Prussian blue nanoparticles coated with tumor cell membranes for precise photothermal therapy and subsequent inflammation reduction.

The utilization of photothermal agents (PTAs) in photothermal therapy (PTT) is faced with challenges such as immune clearance and inadequate concentration, which consequently result in residual tumors and an increased risk of recurrence and metastasis. Conversely, excessive treatment can lead to heightened inflammation and inevitable harm to adjacent healthy tissues. To address these issues, we developed a nanosystem (M@PB) consisting of Prussian blue coated with tumor cell membrane for precise photothermal therapy (PTT) and subsequent reduction of inflammation. This system not only evades immune attack due to the homologous biological characteristics of the encapsulating cell membrane but also exhibits active targeting capabilities towards homologous tumors. Furthermore, it effectively reduces excessive phototoxicity by leveraging the distinctive photothermal and anti-inflammatory characteristics of PB nanoparticles. The resulting M@PB nanosystem demonstrates effective photothermal ablation under 808 nm laser irradiation while mitigating the inflammatory response through inhibiting of local production of inflammatory mediators. Our study provides valuable insights into achieving targeted PTT with high efficiency while minimizing post-treatment inflammatory responses.

Anti-inflammatory effects of neuregulin-1 in HaCaT keratinocytes and atopic dermatitis-like mice stimulated with Der p 38.

Neuregulin (NRG)-1 plays fundamental roles in several organ systems after binding to its receptors, ErbB2 and ErbB4. This study examines the role of NRG-1 in atopic dermatitis (AD), a chronic skin disease that causes dryness, pruritus, and inflammation. In mice administered Der p 38, the skin presents AD-like symptoms including filaggrin downregulation and infiltration of neutrophils and eosinophils. Noticeably, there is an increased expression of NRG-1, ErbB2, and ErbB4 in the skin. Upregulation of these proteins is significantly correlated to the clinical skin severity score. In human keratinocyte HaCaT cells, exposure to Der p 38 decreased filaggrin expression, and NRG-1 alone had no effect on the expression. However, co-treatment of Der p 38 with NRG-1 enhanced the filaggrin expression decreased by Der p 38. Pre-treatment with AG879 (an ErbB2 inhibitor) or ErbB4 siRNA blocked the recovery of filaggrin expression in the cells after co-treatment with Der p 38 and NRG-1. Der p 38 treatment enhanced the secretion of interleukin-6 (IL-6), IL-8, and monocyte chemoattractant protein-1 (MCP-1). Co-treatment of Der p 38 with NRG-1 lowered the cytokine secretion increased by Der p 38, although NRG-1 alone was not effective on cytokine alteration. Neutrophil apoptosis was not altered by NRG-1 or supernatants of cells treated with NRG-1, but the cell supernatants co-treated with Der p 38 and NRG-1 blocked the anti-apoptotic effects of Der p 38-treated supernatants on neutrophils, which was involved in the activation of caspase 9 and caspase 3. Taken together, we determined that NRG-1 has anti-inflammatory effects in AD triggered by Der p 38. These results will pave the way to understanding the functions of NRG-1 and in the future development of AD treatment.

Apo-12'-capsorubinal exhibits anti-inflammatory effects and activates nuclear factor erythroid 2-related factor 2 in RAW264.7 macrophages.

