An integrated network pharmacology and molecular docking approach to reveal the role of Arctigenin against Cutibacterium acnes-induced skin inflammation by targeting the CYP19A1.

Acne caused by inflammation of hair follicles and sebaceous glands is a common chronic skin disease. Arctigenin (ATG) is an extract of Arctium lappa L., which has significant anti-inflammatory effects. However, the effect and mechanism of ATG in cutaneous inflammation mediated by Cutibacterium acnes (C. acnes) has not been fully evaluated. The purpose of this study was to explore the effect and potential mechanism of ATG in the treatment of acne through network pharmacology and experimental confirmation. An acne model was established by injected live C. acnes into living mice and treated with ATG. Our data showed that ATG effectively improved acne induced by live C. acnes, which was confirmed by determining ear swelling rate, estradiol concentration and hematoxylin and eosin (H&E) staining. In addition, ATG inhibited the NLRP3 inflammasome signaling pathway in mice ear tissues and reduced the secretion of pro-inflammatory cytokines IL-1ß to relieve inflammation. The results of network pharmacology and molecular docking confirmed that ATG can regulate 17ß-Estradiol (E2) levels through targeted to CYP19A1, and finally inhibited skin inflammation. Taken together, our results confirmed that ATG regulated E2 secretion by targeting CYP19A1, thereby inhibiting the NLRP3 inflammasome signaling pathway and improving inflammation levels in acne mice. This study provides a basis for the feasibility of ATG in treating acne in clinical practice.

Phase Identification and Discovery of an Elusive Polymorph of Drug-Polymer Inclusion Complex Using Automated 3D Electron Diffraction.

3D electron diffraction (3D ED) has shown great potential in crystal structure determination in materials, small organic molecules, and macromolecules. In this work, an automated, low-dose and low-bias 3D ED protocol has been implemented to identify six phases from a multiple-phase melt-crystallisation product of an active pharmaceutical ingredient, griseofulvin (GSF). Batch data collection under low-dose conditions using a widely available commercial software was combined with automated data analysis to collect and process over 230 datasets in three days. Accurate unit cell parameters obtained from 3D ED data allowed direct phase identification of GSF Forms III, I and the known GSF inclusion complex (IC) with polyethylene glycol (PEG) (GSF-PEG IC-I), as well as three minor phases, namely GSF Forms II, V and an elusive new phase, GSF-PEG IC-II. Their structures were then directly determined by 3D ED. Furthermore, we reveal how the stabilities of the two GSF-PEG IC polymorphs are closely related to their crystal structures. These results demonstrate the power of automated 3D ED for accurate phase identification and direct structure determination of complex, beam-sensitive crystallisation products, which is significant for drug development where solid form screening is crucial for the overall efficacy of the drug product.

Molecular Dynamics Beyond the Monolayer Adsorption as Derived from Langmuir Curve Fitting.

Langmuir adsorption model is a classic physical-chemical adsorption model and is widely used to describe the monolayer adsorption behavior at the material interface in environmental chemistry. Traditional adsorption dynamic modeling solely considered the surface physiochemical interaction between the adsorbent and adsorbate. The surface reaction dynamics resulting from the heterogeneous surface and intrinsic electronic structure of absorbents were rarely considered within the reported adsorption experiments. Herein, by employing the chlorine hybrid graphene oxide (GO-Cl) to adsorb Ag+ in an aqueous solution, complicated molecular dynamics significantly deviated from the monolayer adsorption mechanism, as suggested by Langmuir adsorption curve fitting, has been elucidated down to atomic scale. In the time-dependent Ag adsorption experiments, both Ag single atoms and Ag/AgCl nanoparticle heterostructures are observed to be formed sequentially on GO-Cl. These observations indicate that for the surface adsorption dynamics, not only the surface chemical adsorption process involved but also photoreduction and the C-Cl bond cleavage reaction has been heavily engaged within the GO-Cl interface, suggesting a much more complicated vision rather than the monolayered adsorption algorithm as derived from curve fitting. This study uses GO-Cl as a simple example to disclose the complicated adsorption dynamic process underneath Langmuir adsorption curve fitting. It advocates the necessity of imaging the interfacial atomic-scale dynamic structure with high-resolution microscopy techniques in modern adsorption studies, rather than simply explaining the adsorption dynamics relying on the curve fitting results due to the complicated physiochemical reactivity of the adsorbents.

Pseudoginsenoside-F11 attenuates cognitive impairment by ameliorating oxidative stress and neuroinflammation in d­galactose-treated mice.

Oxidative stress and neuroinflammation are thought to be the two key early events during the process of mild cognitive impairment (MCI). Therefore, effective regulation of oxidative stress and neuroinflammation is an important aspect of preventing and improving MCI. We previously found that pseudoginsenoside-F11 (PF11), an ocotillol-type saponin, markedly reduced cognitive impairment in APP/PS1 mice and oAß1-42-injected mice. In the present study, we further evaluate the effect of PF11 on learning and memory dysfunction in d­galactose (d­gal)-treated mice model of MCI. C57BL/6 mice received daily subcutaneous injections of d­gal (100 mg/kg) and oral administration of PF11 (2, 4, 8, 16 mg/kg) for 9 weeks. We observed that PF11 significantly alleviated d­gal-induced cognitive impairment, attenuated the loss of neuron and the over-activation of microglia in hippocampus of d­gal-treated mice. The elevated levels of nod-like receptor protein 3 (NLRP3) inflammasome in hippocampus of d­gal-treated mice were reduced by PF11 through reducing the accumulation of advanced glycation endproducts (AGEs) and the expression of the receptor of advanced glycation endproducts (RAGE). Moreover, PF11 significantly decreased H2O2 and malondialdehyde (MDA) levels, improved superoxide dismutase (SOD) activity and increased glutathione (GSH) level in d­gal-treated mice. Finally, d­gal treatment reduced the level of nuclear factor erythroid-related factor 2 (Nrf2) and glutathione S-transferase (GST) in hippocampus, which could reverse by PF11. Together, our findings indicated that PF11 exerts a protective effect against MCI-like pathological changes.

