Mechanism of acacetin regulating hepatic stellate cell apoptosis based on network pharmacology and experimental verification.

Background: Hepatic fibrosis is caused by various liver diseases and eventually develops into liver cancer. There is no specific drug approved for the treatment of hepatic fibrosis in the world. Acacetin (AC), a natural flavonoid, is widely present in nature in various plants, such as black locust, Damiana, Silver birch. It has been reported that acacetin can inhibit the proliferation of cancer cells and induce apoptosis. Purpose: In this study, we investigated the effect of acacetin on hepatic stellate cell apoptosis, thereby improving hepatic fibrosis, and combined experimental validation and molecular docking to reveal the underlying mechanism. Result: First, we discovered that acacetin inhibited hepatic stellate cell proliferation as well as the expression of fibrosis-related proteins α-smooth muscle actin (α-SMA) and collagen type I 1 gene (COL1A1) in LX2 cells. Acacetin was then found to promote apoptosis of hepatic stellate cells through the caspase cascade pathway. Network pharmacology screening showed that TP53, CASP3, CASP8, BCL2, PARP1, and BAX were the most important targets related to apoptosis in the PPI network. GO and KEGG analyses of these six important targets were performed, and the top 10 enriched biological processes and related signaling pathways were revealed. Further network pharmacology analysis proved that apoptosis was involved in the biological process of acacetin's action against hepatic stellate cells. Finally, molecular docking revealed that acacetin binds to the active sites of six apoptotic targets. In vitro experiments further confirmed that acacetin could promote the apoptosis of LX2 cells by inducing the activation of P53, thereby improving hepatic fibrosis. Conclusion: acacetin induces P53 activation and promotes apoptosis of hepatic stellate cells thereby ameliorating hepatic fibrosis.

Tetramethylpyrazine Antagonizes the Subchronic Cadmium Exposure-Induced Oxidative Damage in Mouse Livers via the Nrf2/HO-1 Pathway.

Hepatic oxidative stress is an important mechanism of Cd-induced hepatotoxicity, and it is ameliorated by TMP. However, this underlying mechanism remains to be elucidated. To investigate the mechanism of the protective effect of TMP on liver injuries in mice induced by subchronic cadmium exposure, 60 healthy male ICR mice were randomly divided into five groups of 12 mice each, namely, control (CON), Cd (2 mg/kg of CdCl2), Cd + 100 mg/kg of TMP, Cd + 150 mg/kg of TMP, and Cd + 200 mg/kg of TMP, and were acclimatized and fed for 7 d. The five groups of mice were gavaged for 28 consecutive days with a maximum dose of 0.2 mL/10 g/day. Except for the control group, all groups were given fluoride (35 mg/kg) by an intraperitoneal injection on the last day of the experiment. The results of this study show that compared with the Cd group, TMP attenuated CdCl2-induced pathological changes in the liver and improved the ultrastructure of liver cells, and TMP significantly decreased the MDA level (p < 0.05) and increased the levels of T-AOC, T-SOD, and GSH (p < 0.05). The results of mRNA detection show that TMP significantly increased the levels of Nrf2 in the liver compared with the Cd group as well as the HO-1 and mRNA expression levels in the liver (p < 0.05). In conclusion, TMP could inhibit oxidative stress and attenuate Cd group-induced liver injuries by activating the Nrf2 pathway.

The efficacy of antiviral treatment in chronic hepatitis B patients with hepatic steatosis.

Background & aims: With a drastic increase in the number of chronic hepatitis B (CHB) patients with coexisting nonalcoholic fatty liver disease (NAFLD), there is an urgent need to evaluate antiviral treatment effects in this special population. Methods: CHB patients with hepatic steatosis (CHB + HS) were prospectively recruited with followed-up of 3 years. HS and liver fibrosis were assessed by transient elastography. HS was defined as controlled attenuation parameter (CAP) ≥248 dB/m, and fibrosis progression was defined with ≥1-stage fibrosis increment. Multivariate and propensity score matching (PSM) analysis were used to evaluate antiviral therapy effects on fibrosis progression. Results: In total 212 recruited CHB + HS patients (median age 36 years, median ALT 59 U/L), 49.1% (104/212) received antiviral therapy and 50.9% (108/212) did not. Among patients with antiviral therapy, rates of serum HBV DNA undetectable, HBeAg and HBsAg loss, and ALT normalization at year 3 were 88.5%, 31.0%, 8.7% and 70.2%, respectively. Patients with mild-moderate HS didn't differ patients with severe HS regarding biochemical and virological responses. Antiviral therapy was independently associated with a lower risk of fibrosis progression among the entire cohort (odds ratio 0.473, 95% CI 0.245-0.911, P = 0.025). This finding was further verified by PSM analysis. When stratified by the severity of HS, the antiviral therapy benefits in reducing fibrosis progression were mainly seen in patients with mild-moderate HS. Conclusions: Among CHB + HS patients, long-term antiviral treatment effectively inhibits HBV replication and reduces fibrosis progression. Our findings have implications for the optimal management of this population.

