Expression Of Interleukin Research Articles

α-Pyrrolidinooctanophenone facilitates activation of human microglial cells via ROS/STAT3-dependent pathway.

Pyrrolidinophenone derivatives (PPs) are amphetamine-like designer drugs containing a pyrrolidine ring, and their adverse effects resemble those of methamphetamine (METH). Microglial activation has been recently suggested as a key event in eliciting the adverse effects against dysfunction of the central nervous system. The aim of this study is to clarify the mechanisms of microglial activation induced by PPs. We employed the human microglial cell line HMC3 to assess microglial activation induced by PPs and evaluated the capacities for proliferation and interleukin-6 (IL-6) production that are characteristic features of the activation events. The WST-1 assay indicated that viability of HMC3 cells was increased by treatment with sublethal concentrations (5-20µM) of α-pyrrolidinooctanophenone (α-POP), a highly lipophilic PP, whereas it was decreased by treatment with concentrations above 40µM. Treatment with sublethal α-POP concentrations up-regulated the expression and secretion of IL-6. Additionally, α-POP-induced increase in cell viability was restored by pretreating with N-acetyl-L-cysteine, a reactive oxygen species (ROS) scavenger, and stattic, an inhibitor of signal transducer and activator of transcription 3 (STAT3), respectively, suggesting that activation of the ROS/STAT3 pathway is involved in the α-POP-induced activation of HMC3 cells. The increases in cell viability were also observed in HMC3 cells treated with other α-POP derivatives and METH. These results suggest that enhanced productions of ROS and IL-6 are also involved in microglial activation by drug treatment and that HMC3 cell-based system is available to evaluate accurately the microglial activation induced by abused drugs.

Lentiviral Injection of Inter-α-Trypsin Inhibitor Heavy Chain 4 Promotes Female Spinal Cord Injury Mice Recuperation by Diminishing Peripheral and Central Inflammation.

Inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) acts as a mediator of inflammation and extracellular matrix stabilization. The current study intended to delve into the impact of ITIH4 on locomotor performance, nerve injury, neuroinflammation, systemic inflammation, and the downstream pathway in spinal cord injury (SCI) mice. Overexpression lentivirus of ITIH4 (LV-ITIH4) and negative control lentivirus (LV-NC) were intravenously injected into adult C57BL/6 mice on 7days before SCI surgery. All mice were euthanized on day 28 after SCI surgery, and their blood samples and spinal cord tissues were collected. Decreased relative gene expression and protein levels of ITIH4 were observed in SCI mice. LV-ITIH4 improved the locomotor performance compared to LV-NC in SCI mice. In spinal cord of SCI mice, LV-ITIH4 reduced apoptosis and increased survival of neurons compared to LV-NC. By comparison with LV-NC, LV-ITIH4 also reduced relative gene expressions of interleukin (IL)-6 and tumor necrosis factor-α in spinal cord of SCI mice. Moreover, LV-ITIH4 reduced microglia M1 polarization compared with LV-NC in spinal cord of SCI mice. In the serum, LV-ITIH4 decreased the protein levels of IL-6 and IL-1β compared to LV-NC in SCI mice. LV-ITIH4 also inhibited the nuclear factor kappa-B (NF-κB) pathway compared to LV-NC in spinal cord of SCI mice. ITIH4 enhances locomotor performance in SCI mice, and it inhibits nerve injury, neuroinflammation, systemic inflammation, and the NF-κB pathway in SCI mice.

Helicobacter pylori Inhibition, Gastritis Attenuation, and Gut Microbiota Protection in C57BL/6 Mice by Ligilactobacillus salivarius NCUH062003