Apocarotenoids have short carbon chain structures cleaved at a polyene-conjugated double bond. They can be biosynthesized in plants and microorganisms. Animals ingest carotenoids through food and then metabolize them into apocarotenoids. Although several apocarotenoids have been identified in the body, their precise health functions are still poorly understood. This study investigated the anti-inflammatory activities of apo-12'-capsorubinal in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. It was confirmed that apo-12'-capsorubinal was not cytotoxic to the macrophages at the concentrations tested. Apo-12'-capsorubinal treatment led to a marked downregulation of interleukin (IL)-6 protein and Il6 mRNA levels. This apocarotenoid exhibited more potent inhibitory effects than its parent carotenoids, capsanthin and capsorubin. Furthermore, apo-12'-capsorubinal, but not its parent carotenoids, promoted the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulated the expression of Nrf2-target genes, such as heme oxygenase 1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO-1), in a dose-dependent manner. Furthermore, a comparison using apo-12'-zeaxanthinal and 7,8-dihydro-8-oxo-apo-12'-zeaxanthinal revealed that the α, ß-unsaturated carbonyl group on the polyene linear chain mediated the enhanced nuclear Nrf2 translocation, HO-1 expression, and inhibition of IL-6 production. In contrast, apo-12'-mytiloxanthinal, which harbored a hydroxyl group at C-8 of apo-12'-capsorubinal, did not exhibit any of these activities. These results indicated that the ß carbon of the α, ß-unsaturated carbonyl group in the linear part of the polyene chain is crucial to the Nrf2-activating and anti-inflammatory effects of apo-12'-capsorubinal. This study will advance our knowledge of the physiological significance of xanthophyll-derived apocarotenoids and their potential use as nutraceuticals and pharmaceuticals.

Epimedin B exerts an anti-inflammatory effect by regulating the MAPK/NF-κB/NOD-like receptor signalling pathways.

Epimedin B (EB), a predominant compound found in Herba Epimedii, has been shown to be effective in the treatment of osteoporosis and peripheral neuropathy. However, the anti-inflammatory effect of EB has not yet been reported. The anti-inflammatory activity of EB was evaluated in a zebrafish inflammation model induced by copper sulfate (CuSO4) and tail cutting. Our findings demonstrated that EB effectively inhibited acute inflammation, mitigated the accumulation of reactive oxygen species (ROS), and ameliorated the neuroinflammation-associated impairment of locomotion in zebrafish. Moreover, EB regulates several genes related to the mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB)/Nod-like receptor signalling pathways (mapk8b, src, mmp9, akt1, mapk14a, mapk14b, mapk1, egfra, map3k4, nfκb2, iκbαa, pycard, nlrp3 and caspase1) and inflammatory cytokine (stat6, arg1, irfɑ, stat1ɑ, il-1ß, il-4, il-6, il-8, cox-2, ptges, tnf-α and tgf-ß). Therefore, our findings indicate that EB could serve as a promising therapeutic candidate for treating inflammation.

Cardamonin decreases inflammatory mediator expression in IL-1ß-stimulated human periodontal ligament cells.

BACKGROUND: Cardamonin is classified as a natural chalcone, and has been reported to possess various bioactive effects. However, there have been limited attempts to utilize cardamonin in the treatment of periodontitis. This study aimed to investigate whether cardamonin has anti-inflammatory effects on human periodontal ligament cells (HPDLCs), which are a component cell of periodontal tissue. Specifically, the study seeks to determine whether cardamonin affects the expression of inflammatory mediators, such as cytokines and adhesion molecules, induced by interleukin-1ß (IL-1ß) in HPDLCs, as well as the signaling pathways activated by IL-1ß. METHODS: Cytokine and chemokine levels in supernatants of HPDLCs were measured by ELISA. Western blot analysis was used to measure protein expression and signal transduction pathway activation in HPDLCs. RESULTS: We found that IL-1ß-induced CC chemokine ligand (CCL)2, CCL5, CCL20, CXC-chemokine ligand (CXCL)10, and interleukin (IL)-6 production and intercellular adhesion molecule (ICAM)-1 and cyclooxygenase (COX)-2 expression in HPDLCs were suppressed by cardamonin treatment. We also found that cardamonin suppressed IL-1ß-activated nuclear factor (NF)-κB pathway, and the phosphorylation of signal transducer and activator of transcription (STAT)3. Furthermore, cardamonin treatment enhanced the expression of the antioxidant enzymes, heme oxygenase (HO)-1 and NAD(P)H dehydrogenase [quinone] 1 (NQO1), in HPDLCs. CONCLUSION: In this study, we found that cardamonin could suppress the production of inflammatory mediators in HPDLCs as well as the activation of several signaling pathways induced by IL-1ß treatment.

