Anti-ROS and NIR-II-Responsive Hyaluronic Acid Microneedle Loaded With Baicalin Nanoparticles for Treatment of Psoriasis.

In this work, a natural medicine, baicalin, is designed for the treatment of psoriasis with the aid of hyaluronic acid (HA)-based MNs patches. This is also to improve the solubility of baicalin and increase its residence time in infected part, which is made into nanoparticles by complexation with humic acid and Eu2+. The baicalin nanoparticles loaded-MNs exhibit satisfactory rigidity, minimum injury, and controlled drug delivery. The anti-reactive oxygen species (anti-ROS) and anti-inflammatory action are verified by the effective scavenging oxygen and nitrogen radicals. In addition, the loading of baicalin nanoparticles brings remarkable photothermic effect to the MNs, enabling the device to release a controlled drug under near-infrared region II (NIR-II) laser irradiation. With the aid of NIR-II laser, the baicalin-mediated treatment of psoriasis is significantly improved by expediting radical scavenging and suppressing inflammation. The design of baicalin MNs provides a new idea for the treatment of chronic disease.

RASgrf1, a Potential Methylatic Mediator of Anti-epileptogenesis?

Epileptogenesis, induced by status epilepticus (SE), is a chronic process, and intervention in this progress may prevent chronic epilepsy. It has been proposed that DNA methylation might be related with epileptogenesis. RASgrf1 has a differentially methylated region at the promoter which can silence gene expression. We have previously observed the down-regulation of RASgrf1 in epilepsy patients and proved that hypermethylation of RASgrf1 reaches maximal level at the latent period in mice after kainate-induced SE (KA mice), with corresponding alteration of RASgrf1 expression. In the present study, N-phthalyl-L-tryptophan (RG108), a DNA methyltransferase inhibitor, was applied in KA mice at latent phase and the behavior, electroencephalogram and pathological changes were observed in chronic phase. Methylation and expression of RASgrf1 were determined by polymerase chain reaction (PCR), western blotting, and bisulfite sequencing PCR. The results showed that the incidence of spontaneous recurrent seizures (SRS) was significantly lower in the RG108 group than the normal saline (NS) group. Subgroup analysis showed significant hypermethylation and lower expression of RASgrf1 in the RG108-SRS subgroup and the NS-SRS subgroup but not in the RG108-NSRS (no SRS) subgroup and the NS-NSRS subgroup compared with the control group. No significant difference was found between the RG108-SRS and NS-SRS subgroups. Meanwhile, hippocampal neuronal loss was observed in RG108-SRS and NS-SRS subgroups. We thus demonstrated that RG108 could modify the progression of epileptogenesis after KA induced SE and prevent chronic epilepsy. Meanwhile, hypermethylation of RASgrf1 after KA induced SE could be reversed with corresponding changes of RASgrf1 expression. Additionally, we speculated that RASgrf1 might be a potential epigenetic mediator in epileptogenesis and chronic epilepsy.

Preventive Effect of Raw Liubao Tea Polyphenols on Mouse Gastric Injuries Induced by HCl/Ethanol via Anti-Oxidative Stress.

Liubao tea is a type of traditional Chinese tea, belonging to the dark teas. This study is a basic research of the contained polyphenols (active substances) and detected preventive effects of polyphenols of raw Liubao tea (PRLT) on mouse gastric injuries induced by HCl/ethanol. High-pressure liquid chromatography was used to analyze the components of PRLT. Furthermore, a mouse gastric injury model was established to observe the preventive effects. PRLT was shown to contain gallic acid, EGC (epigallocatechin), catechin, caffeine, EC (epicatechin), EGCG (epigallocatechin gallate), GCG (gallocatechin gallate), and ECG (epicatechin gallate). The results of the in vivo study indicate that PRLT can inhibit the observed increase of gastric juice volume and decrease of gastric juice pH caused by gastric injury. PRLT can decrease the serum levels of IL-6 (interleukin-6), IL-12 (interleukin-12), TNF-α (tumor necrosis factor-α), and IFN-γ (interferon-γ) in mice with gastric injuries. Moreover, it can also increase the serum levels of SS (somatostatin) and VIP (vasoactive intestinal peptide) and reduce the serum levels of both SP (substance P) and ET-1 (endothelin-1). PRLT was also shown to increase SOD (superoxide dismutase) and GSH (glutathione) levels and decrease MDA (malondialdehyde) level. The detection of mRNA and protein in gastric tissues indicates that PRLT could also up-regulate the expression of Cu/Zn-SOD (copper/zinc superoxide dismutase), Mn-SOD (manganese superoxide dismutase), CAT (catalase), nNOS (neuronal nitric oxide synthase), and eNOS (endothelial nitric oxide synthase) and down-regulate the expression of both iNOS (inducible nitric oxide synthase) and COX-2 (cyclooxygenase-2). Thus, PRLT possess a good preventive effect on gastric injury, which is directly related to the contained active substance. PRLT show good anti-oxidative and preventive effect in gastric injury and offer promising application value.