Helicobacter pylori (H. pylori), one of the most prevalent pathogenic bacteria worldwide, is the leading cause of gastritis, gastric intestinal metaplasia, and gastric cancer. Antibiotics, the conventional treatment for eliminating H. pylori, often lead to severe bacterial resistance, gut dysbiosis, and hepatic insufficiency and fail to address the inflammatory response or gastric mucosal damage caused by H. pylori infection. In this study, based on 10-week animal experiments, two models of L. salivarius NCUH062003 for the prophylaxis and therapy of H. pylori infection in C57BL/6 mice were established; a comprehensive comparative analysis was performed to investigate the anti-H. pylori effect of probiotics, the reduction in inflammation, and repair of gastric mucosal damage. ELISA, immunohistochemistry, and pathology analyses showed that NCUH062003 decreased the expression of pro-inflammatory cytokine interleukins (IL-1β, IL-6) and myeloperoxidase (MPO) and reduced neutrophil infiltration in the gastric mucosa lamina propria. Immunofluorescence and biochemical analysis showed that NCUH062003 resisted gastric epithelial cell apoptosis, increased the level of superoxide dismutase (SOD) in gastric mucosa, and promoted the expression of tight junction protein ZO1 and Occludin. In addition, through high-throughput sequencing, in the probiotic therapy and prophylactic mode, the diversity and composition of the gut microbiota of HP-infected mice were clarified, the potential functions of the gut microbiota were analyzed, the levels of short-chain fatty acids (SCFAs) were measured, and the effects of L. salivarius NCUH062003 on the gut microbiota and its metabolites in HP-infected mice treated with amoxicillin/metronidazole were revealed. This study provides functional strain resources for the development and application of microbial agents seeking to antagonize H. pylori beyond antibiotics.

The role of inflammasome dysregulation in obstructive and non-obstructive azoospermia: a comparative molecular analysis of blood, tissue, and seminal plasma

BackgroundTo address knowledge gaps, this study aimed to investigate the involvement of inflammasomes in the etiology of azoospermia. This study focused on the gene expression of key inflammasome components, including NLR family pyrin domain containing 3 (NLRP-3), CASPASE-1, Interleukin-1β (IL-1β), Interleukin-18 (IL-18), NLR family CARD domain-containing protein 4/ice protease-activating factor (NLRC-4/IPAF), and Absent in melanoma 2 (AIM-2).MethodsWe analyzed gene expression in blood and testicular tissue from patients with obstructive azoospermia (OA) and non-obstructive azoospermia (NOA). Additionally, we compared IL-1β and IL-18 expression levels in seminal plasma samples using the Enzyme-Linked Immunosorbent Assay (ELISA) method. For comparison, blood samples from normospermic (NS) individuals were also genetically evaluated.ResultsOur results indicated significantly higher gene expression of inflammasome components in NOA patients than those in OA patients either in blood or in testicular tissue. Both azoospermic groups exhibited higher mRNA levels of inflammasome genes comparing with those from blood samples of NS men. Seminal plasma samples showed significantly increased levels of IL-1β and IL-18 in NOA patients compared to men with OA. The ROC curve analysis indicated strong and significant predictive power of IL-18, AIM-2 and NLRC-4/IPAF gene expression profiles between NOA vs. NS patients and NOA vs. OA.ConclusionsOur findings highlight the role of hidden chronic inflammation in azoospermia, particularly within the NOA group. This study provides a foundation for further detailed research, which could aid in the development of diagnostic panels to differentiate between various azoospermic groups.

Necroptosis contributes to deoxynivalenol-induced liver injury and inflammation in weaned piglets

BackgroundThe aim of this study was to investigate the role of necroptosis in deoxynivalenol (DON)-induced liver injury and inflammation in weaned piglets.MethodsIn Exp. 1, 12 weaned piglets were divided into 2 groups including pigs fed basal diet and pigs fed diet contaminated with 4 mg/kg DON for 21 d. In Exp. 2, 12 weaned piglets were divided into 2 groups including control piglets and piglets given a gavage of 2 mg/kg body weight (BW) DON. In Exp. 3, 24 weaned piglets were used in a 2 × 2 factorial design and the main factors including necrostatin-1 (Nec-1) (DMSO or 0.5 mg/kg BW Nec-1) and DON challenge (saline or 2 mg/kg BW DON gavage). On 21 d in Exp. 1, or at 6 h post DON gavage in Exp. 2 and 3, pigs were killed for blood samples and liver tissues. Liver histology, blood biochemical indicators, and liver inflammation and necroptosis signals were tested.ResultsDietary or oral gavage with DON caused liver morphological damage in piglets. Dietary DON led to hepatocyte damage indicated by increased aspartate transaminase (AST) activity and AST/alanine aminotransferase (ALT) ratio, and DON gavage also caused hepatocyte damage and cholestasis indicated by increased AST and alkaline phosphatase (AKP) activities. Dietary DON caused liver necroptosis indicated by increased protein abundance of total receptor interacting protein kinase 3 (t-RIP3) and total mixed lineage kinase domain-like protein (t-MLKL). Moreover, DON gavage increased mRNA expression of interleukin (IL)-6 and IL-1β in liver. DON gavage also induced liver necroptosis demonstrated by increased protein abundance of t-RIP3, phosphorylated-RIP3 (p-RIP3), t-MLKL and p-MLKL. However, pretreatment with Nec-1, a specific inhibitor of necroptosis, inhibited liver necroptosis indicated by decreased protein expression of t-RIP3, p-RIP3, t-MLKL and p-MLKL. Nec-1 pretreatment reduced liver morphological damage after DON gavage. Pretreatment with Nec-1 also attenuated liver damage induced by DON indicated by decreased activities of AST and AKP. Furthermore, Nec-1 pretreatment inhibited liver mRNA expression of IL-6 and IL-1β after DON challenge.ConclusionsOur data demonstrate for the first time that necroptosis contributes to DON-induced liver injury and inflammation in piglets.

