Diosmetin exhibits anti‐proliferative and anti‐inflammatory effects on TNF‐α‐stimulated human rheumatoid arthritis fibroblast‐like synoviocytes through regulating the Akt and NF‐κB signaling pathways

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by inflammation and proliferation of synovial tissues. Diosmetin is a bioflavonoid possessing an anti‐inflammatory property. Herein, we aimed to study the effects of diosmetin on the inflammation and proliferation of RA fibroblast‐like synoviocytes MH7A cells. MH7A cell proliferation was measured using cell counting kit‐8 assay. Cell apoptosis was examined using flow cytometry. The production of inflammatory cytokines including interleukin (IL)‐1β, IL‐6, IL‐8, and matrix metalloproteinase‐1 (MMP‐1) was measured using enzyme‐linked immunosorbent assay (ELISA). Results showed that diosmetin inhibited tumor necrosis factor‐α (TNF‐α)‐induced proliferation increase in MH7A cells in a dose‐dependent manner. Diosmetin treatment resulted in an increase in apoptotic rates and a reduction in TNF‐α‐induced production of IL‐1β, IL‐6, IL‐8, and MMP‐1 in MH7A cells. Furthermore, diosmetin inhibited TNF‐α‐induced activation of protein kinase B (Akt) and nuclear factor‐κB (NF‐κB) pathways in MH7A cells. Suppression of Akt or NF‐κB promoted apoptosis and inhibited TNF‐α‐induced proliferation increase and production of IL‐1β, IL‐6, IL‐8, and MMP‐1 in MH7A cells, and diosmetin treatment enhanced these effects. Taken together, these findings suggested that diosmetin exhibited anti‐proliferative and anti‐inflammatory effects via inhibiting the Akt and NF‐κB pathways in MH7A cells.     

Panax notoginseng saponins suppress lipopolysaccharide‐induced barrier disruption and monocyte adhesion on bEnd.3 cells via the opposite modulation of Nrf2 antioxidant and NF‐κB inflammatory pathways

Dysfunction of the blood‐brain barrier (BBB) is a prerequisite for the pathogenesis of many cerebral diseases. Oxidative stress and inflammation are well‐known factors accounting for BBB injury. Panax notoginseng saponins (PNS), a clinical commonly used drug against cerebrovascular disease, possess efficient antioxidant and anti‐inflammatory activity. In the present study, the protective effects of PNS on lipopolysaccharide (LPS)‐insulted cerebral microvascular endothelial cells (bEnd.3) were assessed and the underlying mechanisms were investigated. The results showed that PNS mitigated the decrease of Trans‐Endothelial Electrical Resistance, increase of paracellular permeability, and loss of tight junction proteins in bEnd.3 BBB model. Meanwhile, PNS suppressed the THP‐1 monocytes adhesion on bEnd.3 monolayer. Moreover, PNS prevented the pro‐inflammatory cytokines secretion and reactive oxygen species generation in bEnd.3 cells stimulated with LPS. Mechanism investigations suggested that PNS promoted the Akt phosphorylation, activated Nrf2 antioxidant signaling, and inhibited the NF‐κB activation. All the effects of PNS could be abolished by PI3K inhibition at different levels. Taken together, these observations suggest that PNS may act as an extrinsic regulator that activates Nrf2 antioxidant defense system depending on PI3K/Akt and inhibits NF‐κB inflammatory signaling to attenuate LPS‐induced BBB disruption and monocytes adhesion on cerebral endothelial cells in vitro.     

