槲皮素对非细菌性前列腺炎治疗作用的实验研究

目的：观察槲皮素对实验性非细菌性前列腺炎的治疗效果。方法：采用五种模型、包括消痔灵诱导的大鼠慢性前列腺炎模型、角叉菜胶诱导的急性前列腺炎模型、巴豆油致耳肿胀模型、光刺激致痛模型、棉球肉芽肿模型及体外测定离体家兔尿道平滑肌张力试验,观察槲皮素的作用。结果：槲皮素对大鼠急慢性非细菌性前列腺炎具有良好的抗炎作用,对耳肿胀试验、肉芽肿试验及光刺激致痛试验具有良好的抑制作用,并对离体的尿道平滑肌具有较好的舒张作用。结论：槲皮素对实验性非细菌性前列腺炎具有良好的抑制作用,并对尿道平滑肌具有一定舒张作用,提示槲皮素具有良好的临床治疗非细菌性前列腺炎作用,并能缓解排尿困难症状。     

Adiponectin: a key fat-derived molecule regulating inflammation

Adiponectin is the abundant adipocyte-derived protein with well-established anti-atherogenic and insulin-sensitising properties. Besides these well characterised biological functions, recent evidence supports a strong anti-inflammatory function. Whereas initial studies demonstrated that adiponectin suppresses the production of the potent pro-inflammatory cytokine TNF-alpha, current studies showed that this adipokine also induces various anti-inflammatory cytokines, such as IL-10 or -1 receptor antagonists. These effects are paralleled by various other immune-regulatory properties, such as specific effects on endothelial cell functions. These in vitro effects are directly translated into various animal models of inflammation, demonstrating a potent anti-inflammatory effect for adiponectin. Thiazolidinediones selectively upregulate peroxisome-proliferator-activated receptor-gamma, leading to increased tissue and serum concentrations of adiponectin. Adiponectin has emerged as a key mediator regulating and affecting the balance between fat and inflammation. Therefore, either adiponectin itself or its inducing agents, such as thiazolidinediones, might be of key therapeutic interest in the near future far beyond diseases being associated with insulin resistance.     

Acrolein oxidizes the cytosolic and mitochondrial thioredoxins in human endothelial cells

Acrolein is a reactive aldehyde that is a widespread environmental pollutant and can be generated endogenously from lipid peroxidation. The thioredoxin (Trx) system in endothelial cells plays a major role in the maintenance of cellular thiol redox balance, and is critical for cell survival. Normally, cells maintain the cytosolic (Trx1) and mitochondrial (Trx2) thioredoxins largely in the reduced state. In human microvascular endothelial cells, Trx1 was more sensitive than Trx2 to oxidation by acrolein. A 30-min exposure to 2.5 microM acrolein caused partial oxidation of Trx1 but not Trx2. The active site dithiol of Trx1 was essentially completely oxidized by 5 microM acrolein whereas 12.5 microM was required for complete oxidation of Trx2. Partial recovery of the Trx1 redox status was observed over a 4h acrolein-free recovery period, with increases in the reduced form and decreases in the fully oxidized form. For cells treated with 2.5 or 5 microM acrolein the recovery did not require protein synthesis, whereas protein synthesis was required for the return of reduced Trx1 in cells treated with 12.5 microM acrolein. Pretreatment of cells with N-acetylcysteine (NAC) resulted in partial protection of Trx1 from oxidation by acrolein. In cells treated with acrolein for 30 min, followed by a 14- to 16-h acrolein-free period, small but significant cytotoxic effects were observed with 2.5 microM acrolein whereas all cells were adversely affected by >or= 12.5 microM. NAC pretreatment significantly decreased the percentage of stressed cells subsequently exposed to 5 or 12.5 microM acrolein. Given the critical role of the thioredoxins in cell survival, the ability of acrolein to oxidize both thioredoxins should be taken into account for a thorough understanding of its cytotoxic effects.     

Hexavalent chromium causes the oxidation of thioredoxin in human bronchial epithelial cells

Hexavalent chromium [Cr(VI)] species such as chromates are cytotoxic. Inhalational exposure is a primary concern in many Cr-related industries and their immediate environments, and bronchial epithelial cells are directly exposed to inhaled Cr(VI). Chromates are readily taken up by cells and are reduced to reactive Cr species which may also result in the generation of reactive oxygen species (ROS). The thioredoxin (Trx) system has a key role in the maintenance of cellular thiol redox balance and is essential for cell survival. Cells normally maintain the cytosolic (Trx1) and mitochondrial (Trx2) thioredoxins largely in the reduced state. Redox Western blots were used to assess the redox status of the thioredoxins in normal human bronchial epithelial cells (BEAS-2B) incubated with soluble Na2CrO4 or insoluble ZnCrO4 for different periods of time. Both chromates caused a dose- and time-dependent oxidation of Trx2 and Trx1. Trx2 was more susceptible in that it could all be converted to the oxidized form, whereas a small amount of reduced Trx1 remained even after prolonged treatment with higher Cr concentrations. Only one of the dithiols, presumably the active site, of Trx1 was oxidized by Cr(VI). Cr(VI) did not cause significant GSH depletion or oxidation indicating that Trx oxidation does not result from a general oxidation of cellular thiols. With purified Trx and thioredoxin reductase (TrxR) in vitro, Cr(VI) also resulted in Trx oxidation. It was determined that purified TrxR has pronounced Cr(VI) reducing activity, so competition for electron flow from TrxR might impair its ability to reduce Trx. The in vitro data also suggested some direct redox interaction between Cr(VI) and Trx. The ability of Cr(VI) to cause Trx oxidation in cells could contribute to its cytotoxic effects, and could have important implications for cell survival, redox-sensitive cell signaling, and the cells' tolerance of other oxidant insults.     

