Inhibition Of NF-κB Signaling Pathway Research Articles

Redox-Mediated Artificial Non-Enzymatic Antioxidant MXene Nanoplatforms for Acute Kidney Injury Alleviation.

Acute kidney injury (AKI), as a common oxidative stress‐related renal disease, causes high mortality in clinics annually, and many other clinical diseases, including the pandemic COVID‐19, have a high potential to cause AKI, yet only rehydration, renal dialysis, and other supportive therapies are available for AKI in the clinics. Nanotechnology‐mediated antioxidant therapy represents a promising therapeutic strategy for AKI treatment. However, current enzyme‐mimicking nanoantioxidants show poor biocompatibility and biodegradability, as well as non‐specific ROS level regulation, further potentially causing deleterious adverse effects. Herein, the authors report a novel non‐enzymatic antioxidant strategy based on ultrathin Ti3C2‐PVP nanosheets (TPNS) with excellent biocompatibility and great chemical reactivity toward multiple ROS for AKI treatment. These TPNS nanosheets exhibit enzyme/ROS‐triggered biodegradability and broad‐spectrum ROS scavenging ability through the readily occurring redox reaction between Ti3C2 and various ROS, as verified by theoretical calculations. Furthermore, both in vivo and in vitro experiments demonstrate that TPNS can serve as efficient antioxidant platforms to scavenge the overexpressed ROS and subsequently suppress oxidative stress‐induced inflammatory response through inhibition of NF‐κB signal pathway for AKI treatment. This study highlights a new type of therapeutic agent, that is, the redox‐mediated non‐enzymatic antioxidant MXene nanoplatforms in treatment of AKI and other ROS‐associated diseases.

MicroRNA-451 (miR-451) Regulates the Apoptosis of Non-Small Cell Lung Cancer Cells by Targeting Macrophage Migration Promoting Factors

MicroRNA (miRNA) participates in cellular activities. This article mainly discusses whether miR-451 has a role in the apoptosis of non-small cell lung cancer (NSCLC) cells. A549 cell was divided into blank group, miR-451 overexpression group and NC group followed by analysis of level of miR-451, MIF mRNA, MIF, NF-κB, and nuclear expression of NF-κB by immunofluorescence, clone formation, cell apoptosis rate and cell cycle. miR-451 overexpression significantly inhibited MIF and NF-κB expression. In the case of miR-451 overexpression, NSCLC clone formation was inhibited time-dependently The nuclear NF-κB expression in miR451 group was significantly inhibited, indicating inhibition of MIF by miR-451, leading to inhibition of NSCLC cell proliferation. Further results showed that cell apoptotic rate of miR-451 high expression group was elevated with increased cell number in G2 phase, confirming that miR-451 overexpression promoted NSCLC cell apoptosis. miR-451 over-expression can inhibit MIF level by inhibiting NF-κB signaling pathway, thereby promoting NSCLC cell apoptosis, providing a new therapeutic approach for the clinical targeted therapy.

Anti-inflammatory effect of a polysaccharide fraction from Craterellus cornucopioides in LPS-stimulated macrophages.

Immunocytes-involved inflammation is considered to modulate the damage in various diseases. Oxidative stress is initiated by oxidative agents such as LPS and ROS, which are strongly involved in chronic inflammation. Our previous study found that a polysaccharide fraction from Craterellus cornucopioides (CCPP-1) showed good antioxidant activity. However, the anti-inflammatory effect of CCPP-1 was still elusive. The objective of this study was to evaluate the anti-inflammatory activity of CCPP-1 and its potential mechanism in LPS-stimulated RAW264.7 macrophages. The results showed that CCPP-1 could inhibit LPS-induced ROS and NO accumulation. Additionally, CCPP-1 could decrease pro-inflammatory cytokines production (TNF-α, IL-1β, and IL-18) and inflammatory mediator (iNOS) expression, which might be associated with its capacity to inhibit NF-κB signaling pathway and NLRP3 inflammasome activation. Therefore, this study suggested that CCPP-1 had an ameliorative effect on the inflammation response and was potential to develop into functional food for treating chronic inflammation. PRACTICAL APPLICATIONS: Craterellus cornucopioides is an edible fungus widely distributed in Southwestern China. It was reported that C. cornucopioides polysaccharide (CCPP-1), as important active ingredient, showed good antioxidant activity. However, the anti-inflammatory effect was still elusive. This study showed that CCPP-1 possessed anti-inflammatory activity. The molecular mechanism might be associated with its capacity to inhibit NF-κB signaling pathway and NLRP3 inflammasome activation. Therefore, polysaccharides from C. cornucopioides have potential to develop into functional food to combat inflammatory condition and thus indirectly halt the progression of various inflammatory response-related chronic diseases.

