A deep learning-driven discovery of berberine derivatives as novel antibacterial against multidrug-resistant Helicobacter pylori.

Helicobacter pylori (H. pylori) is currently recognized as the primary carcinogenic pathogen associated with gastric tumorigenesis, and its high prevalence and resistance make it difficult to tackle. A graph neural network-based deep learning model, employing different training sets of 13,638 molecules for pre-training and fine-tuning, was aided in predicting and exploring novel molecules against H. pylori. A positively predicted novel berberine derivative 8 with 3,13-disubstituted alkene exhibited a potency against all tested drug-susceptible and resistant H. pylori strains with minimum inhibitory concentrations (MICs) of 0.25-0.5 µg/mL. Pharmacokinetic studies demonstrated an ideal gastric retention of 8, with the stomach concentration significantly higher than its MIC at 24 h post dose. Oral administration of 8 and omeprazole (OPZ) showed a comparable gastric bacterial reduction (2.2-log reduction) to the triple-therapy, namely OPZ + amoxicillin (AMX) + clarithromycin (CLA) without obvious disturbance on the intestinal flora. A combination of OPZ, AMX, CLA, and 8 could further decrease the bacteria load (2.8-log reduction). More importantly, the mono-therapy of 8 exhibited comparable eradication to both triple-therapy (OPZ + AMX + CLA) and quadruple-therapy (OPZ + AMX + CLA + bismuth citrate) groups. SecA and BamD, playing a major role in outer membrane protein (OMP) transport and assembling, were identified and verified as the direct targets of 8 by employing the chemoproteomics technique. In summary, by targeting the relatively conserved OMPs transport and assembling system, 8 has the potential to be developed as a novel anti-H. pylori candidate, especially for the eradication of drug-resistant strains.

Palmatine Derivatives as Potential Antiplatelet Aggregation Agents via Protein Kinase G/Vasodilator-Stimulated Phosphoprotein and Phosphatidylinositol 3-Kinase/Akt Phosphorylation.

Sixty palmatine (PMT) derivatives were synthesized and evaluated for antiplatelet aggregation taking berberine as the lead, and the structure-activity relationship was first systematically described. Among them, compound 2v showed the best potency in reducing adenosine diphosphate (ADP)-induced platelet aggregation in a dose-dependent manner. It greatly suppressed ADP-induced platelet aggregation, activation, and Akt phosphorylation in vitro and ex vivo after oral administration to mice. It also effectively inhibited carrageenan-induced thrombus formation in the mouse tail and lung, as well as reduced the serum P-selectin level. Compound 2v might simultaneously bind to protein kinase G to improve vasodilator-stimulated phosphoprotein phosphorylation and bind to phosphatidylinositol 3-kinase to inhibit Akt phosphorylation, which synergically reduced platelet aggregation, thereby achieving antithrombotic efficacy. Therefore, PMT derivatives constituted a novel family of antiplatelet aggregation agents with the advantage of a good safety profile, worthy of further investigation.

Deep Learning-Based Computed Tomography Imaging to Diagnose the Lung Nodule and Treatment Effect of Radiofrequency Ablation.

This study aimed to detect and diagnose the lung nodules as early as possible to effectively treat them, thereby reducing the burden on the medical system and patients. A lung computed tomography (CT) image segmentation algorithm was constructed based on the deep learning convolutional neural network (CNN). The clinical data of 69 patients with lung nodules diagnosed by needle biopsy and pathological comprehensive diagnosis at hospital were collected for specific analysis. The CT image segmentation algorithm was used to distinguish the nature and volume of lung nodules and compared with other computer aided design (CAD) software (Philips ISP). 69 patients with lung nodules were treated by radiofrequency ablation (RFA). The results showed that the diagnostic sensitivity of the CT image segmentation algorithm based on the CNN was obviously higher than that of the Philips ISP for solid nodules <5 mm (63 cases vs. 33 cases) (P < 0.05); it was the same result for the subsolid nodule <5 mm (33 case vs. 5 cases) (P < 0.05) that was slightly higher for solid and subsolid nodules with a diameter of 5-10 mm (37 cases vs. 28 cases) (P < 0.05). In addition, the CNN algorithm can reach all detection for calcified nodules and pleural nodules (7 cases; 5 cases), and the diagnostic sensitivities were much better than those of Philips ISP (2 cases; 3 cases) (P < 0.05). Patients with pulmonary nodules treated by RFA were in good postoperative condition, with a half-year survival rate of 100% and a one-year survival rate of 72.4%. Therefore, it could be concluded that the CT image segmentation algorithm based on the CNN could effectively detect and diagnose the lung nodules early, and the RFA could effectively treat the lung nodules.

