Interleukin Research Articles

Basophils: Regulators of lung inflammation over space and time.

In this issue of JEM, Schuijs et al. (https://doi.org/10.1084/jem.20240103) highlight a novel role for basophils during allergic immune responses to house dust mites (HDM). They reveal that interleukin-33 (IL-33)-activated basophils facilitate the recruitment and extravasation of Th2 cells into the lungs during a specific time frame via their interactions with pulmonary endothelial cells.

Human serum albumin promotes interactions between HSA-IL-2 fusion protein and CD122 for enhancing immunotherapy

Interleukin 2 (IL-2) is a multifunctional cytokine that is crucial for T-lymphocytes proliferation and differentiation. However, IL-2 binds to IL-2Rα (CD25) subunit preferentially and tends to stimulate regulatory T cells (Tregs), which express high-affinity trimeric receptors (IL-2Rαβγ), resulting in immunosuppressive effects. Therefore, development of methods that enhance IL-2/CD122 interactions and activate immune responses without affecting therapeutic efficacy of IL-2 may be desirable. In this work, we constructed a recombinant IL-2 fusion protein (HSA-IL-2), comprising human serum albumin (HSA) and IL-2, there was a new interaction interface between HSA domain and CD122 in HSA-IL-2 fusion protein predicted by AlphaFold2, and followed by determining binding affinity between HSA-IL-2 and CD122 through ForteBio’s Bio-Layer Interferometry technology. Strikingly, HSA did promoted interactions between HSA-IL-2 fusion protein and CD122 compared with wild-type IL-2. In vivo experiments, HSA-IL-2 fusion protein had capacity to promote CD8+ T cells infiltration while reducing Treg cells infiltration for boosting immunotherapeutic efficacy. Furthermore, it facilitated synergistic therapeutic effect with α-PD-L1 to inhibit tumor growth. Overall, our research unveiled an enhanced binding affinity method underlying interactions between IL-2 and CD122 via fusing albumin, and propose a promising therapeutic strategy to facilitate IL-2 administration and broaden its clinical use.

Circulating interleukin-33 levels in obesity and type 2 diabetes: a systematic review and meta-analysis.

Obesity and type 2 diabetes (T2D) are increasingly prevalent worldwide, and there is a critical need for novel interventions. Interleukin-33 (IL-33), an anti-inflammatory cytokine that regulates metabolism, is a promising biomarker for these conditions. The goal of this systematic review and meta-analysis is to examine the role of IL-33 in obesity and T2D, assessing its potential in predicting disease progression. A systematic search was performed on Scopus, Web of Science, and PubMed up until May 30, 2023. Each study was assessed for quality and sources of bias using the relevant critical appraisal checklists. Meta-analyses were conducted to compare IL-33 levels in individuals with obesity and T2D versus healthy controls (HC), and in obesity alone versus HC. Eighteen studies were included in the systematic review, and nine qualified for meta-analyses. The analyses showed insufficient evidence to suggest a significant difference in IL-33 levels between individuals with T2D and HC (mean difference, MD = -79.95, 95% CI [-241.38; 81.48]), with substantial heterogeneity across the studies observed (I2 = 97.1%, τ2 = 33,549.15). Similarly, there was insufficient evidence to suggest a significant difference between nondiabetic individuals with obesity and HC (MD = -7.31, 95% CI [-25.74; 11.13]), and heterogeneity was noted (I2 = 86.2%, τ2 = 342.45). There is insufficient evidence to indicate significant differences in IL-33 levels in individuals with T2D or obesity compared with HC. The results suggest a need for improved IL-33 measurement methods to reduce heterogeneity, enhancing understanding of the role of IL-33 in obesity and T2D, and informing future research and therapeutic strategies.NEW & NOTEWORTHY Our research finds an inconclusive relationship between IL-33 serum levels in individuals with type 2 diabetes (T2D) and nondiabetic individuals with obesity. In addition, we note a potential gender association with IL-33 serum levels. Further studies with larger cohorts are required to assess the significance of serum IL-33 in T2D and obesity. Urgent standardization is needed in IL-33 quantification and reporting methods for reliable comparisons.

