Hypertrophic scar is a fibrous hyperplastic disorder that arises from skin injuries. The current therapeutic modalities are constrained by the dense and rigid scar tissue which impedes effective drug delivery. Additionally, insufficient autophagic activity in fibroblasts hinders their apoptosis, leading to excessive matrix deposition. Here, we developed an active microneedle (MN) system to overcome these challenges by integrating micromotor-driven drug delivery with autophagy regulation to remodel the scar microenvironment. Specifically, sodium bicarbonate and citric acid were introduced into the MNs as a built-in engine to generate CO₂ bubbles, thereby enabling enhanced lateral and vertical drug diffusion into dense scar tissue. The system concurrently encapsulated curcumin (Cur), an autophagy activator, and triamcinolone acetonide (TA), synergistically inducing fibroblast apoptosis by upregulating autophagic activity. In vitro studies demonstrated that active MNs achieved efficient drug penetration within isolated scar tissue. The rabbit hypertrophic scar model revealed that TA-Cur MNs significantly reduced the scar elevation index, suppressed collagen I and transforming growth factor-β1 (TGF-β1) expression, and elevated LC3 protein levels. These findings highlight the potential of the active MN system as an efficacious platform for autonomous augmented drug delivery and autophagy-targeted therapy in fibrotic disorder treatments.

The continuous emergence of SARS-CoV-2 variants as well as other potential future coronavirus has challenged the effectiveness of current COVID-19 vaccines. Therefore, there remains a need for alternative antivirals that target processes less susceptible to mutations, such as the formation of six-helix bundle (6-HB) during the viral fusion step of host cell entry. In this study, a novel high-throughput screening (HTS) assay employing a yeast-two-hybrid (Y2H) system was established to identify inhibitors of HR1/HR2 interaction. The compound IMB-9C, which achieved single-digit micromolar inhibition of SARS-CoV-2 and its Omicron variants with low cytotoxicity, was selected. IMB-9C effectively blocks the HR1/HR2 interaction in vitro and inhibits SARS-CoV-2-S-mediated cell-cell fusion. It binds to both HR1 and HR2 through non-covalent interaction and influences the secondary structure of HR1/HR2 complex. In addition, virtual docking and site-mutagenesis results suggest that amino acid residues A930, I931, K933, T941, and L945 are critical for IMB-9C binding to HR1. Collectively, in this study, we have developed a novel screening method for HR1/HR2 interaction inhibitors and identified IMB-9C as a potential antiviral small molecule against COVID-19 and its variants.

Addressing the challenge of traditional physical/semi physical simulation methods being difficult to achieve full process and full element simulation of extravehicular activities,virtual reality technology is utilized to break through the limitations of physical environments and establish a virtual reality simulation system for extravehicular activities.Based on the application characteristics of space station extravehicular activity engineering,with the goal of improving system practicality and usability,integrating the visual immersion of virtual images,the ontology of real operation,and the consistency of virtual and real space perception,a three-dimensional scene simulation,multi-mode joystick interaction paradigm,continuous operation actions simulation of extravehicular operations,and interactive operation virtual/real space consistency method that were proposed and designed for the realistic visual perception and extravehicular operation.The system has been successfully applied to astronaut training,program validation,joint exercise,and flight control support for sixteen extravehicular activities from SZ-12 to SZ-18.The results showed that the complete reproduction of the static/dynamic realistic comprehensive scene was achieved on the ground for the human-machine operation in the entire process of extravehicular activity,and the system is an essential and important means of ground simulation for extravehicular activity.

Objective To investigate the characteristics,clinical indicators and risk factors of levofloxacin-induced arrhythmias in large hospitalized populations.Methods Using the"Adverse Event Active Monitoring and Intelligent Assessment Alert System-Ⅱ"(ADE-ASAS-Ⅱ),the electronic medical record of inpatients using levofloxacin in 2019 was monitored to obtain relevant data for patients with arrhythmias.Patients without arrhythmia were selected by propensity score matching,and the risk factors of levofloxacin-induced arrhythmias were analyzed by univariate and multivariate conditional logistic regression.Results The incidence of levofloxacin-induced arrhythmias was 1.64％in 12 879 people who used levofloxacin.The incidence in people over 65 years was 3.22％.The main manifestations of levofloxacin-induced arrhythmias were extrasystole(0.84％),tachycardia(0.63％),QT interval prolongation(0.44％),and no severe arrhythmias such as torsades de pointes and ventricular fibrillation.Multivariate Logistic regression analysis showed that the course of administration(OR=1.030,95％CI 1.009 to 1.050,P=0.004)and intravenous administration(OR=2.392,95％CI 1.478 to 3.870,P＜0.001)independent risk factors for levofloxacin-induced arrhythmias.Conclusion Arrhythmias caused by levofloxacin are common and have various types,among which the occurrence of QT interval prolongation is occasional.We should pay more attention to elderly patients who receive intravenous levofloxacin and try to avoid long courses of medication.