Fisetin-loaded chitosan nanoparticles ameliorate pilocarpine-induced temporal lobe epilepsy and associated neurobehavioral alterations in mice: Role of ROS/TNF-α-NLRP3 inflammasomes pathway.

Fisetin has displayed potential as an anticonvulsant in preclinical studies yet lacks clinical validation. Challenges like low solubility and rapid metabolism may limit its efficacy. This study explores fisetin-loaded chitosan nanoparticles (NP) to address these issues. Using a murine model of pilocarpine-induced temporal lobe epilepsy, we evaluated the anticonvulsant and neuroprotective effects of fisetin NP. Pilocarpine-induced seizures and associated neurobehavioral deficits were assessed after administering subtherapeutic doses of free fisetin and fisetin NP. Changes in ROS, inflammatory cytokines, and NLRP3/IL-18 expression in different brain regions were estimated. The results demonstrate that the fisetin NP exerts protection against seizures and associated depression-like behavior and memory impairment. Furthermore, biochemical, and histological examinations supported behavioral findings suggesting attenuation of ROS/TNF-α-NLRP3 inflammasome pathway as a neuroprotective mechanism of fisetin NP. These findings highlight the improved pharmacodynamics of fisetin using fisetin NP against epilepsy, suggesting a promising therapeutic approach against epilepsy and associated behavioral deficits.

Anti-infectious and anti-inflammatory effect of amniopatch in the treatment of spontaneous previable rupture of membranes.

Spontaneous previable rupture of membranes complicates approximately 0.4-0.7% of pregnancies and is associated with severe maternal and neonatal morbidity and mortality. Intra-amniotic inflammation is present in up to 94.4% of cases, most often caused by a bacterial infection. In comparison, the effectiveness of antibiotic therapy in its eradication reaches less than 17%. Inflammatory activity in the amniotic cavity disrupts the physiological development of the fetus with an increase in maternal, fetal, and neonatal inflammatory morbidity through the development of fetal inflammatory response syndrome, maternal chorioamnionitis, and neonatal sepsis. Amniopatch is an invasive therapeutic technique based on intra-amniotic administration of maternal hemoderivates in the form of thromboconcentrate and plasma cryoprecipitate to provide the temporary closure of the fetal membranes defect and secondary restitution of normohydramnios with correction of pressure-volume ratios. The supposed basis of this physical-mechanical action is the aggregation of coagulant components of amniopatch in the area of the defect with the formation of a valve cap. The background for the formulation of the hypothesis on the potential anti-infectious and anti-inflammatory action of non-coagulant components of amniopatch involved: i) clinical-academic and publishing outputs of the authors based on their many years' experience with amniopatch application in the treatment of spontaneous previable rupture of membranes (2008-2019), ii) the documented absence of clinically manifested chorioamnionitis in patients treated this way with a simultaneously reduced incidence of neonatal respiratory distress syndrome compared to expectant management (tocolysis, corticotherapy, antibiotic therapy). The non-coagulant components of plasma cryoprecipitate include mainly naturally occurring isohemagglutinins, albumin, and soluble plasma fibrinogen. Although these components of the amniopatch have not been attributed a significant therapeutic role, the authors assume that due to their opsonizing and aggregative properties, they can significantly participate in optimizing the intrauterine environment through the reduction in bacterial and cytokine charge in the amniotic fluid. The authors think these facts constitute a vital stimulus to future research-academic activity and, at the same time, an idea for reconsidering the therapeutic role of amniopatch as a tool for improving perinatal results of spontaneous previable ruptures of membranes.

Effects of erucin on inflammatory mediators and antioxidant enzymes' expression in TNF-α-stimulated human oral epithelial cells.

