Two Stability Islands of Quadrupole Mass Filter near <i>q</i> = 0.9 Created by Auxiliary Radio Frequency Voltage

We report the numerical investigations of quadrupole mass filters concerning stability islands created by auxiliary radio frequency (RF) voltage with high and low frequencies near q = 0.9. The islands are located along the q axis near boundary value q = 0.908 with a low a parameter. The analysis is based upon the matrix method for stability diagram calculations and ion trajectory numerical simulation. The trajectory of ion motions is generated using Runge-Kutta–Nystrom–Dormand-Prince (RK–N–DP) order integration. The ion source model with Gaussian distribution of initial positions and transverse velocities is used. In RF-only operation mode, a resolution power of about R0.1 = 600 without peak tails is achieved with a separation time of about 50 RF cycles. Relatively high resolution power of about 2000–3000 is observed in DC+RF separation mode with a low frequency auxiliary RF signal. The boundaries of stability diagram for additional RF voltage with high frequency are strongly diffused until the separation time is increased up to n = 300 RF cycles. The strong influence of phase shifts between main drive RF voltage and small auxiliary RF voltage on transmission is also examined. In DC + RF mode, the period of transmission varies with phase shift of π or one period of the main drive RF voltage; and in RF-only mode this period is π/2. </jats:p

Virtual Screening for Potential Allosteric Inhibitors of Cyclin-Dependent Kinase 2 from Traditional Chinese Medicine

Cyclin-dependent kinase 2 (CDK2), a member of Cyclin-dependent kinases (CDKs), plays an important role in cell division and DNA replication. It is regarded as a desired target to treat cancer and tumor by interrupting aberrant cell proliferation. Compared to lower subtype selectivity of CDK2 ATP-competitive inhibitors, CDK2 allosteric inhibitor with higher subtype selectivity has been used to treat CDK2-related diseases. Recently, the first crystal structure of CDK2 with allosteric inhibitor has been reported, which provides new opportunities to design pure allosteric inhibitors of CDK2. The binding site of the ATP-competition inhibitors and the allosteric inhibitors are partially overlapped in space position, so the same compound might interact with the two binding sites. Thus a novel screening strategy was essential for the discovery of pure CDK2 allosteric inhibitors. In this study, pharmacophore and molecular docking were used to screen potential CDK2 allosteric inhibitors and ATP-competition inhibitors from Traditional Chinese Medicine (TCM). In the docking result of the allosteric site, the compounds which can act with the CDK2 ATP site were discarded, and the remaining compounds were regarded as the potential pure allosteric inhibitors. Among the results, prostaglandin E1 and nordihydroguaiaretic acid (NDGA) were available and their growth inhibitory effect on human HepG2 cell lines was determined by MTT assay. The two compounds could substantially inhibit the growth of HepG2 cell lines with an estimated IC50 of 41.223 μmol/L and 45.646 μmol/L. This study provides virtual screening strategy of allosteric compounds and a reliable method to discover potential pure CDK2 allosteric inhibitors from TCM. Prostaglandin E1 and NDGA could be regarded as promising candidates for CDK2 allosteric inhibitors

Lipid-Lowering Efficacy of the Capsaicin in Patients With Metabolic Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

BackgroundPatients with metabolic syndrome (MetS) have increased cardiovascular risk. Capsaicin (CAP) has been shown to reduce lipids, but efficacy for patients with MetS is unknown.MethodsA systematic review was performed according to PRISMA guidelines, to compare the effects of CAP against a placebo. Differences in the weight mean difference (WMD) with 95% confidence intervals (95% CI) were then pooled using a random effects model.ResultsNine randomized controlled trials including 461 patients were identified in the overall analysis. CAP significantly decreased total cholesterol (TC) (WMD = −0.48, 95% CI: −0.63 to −0.34, I2= 0.00%) and low-density lipoprotein cholesterol (LDL-C) (WMD = −0.23, 95% CI: −0.45 to −0.02, I2 = 68.27%) among patients with MetS. No significant effects of CAP were found on triglycerides (TG) or high-density lipoprotein cholesterol (HDL-C) (WMD = −0.40, 95% CI: −1.50 to 0.71, I2 = 98.32%; WMD = −0.08, 95% CI: −0.21 to 0.04, I2 = 86.06%). Subgroup analyses indicated that sex and intervention period were sources of heterogeneity. The results revealed that CAP decreased TG levels in women (WMD = −0.59, 95% CI: −1.07 to −0.10) and intervention period &amp;lt;12 weeks (WMD = −0.65; 95% CI: −1.10 to −0.20). And there was no potential publication bias according to funnel plot, Begg' test and Egger regression test.ConclusionsCAP supplementation is a promising approach to decreasing TC and LCL-C levels in patients with MetS. However, short-term (&amp;lt;12 weeks) use of CAP in women may also reduce TG levels.Systematic Review RegistrationIdentifier: CRD42021228032.</jats:sec