Xanthotoxin and umbelliferone attenuate cognitive dysfunction in a streptozotocin‐induced rat model of sporadic Alzheimer's disease: The role of JAK2/STAT3 and Nrf2/HO‐1 signalling pathway modulation

The aim of the present study was to assess the neuroprotective effects of xanthotoxin and umbelliferone in streptozotocin (STZ)‐induced cognitive dysfunction in rats. Animals were injected intracerebroventricularly (ICV) with STZ (3 mg/kg) once to induce a sporadic Alzheimer's disease (SAD)‐like condition. Xanthotoxin or umbelliferone (15 mg/kg, i.p.) were administered 5 hr after ICV‐STZ and daily for 20 consecutive days. Xanthotoxin or umbelliferone prevented cognitive deficits in the Morris water maze and object recognition tests. In parallel, xanthotoxin or umbelliferone reduced hippocampal acetylcholinestrase activity and malondialdehyde level. Moreover, xanthotoxin or umbelliferone increased glutathione content. These coumarins also modulated neuronal cell death by reducing the level of proinflammatory cytokines (tumour necrosis factor‐alpha and interleukin‐6), inhibiting the overexpression of inflammatory markers (nuclear factor κB [NF‐κB] and cyclooxygenase II), and upregulating the expression of NF‐κB inhibitor (IκB‐α). Interestingly, xanthotoxin diminished phosphorylated JAK2 and phosphorylated STAT3 protein expression, while umbelliferone markedly replenished nuclear factor erythroid‐derived 2‐like 2 (Nrf2) and haem oxygenase‐1 (HO‐1) levels. The current study provides evidence for the protective effect of xanthotoxin and umbelliferone in STZ‐induced cognitive dysfunction in rats. This effect may be attributed, at least in part, to inhibiting acetylcholinestrase and attenuating oxidative stress, neuroinflammation and neuronal loss.     

Isoforskolin and forskolin attenuate lipopolysaccharide‐induced inflammation through TLR4/MyD88/NF‐κB cascades in human mononuclear leukocytes

The principal active component of isoforskolin (ISOF) is from the plant Coleus forskohlii, native to China, which has attracted much attention for its biological effects. We hypothesize that ISOF and forskolin (FSK) pretreatment attenuates inflammation induced by lipopolysaccharide (LPS) related to toll‐like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor kappa B (NF‐κB) signaling. Mononuclear leukocytes (MLs) from healthy donors' blood samples were separated by using density gradient centrifugation. Protein levels of TLR4, MyD88, and NF‐κB were detected using western blot and inflammatory cytokines interleukin (IL) 1β, IL‐2, IL‐6, IL‐21, IL‐23, tumor necrosis factor (TNF) α, and TNF‐β were tested by enzyme‐linked immunosorbent assay and Quantibody array in MLs. Our results showed that LPS augmented the protein levels of TLR4, MyD88, and NF‐κB in MLs and the production of IL‐1β, IL‐2, IL‐6, IL‐21, IL‐23, TNF‐α, and TNF‐β in supernatants of MLs. Despite treatment with ISOF and FSK prior to LPS, the protein levels of TLR4, MyD88, NF‐κB, IL‐1β, IL‐2, IL‐6, IL‐21, IL‐23, TNF‐α, and TNF‐β in MLs were apparently decreased. roflumilast (RF) and dexamethasone (DM) had a similar effect on MLs with ISOF and FSK. Our results, for the first time, have shown that ISOF and FSK attenuate inflammation in MLs induced by LPS through down‐regulating protein levels of IL‐1β and TNF‐α, in which TLR4/MyD88/NF‐κB signal pathway could be involved.     

Artichoke Leaf Extract Inhibits AKR1B1 and Reduces NF‐κB Activity in Human Leukemic Cells