Perfluorooctane sulfonate enhances mRNA expression of PPARγ and ap2 in human mesenchymal stem cells monitored by long-retained intracellular nanosensor.

Perfluorooctane sulfonate (PFOS) has been widely used as a surface coating for household products. It still exists in living environments despite being restricted, due to its bioaccumulation and long half-life. Studies have shown that PFOS has the ability to induce adipogenic differentiation of human cells. Human mesenchymal stem cells (hMSCs) distributed within the adipose tissue might be a potential target of accumulated PFOS. However, traditional end-point toxicity assays failed to examine the subtle changes of cellular function exposed to low-dose persistent organic pollutants in real time. In the present work, highly sensitive and long-retained (more than 30 days) fluorescence based polymeric nanosensors were developed and employed for real-time assessment of cellular functions. hMSCs were engineered with sensor molecules encapsulated poly (lactic-co-glycolic acid) (PLGA) particles. Once internalized by hMSCs, PLGA particles continuously release and replenish sensor molecules to cytoplasm, resulting in prolonged fluorescence signal against photo bleaching and dilution by exocytosis. With this method, the dynamic changes of viability, ROS induction, and adipogenic differentiation related mRNA expression of hMSCs were monitored. PFOS with the concentration as low as 0.1 µM can induce cellular ROS and enhance the PPARγ and ap2 mRNA expression, suggesting the effect on promoting adipogenic differentiation of hMSCs.

Intracellular MicroRNA Imaging with MoS2-Supported Nonenzymatic Catassembly of DNA Hairpins.

Amplification strategies for low-level microRNA detection in living cells are pivotal for gene diagnosis and many cellular bioprocesses. In this work, we develop an amplification strategy for microRNA-21 (miRNA-21) imaging in living cells with MoS2-supported catassembly of DNA hairpins. The MoS2 nanosheet with low cytotoxicity serves as the nanocarrier and excellent fluorescence quencher, which can transfer fluorescent metastable hairpin DNA into the cells easily in a nondestructive manner and significantly reduce background signals. The three-branched catalyzed hairpin assembly (TB-CHA) probes contain three types of designed DNA molecular beacons with the modification of Cy3 in the terminal. In the presence of miRNA-21, the catalyzed hairpin assembly (CHA) reaction would be triggered and a "Y"-shaped three-branched duplex nanostructure would be formed, which would release from the surface of the MoS2 nanosheet due to the reduced affinity between the DNA duplex and MoS2 nanosheet. The multisite fluorescence modification and the circular reaction of TB-CHA probes allowed a significant fluorescence recovery in a live-cell microenvironment. The ultrasensitive detection of miRNA-21 is achieved with a detection limit of 75.6 aM, which is ∼5 orders of magnitude lower than that of a simple strand displacement-based strategy (detection limit: 8.5 pM). This method offers great opportunities for the ultrasensitive live-cell detection of miRNAs and helps in gaining a deeper understanding of the physiological functions of miRNAs in cancer research and life processes.

[Chemical constituents from root barks of Dictamnus dasycarpus and their cytotoxic activities].

