Direct Inhibitory Effect Research Articles

Spatial impact of environmental regulation on firm entry: Empirical evidence from Chinese firm registration data.

Facing severe environmental challenges and a rapidly changing economic landscape, it is important to deeply analyze the specific impact of environmental regulation on firm entry. This paper used data on enterprise registrations from 279 Chinese cities between 2007 and 2020. We employed spatial econometric models to study the spatial impact of environmental regulation on firm entry. The results show that environmental regulation has a significant direct inhibitory effect on firm entry, especially more pronounced for manufacturing firms. At the same time, environmental regulation also has spatial spillover effects, influencing firm entry decisions in neighboring areas. Furthermore, it is found that environmental regulation improves environmental quality, which in turn inhibits the entry of manufacturing firms while attracting service firms. Based on these findings, policymakers need to fully consider the impact of environmental regulations on the entry of manufacturing and service firms, as well as the spatial spillover effects on firm entry in neighboring areas. Moreover, environmental regulation policies should be adjusted according to the specific development situations of cities. This will help achieve a coordinated development of environmental protection and economic growth.

ISG15 increases the apoptosis of β cells in type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease characterized by hyperglycemia caused by the destruction of insulin-producing β cells. Viral infection is an important environmental factor which is associated with the islet autoimmunity in genetically susceptible individuals. Loss of β-cells and triggering of insulitis following viral infection could result from several non-exclusive mechanisms. Despite a significant increase in ISG15 levels following viral infection, the specific role of ISG15 in the impairment of insulin-producing β-cells is unclear. To address this issue at the clinical level, we conducted this experimental work, and found elevated levels of ISG15 in the peripheral blood of T1D patients, suggesting a potential link between ISG15 and T1D. In the T1D animal model, we discovered that both ISG15 levels and cellular apoptosis were increased in pancreatic islet tissue. To investigate at the cellular level, we cultured MIN6 cells in the presence of supernatants derived from iBMDM cells transfected with poly(I:C) (PIC), a viral mimic. This exposure led to an upregulation of ISG15 expression in MIN6 cells, which was accompanied by the suppression of their functional capabilities and viability. Intriguingly, the direct transfection of MIN6 cells with PIC increased the expression of ISG15. We further found that elevated levels of ISG15 had a direct inhibitory effect on insulin secretion and it also contributed to β-cell apoptosis in a TNF-α-dependent manner. In conclusion, our study revealed a potential underlying mechanism through which ISG15 increases the apoptosis of β-cells, providing valuable insights that could facilitate the development of T1D treatment strategies.

Direct Inhibitory Effect of HTLV-1-Infected T Cells on the Production of Anti-Ro/SS-A Antibody by B Cells from Patients with Sjögren's Syndrome.

The reasons for the low frequency of anti-Ro/SS-A antibody in patients with HTLV-1-associated myelopathy complicated with Sjögren's syndrome (SS) are unclear. In this study, we investigated whether HTLV-1-infected T cells can act directly on B cells and suppress B cells' production of antibodies, including anti-Ro/SS-A antibody. For this purpose, we established an in vitro T-cell-free B-cell antibody production system. The productions of total IgG and anti-cytomegalovirus IgG in B cells from healthy subjects and those of total IgG and anti-Ro/SS-A IgG in B cells from SS patients were significantly suppressed by the addition of HTLV-1-positive T-cell lines (MT-2 and HCT-5). Our analysis of co-cultured B cells identified no sign of HTLV-1 infection and revealed that MT-2 and HCT-5 cells act on the early stages of B-cell differentiation, not the activation stage. MT-2 and HCT-5 cells constitutively expressed CD70, ICAM-1, LAP (TGF-β), and PD-L1/2, but blocking monoclonal antibodies to these molecules or PD-L1/2 receptor PD-1 had no significant canceling effect on B-cell IgG production regarding their suppressive activity. Importantly, autologous CD4+CD25+CD127low Treg cells had no inhibitory effect on B-cell IgG production. These results demonstrate that HTLV-1-positive T cells can directly suppress B-cell antibody production through mechanisms that differ from Treg functions.