The human intracellular enzyme AKR1B1 belongs to the aldo‐keto reductase superfamily. The AKR1B1‐catalyzed reduction of aldehydes is part of the intracellular inflammatory pathway leading to the activation of NF‐κB and the expression of pro‐inflammatory genes. The present study is aimed at determining the inhibition of AKR1B1 brought about by an extract of artichoke leaves (bracts), and the effects of this extract and three participating compounds on the expression of AKR1B1, COX‐2, and MMP‐2 proteins in THP‐1 cells. It seeks to identify the ability of the test substances to modulate the lipopolysaccharide (LPS)‐induced activation of NF‐κB in cells and the intracellular oxidant effect of test substances after incubation with LPS. Low concentrations of the extract inhibit the enzyme AKR1B1. After stimulation by LPS, the extract attenuated the activity of NF‐κB in THP‐1 cells, but no changes in the expression of AKR1B1 were recorded. The extract diminished the expression of the inflammation‐related enzymes COX‐2 and MMP‐2, probably by inhibiting the activity of NF‐κB. The extract significantly diminished the intracellular reactive oxygen species after a brief LPS incubation, which may also have reduced intracellular inflammation. The diminished activity of NF‐κB in the cells could be linked to the inhibition of the activity of AKR1B1. Copyright © 2017 John Wiley & Sons, Ltd.     

Calycosin attenuates MPTP‐induced Parkinson's disease by suppressing the activation of TLR/NF‐κB and MAPK pathways

Parkinson is the second common neurodegenerative disease. The characteristics of Parkinson's disease (PD) are the dopamin neurons loss caused by neuroinflammation responses. C alycosin, an isoflavone phytoestrogen isolated from Astragalus membranaceus, has multiple pharmacological activities, such as anti‐inflammation, anti‐tumor, and neuroprotective effects. However, it is unknown whether calycosin can mitigate PD symptoms. This study aims to explore whether calycosin can alleviate PD symptoms and the underlying mechanisms. PD was induced in mice by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) injection, and calycosin was given intracerebroventricularly to these mice. A cell model of nerve inflammation was established by BV2 microglia cells injected with lipopolysaccharide (LPS). The motor states were evaluated by stepping, whisker, and cylinder experiments. The states of dopaminergic neurons and microglia were detected by immunostainning of tyrosine hydroxylase and cluster of differentiation molecule 11b (CD11b). The expression levels of inflammatory factors were detected by qPCR. Toll‐like receptor (TLR)/nuclear factor kappa B (NF‐κB) and mitogen‐activated protein kinase (MAPK) pathways were investigated by western blot. We found that calycosin treatment mitigated the behavioral dysfunctions and inflammatory responses in MPTP‐induced PD mice. The TLR/NF‐κB and MAPK pathways in MPTP‐induced PD mice were inhibited by calycosin treatment, which was coincident with experiments in LPS‐induced BV2 cells. Above all, calycosin mitigates PD symptoms through TLR/NF‐κB and MAPK pathways in mice and cell lines.     

Berberine ameliorates lipopolysaccharide‐induced acute lung injury via the PERK‐mediated Nrf2/HO‐1 signaling axis

A fundamental element of acute lung injury (ALI) is the inflammatory response, which can affect the entire respiratory system, including the respiratory tract and alveoli. Berberine has gained attention because of its anti‐inflammatory effects. Nuclear factor‐erythroid 2‐related factor 2 (Nrf2) and endoplasmic reticulum (ER) stress are involved in lung injury. Nrf2 also acts as a protein kinase‐like ER kinase (PERK) substrate in heart disease. Therefore, this study investigated the effect of berberine against lipopolysaccharide (LPS)‐induced ALI and the role of the PERK‐mediated Nrf2/HO‐1 signaling axis. Berberine promoted Nrf2 nuclear translocation and phosphorylation in vitro. After LPS stimulation, this effect was further enhanced, whereas inflammatory factor (IL‐6 and IL‐8) release and reactive oxygen species generation were significantly decreased. Berberine effectively alleviated lung injury by reducing lung edema and neutrophil infiltration. Berberine also significantly reduced histopathological inflammatory changes via inhibition of ER stress and activation of Nrf2 signaling. Thapsigargin‐induced ER stress and small interference RNA (siRNA)‐mediated Nrf2 inhibition abrogated the protective effects of berberine in vitro, whereas siRNA‐mediated suppression of ER stress and sulforaphane‐induced Nrf2 activation further improved those effects. Importantly, ER stress induction led to Nrf2 activation, whereas PERK depletion partly reduced the level of Nrf2 phosphorylation and translocation in LPS‐induced cells. Therefore, berberine inhibits LPS‐induced ALI through the PERK‐mediated Nrf2/HO‐1 signaling axis.     