Pregnancy-Specific Beta-1-Glycoprotein 1 Increases HTR-8/SVneo Cell Migration through the Orai1/Akt Signaling Pathway.

The impaired invasion ability of trophoblast cells is related to the occurrence of preeclampsia (PE). We previously found that pregnancy-specific beta-1-glycoprotein 1 (PSG1) levels were decreased in the serum of individuals with early-onset preeclampsia (EOPE). This study investigated the effect of PSG1 on Orai1-mediated store-operated calcium entry (SOCE) and the Akt signaling pathway in human trophoblast cell migration. An enzyme-linked immunosorbent assay (ELISA) was used to determine the level of PSG1 in the serum of pregnant women with EOPE. The effects of PSG1 on trophoblast proliferation and migration were examined using cell counting kit-8 (CCK8) and wound healing experiments, respectively. The expression levels of Orai1, Akt, and phosphorylated Akt (p-Akt) were determined through Western blotting. The results confirmed that the serum PSG1 levels were lower in EOPE women than in healthy pregnant women. The PSG1 treatment upregulated the protein expression of Orai1 and p-Akt. The selective inhibitor of Orai1 (MRS1845) weakened the migration-promoting effect mediated by PSG1 via suppressing the Akt signaling pathway. Our findings revealed one of the mechanisms possibly involved in EOPE pathophysiology, which was that downregulated PSG1 may reduce the Orai1/Akt signaling pathway, thereby inhibiting trophoblast migration. PSG1 may serve as a potential target for the treatment and diagnosis of EOPE.

Differences and Correlations of Morphological and Hemodynamic Parameters between Anterior Circulation Bifurcation and Side-wall Aneurysms.

OBJECTIVE: The objective of this research was to explore the difference and correlation of the morphological and hemodynamic features between sidewall and bifurcation aneurysms in anterior circulation arteries, utilizing computational fluid dynamics as a tool for analysis. METHODS: In line with the designated inclusion criteria, this study covered 160 aneurysms identified in 131 patients who received treatment at Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, China, from January 2021 to September 2022. Utilizing follow-up digital subtraction angiography (DSA) data, these cases were classified into two distinct groups: the sidewall aneurysm group and the bifurcation aneurysm group. Morphological and hemodynamic parameters in the immediate preoperative period were meticulously calculated and examined in both groups using a three-dimensional DSA reconstruction model. RESULTS: No significant differences were found in the morphological or hemodynamic parameters of bifurcation aneurysms at varied locations within the anterior circulation. However, pronounced differences were identified between sidewall and bifurcation aneurysms in terms of morphological parameters such as the diameter of the parent vessel (Dvessel), inflow angle (θF), and size ratio (SR), as well as the hemodynamic parameter of inflow concentration index (ICI) (P<0.001). Notably, only the SR exhibited a significant correlation with multiple hemodynamic parameters (P<0.001), while the ICI was closely related to several morphological parameters (R>0.5, P<0.001). CONCLUSIONS: The significant differences in certain morphological and hemodynamic parameters between sidewall and bifurcation aneurysms emphasize the importance to contemplate variances in threshold values for these parameters when evaluating the risk of rupture in anterior circulation aneurysms. Whether it is a bifurcation or sidewall aneurysm, these disparities should be considered. The morphological parameter SR has the potential to be a valuable clinical tool for promptly distinguishing the distinct rupture risks associated with sidewall and bifurcation aneurysms.

The role of the BTLA-HVEM complex in the pathogenesis of breast cancer.

