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Results for “anti-inflammatory mechanisms”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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14 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Tea consumption and risk of bladder cancer in the Bladder Cancer Epidemiology and Nutritional Determinants (BLEND) Study: Pooled analysis of 12 international cohort studies

Tea has been shown to be associated with reduced risk of several diseases including cardiovascular diseases, stroke, metabolic syndrome, and obesity. However, the results on the relationship between tea consumption and bladder cancer are conflicting. This research aimed to assess the association between tea consumption and risk of bladder cancer using a pooled analysis of prospective cohort data. Individual data from 532,949 participants in 12 cohort studies, were pooled for analyses. Cox regression models stratified by study centre was used to estimate hazard ratios (HR) and corresponding 95% CIs. Fractional polynomial regression models were used to examine the dose–response relationship. A higher level of tea consumption was associated with lower risk of bladder cancer incidence (compared with no tea consumption: HR = 0.87, 95% C.I. = 0.77–0.98 for low consumption; HR = 0.86, 95% C.I. = 0.77–0.96 for moderate consumption; HR = 0.84, 95% C.I. = 0.75–0.95 for high consumption). When stratified by sex and smoking status, this reduced risk was statistically significant among men and current and former smokers. In addition, dose–response analyses showed a lower bladder cancer risk with increment of 100 ml of tea consumption per day (HR-increment = 0.97; 95% CI = 0.96–0.98). A similar inverse association was found among males, current and former smokers while never smokers and females showed non-significant results, suggesting potential sex-dependent effect. Higher consumption of tea is associated with reduced risk of bladder cancer with potential interaction with sex and smoking status. Further studies are needed to clarify the mechanisms for a protective effect of tea (e.g. inhibition of the survival and proliferation of cancer cells and anti-inflammatory mechanisms) and its interaction with smoking and sex.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Systems biology predicts that fibrosis in tuberculous granulomas may arise through macrophage-to-myofibroblast transformation

Mycobacterium tuberculosis (Mtb) infection causes tuberculosis (TB), a disease characterized by development of granulomas. Granulomas consist of activated immune cells that cluster together to limit bacterial growth and restrict dissemination. Control of the TB epidemic has been limited by lengthy drug regimens, antibiotic resistance, and lack of a robustly efficacious vaccine. Fibrosis commonly occurs during treatment and is associated with both positive and negative disease outcomes in TB but little is known about the processes that initiate fibrosis in granulomas. Human and nonhuman primate granulomas undergoing fibrosis can have spindle-shaped macrophages with fibroblast-like morphologies suggesting a relationship between macrophages, fibroblasts, and granuloma fibrosis. This relationship has been difficult to investigate because of the limited availability of human pathology samples, the time scale involved in human TB, and overlap between fibroblast and myeloid cell markers in tissues. To better understand the origins of fibrosis in TB, we used a computational model of TB granuloma biology to identify factors that drive fibrosis over the course of local disease progression. We validated the model with granulomas from nonhuman primates to delineate myeloid cells and lung-resident fibroblasts. Our results suggest that peripheral granuloma fibrosis, which is commonly observed, can arise through macrophage-to-myofibroblast transformation (MMT). Further, we hypothesize that MMT is induced in M1 macrophages through a sequential combination of inflammatory and anti-inflammatory signaling in granuloma macrophages. We predict that MMT may be a mechanism underlying granuloma-associated fibrosis and warrants further investigation into myeloid cells as drivers of fibrotic disease.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Alginate–Amorphous Calcium Carbonate Hydrogels for Controlled Therapeutic Release