Nerolidol Protects Against LPS‐induced Acute Kidney Injury via Inhibiting TLR4/NF‐κB Signaling

Acute kidney injury (AKI) is a critical care syndrome, resulting in acute reduction of renal function and up to 22% mortality of hospitalized patients. Nerolidol is a major component in several essential oils that possesses various pharmacological properties. The present study aimed to investigate the potential effect of nerolidol on lipopolysaccharide (LPS)‐induced AKI. Nerolidol dose‐dependently reduced the pathological injuries of kidney induced by LPS in rats. Nerolidol significantly decreased the levels of blood urea nitrogen and creatinine in LPS‐treated rats in a dose‐dependent manner. In addition, nerolidol inhibited LPS‐induced decrease of cell viability in NRK‐52E rat proximal tubular cells, which effect was concentration dependent. Nerolidol notably inhibited the increase of TNFα and IL‐1β in LPS‐treated rats and the mRNA expression of TNFα and IL‐1β in LPS‐treated NRK‐52E cells. Nerolidol suppressed the increase of toll‐like receptor 4 (TLR4) expression, phosphorylation and nuclear translocation of p65 NF‐κB in kidneys of LPS‐treated rats and LPS‐treated NRK‐52E cells. Overexpression of TLR4 and p65 NF‐κB significantly suppressed nerolidol‐induced inhibition of TNFα and IL‐1β expression and increase of cell viability in LPS‐treated cells. In summary, we found that nerolidol played a critical anti‐inflammatory effects through inhibition of TLR4/NF‐κB signaling and protected against LPS‐induced AKI. Copyright © 2017 John Wiley & Sons, Ltd.     

Tectorigenin protects against experimental fulminant hepatic failure by regulating the TLR4/mitogen‐activated protein kinase and TLR4/nuclear factor‐κB pathways and autophagy

Tectorigenin has received attention due to its antiproliferation, anti‐inflammatory, and antioxidant activities. In this study, we investigated the effects of tectorigenin on lipopolysaccharide (LPS)/D‐galactosamine(D‐GalN)‐induced fulminant hepatic failure (FHF) in mice and LPS‐stimulated macrophages (RAW 264.7 cells). Pretreatment with tectorigenin significantly reduced the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), histological injury, apoptosis, and the mortality of FHF mice, by suppressing the production of inflammatory cytokines such as TNF‐α and IL‐6. Tectorigenin also suppressed the activation of the inflammatory response in LPS‐stimulated RAW 264.7 cells. Tectorigenin‐induced protection is mediated through its mitigation of TLR4 expression, inhibition of mitogen‐activated protein kinase (MAPK) and nuclear factor‐κB (NF‐κB) pathway activation, and promotion of autophagy in FHF mice and LPS‐stimulated RAW 264.7 cells. Therefore, tectorigenin has therapeutic potential for FHF in mice via the regulation of TLR4/MAPK and TLR4/NF‐κB pathways and autophagy.     

1,2,3,6‐tetra‐O‐galloyl‐β‐D‐allopyranose gallotannin isolated,from Euphorbia jolkini,attenuates LPS‐induced nitric oxide production in macrophages

