Interleukin Research Articles

CTIM-24. PHASE II TRIAL OF RHIL-7-HYFC IN PATIENTS WITH HIGH-GRADE GLIOMA DEMONSTRATED ACCEPTABLE SAFETY PROFILE AND REDUCED LYMPHOPENIA

Abstract BACKGROUND Lymphopenia, a common finding in patients with high-grade gliomas (HGGs), is associated with poor outcomes including worse survival, fatigue, and in some cases, increased opportunistic infections. Interleukin-7 (IL-7) is a cytokine crucial for lymphocyte survival and proliferation. We previously demonstrated long-acting IL-7 (rhIL-7-hyFc, efineptakin alfa, NT-I7) increases absolute lymphocyte counts (ALCs) and extends survival in preclinical murine models of HGG. Here, we report results using rhIL-7-hyFc to effectively reduce lymphopenia in patients with HGG. METHODS We performed a phase II randomized, placebo-controlled, double-blind study of rhIL-7-hyFc in patients with newly diagnosed HGGs (82% IDH-wildtype glioblastoma in both groups). Patients received rhIL-7-hyFc (720mcg/kg) or placebo one-week post-radiation and temozolomide, with subsequent doses at weeks 13, 25, and 37. The primary endpoint was ALC four weeks post-initial administration; exploratory endpoints included CD4 count, progression-free survival (PFS), and overall survival (OS). RESULTS We enrolled 22 patients (median age 59.5 years, range 33-74; 40.9% female) with HGG. Both groups exhibited comparable demographics, including MGMT methylation status, and received a median of 2 doses of rhIL-7-hyFc or placebo. At 4 weeks, the pre-specified primary endpoint, ALC significantly increased relative to baseline in the treatment group, compared to placebo (median percent change=148% vs. 16.7%, p=0.007), as did CD4 count (121% vs. 10.5%, p=0.011). There were no treatment-related grade 4/5 adverse events. Exploratory endpoints of PFS and OS will be reported at time of conference. CONCLUSIONS rhIL-7-hyFc is safe and effective in improving ALC and CD4 count in patients with newly diagnosed HGG undergoing temozolomide and concurrent radiation therapy. This study was powered to meet the primary endpoint; larger trials will likely be required to demonstrate clinical efficacy. Nevertheless, these data support the continued exploration of rhIL-7-hyFc as an adjunct to standard therapy to mitigate lymphopenia and potentially extend survival for patients with HGG.

AIP1 Regulates Ocular Angiogenesis Via NLRP12-ASC-Caspase-8 Inflammasome-Mediated Endothelial Pyroptosis.

Pathological ocular angiogenesis is a significant cause of irreversible vision loss and blindness worldwide. Currently, most studies have focused on the angiogenesis factors in ocular vascular diseases, and very few endogenous anti-angiogenic compounds have been found. Moreover, although inflammation is closely related to the predominant processes involved in angiogenesis, the mechanisms by which inflammation regulates pathological ocular angiogenesis remain obscure. In this study, a vascular endothelial cells (VECs)-specific anti-angiogenic factor is identified, apoptosis signal-regulating kinase 1(ASK1)-interacting protein-1 (AIP1) as a key pathogenic regulator in a typical ocular angiogenesis model, oxygen-induced retinopathy (OIR), using single-cell RNA sequencing. It is demonstrated that AIP1 inhibited pathological angiogenesis by preventing a particular inflammatory death pathway, namely pyroptosis, in retinal VECs. The assembly of a noncanonical inflammasome is further uncovered, the NLRP12-ASC-caspase-8 inflammasome, which is promoted by decreased AIP1 in OIR. This inflammasome elicited gasdermin D (GSDMD)-dependent endothelial pyroptosis, which in turn promoted the release of vascular endothelial growth factor (VEGF) and interleukin (IL)-1β. Suppression of NLRP12-CASP8-GSDMD axis and AIP1 upregulation reduced VEGF signaling, limiting new vessel formation. These findings reveal a previously uncharacterized inflammatory angiogenic process involving VECs pyroptosis-inducing retinal neovascularization, paving the way for promising therapeutic avenues targeting angiogenesis via AIP1 or pyroptosis.

Clinical characteristics and associated factors of pediatric acute necrotizing encephalopathy: a retrospective study.