Upregulated dynamin 1 in an acute seizure model and in epileptic patients.

Dynamin 1 is a neuron-specific guanosine triphosphatase (GTPase) that is an essential component of membrane fission during synaptic vesicle recycling and endocytosis. This study evaluated the dynamin 1 expression pattern in the acute lithium-pilocarpine rat model and in patients with temporal lobe epilepsy (TLE) and investigated whether altering the dynamin 1 expression pattern affects epileptic seizures in vivo and in vitro. The immunofluorescence, western blot analysis, and reverse transcription-PCR results show that the dynamin 1 expression level increased significantly in experimental rats from day 1 to day 7 after the onset of seizures and was significantly higher in TLE patients. The behavioral study revealed that inhibiting dynamin 1 increased the latency time of the first seizure and decreased the frequency and severity of the seizures. In addition, electrophysiological recordings from brain slices showed that inhibiting dynamin 1 reduces the frequency of Mg-free induced seizure-like activity. The anticonvulsant effect of dynasore was more effective at 10 µM than at 1 µM or 160 µM. These results indicate that the altered level of dynamin 1 may contribute to the development of epileptic seizures and that the targeted regulation of dynamin 1 activity may control epileptic seizures.

Polymer homologue-mediated formation of hydrogel microneedles for controllable transdermal drug delivery.

Poly(ethylene glycol) diacrylate (PEGDA) microneedles (MNs) are hydrogel-based devices that achieve controlled drug delivery kinetics by adjusting the crosslinking density. However, the biosafety of many crosslinking agents used to regulate crosslinking density is not ideal. To avoid crosslinking agents and simplify the preparation process, using two types of polymer homologues with different number-average molecular weights, we have successfully developed a series of PEGDA MNs with controllable crosslinking density (abbreviated as TP-X MNs). The research showed that the mechanical properties and drug release behavior of TP-X MNs could be tuned by simply controlling the weight proportion of two different PEGDA components in MNs. Ex vivo drug delivery experiments indicated that all TP-X MNs exhibited a sustained release profile, and their control range of 336-hour accumulative release rates was from 6.24% to 40.93%. Moreover, we prepared a novel dual-layer PEDGA MN, which can customize the drug loading and release rate in each layer of MN. This work demonstrates a new way to develop hydrogel MNs with adjustable crosslink density and broadens the applications of PEGDA MN in the biomedical field.

Spiderweb-Shaped Iron-Coordinated Polymeric Network as the Novel Coating on Microneedles for Transdermal Drug Delivery Against Infectious Wounds.

Coated microneedles (CMNs) are a minimally invasive platform for immediate-release transdermal drug delivery. However, the practical applications of CMNs have been significantly hindered by the challenges associated with complex formulations, single function, and limited drug loading capacity. This study has developed a spiderweb-shaped iron-coordinated polymeric nanowire network (Fe-IDA NWs). The resulting Fe-IDA NWs are endowed with a certain viscosity due to the synergy of multiple supramolecular interactions. This allows them to replace traditional polymeric thickeners as microneedle coatings. The Fe-IDA NWs-coated microneedles (Fe-IDA MNs) display rapid disintegration in the skin model, which also enables the swift diffusion of Fe-IDA NWs and their payloads into the deeper skin layers. Additionally, Fe-IDA MNs exhibit desirable enzymatic activity and potential antibacterial ability. Thus, Fe-IDA MNs can enhance the therapeutic efficacy against wound infection through synergistic effects, and avoid the overly complicated formulation and the release of nontherapeutic molecules of conventional CMNs. As a proof-of-concept, Fe-IDA MNs loaded with chlorin e6 showed a synergistic chemodynamic-photodynamic antibacterial effect in a methicillin-resistant Staphylococcus aureus-infected wound model in mice. Collectively, this work has significant implications for the future of CMNs-based transdermal drug delivery systems and expands the application fields of metal coordination polymer (MCP) materials.