Napabucasin-loaded PLGA nanoparticles trigger anti-HCC immune responses by metabolic reprogramming of tumor-associated macrophages

BackgroundJAK/STAT3 is one of the critical signaling pathways involved in the occurrence and development of hepatocellular carcinoma (HCC). BBI608 (Napabucasin), as a novel small molecule inhibitor of STAT3, has shown previously excellent anti-HCC effects in vitro and in mouse models. However, low bioavailability, high cytotoxicity and other shortcomings limit its clinical application. In this study, PLGA was selected to prepare Napabucasin PLGA nanoparticles (NPs) by solvent evaporation method, overcoming these limitations and improving the passive targeting effect that nanoparticle mediated. Base on this, we systematically evaluated the anti-HCC effect of Napabucasin-PLGA NPs and explored the underlying mechanisms.MethodsNapabucasin-PLGA NPs were prepared by solvent evaporation method. CCK-8 assay, Annexin V/PI double staining, RT-qPCR, colony formation assay, and Western blotting were performed to evaluate the anti-HCC effect of Napabucasin-PLGA NPs in vitro. Proliferation assay and migration assay were used to detect the effects of Napabucasin-PLGA NPs-treated HCC-TAMs on tumor biological characteristics of HCC cells. Flow cytometry was used to detect anti-HCC immune responses induced by Napabucasin-PLGA NPs in vivo.ResultsOur results demonstrated that Napabucasin-PLGA NPs could improve the bioavailability of Napabucasin and enhance Napabucasin-mediated the anti-HCC effects in vitro and in vivo with no significant drug toxicity. In addition to the direct inhibitory effects on the tumor biological characteristics of HCC cells, Napabucasin-PLGA NPs could promote the polarization of macrophages from tumor-promoting M2-type to anti-tumor M1-type, improving the tumor immune microenvironment and augmenting T cell-mediated anti-tumor responses. The underlining mechanisms showed Napabucasin-PLGA NPs suppressed the STAT3/FAO signaling axis in HCC-induced tumor-associated macrophages (TAMs).ConclusionsThese findings demonstrated Napabucasin-PLGA NPs is a potential therapeutic candidate for HCC, and provided a new theoretical and experimental basis for further development and clinical application of Napabucasin.

The Induction of Disease Resistance by Scopolamine and the Application of Datura Extract Against Potato (Solanum tuberosum L.) Late Blight.

Late blight, caused by Phytophthora infestans, is a devastating disease of potato. Our previous work illustrated that scopolamine, the main bioactive substance of Datura extract, exerts direct inhibitory effects on P. infestans, but it is unclear whether scopolamine and Datura extract can boost resistance to late blight in potato. In this study, P. infestans is used to infect scopolamine-treated potato pieces and leaves, as well as whole potatoes. We found that scopolamine-treated potato is resistant to P. infestans both in vitro and in vivo. The treatment of 4.5 g/L scopolamine reduces the lesion size of whole potato to 54% compared with the control after 20 d of the infection of P. infestans. The disease-resistant substance detection based on the kit method shows that scopolamine triggers the upregulation of polyphenoloxidase, peroxidase, superoxide dismutase activities, and H2O2 contents in potato tubers, and the decline of phenylalanine ammonia lyase and catalase activity. A total of 1682 significantly differentially expressed genes were detected with or without scopolamine treatment through high-throughput transcriptome sequencing and the DESeq2 software (version 1.24.0), including 705 upregulated and 977 downregulated genes. Scopolamine may affect the genes functioning in the cell wall, membrane and the plant-pathogen interaction. The addition of Datura extract could directly inhibit the mycelial growth of P. infestans on rye plate medium. In addition, P. infestans was found to be resistant to late blight in potato pieces treated with Datura extract. Datura extract can also be utilized in combination with the chemical fungicide Infinito in field experiments to lessen late blight symptoms and enhance potato yield. To our knowledge, this is the first study to detect the induction of disease resistance by scopolamine, and it also explores the feasibility of Datura extract in potato disease resistance.

TLR3 activation enhances antitumor effects of sorafenib in hepatocellular carcinoma by activating NK cell functions through ERK and NF-κB pathways