In the clinic, pediatric acute necrotizing encephalopathy (ANE) primarily affects children under five years of age and is characterized by severe brain damage and high mortality. However, some challenges remain regarding the diagnosis and treatment of ANE. In the present study, we analyzed the clinical characteristics and related factors of ANE with the aim of providing improved diagnostic and treatment strategies. Thirty-four pediatric ANE patients admitted to Zhejiang University School of Medicine Hospital between February 2019 and December 2023 were included in this study. To identify the factors associated with mortality, clinical, laboratory and imaging data were analyzed with independent-sample t tests, Mann‒Whitney U tests, Fisher's exact probability tests and receiver operating characteristic (ROC) curve analyses. In this cohort of 34 patients, the most common symptoms were fever, seizures, altered consciousness, vomiting, diarrhea and shock. The mortality rate was 55.9%. Laboratory tests revealed that patients who died had higher creatinine, lactate, activated partial thromboplastin time (APTT), thrombin time (TT), interleukin-6 (IL-6), interleukin-10 (IL-10), creatine kinase (CK), and D-dimer than survivors. Imaging examinations predominantly revealed symmetrical lesions in the thalamus. The fatal group displayed lower Glasgow Coma Scale (GCS) scores and severe complications. Other factors related to mortality included the arterial pH, GCS score and hospitalization duration. The most common symptoms of ANE are fever, seizures, altered consciousness, vomiting, diarrhea and shock, and ANE has a high mortality rate. The GCS score and arterial pH are critical biomarkers for assessing the severity of ANE.

Assessment of Biofilm Formation and Anti-Inflammatory Response of a Probiotic Blend in a Cultured Canine Cell Model

Gut dysbiosis and an inflamed bowel are growing concerns in mammals, including dogs. Probiotic supplements have been used to restore the natural microbial community and improve gastrointestinal health. Biofilm formation, antimicrobial activities, and immunological responses of probiotics are crucial to improving gut health. Thus, we tested a commercial probiotic blend (LabMAX-3), a canine kibble additive comprising Lactobacillus acidophilus, Lacticaseibacillus casei, and Enterococcus faecium for their ability to inactivate common enteric pathogens; their ability to form biofilms; epithelial cell adhesion; and their anti-inflammatory response in the Madin-Darby Canine Kidney (MDCK) cell line. Probiotic LabMAX-3 blend or individual isolates showed a strong inhibitory effect against Salmonella enterica, Listeria monocytogenes, enterotoxigenic Escherichia coli, and Campylobacter jejuni. LabMAX-3 formed biofilms comparable to Staphylococcus aureus. LabMAX-3 adhesion to the MDCK cell line (with or without lipopolysaccharide (LPS) pretreatment) showed comparable adhesion and biofilm formation (p < 0.05) to L. casei ATCC 334 used as a control. LabMAX-3 had no cytotoxic effects on the MDCK cell line during 1 h exposure. The interleukin-10 (IL-10) and tumor necrosis factor alpha (TNFα) ratio of LabMAX-3, compared to the L. casei control, showed a significant increase (p < 0.05), indicating a more pronounced anti-inflammatory response. The data show that LabMAX-3, a canine kibble supplement, can improve gastrointestinal health.

Effects of Nigella sativa on disease activity, T lymphocytes and inflammatory cytokine profiles in pediatric systemic lupus erythematosus: A randomized controlled trial

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with diverse manifestations, requiring long-term treatment that can have side effects, particularly in pediatric patients. Nigella sativa (NS) has shown potential for improving SLE symptoms due to its anti-inflammatory and immunomodulatory effects. The aim of this study was to investigate the immunomodulatory effect of N. sativa oil (NSO) on disease activity, T lymphocyte activity and inflammatory cytokine profiles in pediatric SLE patients. A randomized, double-blinded, placebo-controlled clinical trial was conducted at Saiful Anwar Hospital in Malang, Indonesia, from January 2022 to January 2023. Pediatric patients with SLE were randomly assigned to receive either one gram of NSO or a placebo containing starch in capsule form as adjunct therapy alongside their SLE primary treatment. Blood samples were collected before treatment and after eight weeks of daily capsules. Disease activity was assessed using the SLE Disease Activity Index 2000 (SLEDAI-2K); flow cytometry was used to identify T helper lymphocytes, and serum cytokine levels were measured using ELISA. The statistical analysis tests were performed to compare the outcomes between groups at baseline or after the treatment, and within-group comparisons before and after the study period, as appropriate. A total of 32 patients were included in the study. A significant decrease in the SLEDAI-2K score was observed at post-treatment in both the NSO and placebo groups (p<0.001 and p=0.025, respectively). The percentage of T helper 17 (Th17) cells was significantly reduced in both the NSO and placebo groups post-treatment compared to pre-treatment (p=0.026 and p=0.034, respectively). Conversely, the post-treatment percentage of regulatory T (Treg) cells increased significantly in both groups. A significant reduction in interleukin (IL)-2 levels was observed in the NSO and placebo groups at post-treatment compared to pre-treatment (p=0.006 and p=0.046, respectively). Additionally, there were increases in IL-4 and IL-6 serum levels in both groups at post-treatment compared to pre-treatment (p<0.05). This study highlights that although disease activity was not significantly different between NSO and placebo groups, NSO could affect the inflammatory cytokine profiles in pediatric SLE patients.