IgE-Induced Mast Cell Activation Is Suppressed by Dihydromyricetin through the Inhibition of NF-κB Signaling Pathway.

Mast cells play a crucial role in the pathogenesis of type 1 allergic reactions by binding to IgE and allergen complexes and initiating the degranulation process, releasing pro-inflammatory mediators. Recently, research has focused on finding a stable and effective anti-allergy compound to prevent or treat anaphylaxis. Dihydromyricetin (DHM) is a flavonoid compound with several pharmacological properties, including free radical scavenging, antithrombotic, anticancer, and anti-inflammatory activities. In this study, we investigated the anti-allergic inflammatory effects and the underlying molecular mechanism of DHM in the DNP-IgE-sensitized human mast cell line, KU812. The cytokine levels and mast cell degranulation assays were determined by enzyme-linked immunosorbent assay (ELISA). The possible mechanism of the DHM-mediated anti-allergic signaling pathway was analyzed by western blotting. It was found that treatment with DHM suppressed the levels of inflammatory cytokines TNF-α and IL-6 in DNP-IgE-sensitized KU812 cells. The anti-allergic inflammatory properties of DHM were mediated by inhibition of NF-κB activation. In addition, DHM suppressed the phosphorylation of signal transducer and activator of transcription 5 (STAT5) and mast cell-derived tryptase production. Our study shows that DHM could mitigate mast cell activation in allergic diseases.

Tumor Necrosis Factor-stimulated Gene-6 (TSG-6) Secreted by BMSCs Regulates Activated Astrocytes by Inhibiting NF-κB Signaling Pathway to Ameliorate Blood Brain Barrier Damage After Intracerebral Hemorrhage.

To investigate the influence of tumor necrosis factor-stimulated gene-6 (TSG-6) secreted by bone mesenchymal stem cells (BMSCs) on blood brain barrier (BBB) after intracerebral hemorrhage (ICH) and its related mechanisms. BMSCs and astrocytes were isolated and induced by TNF-α and LPS respectively. The effect of TSG-6 secreted by BMSCs on the proliferation and apoptosis of astrocytes and inflammatory response were assessed by CCK8, flow cytometry, and ELISA respectively. Then we studied the effects of TSG-6 secreted by BMSCs through the paracrine mechanism on the integrity of BBB after ICH via NF-κB signaling pathway in vitro and in vivo. We successfully isolated BMSCs and astrocytes. After LPS treatment of astrocytes, IL-1β, IL-6, and TNF-α showed an upward trend. TSG-6 secreted by TNF-α-activated BMSCs could antagonize the inflammatory response in activated astrocytes. Through the co-culture of astrocytes and BMSCs and the ICH animal model, we found that TSG-6 regulates activated astrocytes by inhibiting the NF-κB signaling pathway and ameliorates BBB damage. Furthermore, we found that TNF-α-activated BMSCs secreted exosomes containing TSG-6 and played an anti-inflammatory effect. TSG-6 secreted by BMSCs regulates activated astrocytes by inhibiting the NF-κB signaling pathway, thereby ameliorating BBB damage.

Bis(ethylmaltolato)oxidovanadium (IV) attenuates amyloid-beta-mediated neuroinflammation by inhibiting NF-κB signaling pathway via a PPARγ-dependent mechanism.