Evaluation of the anti-arthritic properties of Litsea glutinosa (L.) C.B. Rob Bark: An integrated analysis utilizing in-silico, in-vitro, and in-vivo approaches, along with identification of major compounds

The current study explored the anti-arthritic properties of Litsea glutinosa bark extracts. The dried bark of L. glutinosa was defatted with n-hexane and extracted by methanol using a soxhlet apparatus. The bioactive compounds present in the extract were analysed by GC-MS and LC-MS. The methanol extract of L. glutinosa (MELG) was evaluated at different concentrations (25–400 mg/ml) for its in-vitro anti-arthritic efficacy using membrane stabilization and protein denaturation techniques. In in-vivo evaluation paw diameter, arthritic score, arthritic index, body weight, organ weight, and haematological and biochemical parameters were measured to assess anti-arthritic potential. Subsequently, pro-inflammatory and inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), IL-1β, cyclooxygenase-2 (COX-2), IL-13, and IL-10 were determined. The Compounds identified by GC–MS and LC-MS were subjected to an in-silico molecular docking analysis utilizing AutoDock 4.2 and BIOVIA-Discovery Studio Visualizer against COX-2, IL-1β, IL-6, and TNF-α. The in vitro anti-arthritic effect of MELG exhibited a dose-dependent reduction in membrane stabilization (67.9 % at 400 µg/ml) and protein denaturation assay (66.6 % at 400 µg/ml). MELG treated rats improved all arthritic parameters. Significant restoration of pro-inflammatory cytokines was observed in rats administered with MELG (200 & 400 mg/kg). In the MELG (400 mg/kg) treated group, there was a significant reduction in IL-10 (P˂0.001) and IL-13 (P˂0.05) levels and a substantial rise in IL-6 (P˂0.01), TNF-α (P̂˂0.001), and IL-1β (P˂0.01) levels. The presence of phytoconstituents was analyzed by GC–MS (Fourteen compounds) and LC-MS (Ten compounds). Boldine identified by LC-MS analysis, exhibited good docking scores against COX-2 (-8.7), IL-1β (-6.3 kcal/mol), IL-6 (-6.2 kcal/mol), and TNF-α (-6.7 kcal/mol).The presence of bioactive compound, boldine in MELG might be responsible for its anti-arthritic activity.

Maternal hair lead and cytokine pro-inflammatory effects in preterm birth

This case-control study analyzed the lead (Pb), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) levels in pregnant women with preterm birth (PTB) in Central Java, Indonesia. Hair samples from 72 pregnant women were collected non-invasively. The prenatal exposure to Pb was determined with the total reflection X-ray fluorescence (TXRF) method. Serum IL-6 and TNF-α were examined using enzyme-linked immunosorbent assays (ELISA). The Pb concentration in hair was slightly higher in women with PTB than those without PTB; however, this difference was not statistically significant. An elevated hair Pb level was not associated with increased PTB risk (OR 24.69, 95% CI 0.93–653.82, p>0.05). A serum TNF-α level ≥27 pg/ml, a serum IL-6 level ≥9 pg/ml, and the spouse’s smoking frequency were significantly associated with increased PTB risk (TNF-α OR 42.25, 95% CI 5.26–339.61; IL-6 OR 22.33, 95% CI 3.12–158.54; spouse’s smoking frequency OR 1.28, 95% CI 1.09–1.5), while the maternal hemoglobin concentration significantly decreased PTB risk (OR 0.43, 95% CI 0.2–0.927). This study demonstrates that maternal hair Pb concentration has no significant relationship with PTB. Serum TNF-α, IL-6, and the spouse’s smoking frequency potentially increased PTB risk, while the maternal hemoglobin level is a protective factor.

Elevated serum and cerebrospinal fluid levels of Interleukin-4 related to poor outcome of Aneurysmal subarachnoid hemorrhage