Alginate hydrogels are widely explored as biocompatible matrices for transdermal delivery of therapeutic compounds but burst release and mechanical stability remain persistent challenges in drug delivery systems. This experimental study investigated alginate–amorphous calcium carbonate (ACC) hydrogel composites designed to regulate release of model anti-inflammatory compound, ibuprofen. Hydrogels containing 1.6–2.0 wt% sodium alginate were crosslinked with CaCl₂ and combined with ACC through two incorporation pathways: (i) separate addition of ACC and ibuprofen or (ii) co-precipitation of ACC onto ibuprofen prior to hydrogel incorporation. Hydrogels without ACC served as Control. Biocomposite structure and properties were characterized and release profiles quantified using Korsmeyer–Peppas (KP) model.Burst release was curbed as crosslinking time increased, highlighting importance of network density in diffusion control. Co-precipitating ACC with ibuprofen prior to incorporating into the hydrogel suppressed burst release and sustained release for > ~72 h. Rheological measurements indicate ACC reinforces hydrogel network, increasing storage modulus while maintaining hydration and flexibility. KP model indicates release is diffusion-controlled, with deviations reflecting contributions from diffusion barriers and morphologic/structural changes near the ACC coated ibuprofen. ACC within alginate hydrogels provides a strategy for tuning drug release while preserving mechanical properties relevant to transdermal applications.

36 MATERIALS SCIENCE↗
DOE OSTI2020

Structural and antibacterial properties of NSAID-loaded ultra-high molecular weight polyethylene

Peri-articular delivery of pain medication in joint arthroplasty has the potential to address post-operative pain and decrease the use of systemic opioids. Additionally, the sustained release from a delivery vehicle may be especially impactful in the initial post-operative period when pain is most severe. We recently described a novel approach for the sustained intra-articular delivery of an analgesic (bupivacaine) from an ultra-high molecular weight polyethylene (UHMWPE) bearing surface. A secondary but very significant effect of incorporating bupivacaine in UHMWPE was its antibacterial effect against Staphylococcal species, which are associated with the majority of periprosthetic joint infections. Here, we report on the structure, properties, elution characteristics and antibacterial properties of UHMWPE loaded with the non-steroidal anti-inflammatory drug (NSAID) — tolfenamic acid. We showed that 6 wt% drug loading was optimal for eluting clinically relevant intra-articular and systemic concentrations, for maintaining mechanical properties at a clinically relevant level, and for providing anti-colonization potential against low risk (planktonic) and high risk (biofilm forming) Staphylococcal species. We determined the osteoblast response to the tolfenamic acid-loaded UHMWPE to evaluate the cytotoxicity profile of this novel material. Tolfenamic acid-loaded UHMWPE has the potential to be used as a part of multimodal pain management therapy following arthroplasty and may provide prophylaxis for periprosthetic infection.

36 MATERIALS SCIENCE↗
DOE OSTI2022

Editorial: Phenylpropanoid Systems Biology and Biotechnology

Phenylpropanoids are specialized metabolites involved in several aspects of plant growth and development and in the responses of plants to environmental stimuli. These compounds are synthesized from key intermediates of the shikimate pathway, which are structurally modified by the combined activities of lyases, transferases, ligases, reductases and oxygenases, resulting in the organ- and developmental-specific synthesis and accumulation of diverse metabolites (Vogt, 2010). The phenylpropanoid pathway provides the building blocks for lignin, suberin, and condensed tannins that play a role in structural support and mechanical strength. Lignin is a major contributor to feedstock recalcitrance and negatively affects the conversion of plant biomass into downstream products in biorefineries (Liu et al., 2021). Further, this pathway is key for the production of anthocyanins for organ pigmentation, flavonols and flavones for UV protection, various flavonoids and isoflavonoids for plant-microbe interactions, and antimicrobial phytoalexins for protection against pathogens (Deng and Lu, 2017). In addition to their biological functions in planta, phenylpropanoids are economically important metabolites. They constitute important components in the human diet, acting as nutraceutical compounds with antioxidant, chemopreventive, antimitotic, neuroprotective, cardioprotective, and anti-inflammatory activities. Several phenylpropanoids are considered high-value biochemicals employed in the production of fragrances, pharmaceuticals and biopolymers (Lin and Eudes, 2020).

