Martinussenschmitt5692

The expression levels of hub gene mRNAs were positively correlated with each other's expression levels. None of the hub genes was correlated with prognosis (P > 0.05). Curcumin significantly inhibited CAL 27 cell proliferation and migration (P less then 0.05), but significantly promoted cell apoptosis (P less then 0.05). Conclusion Curcumin has potential therapeutic effect on treating TC by suppressing cell proliferation and migration, as well as promoting apoptosis through modulating oxygen-related signaling pathways. © 2020 Ma et al.Background Cancer remains the leading cause of human morbidity universally. Hence, we sought to assess the in vitro antiproliferative activity of new isatin-based conjugates (5a-s) against three human cancer cell lines. Methods The antiproliferative activities of compounds 5a-s were evaluated in vitro and their ADME (absorption, distribution, metabolism and excretion) was carried out using standard protocols. Subsequently, Western blot analysis was conducted to elucidate the potential antiproliferative mechanism of compounds 5a-s. Results The in vitro antiproliferative activities of compounds 5a-s against the tested cancer cell lines ranged from 20.3 to 95.9%. Compound 5m had an IC50 value of 1.17 µM; thus, its antiproliferative potency was approximately seven-fold greater than that of sunitinib (IC50 = 8.11 µM). In-depth pharmacological testing was conducted with compound 5m to gain insight into the potential antiproliferative mechanism of this class of compounds. Compound 5m caused an increase in the number of cells in the G1 phase, with a concomitant reduction of those in the G2/M and S phases. Additionally, compound 5m significantly and dose-dependently reduced the amount of phosphorylated retinoblastoma protein detected. Compound 5m enhanced expression of B cell translocation gene 1, cell cycle-associated proteins (cyclin B1, cyclin D1, and phosphorylated cyclin-dependent kinase 1), and a pro-apoptotic protein (Bcl-2-associated X protein gene), and activated caspase-3. ADME predictions exposed the oral liability of compounds 5a-s. Conclusion Herein, we revealed the antiproliferative activity and ADME predictions of the newly-synthesized compounds 5a-s and provided a detailed insight into the pharmacological profile of compound 5m. Thus, compounds 5a-s can potentially be exploited as new antiproliferative lead compounds for cancer chemotherapeutic. © 2020 Al-Wabli et al.Emicizumab is a bispecific, humanized, monoclonal antibody mimicking the factor (F) VIII cofactor activity in mediating the generation of FXa by FIXa in patients with hemophilia A (HA). This subcutaneous non-factor agent has been recently extensively approved for the prophylaxis of patients of HA patients with and without FVIII-inhibitors of all ages, although few data are currently available in children. In Phase 3 clinical trials and case series, emicizumab prophylaxis significantly reduced bleeding rates compared to previous treatment in HA adolescents and children with or without FVIII-inhibitors and was generally well tolerated. In addition, subcutaneous administration of emicizumab provided beneficial effects on health-related quality of life, and lessened the burden of the disease in HA patients as well as in their caregivers. However, additional prospective studies are required to evaluate the long-term safety of emicizumab prophylaxis in very young patients, including previously untreated patients. The aim of this paper was to review the limited data available on the use of emicizumab prophylaxis in children and to highlight the need for further studies to address remaining concerns. © 2020 Le Quellec.Background Metformin has been shown to inhibit the proliferation and migration of vascular wall cells. However, the mechanism through which metformin acts on atherosclerosis (AS) via the long non-coding RNA taurine up-regulated gene 1 (lncRNA TUG1) is still unknown. Thus, this research investigated the effect of metformin and lncRNA TUG1 on AS. Methods First, qRT-PCR was used to detect the expression of lncRNA TUG1 in patients with coronary heart disease (CHD). selleckchem Then, the correlation between metformin and TUG1 expression in vitro and their effects on proliferation, migration, and autophagy in vascular wall cells were examined. Furthermore, in vivo experiments were performed to verify the anti-AS effect of metformin and TUG1 to provide a new strategy for the prevention and treatment of AS. Results qRT-PCR results suggested that lncRNA TUG1 expression was robustly upregulated in patients with CHD. In vitro experiments indicated that after metformin administration, the expression of lncRNA TUG1 decreased in a time-dependent manner. Metformin and TUG1 knockdown via small interfering RNA both inhibited proliferation and migration while promoted autophagy via the AMPK/mTOR pathway in vascular wall cells. In vivo experiments with a rat AS model further demonstrated that metformin and sh-TUG1 could inhibit the progression of AS. Conclusion Taken together, our data demonstrate that metformin might function to prevent AS by activating the AMPK/mTOR pathway via lncRNA TUG1. © 2020 You et al.Background Novel three-layered (TL) tablet systems were compared with both monolithic matrix (MM) formulations and a commercial immediate-release (IR) capsule to develop once-a-day (OAD) pregabalin tablets. Methods The physical properties of the TL tablets, including dissolution and swelling rates, were compared with those of the MM tablets and the pharmacokinetic parameters of the TL tablet were compared with those of an IR capsule in beagles and humans. Results Our results indicated that the same amount of