Impact of oral flora in tongue coating and saliva on oral cancer risk and the regulatory role of Interleukin-8

BackgroundOral flora and inflammatory factors play a crucial role in oral cancer, but the relationship between them and oral cancer has not been clearly established. MethodsOral flora served as exposure factor, oral cancer as outcome factor, and inflammatory factors as mediating factor. Mendelian randomization (MR) analysis was used to analyze the relationship between oral flora and oral cancer, and the potential mediating effect of inflammatory factors was explored through mediation analysis. Results29 kinds of oral flora in tongue coating and 22 kinds of oral flora in saliva were associated with increased risk of oral cancer. 18 species of oral flora in tongue coating and 25 species in saliva were associated with a reduced risk of oral cancer. Interleukin-8 (IL8) played a mediating role in the relationship between oral flora and oral cancer, and it was associated with an increased risk of oral cancer. Granulicatella, Streptococcus mitis, Saccharimonadaceae and Haemophilus in oral flora caused oral cancer indirectly through IL8. IL8 expression increased in oral cancer, which has good diagnostic value. IL8-related genes in oral cancer are closely associated with immune cell infiltration. What's more, IL8 has potential medicinal properties. ConclusionOral flora of tongue coating and saliva is closely related to oral cancer, and IL8 plays a mediating role in the causal relationship between oral flora and oral cancer.

Proinflammatory cytokines interleukin-18 and interleukin-6 mediate anorexia induction by trichothecene deoxynivalenol and its congeners

As the common foodborne mycotoxins with the highest pollution rate, deoxynivalenol (DON, also named “vomitoxin”) can harm the health of humans and animals by causing anorectic response. It has four congeners: 3-acetyldeoxynivalenol (3-ADON), 15-acetyldeoxynivalenol (15-ADON), nivalenol (NIV), and fusarenon X (FX). These five mycotoxins have been associated with the detrimental effect on food intake. However, its underlying mechanism of anorexia remains unclear. The goal of this research was to compare the anorectic responses to these five mycotoxins and relate these effects to proinflammatory cytokines interleukin-18 (IL-18) and interleukin-6 (IL-6) following intraperitoneal (IP) and oral exposure to a common dose at 2.5 mg/kg BW in mice. Plasma IL-18 and IL-6 were elevated within 1–2 h and returned to basal levels at 6 h after exposure to DON, 3-ADON and 15-ADON. FX promoted IL-18 expression at 6 h. Whereas, FX only promoted IL-6 at 6 h. When NIV was injected intraperitoneally, IL-18 started to rise at 1 h and peaked at 6 h. Whereas, NIV only promoted IL-18 at 2 h following oral exposure. IP exposure to NIV induced an increase in IL-6 that occurred only at 2 h. No effect on IL-6 when exposed orally to NIV. In conclusion, the data indicate that IL-18 and IL-6 play critical roles in anorectic response induced by DON and its four congeners 3-ADON, 15-ADON, NIV, FX.

Encapsulated Chlorhexidine Gel Use in Adolescents Undergoing Orthodontic Treatment: A Randomised Trial