Comparative evaluation of the modulatory role of 1,25-dihydroxy-vitamin D3 on endoplasmic reticulum stress-induced effects in 2D and 3D cultures of the intestinal porcine epithelial cell line IPEC-J2

BackgroundThe use of conventional two-dimensional (2D) culture of the porcine intestinal epithelial cell (IEC) line IPEC-J2 in animal nutrition research has the disadvantage that IEC function is studied under unphysiological conditions, which limits the ability of transferring knowledge to the in vivo-situation. Thus, the aim of the present study was to establish a more convincing and meaningful three-dimensional (3D) culture of IPEC-J2 cells, which allows to study cell function in a more tissue-like environment, and to compare the effect of the endoplasmic reticulum (ER) stress inducer tunicamycin (TM) on ER stress indicators and the expression of tight junction proteins (TJP), inflammatory and apoptosis-related genes and the modulatory role of 1,25-dihydroxy-vitamin D3 (1,25D3) on these parameters in 2D and 3D cultures of IPEC-J2 cells.ResultsA published protocol for 3D culture of Caco-2 cells was successfully adopted to IPEC-J2 cells as evident from fully differentiated 3D IPEC-J2 spheroids showing the characteristic spherical architecture with a single layer of IPEC-J2 cells surrounding a central lumen. Treatment of 2D IPEC-J2 cells and 3D IPEC-J2 spheroids with TM for 24 h markedly increased mRNA and/or protein levels of the ER stress target genes, heat shock protein family A (Hsp70) member 5 (HSPA5) and DNA damage inducible transcript 3 (DDIT3), whereas co-treatment with TM and 1,25D3 did not mitigate TM-induced ER stress in IPEC-J2 cells in the 2D and the 3D cell culture. In contrast, TM-induced expression of pro-inflammatory [interleukin-6 (IL6), IL8] and pro-apoptotic genes [BCL2 associated X, apoptosis regulator (BAX), caspase 3 (CASP3), CASP8] and genes encoding TJP [TJP1, claudin 1 (CLDN1), CLDN3, occludin (OCLN), cadherin 1 (CDH1), junctional adhesion molecule 1 (JAM1)] was reduced by co-treatment with TM and 1,25D3 in 3D IPEC-J2 spheroids but not in the 2D cell culture.ConclusionsThe effect of 1,25D3 in the IPEC-J2 cell culture is dependent on the culture model applied. While 1,25D3 does not inhibit TM-induced expression of genes involved in inflammation, apoptosis and TJP in conventional 2D cultures of IPEC-J2 cells, TM-induced expression of these genes is abrogated by 1,25D3 in the more meaningful 3D IPEC-J2 cell culture model.

C-Phycocyanin and Phycocyanobilin as a Novel Adjuvant in Hepatitis B Vaccine

Background: Vaccine adjuvants are components that enhance immune responses to an antigen. Given the importance of adjuvants, research on novel adjuvants with higher efficacy and fewer adverse effects remains crucial. Spirulina (Arthrospira sp.), an aqueous, photosynthetic, filamentous, spiral, multicellular microalga also classified as a cyanobacterium, is well known for its high protein content, vitamins, essential fatty acids, and amino acids. C-phycocyanin (C-PC) is one of the most significant proteins in Spirulina. Objectives: This study aimed to investigate the adjuvant capabilities of three Spirulina-derived substances—Spirulina extract, C-phycocyanin (C-PC), and phycocyanobilin (PCB)—in conjunction with the Hepatitis B surface antigen (HBsAg). Methods: Vaccine groups received the vaccine and adjuvants three times at two-week intervals, administered either orally or by injection in encapsulated or naked forms. To use the injectable form while preventing antigenic effects from the C-PC protein portion, the PCB portion was isolated and used as an injectable adjuvant. Results: The highest levels of interferon gamma (IFN-γ) and interleukin 4 (IL-4) stimulation were observed in the naked PCB form with the vaccine. In both oral and injectable forms of PCB and C-PC, results indicated an increased expression of Hepatitis B surface antibodies (HBsAb) in response to the antigen. The absence of a significant difference between C-PC and Spirulina extract in oral form suggested that the adjuvant effect of this microalga was primarily due to the C-PC compound. Additionally, the injectable form of PCB led to the highest HBsAb expression level. This enhancement of the humoral immune response indicated that these compounds have potential as adjuvants in both oral and injectable forms. Conclusions: These findings suggest the potential for improved Hepatitis B vaccine efficacy with this novel adjuvant, paving the way for further evaluation with other vaccines.

Comparative Effectiveness of Biologic Classes in Clinical Practice: Month 12 Outcomes from the International Observational Psoriasis Study of Health Outcomes (PSoHO).