Nitric oxide (NO) is a pleiotropic regulator, critical to numerous biological processes, including vasodilatation and macrophage‐mediated immunity. Macrophages express inducible NO synthase (iNOS) and produce NO after lipopolysaccharide (LPS) stimulation. Gallotannins are water‐soluble polyphenols with wide‐ranging biological activities. Various chemical structures of gallotannins occurring in medicinal and food plants that are used worldwide showed several remarkable biological and pharmacological activities. In the present study, we examined the inhibitory effects of gallotannin 1,2,3,6‐tetra‐O‐galloyl‐β‐D‐allopyranose (GT24) isolated from Euphorbia jolkini on the LPS‐induced NO production and underlying mechanisms of action. GT24 dose‐dependently decreased LPS‐induced NO production and iNOS expression in J774A.1 macrophages. In addition, GT24 inhibited LPS‐induced activation of nuclear factor (NF)‐κB as indicated by inhibition of degradation of I‐κBα, nuclear translocation of NF‐κB, and NF‐κB dependent gene reporter assay. Our results suggest that GT24 possesses an inhibitory effect on the LPS‐induced inflammatory reaction. Copyright © 2010 John Wiley & Sons, Ltd.     

Retracted: Baicalin relieves lipopolysaccharide‐evoked inflammatory injury through regulation of miR‐21 in H9c2 cells

Myocarditis is a common heart disease which lacks effective treatment till now. Baicalin possesses plenty of activities, including anti‐inflammation. In this investigation, we attempted to investigate the influences of Baicalin on Lipopolysaccharide (LPS)‐evoked H9c2 cells.Cells viability, apoptosis, and expressions of apoptosis‐associated proteins were, respectively, measured utilizing CCK‐8 assay, flow cytometry and western blot. The levels of IL‐6 and TNF‐α were detected through enzyme‐linked immunosorbent assay, western blot and qRT‐PCR. miR‐21 expression was detected through qRT‐PCR and was silenced using cell transfection. The expressions of NF‐κB and PDCD4/JNK pathways related proteins were measured through western blot. We found that LPS stimulation induced cell apoptosis and upregulation of IL‐6 and TNF‐α. Baicalin treatment effectively suppressed LPS‐induced inflammation and apoptosis. The NF‐κB and PDCD4/JNK pathways were blocked by Baicalin. Additionally, the enhanced expression of miR‐21 triggered by LPS was further elevated by Baicalin. Further study revealed that the inhibiting effects of Baicalin on LPS‐evoked injury were largely attenuated by knockdown of miR‐21. Moreover, the associated NF‐κB and JNK pathways, which were suppressed by Baicalin treatment, were then activated by knockdown of miR‐21. Our present study revealed that Baicalin alleviated LPS‐evoked inflammatory injury via suppressing the NF‐κB and PDCD4/JNK pathways through regulating miR‐21 expression.     

Retracted: Lipopolysaccharides‐mediated injury to chondrogenic ATDC5 cells can be relieved by Sinomenine via downregulating microRNA‐192

Sinomenine (SIN) is an isoquinoline derived from Caulis Sinomenii that has been used to treat rheumatoid arthritis and osteoarthritis for several decades in China. This study aims to reveal the effects of SIN on mouse chondrogenic ATDC5 cells growth and inflammation. SIN was used to treat ATDC5 cells injured by lipopolysaccharides (LPS). The following parameters were determined for evaluating the treatment effects of SIN: cell viability, apoptosis, reactive oxygen species generation, and pro‐inflammatory cytokines release. Besides, the expression of LPS‐sensitive miRNA (miR‐192) and the activation of NF‐κB and MAPK signaling were studied to explain SIN's function. SIN with concentration of 30 μM significantly attenuated LPS‐induced cell damage via increasing cell viability, inhibiting apoptosis and reactive oxygen species generation, and declining IL‐6 and TNF‐α release. miR‐192 was downregulated by SIN treatment. Restoration of miR‐192 expression by miRNA transfection could significantly impede SIN's protective action. Besides, the inhibitory effects of SIN on the activation of NF‐κB and MAPK signaling were attenuated by miR‐192 overexpression. Furthermore, GDF11 was found to be a target gene of miR‐192. LPS‐mediated injury to chondrogenic ATDC5 cells can be relieved by SIN via downregulating miR‐192 and subsequently repressing the activation of NF‐κB and MAPK signaling.     

