- and •OH- active species were produced in MRM-700/NaHSO3 system, and •SO4- played a dominant role in LOM removal. In addition, the potential LOM degradation pathway was analyzed via UPLC-MS technology and density functional theory (DFT) calculation, and the toxicity of the treated LOM solution was tested by the culture of mung bean sprouts. This study not only provided a feasible strategy for the valuable use of RM to activate NaHSO3 but also offered a cost-effective catalyst for the efficient removal of pollutants in wastewater.

Causal Discovery on Discrete Data via Weighted Normalized Wasserstein Distance.

The task of causal discovery from observational data (X,Y) is defined as the task of deciding whether X causes Y , or Y causes X or if there is no causal relationship between X and Y . Causal discovery from observational data is an important problem in many areas of science. In this study, we propose a method to address this problem when the cause-and-effect relationship is represented by a discrete additive noise model (ANM). First, assuming that X causes Y , we estimate the conditional distributions of the noise given X using regression. Similarly, assuming that Y causes X , we also estimate the conditional distributions of noise given Y . Based on the structural characteristics of the discrete ANM, we find that the dissimilarity of the conditional distributions of noise in the causal direction is smaller than that in the anticausal direction. Then, we propose a weighted normalized Wasserstein distance to measure the dissimilarity of the conditional distributions of noise. Finally, we propose a decision rule for casual discovery by comparing two computed weighted normalized Wasserstein distances. An empirical investigation demonstrates that our method performs well on synthetic data and outperforms state-of-the-art methods on real data.

Preparation of a camptothecin analog FLQY2 self-micelle solid dispersion with improved solubility and bioavailability.

BACKGROUND: 7-p-trifluoromethylphenyl-FL118 (FLQY2) is a camptothecin analog with excellent antitumor efficacy against various solid tumors. However, its poor solubility and low bioavailability limited the development of the drug. Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), an emerging carrier for preparing solid dispersion (SD), encapsulated FLQY2 to circumvent the above limitations. RESULTS: In this project, FLQY2-SD was prepared by solvent evaporation method and self-assembled into micelles in aqueous solutions owing to the amphiphilic nature of Soluplus®. The physicochemical characterizations demonstrated that FLQY2 existed in a homogeneous amorphous form in SD and was rapidly dissolved. The micelles did not affect cytotoxicity or cellular uptake of FLQY2 in vitro, and the oral bioavailability was increased by 12.3-fold compared to the FLQY2 cyclodextrin suspension. The pharmacokinetics of FLQY2-SD showed rapid absorption, accumulation in the intestine, and slow elimination via fecal. Metabolite identification studies showed 14 novel metabolites were identified, including 12 phase I metabolites (M1-M12) and 2 phase II metabolites (M13-M14), of which M2 (oxidation after decarboxylation) and M7 (dioxolane ring cleavage) were the primary metabolites in the positive mode and negative mode, respectively. The tumor growth inhibition rate (TGI, 81.1%) of FLQY2-SD (1.5 mpk, p.o./QW) in tumor-bearing mice after oral administration was higher than that of albumin-bound Paclitaxel (15 mpk, i.v./Q4D) and Irinotecan hydrochloride (100 mpk, i.p./QW). CONCLUSIONS: The successful preparation, pharmacokinetics, and pharmacodynamics studies of FLQY2-SD showed that the solubility and bioavailability of FLQY2 were improved, which facilitated the further druggability development of FLQY2.

Valorization of ball-milled waste red mud into heterogeneous catalyst as effective peroxymonosulfate activator for tetracycline hydrochloride degradation.

