Nuclear factor-kappaB Signaling Pathway Research Articles

Conjugated Network Supporting Highly Surface-Exposed Ru Site-Based Artificial Antioxidase for Efficiently Modulating Microenvironment and Alleviating Solar Dermatitis.

Solar dermatitis, a form of acute radiation burn that affects the skin, results from overexposure to ultraviolet B (UVB) radiation in strong sunlight. Cell damage caused by the accumulation of reactive oxygen species (ROS) produced by UVB radiation plays an important role in UVB-induced inflammation in the skin. Here, for efficiently scavenging excess ROS, modulating the microenvironment, and alleviating solar dermatitis, a π-conjugated network polyphthalocyanine supporting a highly surface-exposed Ru active site-based artificial antioxidase (HSE-PPcRu) is designed and fabricated with excellent ROS-scavenging, antioxidant, and anti-inflammatory capabilities. In photodamaged human keratinocyte cells, HSE-PPcRu could modulate mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B signaling pathways, prevent DNA damage, suppress apoptosis, inhibit pro-inflammatory cytokine secretion, and alleviate cell damage. In vivo animal experiments reveal the higher antioxidant and anti-inflammatory efficacies of HSE-PPcRu by reversing the activation of p38 and c-Jun N-terminal kinase, inhibiting expression of cyclooxygenase-2, interleukin-6, interleukin-8, and tumor necrosis factor-α. This work not only provides an idea for alleviating solar dermatitis via catalytically scavenging ROS and modulating the microenvironment but also offers a strategy to design an intelligent conjugated network-based artificial antioxidase with a highly surface-exposed active site.

Kynurenic Acid Plays a Protective Role in Hepatotoxicity Induced by HFPO-DA in Male Mice.

Following its introduction as an alternative to perfluorooctanoic acid, hexafluoropropylene oxide dimer acid (HFPO-DA) has been extensively detected in various environmental matrices. Despite this prevalence, limited information is available regarding its hepatotoxicity biomarkers. In this study, toxicokinetic simulations indicated that under repeated treatment, HFPO-DA in mice serum reached a steady state by the 4th day. To assess its subacute hepatic effects and identify potential biomarkers, mice were administered HFPO-DA orally at doses of 0, 0.1, 0.5, 2.5, 12.5, or 62.5 mg/kg/d for 7 d. Results revealed that the lowest observed adverse effect levels were 0.5 mg/kg/d for hepatomegaly and 2.5 mg/kg/d for hepatic injury. Serum metabolomics analysis identified 34, 58, and 118 differential metabolites in the 0.1, 0.5, and 2.5 mg/kg/d groups, respectively, compared to the control group. Based on weighted gene coexpression network analysis, eight potential hepatotoxicity-related metabolites were identified; among them, kynurenic acid (KA) in mouse serum exhibited the highest correlation with liver injury. Furthermore, liver-targeted metabolomics analysis demonstrated that HFPO-DA exposure induced metabolic migration of the kynurenine pathway from KA to nicotinamide adenine dinucleotide, resulting in the activation of endoplasmic reticulum stress and the nuclear factor kappa-B signaling pathway. Notably, pretreatment with KA significantly attenuated liver injury induced by HFPO-DA exposure in mice, highlighting the pivotal roles of KA in the hepatotoxicity of HFPO-DA.

Nocardia rubra cell-wall skeleton mitigates whole abdominal irradiation-induced intestinal injury via regulating macrophage function.