IntroductionThe majority of orthodontic patients present with plaquebiofilm and related manifestations in the early stages of active fixed orthodontic appliance use. AimsTo evaluate the effects of a slow-delivery chlorhexidine:beta-cyclodextrin (Cx:β-Cd) gel compared with those of free Cx free formulations on clinical parameters in patients undergoing treatment with fixed orthodontic appliances. MethodsPatients aged 12-18 years received prophylaxis and scaling and were randomised to treatment groups in a double-blinded manner. They were treated with Cx:β-Cd, Cx, or placebo gel for 15 or 30 days. Bleeding on probing and the visible plaque index were recorded, and gingival crevicular fluid samples were collected for the assessment of cytokine expression. ResultsAt 15 days, the Cx:β-Cd group exhibited significantly less BOP than did the Cx and control groups (P < 0.001; n = 116). At 15 days, notable decreases in tumour necrosis factor-α and interferon-γ expression, as well as a substantial increase in interleukin-10 expression, were observed in the Cx:β-Cd and Cx groups relative to the control group (P < 0.05). The molecular encapsulation gel resulted in greater saliva Cx concentrations than did the free Cx gel released concentrations of 800 ng g−1. ConclusionCx:β-Cd gel is effective for the slow delivery of Cx, improving the gingival health of adolescents undergoing orthodontic treatment. Clinical relevanceA single application of encapsulated Cx gel, was a more effective antiseptic than a free Cx application in fixed orthodontice appliance wearers.

Sodium Butyrate Ameliorates Postoperative Delirium by Regulating Gut Microbiota Dysbiosis to Inhibit Astrocyte Activation in Aged Mice.

Postoperative delirium (POD) is a common complication in elderly surgical patients, with limited targeted interventions due to incomplete understanding of its pathophysiological mechanisms. Central nervous system (CNS) inflammation, involving glial cell activation, particularly astrocytes, is considered crucial in POD development. Butyrate, a four-carbon fatty acid, has shown protective effects in CNS diseases, but its potential in mitigating POD remains unclear. This study aimed to investigate the impact of sodium butyrate on POD in aged mice. Behavioral tests, including open field, Y maze, and food burying tests, demonstrated that sodium butyrate preconditioning ameliorated laparotomy-induced delirium in aged mice. Pre-treatment with sodium butyrate inhibited astrocyte activation in the hippocampus, reduced interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) expression levels, and protected hippocampal neurons. Furthermore, the study revealed a connection between gut microbiota regulation and central neuroprotective effects mediated by astrocyte activation inhibition. Sodium butyrate improved the intestinal morphological barrier by rebalancing gut microbiota, inhibiting Proteobacteria and Actinobacteria, reducing Allobaculum and Bacteroides abundance, and increasing Oscillospira abundance. This regulation decreased gut permeability, limiting the entry of toxic substances into the bloodstream, thereby reducing inflammation spread and astrocyte overactivation, leading to central anti-inflammatory effects. In conclusion, sodium butyrate may ameliorate POD by inhibiting astrocyte-mediated neuroinflammation through gut microbiota rebalancing.

Roles of S100A1 and S100A10 from hybrid grouper (Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀) in the immune response to Vibrio infection

The S100 proteins are highly conserved EF-hand calcium-binding proteins found only in vertebrates. In the current study, two S100 genes (S100A1 and S100A10) were successfully identified and characterized from hybrid grouper Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀. The deduced S100A10 protein contained two EF-hand domains, and S100A1 only possessed the N-terminal EF-hand. Phylogenetic analysis revealed that S100A1 and S100A10 from hybrid grouper were evolutionarily closely related to their counterparts in other selected vertebrates. Quantitative real-time PCR results revealed that the transcripts of S100A1 and S100A10 mRNA were ubiquitously distributed in all the examined tissues. After Vibrio alginolyticus infection, the expression of S100A1 and S100A10 in the spleen increased significantly. Moreover, overexpression of S100A1 and S100A10 could not only regulate the expression of interleukin 8 (IL-8), IL-10, and IL-16 in the head kidney, liver, and spleen, change the activities of acid phosphatase, catalase, lysozyme, and superoxide dismutase in serum, but also reduce the promoter activities of interferon 3 and nuclear factor kappa-B in vitro. Taken together, this study indicated that S100A1 and S100A10 participate in the immune response of hybrid grouper against bacterial infection.

Untargeted serum metabonomic reveals alleviated ovalbumin-induced asthma by Baijin Pingchuan through primary bile acid biosynthesis.