Red mud (RM), a kind of iron-rich industrial waste produced in the alumina production process, can be utilized as a potential iron-based material for the removal of refractory organic pollutants from wastewater in advanced oxidation processes (AOPs). In this work, high-iron RM (rich in iron) was activated in a ball mill and applied as an effective activator of peroxymonosulfate (PMS) for tetracycline hydrochloride (TC-HCl) degradation. Compared with that of unmilled RM (69.7%), the TC-HCl decomposition ratios of ball-milled RM (BM-RM) (72.2%-92.0%) were all improved in the presence of PMS. Systematic characterization suggested that ball milling could optimize the physicochemical properties of RM, such as increased surface area, increased oxygen vacancies, enhanced electrical conductivity, and increased exposure of Fe(II) sites, all of which could effectively improve RM for PMS activation to degrade TC-HCl. The quenching experiments and electron paramagnetic resonance technique revealed that 1O2 and SO4·- contributed dominantly to the TC-HCl degradation. Ultra performance liquid chromatography mass spectrometry analysis combined with density functional theory calculation revealed that the degradation pathways of TC-HCl were driven by hydroxylation, N-demethylation and dehydration in BM-RM/PMS system. Based on quantitative structure-activity relationship prediction using the Toxicity Estimation Software Tool software, the toxicity of almost all intermediates was significantly reduced. An obvious inhibition effect on TC-HCl was occurred in the presence of Cl-, whereas the presences of NO3- and SO42- had little effect. However, HCO3- improved TC-HCl removal efficiency. BM-RM had a wide working pH range (pH = 3-11) and showed good stability and reusability in use. Overall, this work not only offers a simple and promising approach to improve the catalytic activity of RM, but also opens new insights into the ball-milled RM as an effective PMS activator for wastewater treatment.

Investigation of the Uptake and Transport of Two Novel Camptothecin Derivatives in Caco-2 Cell Monolayers.

Irinotecan and Topotecan are two Camptothecin derivatives (CPTs) whose resistance is associated with the high expression of breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp). To reverse this resistance, two novel CPTs, FL77-28 (7-(3-Fluoro-4-methylphenyl)-10,11-methylenedioxy-20(S)-CPT) and FL77-29 (7-(4-Fluoro-3-methylphenyl)-10,11-methylenedioxy-20(S)-CPT), were synthesized by our group. In this study, the anti-tumor activities of FL77-28, FL77-29, and their parent, FL118 (10,11-methylenedioxy-20(S)-CPT), were evaluated and the results showed that FL77-28 and FL77-29 had stronger anti-tumor activities than FL118. The transport and uptake of FL118, FL77-28, and FL77-29 were investigated in Caco-2 cells for the preliminary prediction of intestinal absorption. The apparent permeability coefficient from apical to basolateral (Papp AP-BL) values of FL77-28 and FL77-29 were (2.32 ± 0.04) × 10-6 cm/s and (2.48 ± 0.18) × 10-6 cm/s, respectively, suggesting that the compounds had moderate absorption. Since the transport property of FL77-28 was passive diffusion and the efflux ratio (ER) was less than 2, two chemical inhibitors were added to further confirm the involvement of efflux proteins. The results showed that FL77-28 was not a substrate of P-gp or BCRP, but FL77-29 was mediated by P-gp. In conclusion, FL77-28 might be a promising candidate to overcome drug resistance induced by multiple efflux proteins.

Far infrared light irradiation enhances Aß clearance via increased exocytotic microglial ATP and ameliorates cognitive deficit in Alzheimer's disease-like mice.

BACKGROUND: Exposure to sunlight may decrease the risk of developing Alzheimer's disease (AD), and visible and near infrared light have been proposed as a possible therapeutic strategy for AD. Here, we investigated the effects of the visible, near infrared and far infrared (FIR) light on the cognitive ability of AD mice, and found that FIR light also showed potential in the improvement of cognitive dysfunction in AD. However, the related mechanism remains to be elucidated. METHODS: Morris water maze was used to evaluate the cognitive ability of APPswe/PSEN1dE9 double-transgenic AD mice after light treatment. Western blot was carried out to detect the expression of protein involved in synaptic function and amyloid-ß (Aß) production. The protein amount of interleukin (IL)-1ß, IL-6, Aß1-40 and Aß1-42 were determined using enzyme-linked immunosorbent assay. The mRNA level of receptors was performed using real-time quantitative polymerase chain reaction. Immunostaining was performed to characterize the Aß burden and microglial Aß phagocytosis in the brain of AD mice. The Aß phagocytosis of primary cultured microglia and BV2 were assessed by flow cytometry. The energy metabolism changes were evaluated using related assay kits, including adenosine triphosphate (ATP), lactate content, mitochondrial respiratory chain complex enzymatic activity and oxidized/reduced nicotinamide adenine dinucleotide assay kits. RESULTS: Our results showed that FIR light reduced Aß burden, a hallmark of AD neuropathology, alleviated neuroinflammation, restored the expression of the presynaptic protein synaptophysin, and ameliorated learning and memory impairment in the AD mice. FIR light enhanced mitochondrial oxidative phosphorylation pathway to increase ATP production. This increased intracellular ATP promoted the extracellular ATP release from microglia stimulated by Aß, leading to the enhanced Aß phagocytosis through phosphoinositide 3-kinase/mammalian target of rapamycin pathways for Aß clearance. CONCLUSIONS: Our findings have uncovered a previously unappreciated function of FIR light in inducing microglial phagocytosis to clean Aß, which may be the mechanisms for FIR light to improve cognitive dysfunction in AD mice. These results suggest that FIR light treatment is a potential therapeutic strategy for AD.

