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RMD Open Jun 2024To investigate the efficacy, safety, pharmacokinetics and pharmacodynamics of nipocalimab in participants with moderate to severe active rheumatoid arthritis (RA) and... (Randomized Controlled Trial)
Randomized Controlled Trial
Nipocalimab, an anti-FcRn monoclonal antibody, in participants with moderate to severe active rheumatoid arthritis and inadequate response or intolerance to anti-TNF therapy: results from the phase 2a IRIS-RA study.
OBJECTIVES
To investigate the efficacy, safety, pharmacokinetics and pharmacodynamics of nipocalimab in participants with moderate to severe active rheumatoid arthritis (RA) and inadequate response or intolerance to ≥1 antitumour necrosis factor agent.
METHODS
In this phase 2a study, participants with RA seropositive for anticitrullinated protein antibodies (ACPA) or rheumatoid factors were randomised 3:2 to nipocalimab (15 mg/kg intravenously every 2 weeks) or placebo from Weeks 0 to 10. Efficacy endpoints (primary endpoint: change from baseline in Disease Activity Score 28 using C reactive protein (DAS28-CRP) at Week 12) and patient-reported outcomes (PROs) were assessed through Week 12. Safety, pharmacokinetics and pharmacodynamics were assessed through Week 18.
RESULTS
53 participants were enrolled (nipocalimab/placebo, n=33/20). Although the primary endpoint did not reach statistical significance for nipocalimab versus placebo, a numerically higher change from baseline in DAS28-CRP at Week 12 was observed (least squares mean (95% CI): -1.03 (-1.66 to -0.40) vs -0.58 (-1.24 to 0.07)), with numerically higher improvements in all secondary efficacy outcomes and PROs. Serious adverse events were reported in three participants (burn infection, infusion-related reaction and deep vein thrombosis). Nipocalimab significantly and reversibly reduced serum immunoglobulin G, ACPA and circulating immune complex levels but not serum inflammatory markers, including CRP. ACPA reduction was associated with DAS28-CRP remission and 50% response rate in American College of Rheumatology (ACR) criteria; participants with a higher baseline ACPA had greater clinical improvement.
CONCLUSIONS
Despite not achieving statistical significance in the primary endpoint, nipocalimab showed consistent, numerical efficacy benefits in participants with moderate to severe active RA, with greater benefit observed for participants with a higher baseline ACPA.
TRIAL REGISTRATION NUMBER
NCT04991753.
Topics: Humans; Arthritis, Rheumatoid; Male; Female; Middle Aged; Treatment Outcome; Antirheumatic Agents; Severity of Illness Index; Antibodies, Monoclonal, Humanized; Aged; Adult; Tumor Necrosis Factor-alpha; Double-Blind Method; Patient Reported Outcome Measures; Anti-Citrullinated Protein Antibodies
PubMed: 38942592
DOI: 10.1136/rmdopen-2024-004278 -
PloS One 2024Body mass index (BMI) is inversely proportional with adiponectin levels among adults, while insulin, C-reactive protein (CRP), interleukin 6 (IL-6), resistin and tumor...
BACKGROUND AND OBJECTIVES
Body mass index (BMI) is inversely proportional with adiponectin levels among adults, while insulin, C-reactive protein (CRP), interleukin 6 (IL-6), resistin and tumor necrosis factor-alpha (TNF-α) have been linked with elevated BMI. The role and relation of these biomarkers with BMI among a Hispanic pediatric population are less known. Thus, the objective of this study was to examine the association of inflammatory markers with the odds of overweight/obesity while controlling for several sociodemographic factors among a Hispanic youth population in Northeast Tennessee.
METHODS
Height, weight, demographic information, and blood samples were collected from 107 Hispanic children aged 2 to 10 years recruited at a large community health center in 2015-2016 in Northeast Tennessee. Data for this research were accessed and analyzed in 2022. Multivariable logistic regression was conducted to assess the relations between adiponectin, insulin, resistin, CRP, TNF-α, and IL-6, and overweight/obesity vs. having a healthy (normal) weight.
RESULTS
Adiponectin levels were significantly lower among overweight/obese Hispanic children (p = 0.0144) compared to healthy weight children. The odds of overweight/obesity decreased by 4% for every one-unit increase in serum adiponectin. Insulin levels were significantly higher among overweight/obese Hispanic children compared to healthy weight children (p = 0.0048). The odds of overweight/obesity increased by 7% for every one-unit increase in serum insulin. Resistin, IL-6, TNF-α, and CRP were not significantly associated with overweight/obesity in this population.