Knowledge development visualization and mapping path of the psychological capital research.

With the respect to the key factors, namely the psychological state of individuals and organizations, psychological capital (PsyCap) is widely used in various fields, such as management decisions and organizational behavior. To fully show the related studies and their knowledge development and mapping path, in this paper, we examine 2,786 papers about the PsyCap related research from 1970 to 2021. Based on the bibliometric analysis and main path demonstration (the tools are Cite-Space and Pajke, respectively), we derive some conclusions as follows: (1) the publication number about the PsyCap study is growing rapidly and it is a highly cross-cutting research topic. (2) The main authors come from Australia, the United States, and China, and also are the core researchers. (3) Refinement and measurement in the PsyCap study are constant and hot topics. (4) Stress, performance and well-being issues among students, health care workers and corporate employees are core research themes, and team organization, creativity, innovation, and COVID-19 are hot topics in this field. The bibliometric analysis are quantitatively analyzed to provide scholars with a more comprehensive insight into PsyCap research. The main path demonstration helps scholars to understand the main lines and key nodes of development in the field of psychological capital.

Dephospho-dynamin 1 coupled to activity-dependent bulk endocytosis participates in epileptic seizure in primary hippocampal neurons.

BACKGROUND AND PURPOSE: Epilepsy is a severe neurological and mental disorder, and not all patients adequately respond to the current treatments. Dynamin 1 plays a key role in synaptic endocytosis and the modulation of neurological function. MATERIAL AND METHODS: Cultured hippocampal neurons were used in the study. First, the viability of neurons was determined by the CCK-8 assay after culturing in magnesium-free medium, DMSO, dynasore (dynamin agonist), and PIP2 (dynamin antagonist). Then, the effect of dynasore on seizure activity was evaluated. Next, we tested the levels of phospho-dynamin 1/total dynamin 1 and dynamin 1 mRNA in the control group and four epilepsy groups. Moreover, the uptake of tetramethylrhodamine-dextran in the different groups was measured. RESULTS: Dephospho-dynamin 1 expression was significantly increased in hyperexcitable neurons, while there was no change in total dynamin 1 level. The level of dephospho-dynamin 1 in hyperexcitable neurons was reduced when cultured with dynasore but increased with PIP2 treatment. Activity-dependent bulk endocytosis (ADBE) was upregulated in hyperexcitable neurons. Along with a decrease in dephospho-dynamin 1 level, ADBE was also downregulated with dynasore treatment, while PIP2 did not affect ABDE. The close link between the dephosphorylation status of dynamin 1 and ADBE suggests that ADBE activation depends on dynamin 1 dephosphorylation. CONCLUSION: Dephospho-dynamin 1 triggers ADBE to meet the requirements of high-frequency discharges during epileptic seizures.

Self-Assembling Porphyrins as a Single Therapeutic Agent for Synergistic Cancer Therapy: A One Stone Three Birds Strategy.

Combining photodynamic therapy (PDT), chemodynamic therapy (CDT), and ferroptosis is a valuable means for an enhanced anticancer effect. However, traditional combination of PDT/CDT/ferroptosis faces several hurdles, including excess glutathione (GSH) neutralization and preparation complexity. In this work, a versatile multifunctional nanoparticle (HCNP) self-assembled from two porphyrin molecules, chlorin e6 and hemin, is developed. The as-constructed HCNPs exhibit a peroxidase-mimic catalytic activity, which can lead to the in situ generation of endogenous O2, thereby enhancing the efficacy of PDT. Furthermore, the generation of hydroxyl radicals (•OH) in the tumor environment in reaction to the high level of H2O2 and the simultaneous disruption of intracellular GSH endow the HCNPs with the capacity of enhanced CDT, resulting in a more effective therapeutic outcome in combination with PDT. More importantly, GSH depletion further leads to the inactivation of GSH peroxide 4 and induced ferroptosis. Both in vitro and in vivo results showed that the combination of PDT/CDT/ferroptosis realizes highest antitumor efficacy significantly under laser irradiation. Therefore, by integrating the superiorities of O2 and •OH generation capacity, GSH-depletion effect, and bioimaging into a single nanosystem, the HCNPs are a promising single therapeutic agent for tumor PDT/CDT/ferroptosis combination therapy.