Discovery of Novel Drug Candidates for Alzheimer's Disease by Molecular Network Modeling.

To identify the molecular mechanisms and novel therapeutic agents of late-onset Alzheimer's disease (AD), we performed integrative network analysis using multiple transcriptomic profiles of human brains. With the hypothesis that AD pathology involves the whole cerebrum, we first identified co-expressed modules across multiple cerebral regions of the aging human brain. Among them, two modules (M3 and M8) consisting of 1,429 protein-coding genes were significantly enriched with AD-correlated genes. Differential expression analysis of microarray, bulk RNA-sequencing (RNA-seq) data revealed the dysregulation of M3 and M8 across different cerebral regions in both normal aging and AD. The cell-type enrichment analysis and differential expression analysis at the single-cell resolution indicated the extensive neuronal vulnerability in AD pathogenesis. Transcriptomic-based drug screening from Connectivity Map proposed Gly-His-Lys acetate salt (GHK) as a potential drug candidate that could probably restore the dysregulated genes of the M3 and M8 network. Pretreatment with GHK showed a neuroprotective effect against amyloid-beta-induced injury in differentiated human neuron-like SH-SY5Y cells. Taken together, our findings uncover a dysregulated network disrupted across multiple cerebral regions in AD and propose pretreatment with GHK as a novel neuroprotective strategy against AD.

Legumain/pH dual-responsive lytic peptide-paclitaxel conjugate for synergistic cancer therapy.

After molecule targeted drug, monoclonal antibody and antibody-drug conjugates (ADCs), peptide-drug conjugates (PDCs) have become the next generation targeted anti-tumor drugs due to its properties of low molecule weight, efficient cell penetration, low immunogenicity, good pharmacokinetic and large-scale synthesis by solid phase synthesis. Herein, we present a lytic peptide PTP7-drug paclitaxel conjugate assembling nanoparticles (named PPP) that can sequentially respond to dual stimuli in the tumor microenvironment, which was designed for passive tumor-targeted delivery and on-demand release of a tumor lytic peptide (PTP-7) as well as a chemotherapeutic agent of paclitaxel (PTX). To achieve this, tumor lytic peptide PTP-7 was connected with polyethylene glycol by a peptide substrate of legumain to serve as hydrophobic segments of nanoparticles to protect the peptide from enzymatic degradation. After that, PTX was connected to the amino group of the polypeptide side chain through an acid-responsive chemical bond (2-propionic-3-methylmaleic anhydride, CDM). Therefore, the nanoparticle (PPP) collapsed when it encountered the weakly acidic tumor microenvironment where PTX molecules fell off, and further triggered the cleavage of the peptide substrate by legumain that is highly expressed in tumor stroma and tumor cell surface. Moreover, PPP presents improved stability, improved drug solubility, prolonged blood circulation and significant inhibition ability on tumor growth, which gives a reasonable strategy to accurately deliver small molecule drugs and active peptides simultaneously to tumor sites.

HMD-Net: A Vehicle Hazmat Marker Detection Benchmark.

