Protective Effects of Kaempferol on Lipopolysaccharide-Induced Mastitis in Mice

Kaempferol isolated from the root of Zingiberaceae plants galangal and other Chinese herbal medicines have been reported to have anti-inflammatory properties. However, the anti-inflammatory effects of kaempferol on lipopolysaccharide (LPS)-induced mastitis are unknown and their underlying molecular mechanisms remain to be explored. The aim of this study was to evaluate the effects of kaempferol on LPS-induced mouse mastitis. The mouse model of mastitis was induced by injection of LPS through the duct of mammary gland. Kaempferol was injected 1 h before and 12 h after induction of LPS intraperitoneally. The present results showed that kaempferol markedly reduced infiltration of neutrophilic granulocyte, activation of myeloperoxidase (MPO), expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in a dose-dependent manner, which were increased in LPS-induced mouse mastitis. Furthermore, kaempferol suppressed the phosphorylation of nuclear factor-κB (NF-κB) p65 subunit and the degradation of its inhibitor IκBα. All results suggest that anti-inflammatory effects of kaempferol against the LPS-induced mastitis possibly through inhibition of the NF-κB signaling pathway. Kaempferol may be a potential therapeutic agent for mastitis.     

Ghrelin对急性心肌梗死后大鼠心脏神经重构的影响及炎性因子的作用

目的:探讨Ghrelin对心肌梗死(MI)后大鼠神经重构的影响及其作用机制。方法:55只SD大鼠分为假手术组(Sham组)、急性心肌梗死(AMI)模型对照组(Control组)和Ghrelin干预组(Ghrelin组)。结扎冠状动脉制作AMI模型40只,Ghrelin组和Control组各20只,Ghrelin组于手术当天给予Ghrelin皮下注射,剂量为100μg/kg,2次/天;Sham组和Control组等量生理盐水作相同部位注射。四周后处死动物。检测梗死及非梗死区左室神经生长因子相关蛋白-43(GAP-43)、酪氨酸羟化酶(TH)、炎症介质白介素-1β(IL-1β),肿瘤坏死因子-α(TNF-α)和内皮素-1(ET-1)的表达。结果:与Control组相比,Ghrelin组梗死区及非梗死区GAP-43及TH的阳性表达明显减少,同时IL-1β、TNF-α和ET-1mRNA表达也明显受抑。结论:Ghrelin干预能够抑制大鼠MI后神经增生;炎性因子可能参与其中。     

Effect of Lipopolysaccharide and Inflammatory Cytokines on Interleukin-6 Production by Healthy Human Gingival Fibroblasts

Cytokines are hormone-like proteins which mediate and regulate inflammatory and immune responses. The purpose of this study was to investigate the effect of lipopolysaccharide (LPS) and inflammatory cytokines on regulation of interleukin-6 (IL-6) production by human gingival fibroblasts (HGF). The HGF cell lines used in this study, H-CL and F-CL, were established by the explant technique from healthy gingival tissue. Cultured cells were grown to confluency and incubated with various concentrations of LPS from Escherichia coli or Porphyromonas gingivalis or with the recombinant human cytokine tumor necrosis factor alpha (TNF-α), IL-1α, or IL-1β. Culture supernatants were collected at various times and assessed for IL-6 production by enzyme-linked immunosorbent assay. Total RNA was isolated from the harvested cells and used to assess levels of IL-6 mRNA by the RNase protection assay. Both LPS preparations induced IL-6 production (1 to 4 ng of IL-6 per ml) by both HGF cell lines. Although TNF-α stimulated IL-6 production by HGF, >10-fold-larger amounts were induced with IL-1α and IL-1β. Furthermore, the addition of both IL-1α and TNF-α to cultured cells resulted in approximately 600- to 800-fold-higher levels of IL-6 than seen in control cultures, suggesting that these cytokines synergistically induced IL-6 production by HGF. IL-6 message in cultured cells was upregulated 20-fold by TNF-α, 1,000-fold by IL-1α and IL-1β, and 1,400-fold by IL-1α plus TNF-α. IL-1α and TNF-α alone upregulate IL-6 production in a dose- and time-dependent fashion. The addition of IL-1α and TNF-α to cultured HGF cells resulted in a synergistic induction of IL-6 after 8 h of incubation and when greater than 10 pg of this combination per ml was used. Our studies show that inflammatory cytokines are hundreds of times more potent than LPS in stimulating IL-6 production by HGF.     