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

A dehydrated, aseptically-processed human amnion/chorion allograft accelerates healing in a delayed murine excisional wound model

Since chronic, non-healing wounds represent an increasing source of economic and temporal burden for patients who suffer from them and healthcare professionals that treat them, therapeutic modalities that promote closure of delayed and non-healing wounds are of utmost importance. Recent clinical results of allografts derived from amnion and chorion placental layers encourage further investigation of the mechanisms underlying clinical efficacy of these products for treatment of wounds. Here, we utilized a diabetic murine splinted excisional wound model to investigate the effects of a dehydrated human amnion/chorion-derived allograft (dHACA) on delayed wound healing, as well as the effects of dehydrated allograft derived solely from amnion tissue of the same donor. We examined wound healing by histological endpoint analysis, and we assessed other parameters relevant to functional wound healing in the wound bed including angiogenesis, macrophage phenotypes, proliferative activity, and gene expression. Herein we demonstrate that application of dHACA to a murine diabetic model of delayed wound progression results in better macroscale wound resolution outcomes, including rate of closure, compared to unaided wound progression, while dehydrated human amnion allograft (dHAA) fails to improve outcomes. Improved gross wound resolution observed with dHACA was accompanied by increased granulation tissue formation, proliferation and vascular ingrowth observed in the wound bed, early macrophage polarization towards anti-inflammatory phenotypes, and downregulation of pro-fibrotic gene expression. Overall, our data suggest that improvements in the rates of delayed wound closure observed from combined amnion/chorion allografts are associated with modulation of critical cellular and tissue processes commonly found to be dysregulated in delayed healing wounds, including proliferation, vascularization, inflammation, and re-epithelialization.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Enhancing Acute Migraine Treatment: Exploring Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for the Nose-to-Brain Route

Migraine has a high prevalence worldwide and is one of the main disabling neurological diseases in individuals under the age of 50. In general, treatment includes the use of oral analgesics or non-steroidal anti-inflammatory drugs (NSAIDs) for mild attacks, and, for moderate or severe attacks, triptans or 5-HT1B/1D receptor agonists. However, the administration of antimigraine drugs in conventional oral pharmaceutical dosage forms is a challenge, since many molecules have difficulty crossing the blood-brain barrier (BBB) to reach the brain, which leads to bioavailability problems. Efforts have been made to find alternative delivery systems and/or routes for antimigraine drugs. In vivo studies have shown that it is possible to administer drugs directly into the brain via the intranasal (IN) or the nose-to-brain route, thus avoiding the need for the molecules to cross the BBB. In this field, the use of lipid nanoparticles, in particular solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), has shown promising results, since they have several advantages for drugs administered via the IN route, including increased absorption and reduced enzymatic degradation, improving bioavailability. Furthermore, SLN and NLC are capable of co-encapsulating drugs, promoting their simultaneous delivery to the site of therapeutic action, which can be a promising approach for the acute migraine treatment. This review highlights the potential of using SLN and NLC to improve the treatment of acute migraine via the nose-to-brain route. First sections describe the pathophysiology and the currently available pharmacological treatment for acute migraine, followed by an outline of the mechanisms underlying the nose-to-brain route. Afterwards, the main features of SLN and NLC and the most recent in vivo studies investigating the use of these nanoparticles for the treatment of acute migraine are presented.

Torres, Joana (ORCID:0000000327276229)↗
DOE OSTI2021

Interleukin-35 inhibits lipopolysaccharide-induced endothelial cell activation by downregulating inflammation and apoptosis