Neuroinflammation plays a pivotal role in the pathophysiology of neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. During brain neuroinflammation, activated microglial cells resulting from amyloid-beta (Aβ) overload trigger toxic proinflammatory responses. Bis(ethylmaltolato)oxidovanadium (BEOV) (IV), an important vanadium compound, has been reported to have anti-diabetic, anti-cancer, and neuroprotective effects, but its anti-inflammatory property has rarely been investigated. In the present study, the inhibitory effects of BEOV on neuroinflammation were revealed in both Aβ-stimulated BV2 microglial cell line and APPswe/PS1E9 transgenic mouse brain. BEOV administration significantly decreased the levels of tumor necrosis factor-α, interleukin-6, interleukin-1β, inducible nitric oxide synthase, and cyclooxygenase-2 both in the hippocampus of APPswe/PS1E9 mice and in the Aβ-stimulated BV2 microglia. Furthermore, BEOV suppressed the Aβ-induced activation of nuclear factor-κB (NF-κB) signaling and upregulated the protein expression level of peroxisome proliferator-activated receptor gamma (PPARγ) in a dose-dependent manner. PPARγ inhibitor GW9662 could eliminate the effect of BEOV on Aβ-induced NF-κB activation and proinflammatory mediator production. Taken altogether, these findings suggested that BEOV ameliorates Aβ-stimulated neuroinflammation by inhibiting NF-κB signaling pathway through a PPARγ-dependent mechanism.

Dietary Curcumin Alleviated Acute Ileum Damage of Ducks (Anas platyrhynchos) Induced by AFB1 through Regulating Nrf2-ARE and NF-κB Signaling Pathways.

Aflatoxin B1 (AFB1) is a stable toxic metabolite threatening health of human and animal and widely contaminated animal feed and human food. This present study aimed to investigate the effects of dietary curcumin on ileum injury in ducks induced by AFB1 administration and explore its underlying mechanisms. Ducks (N = 450, one-day-old male) with a similar weight were randomly assigned to 3 groups, containing the control group, AFB1 group (60 μg AFB1 kg−1 body weight) and curcumin (500 mg curcumin kg−1 diet) + AFB1 group. AFB1 administration markedly increased the ileum damage, AFB1-DNA adducts in the plasma and oxidation stress and inflammation. Adding curcumin into diet protected the ileum against morphology damage induced by AFB1 administration, decreased AFB1-DNA adducts in the plasma and eliminated oxidation stress and inflammation in the ileum of ducks. Anti-oxidation and anti-inflammatory effects of curcumin could protect the ileum against acute damage via activating Nrf2-ARE signaling pathway and inhibiting NF-κB signaling pathway. Conclusively, curcumin was a dietary anti-oxidation and anti-inflammation agent via activating Nrf2-ARE signaling pathway and inhibiting NF-κB signaling pathway to protect ileum against acute damage induced by AFB1 administration.

Inhibition of CDK9 attenuates atherosclerosis by inhibiting inflammation and phenotypic switching of vascular smooth muscle cells.

Background: Recent studies have demonstrated a key role of vascular smooth muscle cell (VSMC) dysfunction in atherosclerosis. Cyclin-dependent kinases 9 (CDK9), a potential biomarker of atherosclerosis, was significantly increased in coronary artery disease patient serum and played an important role in inflammatory diseases. This study was to explore the pharmacological role of CDK9 inhibition in attenuating atherosclerosis.Methods: A small-molecule CDK9 inhibitor, LDC000067, was utilized to treat the high fat diet (HFD)-fed ApoE-/- mice and human VSMCs.Results: The results showed that inflammation and phenotypic switching of VSMCs were observed in HFD-induced atherosclerosis in ApoE-/- mice, which were accompanied with increased CDK9 in the serum and atherosclerotic lesions where it colocalized with VSMCs. LDC000067 treatment significantly suppressed HFD-induced inflammation, proliferation and phenotypic switching of VSMCs, resulting in reduced atherosclerosis in the ApoE-/- mice, while had no effect on plasma lipids. Further in vitro studies confirmed that LDC000067 and siRNA-mediated CDK9 knockdown reversed ox-LDL-induced inflammation and phenotypic switching of VSMCs from a contractile phenotype to a synthetic phenotype via inhibiting NF-κB signaling pathway in human VSMCs.Conclusion: These results indicate that inhibition of CDK9 may be a novel therapeutic target for the prevention of atherosclerosis.