Diosgenin Inhibits Excessive Proliferation and Inflammatory Response of Synovial Fibroblasts in Rheumatoid Arthritis by Targeting PDE3B

Inflammation - Rheumatoid arthritis (RA) is a chronic inflammation that can lead to loss of range of joint abnormalities in severe cases. Diosgenin has anti-inflammatory effects. This paper...     

MyD88 Mediates Instructive Signaling in Dendritic Cells and Protective Inflammatory Response during Rickettsial Infection

Spotted fever group rickettsiae cause potentially life-threatening infections throughout the world. Several members of the Toll-like receptor (TLR) family are involved in host response to rickettsiae, and yet the mechanisms by which these TLRs mediate host immunity remain incompletely understood. In the present study, we found that host susceptibility of MyD88^−/− mice to infection with Rickettsia conorii or Rickettsia australis was significantly greater than in wild-type (WT) mice, in association with severely impaired bacterial clearance in vivo. R. australis-infected MyD88^−/− mice showed significantly lower expression levels of gamma interferon (IFN-γ), interleukin-6 (IL-6), and IL-1β, accompanied by significantly fewer inflammatory infiltrates of macrophages and neutrophils in infected tissues, than WT mice. The serum levels of IFN-γ, IL-12, IL-6, and granulocyte colony-stimulating factor were significantly reduced, while monocyte chemoattractant protein 1, macrophage inflammatory protein 1α, and RANTES were significantly increased in infected MyD88^−/− mice compared to WT mice. Strikingly, R. australis infection was incapable of promoting increased expression of MHC-II^high and production of IL-12p40 in MyD88^−/− bone marrow-derived dendritic cells (BMDCs) compared to WT BMDCs, although costimulatory molecules were upregulated in both types of BMDCs. Furthermore, the secretion levels of IL-1β by Rickettsia-infected BMDCs and in the sera of infected mice were significantly reduced in MyD88^−/− mice compared to WT controls, suggesting that in vitro and in vivo production of IL-1β is MyD88 dependent. Taken together, our results suggest that MyD88 signaling mediates instructive signals in DCs and secretion of IL-1β and type 1 immune cytokines, which may account for the protective inflammatory response during rickettsial infection.     

肾上腺素对内毒素致大鼠炎症性肝损害的保护作用

目的 探讨肾上腺素（Epi）对内毒素（脂多糖，LPS）致大鼠炎症性肝损害的保护作用及其作用机制。方法 50只SD大鼠随机分为5组（每组各10只）：对照组：静脉滴注生理盐水2．4mL·kg^-1·h^-1；LPS组：静脉注射LPS6mg·kg^-1后，静脉滴注生理盐水2．4mL·kg^-1·h^-1；低、中和高剂量Epi组：静脉注射LPS6mg·kg^-1后，分别静脉滴注Epi0．12、0．3和0．6μg·kg^-1·min^-1。在LPS注射前、注射后2和6h3个时点取血，检测血清ALT、AST、TNF-α、IL-1β和IL-10水平，并在6h时点观察肝脏的组织病理学改变。结果 LPS组注射LPS后2、6h血清AST和ALT水平较对照组显著升高。同时血清TNF-α、IL-1β和IL-10水平亦较对照组显著升高（P〈0．05）。病理检查结果示：LPS组肝窦扩张、充血，局灶性肝细胞坏死。高剂量Epi可显著降低血清AST和ALT水平，减轻肝脏病理损伤，并显著可降低TNF-α水平和升高IL-10水平（1）8LPS组，P均〈0．05），但对IL-1β水平无影响。中、低剂量Epi对LPS致炎症性肝损害无明显保护作用。结论 Epi可通过抗炎作用减轻LPS诱导的炎症性肝损害。     