Aneurysmal subarachnoid hemorrhage (aSAH) is a hemorrhagic cerebrovascular disease that seriously jeopardizes human life and health. Some studies have shown that although Interleukin-4 (IL-4) acts as an anti-inflammatory factor, IL-4 levels are elevated when the disease occurs. This study focuses on exploring the relationship between IL and 4 concentrations in the serum and cerebrospinal fluid (CSF) and poor outcome in patients with aSAH. This study was a prospective observational study and 210 aSAH patients who met the inclusion criteria were divided into two groups according to the mRS score at 3 months after discharge, and 210 healthy people were selected as controls. The IL-4 concentrations were quantitatively determined with enzyme-linked adsorption assay (ELISA). We can draw a conclusion that Serum and CSF IL-4 concentrations are generally elevated in patients with poor outcome(P < 0.05), and the CSF IL-4 concentration decreased gradually over the progress of time (P < 0.05). The IL-4 concentration in the CSF was positively correlated with age, platelet-lymphocyte ratio (PLR), C-reactive protein (CRP), Hunt-Hess grade, mRS score, and World Federation of Neurological Surgeons score (WFNS) (P < 0.0001). Additionally, IL-4 concentrations in the CSF were correlated with complications such as intracranial infection (P = 0.01), cerebral edema (P < 0.01), hydrocephalus (P = 0.02), and complications by DCI (P = 0.02). Elevated serum and CSF concentrations of IL-4 may associated with the outcome of aSAH and may be a candidate early biomarkers for outcome of aSAH.

Immunomodulatory Roles of IL-15 in Immune Cells and its Potential for Cancer Immunotherapy.

Interleukin-15 (IL-15) was identified in 1994 as a T-cell growth factor with the capability to mimic the functions of IL-2. IL-15 engages with the IL-15Rα subunit expressed on the surface of antigen-presenting cells (APCs) and, through a trans-presentation mechanism, activates the IL-2/IL-15Rβγ complex receptor on the surface of natural killer (NK) cells and CD8+ T cells. This interaction initiates a cascade of downstream signaling pathways, playing a pivotal role in the activation, proliferation, and anti-apoptotic processes in NK cells, CD8+ T cells, and B cells. It provides a substantial theoretical foundation and potential therapeutic targets for tumor immunotherapy. Whether through active or passive immunotherapeutic strategies, IL-15 has emerged as a critical molecule for stimulating anti-tumor cell proliferation.

Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and their influence on inflammatory biomarkers in pregnancy: Findings from the LIFECODES cohort

BackgroundPer- and polyfluoroalkyl substances (PFAS) are fluorinated chemicals linked to adverse pregnancy and birth outcomes. However, the underlying mechanisms, specifically their effects on maternal inflammatory processes, are not well characterized. ObjectiveWe examined associations between prenatal PFAS exposure and repeated measures of inflammatory biomarkers, including C-reactive protein (CRP) and four cytokines [Interleukin-10 (IL-10), IL-1β, IL-6, and tumor necrosis factor-α (TNF-α)]. MethodsWe analyzed data from 469 pregnant women in a nested case-control study of preterm birth at Brigham and Women’s Hospital in Boston, Massachusetts (2006–2008). We measured nine PFAS in early pregnancy plasma samples (median gestation: 10 weeks), with inflammatory biomarkers measured at median gestations of 10, 18, 26, and 35 weeks. We used linear mixed effects models for repeated measures and multivariable regression for visit-specific analysis to examine associations between each PFAS and inflammation biomarker, adjusting for maternal demographics, pre-pregnancy BMI, and parity. We examined PFAS mixture effects using sum of all PFAS (∑PFAS) and quantile-based g-computation approaches. ResultsWe observed consistent inverse associations between most PFAS and cytokines, specifically IL-10, IL-6, and TNF-α, in both single pollutant and mixture analyses. For example, an interquartile range increase in perfluorooctanesulfonic acid was associated with −10.87 (95% CI: −19.75, −0.99), −13.91 (95% CI: −24.11, −2.34), and −8.63 (95% CI: −14.51, −2.35) percent change in IL-10, IL-6, and TNF-α levels, respectively. Fetal sex, maternal race, and visit-specific analyses showed associations between most PFAS and cytokines were generally stronger in mid-pregnancy and among women who delivered males or identified as African American. ConclusionsThe observed suppression of both regulatory (IL-10) and pro-inflammatory (TNF-α) cytokines suggests that PFAS may alter maternal inflammatory processes or immune functions during pregnancy. Further research is needed to understand the effects of both legacy and newer PFAS on inflammatory pathways and their broader clinical implications.