Inflammation is an essential factor contributing to sepsis-induced endothelial cell (EC) activation. Interleukin-35 (IL-35) is an anti-inflammatory/immunosuppressive cytokine that exerts protective effects on many inflammatory diseases. In this study, we investigated the effects of IL-35 on lipopolysaccharide (LPS)-induced EC activation and the potential underlying mechanism. Human umbilical vein endothelial cells (HUVECs) were incubated with LPS (1 μg/ml) for 24 h and then cocultured with different concentrations (0, 1, 10, or 100 ng/ml) of recombinant human IL-35 (rhIL-35) for 12 h. Flow cytometry analysis revealed that IL-35 inhibited LPS-induced HUVEC apoptosis in a dose-dependent manner. RT-qPCR and Western blot analyses showed significantly higher mRNA and protein levels of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and the inflammatory factors IL-6 and IL-8 in the LPS group than in the control group. These changes were alleviated by IL-35 treatment, suggesting that IL-35 protects ECs by downregulating inflammation. Furthermore, IL-35 induced signal transducer and activator of transcription 1 (STAT1) and STAT4 activation and promoted their interaction. Blocking STAT1 or STAT4 expression by fludarabine (STAT1 inhibitor) treatment or siRNA-STAT4-interfering fragment transfection inhibited the protective effect of IL-35 on ECs. Moreover, we observed a similar protective effect of IL-35 treatment on ECs in a mouse sepsis model induced by intraperitoneal LPS injection. This study indicated that IL-35 exerts anti-inflammatory and antiapoptotic effects on LPS-induced EC activation by activating the STAT1 and STAT4 signaling pathways.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Immunophenotypic characterization and therapeutics effects of human bone marrow- and umbilical cord-derived mesenchymal stromal cells in an experimental model of sepsis

Highlights: • Mesenchymal stromal cells (MSCs) may be a therapeutic option for sepsis. • Bone marrow (BM) vs. umbilical cord (UC) -MSCs induce different M1/M2 gene profiles. • In a CLP model of sepsis, only BM-MSCs improved survival and bacterial clearance. Sepsis is a complicated multi-system disorder characterized by a dysregulated host response to infection. Despite substantial progress in the understanding of mechanisms of sepsis, translation of these advances into clinically effective therapies remains challenging. Mesenchymal Stromal Cells (MSCs) possess immunomodulatory properties that have shown therapeutic promise in preclinical models of sepsis. The therapeutic effects of MSCs may vary depending on the source and type of these cells. In this comparative study, the gene expression pattern and surface markers of bone marrow-derived MSCs (BM-MSCs) and umbilical cord-derived MSCs (UC-MSCs) as well as their therapeutic effects in a clinically relevant mouse model of polymicrobial sepsis, cecal ligation and puncture (CLP), were investigated. The results showed remarkable differences in gene expression profile, surface markers and therapeutic potency in terms of enhancing survival and pro/anti-inflammatory responses between the two MSC types. BM-MSCs improved survival concomitant with an enhanced systemic bacterial clearance and improved inflammatory profile post CLP surgery. Despite some improvement in the inflammatory profile of the septic animals, treatment with UC-MSCs did not enhance survival or bacterial clearance. Overall, the beneficial therapeutic effects of BM-MSCs over UC-MSCs may likely be attributed to their pro-inflammatory function, and to some extent anti-inflammatory features, reflected in their gene expression pattern enhancing macrophage polarization to M1/M2 phenotypes resulting in a balanced pro- and anti-inflammatory response against polymicrobial sepsis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Resveratrol Ameliorates Lipopolysaccharide-Induced Sudden Sensorineural Hearing Loss in In Vitro Model through Multitarget Antiapoptotic Mechanism Based on Network Pharmacology and Molecular Docking

Objective. To explore the effects of resveratrol (RSV) on hair cell apoptosis caused by sudden sensorineural hearing loss (SSNHL) and its effect on lipopolysaccharide-induced apoptosis of HEI-OC1 cells. Methods. We used the network pharmacology method to screen molecules related to RSV for the treatment of SSNHL and analyzed these molecules and their enriched biological processes and signaling pathways through Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis. We selected hub genes related to apoptosis using protein-protein interaction (PPI) analysis for in vitro and molecular docking verification. Results. Eighty overlapping genes were identified as potential targets for RSV treatment of SSNHL. Further GO analysis showed that the biological processes were mainly related to toxicity, cell proliferation, and lipopolysaccharide reactions. KEGG analysis showed that the AGE-RAGE signaling pathway in diabetic complications, Kaposi’s sarcoma-associated herpesvirus infection, FoxO signaling pathway, PI3K-Akt signaling pathway, and other inflammatory signaling pathways were concentrated. AKT1, STAT3, JUN, TNF, TP53, MAPK3, CASP3, and VEGFA were screened as HUB genes using PPI analysis. The apoptosis-related proteins TNF, CASP3, AKT1, and TP53 were selected for in vitro experiments, which showed that mRNA was significantly different before and after RSV intervention, confirming that the corresponding protein receptors could bind well with RSV. Conclusion. RSV mainly affects the prognosis of SSNHL through anti-inflammatory effects and may improve hair cell apoptosis caused by inflammatory factors through multitargeted interventions involving TNF, CASP3, AKT1, and TP53.