Breast cancer (BC) is widely recognized as a prevalent contributor to cancer mortality and ranks as the second most prevalent form of cancer among women across the globe. Hence, the development of innovative therapeutic strategies is imperative to effectively manage BC. The B- and T-lymphocyte attenuator (BTLA)-Herpesvirus entry mediator (HVEM) complex has garnered significant scientific interest as a crucial regulator in various immune contexts. The interaction between BTLA-HVEM ligand on the surface of T cells results in reduced cellular activation, cytokine synthesis, and proliferation. The BTLA-HVEM complex has been investigated in various cancers, yet its specific mechanisms in BC remain indeterminate. In this study, we aim to examine the function of BTLA-HVEM and provide a comprehensive overview of the existing evidence in relation to BC. The obstruction or augmentation of these pathways may potentially enhance the efficacy of BC treatment.

Longitudinal association of spirituality with depressive symptom trajectories among older adults in mainland China.

OBJECTIVES: The relationship between spirituality and depressive symptoms among the Chinese elderly is not well known. The current study explores this relationship using longitudinal data and trajectory modeling of depressive symptoms. METHODS: A longitudinal study design was used to measure depressive symptoms repeatedly from 2012 to 2021 using the Geriatric Depression Scale (GDS). Group-based trajectory modeling analysis was conducted to determine the trajectories of depressive symptoms, and multiple logistic regression was used to explore the association between spirituality and depressive symptom trajectories. RESULTS: A total of 2333 participants completed at least two GDS measures, and these were included in the Group-based trajectory modeling analysis. An optimal model of three trajectories was derived: no depressive symptoms group (75.2%), new-onset depressive symptoms group (14.4%), and persistent depressive symptoms group (10.4%). Logistic regression modeling revealed that higher spirituality was associated with a lower risk of both new-onset depressive symptoms (OR = 0.68, 95% CI = 0.49-0.93) and persistent depressive symptoms (OR = 0.32, 95% CI = 0.23-0.45). CONCLUSIONS: Spirituality predicts a lower risk of new-onset depressive symptoms and persistent symptoms among older adults in mainland China.

In Situ Growth Reaction on Photoelectrodes of Single-Atom Fe Incorporated Bi4O5I2: A General Photoelectrochemical Immunoassay Toward Sensitive Protein Analysis.

As one of the interesting signaling mechanisms, the in situ growth reaction on a photoelectrode has proven its powerful potential in photoelectrochemical (PEC) bioanalysis. However, the specific interaction between the signaling species with the photoactive materials limits the general application of the signal mechanism. Herein, on the basis of an in situ growth reaction on a photoelectrode of single-atom-based photoactive material, a general PEC immunoassay was developed in a split-type mode consisting of the immunoreaction and PEC detection procedure. Specifically, a single-atom photoactive material that incorporates Fe atoms into layered Bi4O5I2 (Bi4O5I2-Fe SAs) was used as a photoelectrode for PEC detection. The sandwich immunoreaction was performed in a well of a 96-well plate using Ag nanoparticles (Ag NPs) as signal tracers. In the PEC detection procedure, the Ag+ converted from Ag NPs were transferred onto the surface of the Bi4O5I2-Fe SAs photoelectrode and thereafter AgI was generated on the Bi4O5I2-Fe SAs in situ to form a heterojunction through the reaction of Ag+ with Bi4O5I2-Fe SAs. The formation of heterojunction greatly promoted the electro-hole separation, boosting the photocurrent response. Exemplified by myoglobin (Myo) as the analyte, the immunosensor achieved a wide linear range from 1.0 × 10-11 to 5.0 × 10-8 g mL-1 with a detection limit of 3.5 × 10-12 g mL-1. This strategy provides a general PEC immunoassay for disease-related proteins, as well as extends the application scope of in situ growth reaction in PEC analysis.

Effects of short- and long-term plant functional group loss on alpine meadow community structure and soil nutrients.