Background Sorafenib is a standard therapeutic agent for advanced hepatocellular carcinoma (HCC). However, its efficacy is moderate, as the survival of patients is prolonged for only a few months, and the response rate is low. The mechanism of low efficacy remains unclear. In this study, we investigated the effect of Toll-like receptor 3 (TLR3) on the effects of sorafenib on HCC. Methods Polyinosinic-polycytidylic acid [poly(I: C)] was used as a double-stranded RNA analog and TLR3 agonist in subsequent experiments. After orthotopic implantation of HCC tumors in BALBc nu/nu or C57BL/6 mice, survival time, tumor growth, and metastasis in the abdomen and lungs were analyzed. Flow cytometry and cytotoxicity assays were used to analyze NK cells isolated from the spleen or peripheral blood. ELISA was used to detect the expression of plasma interferon (IFN)-γ and monocyte chemoattractant protein (MCP)-1. In addition, the expression of phosphorylated-extracellular regulated kinase 1/2 (pERK1/2), phosphorylated-protein kinase B (pAKT), ERK1/2 and AKT was analyzed by Western blotting. Results Sorafenib reduced the number and activity of NK cells in tumor-bearing mice and simultaneously decreased the levels of MCP-1 and IFN-γ in the plasma. The combination of sorafenib and poly(I: C) synergistically inhibited tumor growth and metastasis in tumor xenograft mice and prolonged survival. Poly(I: C) not only exerts a direct inhibitory effect on tumor growth and metastasis by targeting the TLR3 receptor on tumor cells but also facilitates the proliferation and activation of NK cells, indirectly impeding tumor progression. Mechanistically, poly(I: C) decreased the sorafenib-induced inhibition of ERK phosphorylation and increased the phosphorylation of IκB in NK cells, thereby enhancing NK cell function. Conclusion Activation of TLR3 can enhance the antitumor effect of sorafenib on HCC. The combination of a TLR3 activator and sorafenib may be a new strategy for the treatment of HCC.

Biochar as a strategy to manage stem rot disease of groundnut incited by Sclerotium rolfsii

Due to the pathogen’s ability to survive in the soil for longer durations, soil-borne diseases are often difficult to control. This study investigates the multifaceted impacts of biochar on the management of stem rot disease in groundnut and its influence on soil properties and microbial communities. The effects of biochar at different concentrations, such as 0%, 1%, 3%, and 5% on groundnut stem rot disease incited by Sclerotium rolfsii were evaluated thoroughly. Under laboratory conditions, biochar exhibited no direct inhibitory effects on S. rolfsii at varying concentrations but revealed an indirect suppression of sclerotial body production, suggesting a concentration-dependent influence on pathogen resting structures. Further, it was observed that biochar treatments effectively delayed symptom onset and reduced disease progression in groundnut plants, with significant variation observed among genotypes and biochar concentrations. Notably, interactions involving genotypes ICGV 171002 and ICGV 181035 with BC2 + Sr (3% conc. of biochar + S. rolfsii) and BC3 + Sr (5% conc. of biochar + S. rolfsii) treatments showed superior efficacy in disease reduction under controlled conditions. Field evaluations confirmed these findings, highlighting genotype-specific responses to biochar treatments. However, no significant difference was observed between BC2 + Sr (3%) and BC3 + Sr (5%) treatments in managing stem rot disease compared to controls. Biochar application significantly increased soil nutrient levels, including nitrogen, phosphorus, and potassium, and increased soil organic matter content, EC, pH, emphasizing its potential to improve soil fertility. Overall, these findings highlight the potential benefits of biochar for sustainable agriculture through disease management, soil nutrient enrichment, and microbial modulation, warranting further investigation into optimal application strategies across different agricultural contexts.

Direct IL-6 inhibition prevents arterial thrombosis by reducing collagen-mediated platelets activation

Abstract Introduction Interleukin 6 (IL-6) has a pivotal role in atherothrombosis. Yet, targeting IL-6 to prevent atherothrombotic events still requires validation of efficacy and safety. The recent phase 2 RESCUE trial reported that direct inhibition of IL-6 ligand by the monoclonal antibody (mAb) Ziltivekimab is safe in patients with elevated cardiovascular risk. Purpose This project investigated the effects of direct IL-6 inhibition on arterial thrombosis, and assessed the underlying cellular mechanisms. Methods Three month old C56Bl/6 male mice received very-low dose LPS i.p. for 4 weeks. During the last week they were randomized to receive in addition either anti-mouse IL-6 mAb 200 μg i.p. every other day or IgG1 isotype control. Then thrombosis of left common carotid artery (LCCA) was induced by laser injury under anesthesia. Platelets of treated mice were isolated and stimulated with either adenosine di-phosphate (ADP), collagen-related peptide (CRP) or thrombin receptor activating peptide (TRAP). Platelets activation was measured by flow-cytometry, as expression of P-selectin and JON/A.The effect of direct IL-6 inhibition was confirmed in patients with stable coronary artery disease (sCAD) by ex-vivo incubation of isolated platelets with either anti-human IL-6 mAb 1.5 μg/mL or IgG1 isotype control. Platelet activation was measured by flow-cytometry, as expression of P-selectin. Results Mice treated with anti-IL6 antibody displayed a significantly longer time-to-occlusion after the LCCA (Figure 1), without any significant difference in coagulation parameters. After stimulation with CRP, platelets were significantly activated in control mice, but not in mice treated with anti-IL6 mAb. Similarly, activation of isolated platelets from patients with sCAD was significantly reduced (Figure 2) by the ex-vivo treatment with anti-IL6 mAb. Conclusion The direct inhibition of IL-6 reduces platelets reactivity to collagen, thereby blunting arterial thrombosis upon endothelial damage. These results provide a potential mechanism to explain the reduction of cardiovascular risk associated to direct IL-6 inhibition. Conclusion The direct inhibition of IL-6 reduces platelets reactivity to collagen, thereby blunting arterial thrombosis upon endothelial damage. These results provide a potential mechanism to explain the reduction of cardiovascular risk associated to direct IL-6 inhibition.Figure 1Figure 2