Brassinin,a phytoalexin in cruciferous vegetables,suppresses obesity‐induced inflammatory responses through the Nrf2‐HO‐1 signaling pathway in an adipocyte‐macrophage co‐culture system

The aim of this study was to investigate the effect of brassinin (BR), a phytoalexin found in plants belonging to the Brassicaceae family, on the obesity‐induced inflammatory response and its molecular mechanism in co‐culture of 3T3‐L1 adipocytes and RAW264.7 macrophages. BR effectively suppressed lipid accumulation by down‐regulating the expression of adipogenic factors, which in turn, were regulated by early adipogenic factors such as CCAAT‐enhancer‐binding protein‐β and Kruppel‐like factor 2. Production of inflammatory cytokines and reactive oxygen species, induced by adipocyte‐conditioned medium, was significantly decreased in BR‐treated cells. This effect of BR was more prominent in contact co‐culture of adipocytes and macrophages with a 90% and 34% reduction in IL‐6 and MCP‐1 levels, respectively. BR also restored adiponectin expression, which was significantly reduced by culturing adipocytes in macrophage‐conditioned medium. In the transwell system, BR increased the protein levels of nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) and its target molecule, hemoxygenase‐1 (HO‐1), by 55%–93% and 45%–48%, respectively, and also increased Nrf2 translocation into the nucleus. However, knockdown of Nrf2 or HO‐1 in RAW264.7 cells restored this BR‐mediated inhibition of IL‐6 and MCP‐1 production. These results indicated that BR inhibited obesity‐induced inflammation via the Nrf2‐HO‐1 pathway.     

Methylalpinumisoflavone Inhibits Lipopolysaccharide‐Induced Inflammation in Microglial Cells by the NF‐kappaB and MAPK Signaling Pathway

Neuroinflammation is chronic inflammation within the brain that is attributed to prolonged activation of microglial cells and results in neurodegenerative events, such as neuronal dysfunction and neuronal loss. Therefore, suppression of neuroinflammation would theoretically slow progression of neurodegenerative disease. In this study, we investigated the anti‐inflammatory effects of 4′‐O‐methylalpinumisoflavone (methylalpinumisoflavone), isolated from Cudrania tricuspidata, against LPS‐induced microglial activation in BV2 cells. Exposure of BV2 cells to LPS (0.5 µg/mL) significantly increased production of pro‐inflammatory mediators, including NO, PGE₂, and pro‐inflammatory cytokines. Conversely, pre‐treatment with methylalpinumisoflavone (10 and 20 µg/mL) prior to treatment with LPS resulted in a significant decrease of LPS‐induced production of pro‐inflammatory mediators in a dose‐dependent manner. In addition, reduction of pro‐inflammatory mediators by treatment with methylalpinumisoflavone prior to treatment with LPS was accompanied by a decrease in translocation of NF‐κB p50 and p65 from the cytoplasm to the nucleus and by a decrease in activation of mitogen‐activated protein kinases (MAPKs), such as ERK1/2 and JNK. Taken together, these results suggest that methylalpinumisoflavone suppressed LPS‐induced microglial activation and production of pro‐inflammatory mediators by decreasing NF‐κB signaling and by phosphorylation of MAPKs. These results suggest the potential of methylalpinumisoflavone as an anti‐inflammatory drug candidate. Copyright © 2012 John Wiley & Sons, Ltd.     