CONCLUSION
Adiponectin behaves similarly in Hispanic youth as it does in other pediatric populations, possibly making it a valuable marker when examining metabolic health status in this population.
Topics: Humans; Child; Body Mass Index; Male; Female; Hispanic or Latino; Child, Preschool; Biomarkers; Adiponectin; C-Reactive Protein; Interleukin-6; Resistin; Insulin; Tumor Necrosis Factor-alpha; Inflammation; Pediatric Obesity; Overweight; Tennessee
PubMed: 38941300
DOI: 10.1371/journal.pone.0289523 -
Medical Microbiology and Immunology Jun 2024Obesity-associated male infertility is a common complication of obesity and has been increasing in prevalence. Blautia wexlerae has modulation effects on obesity....
BACKGROUND
Obesity-associated male infertility is a common complication of obesity and has been increasing in prevalence. Blautia wexlerae has modulation effects on obesity. However, the action of B. wexlerae on obesity-associated male infertility is unclear. The nod-like receptor protein 3 (NLRP3) inflammasome has become a major target for addressing many diseases, including obesity-associated male infertility. This study aims to investigate the action of B. wexlerae on obesity-associated male infertility and the influence of B. wexlerae on NLRP3 inflammasome.
MATERIALS AND METHODS
The fecal samples were collected from 60 infertile men with or without obesity and 30 healthy men. The obesity mice model was established through high-fat diet (HFD) induction. The mating assays evaluated the male infertility of obese mice. A mouse-derived spermatogonia (GC-1 spg) cell viability was detected using the Cell Counting Kit-8 assay. The reactive oxygen species (ROS) were assessed using flow cytometry. Furthermore, immunofluorescence, enzyme-linked immunosorbent assay, and western blotting were applied to measure the gene expressions.
RESULTS
Blautia wexlerae was decreased and negatively correlated with interleukin-1 beta (IL-1β) or IL-18 levels in infertile men with obesity. On the other hand, B. wexlerae improved the mating capability of obese male mice and suppressed oxidative stress and NLRP3 inflammasome via the activation of the acetate receptor. Furthermore, sodium acetate regulated oxidative stress and NLRP3 inflammasome via the activation of the acetate receptor in GC-1 spg cells in vitro.
CONCLUSION
The administration of Blautia wexlerae improved obesity-associated male infertility and regulated oxidative stress and NLRP3 inflammasome activities. In general, its administration may be an effective strategy for the treatment of obesity-associated male infertility.
Topics: Male; NLR Family, Pyrin Domain-Containing 3 Protein; Animals; Obesity; Oxidative Stress; Humans; Infertility, Male; Inflammasomes; Mice; Adult; Reactive Oxygen Species; Disease Models, Animal; Diet, High-Fat; Interleukin-1beta; Mice, Inbred C57BL
PubMed: 38940844
DOI: 10.1007/s00430-024-00796-x -
Molecular Medicine Reports Aug 2024Elevated levels of blood glucose in patients with ischemic stroke are associated with a worse prognosis. The present study aimed to explore whether hyperglycemia...
Elevated levels of blood glucose in patients with ischemic stroke are associated with a worse prognosis. The present study aimed to explore whether hyperglycemia promotes microglial pyroptosis by increasing the oxygen extraction rate in an acute ischemic stroke model. C57BL/6 mice that underwent middle cerebral artery occlusion were used for assessment of blood glucose level and neurological function. The cerebral oxygen extraction ratio (CERO), oxygen consumption rate (OCR) and partial pressure of brain tissue oxygen (PbtO) were measured. To investigate the significance of the NOD‑like receptor protein 3 (NLRP3) inflammasome, NLRP3 mice were used, and the expression levels of NLRP3, caspase‑1, full‑length gasdermin D (GSDMD‑FL), GSDMD‑N domain (GSDMD‑N), IL‑1β and IL‑18 were evaluated. In addition, Z‑YVAD‑FMK, a caspase‑1 inhibitor, was used to treat microglia to determine whether activation of the NLRP3 inflammasome was required for the enhancing effect of hyperglycemia on pyroptosis. It was revealed that hyperglycemia accelerated cerebral injury in the acute ischemic stroke model, as evidenced by decreased latency to fall and the percentage of foot fault. Hyperglycemia aggravated hypoxia by increasing the oxygen extraction rate, as evidenced by increased CERO and OCR, and decreased PbtO in response to high glucose treatment. Furthermore, hyperglycemia‑induced microglial pyroptosis was confirmed by detection of increased levels of caspase‑1, GSDMD‑N, IL‑1β and IL‑18 and a decreased level of GSDMD‑FL. However, the knockout of NLRP3 attenuated these effects. Pharmacological inhibition of caspase‑1 also reduced the expression levels of GSDMD‑N, IL‑1β and IL‑18 in microglial cells. These results suggested that hyperglycemia stimulated NLRP3 inflammasome activation by increasing the oxygen extraction rate, thus leading to the aggravation of pyroptosis following ischemic stroke.