Combating Oxidative Stress and Inflammation in Gentamicin-Induced Nephrotoxicity Using Hydrogen-Rich Water

Gentamicin-induced nephrotoxicity primarily results from renal inflammatory cascades and increased oxidative stress. This study aims to examine the effects of hydrogen-rich water (HRW) on gentamicin-induced renal damage in rats. Thirty-two rats were equally divided into four groups, including control (no treatment), hydrogen, gentamicin, and gentamicin+hydrogen. At the end of one week, all animals were euthanized following ethical rules, and blood and tissue samples were analyzed for examining Malondialdehyde (MDA), glutathione (GSH), Tumor Necrosis Factor-Alfa (TNF-α), Tumor Necrosis Factor-Beta (TNF-β), Interleukin 6 (IL-6), endoglin, endocan, urea, creatinine, Na+, and K+ parameters. Levels of 8-Hydroxyguanosine (8-OHdG), MDA, and Bax were immunohistochemically analyzed. Data showed that while MDA (control P<0.0001, H2P<0.0001, ‎Genta+H2P<0.0007), TNF-α (control P<0.0002, H2P<0.0040, ‎Genta+H2P<0.0381), IL-6 (control P<0.0044, H2P<0.0070, ‎Genta+H2P<0.0109), endocan (control P<0.0460, H2P<0.0286, ‎Genta+H2P<0.0452), and endoglin (control P<0.0131, H2P<0.0164, ‎Genta+H2P<0.0397), urea (control P<0.0024, H2P<0.0001, ‎Genta+H2P<0.0180), and creatinine parameters (control P<0.0017, H2P<0.0178, ‎Genta+H2P<0.0011) increased in the gentamicin group compared to the other groups, a decrease in these parameters was observed in the gentamicin+hydrogen group compared to the gentamicin group. The Genta group had greater levels of TNF-β than the control (P<0.0042) and H2 groups (P<0.0268). GSH content was higher in the hydrogen group compared to the gentamicin group. Immunohistochemically, 8-OHdG, MDA, and Bax expressions increased in the gentamicin group compared to the control group, whereas they decreased in the gentamicin+hydrogen group compared to the gentamicin group. Hydrogen may be an alternative treatment for oxidative stress-induced nephrotoxicity.

Therapeutic potential of diosgenin against methotrexate-induced testicular damage in the rat.

This study evaluated diosgenin effects on methotrexate-induced testicular injury in the rats. A single dose of methotrexate (MTX) (20mg/kg, i.p) was administered, followed by two weeks of diosgenin treatment via gavage starting one day before methotrexate injection. Testicular damage was evaluated through histological examination of seminiferous tubules, as well as analysis of serum testosterone level, oxidative stress and inflammation biomarkers, and antioxidant levels. The results of this study showed that in the MTX-exposed group, oxidative stress indices of malondialdehyde (MDA), reactive oxygen species (ROS), nitrite and indices of inflammation consisting of tumor necrosis factor α (TNFα), and interleukin 6 (IL-6) have a significant increase compared to the control group. Additionally, reductions were observed in antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). In addition, testosterone level decreased and signs of testicular damage were observed in the MTX group. Conversely, in the group treated with diosgenin alongside MTX at a dosage of 50mg/kg, there was a significant decrease in oxidative stress markers (MDA, ROS, nitrite) and inflammatory markers (TNFα and IL-6). Moreover, there was a significant increase in the levels of antioxidant enzymes (SOD, CAT, and GSH). Diosgenin appears to have the potential to protect testicular tissue from damage caused by the toxic effects of MTX through the reduction of oxidative stress and inflammation.

Bioactive hydrogel synergizes neuroprotection, macrophage polarization, and angiogenesis to improve repair of traumatic brain injury