OBJECTIVES: Periodontitis is a chronic inflammatory disease induced by periodontal disease-causing bacteria. It has been shown that excessive immune response against bacteria is involved in periodontal tissue destruction including alveolar bone resorption. Erucin is a biologically active substance found in cruciferous plants such as arugula and is classified as an isothiocyanate. No previous studies have attempted to use erucin in the treatment of periodontitis, and there are no papers that have examined the effects of erucin on periodontal resident cells. The purpose of this study was to analyze the effects of erucin on the production of inflammatory and antioxidant mediators produced by tumor necrosis factor (TNF)-α-stimulated TR146 cells, an oral epithelial cell line, including its effects on signaling molecules. METHODS: Cytokine and chemokine levels were measured by ELISA. Protein expression in TR146 cells and activations of signal transduction pathway were determined by Western blotting. RESULTS: Our results indicate that erucin suppresses interleukin-6 and CXC-chemokine ligand 10 production and vascular cell adhesion molecule-1 expression in TNF-α-stimulated TR146 cells. In addition, erucin induced the production of the antioxidant enzymes, Heme Oxygenase-1 and NAD(P)H quinone dehydrogenase 1 in TR146 cells. Furthermore, erucin suppressed TNF-α-stimulated nuclear factor-κB, signal transducer and activator of transcription3, and phospho-70S6 Kinase-S6 ribosomal protein signaling pathways in TR146 cells. We have shown that erucin has anti-inflammatory effects on oral epithelial cells and also induces the production of antioxidant mediators. CONCLUSIONS: These results suggest that erucin may provide a new anti-inflammatory agent that can be used in the treatment of periodontitis.

Cardamonin inhibits the expression of inflammatory mediators in TNF-α-stimulated human periodontal ligament cells.

OBJECTIVE: Periodontis is a chronic inflammatory disease induced by periodontopathogenic bacteria. The excessive immune response caused by persistent bacterial infection leads to alveolar bone resorption and ultimately tooth loss. Cardamonin is a biologically active substance that is found in the Zingiberaceae family, such as Alpinia zerumbet, and is classified as a natural chalcone. There have been no attempts to use cardamonin for the treatment of periodontitis, and no reports have examined the effects of cardamonin on periodontal tissue component cells. The aim of this study was to analyze effects of cardamonin on expression of inflammation mediators produced by TNFα-stimulated human periodontal ligament cells (HPDLCs), including its effects on signal transduction molecules. METHODS: Cytokine and chemokine levels were measured by ELISA. Protein expression in HPDLCs and activations of signal transduction pathway were determined by Western blotting. RESULTS: Our results indicate that cardamonin suppresses C-C motif chemokine ligand (CCL)2, CCL20, C-X-C motif chemokine ligand (CXCL)10, and interleukin (IL)-6 production and intercellular adhesion molecule (ICAM)-1 and cyclooxygenase (COX)-2 expression in TNF-α-stimulated HPDLCs. In addition, cardamonin induced the expression of the antioxidant enzyme, Heme Oxygenase (HO)-1, in HPDLCs. Furthermore, cardamonin suppressed TNF-α-stimulated c-Jun N-terminal kinase (JNK), nuclear factor (NF)-κB, and signal transducer and activator of transcription (STAT)3 signaling pathways in HPDLCs. CONCLUSION: We show that cardamonin reduces inflammatory mediator production by inhibiting the activation of several signaling pathways in this manuscript.

Chemical Compositions, Molecular Docking, Anti-Inflammatory, and Anti-Cancer Effects of the Leaf Essential Oils Isolated from Three Species of the Rutaceae Family in Vietnam.