Vehicles carrying hazardous material (hazmat) are severe threats to the safety of highway transportation, and a model that can automatically recognize hazmat markers installed or attached on vehicles is essential for intelligent management systems. However, there is still no public dataset for benchmarking the task of hazmat marker detection. To this end, this paper releases a large-scale vehicle hazmat marker dataset named VisInt-VHM, which includes 10,000 images with a total of 20,023 hazmat markers captured under different environmental conditions from a real-world highway. Meanwhile, we provide an compact hazmat marker detection network named HMD-Net, which utilizes a revised lightweight backbone and is further compressed by channel pruning. As a consequence, the trained-model can be efficiently deployed on a resource-restricted edge device. Experimental results demonstrate that compared with some established methods such as YOLOv3, YOLOv4, their lightweight versions and popular lightweight models, HMD-Net can achieve a better trade-off between the detection accuracy and the inference speed.

Revisiting Local Descriptors via Frequent Pattern Mining for Fine-Grained Image Retrieval.

Fine-grained image retrieval aims at searching relevant images among fine-grained classes given a query. The main difficulty of this task derives from the small interclass distinction and the large intraclass variance of fine-grained images, posing severe challenges to the methods that only resort to global or local features. In this paper, we propose a novel fine-grained image retrieval method, where global-local aware feature representation is learned. Specifically, the global feature is extracted by selecting the most relevant deep descriptors. Meanwhile, we explore the intrinsic relationship of different parts via the frequent pattern mining, thus obtaining the representative local feature. Further, an aggregation feature that learns global-local aware feature representation is designed. Consequently, the discriminative ability among different fine-grained classes is enhanced. We evaluate the proposed method on five popular fine-grained datasets. Extensive experimental results demonstrate that the performance of fine-grained image retrieval is improved with the proposed global-local aware representation.

Preparation and application of a new Fenton-like catalyst from red mud for degradation of sulfamethoxazole.

In this work, using molasses wastewater as a partial acidifying agent and bagasse pith as a pore-enlarging agent, a new low-cost Fenton-like catalyst (ACRMbp) used for degradation of sulfamethoxazole was prepared through a simple process of acidification and calcination using red mud (RM) as the main material. The optimum preparation conditions of ACRMbp were acquired, and the optimum preparation conditions of ACRMbp were as follows: mass ratio of bagasse pith to RM (mbp:mRM) 0.033:1, particle size of bagasse pith 0.10-0.20 mm, calcination temperature 773 K, and calcination time 2 h. The ACRMbp catalyst was characterized by XRD, SEM, EDS, and BET. According to the results of characterizations, it was found that the iron phase of ACRMbp had completely transformed into α-Fe2O3 after the process of acidification and calcination, and the addition of bagasse pith significantly improved the surface area of the prepared ACRMbp. Furthermore, under the reaction conditions of catalyst dosage of 2 g/L, initial pH 3 and reaction time 90 min, the ACRMbp has showed the highest catalytic activity. ACRMbp had significantly higher activity than red mud, and exhibited a remarkable settleability. Besides, ACRMbp retained good recyclability and stability during use. Kinetic studies showed the degradation process could be described with the first-order model. Overall, the prepared ACRMbp was an effective and excellent catalyst in the Fenton-like process.

Cellular Uptake and Transport Characteristics of FL118 Derivatives in Caco-2 Cell Monolayers.

In the evaluation of the druggability of candidate compounds, it was vital to predict the oral bioavailability of compounds from apparent permeability (Papp) across Caco-2 cell-culture model of intestinal epithelium cultured on commercial transwell plate inserts. The study was to investigate the transport characteristics and permeability of FL118 (10, 11-Methylenedioxy-20(S)-camptothecin) derivatives 7-Q6 (7-(4-Ethylphenyl)-10, 11-methylenedioxy-20(S)-camptothecin) and 7-Q20 (7-(4-Trifluoromethylphenyl)-10, 11-methylenedioxy-20(S)-camptothecin). Transport characteristics and permeability of the tested compounds to the small intestine were assessed at different concentrations (0.5, 1 µM) via Caco-2 cell monolayers model in vitro. Uptake studies based on Caco-2 cells, including temperatures, concentrations, and the influence of efflux transporters, were combined to confirm the transport characteristics of the tested compounds. Furthermore, cytotoxicity results showed that the concentrations used in the experiments were non-toxic and harmless to cells. In addition, The Papp of 7-Q6 was (3.69 ± 1.07) × 10-6 cm/s with efflux ratio (ER) 0.98, while the Papp of 7-Q20 was (7.78 ± 0.89) × 10-6 cm/s with ER 1.05 for apical-to-basolateral (AP→BL) at 0.5 µM, suggesting that 7-Q20 might possess higher oral bioavailability in vivo. Furthermore, P-glycoprotein (P-gp) was proved to slightly affect the accumulations of 7-Q20, while the absorption of 7-Q6 was irrelevant with P-gp and breast cancer resistant protein (BCRP) based on the cellular uptake assays. Accordingly, 7-Q6 was completely absorbed by passive diffusion, and 7-Q20 was mainly dependent on passive diffusion with being effluxed by P-gp slightly. Meanwhile, both 7-Q6 and 7-Q20 were potential antitumor drugs that might exhibit high oral bioavailability in the body.

