BRD4 plays an indispensable role in cell cycle regulation, affecting processes such as cell proliferation, apoptosis and transcription. In this article, a three‐dimensional quantitative ...conformational relationship (3D‐QSAR) was used to investigate the molecular simulations related to 45 tetrahydrooxazole BRD4/BD2 selective inhibitors. 3D‐QSAR models were developed based on two different analytical methods, COMFA and COMSIA. All CoMSIA field combinations were compared together and the best CoMSIA model was selected based on external validation and model prediction results. Both CoMSIA (S+E+H+D (q2=0.808, r2=0.99)) and CoMFA models (q2=0.779;,r2=0.962) predicted the internal and external well. Twenty small molecules with higher inhibitory activity than the template compound were designed by 3D‐QSAR model prediction and quantum chemistry analysis, screened by molecular docking and ADMET methods, and five novel compounds were found to have better predicted activity and binding affinity. Molecular dynamics simulations showed that PRO70, PRO371, TYR428, ASN429 and VAL435 are important residues that can interact with the ligands. Moreover, further structural optimization of the more active candidate compounds will provide an essential theoretical basis of the synthesis and design of novel BRD4/BD2 inhibitors.
Then, as shown in Figure, we compared the interactions before and after MD simulations, and then by analyzing the last 10 ns simulations of compounds D1‐D5, we found that in protein and small molecule processes, the compound forms a strong hydrogen bond with 43 newly designed small molecules and the BRD4 protein ASN429, shown by a dotted line on a green label. In addition, kinetic simulations show that compounds D1 and D3 interact with protein complex CYS425 from van der Waals to hydrogen bonding. Similarly, D2 forms a hydrogen bond with an amino acid residue (TYR386) and its kinetics is simulated.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Cerebral ischemia reperfusion injury (CIRI) is still a serious problem threatening human health. Salidroside (SAL) is a natural phenylpropanoid glycoside compound with antioxidant, anti-inflammatory, ...and anti-ischemic properties. This study investigated the protective mechanism of SAL on middle cerebral artery occlusion (MCAO)- and oxygen-glucose deprivation/reoxygenation (OGD/R) model-induced CIRI via regulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/thioredoxin 1 (Trx1) axis. The results indicated that SAL (50 mg/kg or 100 mg/kg, intraperitoneal injection) not only effectively alleviated infarction rate, improved histopathological changes, relieved apoptosis by strengthening the suppression of cleaved caspase-3 and Bax/Bcl-2 proteins and decreased malondialdehyde (MDA) formation, but also increased superoxide dismutase (SOD) and catalase (CAT) activities and upregulated the expressions of Nrf2 and Trx1 on MCAO-induced CIRI rats. SAL also efficiently inhibited apoptosis and decreased oxidative stress in OGD/R-stimulated PC12 cells. Furthermore, blocking the Nrf2/Trx1 pathway using tretinoin, an Nrf2 inhibitor, significantly reversed the protective effect of SAL on OGD/R-induced oxidative stress. Moreover, SAL reduced the expression of apoptosis signal-regulating kinase-1 (ASK1) and mitogen-activated protein kinase (MAPK) family proteins. These results demonstrated that SAL inhibited oxidative stress through Nrf2/Trx1 signaling pathway, and subsequently reduced CIRI-induced apoptosis by inhibiting ASK1/MAPK.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Herein, we aim to investigate the effect of Alpinae Oxyphyllae Fructus (AOF) on cognitive impairments and neuroinflammation in a lipopolysaccharide (LPS)‐induced models of AD. Mice were injected ...intracerebroventricularly with LPS, and then administrated AOF using a gavage for 6 weeks. Spatial working memory was assessed using the Y‐maze and Morris water maze test, whereas the levels of PI3K, AKT, p‐AKT, p‐GSK3β, GSK3β, NF‐κB, IL‐1β, IL‐6, and TNF‐α were evaluated using western blot and ELISA assay. Our data showed that AOF was able to significantly alleviate the memory decline in LPS‐induced AD mice. Moreover, AOF was able to protect neurons through the PI3K/AKT signaling pathway and significantly decrease NF‐κB, IL‐6, IL‐1β, and TNF‐α levels in the hippocampal and cortex tissues, which were reversed through the use of LY294002. Additionally, we discovered that AOF could significantly decrease the high expression of cytokines as well as the expression and translocation of NF‐κB induced by LPS in PC12 cells. These results demonstrate the anti‐neuroinflammatory effect of AOF in both cell and animal models of AD, thereby slowing down the process and development of the disease.