Combined class I and class III antiarrhythmic effects of sotagliflozin - insights from heterologous expressions systems and atrial cardiomyocytes

Abstract Background The demand for more effective treatment options for atrial fibrillation (AF), the most common sustained arrhythmia, is driven by its direct impact on morbidity and mortality. Current therapies, such as antiarrhythmic drugs and catheter ablation, are limited by suboptimal efficacy and adverse effects or periinterventional complications. Therefore, safe and effective treatment of AF remains a major unmet clinical need. Sodium-glucose cotransporter (SGLT) inhibitors have shown promise in reducing the incidence of AF in large cardiovascular endpoint trials. However, the exact mechanisms of action remain unclear. While only two SGLT2 inhibitors are approved and clinically used in Europe, sotagliflozin, which inhibits both SGLT1 and SGLT2, might also have potential for the treatment of AF. Purpose This study aims to elucidate the effects of sotagliflozin on cardiac action potential formation. This understanding could optimise its clinical use, identify new targets for the treatment of atrial fibrillation and ultimately improve the quality of life of patients suffering from AF. Methods The effects of sotagliflozin on cardiac ionic currents were assessed using two-electrode voltage clamp measurements of several sodium and potassium channels heterologously expressed in Xenopus laevis oocytes. Subsequently, ascending concentrations of sotagliflozin were administered to isolated human atrial cardiomyocytes during patch-clamp measurements to investigate its effect on atrial action potential morphology. Results At a concentration of 100 µM, sotagliflozin showed significant inhibitory effects on three out of ten ion channels tested: NaV1.5 sodium channel current was reduced by 22,3 % %, hERG and KV4.3 potassium currents were reduced by 30,4 % and 22,5 % respectively. Patch-clamp experiments, performed on isolated human atrial cardiomyocytes showed a dose-dependent reduction in upstroke velocity and action potential amplitude by 20,8 % and 13,8 % at a concentration of 20 µM, reflecting class-I-antiarrhythmic effects. Furthermore, a prolongation of AP duration measured at 50 % (APD50) and 90 % (APD90) of repolarization by 57,7 % and 27,9 % at a sotagliflozin concentration of 20 µM was noted, implying additional class-III-antiarrhythmic action. Conclusions Sotagliflozin exerts direct inhibitory effects on heterologously expressed NaV1.5, hERG and KV4.3 channels, resulting in a reduction in upstroke velocity and action potential amplitude, as well as a prolongation of APD50 and APD90 levels in isolated human atrial cardiomyocytes. These results extend the pharmacological profile of sotagliflozin and suggest a potential role for the clinical use of combined SGLT1/SGLT2 inhibitors in the treatment of AF.

Antifungal effects of three natural branched medium-chain fatty acids and their potential as fumigants against Aspergillus flavus in stored peanut seeds