Studies directly comparing the effectiveness of different biologics over long observation periods are lacking. As many treatment guidelines are formulated based on drug class, there is a particular need to compare drug classes rather than specific biologic agents. This post hoc analysis compares the effectiveness and durability of biologics that target the interleukin (IL)-17 A ligands or the IL-17 receptor A (IL-17RA) relative to other approved drug classes in patients with moderate-to-severe plaque psoriasis, through 12months in a real-world setting. In the Psoriasis Study of Health Outcomes (PSoHO) (N=1981), patients treated with anti-IL-17A/RA resulted in a higher proportion of patients who achieved the primary outcome [proportion of patients who had at least a 90% improvement in Psoriasis Area and Severity Index score (PASI90) and/or a score of 0 or 1 in static Physician Global Assessment (sPGA)] compared to anti-IL-23-, anti-IL-12/23-, and tumor necrosis factor (TNF)-α-treated patients at week 12, month 6, and month 12, except versus anti-IL-23 at month 12. Similar trends were observed for a 100% improvement in PASI score (PASI100), PASI90, and Dermatology Life Quality Index score of 0 or 1 [DLQI (0,1)]. At month 12, the unadjusted response rates across the drug classes were 53.5-69.1% for the primary outcome, 27.6-40.8% for PASI100, 41.7-55.9% for PASI90, and 31.8-33.0% for DLQI (0,1). Regarding the durability of effectiveness, anti-IL-17A/RA patients had the highest response rate, and for the adjusted analysis, using Frequentist Model Averaging (FMA), patients had 1.4-2.6 times higher odds of achieving the primary durability outcome compared to patients treated with any other drug class. Overall, anti-IL-17A/RA had the highest effectiveness of achieving early response to treatment and maintaining that response through 12months compared to other drug classes. The study was registered at the European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCEPP24207).

Tanshinone IIA inhibits the apoptosis process of nerve cells by upshifting SIRT1 and FOXO3α protein and regulating anti- oxidative stress molecules and inflammatory factors in Cerebral Infarction Model

: Background as a prevalent cerebrovascular disorder, cerebral infarction (CI) has garnered extensive attention globally due to its high incidence and substantial fatality rate. Ischemia-reperfusion injury (IRI) exacerbates not only neuronal demise but also amplifies neural functional impairment. Tanshinone IIA (Tan IIA) has been identified to confer protection against IRI, yet the precise underlying mechanisms remain elusive. This work aimed to delve into the mechanistic role of Tan IIA in CI, with the goal of furnishing more distinct theoretical substantiation for its clinical application. Methods initially, a middle cerebral artery embolization model group (MCAO) model was established, followed by the categorization of rats into distinct groups based on different administration modes. Therapeutic effects were evaluated through indices including mortality rate, cerebral tissue water content, CI proportion, and neural functional scoring. Meanwhile, cellular apoptosis rates in hippocampal and cortical tissues, as well as levels of oxidative stress molecules (OSM), Sirtuin 1 (SIRT1), Forkhead box O3 (FOXO3α), and inflammatory factors, were examined to explore the mechanism of action. Results this work revealed that within varying doses of Tan IIA groups, as dosage escalated, mortality rate, cerebral edema severity, CI proportion, and neural functional scoring gradually diminished. Notably, the 35 mg/kg dose group exhibited the most significant reductions, with decreases of 74.9%, 12.7%, 47.5%, and 54% respectively. Cellular apoptosis rates in hippocampal and cortical tissues displayed a stepwise descending trend, with the 35 mg/kg dose group showcasing the largest reduction. SIRT1 and FOXO3α proteins exhibited a steady increase, with the 35 mg/kg dose group manifesting respective elevations of 87.9% and 65.5%, the highest among all groups. Antioxidant molecules glutathione (GSH) and superoxide dismutase (SOD) contents progressively increased, whereas malondialdehyde (MDA) and nitric oxide (NO) content decreased. The 35 mg/kg dose group recorded the highest increments of 49.1% and 58.1% for GSH and SOD content, while achieving the greatest reductions of 55.6% and 56.2% for MDA and NO content. Expression of inflammatory factors, namely tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), and interleukin-6 (IL-6), gradually declined, with reductions of 42.1%, 32.2%, and 29.1% respectively in the 35 mg/kg dose group, exhibiting drastic differences (P < 0.05). Conclusion In conclusion, this research elucidates that Tan IIA improves cerebral edema and neural function by elevating intracellular expression of SIRT1 and FOXO3α proteins, modulating OSM and inflammatory factors. These findings yielded robust experimental support for the potential use of Tan IIA as a therapeutic agent for CI.

Regulation of ROS metabolism in macrophage via xanthine oxidase is associated with disease progression in pulmonary tuberculosis.