Vitamin D receptor activated by vitamin D administration alleviates Mycobacterium tuberculosis-induced bone destruction by inhibiting NFκB-mediated aberrant osteoclastogenesis.

Clinically, bone destruction caused by Mycobacterium tuberculosis was serious especially in patients with vitamin D (VD) deficiency. However, the role of VD in M. tuberculosis-induced bone destruction remains clear. In this context, we investigate the role of VD and vitamin D receptor (VDR) in the M. tuberculosis-induced bone destruction. First, we infected RAW264.7 and bone marrow-derived macrophages (BMMs) with Mycobacterium bovis Bacillus Calmette-Guérin (M. bovis BCG) in vitro. Then, we activated VDR through VD administration. TRAP and FAK staining, bone resorption assays, immunofluorescence staining, qPCR, and western blot were carried out. In vivo, the M. tuberculosis-induced osteolytic model on the murine skull was established and the μCT and histological analyses were performed. We found that VDR and TRAP were upregulated in bone tuberculosis tissue and proved that M. tuberculosis infection promoted osteoclastogenesis in RAW264.7 and BMMs. VD could inhibit osteoclasts differentiation, fusion, and bone resorption dose-dependently. However, when VDR was knocked down, the inhibitory effect of VD on osteoclasts disappeared. In mechanism, activation of VDR inhibits the phosphorylation of IκB α, thereby inhibiting NFκB signaling pathway and alleviating osteoclastogenesis. Furthermore, in the skull osteolysis model, VD administration reduced osteolysis, but not in VDR-/- mice. Our study, for the first time, demonstrates that activation of VDR by VD administration inhibits M. tuberculosis-induced bone destruction. Our results reveal that VD and VDR are potential therapeutic targets for M. tuberculosis-induced bone destruction, and are of great clinical significance for the development of new therapeutic strategies.

Triptolide dose-dependently improves LPS-induced alveolar hypercoagulation and fibrinolysis inhibition through NF-κB inactivation in ARDS mice

BackgroundAlveolar hypercoagulation and fibrinolysis inhibition were associated with the refractory hypoxemia and the high mortality in patient with acute respiratory distress syndrome (ARDS), and NF-κB pathway was confirmed to contribute to the process. Triptolide (TP) significantly inhibited NF-κB pathway and thus depressed accessive inflammatory response in ARDS. We speculate that TP could improve alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS via NF-κB inactivation. PurposeThe aim of this experiment was to explore the efficacy and potential mechanism of TP on alveolar hypercoagulation and fibrinolysis inhibition in LPS-induced ARDS in mice. Methods50 μl of LPS (5 mg/ml) was inhalationally given to C57BL/6 mice to set up ARDS model. Male mice were randomly accepted with LPS, LPS + TP (1 μg/kg, 10 μg/kg, 50 μg/kg respectively), or with NEMO Binding domain peptide (NBD), an inhibitor of NF-κB. TP (1 μg/kg, 10 μg/kg, 50 μg/kg) were intraperitoneally injected or 10 μg/50 μl of NBD solution were inhaled 30 min before LPS inhalation. A same volume of normal saline (NS) substituted for TP in mice in control. The endpoint of experiment was at 8 hours after LPS stimulation. Pulmonary tissues were taken for hematoxylin-eosin (HE) staining, wet / dry ratio and for lung injury scores (LIS). Tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 in lung tissue were detected by Western-blotting and by quantitative Real-time PCR(qPCR) respectively. Concentrations of TF, PAI-1, thrombin-antithrombin complex (TAT), procollagen peptide type Ⅲ (PⅢP) and activated protein C (APC) in bronchoalveolar lavage fluid (BALF) were measured by ELISA. NF-κB activation and p65-DNA binding activity in pulmonary tissue were simultaneously determined. ResultsLPS stimulation resulted in pulmonary edema, neutrophils infiltration, obvious alveolar collapse, interstitial congestion, with high LIS, which were all dose-dependently ameliorated by Triptolide. LPS also dramatically promoted the expressions of TF and PAI-1 either in mRNA or in protein in lung tissue, and significantly stimulated the secretions of TF, PAI-1, TAT, PⅢP but inhibited APC production in BALF, which were all reversed by triptolide treatment in dose-dependent manner. TP dose-dependently inhibited the activation of NF-κB pathway induced by LPS, indicated by the changes of phosphorylations of p65 (p-p65), p-IKKα/β and p-IκBα, and weakened p65-DNA binding activity. TP and NBD had same efficacies either on alveolar hypercoagulation and fibrinolysis inhibition or on NF-κB signalling pathway in ARDS mice. ConclusionsTP dose-dependently improves alveolar hypercoagulation and fibrinolysis inhibition in ARDS mice through inhibiting NF-κB signaling pathway. Our data demonstrate that TP is expected to be an effective selection in ARDS.