Traumatic brain injury (TBI) can lead to severe neurotrauma, leading to long-term cognitive decline and even death. Massive neuronal loss and excessive neuroinflammation are critical issues in the treatment of secondary TBI. To tackle these challenges, we developed a GelMA and CSMA hydrogel loaded with Erythropoietin (EPO) and Interleukin-4 (IL-4), named GC/I/E. By directly loading the hydrogel with EPO, rapid neuroprotection and angiogenesis were achieved. Meanwhile, by loading Mesoporous silica nanoparticles (MSNs) with IL-4 (MSN@IL-4), sustained inflammation modulation during inflammation was attained. In vitro experiments demonstrated that GC/I/E hydrogel were biocompatible and could provide neuroprotection for HT22 cells in H2O2 environment, regulate RAW264.7 polarization from M1 to M2 phenotype and promote HUVEC angiogenesis. In vivo experiments demonstrated that GC/I/E hydrogel reduced brain oedema and Nissl body damage, inhibited inflammatory expression of G3-FFAP and neural scarring, improved microvascular and vascular function reconstruction, and facilitated neuronal and synaptogenesis, ultimately improving neurofunctional recovery in TBI. RNA sequencing results demonstrated that GC/I/E hydrogel treatment significantly correlated with the regulation of genes such as apoptosis, inflammation regulation, and neural regeneration. This bioactive hydrogel with neuroprotection, inflammation modulation and promotion of angiogenesis has great potential for TBI treatment.

Peficitinib Halts Acute Kidney Injury Via JAK/STAT3 and Growth Factors Immunomodulation

Acute Kidney Injury (AKI) is characterized by a sudden loss of kidney function and its management continues to be a challenge. In this study the effect of peficitinib, a Janus kinase inhibitor (JAKi), was studied in an aim to stop the progression of AKI at an early point of injury. Adult male mice were injected with aristolochic acid (AA) a single dose (10 mg/kg, i.p) to induce AKI. Peficitinib was injected in one of the two tested doses (5 or 10 mg/kg, i.p) one hour after AA injection and was continued daily for seven days. Histopathological evaluation showed that peficitinib alleviated necrosis and hyaline cast formation induced by aristolochic acid. It decreased serum creatinine and the kidney injury molecule-1 (KIM-1) elevated by AA. Peficitinib also mitigated AA induced oxidative stress through regulating total antioxidant capacity (TAC) and reduced glutathione (GSH) level in renal tissue. Additionally, renal sections isolated from groups that received peficitinib revealed a decrease in vascular endothelial growth factor receptor 1 interstitial expression and transforming growth factor-beta 1 (TGF-β1) renal level. Peficitinib received groups showed a decrease in the active phosphorylated form of signal transducers and activators of transcription (STAT3). Moreover, peficitinib decreased renal protein levels and gene expression of the pro-inflammatory cytokines; interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and interferon gamma (IFN-γ). These findings suggest that peficitinib is helpful in halting AKI progression into chronic kidney disease through modulating JAK/STAT3 dependent inflammatory pathways and growth factors involved in normal glomerular function.

Effect of continuous positive airway pressure therapy on blood levels of IL-6, IL-10, IL-18, IL-1β, IL-4, and IL-17 in obstructive sleep apnoea adults: A systematic review, meta-analysis and trial sequential analysis

Obstructive sleep apnoea (OSA) is a long-term disorder characterized by frequent blockages in the upper respiratory tract during sleep, often leading to abrupt awakenings, with or without a decrease in oxygen levels. The systematic review and meta-analysis aimed to assess the effect of continuous positive airway pressure therapy (CPAP) on blood interleukin (IL) levels of IL-6, IL-10, IL-18, IL-1β, IL-4, and IL-17 in OSA adults. The published databases from PubMed, Scopus, Web of Science, and Cochrane Library were searched from 2003 to 2024, without any restrictions. The Review Manager software 5.3 was employed to compute effect sizes, which were presented as the standardized mean difference (SMD) along with a 95% confidence interval (CI). In total, 320 records were identified through database searching; ultimately, 42 articles were included in the qualitative synthesis and then the meta-analysis. The CPAP therapy significantly reduces IL-6 levels, as indicated SMD=0.64 [95% CI: 0.35, 0.93] and P<0.0001. CPAP therapy significantly reduced IL-18 and IL-1β levels in adults with OSA, but there is no significant difference in IL-10, IL-4, or IL-17 levels. Age, blood sample, body mass index, ethnicity, and treatment duration for IL-6 and apnoea-hypopnea index with IL-10 levels were effective factors in the pooled results. Experimentally, there was an interaction between IL-18 and IL-1β. CPAP therapy has a positive impact on inflammatory markers in OSA adults; remarkably, it reduces IL-6 and IL-1β levels. Nevertheless, more evidence (such as the role of ethnicity) and understanding of interactions are needed.