Ionizing radiation (IR)-induced intestinal injury is a major side effect and dose-limiting toxicity in patients receiving radiotherapy. There is an urgent need to identify an effective and safe radioprotectant to reduce radiation-induced intestinal injury. Immunoregulation is considered an effective strategy against IR-induced injury. The purpose of this article was to investigate the protective effect of Nocardia rubra cell wall skeleton (Nr-CWS), an immunomodulator, on radiation-induced intestinal damage and to explore its potential mechanism. C57BL/6J male mice exposed to 12Gy whole abdominal irradiation (WAI) were examined for survival rate, morphology and function of the intestine and spleen, as well as the gut microbiota, to comprehensively evaluate the therapeutic effects of Nr-CWS on radiation-induced intestinal and splenetic injury. To further elucidate the underlying mechanisms of Nr-CWS-mediated intestinal protection, macrophages were depleted by clodronate liposomes to determine whether Nr-CWS-induced radioprotection is macrophage dependent, and the function of peritoneal macrophages stimulated by Nr-CWS was detected in vitro. Our data showed that Nr-CWS promoted the recovery of intestinal barrier function, enhanced leucine-rich repeat-containing G protein-coupled receptor 5+ intestinal stem cell survival and the regeneration of intestinal epithelial cells, maintained intestinal flora homeostasis, protected spleen morphology and function, and improved the outcome of mice exposed to 12Gy WAI. Mechanistic studies indicated that Nr-CWS recruited macrophages to reduce WAI-induced intestinal damage. Moreover, macrophage depletion by clodronate liposomes blocked Nr-CWS-induced radioprotection. In vitro, we found that Nr-CWS activated the nuclear factor kappa-B signaling pathway and promoted the phagocytosis and migration ability of peritoneal macrophages. Our study suggests the therapeutic effect of Nr-CWS on radiation-induced intestinal injury, and provides possible therapeutic strategy and potential preventive and therapeutic drugs to alleviate it.

Updates of primary central nervous system lymphoma.

Lymphoma occurring in the central nervous system is considered primary central nervous system lymphoma (PCNSL), usually without systematic lesions. Over the last few decades, a deep understanding of PCNSL has been lacking due to the low incidence rate, and the overall survival and progression-free survival of patients with PCNSL are lower than those with other types of non-Hodgkin lymphoma. Recently, there have been several advancements in research on PCNSL. Advances in diagnosis of the disease are primarily reflected in the promising diagnostic efficiency of novel biomarkers. Pathogenesis mainly involves abnormal activation of nuclear factor kappa-B signaling pathways, copy number variations, and DNA methylation. Novel therapies such as Bruton's tyrosine kinase inhibitors, immunomodulatory drugs, immune checkpoint inhibitors, and phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors are being evaluated as possible treatment options for PCNSL, especially for relapsed/refractory (R/R) cases. Several clinical trials also indicated the promising feasibility and efficacy of chimeric antigen receptor T-cell therapy for selected R/R PCNSL patients. This review focuses on discussing recent updates, including the diagnosis, pathogenesis, and novel therapy of PCNSL.

S100A8/9 modulates perturbation and glycolysis of macrophages in allergic asthma mice.

Allergic asthma is the most prevalent asthma phenotype and is associated with the disorders of immune cells and glycolysis. Macrophages are the most common type of immune cells in the lungs. Calprotectin (S100A8 and S100A9) are two pro-inflammatory molecules that target the Toll-like receptor 4 (TLR4) and are substantially increased in the serum of patients with severe asthma. This study aimed to determine the effects of S100A8/A9 on macrophage polarization and glycolysis associated with allergic asthma. To better understand the roles of S100A8 and S100A9 in the pathogenesis of allergic asthma, we used ovalbumin (OVA)-induced MH-S cells, and OVA-sensitized and challenged mouse models (wild-type male BALB/c mice). Enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, flow cytometry, hematoxylin-eosin staining, and western blotting were performed. The glycolysis inhibitor 3-bromopyruvate (3-BP) was used to observe changes in glycolysis in mice. We found knockdown of S100A8 or S100A9 in OVA-induced MH-S cells inhibited inflammatory cytokines, macrophage polarization biomarker expression, and pyroptosis cell proportion, but increased anti-inflammatory cytokine interleukin (IL)-10 mRNA; also, glycolysis was inhibited, as evidenced by decreased lactate and key enzyme expression; especially, knockdown of S100A8 or S100A9 inhibited the activity of TLR4/myeloid differentiation primary response gene 88 (MyD88)/Nuclear factor kappa-B (NF-κB) signaling pathway. Intervention with lipopolysaccharides (LPS) abolished the beneficial effects of S100A8 and S100A9 knockdown. The observation of OVA-sensitized and challenged mice showed that S100A8 or S100A9 knockdown promoted respiratory function, improved lung injury, and inhibited inflammation; knockdown of S100A8 or S100A9 also suppressed macrophage polarization, glycolysis levels, and activation of the TLR4/MyD88/NF-κB signaling pathway in the lung. Conversely, S100A9 overexpression exacerbated lung injury and inflammation, promoting macrophage polarization and glycolysis, which were antagonized by the glycolysis inhibitor 3-BP. S100A8 and S100A9 play critical roles in allergic asthma pathogenesis by promoting macrophage perturbation and glycolysis through the TLR4/MyD88/NF-κB signaling pathway. Inhibition of S100A8 and S100A9 may be a potential therapeutic strategy for allergic asthma.