The rapid loss of global biodiversity can greatly affect the normal functioning of ecosystems. However, how biodiversity losses affect plant community structure and soil nutrients is unclear. We conducted a field experiment to examine the short- and long-term effects of removing plant functional groups (Gramineae, Cyperaceae, legumes, and forbs) on the interrelationships among the species diversity, productivity, community structure, and soil nutrients in an alpine meadow ecosystem at Menyuan County, Qinghai Province. The variations in the species richness, above- and belowground biomass of the community gradually decreased over time. Species richness and productivity were positively correlated, and this correlation tended to be increasingly significant over time. Removal of the Cyperaceae, legumes, and other forbs resulted in fewer Gramineae species in the community. Soil total nitrogen, phosphorus, organic matter, and moisture contents increased significantly in the legume removal treatment. The removal of other forbs led to the lowest negative cohesion values, suggesting that this community may have difficulty recovering its previous equilibrium state within a short time. The effects of species removal on the ecosystem were likely influenced by the species structure and composition within the community. Changes in the number of Gramineae species indicated that they were more sensitive and less resistant to plant functional group removal. Legume removal may also indirectly cause distinct community responses through starvation and compensation effects. In summary, species loss at the community level led to extensive species niche shifts, which caused community resource redistribution and significant changes in community structure.

A novel MPPT technology based on dung beetle optimization algorithm for PV systems under complex partial shade conditions.

Solar power is a renewable energy source, and its efficient development and utilization are important for achieving global carbon neutrality. However, partial shading conditions cause the output of PV systems to exhibit nonlinear and multipeak characteristics, resulting in a loss of output power. In this paper, we propose a novel Maximum Power Point Tracking (MPPT) technique for PV systems based on the Dung Beetle Optimization Algorithm (DBO) to maximize the output power of PV systems under various weather conditions. We performed a performance comparison analysis of the DBO technique with existing renowned MPPT techniques such as Squirrel Search Algorithm, Cuckoo search Optimization, Horse Herd Optimization Algorithm, Particle Swarm Optimization, Adaptive Factorized Particle Swarm Algorithm and Gray Wolf Optimization Hybrid Nelder-mead. The experimental validation is carried out on the HIL + RCP physical platform, which fully demonstrates the advantages of the DBO technique in terms of tracking speed and accuracy. The results show that the proposed DBO achieves 99.99% global maximum power point (GMPP) tracking efficiency, as well as a maximum improvement of 80% in convergence rate stabilization rate, and a maximum improvement of 8% in average power. A faster, more efficient and robust GMPP tracking performance is a significant contribution of the DBO controller.

[Genome-wide identification and expression analysis of TCP gene family of Andrographis paniculata under abiotic stress].

Andrographis paniculata is an important medicinal plant in the Lingnan region of China, which has the functions of clearing heat, removing toxins, and resisting bacteria and inflammation. The TCP gene family is a class of transcription factors that regulate plant growth, development, and stress response. In order to analysis the role of the TCP gene family under abiotic stress in A. paniculata, this study identified the TCP gene family of A. paniculata at the genome-wide level and analyzed its expression pattern in response to abiotic stress. The results showed that the A. paniculata TCP gene family had 23 members, with length of amino acid ranging from 136 to 508, the relative molecular mass between 14 854.71 and 55 944.90 kDa, and the isoelectric point between 5.67 and 10.39. All members were located in the nucleus and unevenly distributed on 13 chromosomes. Phylogenetic analysis classified them into three subfamilies: PCF, CIN and CYC/TB1. Gene structure and conserved motif analysis showed that most members of the TCP gene family contained motif 1, motif 2, motif 3 in the same order and 1-3 CDS. The analysis of promoter cis-acting elements showed that the transcriptional expression of the TCP gene family in A. paniculata might be induced by light, hormones, and adversity stress. In light of the expression pattern analysis and qRT-PCR verification, the expression of ApTCP4, ApTCP5, ApTCP6, and ApTCP11 involved in response by various abiotic stresses such as drought, high temperature, and MeJA. This study lays the foundation for in-depth exploration of the functions of A. paniculata TCP genes in response to abiotic stress.

The GRHL3-regulated long non-coding RNA lnc-DC modulates keratinocytes differentiation by interacting with IGF2BP2 and up-regulating ZNF750.