Three species of the Rutaceae family, including Acronychia pedunculata, Euodia lepta, and Severinia monophylla have been used in traditional medicine. However, the comparison of the chemical composition, anti-cancer, and anti-inflammatory effects of the leaf essential oils of these species have not been investigated yet. A total of 38 compounds were identified via gas chromatography-mass spectrometry, comprising 96.5-99.8% of the total composition.  Both A. pedunculata and E. lepta essential oils exhibited strong inhibitory effects against cancer cells (IC50: 59.04-97.52 µg/mL) while that of S. monophylla showed a lower anti-cancer effect (IC50>100 µg/mL). Among three essential oils, only the E. lepta leaf oil demonstrated a high anti-inflammatory effect on LPS-stimulated macrophages (IC50=6.47 ± 0.65 µg/mL), while the other showed a moderate anti-inflammatory effect (IC50>50 µg/mL). Molecular docking studies also suggested the binding potential of the key compounds from three essential oils against inducible nitric oxide synthase and cyclooxygenase-2, two proteins associated with inflammatory response, with the negative energies ranging from -41.0 to -71.9 kcal/mol. The present findings suggest the leaf essential oils from these species as potential medicines for treatment of cancer or inflammation associated diseases, especially the ones from A. pedunculata and E. lepta oils.

Discovery of sesquiterpene lactones with anti-inflammatory effect from Youngia japonica.

The preliminary study revealed that the ethyl acetate eluate of Youngia japonica (YJ-E) could inhibit the expression of key proteins of p-p65, p-IκBα, p-IKKα/ß, and p-AKT in LPS stimulated BV2 cell. Further phytochemical study led to the isolation of eight compounds from YJ-E, including one new sesquiterpene lactone. Their structures were elucidated by several spectroscopic data, and comparing the NMR data of known compound. In addition, all of the isolates were evaluated for the anti-inflammatory effect. As a result, compounds 3 and 4 distinctly attenuated the expressions of p-IκBα, p-p65, and p-AKT in LPS stimulated BV2 cell, respectively.

Block Synthesis and Step-Growth Polymerization of C-6-Sulfonatomethyl-Containing Sulfated Malto-Oligosaccharides and Their Biological Profiling.

Highly sulfated malto-oligomers, similar to heparin and heparan-sulfate, have good antiviral, antimetastatic, anti-inflammatory and cell growth inhibitory effects. Due to their broad biological activities and simple structure, sulfated malto-oligomer derivatives have a great therapeutic potential, therefore, the development of efficient synthesis methods for their production is of utmost importance. In this work, preparation of α-(1→4)-linked oligoglucosides containing a sulfonatomethyl moiety at position C-6 of each glucose unit was studied by different approaches. Malto-oligomeric sulfonic acid derivatives up to dodecasaccharides were prepared by polymerization using different protecting groups, and the composition of the product mixtures was analyzed by MALDI-MS methods and size-exclusion chromatography. Synthesis of lower oligomers was also accomplished by stepwise and block synthetic methods, and then the oligosaccharide products were persulfated. The antiviral, anti-inflammatory and cell growth inhibitory activity of the fully sulfated malto-oligosaccharide sulfonic acids were determined by in vitro tests. Four tested di- and trisaccharide sulfonic acids effectively inhibited the activation of the TNF-α-mediated inflammatory pathway without showing cytotoxicity.

Metabolic Composition of Methanolic Extract of the Balkan Endemic Species Micromeria frivaldszkyana (Degen) Velen and Its Anti-Inflammatory Effect on Male Wistar Rats.