The contamination of peanuts with aflatoxins predominantly produced by Aspergillus flavus poses a worldwide threat to both food safety and agricultural economies. Antifungal compounds from natural sources may offer a safe and effective alternative strategy to control A. flavus in peanuts. We evaluated the contact and fumigant antifungal effects of three natural branched medium-chain fatty acids (branched-MCFAs), (E)-2-methyl-2-pentenoic acid, 2-methylhexanoic acid, and 2-methylheptanoic acid against A. flavus relative to their straight-chain isomers and sorbic acid a commonly used preservative. In vitro experiments showed that the inhibitory effects of these three branched-MCFAs on A. flavus were stronger than their straight-chain isomers and sorbic acid. In addition, fumigant effects of the branched-MCFAs were more effective than their direct contact inhibitory effects against the growth of A. flavus. 2-Methylhexanoic acid, 2-methylheptanoic acid, and (E)-2-methyl-2-pentenoic acid showed significant fumigant activity, with the minimum inhibitory concentration (MIC) values of 0.10, 0.10, and 0.12 g/l air, respectively. Fumigation of these branched-MCFAs also significantly slowed the growth of A. flavus in peanut seeds, and completely inhibited A. flavus growth at 2.0 g/l air. After 24 h of fumigation exposure to the branched-MCFAs, the fumigated A. flavus on medium or peanut seeds was re-incubated to observe whether the A. flavus could continue to grow, and the results revealed that the in vitro and in vivo minimum fungicidal concentrations (MFC) were 0.15 and 2.5 g/l air, respectively. This study indicated that these three natural branched-MCFAs have strong antifungal fumigation activity with application potential in protecting peanut seeds from A. flavus contamination during storage.

Daphnetin weakened the pathogenicity of methicillin-resistant Staphylococcus aureus by inhibiting Sortase A and α-hemolysin

The increasing prevalence of antibiotic-resistant bacteria, represented by Methicillin-resistant Staphylococcus aureus (MRSA), has necessitated a shift towards anti-virulence strategies in treatment approaches. This research demonstrated that daphnetin effectively disrupted MRSA virulence by targeting Sortase A (SrtA), an enzyme in Staphylococcus aureus (S. aureus) responsible for adhesion and invasion, as well as the toxin α-hemolysin (Hla) that leads to cell lysis. Utilizing Fluorescence Resonance Energy Transfer, daphnetin showed direct inhibitory effect on SrtA activity, with an IC50 of 25.98 μg/mL. Additionally, daphnetin hindered various SrtA-mediated processes in S. aureus, such as fibronectin adherence, A549 cell invasion, biofilm formation, and bacterial motility. Daphnetin inhibited S. aureus-induced hemolysis and reduced Hla expression as confirmed by Western blot analysis. Molecular docking studies identified specific binding sites of daphnetin with SrtA, highlighting key amino acid residues like GLU-77, TYR-75, and LYS-145, with a docking score of −7.139 kcal/mol. Besides that, daphnetin exhibited a protective effect on MRSA-induced pneumonia in vivo. In summary, daphnetin, a natural compound, effectively inhibited SrtA and Hla activities, attenuating MRSA virulence and showcasing potential for treating bacterial infections.

A novel high-level phenyllactic acid fungal producer, Kodamaea ohmeri w5 screened from fermented broad bean-chili-paste

Phenyllactic acid (PLA) is a broad-spectrum and efficient antimicrobial phenolic acid with potential applications in the food industry. Previous studies have demonstrated that fungi may be ideal producers of PLA. In this study, 15 fungi screened from Doubanjiang with the ability to produce PLA were first reported, including Wickerhamomyces anomalus, Candida etchellsii, Candida parasitosis, Pichia kudriavzevii, Pichia membranifaciens and Kodamaea ohmeri. Among them, K. ohmeri w5 had the highest PLA yield, producing up to 7160 mg/L PLA in shake flask fermentation with phenylalanine as substrate, which was more than ten times higher than the PLA produced by wild-type LAB under the similar conditions. In addition, K. ohmeri w5 was able to grow under extreme hypertonic conditions of 20 % NaCl (w/v) and 50 % glucose (w/v) as well as produce 57.12 ± 0.42 and 1609.22 ± 36.26 mg/L of PLA, respectively. Furthermore, the fermentation supernatant of K. ohmeri w5 demonstrated direct inhibitory effects against foodborne pathogenic microorganisms, Aspergillus flavus and Bacillus cereus. However, the inhibitory effect was weaker than that of the PLA standard at the same concentration. Further, 12,497,932 bp of w5 genome-wide information was obtained by sequencing and assembling. And its gene model was predicted based on transcriptomic evidence, which showed that a total of 7 genes related to PLA synthesis were identified in the w5 genome. Based on qRT-PCR, structure prediction, and molecular docking, a potentially key genetic resource from K. ohmeri w5 for PLA production was uncovered. The results will provide novel producers of PLA and its potential genetic resources.