Yanghe Pingchuan granules mitigates oxidative stress and inflammation in a bronchial asthma rat model: role of the IKK/IκB/NF-κB signalling pathway.

Bronchial asthma (BA) is a chronic inflammatory airway disease. Previous research has shown that Yanghe Pingchuan granules (YPG), among the granules formulated by the First Affiliated Hospital of the Anhui University of Chinese Medicine, exerts a precise therapeutic effect on BA. We previously showed that YPG improves airway inflammation in BA rats. Other studies have shown that the inhibitor of kappa-B kinase (IKK)/inhibitor of NF-κB (IκB)/nuclear factor kappa-B (NF-κB) signalling pathway plays a key role in inflammation mediation. Therefore, this study explored whether YPG could intervene in BA through the IKK/IκB/NF-κB signalling pathway. Ovalbumin-induced method was used to established BA rat model. After successful modelling, the authors used YPG to intervene the rats in BA rats. Hematoxylin-eosin (HE) staining was used to detect the bronchial pathological changes in BA rats, enzyme-linked immunosorbent assay (ELISA) was used to detect the changes of inflammatory factors (IL-1β and IL-6) and oxidative stress indexes malondialdehyde (MDA), superoxide dismutase (SOD) and nitrogen monoxide (NO), Quantitative real-time polymerase chain reactionCR and western blot were used to detect the expression of IKK/IκB/NF-κB signalling pathway. In BA model rats, YPG significantly improved the inflammatory response in bronchial tissues, reduced inflammatory factors IL-1β and IL-6, alleviated oxidative stress, reduced MDA and NO, and increased SOD. Quantitative real-time polymerase chain reaction and western blot results showed that YPG could block the IKK/IκB/NF-κB signalling pathway. These findings showed that YPG had a definite therapeutic effect on BA, which may be related to blocking the IKK/IκB/NF-κB signalling pathway and improving inflammation and oxidative stress.

REGγ deficiency ameliorates hepatic ischemia and reperfusion injury in a mitochondrial p66shc dependent manner in mice.

Hepatic ischemia and reperfusion (I/R) injury is a common problem faced by patients undergoing clinical liver transplantation and hepatectomy, but the specific mechanism of liver I/R injury has not been fully elucidated. The protein degradation complex 11S proteasome is involved in apoptosis, proliferation and cell cycle regulation by regulating the 11S proteasome regulatory complex (REG)γ. The main objective of this study is to explore the role and specific mechanism of REGγ in liver I/R. By constructing a model of in vivo hepatic I/R injury in mice and a model of hypoxia and reoxygenation (H/R) in isolated hepatocytes. First, the REGγ expression were detected during hepatic I/R in mice. Second, to investigate the effects of REGγ knockout (KO) on liver necrosis, inflammatory response, apoptosis and mitochondrial function. Finally, mouse liver Src homology collagen (p66shc) mitochondrial translocation was detected. The expression of REGγ was up-regulated during hepatic I/R. REGγ KO had significantly reduced liver tissue infarct size, liver transaminases, inflammatory cells infiltration, inflammatory cytokine and activation of nuclear factor kappa-B (NF-κB) signaling pathway and cell apoptosis. REGγ KO had significantly alleviated the mitochondrial damage, decreased the up-regulated level of cytochrome C, reactive oxygen species (ROS). REGγ KO had significantly reduced p66shc mitochondrial translocation in mice. The experimental results of this study indicated that REGγ has an important role in preventing liver I/R injury and may play a role through the mitochondrial p66shc signaling pathway.