Extracts from medicinal plants are widely used in the treatment and prevention of different diseases. Micromeria frivaldszkyana is a Balkan endemic species with reported antioxidant and antimicrobial characteristics; however, its phytochemical composition is not well defined. Here, we examined the metabolome of M. frivaldszkyana by chromatography-mass spectrometry (GC-MS), ultra-performance liquid chromatography-mass spectrometry (UPLC-MS-MS), and inductively coupled plasma mass spectrometry (ICP-MS). Amino acids, organic acids, sugars, and sugar alcohols were the primary metabolites with the highest levels in the plant extract. Detailed analysis of the sugar content identified high levels of sucrose, glucose, mannose, and fructose. Lipids are primary plant metabolites, and the analysis revealed triacylglycerols as the most abundant lipid group. Potassium (K), magnesium (Mg), zinc (Zn), and calcium (Ca) were the elements with the highest content. The results showed linarin, 3-caffeoil-quinic acid, and rosmarinic acid, as well as a number of polyphenols, as the most abundant secondary metabolites. Among the flavonoids and polyphenols with a high presence were eupatorin, kaempferol, and apigenin-compounds widely known for their bioactive properties. Further, the acute toxicity and potential anti-inflammatory activity of the methanolic extract were evaluated in Wistar rats. No toxic effects were registered after a single oral application of the extract in doses of between 200 and 5000 mg/kg bw. A fourteen-day pre-treatment with methanolic extract of M. frivaldszkyana in doses of 250, 400, and 500 mg/kg bw induced anti-inflammatory activity in the 1st, 2nd, and 3rd hours after carrageenan injection in a model of rat paw edema. This effect was also present in the 4th hour only in the group treated with a dose of 500 mg/kg. In conclusion, M. frivaldszkyana extract is particularly rich in linarin, rosmarinic acid, and flavonoids (eupatorin, kaempferol, and apigenin). Its methanolic extract induced no toxicity in male Wistar rats after oral application in doses of up to 5000 mg/kg bw. Additionally, treatment with the methanolic extract for 14 days revealed anti-inflammatory potential in a model of rat paw edema on the 1st, 2nd, and 3rd hours after the carrageenan injection. These results show the anti-inflammatory potential of the plant, which might be considered for further exploration and eventual application as a phytotherapeutic agent.

Anti-inflammatory Effect of Symplocos prunifolia Extract in an In Vitro Model of Acute Pneumonia.

Acute pneumonia is a respiratory disease characterized by inflammation within the lung tissue, exhibiting higher morbidity rates and mortality rates among immunocompromised children and older adults. Symplocos species have been traditionally used as herbal remedies for conditions like dysentery, skin ulcers, diarrhea, and dyspepsia. Contemporary research has employed various Symplocos species in the study of diverse diseases. However, the exact efficacy and mechanisms of action of Symplocos Prunifolia remain unknown. Therefore, this study investigated the anti-inflammatory mechanism of S. prunifolia extract (SPE) in A549 and RAW264.7 cells stimulated by lipopolysaccharide (LPS). SPE significantly reduced nitric oxide (NO) production and the protein expression levels of like inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated RAW 264.7 cells. Furthermore, it reduced the protein expression levels of iNOS, COX-2 and the levels of pro-inflammatory cytokines in LPS-stimulated A549 cells. The mechanism underlying the anti-inflammatory effect of SPE was associated with the inhibition of LPS stimulated the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) and Mitogen-activated protein kinase (MAPK) phosphorylation. Moreover, we confirmed that SPE decreased the nuclear translocation of nuclear factor-κB (NF-κB)/p65 stimulated by LPS. In conclusion, these results demonstrate that SPE alleviates inflammatory responses by deactivating the PI3K/Akt, MAPK, and NF-κB signaling pathways. Our findings suggest that SPE is a potential candidate for acute pneumonia prevention.

[Anthocyanins as an element of nutritional support for athletes: effects and molecular mechanisms of action].