Neuronal-targeted TFEB rescues dysfunction of the autophagy-lysosomal pathway and alleviates ischemic injury in permanent cerebral ischemia.

Mounting attention has been focused on defects in macroautophagy/autophagy and the autophagy-lysosomal pathway (ALP) in cerebral ischemia. TFEB (transcription factor EB)-mediated induction of ALP has been recently considered as the common mechanism in ameliorating the pathological lesion of myocardial ischemia and neurodegenerative diseases. Here we explored the vital role of TFEB in permanent middle cerebral artery occlusion (pMCAO)-mediated dysfunction of ALP and ischemic insult in rats. The results showed that ALP function was first enhanced in the early stage of the ischemic process, especially in neurons of the cortex, and this was accompanied by increased TFEB expression and translocation to the nucleus, which was mediated at least in part through activation by PPP3/calcineurin. At the later stages of ischemia, a gradual decrease in the level of nuclear TFEB was coupled with a progressive decline in lysosomal activity, accumulation of autophagosomes and autophagy substrates, and exacerbation of the ischemic injury. Notably, neuron-specific overexpression of TFEB significantly enhanced ALP function and rescued the ischemic damage, starting as early as 6 h and even lasting to 48 h after ischemia. Furthermore, neuron-specific knockdown of TFEB markedly reversed the activation of ALP and further aggravated the neurological deficits and ischemic outcome at the early stage of pMCAO. These results highlight neuronal-targeted TFEB as one of the key players in the pMCAO-mediated dysfunction of ALP and ischemic injury, and identify TFEB as a promising target for therapies aimed at neuroprotection in cerebral ischemia. Abbreviations: AAV, adeno-associated virus; AIF1/IBA1, allograft inflammatory factor 1; ALP, autophagy-lysosomal pathway; CQ, chloroquine; CTSB, cathepsin B; CTSD, cathepsin D; CsA, cyclosporin A; GFAP, glial fibrillary acidic protein; LAMP, lysosomal-associated membrane protein; LC3, microtubule-associated protein 1 light chain 3; MAP2, microtubule-associated protein 2; mNSS, modified Neurological Severity Score; MTOR, mechanistic target of rapamycin kinase; OGD, oxygen and glucose deprivation; pMCAO, permanent middle cerebral artery occlusion; RBFOX3/NeuN, RNA binding fox-1 homolog 3; SQSTM1, sequestosome1; TFEB, transcription factor EB; TTC, 2,3,5-triphenyltetrazolium chloride.

MOF-Derived Porous Ni2P/Graphene Composites with Enhanced Electrochemical Properties for Sensitive Nonenzymatic Glucose Sensing.

Herein, we report a high-performance electrocatalyst by orientationally growing Ni2P nanoparticles in situ on graphene film (Ni2P/G) for nonenzymatic glucose sensors in alkaline media. The combination of highly active Ni2P and stable graphene film with rapid conductivity enables this composite to display excellent electrochemical activity toward glucose with enhanced electron transfer rate and steadiness. With Ni-MOF-74 as a precursor, Ni2P/G showed even metal distribution, massive exposure of active sites, and spatially ordered structure. Benefiting from the synergistic reaction of Ni2P particles and graphene, this metal-organic frameworks (MOF)-derived composite exhibited high electrocatalytic activity and specificity toward glucose electrooxidation. Under optimized conditions, a wide linear response was obtained from 5 µM to 1.4 mM with a detection limit of 0.44 µM. Furthermore, an excellent linear response ( R2 = 0.9897) was also obtained by a Ni2P/G modified electrode in human serum with the concentration of glucose ranging from 1 to 8 mM, indicating that the Ni2P/G platform could be utilized for glucose monitoring in practical life.

Phosphomolybdic acid functionalized graphene loading copper nanoparticles modified electrodes for non-enzymatic electrochemical sensing of glucose.

A sensitive non-enzymatic glucose electrochemical biosensor (Cu/PMo12-GR/GCE) was developed based on the combination of copper nanoparticles (CuNPs) and phosphomolybdic acid functionalized graphene (PMo12-GR). PMo12-GR films were modified on the surface of glassy carbon electrode (GCE) through electrostatic self-assembly with the aid of poly diallyl dimethyl ammonium chloride (PDDA). Then CuNPs were successfully decorated onto the PMo12-GR modified GCE through electrodeposition. The morphology of Cu/PMo12-GR/GCE was characterized by scanning electron microscope (SEM). Cyclic voltammetry (CV) and chronoamperometry were used to investigate the electrochemical performances of the biosensor. The results indicated that the modified electrode displayed a synergistic effect of PMo12-GR sheets and CuNPs towards the electro-oxidation of glucose in the alkaline solution. At the optimal detection potential of 0.50 V, the response towards glucose presented a linear response ranging from 0.10 µM to 1.0 mM with a detection limit of 3.0 × 10(-2) µM (S/N = 3). In addition, Cu/PMo12-GR/GCE possessed a high selectivity, good reproducibility, excellent stability and acceptable recovery, which indicating the potential application in clinical field.