Effect of Cyclosporin A on the in Situ Inflammatory Response of Rat Renal Allograft Rejection

The impact of cyclosporin A (CyA) on a normal kidney parenchyma and on the in situ inflammatory response of rejection was investigated in normal DA rats and after transplantation of DA renal allografts to Lewis recipients. In a normal, non-transplanted DA kidney more than 80 mg/kg/day of CyA induced light-microscopic changes in the distal tubular cells of the renal cortex and outer medulla. These changes were not accompanied by any visible inflammation and were directly proportional to the dose of the drug and to the duration of drug administration. Treatment of a transplant recipient with 40 mg/kg/day of CyA abolished or at least efficiently reduced the in situ inflammatory response of rejection both as analysed from tissue sections and as quantified from the recovery of inflammatory cells after enzymatic digestion. It also reduced efficiently not only the number of T and B blast cells of the inflammatory infiltrate but also the number of other inflammatory cells, such as in situ lymphocytes, monocytes, and macrophages, and abolished or at least reduced the generation of (T) killer cells in situ and in the recipient spleen. These effects were inversely proportional to the time elapsed between grafting and initiation of treatment: although a complete suppression of all three features was obtained if the drug treatment was initiated already on the day of transplantation, a significant reduction of these functions was still found if the treatment was initiated later when the blastogenic response was already underway.     

Effect of Cyclosporin A on the in Situ Inflammatory Response of Human Renal Allograft Rejection

Twenty cadaveric kidney allograft recipients were prerandomized into two groups. Ten patients (control group) were treated postoperatively with azathioprine (AZA) plus methylprednisolone (MP); the other ten received cyclosporin A (CyA) as the only immunosuppressive agent. Both groups received MP during rejection. One patient was excluded from the CyA group because of an early postoperative cardiac infarction and death. All transplants were monitored by alternate-day fine-needle aspiration biopsy and transplant aspiration cytology. Some patients treated with CyA had a significant initial decrease in urine output, reaching control values approximately 1 week postoperatively. The mechanism behind this deteriorated renal function is not clear, but it seemed to have been caused by injuries to the kidney tubular component, since a distinct monocytic-lymphocytic inflammation and severe cytological changes resembling pronounced acute tubular necrosis were observed concomitantly in transplant aspiration cytology. The CyA-treated patients had normal levels of blood leucocytes, thrombocytes and lymphocytes but displayed a strong early blood eosinophilia that was absent in the control subjects. During the first 30 days after transplantation 15 in situ episodes of inflammation were recorded in the nine transplants treated with CyA, whereas only 6 episodes were found in the 10 transplants receiving AZA + MP (P<0.01). The first inflammatory episode in the CyA-treated transplants peaked between days 5 and 8 after transplantation and was followed by another distinct inflammatory episode between days 23 and 26. In the AZA- plus MP-treated transplants, only one inflammation episode was observed, with a peak on day 14 postoperatively. The inflammatory cell types most prominently present in the CyA-treated transplants were lymphocytes, B plasmablasts and monocytes. The early inflammatory episodes in the CyA-treated transplants may have been related to the fact that during the initial intramuscular administration, therapeutic CyA concentrations in patient serum were not achieved until the fourth postoperative day during peroral administration. The onset of transplant function had no impact on the in situ inflammatory response of rejection in the CyA-treated transplants or on the concentration of CyA in patient serum. This indicates that CyA may also be used in initially non functioning transplants. Confirming our earlier results, we were unable to demonstrate the major histocompatibility complex (MHC) antigens on the healthy grafts treated with AZA plus MP. However, in healthy allografts treated with CyA, both classes of MHC antigens were nearly invariably demonstrable on the graft endothelial cell surface. Approximately 60% allograft survivals were recorded in both groups at 6 months, and all patients with functioning grafts were able to work.     

