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The Journal of Clinical Investigation Apr 2024BACKGROUNDThe molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific... (Clinical Trial)
Clinical Trial
BACKGROUNDThe molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific tissue injury contributes to outcomes is unknown. Therefore, we profiled inflammation and tissue injury dynamics over the first 7 days of ARDS, and associated specific biomarkers with mortality, persistent ARDS, and persistent multiple organ dysfunction syndrome (MODS).METHODSIn a single-center prospective cohort of intubated pediatric patients with ARDS, we collected plasma on days 0, 3, and 7. Nineteen biomarkers reflecting inflammation, tissue injury, and damage-associated molecular patterns (DAMPs) were measured. We assessed the relationship between biomarkers and trajectories with mortality, persistent ARDS, or persistent MODS using multivariable mixed effect models.RESULTSIn 279 patients (64 [23%] nonsurvivors), hyperinflammatory cytokines, tissue injury markers, and DAMPs were higher in nonsurvivors. Survivors and nonsurvivors showed different biomarker trajectories. IL-1α, soluble tumor necrosis factor receptor 1, angiopoietin 2 (ANG2), and surfactant protein D increased in nonsurvivors, while DAMPs remained persistently elevated. ANG2 and procollagen type III N-terminal peptide were associated with persistent ARDS, whereas multiple cytokines, tissue injury markers, and DAMPs were associated with persistent MODS. Corticosteroid use did not impact the association of biomarker levels or trajectory with mortality.CONCLUSIONSPediatric ARDS survivors and nonsurvivors had distinct biomarker trajectories, with cytokines, endothelial and alveolar epithelial injury, and DAMPs elevated in nonsurvivors. Mortality markers overlapped with markers associated with persistent MODS, rather than persistent ARDS.FUNDINGNIH (K23HL-136688, R01-HL148054).
Topics: Humans; Biomarkers; Male; Female; Child; Child, Preschool; Respiratory Distress Syndrome; Infant; Inflammation; Prospective Studies; Adolescent; Multiple Organ Failure; Cytokines
PubMed: 38573766
DOI: 10.1172/JCI177896 -
Endocrine and Metabolic Science Mar 2024Vitamin D is a key regulator of bone mineral homeostasis and may modulate maternal bone health during pregnancy and postpartum. Using previously-collected data from the...
Prenatal but not continued postpartum vitamin D supplementation reduces maternal bone resorption as measured by C-terminal telopeptide of type 1 collagen without effects on other biomarkers of bone metabolism.
Vitamin D is a key regulator of bone mineral homeostasis and may modulate maternal bone health during pregnancy and postpartum. Using previously-collected data from the Maternal Vitamin D for Infant Growth (MDIG) trial in Dhaka, Bangladesh, we aimed to investigate the effects of prenatal and postpartum vitamin D supplementation on circulating biomarkers of bone formation and resorption at delivery and 6 months postpartum. MDIG trial participants were randomized to receive a prenatal;postpartum regimen of placebo or vitamin D (IU/week) as either 0;0 (Group A), 4200;0 (B), 16,800;0 (C), 28,000;0 (D) or 28,000;28,000 (E) from 17 to 24 weeks' gestation to 6 months postpartum. As this sub-study was not pre-planned, the study sample included MDIG participants who had data for at least 1 biomarker of interest at delivery or 6 months postpartum, with a corresponding baseline measurement ( = 690; 53 % of 1300 enrolled trial participants). Biomarkers related to bone turnover were measured in maternal venous blood samples collected at enrolment, delivery, and 6 months postpartum: osteoprotegerin (OPG), osteocalcin (OC), receptor activator nuclear factor kappa-B ligand (RANKL), fibroblast growth factor 23 (FGF23), procollagen type 1 N-terminal propeptide, (P1NP) and carboxy terminal telopeptide of type 1 collagen (CTx). Supplementation effects were expressed as percent differences between each vitamin D group and placebo with 95 % confidence intervals (95 % CI). Of 690 participants, 64 % had 25-hydroxyvitamin D concentrations (25OHD) <30 nmol/L and 94 % had 25OHD < 50 nmol/L at trial enrolment. At delivery, mean CTx concentrations were 27 % lower in group E versus placebo (95 % CI: -38, -13; < 0.001), adjusting for enrolment concentrations. However, at 6 months postpartum, CTx concentrations were not statistically different in group E versus placebo (14 %; 95 % CI: -5.3, 37; = 0.168), adjusting for delivery CTx concentrations. Effects on other biomarkers at delivery or postpartum were not statistically significant. In conclusion, prenatal high-dose vitamin D supplementation reduced bone resorption during pregnancy, albeit by only one biomarker, and without evidence of a sustained effect in the postpartum period. However, further evidence is needed to substantiate potential maternal bone health benefits of vitamin D in the postpartum period.