The direct inhibitory effects of Lactobacillus acidophilus, a commensal urinary bacterium, on calcium oxalate stone development

BackgroundLactobacillus acidophilus is a commensal urinary bacterium found more abundantly in healthy individuals than in stone patients. Hence, it has been proposed to play an inhibitory role in kidney stone disease (KSD) but with unclear mechanisms. We therefore investigated the direct effects of L. acidophilus on calcium oxalate (CaOx) stone development compared with Escherichia coli, which is known to promote CaOx stone formation.ResultsL. acidophilus at 1 × 103 CFU/ml significantly reduced the abundance of newly formed crystals, enlargement and aggregation of seeded crystals, and crystal adhesion on renal cell membranes. By contrast, E. coli at 1 × 103 CFU/ml significantly enhanced crystal growth and aggregation but did not affect crystallization and crystal-cell adhesion. Oxalate consumption assay showed that neither L. acidophilus nor E. coli significantly reduced the remaining oxalate level after 1 − 3 h incubation. However, both of them adhered to CaOx crystals. Surface component detection revealed that only L. acidophilus expressed S-layer protein, whereas only E. coli exhibited flagella on their surfaces. Removal of L. acidophilus S-layer protein and E. coli flagella completely abolished the inhibitory and promoting effects of L. acidophilus and E. coli, respectively.ConclusionsL. acidophilus inhibits CaOx stone development by hampering crystallization, growth, aggregation and cell-adhesive ability of CaOx. By contrast, E. coli enhances CaOx stone development by promoting CaOx growth and aggregation. Their contradictory effects are most likely from differential surface components (i.e., S-layer protein on L. acidophilus and flagella on E. coli) not from oxalate-degrading ability.D_jrSVq7xgjsSvuNUfqm6AVideo

MiR-193b-3p/ PGC-1α pathway regulates an insulin dependent anti-inflammatory response in Parkinson's disease

It has been shown that many miRNAs, including miR-193b-3p, are differentially expressed in Parkinson's disease (PD). Dysregulation of miR-193b-3p/PGC-1α axis may alter homeostasis in cells and can induce an inflammatory response commonly accompanied by metabolic disturbances. The aim of the present study is to investigate if dysregulation of the miR-193-3p/PGC-1α axis may contribute to the pathological changes observed in the PD brain. Brain tissue were obtained from middle frontal gyrus of non-demented controls and individuals with a PD diagnosis. RT-qPCR was used to determine the expression of miR-193b-3p and in situ hybridization (ISH) and immunological analysis were employed to establish the cellular distribution of miR-193b-3p. Functional assays were performed using SH-SY5Y cells, including transfection and knock-down of miR-193b-3p. We found significantly lower expression of miR-193b-3p in the early stages of PD (PD4) which increased throughout disease progression. Furthermore, altered expression of PGC-1α suggested a direct inhibitory effect of miR-193b-3p in the brain of individuals with PD. Moreover, we observed changes in expression of insulin after transfection of SH-SY5Y cells with miR-193b-3p, which led to dysregulation in the expression of several pro- or anti - inflammatory genes. Our findings indicate that the miR-193b-3p/PGC-1α axis is involved in the regulation of insulin signaling. This regulation is crucial, since insulin induced inflammatory response may serve as a protective mechanism during acute situations but potentially evolve into a pathological process in chronic conditions. This novel regulatory mechanism may represent an interesting therapeutic target with potential benefits for various neurodegenerative diseases.

Vitamin D and Atherosclerosis: Unraveling the Impact on Macrophage Function.

Vitamin D plays a crucial role in preventing atherosclerosis and in the regulation of macrophage function. This review aims to provide a comprehensive summary of the clinical evidence regarding the impact of vitamin D on atherosclerotic cardiovascular disease, atherosclerotic cerebrovascular disease, peripheral arterial disease, and associated risk factors. Additionally, it explores the mechanistic studies investigating the influence of vitamin D on macrophage function in atherosclerosis. Numerous findings indicate that vitamin D inhibits monocyte or macrophage recruitment, macrophage cholesterol uptake, and esterification. Moreover, it induces autophagy of lipid droplets in macrophages, promotes cholesterol efflux from macrophages, and regulates macrophage polarization. This review particularly focuses on analyzing the molecular mechanisms and signaling pathways through which vitamin D modulates macrophage function in atherosclerosis. It claims that vitamin D has a direct inhibitory effect on the formation, adhesion, and migration of lipid-loaded monocytes, thus exerting anti-atherosclerotic effects. Therefore, this review emphasizes the crucial role of vitamin D in regulating macrophage function and preventing the development of atherosclerosis.