Attenuation of inflammation, oxidative stress and TGF-β1/Smad3 signaling and upregulation of Nrf2/HO-1 signaling mediate the protective effect of diallyl disulfide against cadmium nephrotoxicity

Heavy metals are toxic environmental pollutants with serious health effects on humans and animals. Cadmium (Cd) is known for its serious nephrotoxic effect and its toxicity involves oxidative stress (OS) and inflammation. Diallyl disulfide (DADS), a main constituent of garlic, exhibited cytoprotective and antioxidant activities. This study investigated the effect of DADS on OS, inflammation, and fibrosis induced by Cd in rat kidney, pointing to the involvement of transforming growth factor-β (TGF-β)/Smad3 and nuclear factor erythroid 2–related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling, and peroxisome proliferator-activated receptor gamma (PPARγ). Rats received DADS for 14 days and Cd on day 7 and blood and kidney samples were collected. Cd elevated serum creatinine, urea and uric acid, provoked kidney histopathological alterations and collagen deposition, increased kidney malondialdehyde (MDA) level, and decreased glutathione (GSH) and antioxidant enzymes. Nuclear factor-kappaB (NF-κB) p65, interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1β, and CD68 were upregulated in Cd-administered rat kidney. DADS prevented kidney injury, mitigated OS, suppressed NF-κB, CD68 and pro-inflammatory mediators, and boosted antioxidants. DADS downregulated TGF-β1, Smad3 phosphorylation and Kelch-like ECH-associated protein-1 (Keap1), and increased Nrf2, HO-1, cytoglobin, and PPARγ. In conclusion, DADS protects the kidney against Cd toxicity by attenuating OS, inflammation, and TGF-β1/Smad3 signaling, and enhancement of Nrf2/HO-1 signaling, antioxidants, and PPARγ.

LncRNA MALAT1 to Enhance Pyroptosis in Viral Myocarditis Through UPF1-Mediated SIRT6 mRNA Decay and Wnt-β-Catenin Signal Pathway.

Viral myocarditis (VMC) is an inflammatory disease of the myocardium caused by cardioviral infection, especially coxsackievirus B3 (CVB3), and is a major contributor to acute heart failure and sudden cardiac death in children and adolescents. LncRNA MALAT1 knockdown reportedly inhibits the differentiation of Th17 cells to attenuate CVB3-induced VMC in mice. Moreover, long non-coding RNAs (lncRNAs) interact with RNA-binding proteins (RBPs) to regulate UPF1-mediated mRNA decay. However, it remains unclear whether MALAT1 can bind to UPF1 to mediate the mRNA decay of its target genes in VMC. Herein, we aimed to explore the effect of lncRNA MALAT1 on UPF1-mediated SIRT6 mRNA decay in VMC using in vivo and in vitro experiments. CVB3-infected BABL/C mice were used as VMC models, and MALAT1 interfering adenovirus was injected to achieve MALAT1 knockdown. The heart function of the VMC mice was assessed using echocardiography. Pathological changes in myocardial tissues were assessed after hematoxylin-eosin staining. Myocardial injury and inflammation were evaluated by measuring creatine kinase isoenzyme B, cardiac troponin T, interleukin (IL)-1β, and IL-18. TUNEL staining was performed to assess apoptosis in myocardial tissues. In vitro experiments were performed using H9c2 cells after transfection and CVB3 infection. The lactic dehydrogenase release, caspase-1 activity, and IL-1β and IL-18 levels in the cellular supernatant were detected. Western blotting was performed to determine the expression of pyroptosis-related proteins (GSDMD-N, NLRP3, ASC, and Cleaved-Caspase-1) and Wnt/β-catenin signal pathway-related proteins (Wnt1, β-catenin, and p-GSK-3β). RNA immunoprecipitation and RNA stability assays assessed the relationship between MALAT1, UPF1, and SIRT6. CVB3-infected mice and H9c2 cells exhibited elevated MALAT1 and reduced SIRT6 expression. MALAT1 knockdown or SIRT6 overexpression suppressed inflammation and pyroptosis and inhibited the activation of the Wnt/β-catenin signal pathway in myocardial tissues and cells. MALAT1 enhanced the enrichment of SIRT6 mRNA by UPF1 and disturbed the stability of SIRT6 mRNA to promote the development of VMC. MALAT1 can bind UPF1 to mediate SIRT6 mRNA decay and activate the Wnt/β-catenin signal pathway in VMC.