PubMed: 38558882
DOI: 10.1016/j.endmts.2023.100154 -
Current Issues in Molecular Biology Mar 2024Inflammation and collagen-degrading enzymes' overexpression promote collagen decomposition, which affects the structural integrity of the extracellular matrix. The...
Inflammation and collagen-degrading enzymes' overexpression promote collagen decomposition, which affects the structural integrity of the extracellular matrix. The polysaccharide and peptide extracts of the green alga () have been proven to have anti-inflammatory, wound healing, and antioxidant effects in vivo and in vitro. However, the biological properties of the non-water-soluble components of are still unknown. In the present study, we demonstrated the higher effective anti-inflammatory functions of ethyl acetate (EA) extract than water extract up to 16-30% in LPS-induced HaCaT cells, including reducing the production of interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α (TNF-α). Furthermore, the excellent collagen homeostasis effects from were proven by suppressing the matrix metalloproteinase-1 (MMP-1) secretion, enhancing type 1 procollagen and collagen expressions dose-dependently in WS1 cells. Moreover, using UHPLC-QTOF-MS analysis, four terpenoids, siphonaxanthin, caulerpenyne, caulerpal A, and caulerpal B, were identified and may be involved in the superior collagen homeostasis and anti-inflammatory effects of the EA extract.
PubMed: 38534786
DOI: 10.3390/cimb46030170 -
Cells Mar 2024Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease characterized by the relentless deposition of extracellular matrix (ECM), causing lung...
Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease characterized by the relentless deposition of extracellular matrix (ECM), causing lung distortions and dysfunction. Animal models of human IPF can provide great insight into the mechanistic pathways underlying disease progression and a means for evaluating novel therapeutic approaches. In this study, we describe the effect of bleomycin concentration on disease progression in the classical rat bleomycin model. In a dose-response study (1.5, 2, 2.5 U/kg i.t), we characterized lung fibrosis at day 14 after bleomycin challenge using endpoints including clinical signs, inflammatory cell infiltration, collagen content, and bronchoalveolar lavage fluid-soluble profibrotic mediators. Furthermore, we investigated fibrotic disease progression after 2 U/kg i.t. bleomycin administration at days 3, 7, and 14 by quantifying the expression of clinically relevant signaling molecules and pathways, epithelial mesenchymal transition (EMT) biomarkers, ECM components, and histopathology of the lung. A single bleomycin challenge resulted in a progressive fibrotic response in rat lung tissue over 14 days based on lung collagen content, histopathological changes, and modified Ashcroft score. The early fibrogenesis phase (days 3 to 7) is associated with an increase in profibrotic mediators including TGFβ1, IL6, TNFα, IL1β, CINC1, WISP1, VEGF, and TIMP1. In the mid and late fibrotic stages, the TGFβ/Smad and PDGF/AKT signaling pathways are involved, and clinically relevant proteins targeting galectin-3, LPA1, transglutaminase-2, and lysyl oxidase 2 are upregulated on days 7 and 14. Between days 7 and 14, the expressions of vimentin and α-SMA proteins increase, which is a sign of EMT activation. We confirmed ECM formation by increased expressions of procollagen-1Aα, procollagen-3Aα, fibronectin, and CTGF in the lung on days 7 and 14. Our data provide insights on a complex network of several soluble mediators, clinically relevant signaling pathways, and target proteins that contribute to drive the progressive fibrotic phenotype from the early to late phase (active) in the rat bleomycin model. The framework of endpoints of our study highlights the translational value for pharmacological interventions and mechanistic studies using this model.