Objective:To assess the efficiency and safety of combining lenvatinib with DEB-TACE for the treatment of unresectable large hepatocellular carcinoma,accompanied by PVTT,in order to provide insights into its potential as a therapeutic approach.Method:Patients with hepa-tocellular carcinoma and portal vein tumor thrombus,who were diagnosed and treated at Linyi Can-cer Hospital between June 2019 and June 2021,were chosen as the subjects of this study.Patient allocation into the experimental group(23 cases)and control group(27 cases)was based on indi-vidual preferences,ensuring a random distribution of participants.The DEB-TACE treatment was administered to the control group,while the experimental group received a combination of DEB-TACE and lenvatinib.The effectiveness of lenvatinib was assessed in the immediate post-surgery period,the patients'survival was monitored,and any associated side effects were documented.Result:3 months after treatment,the objective remission rates of the experimental group and the control group were 91.31％and 66.67％,and the disease control rates were 100％and 77.78％.The difference was statistically significant(P＜0.05).3 months after treatment,the regression rates of tumor thrombus in the experimental group and the control group were 60.87％and 29.63％,the difference was statistically significant(P＜0.05).The progression free survival time of the experi-mental group and the control group was 11 months and 8 months,the difference was statistically significant(P＜0.05);The median survival time of the experimental group and the control group was 20 months and 14 months,and the difference was statistically significant(P＜0.05).The main ad-verse reactions of the experimental group were hypertension,diarrhea,hand foot syndrome,rash,fatigue,loss of appetite,etc.,all of which were less than or equal to grade 3,and could be basically relieved after symptomatic treatment.Conclusion:The combination of DEB-TACE and lenvatinib is proven to be a safe and well-tolerated treatment for unresectable large hepatocellular carcinoma with portal vein tumor thrombus.This therapy not only effectively controls tumor progression but also prolongs survival time.

Aim To screen and study the effects of Tao Hong Si Wu decoction(THSWD)-mediated treat-ment on circular RNA(circRNA)expression profiles in rats with middle cerebral artery occlusion(MCAO),and investigate the possible roles and molecular mecha-nisms of THSWD.Methods Next-generation RNA sequencing was conducted to identify circRNA expres-sion profiles in MCAO rats after treatment with THSWD and compared with the MCAO model group and control group.Bioinformatics analysis was performed to predict the potential target microRNAs and mRNAs.Gene On-tology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses for the potential target mRNAs were applied to explore the potential roles of differentially expressed circRNAs.RT-qPCR was performed to verify circRNAs with significant differences in expression.Results We identified 87 significantly differentially expressed circRNAs between the MCAO group versus the control group,and 86 sig-nificantly differentially expressed circRNAs between the MCAO group versus the THSWD group.respective-ly.Among them,17 circRNAs induced by the MCAO model were reversed via treatment with THSWD.To demonstrate the roles of mRNAs targeted by DECs,the GO and KEGG databases were used.Further analysis revealed that five circRNAs may play important roles in the development of MCAO.Conclusions The com-prehensive expression profile of circRNAs in rats with middle cerebral artery occlusion after THSWD treat-ment is determined for the first time,suggesting that the therapeutic effect of THSWD on MCAO may be a-chieved by regulating the expression of circRNAs.

Aim To explore the effect of quercetin(Que)on ferroptosis and the potential mechanisms in an Erastin-induced ferroptosis model in chondrocytes.Methods A model of Erastin-induced ferroptosis was established in C28/I2 chondrocytes.Cells were treated with different concentrations of Que.Cell viability and cytotoxicity were assessed by MTT and LDH assays.The expression levels of Prdx6 and ferroptosis-related proteins ACSL4 and GPX4 in chondrocytes were deter-mined by Western blot.Lipid ROS production in chon-drocytes was measured by flow cytometry,while the changes in mitochondrial membrane potential were de-tected by RH123 staining.Prdx6 mRNA expression in chondrocytes was quantified by RT-qPCR.The chan-ges in the expression of the ferroptosis-related proteins ACSL4 and GPX4 were detected by immunofluores-cence staining.Results Compared to the Erastin-in-duced ferroptosis model group,Que significantly im-proved the viability of C28/I2 chondrocytes and re-duced cell cytotoxicity.It decreased the expression of the ferroptosis-related protein ACSL4 and increased the expression of GPX4.Que also inhibited the production of lipid ROS in chondrocytes and strengthened their mitochondrial membrane potential.In addition,the ex-pression of Prdx6 was significantly reduced in the Eras-tin group compared to the control group,while Que treatment upregulated the expression of Prdx6.Mean-while,the inhibitory effect of Que on chondrocyte fer-roptosis was reduced by the use of MJ33,an inhibitor of Prdx6.Conclusion Que can inhibit Erastin-induced ferroptosis of C28/I2 chondrocytes,possibly by upregu-lating Prdx6,and thus play a protective role in chon-drocytes.