Rubusoside mitigates neuroinflammation and cellular apoptosis in Parkinson's disease, and alters gut microbiota and metabolite composition

BackgroundParkinson's disease (PD) is a neurodegenerative condition characterized by the progressive loss of dopaminergic neurons within the substantia nigra. Neuroinflammation plays a pivotal role in the pathogenesis of PD, involving the activation of microglia cells, heightened production of proinflammatory cytokines, and perturbations in the composition of the gut microbiota. Rubusoside (Ru), the principal steviol bisglucoside present in Rubus chingii var. suavissimus (S.K.Lee) L.T.Lu (Rosaceae), has been documented for its anti-inflammatory properties in diverse disease models. Nonetheless, there is an imperative need to comprehensively assess and elucidate the protective and anti-inflammatory attributes of Ru concerning PD, as well as to uncover the underlying mechanism involved. ObjectiveThe aim of this study is to evaluate the neuroprotective and anti-inflammatory effects of Ru on PD and investigate its potential mechanisms associated with microbes. Research design and methodsWe pre-treated mice and cell lines with Ru in order to simulate the progression of PD and the neuroinflammatory state. The mouse model was induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), SN4741 cells were induced by 1-methyl-4-phenylpyridine (mpp+), and BV-2 cells were induced by lipopolysaccharide (LPS). We assessed the impact of Ru on motor function, neuroinflammation, neuron apoptosis, the composition of gut microbes, and their metabolites. ResultsRu treatment reduces the release of pro-inflammatory mediators by inhibiting microglia activation. It also prevents neuronal apoptosis, thereby safeguarding dopaminergic neurons and ameliorating motor dysfunction. Furthermore, it induces alterations in the fecal microbiota composition and metabolites profile in PD mice. In vitro experiments have demonstrated that Ru inhibits neuronal apoptosis in SN4741 cells induced by mpp+, suppresses the production of pro-inflammatory mediators, and activates the c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase (p38 MAPK), and nuclear factor kappa-B (NF-κB) signaling pathways. ConclusionRu exhibits inhibitory effects on the MPTP-induced PD model by mitigating neuroinflammation and neuronal apoptosis while also inducing changes in the gut microbiota and metabolite composition.

Transcriptome analysis reveals immune function-related mRNA expression in donkey mammary glands during four developmental stages

The low susceptibility to mastitis of female donkey (jenny) mammary glands and the strong immune properties of donkey milk are acknowledged, but little is known about the genes involved in mammary gland immunity in jennies. Herein, we used RNA-sequencing and bioinformatics analyses to explore jenny mammary gland transcriptomes and detect potential functional differentially expressed (DE) mRNAs related to immunity during four specific developmental stages: foetal (F), pubertal (P), adult parous nonlactation (N) and lactation (L). A total of 2497, 583 and 1820 DE mRNAs were identified in jenny mammary glands at F vs. P, P vs. N, and N vs. L, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genomes (KEGG) analyses revealed numerous GO terms related to immune function, especially between F and P. Seven significantly enriched profiles were identified, among which 497 and 1261 DE mRNAs were upregulated in profiles 19 and 17. Eleven mRNAs were enriched in over 10 KEGG pathways. β-2-microglobulin (B2M), immunoglobulin heavy constant mu (IGHM), toll like receptor 2 (TLR2), toll like receptor 4 (TLR4) and myeloid differentiation factor 88 (MYD88) were mainly involved in phosphoinositide 3-kinase (PI3K)-Akt signalling, phagosome and nuclear factor kappa-B (NF-kappa B) signalling pathways. The findings provide insight into the molecular features underpinning the low prevalence of intramammary infections (i.e., mastitis) in donkeys.

Mechanism of simulated lunar dust-induced lung injury in rats based on transcriptomics.

Lunar dust particles are an environmental threat to lunar astronauts, and inhalation of lunar dust can cause lung damage. The current study explored the mechanism of lunar dust simulant (CLDS-i) inducing inflammatory pulmonary injury. Wistar rats were exposed to CLDS-i for 4 h/d and 7d/week for 4 weeks. Pathological results showed that a large number of inflammatory cells gathered and infiltrated in the lung tissues of the simulated lunar dust group, and the alveolar structures were destroyed. Transcriptome analysis confirmed that CLDS-i was mainly involved in the regulation of activation and differentiation of immune inflammatory cells, activated signaling pathways related to inflammatory diseases, and promoted the occurrence and development of inflammatory injury in the lung. Combined with metabolomics analysis, the results of joint analysis of omics were found that the genes Kmo, Kynu, Nos3, Arg1 and Adh7 were involved in the regulation of amino acid metabolism in rat lung tissues, and these genes might be the key targets for the treatment of amino acid metabolic diseases. In addition, the imbalance of amino acid metabolism might be related to the activation of nuclear factor kappaB (NF-κB) signaling pathway. The results of quantitative real-time polymerase chain reaction and Western blot further confirmed that CLDS-i may promote the occurrence and development of lung inflammation and lead to abnormal amino acid metabolism by activating the B cell activation factor (BAFF)/ B cell activation factor receptor (BAFFR)-mediated NF-κB signaling pathway.