Topics: Rats; Humans; Animals; Procollagen; Idiopathic Pulmonary Fibrosis; Fibrosis; Collagen; Bleomycin; Disease Progression
PubMed: 38534359
DOI: 10.3390/cells13060515 -
Heliyon Mar 2024Procollagen c-protease enhancer protein (PCOLCE) performs an essential action in improving the recreation of procollagen c-protease and promoting the reconstruction of...
Procollagen c-protease enhancer protein (PCOLCE) performs an essential action in improving the recreation of procollagen c-protease and promoting the reconstruction of extracellular matrix. High PCOLCE expression was associated with a negative prognosis of stomach cancer, ovarian cancer, and osteosarcoma. The goal of this work is to investigate the function of PCOLCE in glioma. Multiple bioinformatics techniques have been employed to investigate the roles of PCOLCE in glioma, consisting of the correlation between PCOLCE and prognosis, immune checkpoints, immune cell infiltrates, and tumor microenvironment (TME). The gene ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to assess the potential function of PCOLCE in glioma. PCOLCE was found to be increased in glioma. We revealed that PCOLCE was a potential prognostic factor and related to tumor grade. Up-regulated PCOLCE was related to poor prognosis in lower-grade glioma (LGG), glioblastoma multiforme (GBM), and recurrent glioma. PCOLCE was correlated with immune cell infiltration, particularly B cells, CD4 T cells, macrophages, neutrophils, and dendritic cells (DCs) in LGG, and DCs infiltration in GBM. PCOLCE was co-expressed with many genes related to the immune and the immune checkpoint. In addition, glioma patients with low expression of PCOLCE had a higher response to the immunological checkpoint blockade (ICB). Additionally, PCOLCE may exert its roles via several immune-related biological processes or pathways, such as leukocyte migration, activation of T cells, adaptive immune response, neutrophil-mediated immunity, NF-κB, and TNF signaling pathways. In conclusion, PCOLCE may be a new immune-related gene and regulate tumor development through immunological pathways.
PubMed: 38533063
DOI: 10.1016/j.heliyon.2024.e28089 -
JBMR Plus Apr 2024Children with hemato-oncological diseases may have significant skeletal morbidity, not only during and after treatment but also at the time of diagnosis before cancer...
Children with hemato-oncological diseases may have significant skeletal morbidity, not only during and after treatment but also at the time of diagnosis before cancer treatment. This study was designed to evaluate the vitamin D status and circulating bone metabolic markers and their determinants in children at the time of diagnostic evaluation for hemato-oncological disease. This cross-sectional study included 165 children (91 males, median age 6.9 yr range 0.2-17.7 yr). Of them, 76 patients were diagnosed with extracranial or intracranial solid tumors, 83 with leukemia, and 6 with bone marrow failure. Bone metabolism was assessed by measuring serum 25OHD, PTH, bone alkaline phosphatase, intact N-terminal propeptide of type I procollagen, and C-terminal cross-linked telopeptide of type I collagen. Vitamin D deficiency was found in 30.9% of children. Lower 25OHD levels were associated with older age, lack of vitamin D supplementation, season outside summer, and a country of parental origin located between latitudes -45° and 45°. Children diagnosed with leukemia had lower levels of markers of bone formation and bone resorption than those who had solid tumors or bone marrow failure. In conclusion, vitamin D deficiency was observed in one-third of children with newly diagnosed cancer. Bone turnover markers were decreased in children with leukemia, possibly because of the suppression of osteoblasts and osteoclasts by leukemic cells. The identification of patients with suboptimal vitamin D status and compromised bone remodeling at cancer diagnosis may aid in the development of supportive treatment to reduce the adverse effects of cancer and its treatment.