The Effects of Intestinal LPS Exposure on Inflammatory Responses in a Porcine Enterohepatic Co-culture System

A porcine enterohepatic co-culture system, with primary hepatocytes as bottom layer and IPEC-J2 epithelial cells as upper layer, was developed to study the effects of lipopolysaccharides (LPS) on the gene expression profile of pro-inflammatory cytokines (interleukin-8 (IL-8) and tumor necrosis factor-α) and CYP enzymes (CYP1A1, CYP1A2, CYP3A29). The barrier integrity of IPEC-J2 cells was investigated by transepithelial electrical resistance measurements and by fluorescein isothiocyanate–dextran-based test. Basolateral IL-8 production was significantly elevated in LPS-treated IPEC-J2 and primary hepatocyte mono-cultures as well as in the co-culture system, in a dose-independent manner. The LPS-induced changes in the expression of the CYP1A2 and CYP3A29 genes in hepatocyte mono-cultures differed from those in co-culture after LPS treatment on the apical side of the IPEC-J2 cell layer. CYP1A2 was downregulated by the LPS treatment in mono-cultures but upregulated at 10 μg/ml LPS in co-culture; gene expression of CYP3A29 showed no significant LPS-induced change in the hepatocyte mono-culture but was significantly downregulated in co-culture. The newly established co-culture system capable of mimicking enterohepatic interplay in LPS-induced inflammatory responses in vitro can be used in the future for reliable screening of potential anti-inflammatory compounds.     

白藜芦醇通过影响炎症因子保护LPS刺激后HUVEC细胞

摘要目的：观察白藜芦醇对脂多糖（LPS）刺激人脐静脉血管内皮细胞（HUVEc）后细胞活力及释放炎症因子的影响。方法：体外培养HUVEC,LPS0．1μg·ml^-1刺激,并以不同浓度白藜芦醇干预,采用CCK-8法检测细胞活性,ELISA法检测培养上清液中炎症因子IL-6和PGE2含量。结果：与模型组比较,白藜芦醇5μmol·L^-1以上可提高LPS刺激后HUVEC细胞活力,抑制炎症因子IL-6和PGE2释放（P〈0．05）,并呈一定的量效关系。结论：白藜芦醇对LPS刺激HUVEC细胞有保护作用,此作用可能与抑制炎症因子释放有关。     

小剂量氢化考的松对LPS攻击大鼠肝脏的保护作用

目的： 探讨不同剂量氢化考的松对于LPS攻击大鼠肝脏的作用。方法：建立大鼠LPS攻击模型，并给予不同剂量的激素，取血检测血浆ALT和AST，并观察肝脏HE染色的形态学改变。结果：LPS组血ALT、AST水平明显高于正常组。各干预组ALT水平低于LPS组，但高剂量HD组与LPS组间并无显著差异，低剂量LD组与正常对照组间差异无显著。AST水平的改变是：HD组与LPS组间无显著差异，HD组与正常对照组差异显著，LD组与正常对照组差异显著。形态学上HD组与LPS组相似，肝脏明显淤血，肝细胞变性明显，且有较多的炎性细胞浸润；LD组肝脏淤血明显轻于LPS组，炎性细胞浸润及肝细胞变性也较轻。结论：小剂量的氢化考的松对于LPS攻击大鼠的肝脏具有保护作用，中剂量和高剂量的氢化考的松对肝脏无明显的保护作用。     

Priming Effect of Fibronectin Fragments on the Macrophage Inflammatory Response: Potential Contribution to Periodontitis