Ro 90-7501 suppresses colon cancer progression by inducing immunogenic cell death and promoting RIG-1-mediated autophagy.

Colon cancer is one of the leading causes of cancer-related mortality worldwide. Current treatments, including surgery, chemotherapy, and radiation therapy, often have limited efficacy due to tumor heterogeneity and resistance mechanisms. Therefore, there is a critical need for novel therapeutic strategies that can enhance the immune response against colon cancer cells while promoting their efficient clearance. In this study, we investigated the anti-tumor effects of Ro 90-7501, a specific small molecule, in colon cancer cell lines (HCT8 and SW480) and in vivo models. MTS, EdU, Scratch Wound and Transwell assays were performed to detect the cell proliferation and metastasis. Additionally, flow cytometry and immunofluorescence staining were used to analyze changes in apoptosis and necrosis. Furthermore, we examined its ability to induce immunogenic cell death (ICD) and promote retinoic acid-inducible gene I (RIG-I)-mediated autophagy. The expression levels of key molecules involved in ICD and autophagy were assessed using Western blot analysis, immunofluorescence staining, and enzyme-linked immunosorbent assay (ELISA). Our findings demonstrated that Ro 90-7501 significantly suppressed colon cancer cell proliferation and metastasis, inducing apoptosis and necrosis. Mechanistically, Ro 90-7501 triggered ICD by upregulating the exposure of calreticulin (CRT) on the cell surface and increasing the release of high mobility group box 1 (HMGB1) and extracellular ATP levels. Concurrently, it promoted RIG-I-mediated autophagy via the MAVS-TRAF6 signaling axis, evidenced by increased expression of autophagy-related genes, such as microtubule-associated protein 1 light chain 3 (LC3) and Beclin 1 proteins, coupled with a reduction in P62 protein. Additionally, Ro 90-7501 treatment activated the RIG-I-MAVS-TRAF6 signaling axis in colon cancer cells. Furthermore, Ro 90-7501 enhanced the secretion of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFα), thereby activating the immune response. In conclusion, Ro 90-7501 exhibits potent anti-tumor activity against colon cancer by inducing ICD and promoting RIG-I-mediated autophagy. These results suggest that Ro 90-7501 may serve as a promising therapeutic candidate for colon cancer treatment by enhancing both intrinsic cellular processes and adaptive immune responses. Further studies are warranted to elucidate the detailed mechanisms underlying these effects and to evaluate its therapeutic potential in clinical settings.

Indole-3-propionic acid enhances growth performance and reduces diarrhea via modulating redox status and intestinal inflammation in weaned piglets

Indole-3-propionic acid (IPA) has anti-inflammatory properties, which can be beneficial for weaned piglets with underdeveloped immune systems. The study explores the impact of IPA supplementation on growth performance, oxidative stress, and inflammation response in weaned piglets. In experiment (Exp.) 1, ninety weaned piglets were divided into six groups (five replicates per group, three pigs per replicate), with each group receiving a basal diet with varying amounts of IPA (0, 50, 100, 200, 400, or 600 mg/kg) for 42 d. Piglets fed the diets with 50, 100, and 200 mg/kg of IPA exhibited reduced feed conversion ratios (F: G) compared to the control piglets (P = 0.035). Notably, 50 and 100 mg/kg IPA treatments significantly reduced diarrhea incidence and serum interleukin (IL)-6 content (P < 0.05). Conversely, a high dosage of 600 mg/kg IPA led to increased serum contents of tumor necrosis factor (TNF)-α, and IL-6 (P < 0.05). Optimal antioxidant benefits were observed at 100 mg/kg IPA supplementation, which significantly reduced malondialdehyde levels while enhancing serum total antioxidant capacity and total superoxide dismutase activity on d 14 (P < 0.05). Exp. 2 investigated the effects of IPA on lipopolysaccharide (LPS) challenge in weaned piglets. The study consisted of 32 weaned piglets allocated into 4 groups, with 8 replicates per group and 1 piglet per replicate: a control group, a LPS challenge group, a LPS challenge group supplemented with 100 mg/kg IPA, and a group supplemented with 100 mg/kg IPA alone. Upon administration of LPS or saline injection, the results indicated that dietary IPA supplementation in challenged piglets enhanced villus height: crypt depth, modulated IL-8 and IL-22 mRNA relative expression, and increased the tight junction protein claudin-1 mRNA relative expression in the intestinal mucosa (P < 0.05). These findings suggest that dietary supplementation of IPA at specific concentrations significantly improves growth performance, reduces diarrhea incidence, and mitigates inflammation and oxidative stress in weaned piglets. It may be concluded that incorporating IPA into the diet of weaned piglets can effectively improve their health and development.

