Exploring drug repositioning possibilities of kinase inhibitors via molecular simulation.

Kinases, a class of enzymes controlling various substrates phosphorylation, are pivotal in both physiological and pathological processes. Although their conserved ATP binding pockets pose challenges for achieving selectivity, this feature offers opportunities for drug repositioning of kinase inhibitors (KIs). This study presents a cost-effective in silico prediction of KIs drug repositioning via analyzing cross-docking results. We established the KIs database (278 unique KIs, 1834 bioactivity data points) and kinases database (357 kinase structures categorized by the DFG motif) for carrying out cross-docking. Comparative analysis of the docking scores and reported experimental bioactivity revealed that the Atypical, TK, and TKL superfamilies are suitable for drug repositioning. Among these kinase superfamilies, Olverematinib, Lapatinib, and Abemaciclib displayed enzymatic activity in our focused AKT-PI3K-mTOR pathway with IC50 values of 3.3, 3.2 and 5.8 µM. Further cell assays showed IC50 values of 0.2, 1.2 and 0.6 µM in tumor cells. The consistent result between prediction and validation demonstrated that repositioning KIs via in silico method is feasible.

Preclinical characterization of danatinib as a novel FLT3 inhibitor with excellent efficacy against resistant acute myeloid leukemia.

The therapeutic benefits of available FLT3 inhibitors for AML are limited by drug resistance, which is related to mutations, as well toxicity caused by off-target effects. In this study, we introduce a new small molecule FLT3 inhibitor called danatinib, which was designed to overcome the limitations of currently approved agents. Danatinib demonstrated greater potency and selectivity, resulting in cytotoxic activity specific to FLT3-ITD and/or FLT3-TKD mutated models. It also showed a superior kinome inhibition profile compared to several currently approved FLT3 inhibitors. In diverse FLT3-TKD models, danatinib exhibited substantially improved activity at clinically relevant doses, outperforming approved FLT3 inhibitors. In vivo safety evaluations performed on the granulopoiesis of transgenic myeloperoxidase (MPO) zebrafish and mice models proved danatinib to have an acceptable safety profile. Danatinib holds promise as a new and improved FLT3 inhibitor for the treatment of AML, offering long-lasting remissions and improved overall survival rates.

Application of image overlapping in percutaneous nephrolithotomy.

OBJECTIVE: To investigate the application of ultrasound and CT image overlap in percutaneous nephrolithotomy (PCNL). METHODS: A total of 140 patients with complicated kidney stones requiring PCNL were prospectively enrolled, from January 2020 to December 2022. These patients were randomly divided into 2 groups, with 70 patients each in the research group and the control group. All participants underwent dual-source, non-contrast CT scan of both kidneys and pelvis before surgery. Preoperative three-dimensional CT reconstruction and simulated puncture were performed in patients from the research group. The best puncture path was determined through ultrasound and CT image overlap. Puncture guided by regular CT and ultrasound was conducted in patients from the control group. Differences in the surgical outcomes between the two groups were compared. RESULTS: Compared to the control group, the research group had higher stone clearance rate in stage I PCNL, success rate of one-time puncture, less percutaneous channels, less reduction of hemoglobin and shorter procedure time. Complications in stage I PCNL were comparable in the two groups, and there was no significant change in the final stone clearance rates between the two groups. CONCLUSION: An optimal puncture channel can be chosen using ultrasound and CT image overlap. PCNL can be achieved with precise puncturing, thus achieving coincidence between imaging and anatomy and reducing the amount of blood loss during stage I of PCNL. It also shortens the procedure time and improves stone clearance rate of PCNL.

Innovative method for the enrichment of high-polarity bioactive molecules present at low concentrations in complex matrices.

Ginsenoside Rg1 is a valuable bioactive molecule but its high polarity and low concentration in complex mixtures makes it a challenge to separate Ginsenoside Rg1 from other saponins with similar structures, resulting in low extraction efficiency. The successful development of effective Rg1 molecularly imprinted polymers that exhibit high selectivity and adsorption may offer an improved method for the enrichment of active compounds. In this work, molecularly imprinted polymers were prepared with two different methods, precipitation polymerization or surface imprinted polymerization. Comparison of the adsorption abilities showed higher adsorption of the surface molecularly imprinted polymers prepared by surface imprinted polymerization, 46.80 mg/g, compared to the 27.74 mg/g observed for the molecularly imprinted polymers prepared by precipitation polymerization. Therefore, for higher adsorption of the highly polar Rg1, surface imprinted polymerization is a superior technique to make Rg1 molecularly imprinted polymers. The prepared surface molecularly imprinted polymers were tested as a solid-phase extraction column to directionally enrich Rg1 and its analogues from ginseng tea and total ginseng extracts. The column with surface molecularly imprinted polymers showed higher enrichment efficiency and better selectivity than a C18 solid-phase extraction column. Overall, a new, innovative method was developed to efficiently enrich high-polarity bioactive molecules present at low concentrations in complex matrices.