To investigate the effect of baijinpingchuan (, BJPC) on the asthma rat model and identify differential metabolites and disturbed metabolic pathways. The rats were categorized into six groups: control, dexamethasone (DEX), ovalbumin (OVA), and low-, median-, and high-dose BJPC. The rats, except for the control group, were initially treated with OVA to develop the asthma model, which was then activated using DEX, OVA, and low-, median-, and high-dose BJPC. Enzyme-linked immunosorbent assay kit was used to detect the expression of interleukin (IL)-33, IL-25, thymic stromal lymphopoietin (TSLP), and transforming growth factor-beta 1 (TGF-β1). Hematoxylin and eosin staining were performed to observe the pathological condition of the lung. Untargeted serum metabonomic analysis was conducted to identify differential metabolites and disturbed metabolic pathways. High-dose BJPC significantly inhibited the expression of IL-33, IL-25, TSLP, and TGF-β1 (P < 0.0001). Further, high-dose BJPC improved inflammatory cell infiltration, which plays a similar role in asthma as DEX. OVA-induced and BJPC-treated rats were identified through 17 differential metabolites, especially cholic acid. Furthermore, primary bile acid biosynthesis was a significantly differential pathway in the mechanism of BJPC for treating asthma. BJPC plays an anti-inflammation role in asthma, which might be a promising therapy through mediating primary bile acid biosynthesis.

Expression of periostin in the epithelium of cholesteatoma with different degrees of ossicular chain destruction and its clinical value in predicting postoperative hearing recovery

ObjectivesTo explore the expression of periostin in the epithelium of cholesteatoma with different destruction degrees of the ossicular chain and its clinical value in predicting postoperative hearing recovery.MethodsRetrospective analysis was conducted on the clinical data of 100 patients with middle ear cholesteatoma (the cholesteatoma group) admitted to our hospital. Another 100 patients without middle ear cholesteatoma treated in our hospital during the same period were included in the non-cholesteatoma group. Middle ear cholesteatoma patients were further divided into a normal group, a partial destruction group, and a complete destruction group based on the destruction degree of the ossicular chain (Maresh grading). After the treatment, 75 cases were considered as the effective group and 25 cases as the ineffective group. The expression of tumor necrosis factor-alpha, Interleukin 6, and periostin in the epithelium of middle ear cholesteatoma patients with different destruction degrees of the ossicular chain and different therapeutic effects were compared. The correlation between periostin and inflammatory factors was analyzed using Pearson analysis. The predictive value of tumor necrosis factor-alpha, Interleukin 6, and periostin on treatment effect was valued using the receiver operating characteristic curve.ResultsPatients in the cholesteatoma group had a much higher content of tumor necrosis factor-alpha, Interleukin 6, and periostin than those in the non-cholesteatoma group (P < 0.001). The expression of tumor necrosis factor-alpha, Interleukin 6, and periostin was also largely increased with the destruction group of the ossicular chain. Patients in the ineffective group had much higher expression of tumor necrosis factor-alpha, Interleukin 6, and periostin than those in the effective group (P < 0.001). The Pearson correlation analysis results showed that periostin was positively correlated with the content of tumor necrosis factor-alpha and interleukin 6 (P = 0.868, 0.880, P < 0.001). The areas under the curve of individual or joint tumor necrosis factor-alpha, Interleukin 6, and periostin were 0.627, 0.793, 0.822, and 0.892, respectively.ConclusionsThe expressions of periostin, Interleukin 6, and tumor necrosis factor-alpha were markedly increased in the epithelium of middle ear cholesteatoma patients, which were gradually increased with the aggravation of the ossicular chain destruction. Periostin, Interleukin 6, and tumor necrosis factor-alpha could be used as important indicators to predict postoperative hearing recovery.

Bioinformatics and molecular docking reveal Cryptotanshinone as the active anti-inflammation component of Qu-Shi-Xie-Zhuo decoction by inhibiting S100A8/A9-NLRP3-IL-1β signaling

BackgroundGout is a common type of arthritis marked by monosodium urate (MSU) crystal deposition in joints, triggering an inflammatory response. Qu-Shi-Xie-Zhuo (QSXZ), a traditional Chinese medicine (TCM) formula, has been clinically used for the treatment of gouty arthritis (GA). PurposeThe study sought to examine the impact of QSXZ on GA and to delve into the pharmacological mechanisms that underlie its effects. MethodsThe chemical constituents of QSXZ were analyzed through UPLC-MS. MSU-induced acute gouty arthritis (AGA) and subcutaneous (SC) air pouch models in mice were employed to evaluate the anti-inflammatory properties of QSXZ and its primary active compound, Cryptotanshinone (CTS). To investigate the therapeutic mechanisms of QSXZ, we used MS-based network pharmacology, transcriptomic analysis, molecular docking and multiscale bioassays. ResultsTreatment of QSXZ revealed a significant reduction of inflammatory cell infiltration and the expression of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin -1β (IL-1β). Based on UPLC/MS/MS results, 49 components were considered the active ingredients of QSXZ. Network pharmacology analysis indicated that QSXZ regulates multiple inflammation-related pathways. Subsequent transcriptomic analysis showed that QSXZ regulates gene expression of S100A8 and S100A9. Our investigation observed an increased expression of S100A8 and S100A9 in monocytes derived from gout patients. Molecular docking and molecular dynamics simulation analysis revealed the binding pattern and interaction between QSXZ active compound CTS and S100A8/A9, and subsequent surface plasmon resonance (SPR) and cell thermal shift assay (CETSA) experiments verified the direct interaction between them. To investigate the mechanisms of action, we conducted RT-PCR, Western blotting, immunohistochemistry, flow cytometry, and measured the inflammatory response. Our findings highlight the pathogenic role of S100A8/A9 mediated TLR4-NLRP3 axis in gout and review outstanding therapeutic effects of QSXZ and its primary active compound CTS on MSU-induced experimental models. ConclusionsIn summary, this study substantiates the therapeutic potential of QSXZ and its primary active compound CTS, as promising alternative treatments for GA. Our findings provide valuable insight into the critical pharmacological mechanism of QSXZ in regulating inflammation, highlighting its potential therapeutic effects in GA management.