Antioxidants are among the common components of sports nutrition designed to counteract oxidative stress that develops during intense physical activity. One of the promising antioxidants are anthocyanins which belong to polyphenolic compounds of plant origin (class of flavonoids). The purpose of the research was to analyze the results of prospective controlled studies on the effect of anthocyanins on physical performance, and to consider the possible molecular mechanisms of their action. Material and methods. Sources were searched in PubMed, Google Scholar, and CyberLeninka databases of peer-reviewed scientific literature without restrictions on the year of publication using the following keywords: anthocyanins, physical performance, recovery, sport and exercise nutrition, oxidative stress, inflammation. Results. The main data set on the effects of anthocyanins in athletes was obtained using extracts of blackcurrant and Montmorency tart cherry. Volunteers received anthocyanins at a dose of 86-547 mg per day for 1 to 10 days with subsequent evaluation of their performance in cycling, running and fitness activities. The possibility of favorable effect of anthocyanins on physical performance and acceleration of its recovery after exertion has been shown. The source, dose and duration of intake did not significantly influence the established effects of anthocyanins. Acting as exogenous regulators of metabolism, anthocyanins can activate several mechanisms of performance enhancement, including influence on antioxidant and immune status and apoptosis intensity. Anthocyanins prevent the formation of reactive oxygen species, neutralize electrophilic compounds by direct interaction or through activation of Nrf2 factor, which regulates the transcription of antioxidant enzyme genes. The basis of the anti-inflammatory action of anthocyanins is their ability to inhibit MARK and NF-κB mediated signal transduction. Inclusion of bilberry and blackcurrant extract in the diet prevented the intensification of myocyte apoptosis and suppression of cellular immunity induced by exhausting exercise. An additional mechanism of anthocyanin action on physical performance may be an increase in blood supply of organs and tissues due to vascular dilation caused by activation of endothelial nitric oxide synthase. Conclusion. The intake of plant extracts with a high anthocyanin content can increase physical performance and improve recovery after physical exertion, which may be due to the antioxidant and anti-inflammatory effects of anthocyanins, their ability to regulate apoptosis processes and improve blood supply to organs and tissues.

Induction of tetraspanin 13 contributes to the synergistic anti-inflammatory effects of parasympathetic and sympathetic stimulation in macrophages.

The autonomic nervous system plays an important role in the regulation of peripheral inflammation. Sympathetic nervous activation stimulates inflammatory gene expression and cytokines, whereas parasympathetic nervous activation suppresses the production of inflammatory cytokines by immune cells. However, most studies on the relationship between the autonomic nervous system and immune processes have analyzed a single branch of the autonomic nerves in isolation. Therefore, this study aimed to examine the effects of sympathetic and parasympathetic stimulation on macrophages, which are controlled by autonomic regulation. Macrophages were stimulated with lipopolysaccharide (LPS) to induce TNF-α. Then, the effects of ß2 adrenergic receptor and α7 nicotinic acetylcholine receptor activation on TNF-α production were assessed using concentration-dependent assays. RNA-seq data were also used to identify genes whose expression was enhanced by parasympathetic and sympathetic stimulation. The simultaneous activation of ß2 adrenergic receptors and α7 nicotinic acetylcholine receptors suppressed LPS-induced TNF-α production in a concentration-dependent manner. Moreover, simultaneous activation of these receptors had synergistic anti-inflammatory effects and induced Tspan13 expression, thereby contributing to anti-inflammatory mechanisms in macrophages. Our study revealed the synergistic anti-inflammatory effects of the parasympathetic and sympathetic stimulation of macrophages. Our results suggest that targeting both sympathetic and parasympathetic signaling is a promising therapeutic approach for inflammatory diseases.

Systemic single administration of anti-inflammatory microRNA 146a-5p loaded in polymeric nanomedicines with active targetability attenuates neointimal hyperplasia by controlling inflammation in injured arteries in a rat model.

Neointimal hyperplasia (NIH) after revascularization is a key unsolved clinical problem. Various studies have shown that attenuation of the acute inflammatory response on the vascular wall can prevent NIH. MicroRNA146a-5p (miR146a-5p) has been reported to show anti-inflammatory effects by inhibiting the NF-κB pathway, a well-known key player of inflammation of the vascular wall. Here, a nanomedicine, which can reach the vascular injury site, based on polymeric micelles was applied to deliver miR146a-5p in a rat carotid artery balloon injury model. In vitro studies using inflammation-induced vascular smooth muscle cell (VSMC) was performed. Results showed anti-inflammatory response as an inhibitor of the NF-κB pathway and VSMC migration, suppression of reactive oxygen species production, and proinflammatory cytokine gene expression in VSMCs. A single systemic administration of miR146a-5p attenuated NIH and vessel remodeling in a carotid artery balloon injury model in both male and female rats in vivo. MiR146a-5p reduced proinflammatory cytokine gene expression in injured arteries and monocyte/macrophage infiltration into the vascular wall. Therefore, miR146a-5p delivery to the injury site demonstrated therapeutic potential against NIH after revascularization.