BACKGROUND: Aberrant keratinocytes differentiation has been demonstrated to be associated with a number of skin diseases. The roles of lncRNAs in keratinocytes differentiation remain to be largely unknown. OBJECTIVE: Here we aim to investigate the role of lnc-DC in regulating epidermal keratinocytes differentiation. METHODS: Expression of lnc-DC in the skin was queried in AnnoLnc and verified by FISH. The lncRNA expression profiles during keratinocytes differentiation were reanalyzed and verified by qPCR and FISH. Gene knock-down and over-expression were used to explore the role of lnc-DC in keratinocytes differentiation. The downstream target of lnc-DC was screened by whole transcriptome sequencing. CUT&RUN assay and siRNAs transfection was used to reveal the regulatory effect of GRHL3 on lnc-DC. The mechanism of lnc-DC regulating ZNF750 was revealed by RIP assay and RNA stability assay. RESULTS: Lnc-DC was biasedly expressed in skin and up-regulated during epidermal keratinocytes differentiation. Knockdown lnc-DC repressed epidermal keratinocytes differentiation while over-express lnc-DC showed the opposite effect. GRHL3, a well-known transcription factor regulating keratinocytes differentiation, could bind to the promoter of lnc-DC and regulate its expression. By whole transcriptome sequencing, we identified that ZNF750 was a downstream target of lnc-DC during keratinocytes differentiation. Mechanistically, lnc-DC interacted with RNA binding protein IGF2BP2 to stabilize ZNF750 mRNA and up- regulated its downstream targets TINCR and KLF4. CONCLUSION: Our study revealed the novel role of GRHL3/lnc-DC/ZNF750 axis in regulating epidermal keratinocytes differentiation, which may provide new therapeutic targets of aberrant keratinocytes differentiation related skin diseases.

Effectiveness of a broad-spectrum bivalent mRNA vaccine against SARS-CoV-2 variants in preclinical studies.

Vaccines utilizing modified messenger RNA (mRNA) technology have shown robust protective efficacy against SARS-CoV-2 in humans. As the virus continues to evolve in both human and non-human hosts, risk remains that the performance of the vaccines can be compromised by new variants with strong immune escape abilities. Here we present preclinical characterizations of a novel bivalent mRNA vaccine RQ3025 for its safety and effectiveness in animal models. The mRNA sequence of the vaccine is designed to incorporate common mutations on the SARS-CoV-2 spike protein that have been discovered along the evolutionary paths of different variants. Broad-spectrum, high-titer neutralizing antibodies against multiple variants were induced in mice (BALB/c and K18-hACE2), hamsters and rats upon injections of RQ3025, demonstrating advantages over the monovalent mRNA vaccines. Effectiveness in protection against several newly emerged variants is also evident in RQ3025-vaccinated rats. Analysis of splenocytes derived cytokines in BALB/c mice suggested that a Th1-biased cellular immune response was induced by RQ3025. Histological analysis of multiple organs in rats following injection of a high dose of RQ3025 showed no evidence of pathological changes. This study proves the safety and effectiveness of RQ3025 as a broad-spectrum vaccine against SARS-CoV-2 variants in animal models and lays the foundation for its potential clinical application in the future.

Causal Relationship Between Gut Microbiota and Liver Cirrhosis: 16S rRNA Sequencing and Mendelian Randomization Analyses.

Background and Aims: Accumulating evidence highlights the association between the gut microbiota and liver cirrhosis. However, the role of the gut microbiota in liver cirrhosis remains unclear. Methods: We first assessed the differences in the composition of the bacterial community between CCl4-induced liver cirrhosis and control mice using 16S rRNA sequencing. We then performed a two-sample Mendelian randomization (MR) analysis to reveal the underlying causal relationship between the gut microbiota and liver cirrhosis. Causal relationships were analyzed using primary inverse variance weighting (IVW) and other supplemental MR methods. Furthermore, fecal samples from liver cirrhosis patients and healthy controls were collected to validate the results of the MR analysis. Results: Analysis of 16S rRNA sequencing indicated significant differences in gut microbiota composition between the cirrhosis and control groups. IVW analyses suggested that Alphaproteobacteria, Bacillales, NB1n, Rhodospirillales, Dorea, Lachnospiraceae, and Rhodospirillaceae were positively correlated with the risk of liver cirrhosis, whereas Butyricicoccus, Hungatella, Marvinbryantia, and Lactobacillaceae displayed the opposite effects. However, the weighted median and MR-PRESSO estimates further showed that only Butyricicoccus and Marvinbryantia presented stable negative associations with liver cirrhosis. No significant heterogeneity or horizontal pleiotropy was observed in the sensitivity analysis. Furthermore, the result of 16S rRNA sequencing also showed that healthy controls had a higher relative abundance of Butyricicoccus and Marvinbryantia than liver cirrhosis patients. Conclusions: Our study provides new causal evidence for the link between gut microbiota and liver cirrhosis, which may contribute to the discovery of novel strategies to prevent liver cirrhosis.