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by a disorder of both the motor and nonmotor systems due to a loss of dopaminergic (DA) neurons. Herein, we aimed to ...investigate the potential neuroprotective role of Schisandra chinensis (Sch) and to determine the mechanism by which Sch functions to ameliorate PD in a 6-hydroxydopamin (6-OHDA)-induced PD model. The open field test, sucrose preference test, and Y-maze test were utilized to evaluate the motor and nonmotor symptoms. We found that administration of Sch improved both disorders and DA neurodegeneration in 6-OHDA-induced mice. Additional data confirmed that Sch treatment significantly increased BDNF expression and decreased the activity of GSK-3β in the striatum and hippocampus. Moreover, Sch was able to alleviate the abnormal levels of ROS and increase SOD by boosting Nrf2 expression. The nuclear translocation of NF-κB was inhibited by Sch, which subsequently led to a downregulation of proinflammatory cytokines. Sch effectively suppressed apoptosis by decreasing expressions of caspase 3, caspase 9, and p53 in the PD mouse model. Our findings demonstrate that Sch protects against DA neurodegeneration in 6-OHDA-induced PD mice by suppressing oxidative stress, neuroinflammation and apoptosis through the involvement of the BDNF/Nrf2/NF-κB signaling pathway.
Background. In daily inspection, the nonstandard management of sterile articles in clinical departments of hospitals often leads to the destruction of the sterilization effectiveness of sterile ...articles. Therefore, it is necessary to strengthen governance and improve this phenomenon. This study intends to investigate the mode in which the disinfection supply center participates in the supervision and management of the management of sterile items in clinical departments. It played a role in improving the standardization of the management of sterile articles in clinical departments and ensured the closed-loop management of the sterilization effectiveness of sterile articles. Methods. Every quarter, the disinfection supply center of our hospital will inspect the standardized management of sterile articles in all clinical departments of the hospital, mainly including the storage environment and facilities of sterile articles, the cleanliness of storage cabinets, placement principles, whether they are stored by category, and the quality and validity management of sterile articles. The quarterly inspection results were summarized and analyzed to find the existing problems and the causes. The disinfection supply center shall supervise the improvement. After the disinfection supply center inspected the standardized management of sterile articles in all clinical departments of the hospital for the first time according to the inspection contents, under the guidance and assistance of the nursing department and the hospital infection department, it improved the sterile article management system, conducted knowledge training for the whole hospital, and incorporated the standardized management of clinical sterile articles into the quality control inspection of the nursing department. In the later stage, the disinfection supply center is responsible for conducting routine inspection and supervision on the standardized management of sterile articles in all clinical departments of the hospital every quarter according to the inspection contents, including summarizing, analyzing, and urging the clinical departments to achieve the improvement of the management of sterile articles in clinical departments. Results. The standardization of aseptic articles after improvement was significantly higher than before and during improvement, and the qualified rate was significantly different (99.4% vs 97.9% vs 89.5%, P<0.05). The average number of lost packages caused by nonstandard management in the department was significantly reduced. The average rate of lost sterile packages during and after the improvement was significantly lower than that before the improvement (10.5% vs 97.9% vs 89.5%, P<0.05). It also effectively reduced the cost caused by the loss of sterile packages. Conclusion. The disinfection supply center participates in the quality control and management of sterile articles in the nursing department and regularly inspects and supervises the management of sterile articles in clinical departments. It can effectively improve the standardized management of sterile articles in clinical departments, ensure the safety of sterile articles, and form a closed loop of sterilization effectiveness.