Astragaloside IV Attenuates Injury Caused by Myocardial Ischemia/Reperfusion in Rats via Regulation of Toll‐Like Receptor 4/Nuclear Factor‐κB Signaling Pathway

Myocardial ischemia/reperfusion (MI/R) injury, in which inflammatory response and cell apoptosis play a vital role, is frequently encountered in clinical practice. Astragaloside IV (AsIV), a small molecular saponin of Astragalus membranaceus, has been shown to confer protective effects against many cardiovascular diseases. The present study was aimed to investigate the antiinflammatory and antiapoptotic effects and the possible mechanism of AsIV on MI/R injury in rats. Rats were randomly divided into sham operation group, MI/R group and groups with combinations of MI/R and different doses of AsIV. The results showed that the expressions of myocardial toll‐like receptor 4 (TLR4) and nuclear factor‐κB (NF‐κB) were significantly increased, and apoptosis of cardiomyocytes was induced in MI/R group compared with that in sham operation group. Administration of AsIV attenuated MI/R injury, downregulated the expressions of TLR4 and NF‐κB and inhibited cell apoptosis as evidenced by decreased terminal deoxynucleotidyl transferase dUTP nick end labeling positive cells, B‐cell lymphoma‐2 associated X protein and caspase‐3 expressions and increased B‐cell lymphoma‐2 expression compared with that in MI/R group. In addition, AsIV treatment reduced levels of inflammatory cytokines induced by MI/R injury. In conclusion, our results demonstrated that AsIV downregulates TLR4/NF‐κB signaling pathway and inhibits cell apoptosis, subsequently attenuating MI/R injury in rats. Copyright © 2015 John Wiley & Sons, Ltd.     

Chelidonine inhibits TNF‐α‐induced inflammation by suppressing the NF‐κB pathways in HCT116 cells

Nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) is a complex that regulates several hundreds of genes, including those involved in immunity and inflammation, survival, proliferation, and the negative feedback of NF‐κB signaling. Chelidonine, a major bioactive, isoquinoline alkaloid ingredient in Chelidonium majus, exhibits antiinflammatory pharmacological properties. However, its antiinflammatory molecular mechanisms remain unclear. In this work, we explored the effect of chelidonine on TNF‐induced NF‐κB activation in HCT116 cells. We found chelidonine inhibited the phosphorylation and degradation of the inhibitor of NF‐κB alpha and nuclear translocation of RELA. Furthermore, by inhibiting the activation of NF‐κB, chelidonine downregulated target genes involved in inflammation, proliferation, and apoptosis. Chelidonine also inhibited mitogen‐activated protein kinase pathway activation by blocking c‐Jun N‐terminal kinase and p38 phosphorylation. These results suggest that chelidonine may be a potential therapeutic agent against inflammatory diseases in which inhibition of NF‐κB activity plays an important role.     

Quercetin protects against cisplatin‐induced acute kidney injury by inhibiting Mincle/Syk/NF‐κB signaling maintained macrophage inflammation

Acute kidney injury (AKI) with high incidence and mortality is the main cause of chronic kidney disease. Previous studies have indicated that quercetin, an abundant flavonoid in plants, exhibited renoprotective role in AKI. However, the underlying mechanism is largely unknown. In this study, we try to explore whether quercetin protects against AKI by inhibiting macrophage inflammation via regulation of Mincle/Syk/NF‐κB signaling. The results demonstrated that quercetin can significantly inhibit expression and secretion of IL‐1β, IL‐6, and TNF‐α in LPS‐induced bone marrow‐derived macrophages (BMDMs) and reduce activity of Mincle/Syk/NF‐κB signaling in vitro. We also found that quercetin can strongly reduce the concentration of serum creatinine, BUN, IL‐1β, IL‐6, and TNF‐α in cisplatin‐induced AKI model. Furthermore, quercetin down‐regulated protein levels of Mincle, phosphorylated Syk and NF‐κB in kidney macrophages of AKI, as well as inhibited M1, up‐regulated M2 macrophage activity. Notably, the down‐regulation of LPS‐induced inflammation by quercetin was reversed after adding TDB (an agonist of Mincle) in BMDMs, suggesting that quercetin suppresses macrophage inflammation may mainly through inhibiting Mincle and its downstream signaling. In summary, these findings clarified a new mechanism of quercetin improving AKI‐induced kidney inflammation and injury, which provides a new drug option for the clinical treatment of AKI.