Metabolomic analyses reveal the crucial metabolites involved in the transplantation response of pearl oyster Pinctada fucata martensii

The immune response after transplantation during pearl production is a major factor that cause nucleus rejection and death of the host pearl oysters. To find out the crucial metabolites involved in the immune response after transplantation, we performed metabolomic analysis of the serum before and after transplantation from pearl oyster Pinctada fucata martensii. The analysis detected a total of 201 metabolites, which included many amino acids. Among the 201 metabolites, 35 were revealed as significantly diff ;erential metabolites (SDMs), such as acetylcholine (ACh) and d-glutamine. Pathway analysis indicated that the identified SDMs were involved in six pathways, such as sphingolipid metabolism and d-glutamine and d-glutamate metabolism. Transcriptomic analysis showed 19 and 18 nAChRs were induced by 2–3000-fold through the pre-conditioning treatment or transplantation surgery, respectively. Dual-Luciferase analysis demonstrated that overexpression of nAChRs downregulated the luciferase activity of the pNF-κB-Luc reporter, and stimulation of nAChRs could inhibit the LPS-induced up-regulation of NF-κb, IKK and IL-17, suggesting that the upregulated ACh after transplantation may function through nAChRs by inhibiting NF-κb signal pathway. These findings could help elucidate the corresponding metabolites after transplantation, thereby providing useful information in regulating the immune response to improve the survival rate of pearl oyster after transplantation.

MicroRNA-155-5p regulates survival of human decidua stromal cells through NF-κB in recurrent miscarriage

Recurrent miscarriage (RM) occurs in approximately 1% of all couples trying to conceive. Most of the research about recurrent miscarriage mainly focuses on immunology. However, the roles of microRNAs plays (miRNAs) in RM remain elusive. Here, the function of miR-155-5p in regulating survival of human decidua stromal cells through NF-κB signaling was explored in RM. The quantitative real-time polymerase chain reaction (qRT-PCR) results showed that miR-155-5p was downregulated in both decidua tissues and serum from RM patients. While, the ELISA assay revealed that the overexpression of miR-155-5p reduced the inflammatory cytokines secretion including IL-6, IFN-γ, TNF-α and IL-10 in decidua stromal cells. The results of cell counting Kit8 (CCK-8) and immunofluorescence experiments suggested that transfection of miR-155-5p into decidua stromal cells can promote the growth and proliferation of cells. In addition, overexpression of miR-155-5p can also inhibit the apoptosis of decidua stromal cells. The western blot assay results demonstrated that the miR-155-5p exerted effect mainly through activating NF-κB signaling pathway in RM. In conclusion, the miRNA-155-5p can not only promote the growth and proliferation but also inhibit the apoptosis of decidua stromal cells depending on inhibiting NF-κB signaling pathway in recurrent miscarriage.

Alantolactone exerts anti-proliferative and apoptotic effects on BGC823 and SGC7901 cells via activation of p38MAPK and inhibition of NF-κB signaling pathway