Full text
Available for:
DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
5-Hydroxymethylfurfural (5-HMF) is a main effective compound of Alpinia oxyphylla Miq. ethanol extract, which showed memory improvement activity against Alzheimer's disease in previous study. In ...order to identify a potential therapeutic agent, the neuroprotective effects of 5-HMF on impairment of cognition and memory function induced by intracerebroventricular (ICV) injection of Aβ1–42 were investigated in vivo. The mice were treated with 5-HMF at dose of 15μg/kg and 150μg/kg (ICV) for five consecutive days after ICV-Aβ1–42. The results showed that 5-HMF significantly ameliorated learning and memory impairment evaluated by the locomotor activity, Y-maze test, and Morris water maze test. Furthermore, 5-HMF significantly inhibited the β-secretase activity, decreased the content of Aβ1–42 and malondialdehyde (MDA), and increased the antioxidative enzyme activities including superoxide dismutase (SOD) and glutathione peroxidase (GPx). Results of hippocampus slices showed that neuronal were integrated and regularly arranged in the groups which were administered along with 5-HMF, indicating that 5-HMF could mitigate the degree of neuronal damage. The present study indicated that 5-HMF may serve as a potential therapeutic agent for the treatment of Alzheimer's disease.
•We authenticated that 5-HMF has neuroprotective effects firstly.•5-HMF decreased the escape latency in Morris water maze test.•5-HMF attenuated the level of Aβ and β-secretase.•5-HMF reduced oxidative stress levels through SOD, GPx, and MDA.•The feasibility of ventricle-implanted cannula system was verified.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A series of novel and efficient Sr2GdNbO6 (SGNO):Mn4+ red phosphors were synthesized by traditional high-temperature solid-state method. The composition, morphology, luminescent properties and ...thermal quenching mechanism of the materials were studied by X-ray diffraction (XRD), field emission electron scanning microscopy (FE-SEM), ultraviolet–visible diffuse reflectance (UV–vis DR) spectroscopy and fluorophotometer. The phosphors can be excited by 300–500 nm light and emit a deep-red light. The characteristic emission band peaked at 687 nm corresponds to the spin-forbidden transition of Mn4+. The temperature-dependent on photoluminescence (PL) emission spectra from 298 K to 498 K manifest that SGNO:Mn4+ phosphor has an activation energy of 0.412 eV, which confirms the excellent thermal stability of the phosphor. Moreover, the IQE value of SGNO:Mn4+ phosphor is 36.37%. The above results illustrated that SGNO:Mn4+ phosphors are expected to make a contribution to indoor plant cultivation.
•Sr2GdNbO6:Mn4+ deep-red emitting phosphors were prepared.•SGNO:Mn4+ phosphor can be excited by 300–500 nm light and emit a deep-red light.•SGNO:Mn4+ phosphors are suitable for indoor plant growth lighting.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The fruits of Schisandra chinensis have been used for the treatment of insomnia in oriental countries for more than thousands of years. However, the pharmacological properties and the mechanism of ...sedative and hypnotic effects have not yet been studied. Gomisin N is one of the major bioactive constituents from the fruits of Schisandra chinensis, and in this paper we reported a detailed study on the effects and mechanisms of Gomisin N on its sedative and hypnotic activity for the first time. These results implied that Gomisin N possessed weak sedative effects on locomotion activity in normal mice, and produced a dose-dependent(5–45mg/kg, i.p.) increase in sleep duration in pentobarbital-treated mice, thus, itself did not induce sleep at higher dose which was used in this experiment (45mg/kg, i.p.). It also can reverse the rodent models of insomnia induced by p-chlorophenylalanine (PCPA) and caffeine, which could exhibit a synergistic effect with 5-hydroxytryptophan (5-HTP) as well; furthermore, the hypnotic effects of Gomisin N were inhibited by flumazenil (a specific GABAA-BZD receptor antagonist). Altogether, these results indicated that Gomisin N produced beneficial sedative and hypnotic bioactivity, which might be mediated by the modification of the serotonergic and GABAergic system.
Display omitted
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
PDF