a hydrophilic polymer in the formulations had similar dissolution profiles at 12 h, regardless of the tablet geometry. However, the degree of tablet swelling differed, with larger amounts of polymer in the tablets showing a greater degree of swelling. In addition, TL tablets swelled more rapidly compared with MM tablets. For the pharmacokinetic study of the TL tablet, the beagles demonstrated absorption results similar to those of an IR capsule, whereas the humans demonstrated low total absorption compared with an IR capsule. The time of the peak plasma concentration at 6 h in the fed state of humans coincided with the results of the study on beagles. Conclusion The novel TL tablet system of pregabalin may prove to be helpful in developing improved formulations with better continuous drug absorption for OAD administration. © 2020 Kim et al.Objective To evaluate the pharmacokinetics (PK), bioequivalence and safety profile of the recombinant human chorionic gonadotropin (r-hCG) injection formulation LZM003 (test drug) comparing with that of Ovidrel® (reference drug) in healthy Chinese subjects. Methods This is a randomized, single-blind, single-dose, two-arm and two-period crossover Phase I study. Subjects were randomized evenly to a single dose of LZM003 or reference drug injected subcutaneously, with a 10-day or longer between-treatment washout period. PK parameters, anti-drug antibodies (ADAs), and adverse events (AEs) were assessed. The primary PK endpoints were area under the curve (AUC) of the concentration-time curve from zero to last quantifiable concentration (AUC0-t), AUC from zero to infinity (AUC0-∞), and peak concentration (Cmax). link2 Bioequivalence was determined by assessing whether the 90% confidence intervals (CIs) for the geometric mean ratio (GMR) of LZM003 to reference drug fell within predefined margins of 80% -125%. Results Forty-eight subjects (24 males and 24 females) were enrolled and one subject withdrew for personal reasons. Mean values of primary PK parameters were similar (p > 0.05) between LZM003 and the reference drug. The 90% CIs for primary PK endpoints' GMR of LZM003 to reference drug ranged between 0.9144 and 1.1845, which were within bioequivalence margins of 80-125%. Incidence of AEs was similar (p > 0.05) between the two groups. Neither LZM003 nor reference drug produced anti-drug antibody (ADA) in healthy subjects. Conclusion LZM003 and reference drug were bioequivalent. The PK and safety assessments were similar (p > 0.05) between the two formulations in healthy Chinese subjects. Trial Registration Number ChiCTR-IIR-16010158 (http//www.chictr.org.cn). Trial Registration Date December 15, 2016. © 2020 Wang et al.Background Calycosin (CAL), a type of O-methylated isoflavone extracted from the herb Astralagusmembranaceus (AM), is a bioactive chemical with antioxidative, antiphlogistic and antineoplastic activities commonly used in traditional alternative Chinese medicine. AM has been shown to confer health benefits as an adjuvant in the treatment of a variety of diseases. Aim The main objective of this study was to determine whether CAL influences the cytochrome P450 (CYP450) system involved in drug metabolism. Methods Midazolam, tolbutamide, omeprazole, metoprolol and phenacetin were selected as probe drugs. Rats were randomly divided into three groups, specifically, 5% Carboxymethyl cellulose (CMC) for 8 days (Control), 5% CMC for 7 days + CAL for 1 day (single CAL) and CAL for 8 days (conc CAL), and metabolism of the five probe drugs evaluated using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Results No significant differences were observed for omeprazole and midazolam, compared to the control group. T max and t1/2 values of only one probe drug, phenacetin, in the conc CAL group were significantly different from those of the control group (T max h 0.50±0.00 vs 0.23±0.15; control vs conc CAL). C max of tolbutamide was decreased about two-fold in the conc CAL treatment group (conc vs control 219.48 vs 429.56, P less then 0.001). Conclusion Calycosin inhibits the catalytic activities of CYP1A2, CYP2D6 and CYP2C9. Accordingly, we recommend caution, particularly when combining CAL as a modality therapy with drugs metabolized by CYP1A2, CYP2D6 and CYP2C9, to reduce the potential risks of drug accumulation or ineffective treatment. © 2020 Wu et al.Background Baicalin, a natural product isolated from Scutellaria radix, has been reported to exert anti-oxidant and anti-apoptotic effects on skin, but the underlying mechanism remains poorly understood. This study aimed to investigate the possible mechanism of anti-UVB effect of baicalin in human skin fibroblasts. Methods Cell proliferation was estimated by CCK-8 Kit. Apoptotic incidence was detected by flow cytometry with Annexin V-PE/PI apoptosis detection kit. Autophagy was determined by the evaluation of fluorescent LC3 puncta and Western blotting. Cell signalling was analysed by Western blotting. link3 Results Baicalin exerted cytoprotective effects in UVB-induced HSFs. Moreover, baicalin increased autophagy and suppressed UVB-induced apoptosis of HSFs. Pretreatment with 3-MA, an autophagy inhibitor, attenuated baicalin-induced HSFs autophagy and promoted apoptosis. Baicalin activated AMPK, which leads to suppression of basal mTOR activity in cultured HSFs. Administration of compound C, an AMPK inhibitor, abrogated AMPK phosphorylation and increased mTOR phosphorylation and apoptosis compared with baicalin alone. Conclusion Taken together, these results indicate the important role of mTOR inhibition in UVB protection by baicalin and provide a new target and strategy for better prevention of UV-induced skin disorders. © 2020 Zhang et al.