Lenvatinib-activated NDUFA4L2/IL33/PADI4 pathway induces neutrophil extracellular traps that inhibit cuproptosis in hepatocellular carcinoma.

Lenvatinib is a potent first-line therapy for patients with hepatocellular carcinoma (HCC), but it also increased the number of neutrophils in HCC tumor microenvironment. CitH3, MPO-DNA, elastase and MPO activity were measured for assessing neutrophil extracellular traps (NETs) in vivo and in vitro. Cell cuproptosis was assessed by measurement of copper content, FDX1, and pyruvate. The functions of lenvatinib, DNase I, interleukin 33 (IL33) neutralizing antibody and GPX4 in tumor growth were explored in mice. Lenvatinib induced NETs in the HCC tumor microenvironment via HCC cells, but not through the direct stimulation of neutrophils. In addition, NET clearance by DNase I improves the efficacy of lenvatinib therapy in HCC mouse models. Mechanistically, lenvatinib promoted the expression and secretion of IL33 by HCC cells that triggered NET formation. Moreover, IL33 knockdown in Hepa1-6 cells improved lenvatinib efficacy in Hepa1-6-bearing HCC model mice and reduced NET formation in the tumor microenvironment. Subsequently, lenvatinib increased IL33 production by increasing the NDUFA4L2 expression in HCC cells. Furthermore, we found that IL33 triggered NET formation in neutrophils by increasing the protein expression of PADI4 via the Akt/mTOR signaling pathway. Rapamycin inhibition of mTOR reduced PADI4 expression and NET formation. Consistently, PADI4 inhibition by the selective PAD4 inhibitor GSK484 hydrochloride (GSK484) improved lenvatinib response to HCC therapy. Importantly, NETs contribute to lenvatinib resistance by inhibiting cuproptosis, but not apoptosis, pyroptosis, or ferroptosis in HCC cells. Treatment with GSK484 reversed the inhibitory effects of NETs on cuproptosis and sensitized the HCC cells to lenvatinib. Our study revealed that lenvatinib-induced NETs inhibited the cuproptosis of HCC cells, suggesting that targeting the IL33/PADI4/NET axis represents a promising therapeutic strategy for ameliorating lenvatinib resistance in HCC.

Extracellular matrix stiffness facilitates neurite outgrowth by reprogramming the fatty acid oxidation-dependent macrophage polarization

The extracellular matrix (ECM) is involved in various of pathophysiology processes, such as wound healing and neurogenesis. During tissue injury, the recruited bone marrow-derived monocytes in the impaired site undergo functional and phenotypic changes and participate in the initiation, maintenance, and resolution phases of tissue repair. However, the effects of ECM stiffness on monocyte differentiation and function remain largely unknown. Herein, we developed a gelatin-hydroxyphenylpropionic acid-based hydrogel with different substrate stiffnesses by varying hydrogen peroxide concentrations, which demonstrated good biocompatibility. Furthermore, the high substrate stiffness hydrogel could polarize macrophage into immunosuppressive phenotype with increased expression of interleukin 10, transforming growth factor β, CD206, and CD163. Twenty three differentially expressed metabolites were identified in stiff hydrogel-cultured macrophages in comparison with soft hydrogel cultured macrophages via metabolite analysis. In addition, 4-hydroxybenzoic acid was the most upregulated metabolite, which could confer protection against neuronal and acute inflammation. Mechanistically, the high substrate stiffness induced macrophage immunosuppressive differentiation by upregulating the expression of the fatty acid oxidation (FAO)-related proteins peroxisome proliferator-activated receptor (PPAR)-γ and PPAR-δ. Consistently, the FAO inhibitor etomoxir reversed the high substrate stiffness mediated macrophage immunosuppressive polarization and neurite outgrowth. Therefore, the alteration in macrophage phenotype induced by increased substrate stiffness can promote tissue repair in clinical applications.