Pulmonary tuberculosis (PTB) exacerbation can lead to respiratory failure, multi-organ failure, and symptoms related to central nervous system diseases. The purpose of this study is to screen biomarkers and metabolic pathways that can predict the progression of PTB, and to verify the role of the metabolic enzyme xanthine oxidase (XO) in the progression of PTB. To explore the biomarkers and mechanisms underlying the progression of PTB, plasma metabolomics sequencing was conducted on patients with severe PTB, non-severe PTB, and healthy individuals. Screening differential metabolites and metabolic pathways that can predict the progression of PTB, and verifying the function and mechanism of action of XO through experiments. The purine metabolism, sphingolipid metabolism, and amino acid metabolism between the three groups differ. In patients with severe PTB, the levels of xanthosine and hypoxanthine are increased, while the levels of D-tryptophan, dihydroceramide and uric acid are decreased. Inhibition of XO activity has been observed to reduce the levels of tumor necrosis factor (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), as well as to suppress the production of reactive oxygen species (ROS) and the activation of the NF-κB pathway, while also promoting the growth of MTB within cells. D-tryptophan, xanthosine, and dihydroceramide can be utilized as biomarkers for progression of PTB, assisting in the evaluation of disease progression, and XO stands out as a potential therapeutic target for impeding the progression of PTB.

Haloxylon salicornicum Phytochemicals Suppress NF-κB, iNOS and Pro-inflammatory Cytokines in Lipopolysaccharide-induced Macrophages.

Haloxylon salicornicum is traditionally used for the treatment of several disorders associated with inflammation. Despite it is a defense response against tissue injury and infections, inflammation can become a chronic condition that can negatively impact the body. This study investigated the effect of H. salicornicum phytochemicals nuclear factor-kappaB (NF-κB), inducible nitric oxide synthase (iNOS) and cytokines release by lipopolysaccharide (LPS)-challenged macrophages in vitro. The binding affinity of the tested phytochemical towards NF-κB and iNOS was investigated using molecular docking. Ten compounds (four coumarins, three sterols and three flavonoids) were isolated from the ethanolic extract of H. salicornicum. Treatment of LPS-challenged macrophages with the compounds resulted in remarkable decrease in NF-κB p65 and iNOS mRNA abundance. All compounds suppressed the production of nitric oxide (NO) and the pro-inflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-6) from macrophages challenged with LPS. Molecular docking revealed the ability of the isolated phytochemicals to bind NF-κB p65 and iNOS. In conclusion, H. salicornicum is a rich source of phytochemicals with anti-inflammatory properties. The anti-inflammatory efficacy of H. salicornicum phytoconstituents is mediated via their ability to modulate NF-κB and iNOS, and suppress the release of NO, TNF-α, and IL-6 from macrophages.

Elevated Interleukin-6 Levels as a Potential Marker of Neonatal Morbidity in Full-term Infants With Polycythemia: A Prospective Study.

To research and show that interleukin-6 (IL-6) and c-reactive protein (CRP), which can be used as infection markers, are also higher among newborns with polycythemia. The study took place in the neonatal intensive care unit of Zekai Tahir Burak Maternity Teaching and Research Hospital. Infants with a gestational age of >37 weeks were included in the study. Infants with chorioamnionitis, perinatal asphyxia, and positive blood culture were excluded from the study. Blood samples were obtained six hours after the delivery from the peripheral vein of the infants for measurements of central hematocrit, blood culture, IL-6, and CRP. Infants with a venous hematocrit value of >65% were grouped as the "polycythemia group," and the ones with a venous hematocrit value of <65% were designated as the "control group." Observation of significantly higher levels of CRP and IL-6 among newborns admitted to the neonatal intensive care unit due to different causes (such as respiratory distress, hypoglycemia, and feeding intolerance), but significantly higher IL-6 levels in newborns with polycythemia. Thirty-five newborns (18 infants in the polycythemia group and 17 infants in the control group) were enrolled in the study. The IL-6 values for the polycythemia group were higher than the upper normal limits (mean ± 2SD, 37.6 ± 55 vs 12 ± 5pg/dL, respectively; P = 0.00). The IL-6 values of the polycythemia group were found to be higher than the IL-6 values of the control group, with a mean ± 2SD of 37.6 ± 55 vs 6.3 ± 3.4pg/dL, respectively; this was significant (P = 0.00). Although the CRP values of the polycythemia group were found to be slightly higher than those of the control group (a mean ± 2SD of 3.06 ± 4.07 vs 1.54 ± 2.21mg/dL, respectively, P > 0.05), this was not significant. This study found a significant and robust statistical correlation between IL-6 and v. Hct values (P = 0.01, rs = 0.641). Contrary to IL-6 levels, however, a meaningful relationship was not found between CRP and v.htc values (P = 0.286; rs = 0.184).