Analysis of fibrin networks using topological data analysis – a feasibility study

Blood clot formation, a crucial process in hemostasis and thrombosis, has garnered substantial attention for its implications in various medical conditions. Microscopic examination of blood clots provides vital insights into their composition and structure, aiding in the understanding of clot pathophysiology and the development of targeted therapeutic strategies. This study explores the use of topological data analysis (TDA) to assess plasma clot characteristics microscopically, focusing on the identification of the elements components, holes and Wasserstein distances. This approach should enable researchers to objectively classify fibrin networks based on their topologic architecture. We tested this mathematical characterization approach on plasma clots formed in static conditions from porcine and human citrated plasma samples, where the effect of dilution and direct thrombin inhibition was explored. Confocal microscopy images showing fluorescence labeled fibrin networks were analyzed. Both treatments resulted in visual differences in plasma clot architecture, which could be quantified using TDA. Significant differences between baseline and diluted samples, as well as blood anticoagulated with argatroban, were detected mathematically. Therefore, TDA could be indicative of clots with compromised stability, providing a valuable tool for thrombosis risk assessment. In conclusion, microscopic examination of plasma clots, coupled with Topological Data Analysis, offers a promising avenue for comprehensive characterization of clot microstructure. This method could contribute to a deeper understanding of clot pathophysiology and thereby refine our ability to assess clot characteristics.

Production of Disinfective Coating Layer to Facial Masks Supplemented with Camellia sinensis Extract.

Although usefulness of masks for protection against respiratory pathogens, accumulation of pathogens on their surface represents a source of infection spread. Here we prepared a plant extract-based disinfecting layer to be used in coating masks thus inhibiting their capacity to transmit airborne pathogens. To reach this, a polypropylene membrane base was coated with a layer of polyvinyledine difluoride polymer containing 500μg/ml of Camellia sinensis (Black tea) methanolic extract. Direct inhibitory effects of C. sinensis were initially demonstrated against Staphylococcus aureus (respiratory bacteria), influenza A virus (enveloped virus) and adenovirus 1 (non-enveloped virus) which were directly proportional to both extract concentration and incubation time with the pathogen. This was later confirmed by the capacity of the supplemented membrane with the plant extract to block infectivity of the above mentioned pathogens, recorded % inhibition values were 61, 72 and 50 for S. aureus, influenza and adenovirus, respectively. In addition to the disinfecting capacity of the membrane its hydrophobic nature and pore size (154nm) prevented penetration of dust particles or water droplets carrying respiratory pathogens. In summary, introducing this layer could protect users from infection and decrease infection risk upon handling contaminated masks surfaces.

High-efficiency lanthanum-modified zeolite adsorbents for phosphorus control and algal suppression: Preparation, characterization and mechanistic insights

The use of lanthanum (La)-based materials for phosphate removal from water has received increasing attention. However, challenges remain to enhance phosphate (P) sorption capacities and remove P at low concentrations. In this study, lanthanum modified zeolite materials loaded with different lanthanum types were synthesized by hydrothermal method. Based upon preliminary screening of synthesized La-modified zeolite materials in terms of phosphate sorption capacity and La content, lanthanum chloride-modified zeolite (LZ) is chosen for further study. Specifically, for these materials, phosphate sorption kinetics and isotherm behavior, and solution matrix effects (solution pH, and ionic strength) are reported. The developed LZ has a high sorption capacity of 124.38 mg/g, which exceeds that of most La-based adsorbents currently available. P uptake by LZ was pH-dependent with the highest sorption capacities observed over a pH range of 3 ∼ 9. The presence of coexisting ions (Cl-, SO42-, HCO3–) does not significantly affect the adsorption capacity of LZ. In a real treated wastewater effluent with phosphate concentration of 1.92 mg/L and 0.155 mg/L, 0.1 g/L and 0.01 g/L of LZ efficiently reduced the phosphate concentration to below 0.01 mg P/L. Electrostatic attraction and inner-sphere complexation were identified as the sorption mechanisms of phosphate by LZ. The acute toxicity test confirms that the addition of LZ has no acute toxicity effect on aquatic organisms. However, LZ shows indirect and direct inhibitory effects on algae growth, which is beneficial for the control of eutrophic water. Moreover, the exhausted LZ can be easily regenerated with over 70 % adsorption capacity remained during five recycles. Overall, LZ shows great application potential, and this work provides new insights into the molecular-level mechanism of phosphate sequestration by LZ.

LP340, a novel histone deacetylase inhibitor, decreases liver injury and fibrosis in mice: role of oxidative stress and microRNA-23a.

