Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease that exhibits constitutive activation of phosphoinositide 3-kinase (PI3K) driven by chronic B-cell receptor signaling or PTEN deficiency. Since pan-PI3K inhibitors cause severe side effects, we investigated the anti-lymphoma efficacy of the specific PI3Kβ/δ inhibitor AZD8186. We identified a subset of DLBCL models within activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL that were sensitive to AZD8186 treatment. On the molecular level, PI3Kβ/δ inhibition decreased the pro-survival NF-κB and AP-1 activity or led to downregulation of the oncogenic transcription factor MYC. In AZD8186-resistant models, we detected a feedback activation of the PI3K/AKT/mTOR pathway following PI3Kβ/δ inhibition, which limited AZD8186 efficacy. The combined treatment with AZD8186 and the mTOR inhibitor AZD2014 overcame resistance to PI3Kβ/δ inhibition and completely prevented outgrowth of lymphoma cells in vivo in cell line- and patient-derived xenograft mouse models. Collectively, our study reveals that subsets of DLBCLs are addicted to PI3Kβ/δ signaling and thus identifies a previously unappreciated role of the PI3Kβ isoform in DLBCL survival. Furthermore, our data demonstrate that combined targeting of PI3Kβ/δ and mTOR is effective in all major DLBCL subtypes supporting the evaluation of this strategy in a clinical trial setting.

• MeSH
• Lymphoma, Large B-Cell, Diffuse * pathology   MeSH
• Phosphatidylinositol 3-Kinases * metabolism   MeSH
• Humans MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Signal Transduction MeSH
• TOR Serine-Threonine Kinases metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.

• MeSH
• Gain of Function Mutation MeSH
• Autoantibodies * immunology   MeSH
• COVID-19 genetics   immunology   MeSH
• Thyroid Epithelial Cells metabolism   pathology   MeSH
• Genetic Predisposition to Disease * MeSH
• Heterozygote MeSH
• Interferon Type I * antagonists & inhibitors   immunology   MeSH
• NF-kappaB-Inducing Kinase MeSH
• Humans MeSH
• Loss of Function Mutation MeSH
• NF-kappa B p52 Subunit deficiency   genetics   MeSH
• NF-kappa B * deficiency   genetics   MeSH
• AIRE Protein MeSH
• I-kappa B Proteins deficiency   genetics   MeSH
• Thymus Gland abnormalities   immunology   pathology   MeSH
• Pneumonia, Viral genetics   immunology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

ETHNOPHARMACOLOGICAL RELEVANCE: Paulownia tomentosa Steud., a traditional Chinese medicinal plant, was used for many centuries in Chinese herbal medicine as a component of remedies for many illnesses, including inflammatory diseases. It is a rich source of phenolic compounds, mainly geranylated flavonoids, which are currently studied for their promising biological activities. AIM OF THE STUDY: The study aimed to isolate minor geranylated flavanones and flavones from P. tomentosa fruit and evaluate their cytotoxicity and possible anti-inflammatory effects in a cell-based model of inflammation. MATERIALS AND METHODS: Chromatographic separation of chloroform portion of the ethanolic extract of P. tomentosa fruit led to the isolation of twenty-seven flavonoids (1-27), twenty-six of them geranylated with different modifications and one non-geranylated flavanone, and two phenolic compounds. Compounds were identified using UV, IR, HRMS, NMR, and CD spectroscopy. Ten of these compounds (7-10, 12, 21, 22, 24, 25, and 27) were determined to be new flavonoid derivatives obtained from a natural source for the first time. Selected compounds were analyzed for cytotoxicity and anti-inflammatory potential to affect the activation of nuclear factor κB/activator protein 1 (NF-κB/AP-1) after lipopolysaccharide (LPS) stimulation. RESULTS: All the test compounds (1-21 and 23-26) reduced the activation of NF-κB/AP-1 24 h after the addition of LPS. Eight compounds (5, 14-18, 21, and 26) were more active than prednisone, a widely used anti-inflammatory drug. However, this effect was not seen significantly on the level of TNF-α and IL-1β, which can be explained by the plurality of possible outcomes of activation of the NF-κB pathway in cells. CONCLUSIONS: Results of the presented study confirmed that constituents from traditional Chinese medicinal plant P. tomentosa Steud. have promising anti-inflammatory activities and can serve as a potential source of inspiration for new anti-inflammatory medications.