Exploring the interplay between methylation patterns and non-coding RNAs in non-small cell lung cancer: Implications for pathogenesis and therapeutic targets.

Lung cancer is a global public health issue, with non-small cell lung cancer (NSCLC) accounting for 80-85 % of cases. With over two million new diagnoses annually, understanding the complex evolution of this disease is crucial. The development of lung cancer involves a complex interplay of genetic, epigenetic, and environmental factors, leading the key oncogenes and tumor suppressor genes to disorder, and activating the cancer related signaling pathway. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNA (lncRNAs), and circular RNA (circRNAs) are unique RNA transcripts with diverse biological functions. These ncRNAs are generated through genome transcription and play essential roles in cellular processes. Epigenetic modifications such as DNA methylation, N6-methyladenosine (m6A) modification, and histone methylation have gained significant attention in NSCLC research. The complexity of the interactions among these methylation modifications and ncRNAs contribute to the precise regulation of NSCLC development. This review comprehensively summarizes the associations between ncRNAs and different methylation modifications and discusses their effects on NSCLC. By elucidating these relationships, we aim to advance our understanding of NSCLC pathogenesis and identify potential therapeutic targets for this devastating disease.

Photobiomodulation Increases M2-Type Polarization of Macrophages by Inhibiting Versican Production After Spinal Cord Injury.

Spinal cord injury (SCI) is a catastrophic accidence with little effective treatment, and inflammation played an important role in that. Previous studies showed photobiomodulation (PBM) could effectively downregulate the process of inflammation with modification of macrophage polarization after SCI; however, the potential mechanism behind that is still unclear. In the presented study, we aimed to investigate the effect of PBM on the expression level of versican, a matrix molecular believed to be associated with inflammation, and tried to find the mechanism on how that could regulate the inflammation process. Using immunofluorescence technique and western blot, we found the expression level of versican is increased after injury and markedly downregulated by irradiation treatment. Using virus intrathecal injection, we found the knock-down of versican could produce the effect similar to that of PBM and might have an effect on inflammation and macrophage polarization after SCI. To further verify the deduction, we peptide the supernatant of astrocytes to induce M0, M1, and M2 macrophages. We found that the versican produced by astrocytes might have a role on the promotion of M2 macrophages to inflammatory polarization. Finally, we investigated the potential pathway in the regulation of M2 polarization with the induction of versican. This study tried to give an interpretation on the mechanism of inflammation inhibition for PBM in the perspective of matrix regulation. Our results might provide light on the inflammation regulation after SCI.

Modified Theoretical Model Predicts Radial Support Capacity of Polymer Braided Stents.

BACKGROUND AND OBJECTIVE: Self-expanding polymer braided stents are expected to replace metallic stents in the treatment of Peripheral Arterial Disease, which seriously endangers human health. To restore the patency of blocked peripheral arteries with different properties and functions, the radial supporting capacity of the stent should be considered corresponding to the vessel. A theoretical model can be established as an effective method to study the radial supporting capacity of the stent which can shorten the stent design cycle and realize the customization of the stent according to lesion site. However, the classical model developed by Jedwab and Clerc of radial force is only limited to metallic braided stents, and the predictions for polymer braided stents are deviated. METHODS: In this paper, based on the limitation of the J&C model for polymer braided stents, a modified radial force model for polymer braided stents was proposed, which considered the friction between monofilaments and the torsion of the monofilaments. And the modified model was verified by radial force tests of polymer braided stents with different structures and monofilaments. RESULTS: Compared with the J&C model, the proposed modified model has better predictability for the radial force of polymer braided stents that prepared with different braided structure and polymer monofilaments. The root mean squared error of modified model is 0.041±0.026, while that of the J&C model is 0.246±0.111. CONCLUSIONS: For polymer braided stents, the friction between the polymer monofilaments and the torsion of the monofilaments during the radial compression cannot be ignored. The radial force prediction accuracy of the modified model considering these factors was significantly improved. This work provides a research basis on the theoretical model of polymer braided stents, and improves the feasibility of rapid personalized customization of polymer braided stents.

IKBKE promotes the ZEB2-mediated EMT process by phosphorylating HMGA1a in glioblastoma.