Effects of intranasal administration with a symbiotic strain of Bacillus velezensis NSV2 on nasal cavity mucosal barrier in lambs.

The nasal mucosa is composed of multiple layers of barrier structures and is the first line of defense against infection by respiratory pathogenic microorganisms. A large number of commensal microorganisms are present in the nasal mucosa that mediate and regulate nasal mucosal barrier function. The objective of this research was to investigate the effects of commensal microorganisms on the nasal mucosal barrier. The results revealed that the strain of Bacillus velezensis (B. velezensis) NSV2 from the nasal cavity has good probiotic abilities to resist Pasteurella multocida, Staphylococcus aureus, Escherichia coli and Salmonella typhimurium. Lambs were subsequently administered intranasally with B. velezensis NSV2 at 3, 12, 21, and 26 days old, respectively. For the microbial barrier, although B. velezensis NSV2 reduces the diversity of nasal microbiota, it significantly increased the relative abundance of beneficial bacteria in the nasal cavity, and reduced the abundance of potential pathogenic bacteria. For the mucus barrier, the number of goblet cells in the nasal mucosa significantly increased after B. velezensis NSV2 treatment. For the immune barrier, B. velezensis NSV2 also significantly increased the number of IgA+ B cells, CD3+ T cells and dendritic cells in the nasal mucosa, as well as the mRNA expression of interleukin (IL) 6, IL11, CCL2, and CCL20 (P < 0.05). The protein level of CCL20 also significantly raised in nasal washings (P < 0.05). Moreover, the heat-inactivated and culture products of B. velezensis NSV2 also drastically induced the expression of CCL20 in nasal mucosa explants (P < 0.05), but lower than that of the live bacteria. This study demonstrated that a symbiotic strain of B. velezensis NSV2 could improve the nasal mucosal barrier, and emphasized the important role of nasal symbiotic microbiota.

Silibinin-Loaded Liposomes: The Influence of Modifications on Physicochemical Characteristics, Stability, and Bioactivity Associated with Dermal Application.

The aims of the presented study were the development of four types of silibinin-loaded liposomes (multilamellar liposomes-MLVs, sonicated small unilamellar liposomes-SUVs, UV-irradiated liposomes, and lyophilized liposomes) and their physicochemical characterization and biological potential related to skin health benefits. The characterization was performed via the determination of the encapsulation efficiency (EE), particle size, polydispersity index, zeta potential, conductivity, mobility, storage stability, density, surface tension, viscosity, FT-IR, and Raman spectra. In addition, cytotoxicity on the keratinocytes and antioxidant and anti-inflammatory potential were also determined. UV irradiation significantly changed the rheological and chemical properties of the liposomes and increased their cytotoxic effect. The lyophilization of the liposomes caused significant changes in their EE and physical characteristics, decreased their ABTS and DPPH radical scavenging potential, and increased their potential to reduce the expression of interleukin 1 beta (IL-1β) in cells treated with bacterial lipopolysaccharide. Sonication significantly changed the EE and physical and rheological properties of the liposomes, and slightly increased their cytotoxicity and reduction effect on IL-1β, while the anti-ABTS and anti-DPPH capacity of the liposomes significantly increased. All developed liposomes showed an increasing trend in particle size and a decreasing trend in zeta potential (absolute values) during storage. Silibinin-loaded liposomes (MLVs and lyophilized) showed promising antioxidant activity (toward reactive oxygen species generated in cells) and anti-inflammatory effects (reducing macrophage inhibitory factor expression) on keratinocytes and did not lead to a change in their viability. Future perspectives will focus on wound healing, anti-aging, and other potential of developed liposomes with silibinin in sophisticated cell-based models of skin diseases, wounds, and aging.