• MeSH
• Anti-Inflammatory Agents chemistry   MeSH
• Flavonoids analysis   MeSH
• Lamiales * MeSH
• Plants, Medicinal * metabolism   MeSH
• Lipopolysaccharides pharmacology   MeSH
• NF-kappa B metabolism   MeSH
• Fruit chemistry   MeSH
• Plant Extracts analysis   pharmacology   MeSH
• Transcription Factor AP-1 metabolism   MeSH
• Publication type
• Journal Article MeSH

Yeast glucan particles (GPs) are promising agents for the delivery of biologically active compounds as drugs. GPs possess their own biological activities and can act synergistically with their cargo. This study aimed to determine how incorporating artemisinin, ellagic acid, (-)-epigallocatechin gallate, morusin, or trans-resveratrol into GPs affects their anti-inflammatory and antioxidant potential in vitro. Two different methods - slurry evaporation and spray drying - were used to prepare composites (GPs + bioactive compound) and the anti-inflammatory and antioxidative properties of the resultant products were compared. Several of the natural compounds showed the beneficial effects of being combined with GPs. The materials prepared by spray drying showed greater activity than those made using a rotary evaporator. Natural compounds incorporated into yeast GPs showed greater anti-inflammatory potential in vitro than simple suspensions of these compounds as demonstrated by their inhibition of the activity of transcription factors NF-κB/AP-1 and the secretion of the pro-inflammatory cytokine TNF-α.

• MeSH
• Anti-Inflammatory Agents pharmacology   MeSH
• Antioxidants pharmacology   MeSH
• Artemisinins pharmacology   MeSH
• Cytokines MeSH
• Flavonoids chemistry   pharmacology   MeSH
• Glucans chemistry   pharmacology   MeSH
• Catechin analogs & derivatives   chemistry   pharmacology   MeSH
• Ellagic Acid chemistry   pharmacology   MeSH
• Monocytes drug effects   MeSH
• NF-kappa B MeSH
• Resveratrol chemistry   pharmacology   MeSH
• Saccharomyces cerevisiae Proteins MeSH
• Saccharomyces cerevisiae MeSH
• Publication type
• Journal Article MeSH

A series of new heteroleptic copper(II) complexes of the composition [Cu(L)(bpy)]NO3·2MeOH (1), [Cu(L)(dimebpy)]NO3·2H2O (2), [Cu(L)(phen)]NO3·2MeOH (3), [Cu(L)(bphen)]NO3·MeOH (4), [Cu(L)(dppz)]NO3·MeOH (5) was prepared, where HL = 3-(3,4-dihydroxyphenyl)-5-hydroxy-8,8-dimethyl-6-(3-methylbut-2-ene-1-yl)-4H,8H-benzo[1,2-b:3,4-b']dipyran-4-one, (pomiferin) and bpy = 2,2'-bipyridine, dimebpy = 4,4'-dimethyl-2,2'-bipyridine, phen = 1,10-phenanthroline, bphen = 4,7-diphenyl-1,10-phenanthroline, and dppz = dipyrido[3,2-a:2',3'-c]phenazine. The complexes were characterized using elemental analysis, infrared and UV/Vis spectroscopies, mass spectrometry, thermal analysis and conductivity measurements. The in vitro cytotoxicity, screened against eight human cancer cell lines (breast adenocarcinoma (MCF-7), osteosarcoma (HOS), lung adenocarcinoma (A549), prostate adenocarcinoma (PC-3), ovarian carcinoma (A2780), cisplatin-resistant ovarian carcinoma (A2780R), colorectal adenocarcinoma (Caco-2) and monocytic leukemia (THP-1), revealed the complexes as effective antiproliferative agents, with the IC50 values of 2.2-13.0 μM for the best performing complexes 3 and 5. All the complexes 1-5 showed the best activity against the A2780R cells (IC50 = 2.2-6.6 μM), and moreover, the complexes demonstrated relatively low toxicity on healthy human hepatocytes, with IC50 > 100 μM. The complexes were evaluated by the Annexin V/propidium iodide apoptosis assay, induction of cell cycle modifications in A2780 cells, production of reactive oxygen species (ROS), perturbation of mitochondrial membrane potential, inhibition of apoptosis and inflammation-related signaling pathways (NF-κB/AP-1 activity, NF-κB translocation, TNF-α secretion), and tested for nuclease mimicking activity. The obtained results revealed the corresponding complexes to be effective antiproliferative and anti-inflammatory agents.