Correlation between the levels of NLRP3, Hcy, IL-1ß, IL-18 and the prognosis in patients with hemorrhagic stroke.

OBJECTIVE: To explore the connection of nucleotide-binding oligomerization domain-like receptors 3 (NLRP3), homocysteine (Hcy), interleukin-1ß (IL-1ß), interleukin-18 (IL-18) in peripheral blood and prognosis in patients with hemorrhagic stroke. METHODS: A total of 84 patients with hemorrhagic stroke treated in our hospital were selected and divided into the good prognosis group (48 cases) and the poor prognosis group (36 cases) according to the Glasgow Prognostic Scale (GOS) at month 6 after discharge. 40 people who were matched for age, sex and risk factors for cerebral hemorrhage, but did not have cerebral hemorrhage, were selected as a control group. We detected the levels of NLRP3, Hcy, IL-1ß and IL-18 in peripheral blood, and analyzed their correlation with GOS score. Then we performed Logistic regression analysis to investigate the risk factors for poor prognosis. RESULTS: The expressions of NLRP3 mRNA, Hcy, IL-1ß and IL-18 in peripheral blood in the poor prognosis group were higher than those in the good prognosis group (P<0.05). The expression levels of NLRP3 mRNA, Hcy, IL-1ß and IL-18 were negatively correlated with GOS scores (P<0.05). Regression analysis showed that the expression of NLRP3 mRNA, serum Hcy, bleeding volume and ventricular system penetration were independent risk factors for poor prognosis. CONCLUSION: In patients with poor prognosis of hemorrhagic stroke, the mRNA levels of NLRP3 and serum Hcy, IL-1ß and IL-18 levels in peripheral blood elevated. High NLRP3 mRNA levels, Hcy levels, bleeding volume and ventricle system penetration are independent risk factors for poor prognosis.

In Vitro Metabolism of E2, G2: Novel Bile Acid-Coupling Camptothecin Analogues, in Rat Liver Microsomes.

BACKGROUND: E2 (Camptothecin - 20 (S) - O- glycine - deoxycholic acid), and G2 (Camptothecin - 20 (S) - O - acetate - deoxycholic acid) are two novel bile acid-derived camptothecin analogues, modified deoxycholic acid at 20-position of CPT(camptothecin) with greater anticancer activity and lower systematic toxicity in vivo. OBJECTIVE: We aimed to investigate the metabolism of E2 and G2 by Rat Liver Microsomes (RLM). METHODS: Phase I and Phase II metabolism of E2 and G2 in rat liver microsomes were performed, respectively, and the mixed incubation of phase I and phase II metabolism of E2 and G2 was also processed. Metabolites were identified by liquid chromatographic/mass spectrometry. RESULTS: The results showed that phase I metabolism was the major biotransformation route for both E2 and G2. The isoenzyme involved in their metabolism had some difference. The intrinsic clearance of G2 was 174.7 mL/min. mg protein, more than three times that of E2 (51.3 mL/min . mg protein), indicating a greater metabolism stability of E2. 10 metabolites of E2 and 14 metabolites of G2 were detected, including phase I metabolites (mainly via hydroxylations and hydrolysis) and their further glucuronidation products. CONCLUSION: These findings suggested that E2 and G2 have similar biotransformation pathways except for some differences in the hydrolysis ability of the ester bond and amino bond from the parent compounds, which may result in the diversity of their metabolism stability and responsible CYPs(Cytochrome P450 proteins).