Topics: Animals; Pyroptosis; Microglia; Ischemic Stroke; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Oxygen; Male; Hyperglycemia; Inflammasomes; Mice, Inbred C57BL; Caspase 1; Disease Models, Animal; Mice, Knockout; Interleukin-1beta; Phosphate-Binding Proteins; Oxygen Consumption; Gasdermins
PubMed: 38940333
DOI: 10.3892/mmr.2024.13270 -
Molecular Medicine Reports Aug 2024Osteoarthritis (OA) is a chronic disease that involves chondrocyte injury. ADAMTS5 has been confirmed to mediate chondrocyte injury and thus regulate OA progression, but...
Osteoarthritis (OA) is a chronic disease that involves chondrocyte injury. ADAMTS5 has been confirmed to mediate chondrocyte injury and thus regulate OA progression, but its underlying molecular mechanisms remain unclear. In the present study, interleukin‑1β (IL‑1β)‑induced chondrocytes were used to mimic OA . Cell proliferation and apoptosis were assessed by MTT assay, EdU assay and flow cytometry, and protein levels of ADAMTS5, specificity protein 1 (SP1), matrix‑related markers and Wnt/β‑catenin pathway‑related markers were examined using western blotting. In addition, ELISA was performed to measure the concentrations of inflammation factors, and oxidative stress was evaluated by detecting SOD activity and MDA levels. The mRNA expression levels of ADAMTS5 and SP1 were determined by reverse transcription‑quantitative PCR, and the interaction between SP1 and ADAMTS5 was analyzed using a dual‑luciferase reporter assay and chromatin immunoprecipitation assay. IL‑1β suppressed proliferation, but promoted apoptosis, extracellular matrix degradation, inflammation and oxidative stress in chondrocytes. ADAMTS5 was upregulated in IL‑1β‑induced chondrocytes, and its knockdown alleviated IL‑1β‑induced chondrocyte injury. SP1 could bind to the ADAMTS5 promoter region to promote its transcription, and SP1 knockdown relieved IL‑1β‑induced chondrocyte injury by reducing ADAMTS5 expression. The SP1/ADAMTS5 axis activated the Wnt/β‑catenin pathway, and the Wnt/β‑catenin pathway agonist, SKL2001, reversed the protective effect of ADAMTS5 knockdown on chondrocyte injury induced by IL‑1β. To the best of our knowledge, the present study was the first to reveal the interaction between SP1 and ADAMTS5 in OA progression and indicated that the SP1/ADAMTS5 axis mediates OA progression by regulating the Wnt/β‑catenin pathway.
Topics: Chondrocytes; Sp1 Transcription Factor; ADAMTS5 Protein; Interleukin-1beta; Wnt Signaling Pathway; Osteoarthritis; Humans; Cell Proliferation; Apoptosis; Oxidative Stress; beta Catenin
PubMed: 38940327
DOI: 10.3892/mmr.2024.13273 -
Biomeditsinskaia Khimiia Jun 2024The cytokine profile of primary coronary artery endothelial cells cultivated in the presence of doxorubicin (2 μg/ml and 6 μg/ml) was evaluated using enzyme-linked...
The cytokine profile of primary coronary artery endothelial cells cultivated in the presence of doxorubicin (2 μg/ml and 6 μg/ml) was evaluated using enzyme-linked immunosorbent assay and qPCR. Cultivation of cells in the presence of these concentrations of doxorubicin for 24 h, upregulated expression of the following genes: IL6 (by 2.30 and 2.66 times, respectively), IL1B (by 1.25 and 3.44 times), and CXCL8 (by 6.47 times and 6.42 times), MIF (2.34 and 2.28 times), CCL2 (4.22 and 3.98 times). Under these conditions the following genes were downregulated: IL10, IL1R2, TNF. Cultivation of cells in the presence of doxorubicin (2 μg/ml and 6 μg/ml) for 24 h also increased the secretion of IL-6.