• MeSH
• Anti-Inflammatory Agents pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Benzopyrans chemistry   pharmacology   MeSH
• Flavonoids metabolism   pharmacology   MeSH
• Isoflavones chemistry   pharmacology   MeSH
• Coordination Complexes chemistry   pharmacology   MeSH
• Humans MeSH
• Copper chemistry   metabolism   pharmacology   MeSH
• Cell Line, Tumor MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Geranylovaný flavanon diplakon je látka izolovaná z Paulownia tomentosa (Thunb.) Steud. (Paulowniaceae) vykazující protizánětlivé a antioxidační vlastnosti a také vysokou lipofilitu a nízkou rozpustnost ve vodě. Jako modelová molekula byl proto použit k inkorporaci do glukanových částic (GP) s cílem zvýšit jeho potenciální biodostupnost. GP jsou v principu duté schránky připravené čištěním kvasinek Saccharomyces cerevisiae pro získání buněčné stěny, obsahující převážně β-(1→3)/β-(1→6) glukan. Cílem práce je porovnat antiflogistické působení kompozitů diplakonu a glukanového nosiče s působením samotné látky, samotných glukanových částic a fyzické směsi čistých glukanových částic s čistým diplakonem. Na buněčné linii odvozené z lidských leukemických monocytů THP1-XBlueTM-MD2-CD14 byla simulována zánětlivá reakce stimulací buněk lipopolysacharidem (LPS) z Escherichia coli. Kompozity GP a diplakonu signifikantně snížily aktivitu prozánětlivých transkripčních faktorů nukleárního faktoru κB (NF-κB) a aktivátorového proteinu 1 (AP-1) v porovnání s čistou látkou.

Geranylated flavanone diplacone is a flavanone isolated from Paulownia tomentosa (Thunb.) Steud. (Paulowniaceae) with anti-inflammatory and antioxidant properties, nevertheless showing high lipophilicity and low solubility in water. Diplacone was therefore used as a model molecule for incorporation into glucan particles (GPs). GPs are prepared by intensive washing of yeast (Saccharomyces cerevisiae) leading to hollow shells consisting of β-(1→3)/β-(1→6) glucan mainly. The aim of this study was to compare anti-inflammatory potential of GPs-diplacone composites with the compound itself, GPs themselves and the physical mixture of GPs and diplacone. The cell line THP1-XBlueTM-MD2-CD14 derived from human leukemic monocytes was stimulated with lipopolysaccharide (LPS) from Escherichia coli to trigger inflammatory reaction. The composites of GPs with diplacone significantly decreased the activity of pro-inflammatory transcription factors nuclear factor κB (NF-κB) and activator protein 1 (AP-1).

• Keywords
• diplakon,
• MeSH
• Cell Encapsulation MeSH
• Glucans therapeutic use   MeSH
• Clinical Studies as Topic MeSH
• Humans MeSH
• Inflammation * drug therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH

Extensive phytochemical analysis of the CHCl3-soluble part of an ethanolic extract of branches and twigs of Broussonetia papyrifera led to the isolation of fourteen compounds, including a novel 5,11-dioxabenzo[b]fluoren-10-one derivative named broussofluorenone C (12). The isolated compounds 1-14 were characterized based on their NMR and HRMS data, and examined for their anti-inflammatory activities in LPS-stimulated THP-1 cells as well as for their cellular antioxidant effects. Compounds 7-10 and 12 showed inhibitory effects on NF-κB/AP-1 activation and compounds 7-9 were subsequently confirmed to suppress the secretion of both IL-1β and TNF-α in LPS-stimulated THP-1 cells more significantly than the prednisone used as a positive control. In the CAA assay, compound 10 exhibited the greatest antioxidant effect, greater than that of the quercetin used as a positive control. The results show possible beneficial effects and utilization of B. papyrifera wood in the treatment of inflammatory diseases as well as oxidative stress.

• MeSH
• Anti-Inflammatory Agents chemistry   isolation & purification   pharmacology   MeSH
• Antioxidants chemistry   isolation & purification   pharmacology   MeSH
• Broussonetia chemistry   MeSH
• Interleukin-1beta antagonists & inhibitors   biosynthesis   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Lipopolysaccharides antagonists & inhibitors   pharmacology   MeSH
• Molecular Structure MeSH
• NF-kappa B analysis   antagonists & inhibitors   biosynthesis   MeSH
• Oxidative Stress drug effects   MeSH
• THP-1 Cells MeSH
• Tumor Necrosis Factor-alpha antagonists & inhibitors   biosynthesis   MeSH
• Transcription Factor AP-1 analysis   antagonists & inhibitors   biosynthesis   MeSH
• Cell Survival drug effects   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The role of glutathione in autism spectrum disorder (ASD) is emerging as a major topic, due to its role in the maintenance of the intracellular redox balance. Several studies have implicated glutathione redox imbalance as a leading factor in ASD, and both ASD and many other neurodevelopmental disorders involve low levels of reduced glutathione (GSH), high levels of oxidized glutathione (GSSG), and abnormalities in the expressions of glutathione-related enzymes in the blood or brain. Glutathione metabolism, through its impact on redox environment or redox-independent mechanisms, interferes with multiple mechanisms involved in ASD pathogenesis. Glutathione-mediated regulation of glutamate receptors [e.g., N-methyl-d-aspartate (NMDA) receptor], as well as the role of glutamate as a substrate for glutathione synthesis, may be involved in the regulation of glutamate excitotoxicity. However, the interaction between glutathione and glutamate in the pathogenesis of brain diseases may vary from synergism to antagonism. Modulation of glutathione is also associated with regulation of redox-sensitive transcription factors nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1) and downstream signaling (proinflammatory cytokines and inducible enzymes), thus providing a significant impact on neuroinflammation. Mitochondrial dysfunction, as well as neuronal apoptosis, may also provide a significant link between glutathione metabolism and ASD. Furthermore, it has been recently highlighted that glutathione can affect and modulate DNA methylation and epigenetics. Review analysis including research studies meeting the required criteria for analysis showed statistically significant differences between the plasma GSH and GSSG levels as well as GSH:GSSG ratio in autistic patients compared with healthy individuals (P = 0.0145, P = 0.0150 and P = 0.0202, respectively). Therefore, the existing data provide a strong background on the role of the glutathione system in ASD pathogenesis. Future research is necessary to investigate the role of glutathione redox signaling in ASD, which could potentially also lead to promising therapeutics.