The IL-33/ST2 Axis Affects Adipogenesis Through Regulating the TRAF6/RelA Pathway

Understanding the regulatory mechanisms of adipogenesis is essential for preventing obesity. Interleukin-33 (IL-33) has recently attracted increasing attention for its role in adipogenesis. The purpose of this study was to explore the function and regulatory mechanism of IL-33 and its receptor suppression of tumorigenicity 2 (ST2) on adipogenesis. Here, Oil Red O staining was used to detect the accumulation of intracellular lipid droplets. Molecular techniques such as qRT-PCR and Western blotting were used to detect the expression of pivotal genes and adipogenic marker genes. Gains and losses of function experiments were used to explore the potential regulatory mechanism of the IL-33/ST2 axis in adipogenesis. Functionally, IL-33 is negatively associated with adipogenesis in 3T3-L1 preadipocytes, while ST2 is positively associated with it, encompassing both the trans-membrane receptor ST2 (ST2L) and the soluble ST2 (sST2). Mechanistically, the IL-33/ST2 axis affects adipogenesis by regulating the expression of the TRAF6/RelA pathway in 3T3-L1 preadipocytes. Downregulating the expression of ST2 suppressed the activation of the IL-33/ST2 axis, which subsequently inhibits the expression of TRAF6. This further attenuates the expression of RelA, ultimately resulting in the suppression of adipogenesis in 3T3-L1 preadipocytes. This study reveals a new mechanism by which the IL-33/ST2 axis regulates the differentiation of preadipocytes and provides a new idea for improving obesity prevention.

TCR-CD3 signal strength regulates plastic coexpression of IL-4 and IFN-γ in Tfh-like cells

The development of T follicular helper (Tfh) cells is an ongoing process resulting in the formation of various Tfh subsets. Despite advancements, the precise impact of T cell receptor (TCR) stimulation on this process remains incompletely understood. This study explores how TCR-CD3 signaling strength influences naive CD4+ T cell differentiation into Tfh-like cells and the concurrent expression of interleukin-21 (IL-21), interleukin-4 (IL-4), and interferon-gamma (IFN-γ). Strong TCR-CD3 stimulation induces proliferation and increased IL-21 expression in Tfh-like cells, which exhibit a characteristic phenotype expressing CXCR5 and PD1. The coexpression of IL-4 and IFN-γ in IL-21-producing Tfh-like cells is controlled by the strength TCR-CD3 stimulation; low stimulation favors IL-4, while strong stimulation enhances IFN-γ secretion. Exogenous addition of the effector cytokines IL-21 and IL-4 further modulate cytokine coexpression. These findings highlight the intricate regulatory mechanisms governing cytokine production and plasticity in Tfh-like cells, providing insights into B cell response modulation. In vivo, antigen availability may regulate Tfh cell plasticity, impacting subsequent B cell differentiation, emphasizing the need for further exploration through animal models or antigen-specific Tfh cell analyses in human lymph node biopsies

The Predictive Role of Inflammatory Biomarkers and Their Correlation with the Biochemical Profile in Patients with Vasculopathy Undergoing Surgery

Inflammation is involved in the pathomechanism of vascular diseases. Pro-inflammatory cytokines are important in perioperative monitoring. The aim of the study was the perioperative assessment of biochemical tests and inflammatory markers in patients with vasculopathy, focusing on the identification of subjects prone to complications. The study was performed between 2020 and 2023 at the Clinical County Hospital in Târgu Mureș on enrolled diabetic and non-diabetic patients with vasculopathy and lower limb surgery (amputation or necrectomy). Pre- and postoperative inflammatory markers, biochemical, and hematological tests (n = 62) were performed. Positive correlation was found between preoperative C-reactive protein (CRP) and interleukin-6 (IL-6) levels, and between preoperative triglyceridemia and glycemia/cholesterolemia. Positive correlation was present between pre- and postoperative values of IL-6, tumor necrosis factor-alfa (TNF-α), CRP, and fibrinogen. Preoperative TNF-α values positively correlated with malondialdehyde (MDA) levels, postoperative TNF-α values with transaminase enzymes. Diabetic patients presented higher IL-6 results compared to non-diabetic subjects. We can conclude that dynamic assessment of inflammatory markers is appropriate for monitoring perioperative course. Half of the subjects presented moderately increased preoperative IL-6 levels, and one quarter had critically high values, which might predict prolonged hospitalization. The assessment of oxidative stress, inflammatory markers and biochemical parameters enables the identification of patients prone to complications, so they can benefit from more complex management.