PRMT5 participates in B cell overactivation in patients with primary Sjogren's syndrome (pSS) through RSAD2-mediated NF-κB signaling.

There are new evidences that protein arginine methyltransferase 5 (PRMT5) is widely involved in the progression of various diseases, but its effect is unclear on Primary Sjogren's syndrome (pSS). The main purpose of this study is to explore the regulatory effect of PRMT5 on pSS and its potential mechanisms. CD40L treated CD19 + B cells to construct a cell model of pSS. CCK-8 assay and Annexin V-FITC/PI kits were used to measure cell proliferation and apoptosis. ELISA assay was used to determine the contents of IL-6 and TNF-α in CD19 + B cells. And commercial kits were used to detect the levels of immunoglobins (IgG, IgM, and IgA) in CD40L-treated CD19 + B cells. And successfully constructed a pSS mouse model. The results revealed an increase in the expression of PRMT5 in CD19 + B cells from patients with pSS. After CD40L treatment, the knockdown of PRMT5 prominently decreased cell viability, the production level of immunoglobulins (IgG, IgM, and IgA), and the content of IL-10, increased the content of IL-6 and IL-8, and promoted the apoptosis of pSS CD19 + B cells. Mechanistically, PRMT5 negatively regulated the RSAD2 and nuclear factor kappa-B (NF-κB) signaling pathway. Furthermore, overexpression of RSAD2 and p65 significantly rescued the effect of PRMT5 knockdown on proliferation, immunoglobin production and secreting cytokines in CD40L-treated CD19 + B cells. More importantly, inhibition of PRMT5 significantly inhibited the symptoms of pSS mice. Low-expression of PRMT5 through inactivation of RSAD2/NF-κB signalling pathway alleviates the hyperactivity of B cells, which may provide theoretical basis and potential therapeutic targets for clinical treatment of pSS.

Aldehyde dehydrogenase 2-mediated aldehyde metabolism promotes tumor immune evasion by regulating the NOD/VISTA axis

BackgroundAldehyde dehydrogenase 2 (ALDH2) is a crucial enzyme involved in endogenous aldehyde detoxification and has been implicated in tumor progression. However, its role in tumor immune evasion remains unclear.MethodsHere, we...

Skin irritation assessment and potential mechanism of Capparis spinosa L. fruits

Ethnopharmacological relevanceIn China, Capparis spinosa L. fruits (CSF) are often used topically in Uyghur folk medicine in treating rheumatic diseases with remarkable efficacy. However, it has noticed severe skin irritation after a short time application with high dose of CSF, which limited long-term clinical use. To date, there is almost no research related to skin irritation of CSF.Aim of the study: This study was intended to perform the first systematic assessment of morphological and histological changes in skin after stimulation with CSF. Furthermore, potential irritant components in CSF and related mechanisms were explored by in vitro transdermal techniques, network pharmacology, molecular docking, and experimental validation. Materials and methodsSkin changes after single and multiple stimulations with CSF were observed and subjected to skin irritation response scoring, irritation strength assessment, and histopathological analysis. In addition, in vitro transdermal technology, liquid chromatography-mass spectrometry (LC-MS) method, network pharmacology, molecular docking, and experimental validation were used to further exploit underlying skin irritant components and possible mechanisms of action. ResultsCSF induced significant morphological (erythema and edema) and histological (epidermal thickening and inflammatory infiltration) changes in skin of mice, which were similar to the clinical presentation of irritation contact dermatitis (ICD). The ethyl acetate fraction of CSF (CFEAF) was the main source of CSF-induced skin irritation. Kaempferol, flazin, and gallic acid were potential major irritant compounds. Moreover, CFEAF, kaempferol, flazin, and gallic acid could increase the levels of pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and interleukin-17A (IL-17A) to promote skin inflammation. The potential mechanism of CSF-induced skin irritation may be activation of the nuclear factor kappa-B (NF-κB) signaling pathway, including phosphorylation of NF-κB p65 (p65) and nuclear factor-kappa B inhibitor alpha (IκBα). ConclusionKaempferol, flazin, and gallic acid are potential skin irritant components from CSF. Altogether, they induce skin irritation responses through promoting the release of the inflammatory factors TNF-α and ICAM-1, as well as activating the NF-κB signaling pathway. In addition, IL-17A may be an important pro-inflammatory factor in skin irritation.