Ye, Shiming↗
DOE OSTI2022

Xanthohumol microbiome and signature in adults with Crohn’s disease (the XMaS trial): a protocol for a phase II triple-masked, placebo-controlled clinical trial

Xanthohumol (XN), a bioactive flavonoid from Humulus lupulus with anti-inflammatory properties, has potential benefits for patients with Crohn’s disease (CD), a type of inflammatory bowel disease. We recently completed and published results of a placebo-controlled phase I clinical trial demonstrating the safety and tolerability of 24 mg XN daily for 8 weeks. The present study aims to evaluate the safety and tolerability of the same dose of XN adults with clinically active CD in a placebo-controlled phase II clinical trial. Additional aims will assess the impact of XN on inflammatory biomarkers, platelet function, CD clinical activity, and stool microbial composition. The metabolism of XN will also be evaluated. This article provides a model protocol for consideration in investigations of XN or other natural products in disease states. A triple-masked, randomized, placebo-controlled trial will be conducted in adults with clinically active CD. Participants (n ≤ 32) will be randomized to either 24 mg encapsulated XN per day or placebo and followed for 8 weeks. Throughout the trial, participants will be queried for adverse events. Biomarkers of clinical safety, blood and stool markers of inflammation, platelet function, Crohn’s Disease Activity Index score, stool microbial composition, and XN metabolite profiles in blood, urine, and stool will be assessed every 2 weeks. We describe the protocol for a phase II clinical trial that evaluates the safety and tolerability of XN in adults with active CD, as well as evaluate metabolism and mechanisms that are relevant to CD and other diseases with underlying inflammation and/or gut permeability. The effects of XN on inflammatory biomarkers, platelet function, the microbiota, and multi-omics biomarkers measured in this phase II trial of adults with CD will be compared to the effects of XN in healthy adults in our previous phase I trial. The results of the study will advance the evidence guiding the use of XN in patients with CD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Loss of Mitochondrial Tusc2/Fus1 Triggers a Brain Pro-Inflammatory Microenvironment and Early Spatial Memory Impairment

Brain pathological changes impair cognition early in disease etiology. There is an urgent need to understand aging-linked mechanisms of early memory loss to develop therapeutic strategies and prevent the development of cognitive impairment. Tusc2 is a mitochondrial-resident protein regulating Ca 2+ fluxes to and from mitochondria impacting overall health. We previously reported that Tusc2 –/– female mice develop chronic inflammation and age prematurely, causing age- and sex-dependent spatial memory deficits at 5 months old. Therefore, we investigated Tusc2-dependent mechanisms of memory impairment in 4-month-old mice, comparing changes in resident and brain-infiltrating immune cells. Interestingly, Tusc2 –/– female mice demonstrated a pro-inflammatory increase in astrocytes, expression of IFN-γ in CD4 + T cells and Granzyme-B in CD8 + T cells. We also found fewer FOXP3 + T-regulatory cells and Ly49G + NK and Ly49G + NKT cells in female Tusc2 –/– brains, suggesting a dampened anti-inflammatory response. Moreover, Tusc2 –/– hippocampi exhibited Tusc2- and sex-specific protein changes associated with brain plasticity, including mTOR activation, and Calbindin and CamKII dysregulation affecting intracellular Ca2 + dynamics. Overall, the data suggest that dysregulation of Ca 2+ -dependent processes and a heightened pro-inflammatory brain microenvironment in Tusc2 –/– mice could underlie cognitive impairment. Thus, strategies to modulate the mitochondrial Tusc2- and Ca 2+ - signaling pathways in the brain should be explored to improve cognitive health.

59 BASIC BIOLOGICAL SCIENCES↗