A natural polysaccharide mediated MOF-based Ce6 delivery system with improved biological properties for photodynamic therapy.

Chlorin e6 (Ce6) is a second generation photosensitizer for photodynamic therapy (PDT). However, free Ce6 still has some defects leading to reduced clinical efficacy, such as easy agglomeration in a physiological environment and poor accumulation in tumor tissue. In order to solve these problems, a hyaluronic acid (HA) modified zeolitic imidazolate framework-8 (ZIF-8) based Ce6 (ZIF-8@Ce6-HA) therapeutic agent is constructed for PDT by one-pot encapsulation and self-assembly. ZIF-8@Ce6-HA exhibits acceptable encapsulation efficiency, effective cell uptake and good biocompatibility. Moreover, the results of in vitro anticancer experiments demonstrated that the ZIF-8@Ce6-HA group exhibited greater cytotoxicity after irradiation than the free Ce6 group, which caused about 88.4% of HepG2 cells to die since ROS is produced by PDT. Additionally, the data of inductively coupled plasma mass spectrometry indicated that modification of HA increased the blood circulation time and reduced the systemic toxicity of ZIF-8@Ce6. In summary, this work created an interesting Ce6 therapeutic agent for PDT and provided the data for HA regarding the improvement in biocompatibility and biological half-life of metal organic frameworks.

Association of RASgrf1 methylation with epileptic seizures.

DNA methylation, one of the mechanisms of epigenetic regulation, has been suggested to be related with epilepsy. RASgrf1 is a paternally imprinted gene and has a differentially methylated region (DMR) at the promoter that can silence gene expression. We have previously observed the down-regulation of RASgrf1 in the temporal neocortex of epilepsy patients and in the hippocampus of epileptic animals. Here, we further explored the dynamic change (1-day acute period, 10-day latent period and 45-day chronic phase) of DNA methylation and RASgrf1 expression after acute epileptic seizures in kainic acid (KA)-treated mice, and we observed the impact of N-phthalyl-L-tryptophan (RG108), a DNA methyltransferase (DNMT) inhibitor, on an acute epileptic model by polymerase chain reaction (PCR), western blotting, and bisulfite sequencing PCR (BSP). The results directly showed that the methylation of the RASgrf1 promoter gradually increased and reached a maximal level at the latent period, with subsequent suppression of RASgrf1 mRNA and protein expression levels, which reached a minimum level in the chronic phase. RG108 inhibited the increased methylation of the RASgrf1 gene, with significant inhibition occurring at the latent period, and restored RASgrf1 expression levels in the chronic phase. In addition, we demonstrated that RG108 could suppress acute epileptic seizures in KA-treated mice and epileptic discharges in 4-aminopyridine (4-AP)-treated hippocampal slices. These findings demonstrate that RASgrf1 is closely associated with epilepsy via the aberrant methylation of RASgrf1, and regulating the methylation status of relevant genes might be an intriguing topic in future research on epilepsy.

DNA Methylation Profiling Reveals Correlation of Differential Methylation Patterns with Gene Expression in Human Epilepsy.

DNA methylation plays important roles in regulating gene expression and has been reported to be related with epilepsy. This study aimed to define differential DNA methylation patterns in drug-refractory epilepsy patients and to investigate the role of DNA methylation in human epilepsy. We performed DNA methylation profiling in brain tissues from epileptic and control patients via methylated-cytosine DNA immunoprecipitation microarray chip. Differentially methylated loci were validated by bisulfite sequencing PCR, and the messenger RNA (mRNA) levels of candidate genes were evaluated by reverse transcriptase PCR. We found 224 genes that showed differential DNA methylation between epileptic patients and controls. Among the seven candidate genes, three genes (TUBB2B, ATPGD1, and HTR6) showed relative transcriptional regulation by DNA methylation. TUBB2B and ATPGD1 exhibited hypermethylation and decreased mRNA levels, whereas HTR6 displayed hypomethylation and increased mRNA levels in the epileptic samples. Our findings suggest that certain genes become differentially regulated by DNA methylation in human epilepsy.