PubMed: 38523666
DOI: 10.1093/jbmrpl/ziae017 -
Advanced Science (Weinheim,... Jun 2024Pelvic organ prolapse (POP) is one of the most common pelvic floor dysfunction disorders worldwide. The weakening of pelvic connective tissues initiated by excessive...
Pelvic organ prolapse (POP) is one of the most common pelvic floor dysfunction disorders worldwide. The weakening of pelvic connective tissues initiated by excessive collagen degradation is a leading cause of POP. However, the patches currently used in the clinic trigger an unfavorable inflammatory response, which often leads to implantation failure and the inability to simultaneously reverse progressive collagen degradation. Therefore, to overcome the present challenges, a new strategy is applied by introducing puerarin (Pue) into poly(l-lactic acid) (PLLA) using electrospinning technology. PLLA improves the mechanical properties of the patch, while Pue offers intrinsic anti-inflammatory and pro-collagen synthesis effects. The results show that Pue is released from PLLA@Pue in a sustained manner for more than 20 days, with a total release rate exceeding 80%. The PLLA@Pue electrospun patches also show good biocompatibility and low cytotoxicity. The excellent anti-inflammatory and pro-collagen synthesis properties of the PLLA@Pue patch are demonstrated both in vitro in HO-stimulated mouse fibroblasts and in vivo in rat abdominal wall muscle defects. Therefore, it is believed that this multifunctional electrospun patch integrating anti-inflammatory and pro-collagen synthesis properties can overcome the limitations of traditional patches and has great prospects for efficient pelvic floor reconstruction.
Topics: Animals; Isoflavones; Rats; Pelvic Floor; Anti-Inflammatory Agents; Mice; Collagen; Pelvic Organ Prolapse; Polyesters; Disease Models, Animal; Rats, Sprague-Dawley
PubMed: 38509840
DOI: 10.1002/advs.202308590 -
JBMR Plus Feb 2024Bone development and remodeling are controlled by the phosphoinositide-3-kinase (Pi3k) signaling pathway. We investigated the effects of downregulation of phosphatase...
Bone development and remodeling are controlled by the phosphoinositide-3-kinase (Pi3k) signaling pathway. We investigated the effects of downregulation of phosphatase and tensin homolog (Pten), a negative regulator of Pi3k signaling, in a mouse model of Pten deficiency in preosteoblasts. We aimed to identify mechanisms that are involved in the regulation of bone turnover and are linked to bone disorders. Femora, tibiae, and bone marrow stromal cells (BMSCs) isolated from mice with a conditional deletion of Pten (Pten cKO) in -expressing osteoprogenitor cells were compared to Cre-negative controls. Bone phenotyping was performed by μCT measurements, bone histomorphometry, quantification of bone turnover markers CTX and procollagen type 1 N propeptide (P1NP), and three-point bending test. Proliferation of BMSCs was measured by counting nuclei and Ki-67-stained cells. In vitro, osteogenic differentiation capacity was determined by ALP staining, as well as by detecting gene expression of osteogenic markers. BMSCs from Pten cKO mice were functionally different from control BMSCs. Osteogenic markers were increased in BMSCs derived from Pten cKO mice, while Pten protein expression was lower and Akt phosphorylation was increased. We detected a higher trabecular bone volume and an altered cortical bone morphology in Pten cKO bones with a progressive decrease in bone and tissue mineral density. Pten cKO bones displayed fewer osteoclasts and more osteoblasts ( = .00095) per trabecular bone surface and a higher trabecular bone formation rate. Biomechanical analysis revealed a significantly higher bone strength ( = .00012 for males) and elasticity of Pten cKO femora. On the cellular level, both proliferation and osteogenic differentiation capacity of Pten cKO BMSCs were significantly increased compared to controls. Our findings suggest that Pten knockout in osteoprogenitor cells increases bone stability and elasticity by increasing trabecular bone mass and leads to increased proliferation and osteogenic differentiation of BMSCs.