Topics: Humans; Doxorubicin; Coronary Vessels; Endothelial Cells; Interleukin-6; Cells, Cultured; Interleukin-1beta; Cytokines; Gene Expression Regulation; Interleukin-8; Chemokine CCL2; Tumor Necrosis Factor-alpha; Interleukin-10
PubMed: 38940204
DOI: 10.18097/PBMC20247003156 -
Frontiers in Bioscience (Landmark... Jun 2024Although umbilical cord mesenchymal stem cell (UCMSC) infusion has been proposed as a promising strategy for the treatment of acute lung injury (ALI), the parameters of... (Comparative Study)
Comparative Study
BACKGROUND
Although umbilical cord mesenchymal stem cell (UCMSC) infusion has been proposed as a promising strategy for the treatment of acute lung injury (ALI), the parameters of UCMSC transplantation, such as infusion routes and doses, need to be further optimized.
METHODS
In this study, we compared the therapeutic effects of UCMSCs transplanted via intravenous injection and intratracheal instillation on lipopolysaccharide-induced ALI using a rat model. Following transplantation, levels of inflammatory factors in serum; neutrophils, total white blood cells, and lymphocytes in bronchoalveolar lavage fluid (BALF); and lung damage levels were analyzed.
RESULTS
The results indicated that UCMSCs administered via both intravenous and intratracheal routes were effective in alleviating ALI, as determined by analyses of arterial blood gas, lung histopathology, BALF contents, and levels of inflammatory factors. Comparatively, the intratracheal instillation of UCMSCs was found to result in lower levels of lymphocytes and total proteins in BALF, whereas greater reductions in the serum levels of tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) were detected in rats receiving intravenously injected stem cells.
CONCLUSIONS
Our findings in this study provide convincing evidence to indicate the efficacy of UCMSC therapy in the treatment of ALI mediated via different delivery routes, thereby providing a reliable theoretical basis for further clinical studies. Moreover, these findings imply that the effects obtained using the two assessed delivery routes for UCMSC transplantation are mediated via different mechanisms, which could be attributable to different cellular or molecular targets.
Topics: Animals; Acute Lung Injury; Lipopolysaccharides; Mesenchymal Stem Cell Transplantation; Umbilical Cord; Rats, Sprague-Dawley; Rats; Male; Bronchoalveolar Lavage Fluid; Mesenchymal Stem Cells; Tumor Necrosis Factor-alpha; Injections, Intravenous
PubMed: 38940047
DOI: 10.31083/j.fbl2906217 -
Sheng Li Xue Bao : [Acta Physiologica... Jun 2024The role of the aryl hydrocarbon receptor (AhR) in regulating oxidative stress and immune responses has been increasingly recognized. However, its involvement in...
The role of the aryl hydrocarbon receptor (AhR) in regulating oxidative stress and immune responses has been increasingly recognized. However, its involvement in depression and the underlying mechanisms remain poorly understood. This study aimed to investigate the effect of 6-formylindolo[3,2-b]carbazole (FICZ), an endogenous AhR ligand, on a lipopolysaccharide (LPS)-induced depression model and the underlying mechanism. After being treated with FICZ (50 mg/kg), male C57BL/6J mice received intraperitoneal injection of LPS and underwent behavioral tests 24 h later. The levels of inflammatory cytokines, including IL-1β, IL-6, and TNF-α, were measured in the hippocampus and serum using enzyme-linked immunosorbent assay (ELISA). The expression levels of CYP1A1, AhR and NLRP3 were analyzed using qPCR and Western blot. The results showed that, compared with control group, LPS alone significantly down-regulated the expression levels of CYP1A1 mRNA and AhR protein in the hippocampus of mice, reduced glucose preference, prolonged immobility time in forced swimming test, increased IL-6 and IL-1β levels in the hippocampus, increased serum IL-1β level, and up-regulated NLRP3 mRNA and protein expression levels in mouse hippocampus, while FICZ significantly reversed the aforementioned effects of LPS. These findings suggest that AhR activation attenuates the inflammatory response associated with depression and modulates the expression of NLRP3. The present study provides novel insights into the role of AhR in the development of depression, and presents AhR as a potential therapeutic target for the treatment of depression.
Topics: Animals; Receptors, Aryl Hydrocarbon; Male; Mice; Lipopolysaccharides; Depression; Mice, Inbred C57BL; Cytochrome P-450 CYP1A1; Hippocampus; Carbazoles; NLR Family, Pyrin Domain-Containing 3 Protein; Interleukin-1beta; Interleukin-6; Tumor Necrosis Factor-alpha; Behavior, Animal; Cytokines
PubMed: 38939930
DOI: No ID Found -
Frontiers in Cellular and Infection... 2024Recent studies have demonstrated a positive role of hyaluronic acid (HA) on periodontal clinical outcomes. This study aimed to investigate the impact of four different...