Purpose: To investigate the anti-proliferative and apoptotic influences of alantolactone on gastric carcinoma (GC) cell lines, and the mechanism(s) involved.
 Methods: Human gastric cancer cell line (BGC823) and gastric adenocarcinoma lymph node metastasis cell line (SGC7901) were maintained in Ham’s F12 medium supplemented with 10 % heatinactivated fetal bovine serum (FBS). In each group of cancer cell line, 5 groups of cells were used: control and four alantolactone groups which were treated with increasing concentrations of alantolactone (5 - 30 μM) for varying periods. Proliferation was determined using MTT assay, while realtime quantitative polymerase chain reaction (qRT-PCR) was used to assay the expressions of apoptosis- and metastasis-related genes. The expressions of p38MAPK and nuclear transcription factor-κB (NF-κB) in BGC823 and SGC7901 cells were measured with Western blotting.
 Results: Phosphorylated protein (p-p38 protein) expression was significantly higher in both groups of GC cells, relative to control (p < 0.05). The expressions of NF-κB in plasma protein were markedly higher in both groups of GC cells than in control group, but the corresponding expressions in nuclear protein were significantly lower in both groups of GC cells, relative to control (p < 0.05).
 Conclusion: Alantolactone exerts anti-proliferative and apoptotic effects on BGC823 and SGC7901 cells via mechanisms involving activation of the p38MAPK, and inhibition of the NF-κB signaling pathways. Thus, alantolactone may be a new and effective anti-gastric cancer drug.

Inhibition of CD38 and supplementation of nicotinamide riboside ameliorate lipopolysaccharide-induced microglial and astrocytic neuroinflammation by increasing NAD.

Neuroinflammation is initiated by activation of the brain's innate immune system in response to an inflammatory challenge. Insufficient control of neuroinflammation leads to enhanced or prolonged pathology in various neurological conditions including multiple sclerosis and Alzheimer's disease. Nicotinamide adenine dinucleotide (NAD+ ) plays critical roles in cellular energy metabolism and calcium homeostasis. Our previous study demonstrated that deletion of CD38, which consumes NAD+ , suppressed cuprizone-induced demyelination, neuroinflammation, and glial activation. However, it is still unknown whether CD38 directly affects neuroinflammation through regulating brain NAD+ level. In this study, we investigated the effect of CD38 deletion and inhibition and supplementation of NAD+ on lipopolysaccharide (LPS)-induced neuroinflammation in mice. Intracerebroventricular injection of LPS significantly increased CD38 expression especially in the hippocampus. Deletion of CD38 decreased LPS-induced inflammatory responses and glial activation. Pre-administration of apigenin, a flavonoid with CD38 inhibitory activity, or nicotinamide riboside (NR), an NAD+ precursor, increased NAD+ level, and significantly suppressed induction of cytokines and chemokines, glial activation and subsequent neurodegeneration after LPS administration. In cell culture, LPS-induced inflammatory responses were suppressed by treatment of primary astrocytes or microglia with apigenin, NAD+ , NR or 78c, the latter a specific CD38 inhibitor. Finally, all these compounds suppressed NF-κB signaling pathway in microglia. These results suggest that CD38-mediated neuroinflammation is linked to NAD+ consumption and that boosting NAD+ by CD38 inhibition and NR supplementation directly suppress neuroinflammation in the brain.

Anti-inflammatory effects of three withanolides isolated from Physalis angulata L. in LPS-activated RAW 264.7 cells through blocking NF-κB signaling pathway

Ethnopharmacological relevancePhysalis angulata L. is commonly used in many countries as popular medicine for the treatment of a variety of diseases such as malaria, hepatitis, dermatitis and rheumatism. But the anti-inflammatory active constituents of this medicinal plant and their molecular mechanism are still not elucidated clearly. Aim of the studyThe aim of the study is to isolate and identify a series of compounds from the ethanolic extract of Physalis angulata L., and to investigate the anti-inflammatory activities in vitro and the molecular mechanism of physagulin A, physagulin C, and physagulin H. Materials and methodsIn order to further understand the anti-inflammatory mechanism of the three compounds, their potential anti-inflammatory activities were investigated in vitro in LPS-activated RAW 264.7 macrophage cells by Griess assay, ELISA, Western blot and immunofluorescence methods in the present study. ResultsPhysagulin A, physagulin C, and physagulin H could not only inhibit the release of NO, PGE2, IL-6 and TNF-α, but also could down-regulate the expression of iNOS and COX-2 proteins. Furthermore, physagulin A, physagulin C, and physagulin H could remarkably block the degradation of IκB-α and the nuclear translocation of NF-κB/p65 in LPS-activated RAW 264.7 cells. However, none of them could inhibit the phosphorylation of MAPKs family proteins ERK, JNK and p38. Thus, the anti-inflammatory actions of physagulin A, physagulin C, and physagulin H were mainly due to the significant inhibition of NF-κB signaling pathway rather than MAPKs signaling pathway. ConclusionsAll the results clearly showed that physagulin A, physagulin C, and physagulin H demonstrated potent anti-inflammatory activity and can be used as novel NF-κB inhibitors. They are potential to be developed as an alternative or complementary agents for inflammatory diseases.