PubMed: 38505222
DOI: 10.1093/jbmrpl/ziad016 -
Nutrients Feb 2024Menopause marks a critical life stage characterized by hormonal changes that significantly impact bone health, leading to a heightened susceptibility to bone fractures....
Menopause marks a critical life stage characterized by hormonal changes that significantly impact bone health, leading to a heightened susceptibility to bone fractures. This research seeks to elucidate the impact of daidzein and tempeh on calcium status, calcium transporters, and bone metabolism in an ovariectomized rat model. Forty female Wistar rats, aged 3 months, participated in a two-phase experiment. The initial phase involved inducing a calcium deficit, while the second phase comprised dietary interventions across five groups: Sham (S) and Ovariectomy (O) with a standard diet, O with bisphosphonate (OB), O with pure daidzein (OD), and O with tempeh (OT). Multiple parameters, encompassing calcium levels, calcium transporters, bone histopathology, and serum bone metabolism markers, were evaluated. The findings revealed that the OT group showcased heightened levels of bone turnover markers, such as pyridinoline, C-telopeptide of type I collagen, bone alkaline phosphatase, and procollagen type I N-terminal propeptide, in contrast to S and O groups, with statistical significance ( < 0.05). Histopathologically, both the OD and OT groups exhibited effects akin to the OB group, indicating a decrease in the surface area occupied by adipocytes in the femoral bone structure, although statistically non-equivalent, supporting the directionally similar trends. Although TRPV5 and TRPV6 mRNA expression levels in the jejunum and duodenum did not display statistically significant differences ( > 0.05), the OD and OT groups exhibited increased expression compared to the O group. We hypothesized that obtained results may be related to the effect of isoflavones on estrogen pathways because of their structurally similar to endogenous estrogen and weak estrogenic properties. In conclusion, the daily consumption of pure daidzein and tempeh could potentially improve and reinstate calcium status, calcium transport, and bone metabolism in ovariectomized rats. Additionally, isoflavone products demonstrate effects similar to bisphosphonate drugs on these parameters in ovariectomized rats.
Topics: Rats; Female; Animals; Humans; Calcium; Osteoporosis; Rats, Wistar; Soy Foods; Calcium, Dietary; Isoflavones; Estrogens; Biomarkers; Diphosphonates; Ovariectomy; Bone Density
PubMed: 38474779
DOI: 10.3390/nu16050651 -
Nutrients Feb 2024Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing healthcare problem with limited therapeutic options. Progress in this field depends on the...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing healthcare problem with limited therapeutic options. Progress in this field depends on the availability of reliable preclinical models. Human precision-cut liver slices (PCLSs) have been employed to replicate the initiation of MASLD, but a comprehensive investigation into MASLD progression is still missing. This study aimed to extend the current incubation time of human PCLSs to examine different stages in MASLD. Healthy human PCLSs were cultured for up to 96 h in a medium enriched with high sugar, high insulin, and high fatty acids to induce MASLD. PCLSs displayed hepatic steatosis, characterized by accumulated intracellular fat. The development of hepatic steatosis appeared to involve a time-dependent impact on lipid metabolism, with an initial increase in fatty acid uptake and storage, and a subsequent down-regulation of lipid oxidation and secretion. PCLSs also demonstrated liver inflammation, including increased pro-inflammatory gene expression and cytokine production. Additionally, liver fibrosis was also observed through the elevated production of pro-collagen 1a1 and tissue inhibitor of metalloproteinase-1 (TIMP1). RNA sequencing showed that the tumor necrosis factor alpha (TNFα) signaling pathway and transforming growth factor beta (TGFβ) signaling pathway were consistently activated, potentially contributing to the development of inflammation and fibrosis. In conclusion, the prolonged incubation of human PCLSs can establish a robust ex vivo model for MASLD, facilitating the identification and evaluation of potential therapeutic interventions.
Topics: Humans; Drug Evaluation, Preclinical; Tissue Inhibitor of Metalloproteinase-1; Fatty Liver; Metabolic Diseases; Inflammation
PubMed: 38474754
DOI: 10.3390/nu16050626