Harnessing the regenerative potential of interleukin11 to enhance heart repair

Balancing between regenerative processes and fibrosis is crucial for heart repair, yet strategies regulating this balance remain a barrier to developing therapies. The role of Interleukin 11 (IL11) in heart regeneration remains controversial, as both regenerative and fibrotic functions have been reported. We uncovered that il11a, an Il11 homolog in zebrafish, can trigger robust regenerative programs in zebrafish hearts, including cardiomyocytes proliferation and coronary expansion, even in the absence of injury. Notably, il11a induction in uninjured hearts also activates the quiescent epicardium to produce epicardial progenitor cells, which later differentiate into cardiac fibroblasts. Consequently, prolonged il11a induction indirectly leads to persistent fibroblast emergence, resulting in cardiac fibrosis. While deciphering the regenerative and fibrotic effects of il11a, we found that il11-dependent fibrosis, but not regeneration, is mediated through ERK activity, suggesting to potentially uncouple il11a dual effects on regeneration and fibrosis. To harness the il11a’s regenerative ability, we devised a combinatorial treatment through il11a induction with ERK inhibition. This approach enhances cardiomyocyte proliferation with mitigated fibrosis, achieving a balance between regenerative processes and fibrosis. Thus, we unveil the mechanistic insights into regenerative il11 roles, offering therapeutic avenues to foster cardiac repair without exacerbating fibrosis.

Impact of DPP-4 inhibitors on interleukin levels in type 2 diabetes mellitus.

Accumulating evidence had implicated pathological involvement of interleukins (ILs) in progression and complications in patients with type 2 diabetes mellitus (T2DM). Dipeptidyl peptidase-4 inhibitors (DPP-4i) produced favorable effects on glucose homeostasis in T2DM. This study aimed to evaluate the impact of DPP-4i on interleukins (ILs) concentrations in T2DM. PubMed, Embase and the Cochrane library were systematically searched for relevant articles from inception to May 31, 2024. Related searching items were used including DPP-4i, T2DM and randomized controlled trials (RCTs). Placebo- or active agents-controlled human studies were screened. All the RCTs were identified if they provided detailed information on changes of ILs during DPP-4i treatment. A total of 14 RCTs involving 850 participants were identified. Pooled estimates revealed that DPP-4i significantly lower IL-6 concentrations (-0.54 pg/mL, 95% CI, -0.82 to -0.25, I2 = 10%, P = 0.0003) compared to placebo. Similar effects were demonstrated for IL-1β (-16.33 pg/mL, 95% CI, -19.56 to -13.11, I2 = 0%, P<0.00001), whereas the effect on IL-18 was not statistically significant (-13.55 pg/mL, 95% CI, -76.95 to 49.85, I2 = 0%, P = 0.68). Subgroup analysis on IL-6 demonstrated that marked effects were found in groups of basal IL-6 concentrations (< 5 pg/mL), BMI (≥ 28 kg/m2) and type of DPP-4i (linagliptin). DPP-4i favorably decreased concentrations of IL-6 in patients with T2DM. The impact of DPP-4i on IL-1β and IL-18 needed to be explored with more studies. Further trials should be performed to elucidate this anti-inflammatory effect of DPP-4i during treatment of T2DM.

The Expression Level of Inflammation-Related Genes in Patients With Bone Nonunion and the Effect of BMP-2 Infected Mesenchymal Stem Cells Combined With nHA/PA66 on the Inflammation Level of Femoral Bone Nonunion Rats

Bone nonunion delays fracture end repair and is associated with inflammation. Although bone nonunion can be effectively repaired in clinical practice, many cases of failure. Studies have confirmed that BMP-2 and nHA/PA66 repaired bone defects successfully. There are few studies on the effects of the combined application of BMP-2 and NHA/PA66 on bone nonunion osteogenesis and inflammation. We aimed to investigate the expression level of inflammation-related genes in patients with bone nonunion and the effect of BMP-2-infected mesenchymal stem cells combined with nHA/PA66 on the level of inflammation in femur nonunion rats. We searched for a gene expression profile related to bone nonunion inflammation (GSE93138) in the GEO public database. Bone marrow mesenchymal stem cells (MSCs) of SD rats were cultured and passed through. We infected the third generation of MSCs with lentivirus carrying BMP-2 and induced the infected MSCs to bone orientation. We detected the expression level of BMP-2 by RT-PCR and the cell viability and alkaline phosphatase (ALP) activity by CCK8 and then analyzed the cell adhesion ability. Finally, the levels of related inflammatory factors, including C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and Erythrocyte Sedimentation Rate (ESR), were detected in nonunion rats. Our findings: The patients with nonunion had up-regulated expression of 26 differentially inflammatory genes. These genes are mainly enriched in innate immune response, extracellular region, calcium ion binding, Pantothenate and CoA biosynthesis pathways. The expression level of BMP-2 in the Lenti-BMP-2 group was higher (vs. empty lentivirus vector group: t=5.699; vs. uninfected group t=3.996). The cell activity of the MSCs + BMP-2 + nHA/PA66 group increased gradually. After being combined with nHA/PA66, MSCs transfected with BMP-2 spread all over the surface of nHA/PA66 and grew into the material pores. MSCs + BMP-2 + nHA/PA66 cells showed positive ALP staining, and the OD value of ALP was the highest. The levels of CRP, IL-6, TNF-α, and ESR in the MSCs + BMP-2 + nHA/PA66 group were lower than those in the MSCs and MSCs + nHA/PA66 group but higher than those in MSCs + BMP-2 group. The above comparisons were all P˂0.05. The findings demonstrated that the expression level of inflammation-related genes increased in the patients with bone nonunion. The infection of MSCs by BMP-2 could promote the directed differentiation of MSCs into osteoblasts in the bone marrow of rats, enhance the cell adhesion ability and ALP activity, and reduce inflammation in rats with bone nonunion.