Oral administration of punicalagin attenuates imiquimod-induced psoriasis by reducing ROS generation and inflammation via MAPK/ERK and NF-κB signaling pathways.

Psoriasis, an immune-mediated chronic inflammatory skin disease, imposes a huge mental and physical burden on patients and severely affects their quality of life. Punicalagin (PU), the most abundant ellagitannin in pomegranates, has become a research hotspot owing to its diverse biological activities. However, its effects on psoriasis remain unclear. We explored the impact and molecular mechanism of PU on M5-stimulated keratinocyte cell lines and imiquimod (IMQ)-induced psoriasis-like skin inflammation in BABL/c mice using western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), hematoxylin and eosin (H&E) stain, immunohistochemistry, and immunofluorescent. Administration of PU-enriched pomegranate extract at dosages of 150 and 250 mg/kg/day markedly attenuated psoriatic severity, abrogated splenomegaly, and reduced IMQ-induced abnormal epidermal proliferation, CD4+ T-cell infiltration, and inflammatory factor expression. Moreover, PU could decrease expression levels of pro-inflammatory cytokines, such as IL-1β, IL-1α, IL-6, IL-8, TNF-α, IL-17A, IL-22, IL-23A, and reactive oxygen species (ROS), followed by keratinocyte proliferation inhibition in the M5-stimulated cell line model of inflammation through inhibition of mitogen-activated protein kinases/extracellular regulated protein kinases (MAPK/ERK) and nuclear factor kappaB (NF-κB) signaling pathways. Our results indicate that PU may serve as a promising nutritional intervention for psoriasis by ameliorating cellular oxidative stress and inflammation.

Site-selective synthesis and pharmacological elucidation of novel semi-synthetic analogues of koenimbine as a potential anti-inflammatory agent

Koenimbine (1), a carbazole alkaloid isolated from Murraya koenigii, belongs to the Rutaceae family. Various pharmacological effects such as anti-diabetic, melanogenesis inhibition, anti-diarrheal, anti-cancer, and anti-inflammatory properties of koenimbine have already been reported. In the current study, we investigated the anti-inflammatory role of koenimbine (1) and its novel semi-synthetic derivative 8-methoxy-3,3,5-trimethylpyrano[3,2-a] carbazole-11(3H)-yl) (3-(trifluoromethyl) phenyl) methanone (1G) in both in vitro and in vivo biological systems. Our results demonstrated that the anti-inflammatory activity of 1G significantly lowered the production of NO, pro-inflammatory cytokines (IL-6, TNF-α & IL-1β), LTB4 following LPS stimulation in RAW 264.7 macrophages. Furthermore, 1G significantly attenuated the expression levels of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in a dose dependent manner and also decreased the production of reactive oxygen species (ROS) in LPS-activated RAW 264.7 cells. In addition, the oral administration of 1G reduced the inflammatory response in carrageenan-induced paw edema in BALB/C mice. Moreover, it effectively reduced NO, IL-6, IL-1β & TNF-α levels, liver markers (AST, ALT), and kidney markers (BUN, CRE, and Urea). Also, 1G reverted the infiltration of inflammatory cells and tissue damage in lungs, liver and kidney enhanced the survival rate in LPS-challenged mice. 1G blocks NF-κB p65 from translocating into the nucleus and activating inflammatory gene transcription. These results illustrated that 1G suppresses the inflammatory effects both in-vitro and in-vivo studies via downregulating the nuclear factor kappa-B (NF-κB) signaling pathway. In conclusion, our results demonstrate that semi-synthetic derivative 1G can effectively attenuate the inflammatory response via NF-κB and MAPK signaling pathways; suggesting 1G is a potential novel anti-inflammatory drug candidate in treating inflammatory disorders.