Fibronectin, an extracellular matrix component, is a substrate for multiple host and bacterial proteinases found in inflamed periodontal sites. In the present study, we investigated the potential contribution of various fibronectin fragments to the inflammatory process of periodontitis. Our results showed that the smaller fragments of fibronectin (30 and 45?kDa) were the most potent inflammatory inducers as they dose-dependently increased the secretion of TNF-α, IL-1β, and IL-8 by human macrophages. The 120-kDa fragment did not induce the secretion of all the cytokines tested, while intact fibronectin only increased IL-8 secretion and to a lesser extent TNF-α secretion. Cytokine secretion was associated with increased amounts of phosphorylated ERK1/2, JNK2, and p38α MAPK in treated macrophages. The combination of fibronectin or fibronectin fragments with Porphyromonas gingivalis lipopolysaccharide had an additive effect, but no synergism appeared to occur. It was also demonstrated that gingival crevicular fluid samples recovered from patients with moderate to severe periodontitis contained more fibronectin fragments than samples obtained from healthy subjects. Finally, both Arg- and Lys-gingipains purified from P. gingivalis were found to modulate fibronectin fragmentation. In conclusion, we showed that specific fibronectin fragments that may be present in diseased periodontal sites may contribute to maintaining and amplifying the inflammatory state and that P. gingivalis gingipains may be involved in the production of these fragments.     

Protective properties afforded by pioglitazone against intrastriatal LPS in Sprague-Dawley rats

We created an inflammation-induced Parkinson's disease model, where microglia activation leads to oxidative stress, mitochondrial dysfunction, and dopaminergic neurodegeneration in the substantia nigra. Pioglitazone, an agonist of peroxisome proliferator activated receptor-gamma (PPAR-gamma), can prevent these deficits and protect dopaminergic neurons. To continue exploring the effects of pioglitazone in this model we focused on the expression of PPAR-gamma, uncoupling protein 2 (UCP2), and mitoNEET. We report that intrastriatal lipopolysaccharide (LPS) increases striatal PPAR-gamma, UCP2, and mitoNEET expression, and pioglitazone attenuates these LPS-induced changes.     

Kaempferol Protects Ischemia/Reperfusion-Induced Cardiac Damage Through the Regulation of Endoplasmic Reticulum Stress

This study examined whether or not the ER stress and Bcl-2 proteins are linked to the protective effect of kaempferol, a phytoestrogen, on ischemia-reperfusion (I/R)-induced cardiac damage. In order to determine if kaempferol modifies the I/R-induced response in H9c2 cardiac muscle cells, the cells were exposed to kaempferol followed by ischemia 12h/reperfusion 4h. kaempferol had a protective effect on the apoptosis induced by I/R in the cardiac muscle cells. The Kaempferol treatment significantly increased the expression level of the anti-apoptotic protein, Bcl-2, but decreased the level of the pro-apoptotic protein, bax. Kaempferol down-regulated the expressions of the endoplasmic reticulum (ER) stress proteins, GRP78, ATF-6alpha, XBP-2, IRE1-alpha, phosphor-eIF-2alpha and CHOP. In ex vivo-Langendorff experiment, the kaempferol treatment regulated the expression of ER stress proteins-CHOP and GRP78. The kaempferol also improved the post-ischemic LVEDP and LVDP significantly after 20, 30, 40 and 50 min of reperfusion compared with the untreated control hearts, which shows that kaempferol offers protection against I/R-associated cardiac dysfunction.     

Protective Effects of Radon Inhalation on Carrageenan-Induced Inflammatory Paw Edema in Mice

We assessed whether radon inhalation inhibited carrageenan-induced inflammation in mice. Carrageenan (1% v/v) was injected subcutaneously into paws of mice that had or had not inhaled approximately 2,000 Bq/m³ of radon for 24 h. Radon inhalation significantly increased superoxide dismutase (SOD) and catalase activities and significantly decreased lipid peroxide levels in mouse paws, indicating that radon inhalation activates antioxidative functions. Carrageenan administration induced paw edema and significantly increased tumor necrosis factor-alpha (TNF-α) and nitric oxide in serum. However, radon inhalation significantly reduced carrageenan-induced paw edema. Serum TNF-α levels were lower in the radon-treated mice than in sham-treated mice. In addition, SOD and catalase activities in paws were significantly higher in the radon-treated mice than in the sham-treated mice. These findings indicated that radon inhalation had anti-inflammatory effects and inhibited carrageenan-induced inflammatory paw edema.