Synergistic Effect of NF-κB Signaling Pathway Inhibitor and Oncolytic Measles Virus Vaccine Strain against Lung Cancer and Underlying Mechanisms

背景与目的肺癌已成为我国发病率和死亡率居首位的恶性肿瘤。能自我复制、选择性杀伤肿瘤的溶瘤病毒，是治疗恶性肿瘤的有效策略，而其中溶瘤麻疹病毒疫苗株因其良好的溶瘤效果，且对正常细胞无损伤或微损伤，已进入几项临床试验。本研究旨在探讨核转录因子κB（nuclear factor kappa B, NF-κB）信号通路抑制剂与溶瘤麻疹病毒疫苗株协同抗肺癌的作用及机制。方法应用Western blot方法检测MV-Edm感染人肺癌细胞A549和H1299并应用细胞自噬相关的siRNA或者应用NF-кB通路抑制剂PS1145后SQSTM1、p-IκBα、IκBα、PARP及BAX的表达水平，运用流式细胞术分析各组细胞凋亡率的变化，同时采用噻唑蓝[3-(4, 5)-dimethylthiahiazo(-z-y1)-3, 5-di-phenytetrazoliumromide, MTT]法检测各组细胞的存活率。结果Western blot结果显示MV-Edm感染人肺癌细胞A549和H1299后，自噬引起NF-κB通路的激活，进而抑制细胞凋亡。抑制细胞自噬可抑制NF-κB通路的激活，MV-Edm感染后p-IκBα表达水平随着感染时间有不同程度的升高，IκBα的表达水平则降低，NF-κB通路抑制剂PS1145可促进人肺癌细胞A549和H1299凋亡（P < 0.01），并增强其溶瘤效果。结论NF-κB信号通路抑制剂PS1145与溶瘤麻疹病毒疫苗株联合可促进人肺癌细胞A549和H1299凋亡，并增强其溶瘤效果。

Small molecule natural compound targets the NF-κB signaling and ameliorates the development of osteoarthritis.

Osteoarthritis (OA) is a multifactorial and chronic disease describing the destruction of cartilage that can lead to defects in the elderly. There is currently no practical strategy that can reverse the OA process. Here, we describe nepetin, a small natural compound with extracellular matrix (ECM) and inflammation regulating functions. In this study, we investigated the therapeutic effects of nepetin on interleukin-1β (IL-1β)-induced inflammation in mice chondrocyte and OA model. In chondrocytes, treatment with nepetin inhibited the overexpression of pro-inflammatory cytokines and mediators induced by IL-1β. Moreover, pretreatment or posttreatment with nepetin also reduced the ECM catabolism and enhanced the ECM anabolism. Mechanistically, nepetin suppressed NF-κB signaling pathway in IL-1β stimulated chondrocyte. Meanwhile, our molecular docking studies indicated nepetin had a powerful binding capacity to p65. Furthermore, nepetin showed a protective and therapeutic effect on the mouse OA model. To sum up, this study indicated nepetin had a new potential therapeutic option in OA.