Effective therapy for liver fibrosis is lacking. Here, we examined whether LP340, the lead candidate of a new-generation of hydrazide-based HDAC1,2,3 inhibitors (HDACi), decreases liver fibrosis. Liver fibrosis was induced by CCl4 treatment and bile duct ligation (BDL) in mice. At 6 weeks after CCl4, serum alanine aminotransferase increased, and necrotic cell death and leukocyte infiltration occurred in the liver. Tumor necrosis factor-α and myeloperoxidase markedly increased, indicating inflammation. After 6 weeks, α-smooth muscle actin (αSMA) and collagen-1 expression increased by 80% and 575%, respectively, indicating hepatic stellate cell (HSC) activation and fibrogenesis. Fibrosis detected by trichrome and Sirius-red staining occurred primarily in pericentral regions with some bridging fibrosis in liver sections. 4-Hydroxynonenal adducts (indicator of oxidative stress), profibrotic cytokine transforming growth factor-β (TGFβ), and TGFβ downstream signaling molecules phospho-Smad2/3 also markedly increased. LP340 attenuated indices of liver injury, inflammation, and fibrosis markedly. Moreover, Ski-related novel protein-N (SnoN), an endogenous inhibitor of TGFβ signaling, decreased, whereas SnoN expression suppressor microRNA-23a (miR23a) increased markedly. LP340 (0.05mg/kg, ig., daily during the last 2weeks of CCl4 treatment) decreased 4-hydroxynonenal adducts and miR23a production, blunted SnoN decreases, and inhibited the TGFβ/Smad signaling. By contrast, LP340 had no effect on matrix metalloproteinase-9 expression. LP340 increased histone-3 acetylation but not tubulin acetylation, indicating that LP340 inhibited Class-I but not Class-II HDAC in vivo. After BDL, focal necrosis, inflammation, ductular reactions, and portal and bridging fibrosis occurred at 2 weeks, and αSMA and collagen-1 expression increased by 256% and 560%, respectively. LP340 attenuated liver injury, ductular reactions, inflammation, and liver fibrosis. LP340 also decreased 4-hydroxynonenal adducts and miR23a production, prevented SnoN decreases, and inhibited the TGFβ/Smad signaling after BDL. In vitro, LP340 inhibited immortal human hepatic stellate cells (hTERT-HSC) activation in culture (αSMA and collagen-1 expression) as well as miR23a production, demonstrating its direct inhibitory effects on HSC. In conclusions, LP340 is a promising therapy for both portal and pericentral liver fibrosis, and it works by inhibiting oxidative stress and decreasing miR23a.

Cyclosporin A inhibits PDGF-BB induced hyaluronan synthesis in orbital fibroblasts

Orbital connective tissue changes are contributors to the pathogenesis in thyroid eye disease (TED). Activated fibroblasts respond to immune stimuli with proliferation and increased hyaluronan (HA) production. Cyclosporin A (CsA) was reported to be beneficial in the treatment of TED. PDGF isoforms are increased in orbital tissue of TED patients and enhance HA production. We aimed to study the effect of CsA on HA production and hyaluronan synthase (HAS1, 2 and 3) and hyaluronidase (HYAL1 and 2) mRNA expressions in orbital fibroblasts (OFs). Measurements were performed in the presence or absence of CsA (10 μM) in unstimulated or PDGF-BB (10 ng/ml) stimulated OFs. The HA production of TED OFs (n = 7) and NON-TED OFs (n = 6) were measured by ELISA. The levels of mRNA expressions were examined using RT-PCR. The proliferation rate and metabolic activity were measured by BrdU incorporation and MTT assays, respectively. Treatment with CsA resulted in an average 42% decrease in HA production of OFs (p < 0.0001). CsA decreased the expression levels of HAS2, HAS3 and HYAL2 (p = 0.005, p = 0.005 and p = 0.002, respectively.) PDGF-BB increased HA production (p < 0.001) and HAS2 expression (p = 0.004). CsA could reduce the PDGF-BB-stimulated HA production (p < 0.001) and HAS2 expression (p = 0.005) below the untreated level. In addition, CsA treatment caused a decrease in proliferation potential (p = 0.002) and metabolic activity (p < 0.0001). These findings point to the fact that CsA affects HA metabolism via HAS2, HAS3 and HYAL2 inhibition in OFs. In addition to its well characterized immunosuppressant properties, CsA's beneficial effect in TED may be related to its direct inhibitory effect on basal and growth factor stimulated HA production.