Optogenetic stimulation of basal forebrain cholinergic neurons prevents neuroinflammation and neuropsychiatric manifestations in pristane induced lupus mice.

BACKGROUND: Neuroinflammation has been identified as one of the primary pathogenic factors of neuropsychiatric systemic lupus erythematosus (NPSLE). However, there are no dedicated treatments available in clinics to alleviate neuroinflammation in NPSLE. It has been proposed that stimulating basal forebrain (BF) cholinergic neurons may provide potent anti-inflammatory effects in several inflammatory diseases, but its potential role in NPSLE remains unexplored. This study aims to investigate whether and how stimulating BF cholinergic neurons has a protective effect on NPSLE. RESULTS: Optogenetic stimulation of BF cholinergic neurons significantly ameliorated olfactory dysfunction and anxiety- and depression-like phenotype in pristane induced lupus (PIL) mice. The increased expression of adhesion molecules (P-selectin and vascular cell adhesion molecule-1 (VCAM-1)), leukocyte recruitment, blood-brain barrier (BBB) leakage were significantly decreased. Notably, the brain histopathological changes, including the elevated levels of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1ß), IgG deposition in the choroid plexus and lateral ventricle wall and lipofuscin accumulation in the cortical and hippocampal neurons, were also significantly attenuated. Furthermore, we confirmed the colocalization between the BF cholinergic projections and the cerebral vessels, and the expression of α7-nicotinic acetylcholine receptor (α7nAChR) on the cerebral vessels. CONCLUSION: Our data indicate that stimulation of BF cholinergic neurons could play a neuroprotective role in the brain through its cholinergic anti-inflammatory effects on cerebral vessels. Therefore, this may be a promising preventive target for NPSLE.

Synthesis of 1-(4-(dimethylamino)phenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione analogues and their anti-inflammatory activities in lipopolysaccharide-induced BV2 cells.

A series of thalidomide analogues, where the fused benzene ring in the phthalimide moiety was converted into two separated diphenyl rings in maleimide moiety and N-aminoglutarimide moiety was replaced by substituted phenyl moiety, were synthesized and evaluated for their NO inhibitory activities on BV2 cells stimulated with lipopolysaccharide (LPS). Among the synthesized compounds, the dimethylaminophenyl analogue 1s (IC50 = 7.1 µM) showed significantly higher inhibitory activity than the glutarimide analogue 1a (IC50 > 50 µM) and suppressed NO production dose-dependently without cytotoxicity. In addition, 1s inhibited the production of pro-inflammatory cytokines and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) by blocking nuclear factor-kappa B (NF-κB) and p38 MAPK pathways. These results demonstrated that 1s showed good anti-inflammatory activity and could become a leading compound for the treatment of neuroinflammatory diseases.

Synthesis of 1-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-2-morpholinoethane-1,2-dione analogues and their inhibitory activities with reduced cytotoxicity in lipopolysaccharide-induced BV2 cells.

A series of rimonabant analogues, where the N-aminopiperidine moiety was replaced by various amines and an additional carbonyl group, were synthesized and their inhibition of nitric oxide (NO) production was evaluated in lipopolysaccharide (LPS)-induced BV2 microglial cells. Among the synthesized compounds, the morpholine analogue 7y (IC50 = 4.71 ±â€¯0.11 µM) showed significantly higher inhibitory activity than rimonabant (IC50 = 16.17 ±â€¯0.56 µM), and suppressed NO production dose-dependently without cytotoxicity. In addition, 7y inhibited the expression of iNOS, COX-2 and pro-inflammatory cytokines and attenuated LPS-induced activation of nuclear factor-kappa B (NF-κB) and ERK MAPK phosphorylation in BV2 cells. These results demonstrated that 7y exerted anti-inflammatory effects by ERK pathway in BV2 cells, which can be used for the prevention and treatment of neuroinflammatory diseases.