N-Feruloylserotonin inhibits lipopolysaccharide-induced inflammation via SIRT1-stimulated FOXO1 and NF-κB signaling pathways in RAW 264.7 cells.

Macrophages become activated by a variety of stimuli such as lipopolysaccharide (LPS) and participate in the process of immune responses. Activated macrophages produce various inflammatory mediators. In the present study, we investigated the anti-inflammatory mechanism of a serotonin derivative, N-feruloylserotonin, isolated from safflower seeds in RAW 264.7 macrophages. N-Feruloylserotonin treatment significantly attenuated these effects on LPS-induced reactive oxygen species, nitric oxide, and prostaglandin E2 production in RAW 264.7 macrophages. Furthermore, N-feruloylserotonin significantly decreased the abnormal expression of mitogen-activated protein kinase, such as phosphor (p)-c-Jun N-terminal kinase and p-extracellular-signal regulated kinase activation. Further research revealed that N-feruloylserotonin could stimulate sirtuin1 (SIRT1), then promote the forkhead box protein O1 (FOXO1), and suppress nuclear factor-kappa B (NF-kB) signaling pathways. The present study suggests that N-feruloylserotonin may be a new anti-inflammatory component and a promising candidate for anti-inflammatory therapeutic agents through the regulation of SIRT1-stimulated FOXO1 and NF-kB signaling pathways.

Therapeutic Effect and Safety Evaluation of Naringin on Klebsiella pneumoniae in Mice

Critically ill patients with Corona Virus Disease 2019 (COVID-19) often develop secondary bacterial infections that pose a significant threat to patient life safety, making the development of drugs to prevent bacterial infections in the lungs critical to clinical care. Naringin (NAR) is one of the significant natural flavonoids rich in Pummelo Peel (Hua Ju Hong), with anti-inflammatory, antimicrobial, and antioxidant activities, and is commonly used in treating respiratory tract infectious diseases. In this study, the in vitro and in vivo findings revealed that, after Klebsiella pneumoniae (Kpn) infection, NAR inhibited overactivation of the nuclear factor kappa-B(NF-κB) signaling pathway in alveolar macrophages of mice, reduced neutrophil (NEs) recruitment, and lowered the induced production of proinflammatory markers, such as Interleukin-6(IL-6) and tumor necrosis factor α(TNF-α). Thus, it suppressed excessive immune responses in the lungs, as well as attenuated the induced pulmonary fibrosis and inflammatory infiltrates. These results suggest that NAR has a preventive effect against Kpn in mice. In addition, the study evaluated NAR’s potential toxicity, demonstrating that NAR is safe at effective doses. These results suggested that NAR effectively reduces excessive inflammatory damage in the lungs induced by Kpn and enhances the body’s ability to clear bacteria. Therefore, NAR may be an effective and safe healthcare drug for preventing and caring for bacterial pneumonia.

Investigating the mechanism of action of Yanghe Pingchuan Granule in the treatment of bronchial asthma based on bioinformatics and experimental validation

BackgroundYanghe Pingchuan Granule (YPG) is a patented Chinese medicine developed independently by the Anhui Provincial Hospital of Traditional Chinese Medicine. For many years, it has been used for the treatment of asthma with remarkable clinical effects. However, the composition of YPG is complex, and its potential active ingredients and mechanism of action for the treatment of asthma are unknown. Materials and methodsIn this study, we investigated the potential mechanism of action of YPG in the treatment of asthma through a combination of bioinformatics and in vivo experimental validation. We searched for active compounds in YPG and asthma targets from multiple databases and obtained common targets. Subsequently, a protein-protein interaction (PPI) network for compound disease was constructed using the protein interaction database for Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Finally, hematoxylin and eosin (H&E) staining, Masson staining, enzyme-linked immunosorbent assay (ELISA) analysis, immunofluorescence (IF) experiments, and Western blot (WB) experiments were performed to verify the possible mechanism of action of YPG for asthma treatment. ResultsWe obtained 72 active ingredients and 318 drug target genes that overlap with asthma. Serine/threonine-protein kinase (AKT1), tumor protein p53 (TP53), tumor necrosis factor (TNF), interleukin (IL)-6, IL-1β, vascular endothelial growth factor-A (VEGFA), prostaglandin-endoperoxide synthase 2 (PTGS2), caspase-3 (CASP3), mitogen-activated protein kinase 3 (MAPK3) and epidermal growth factor receptor (EGFR) were the most relevant genes in the PPI network. KEGG analysis showed a high number of genes enriched for the nuclear factor kappa-B (NF-κB) signaling pathway. Animal experiments confirmed that YPG reduced inflammatory cell infiltration and down-regulated the expression of ovalbumin-induced inflammatory factors. Furthermore, YPG treatment decreased the protein expression of NFĸB1, nuclear factor kappa B kinase subunit beta (IKBKB), vascular endothelial growth factor (VEGF), and vascular endothelial growth factor receptor 2 (VEGFR2) in lung tissue. ConclusionYPG has a positive effect on asthma by interfering with multiple targets. Furthermore, YPG may significantly inhibit the follicle-induced inflammatory response through the NF-ĸB signaling pathway.