• MeSH
• Autistic Disorder * MeSH
• Glutathione metabolism   MeSH
• Glutathione Disulfide metabolism   MeSH
• Humans MeSH
• Oxidation-Reduction MeSH
• Oxidative Stress MeSH
• Autism Spectrum Disorder * genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Here we report the comprehensive characterization of the secondary metabolites from the leaves of Colebrookea oppositifolia Smith, a species used as medicinal plant in the traditional medicine of Nepal. Phytochemical screening of bioactives was performed using an integrated LC-MSn and high resolution MS (Mass Spectrometry) approach. Forty-three compounds were tentatively identified, mainly aglyconic and glycosilated flavonoids and phenolic acids, as well as other bioactives such as coumarins and terpenes were detected. Furthermore, the NF-κB and AP-1 inhibitory activity of C. oppositifolia extract were evaluated, as well as its cytotoxicity against THP-1 cells, in order to assess the potential use of this herb as a source of anti-inflammatory and cytotoxic compounds. The results so far obtained indicate that C. oppositifolia leaves extract could significantly reduce the viability of THP-1 cells (IC50 = 6.2 ± 1.2 µg/mL), as well as the activation of both NF-κB and AP-1 at the concentration of 2 μg/mL. Our results indicate that Nepalese C. oppositifolia is a valuable source of anti-inflammatory and cytotoxic compounds. The phytochemical composition reported here can partially justify the traditional uses of C. oppositifolia in Nepal, especially in the treatment of inflammatory diseases, although further research will be needed to assess the full potential of this species.

• MeSH
• Anti-Inflammatory Agents isolation & purification   pharmacology   toxicity   MeSH
• Chromatography, Liquid MeSH
• Flavonoids analysis   isolation & purification   MeSH
• Lamiaceae metabolism   MeSH
• Mass Spectrometry MeSH
• Hydroxybenzoates analysis   isolation & purification   MeSH
• Plants, Medicinal metabolism   MeSH
• Humans MeSH
• Plant Leaves metabolism   MeSH
• Metabolome MeSH
• Methanol MeSH
• NF-kappa B antagonists & inhibitors   MeSH
• Plant Extracts chemistry   isolation & purification   pharmacology   toxicity   MeSH
• THP-1 Cells MeSH
• Transcription Factor AP-1 antagonists & inhibitors   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Nepal MeSH

Clinical studies, as well as in vitro and in vivo experiments have demonstrated that byproducts from joint replacements induce an inflammatory reaction that can result in periprosthetic osteolysis (PPOL) and aseptic loosening (AL). Particle-stimulated macrophages and other cells release cytokines, chemokines, and other pro-inflammatory substances that perpetuate chronic inflammation, induce osteoclastic bone resorption and suppress bone formation. Differentiation, maturation, activation, and survival of osteoclasts at the bone-implant interface are under the control of the receptor activator of nuclear factor kappa-Β ligand (RANKL)-dependent pathways, and the transcription factors like nuclear factor κB (NF-κB) and activator protein-1 (AP-1). Mechanical factors such as prosthetic micromotion and oscillations in fluid pressures also contribute to PPOL. The treatment for progressive PPOL is only surgical. In order to mitigate ongoing loss of host bone, a number of non-operative approaches have been proposed. However, except for the use of bisphosphonates in selected cases, none are evidence based. To date, the most successful and effective approach to preventing PPOL is usage of wear-resistant bearing couples in combination with advanced implant designs, reducing the load of metallic and polymer particles. These innovations have significantly decreased the revision rate due to AL and PPOL in the last decade.

• Publication type
• Journal Article MeSH
• Review MeSH