Nineteen compounds, including kihadanin D (1), obacunone (2), kihadanin A (3), kihadanin B (4), kihadanin C (5), limonin (6), evodol (7), fraxinellone (8), furo[2,3-b]quinolin-4-ol (9), preskimmianine (10), ifflaiamine (11), dictamnol (12), naringenin (13), diosmetin (14), wogonin (15), scopoletin (16), cleomiscosin A (17), apocynin (18), and methyl pyroglutamate (19), were isolated from the methanol extract of the root barks of Dictamnus dasycarpus by using various column chromatographies. Their chemical structures were extensively determined on basis of UV, IR, NMR, MS, and CD spectroscopic data analyses. Among them, 1 is a new limonoid, 9 was isolated from plant kingdom for the first time, 11, 13-14 and 17-19 were obtained from the genus Dictamnnus for the first time. Cytotoxicities of compounds 1-18 were tested, and the results indicated that 1 exhibited cytotoxicities against three human cancer cell lines MDA-MB-231, A549 and HT29 with IC58 values of 16.22, 21.72 and 31.06 µmol·L⁻¹, respectively.

FoxO6 inhibits cell proliferation in lung carcinoma through up-regulation of USP7.

Emerging evidence has suggested that misregulation of oncogenes and/or tumor suppressors has a crucial role in the development of lung carcinoma. The present study demonstrated that the expression levels of forkhead box O6 (FOXO6) were downregulated in lung cancer tissue samples, as compared with those in adjacent normal tissue. Overexpression of FOXO6 inhibited the proliferation of A549 human lung cancer cells, whereas knockdown of endogenous FOXO6 expression enhanced cell proliferation. Furthermore, ectopic FOXO6 expression induced the expression of ubiquitin-specific-processing protease 7 (USP7). As a result of this regulation, FOXO6 overexpression led to an elevation of p53 protein expression levels in A549 cells. In conclusion, the results of the present study indicated that the FOXO6/USP7 molecular network has an important role in the regulation of lung cancer development.

Clinical significance of serum T helper 1/T helper 2 cytokine shift in patients with non-small cell lung cancer.

The aim of this study was to explore the T helper 1 (Th1)/Th2 cytokine shift and its clinical significance in the peripheral blood and tumor tissues of non-small cell lung cancer (NSCLC) patients. In total, 124 NSCLC patients who were admitted to Xinxiang Central Hospital were selected, along with 124 healthy individuals undergoing physical examination at the same hospital during this period (as controls). ELISA was conducted to detect the Th1 and Th2 cytokine levels in the peripheral blood of patients in the two groups prior to and following radical surgery treatment. In addition, the Th1 and Th2 cytokine levels in the peripheral blood of the observation group were measured following surgery to analyze the correlation between relapse and survival. Compared with the control group, interleukin 4 (IL-4) and IL-10 concentrations in the peripheral blood of the observation group, prior to and following surgery, were significantly higher, whilst IL-2 and interferon-γ (INF-γ) concentrations were significantly lower (P<0.05). In the observation group, the IL-4 and IL-10 concentrations were significantly decreased following surgery, as compared with prior to surgery (P<0.05), whilst the IL-2 and INF-γ concentrations increased significantly (P<0.05). The one- and three-year cumulative relapse frequencies of patients with postoperative IL-4 abnormalities were significantly increased compared with those in patients with normal IL-4 levels following surgery (P<0.05), and the median survival time and survival rate significantly decreased in patients with postoperative IL-4 abnormalities (P<0.05). In terms of the three-year cumulative relapse rate, median survival time, and one- and three-year cumulative survival rate, patients with postoperative IL-2, IL-10 and INF-γ level abnormalities did not present any statistical significance compared with those without such abnormalities (P>0.05). In conclusion, Th2 cytokines dominate the peripheral blood of NSCLC patients and radical surgery treatment may improve the Th1/Th2 shift in patients. Furthermore, postoperative IL-4 levels were observed to correlate with relapse and the survival rate of patients; therefore, IL-4 may be considered as an auxiliary in the postoperative diagnosis during clinical practice.