Catalpol ameliorates LPS-induced inflammatory response by activating AMPK/mTOR signaling pathway in rat intestinal epithelial cells

Intestinal inflammation is a common clinical intestinal disease. Catalpol, a natural iridoid compound, has been shown to have anti-inflammatory, anti-oxidant and anti-apoptotic functions, but the mechanism of its protection against intestinal inflammation is still unclear. This study investigated the protective effect and potential mechanism of catalpol on the lipopolysaccharide (LPS)-induced inflammatory response of intestinal epithelial cell-6 (IEC-6). The results showed that catalpol could inhibit LPS-induced inflammatory response by dose-dependently reducing the release of inflammatory factors, such as tumor necrosis (TNF)-α, interleukin (IL)-1β and IL-6, and inhibiting the nuclear factor kappa-B (NF-κB) signaling pathway. Catalpol ameliorated cellular oxidative stress by reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels and increasing superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) expression. Meanwhile, catalpol also inhibited cell apoptosis, decreased the expression of B-cell lymphoma 2 (Bcl-2) - associated X (Bax), caspase 3 and caspase 9, and increased the expression of Bcl-2. This study found that catalpol activates AMP-activated protein kinase (AMPK) signaling pathway and inhibit mammalian target of rapamycin (mTOR) phosphorylationthe. In a further study, after inhibiting AMPK with dorsomorphin, the anti-inflammatory effects of catalpol were significantly reduced. Therefore, catalpol ameliorates LPS-induced inflammatory response by activating AMPK/mTOR signaling pathway in IEC-6 cells.

Macroporous Granular Hydrogels Functionalized with Aligned Architecture and Small Extracellular Vesicles Stimulate Osteoporotic Tendon-To-Bone Healing.

Osteoporotic tendon-to-bone healing (TBH) after rotator cuff repair (RCR) is a significant orthopedic challenge. Considering the aligned architecture of the tendon, inflammatory microenvironment at the injury site, and the need for endogenous cell/tissue infiltration, there is an imminent need for an ideal scaffold to promote TBH that has aligned architecture, ability to modulate inflammation, and macroporous structure. Herein, a novel macroporous hydrogel comprising sodium alginate/hyaluronic acid/small extracellular vesicles from adipose-derived stem cells (sEVs) (MHA-sEVs) with aligned architecture and immunomodulatory ability is fabricated. When implanted subcutaneously, MHA-sEVs significantly improve cell infiltration and tissue integration through its macroporous structure. When applied to the osteoporotic RCR model, MHA-sEVs promote TBH by improving tendon repair through macroporous aligned architecture while enhancing bone regeneration by modulating inflammation. Notably, the biomechanical strength of MHA-sEVs is approximately two times higher than the control group, indicating great potential in reducing postoperative retear rates. Further cell-hydrogel interaction studies reveal that the alignment of microfiber gels in MHA-sEVs induces tenogenic differentiation of tendon-derived stem cells, while sEVs improve mitochondrial dysfunction in M1 macrophages (Mφ) and inhibit Mφ polarization toward M1 via nuclear factor-kappaB (NF-κb) signaling pathway. Taken together, MHA-sEVs provide a promising strategy for future clinical application in promoting osteoporotic TBH.