Fertility protective effects of Brillantaisia patula leaf extract against cyclophosphamide-induced ovarian damage in Wistar rats

BackgroundThe primary indication of infertility is the incapacity to conceive, and in females, the majority of instances of female infertility stem from ovulation disorders. This study evaluated the female fertility-enhancing effects and safety of aqueous leaf extract of Brillantaisia patula (ALEBP) in a cyclophosphamide (CYP) model of sterility in Wistar rats.MethodSixty-six female rats randomly allotted to six groups (n = 11) were administered with the appropriate regimen for 21 days and then mated with male rats. Group 1 (control) received distilled water. Groups 2–6 were treated with a single dose (200 mgkg− 1 body weight) of cyclophosphamide intraperitoneally and, in addition, received the same volume (0.5 mL) of distilled water, 18, 36, 72 mgkg− 1 body weight of ALEBP and 200 mg per body weight of vitamin C orally. Mating lasted 11 days; on day 20, the female Wistar rats were sacrificed. Data were analysed using One-way Analysis of Variance (ANOVA) followed by Dunett’s posthoc analysis, and GraphPad (at p < 0.05).ResultsResults herein showed that ALEBP significantly (p < 0.05) increased the diminution in activities/levels of glutathione peroxidase (GPx), reduced glutathione (GSH), total antioxidant capacity (TAC), cholesterol, alkaline phosphatase (ALP), acid phosphatase (ACP), estrogen (ES), and luteinising hormone (LH) induced by cyclophosphamide. ALEBP further reversed the increased level of malondialdehyde (MDA), tumour necrosis factor-α (TNFα), interleukin 8 (IL-8), and follicle-stimulating hormone (FSH) caused by cyclophosphamide (p < 0.05). In addition, ALEBP, while it significantly increased the cyclophosphamide-induced reduction in the number of implantations in each animal, the total number of viable fetuses, the total number of corpora lutea, and the fertility index, also significantly reduced the number of fetal resorptions in each animal and pre-implantation loss that was increased by cyclophosphamide. Moreover, the cyclophosphamide-induced degenerative and necrotic changes in the ovarian cells and uterus were reversed by ALEBP.ConclusionsConsidered as a whole, the aqueous leaf extract of Brillantaisia patula reversed oxidative stress and inflammatory side effects of cyclophosphamide, preserving ovarian function and fertility in the rats. This may suggest its exploration as a safe agent against toxic side effects of chemotherapy and fertility-related disorders of the uterus and ovary.

Cadmium-Induced Hepatotoxicity in Mice – Prophylactic Supplementation of Quercetin Exerts Hepatoprotective Effect by Modulating PI3K/Akt/NF-κB Signaling Pathway

This current study seeks to examine the pre-protective function of Quercetin in Cadmium (Cd)-induced liver damage, along with its modulation of the PI3K/Akt/NF-κB signaling pathway. A total of 60 male C57BL/6J mice were randomly assigned to four groups: control (C), quercetin (Q, 100 mg/kg/day), Cd (Cd, 2.5 mg/kg/day), and quercetin and Cd (Q+Cd). Before receiving Cd treatment, quercetin was administered intragastrically for 4 weeks. In the present study, liver markers, oxidative stress parameters, pro-inflammatory cytokines, liver histopathology, apoptotic markers and PI3K/Akt/NF-κB signaling molecules were examined. We observed that the body weight of the Cd-treated mice dramatically rise after 4 weeks of quercetin pre-administration, and the Cd concentration was significantly decreased. Liver function markers like alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) were significantly reduced in quercetin treatment in Cd-induced mice. Additionally, we observed that quercetin reduced Cd-mediated liver injury in mice by assessing the level of malondialdehyde (MDA), and the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) concentrations and the histological alterations. By monitoring tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), quercetin successfully reduced the inflammatory cytokines that the Cd metal caused in the liver. Additionally, in the liver tissues of Cd-mediated, quercetin could enhance the expression of Bcl-2 and decrease the expression of p-Akt, p-PI3K, Bax, Caspase-9, Caspase-3, NF-κB. In conclusion, quercetin protects against Cd induced liver injury via several pathways, including oxidative stress, inflammation and apoptosis, and its protective effect correlates with antioxidant activity.