Microbiota profiling in esophageal diseases: novel insights into molecular staining and clinical outcomes

Gut microbiota is recognized nowadays as one of the key players in the development of several gastro-intestinal diseases. The first studies focused mainly on healthy subjects with staining of main bacterial species via culture-based techniques. Subsequently, lots of studies tried to focus on principal esophageal disease enlarged the knowledge on esophageal microbial environment and its role in pathogenesis.Gastro Esophageal Reflux Disease (GERD), the most widespread esophageal condition, seems related to a certain degree of mucosal inflammation, via interleukin (IL) 8 potentially enhanced by bacterial components, lipopolysaccharide (LPS) above all. Gram- bacteria, producing LPS), such as Campylobacter genus, have been found associated with GERD.Barrett esophagus (BE) seems characterized by a Gram- and microaerophils-shaped microbiota.Esophageal cancer (EC) development leads to an overturn in the esophageal environment with the shift from an oral-like microbiome to a prevalently low-abundant and low-diverse Gram--shaped microbiome.Although underinvestigated, also changes in the esophageal microbiome are associated with rare chronic inflammatory or neuropathic disease pathogenesis.The paucity of knowledge about the microbiota-driven mechanisms in esophageal disease pathogenesis is mainly due to the scarce sensitivity of sequencing technology and culture methods applied so far to study commensals in the esophagus.However, the recent advances in molecular techniques, especially with the advent of non-culture-based genomic sequencing tools and the implementation of multi-omics approaches, have revolutionized the microbiome field, with promises of implementing the current knowledge, discovering more mechanisms underneath, and giving insights into the development of novel therapies aimed to re-establish the microbial equilibrium for ameliorating esophageal diseases.

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.

Cannabiorcol as a novel inhibitor of the p38/MSK-1/NF-κB signaling pathway, reducing matrix metalloproteinases in osteoarthritis

BackgroundThe bioactivity and potential medicinal applications of cannabiorcol, a lesser-known derivative of Cannabis sativa, require further investigation. Osteoarthritis (OA) is a chronic joint condition marked by gradual degradation of the cartilage and commonly associated with elevated levels of matrix metalloproteinases (MMPs). However, the influence of cannabiorcol on OA and its underlying mechanisms remains unclear. MethodsIn silico analysis investigated the key transcription factors that regulate MMP expression. A chondrocyte cell model [interleukin (IL)-1β and IL-1⍺-treated C20A4 cell line] was established and treated with cannabiorcol. Associated cytotoxicity was assessed using a WST-8 assay. A monoiodoacetate-induced OA rat model was established and treated with cannabiorcol. Protein translocation and transactivation analyses were conducted using immunofluorescence and dual-luciferase reporter assays, respectively. Western blotting and real-time PCR analyzed relevant markers to examine cannabiorcol's effects on OA and its fundamental mechanisms. ResultsCannabiorcol inhibits the expression of IL-1β-induced MMPs compared to other cannabis-related compounds. In silico analysis revealed that the nuclear factor-kappa β (NF-κβ) and mitogen-activated protein kinase (MAPK) pathways are associated with MMP expression as key regulators. In vitro, cannabiorcol inhibits the NF-κB and p38 MAPK pathways independently cannabinoid receptors and transient receptor potential vanilloids. In vivo, cannabiorcol reduces MMP expression and ameliorates monoiodoacetate-induced OA traits in rats. ConclusionCannabiorcol inhibits IL-1β-induced MMP expression in vitro and alleviates OA in an MIA-induced OA rat model by reducing MMP expression and inhibiting the p65/p38 axis.