[Neuro-protective effects and mechanism of Terminalia chebula extract HZ4 on cerebral infarction models].

To study the effect and possible molecular mechanisms of Terminalia chebula extract HZ4 on focal cerebral infarction in rats, 90 healthy male SD rats were randomly divided into sham-operation group, model group, T. chebula extract HZ4 high dose, middle dose and low dose groups (80, 40, 20 mg•kg ⁻¹â€¢d ⁻¹, ig) and positive control group (Panax notoginseng saponins, PNS 30 mg•kg ⁻¹â€¢d ⁻¹, ig). The focal cerebral infarction models were established by photochemical method. After the rats were administered for 7 consecutive days, neurogenic behavior rating of these rats was done by balance beam test and foot fault test. The cells morphological changes of penumbra in focal cerebral infarction were investigated by HE staining method; the infarct volume was detected by TTC staining. The expression levels of ß-catenin and cyclin D1, the key node genes in Wnt signaling pathway of the focal penumbra tissues were detected via RT-PCR. The results showed that, as compared with the model group, behavioural indicators were improved significantly in the rats of administration groups, and the infarct volume and pathological changes of penumbra tissues were also improved at the same time. Compared with the model group, the expression levels of ß-catenin and cyclin D1 in Wnt signaling pathway were significantly up-regulated in administration groups(P<0.01). This study first confirmed that T. chebula extract HZ4 can decrease infarct volume, improve the sport ability score, and promote rehabilitation of model animals. In addition, it could significant up-regulated the expression levels of ß-catenin and cyclin D1, and the mechanism may be associated with Wnt signaling pathway. The study is innovative to a certain extent.

[Comparative study on two polymerization methods for preparing ginsenoside Rg1 molecularly imprinted polymer separating materials].

To obtain ginsenoside Rg1 molecularly imprinted polymer (MIP) separating materials with high selectivity, enrichment and adsorption performance through directional separation of ginsenoside Rg1 and analogues. In this study, MIPs were respectively prepared by precipitation polymerization and surface imprinted polymerization. Their adsorption performances were compared. The results showed that ginsenoside Rg1 MIPs prepared by the above two methods had a high adsorption performance to template molecules, with the maximum apparent adsorbing capacity of up to 27.74, 46. 80 mg x g(-1), respectively. Moreover, MIPs prepared by surface imprinted polymerization showed higher adsorption capacity than that by precipitation polymerization. The experimental results indicated that as for ginsenoside Rg1 with higher polarity, MIPs prepared by surface imprinted polymerization showed higher selectivity and adsorption performance, which provides provide important reference for preparing imprinted polymers with good adsorption performance with active molecules with strong polarity.

Determination of hyperoside and isoquercitrin in rat plasma by membrane-protected micro-solid-phase extraction with high-performance liquid chromatography.

A novel method, micro-solid-phase extraction based on membrane-protected molecularly imprinted polymer, was developed to extract hyperoside and isoquercitrin in rat plasma. Synthesized hyperoside MIPs were packed in a porous polyether sulfone membrane envelope to perform extraction. The parameters sorbent materials, membrane types, extraction time and desorption conditions were optimized for micro-solid-phase extraction. Under the optimal conditions, correlation coefficients, 0.998 and 0.999, were obtained for hyperoside and isoquercitrin, respectively, with the linear range between 1 and 120 µg/mL. The absolute extraction recoveries from 84.5 to 89.3% were found. The method detection limits of hyperoside and isoquercitrin were 0.24 and 0.22 µg/mL, respectively. Compared with traditional methods, solid-phase extraction, liquid-liquid extraction and protein precipitation, the developed method was simple, highly efficient for extraction, environmentally friendly, and particularly suitable for complex biological samples.

High XRCC1 protein expression is associated with poorer survival in patients with head and neck squamous cell carcinoma.

PURPOSE: We evaluated X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) protein in head and neck squamous cell carcinoma (HNSCC) patients in association with outcome. EXPERIMENTAL DESIGN: XRCC1 protein expression was assessed by immunohistochemical (IHC) staining of pretreatment tissue samples in 138 consecutive HNSCC patients treated with surgery (n = 31), radiation (15), surgery and radiation (23), surgery and adjuvant chemoradiation (17), primary chemoradiation (51), and palliative measures (1). RESULTS: Patients with high XRCC1 expression by IHC (n = 77) compared with patients with low XRCC1 expression (n = 60) had poorer median overall survival (OS; 41.0 months vs. OS not reached, P = 0.009) and poorer progression-free survival (28.0 months vs. 73.0 months, P = 0.031). This association was primarily due to patients who received chemoradiation (median OS of high- and low-XRCC1 expression patients, 35.5 months and not reached respectively, HR 3.48; 95% CI: 1.44-8.38; P = 0.006). In patients treated with nonchemoradiation modalities, there was no survival difference by XRCC1 expression. In multivariable analysis, high XRCC1 expression and p16(INK4a)-positive status were independently associated with survival in the overall study population (HR = 2.62; 95% CI: 1.52-4.52; P < 0.001 and HR = 0.21; 95% CI: 0.06-0.71; P = 0.012, respectively) and among chemoradiation patients (HR = 6.02; 95% CI: 2.36-15.37; P < 0.001 and HR = 0.26; 95% CI: 0.08-0.92, respectively; P = 0.037). CONCLUSIONS: In HNSCC, high XRCC1 protein expression is associated with poorer survival, particularly in patients receiving chemoradiation. Future validation of these findings may enable identification of HNSCC expressing patients who benefit from chemoradiation treatment.