INTRODUCTION
Recent studies have demonstrated a positive role of hyaluronic acid (HA) on periodontal clinical outcomes. This study aimed to investigate the impact of four different HAs on interactions between periodontal biofilm and immune cells.
METHODS
The four HAs included: high-molecular-weight HA (HHA, non-cross-linked), low-molecular-weight HA (LHA), oligomers HA (OHA), and cross-linked high-molecular-weight HA (CHA). Serial experiments were conducted to verify the influence of HAs on: (i) 12-species periodontal biofilm (formation and pre-existing); (ii) expression of inflammatory cytokines and HA receptors in monocytic (MONO-MAC-6) cells and periodontal ligament fibroblasts (PDLF) with or without exposure to periodontal biofilms; (iii) generation of reactive oxygen species (ROS) in MONO-MAC-6 cells and PDLF with presence of biofilm and HA.
RESULTS
The results indicated that HHA and CHA reduced the bacterial counts in a newly formed (4-h) biofilm and in a pre-existing five-day-old biofilm. Without biofilm challenge, OHA triggered inflammatory reaction by increasing IL-1β and IL-10 levels in MONO-MAC cells and IL-8 in PDLF in a time-dependent manner, whereas CHA suppressed this response by inhibiting the expression of IL-10 in MONO-MAC cells and IL-8 in PDLF. Under biofilm challenge, HA decreased the expression of IL-1β (most decreasing HHA) and increased IL-10 levels in MONO-MAC-6 cells in a molecular weight dependent manner (most increasing CHA). The interaction between HA and both cells may occur via ICAM-1 receptor. Biofilm stimulus increased ROS levels in MONO-MAC-6 cells and PDLF, but only HHA slightly suppressed the high generation of ROS induced by biofilm stimulation in both cells.
CONCLUSION
Overall, these results indicate that OHA induces inflammation, while HHA and CHA exhibit anti-biofilm, primarily anti-inflammatory, and antioxidant properties in the periodontal environment.
Topics: Biofilms; Hyaluronic Acid; Humans; Reactive Oxygen Species; Fibroblasts; Cytokines; Monocytes; Periodontal Ligament; Cell Line; Interleukin-1beta; Interleukin-10
PubMed: 38938883
DOI: 10.3389/fcimb.2024.1414861 -
Immunity, Inflammation and Disease Jun 2024To explore the efficacy and potential mechanism of Fengshi Gutong capsule (FSGTC) in osteoarthritis (OA) inflammation.
OBJECTIVE
To explore the efficacy and potential mechanism of Fengshi Gutong capsule (FSGTC) in osteoarthritis (OA) inflammation.
METHODS
The impact of FSGTC on laboratory indicators of OA patients was explored using data mining technology and association rule analysis. Then, the OA cell model was constructed by inducing chondrocytes (CHs) with interleukin-1β (IL-1β). In the presence of FSGTC intervention, the regulatory mechanism of PACER/COX2/PGE2 in OA-CH viability and inflammatory responses was evaluated.
RESULTS
Retrospective data mining showed that FSGTC effectively reduced inflammation indexes (ESR, HCRP) of OA patients. Cell experiments showed that LncRNA PACER (PACER) silencing inhibited the proliferation activity of OA-CHs, increased the level of COX2 protein, elevated the levels of PGE2, TNF-α, and IL-1β, and decreased the levels of IL-4 and IL-10 (p < .01). On the contrary, FSGTC-containing serum reversed the effect of PACER silencing on OA-CHs (p < .01). After the addition of COX2 pathway inhibitor, the proliferation activity of OA-CHs was enhanced; the levels of PGE2, TNF-α, and IL-1β were decreased while the levels of IL-4 and IL-10 were increased (p < .01).
CONCLUSION
FSGTC inhibits IL-1β-induced inflammation in CHs and ameliorates OA by upregulating PACER and downregulating COX2/PGE2.
Topics: Chondrocytes; RNA, Long Noncoding; Humans; Interleukin-1beta; Cyclooxygenase 2; Dinoprostone; Osteoarthritis; Inflammation; Drugs, Chinese Herbal; Down-Regulation; Male; Female; Up-Regulation; Middle Aged
PubMed: 38938021
DOI: 10.1002/iid3.1334