Objective To study the influence of rosemary essential oil inhalation on the memory of mice experiencing sleep deprivation and to delineate the possible mechanisms involved.Methods C57BL/6J mice were randomly divided into four experimental groups in this study:a control group(Con),a control group with rosemary essential oil inhalation(Con+REO),a sleep deprivation group(SD)and a sleep deprivation group with rosemary essential oil inhalation(SD+REO).A 72-hour sleep deprivation model was induced using the multiple platform water environment method,with the Con+REO and SD+REO groups exposed to rosemary essential oil inhalation.Cognitive function was evaluated through Y-maze and novel object recognition tests.The hippocampal tissue was analyzed for superoxide dismutase(SOD)activity and the concentrations of malondialdehyde(MDA)and glutathione(GSH).ELISA was used to determine the levels of norepinephrine(NE),dopamine(DA),and serotonin 5-hydroxytryptamine(5-HT)in the hippocampus.The expression levels of postsynaptic density 95(PSD95)and brain-derived neurotrophic factor(BDNF)in the hippocampus were determined using immunoblotting techniques.Results Compared with the Con and Con+REO groups,the SD group demonstrated a significant reduction in the spontaneous alternation percentage in the Y-maze as well as the novel object recognition index.Additionally,there was a pronounced decrease in hippocampal SOD activity and GSH content,a substantial elevation in MDA levels,and a decrease in the levels of DA,NE,and 5-HT.The expressions of PSD95 and BDNF proteins also decreased.In comparison with the SD group,the SD+REO group exhibited a significant increase in the spontaneous alternation percentage in the Y-maze and the novel object recognition index.There was also a marked increase in hippocampal SOD activity and GSH content,a reduction in MDA levels and elevated levels of NE and DA.Moreover,the expressions of PSD95 and BDNF proteins were upregulated.Conclusion The inhalation of rosemary essential oil enhances the memory of sleep-deprived mice,and the underlying mechanism may involve the mitigation of oxidative stress within the hippocampal tissue,the modulation of neurotransmitter levels,and the facilitation of synaptic plasticity.

AIM To explore the ameliorative effects of Ziyin Mingmu Pills on mouse retinitis pigmentosa(RP)and the possible mechanism.METHODS The RP transgenic mice(rd10)were randomly divided into the model group,the Leding group(0.15 g/kg)and the low and high dose Ziyin Mingmu Pills groups(4.50,9.00 g/kg),in contrast to the C57BL/6 mice of the normal group,with 12 mice in each group.The mice had their retinal pathological changes detected by HE staining;their visual function detected by electroretinogram(ERG);their fundus conditions and retinal thickness detected by optical coherence tomography(OCT);their retinal blood perfusion detected by laser speckle blood flow technique;their mRNA expressions of Shh,Ptc,Smo,Gli1,N-myc and Cyclin mRNA detected by digital PCR;and their protein expressions of Shh,Ptc,Smo,Gli1,N-myc and Cyclin detected by immunofluorescence staining.RESULTS Compared with the normal group,the model group displayed pathological changes in the fundus and retina and decreased amplitudes of ERG a wave and b wave(P＜0.01);decreased retinal thickness(P＜0.01);decreased retinal blood perfusion(P＜0.01);and decreased retinal expressions of Shh,Ptc,Smo,Gli1,N-myc,Cyclin mRNA and protein(P＜0.01).Compared with the model group,the groups intervened with Ziyin Mingmu Pills or Leding shared improved pathological changes in the fundus and retina tissue,and increased retinal thickness(P＜0.01);increased retinal blood flow(P＜0.01);increased amplitudes of ERG a wave and b wave(P＜0.01);and increased retinal Shh,Ptc,Smo,Gli1,N-myc and Cyclin mRNA and protein expressions(P＜0.01).CONCLUSION Ziyin Mingmu Pills can improve the fundus pathological changes and visual function to delay RP in mice because of their efficacy in ameliorating retinal thickness and blood flow possibly by activating Shh signaling pathway.