Melatonin attenuates hepatic ischemia-reperfusion injury in rats by inhibiting NF-κB signaling pathway

BackgroundThe sterile inflammatory response is one of the key mechanisms leading to hepatic ischemia-reperfusion injury. Melatonin has been shown to prevent organ injuries, but its roles in the inflammatory response after hepatic ischemia-reperfusion injury have not been fully explored, especially in late ischemia-reperfusion injury. The present study aimed to investigate the roles and possible mechanisms of melatonin in the inflammatory response after hepatic ischemia-reperfusion injury. MethodsSixty Sprague-Dawley rats were randomly divided into a sham group, ischemia-reperfusion injury group (I/R group), and melatonin-treated group (M + I/R group). The rats in the I/R group were subjected to 70% hepatic ischemia for 45 min, followed by 5 or 24 h of reperfusion. The rats in the M + I/R group were injected with melatonin (10 mg/kg, intravenous injection) 15 min prior to ischemia and immediately before reperfusion. Serum and samples of ischemic liver lobes were harvested for future analysis, and the 7-day survival rate was assessed after hepatic ischemia-reperfusion surgery. ResultsIn comparison with the I/R group, the M + I/R group showed markedly decreased expression levels of inflammatory cytokines (IL-6 and TNF-α) and numbers of apoptotic hepatocytes (P < 0.05). Immunoblotting showed that the expression levels of IL-6, p-NF-κBp65/t-NF-κBp65 and p-IκB-α/t-IκB-α in the M + I/R group were significantly lower than those in the I/R group, and immunofluorescence staining showed that the expression level of p-NF-κBp65 in the M + I/R group was lower than that in the I/R group (P < 0.05). The 7-day survival rates were 20% in the I/R group and 50% in the M + I/R group (P < 0.05). ConclusionsMelatonin downregulated the activity of the NF-κB signaling pathway in the early and late stages of hepatic ischemia-reperfusion injury, alleviated the inflammatory response, protected the liver from ischemia-reperfusion injury, and increased the survival rate.

Rapid identification, isolation, and evaluation on anti-neuroinflammatory activity of limonoids derivatives from the root bark of Dictamnus dasycarpus

A total of 49 limonoids derivatives were rapidly identified by UNIFI software and three new limonoids derivatives, named dasycarinone (1, DAS), isodictamdiol C (2) and dasycarinone A (3), along with nineteen known compounds, were isolated from the root bark of Dictamnus dasycarpus, named as “Baixianpi” in Chinese. Their structures were elucidated on the basis of spectroscopic data (UV, IR, HR-ESI-MS, NMR, CD spectra and OR). All the compounds were tested for anti-inflammatory activities by suppressing the nitric oxide (NO) production in lipopolysaccharide (LPS) induced BV-2 cells. DAS exhibited a strong anti-inflammatory activity with IC50 value of 1.8 μM. Nuclear Factor kappa B (NF-κB) luciferase assay and enzyme-linked immune sorbent assay indicated that DAS can suppress the release of inflammatory cytokines such as Tumor Necrosis Factor α (TNF-α), interleukin 6 (IL-6) via inactivating NF-κB signaling pathways. Moreover, we found that anti-inflammatory activities of obacunone-class are better than those of limonin-class by analyzing structure-activity relationship. Our results suggested that obacunone derivatives play an important role on anti-inflammation of Baixianpi. As a representative among them, DAS showed a strong anti-inflammatory activity via suppressing NF-κB signaling pathways.

Structural characterization and anti-inflammatory activity of a polysaccharide from the lignified okra

The polysaccharide (AP1-b) of molecular weight 6.59 × 105 Da was isolated from lignified okra (Abelmoschus esculentus (L.) Moench) by hot-water extraction, 40 % ethanol precipitation and purified by DEAE Cellulose chromatography, respectively. The structure and anti-inflammatory activity of AP1-b were investigated. AP1-b was composed of galactose, rhamnose, gluctose, arabinose and galacturonic acid in a molar ratio of 1.98:1.00:0.15:0.32:0.29. The structural features showed that the AP1-b consisted of →2)-α-d-Rhap-(1→, →4)-β-d-Galp-(1→, →4)-α-d-GalpA-(1→, →6)-β-d-Galp-(1→, β-d-Glcp-(1→ and α-l-Araf-(1→. AP1-b could observably improve the inflammatory injury of LPS-induced RAW 264.7 cells by inhibiting the secretion of NO and decreasing the levels of pro-inflammatory factors (IL-1β, iNOS and TNF-α). AP1-b also inhibited the phosphorylation levels of IκB and p65 proteins, manifesting the anti-inflammatory activity of AP1-b may associated with inhibition of NF-κB signaling pathway. Therefore, AP1-b had potential value in treating inflammatory injury.