The Protective Effects of Citrulline on Testicular Injury Induced by Torsion and Detorsion in Adult Male Rats: An Experimental Study

Background: Testicular torsion is a critical urological emergency that can lead to testicular ischemia and significant tissue damage. Citrulline, a supplement known for enhancing cellular metabolism and mitigating oxidative stress and inflammation, has been explored for its protective effects against testicular injury resulting from torsion and detorsion in rat models. Methods: This study involved 42 Wistar rats, divided into six groups: Sham, torsion/detorsion (T/D), and four groups receiving varying doses of Citrulline (300, 600, 900 mg/kg) and vitamin E (20 mg/kg). A surgical procedure was performed to induce torsion by rotating the left testicle for 4 hr, followed by reperfusion. Daily oral administration of the supplements continued for one week post-surgery. Assessments included oxidative stress markers, apoptosis, inflammation, pathology, and sperm parameters. Statistical analysis was conducted using GraphPad Prism. Results: Citrulline administration at doses of 600 and 900 mg/kg significantly reduced malondialdehyde (MDA) and reactive oxygen species (ROS) levels. Additionally, it increased glutathione (GSH) levels and decreased protein carbonyl levels at the 900 mg/kg dose. The expression of interleukin-6 (IL-6) decreased at 900 mg/ kg, tumor necrosis factor-alpha (TNF-α) levels dropped at 600 and 900 mg/kg, and the pro-apoptotic factor Bax was reduced at all doses. Sperm analysis showed improved sperm count and motility at the 900 mg/kg dose. Histological examination revealed significant positive effects of Citrulline on testicular tissue. Conclusion: Citrulline effectively lowers oxidative stress, inflammation, while enhancing sperm quality and pathological outcomes. These results indicate that Citrulline has potential as a therapeutic agent for testicular torsion.

Antioxidative hydrogel based on hyaluronic acid/polyethylene glycol loaded with shikonin-coated flexible liposome and evaluation of its therapeutic effect on eczema

Eczema, a common skin condition, is gaining attention due to its increasing annual prevalence and severe influence on both bodily and mental health. Existing treatments for this disease often have significant side effects and safety concerns. Comfrey, a traditional Chinese herbal remedy, is commonly used to treat skin conditions. Shikonin, the primary active compound in comfrey, has demonstrated efficacy in treating eczema. Herein, a flexible liposome-containing SHI was dispersed in hydrogels based on hyaluronic acid (HA) and polyethylene glycol(PEG) for the treatment of eczema. The hydrogel performed well in delaying drug release. SHI-F-Gel demonstrated notable antioxidant properties, effectively eliminating over 80 % of free radicals. Compared to the SHI solution, SHI-F-Gel significantly increased drug skin retention by 312.9 %. In animal studies, SHI-F-Gel administration reduced epidermal thickness in the affected area by approximately 36.8 % and increased collagen deposition by 90.23 %. Additionally, SHI-F-Gel inhibited the expression of pro-inflammatory cytokines interleukin-4 (IL-4) and IL-17. This observed reduction in inflammation suggests that the treatment is effective. In conclusion, the flexible SHI-based liposome hydrogel demonstrates excellent adhesion and biocompatibility, making it a promising candidate for enhancing eczema treatment.

P75NTR Modulation Reduces Oxidative Stress and the Expression of Pro-Inflammatory Mediators in a Cell Model of Rett Syndrome.

Background: Rett syndrome (RTT) is an early-onset neurological disorder primarily affecting females, leading to severe cognitive and physical disabilities. Recent studies indicate that an imbalance of redox homeostasis and exacerbated inflammatory responses are key players in the clinical manifestations of the disease. Emerging evidence highlights that the p75 neurotrophin receptor (p75NTR) is implicated in the regulation of oxidative stress (OS) and inflammation. Thus, this study is aimed at investigating the effects of p75NTR modulation by LM11A-31 on fibroblasts derived from RTT donors. Methods: RTT cells were treated with 0.1 µM of LM11A-31 for 24 h, and results were obtained using qPCR, immunofluorescence, ELISA, and Western blot techniques. Results: Our findings demonstrate that LM11A-31 reduces OS markers in RTT fibroblasts. Specifically, p75NTR modulation by LM11A-31 restores protein glutathionylation and reduces the expression of the pro-oxidant enzyme NOX4. Additionally, LM11A-31 significantly decreases the expression of the pro-inflammatory mediators interleukin-6 and interleukin-8. Additionally, LM11A-31 normalizes the expression levels of transcription factors involved in the regulation of the antioxidant response and inflammation. Conclusions: Collectively, these data suggest that p75NTR modulation may represent an effective therapeutic target to improve redox balance and reduce inflammation in RTT.