Effective compounds group of Mongolian prescriptions BAIMAI-SAN protect against peripheral neuropathy in lower limbs of rats through neuro protective effect.

ETHNOPHARMACOLOGICAL RELEVANCE: BAIMAI-SAN prescription is a famous Chinese minority complex prescription used for curing neuropathy. MATERIALS AND METHODS: The Effective Compounds Groups of BAIMAI-SAN (ECGBM) is determined by high through-put screening, and it includes picroside II, verbascose, taurine and ellagic acid and borneol. To research the potential protective effect of ECGBM on the function of peripheral neuropathy, diabetic rats with peripheral neuropathy were induced by streptozotocin and treated with ECGBM (0.1, 0.3, 0.9 mg/kg/day i.g.) for 75 days. Primary cortical neuronal cultures were subjected to high d-glucitol, and treated with ECGBM prophylactically. RESULTS: The administration resulted in reductions in speed of sciatic motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV) and response speed to pain in the sciatic nerve fiber. Data from primary cortical neuronal cultures experiments indicated that neuronal survival rates were increased, and LDH release was decreased and the loss of neurite length was alleviated in ECGBM group. CONCLUSIONS: It is first report that ECGBM could protect the peripheral neuron in diabetic rat in vivo and in vitro. This activity may be associated with the neuron protective effect.

[The spectroscopy analysis of intermolecular interaction between the template molecule and functional monomer before polymerization].

To prepare the non-covalent molecularly imprinted polymers (MIPs) with good adsorption properties,the degree of interaction is important factor between the template molecule and functional monomer before polymerization. The correlative research has been reported less. In the present paper, UV combined with infrared spectra was applied to study intermolecular interaction of the template molecule and functional monomer. andrographolide was used as the template molecule, acrylamide (AM) as the functional monomer in the three kinds of solvents, namely acetonitrile, tetrahydrofuran and ethyl acetate. The experimental results showed that the UV absorption peaks at 224 nm exhibited blue-shift of 5 nm, and the absorption peak increased for andrographolide and AM in acetonitrile solvent. In IR spectra, the O--H stretching vibration was also blue-shifted by nearly 8 cm(-1), while the N--H stretching vibration of blue shift was about 6 cm(-1). The data showed that the strong interaction of blue-shifted hydrogen bonds generated between the molecules of andrographolide and AM. And intermolecular interaction was very weak in other two solvents. It is obvious that the stronger the intermolecular interaction, the greater the spectroscopy changes, the better the selectivity of identification points, and thus the better the adsorption properties of MIPs are.

Manipulating supramolecular self-assembly via tailoring pendant group size of linear vinyl polymers.

In a series of poly[di(alkyl) vinylterephthalates] (PDAVTs) synthesized via radical polymerization, fine-tuning the size and shape of the side groups manipulated the supramolecular self-assembly and led to control over the formations between amorphous and 2D ordered hexagonal phases. To introduce the 2D long-range ordered structure, the size of the ester side groups at the 2- and 5-positions of the phenyl rings laterally attached to the backbones had to be in the range of propyl/isopropyl to hexyl. The relatively extended backbones observed in these polymers were attributed to steric effects from the side groups. When the n-alkyl groups were larger than hexyl, the ability to form the liquid crystalline phase gradually decreased. A completely disordered phase could be observed by substituting dodecyl groups as side groups.

Pag, a putative tumor suppressor, interacts with the Myc Box II domain of c-Myc and selectively alters its biological function and target gene expression.

The highly conserved Myc Box II (MBII) domain of c-Myc is critically important for transformation and transcriptional regulation. A yeast two-hybrid screen identified Pag as a MBII-interacting protein. Pag, a member of the peroxiredoxin family, has been reported previously to bind to and inhibit the cytostatic properties of the c-Abl oncoprotein. We now show that Pag promotes increased cell size and confers a proapoptotic phenotype, two hallmark features of ectopic c-Myc overexpression. Pag and c-Myc also confer resistance to oxidative stress, a previously unrecognized property of the latter protein. In contrast, Pag inhibits tumorigenesis by c-Myc-overexpressing fibroblasts and causes a broad but selective loss of c-Myc target gene regulation. Pag is therefore an MBII-interacting protein that can either mimic or enhance some of the c-Myc properties while at the same inhibiting others. These features, along with the previously identified interaction with c-Abl, provide support for the idea that Pag functions as a tumor suppressor.