IKBKE (Inhibitor of Nuclear Factor Kappa-B Kinase Subunit Epsilon) is an important oncogenic protein in a variety of tumors, which can promote tumor growth, proliferation, invasion and drug resistance, and plays a critical regulatory role in the occurrence and progression of malignant tumors. HMGA1a (High Mobility Group AT-hook 1a) functions as a cofactor for proper transcriptional regulation and is highly expressed in multiple types of tumors. ZEB2 (Zinc finger E-box Binding homeobox 2) exerts active functions in epithelial mesenchymal transformation (EMT). In our current study, we confirmed that IKBKE can increase the proliferation, invasion and migration of glioblastoma cells. We then found that IKBKE can phosphorylate HMGA1a at Ser 36 and/or Ser 44 sites and inhibit the degradation process of HMGA1a, and regulate the nuclear translocation of HMGA1a. Crucially, we observed that HMGA1a can regulate ZEB2 gene expression by interacting with ZEB2 promoter region. Hence, HMGA1a was found to promote the ZEB2-related metastasis. Consequently, we demonstrated that IKBKE can exert its oncogenic functions via the IKBKE/HMGA1a/ZEB2 signalling axis, and IKBKE may be a prominent biomarker for the treatment of glioblastoma in the future.

Novel antiviral discoveries for Japanese encephalitis virus infections through reporter virus-based high-throughput screening.

Japanese encephalitis (JE) caused by JE virus (JEV), remains a global public health concern. Currently, there is no specific antiviral drug approved for the treatment of JE. While vaccines are available for prevention, they may not cover all at-risk populations. This underscores the urgent need for prophylaxis and potent anti-JEV drugs. In this context, a high-content JEV reporter system expressing Nanoluciferase (Nluc) was developed and utilized for a high-throughput screening (HTS) of a commercial antiviral library to identify potential JEV drug candidates. Remarkably, this screening process led to the discovery of five drugs with outstanding antiviral activity. Further mechanism of action analysis revealed that cepharanthine, an old clinically approved drug, directly inhibited virus replication by blocking GTP binding to the JEV RNA-dependent RNA polymerase. Additionally, treatment with cepharanthine in mice models alleviated JEV infection. These findings warrant further investigation into the potential anti-JEV activity of cepharanthine as a new therapeutic approach for the treatment of JEV infection. The HTS method employed here proves to be an accurate and convenient approach that facilitates the rapid development of antiviral drugs.

Selection of reference genes in liproxstatin-1-treated K562 Leukemia cells via RT-qPCR and RNA sequencing.

BACKGROUND: Reverse transcription quantitative polymerase chain reaction (RT-qPCR) can accurately detect relative gene expression levels in biological samples. However, widely used reference genes exhibit unstable expression under certain conditions. METHODS AND RESULTS: Here, we compared the expression stability of eight reference genes (RPLP0, RPS18, RPL13, EEF1A1, ß-actin, GAPDH, HPRT1, and TUBB) commonly used in liproxstatin-1 (Lip-1)-treated K562 cells using RNA-sequencing and RT-qPCR. The expression of EEF1A1, ACTB, GAPDH, HPRT1, and TUBB was considerably lower in cells treated with 20 µM Lip-1 than in the control, and GAPDH also showed significant downregulation in the 10 µM Lip-1 group. Meanwhile, when we used geNorm, NormFinder, and BestKeeper to compare expression stability, we found that GAPDH and HPRT1 were the most unstable reference genes among all those tested. Stability analysis yielded very similar results when geNorm or BestKeeper was used but not when NormFinder was used. Specifically, geNorm and BestKeeper identified RPL13 and RPLP0 as the most stable genes under 20 µM Lip-1 treatment, whereas RPL13, EEF1A1, and TUBB were the most stable under 10 µM Lip-1 treatment. TUBB and EEF1A1 were the most stable genes in both treatment groups according to the results obtained using NormFinder. An assumed most stable gene was incorporated into each software to validate the accuracy. The results suggest that NormFinder is not an appropriate algorithm for this study. CONCLUSIONS: Stable reference genes were recognized using geNorm and BestKeeper but not NormFinder. Overall, RPL13 and RPLP0 were the most stable reference genes under 20 µM Lip-1 treatment, whereas RPL13, EEF1A1, and TUBB were the most stable genes under 10 µM Lip-1 treatment.