Virtual Screening for Potential Allosteric Inhibitors of Cyclin-Dependent Kinase 2 from Traditional Chinese Medicine

Cyclin-dependent kinase 2 (CDK2), a member of Cyclin-dependent kinases (CDKs), plays an important role in cell division and DNA replication. It is regarded as a desired target to treat cancer and tumor by interrupting aberrant cell proliferation. Compared to lower subtype selectivity of CDK2 ATP-competitive inhibitors, CDK2 allosteric inhibitor with higher subtype selectivity has been used to treat CDK2-related diseases. Recently, the first crystal structure of CDK2 with allosteric inhibitor has been reported, which provides new opportunities to design pure allosteric inhibitors of CDK2. The binding site of the ATP-competition inhibitors and the allosteric inhibitors are partially overlapped in space position, so the same compound might interact with the two binding sites. Thus a novel screening strategy was essential for the discovery of pure CDK2 allosteric inhibitors. In this study, pharmacophore and molecular docking were used to screen potential CDK2 allosteric inhibitors and ATP-competition inhibitors from Traditional Chinese Medicine (TCM). In the docking result of the allosteric site, the compounds which can act with the CDK2 ATP site were discarded, and the remaining compounds were regarded as the potential pure allosteric inhibitors. Among the results, prostaglandin E1 and nordihydroguaiaretic acid (NDGA) were available and their growth inhibitory effect on human HepG2 cell lines was determined by MTT assay. The two compounds could substantially inhibit the growth of HepG2 cell lines with an estimated IC50 of 41.223 μmol/L and 45.646 μmol/L. This study provides virtual screening strategy of allosteric compounds and a reliable method to discover potential pure CDK2 allosteric inhibitors from TCM. Prostaglandin E1 and NDGA could be regarded as promising candidates for CDK2 allosteric inhibitors

Inherently anti-metastatic peptide hydrogels for sonodynamic-amplified ferroptosis in cancer therapy

Cancer metastasis remains a significant challenge in oncology, prompting the exploration of innovative biomaterials to enhance treatment efficacy. While many hydrogels only serve as passive carriers, this study presents two novel self-assembling peptides, CWEWTWY and NapFFSGP, which form supramolecular hydrogels with intrinsic anti-metastatic properties. We demonstrate a correlation between the nanofibrous morphology of these peptides and their enhanced anti-metastatic activity, mediated by disruption of F-actin organization and impacting pathways related to cancer cell adhesion and actin filament dynamics. In vivo studies confirm a significant reduction in lung metastasis using a 4T1 pulmonary metastasis model. We also demonstrate their potential as a simple, synergistic platform integrating sonodynamic therapy (SDT) and ferroptosis. Ironporphyrin (FP), incorporated into Gel@FP, acts as both a sonosensitizer and ferroptosis inducer. Upon ultrasound irradiation, FP generates localized reactive oxygen species, further amplifying ferroptosis through enhanced lipid peroxidation. Gel@FP combined with ultrasound demonstrates potent antitumor efficacy in vitro and in vivo, promoting apoptosis, ferroptosis, and immunogenic cell death, leading to enhanced tumor regression and robust immune activation. Our findings highlight the potential of anti-metastatic hydrogels as a promising multifunctional platform to address the challenges of metastasis while enhancing antitumor immunity

Discovery of potential negative allosteric modulators of mGluR5 from natural products using pharmacophore modeling, molecular docking, and molecular dynamics simulation studies

mGluR5, which belongs to the G-protein-coupled receptor superfamily, is believed to be associated with many human diseases, such as a wide range of neurological disorders, gastroesophageal reflux disease, and cancer. Comparing with compounds that target on the orthosteric binding site, significant roles have been established for mGluR5 negative allosteric modulators (NAMs) due to their higher subtype selectivity and more suitable pharmacokinetic profiles. Nevertheless, to date, none of them have come to market for various reasons. In this study, a 3D quantitative pharmacophore model was generated by using the HypoGen module in Discovery Studio 4.0. With several validation methods ultilized, the optimal pharmacophore model Hypo2 was selected to discover potential mGluR5 NAMs from natural products. Two hundred and seventeen potential NAMs were obtained after being filtered by Lipinski’s rule (≥4). Then, molecular docking was used to refine the pharmacophore-based screening results and analyze the binding mode of NAMs and mGluR5. Three compounds, aglaiduline, 5-O-ethyl-hirsutanonol, and yakuchinone A, with good ADMET properties, acceptable Fit value and estimated value, and high docking score, were reserved for a molecular dynamics simulation study. All of them have stability of ligand binding. From our computational results, there might exhibit drug-like negative allosteric moderating effects on mGluR5 in these natural products. This work provides a reliable method for discovering mGluR5 NAMs from natural products. </jats:p