Animal models for the study of atypical anti-inflammatory agents

In contrast to the approach focusing on aspirin and cortisone as models for research, a physiopathologically-oriented approach provides the rationale for developing animal models suitable for detecting anti-inflammatory agents with a profile of therapeutic and side effects unlike that of currently used drugs. The so-called 'primary' anti-inflammatory agents have a marked efficacy in animal models of acute inflammation and lack significant anti-PG effects. Clinically, they relieve the symptoms of acute inflammatory conditions, both topically and systemically, are practically inactive in rheumatic disorders and have a profile of side-effects different from that of aspirin or cortisone. Available data suggest that their characteristic profile of side and therapeutic effects reflect qualitative, rather than quantitative differences, from aspirin and cortisone. The so-called 'secondary' anti-inflammatory agents affect the conditioning factors for some inflammatory diseases, including rheumatoid arthritis, rather than the inflammatory process itself. Besides the derangement of the immune system and the consequent development of immunomodulators, the role of specific protein changes as a conditioning factor is discussed and animal models are illustrated focusing on this phenomenon. The possibility is also discussed that protein denaturation is not only responsible for the formation of new antigenic determinants, but also for necrotic lesions accompanying some inflammatory disorders. Results obtained with animal models of conditioned inflammation with marked necrotic lesions are presented. The interest for this approach is that conditioning factors for inflammation appear a more specific target for drug treatment, rather than inflammation itself.     

Anti-inflammatory activity of Bambusae Caulis in Taeniam through heme oxygenase-1 expression via Nrf-2 and p38 MAPK signaling in macrophages

Recently, it has been reported that several natural extracts have anti-inflammatory effects through HO-1 induction. In this study, we used the ethyl acetate fraction of Bambusae Caulis in Taeniam (BCE) to investigate its anti-inflammatory effect on macrophages stimulated with LPS from Porphyromonas gingivalis. BCE inhibited the production of pro-inflammatory cytokines in P. gingivalis LPS-stimulated RAW264.7 cells. BCE also suppressed the nuclear translocation of NF-κB and AP-1. A selective inhibitor of HO-1 attenuated BCE's inhibitory effects on the production of pro-inflammatory cytokines. BCE also dose-dependently increased HO-1 expression at both the mRNA and the protein levels. BCE increased nuclear translocation of Nrf-2. Finally, a specific inhibitor of p38 reduced BCE-induced HO-1 expression and BCE-induced phosphorylation of p38 MAPK. BCE induced anti-inflammatory effects by activating Nrf-2-mediated HO-1 induction via p38 signaling in P. gingivalis LPS-stimulated macrophages. This result indicates that BCE is a promising therapeutic agent for combating periodontitis.     

Anti-thrombotic effect of activated protein C

Protein C (PC) is an important anticoagulant protein in blood and converted to its active form, activated protein C (APC), by thrombin bound with thrombomodulin. APC exhibits an anticoagulant effect by the inactivation of FV a and FVIII a. In addition, APC exerts a profibrinolytic effect by inactivation of PAI-1 and inhibition of TAFI activation. APC is strongly anti-thrombotic because of its anticoagulant and profibrinolytic effect. APC has gamma-carboxyglutamic acid residues that bind to acidic phospholipids expressed on activated platelet or injured endothelial cells. Thus APC works only at the site where clots are formed and has a weak effect in primary hemostasis; this means that the use of APC is expected not to have any hemorrhagic risk. In both DIC animal models and clinical studies, we confirmed safer amelioration by APC than heparin. Recently, a specific receptor for PC/APC was found on endothelial cell membrane and anti-inflammatory effects of APC were also reported. Thus APC is thought to play an important regulatory role in blood coagulation, fibrinolysis and inflammation, especially in thrombotic diseases.     

Protective Role of Transduced Tat-Thioredoxin1 (Trx1) against Oxidative Stress-Induced Neuronal Cell Death via ASK1-MAPK Signal Pathway

Oxidative stress plays a crucial role in the development of neuronal disorders including brain ischemic injury. Thioredoxin 1 (Trx1), a 12 kDa oxidoreductase, has anti-oxidant and anti-apoptotic functions in various cells. It has been highly implicated in brain ischemic injury. However, the protective mechanism of Trx1 against hippocampal neuronal cell death is not identified yet. Using a cell permeable Tat-Trx1 protein, protective mechanism of Trx1 against hydrogen peroxide-induced cell death was examined using HT-22 cells and an ischemic animal model. Transduced Tat-Trx1 markedly inhibited intracellular ROS levels, DNA fragmentation, and cell death in H₂O₂-treatment HT-22 cells. Tat-Trx1 also significantly inhibited phosphorylation of ASK1 and MAPKs in signaling pathways of HT-22 cells. In addition, Tat-Trx1 regulated expression levels of Akt, NF-κB, and apoptosis related proteins. In an ischemia animal model, Tat-Trx1 markedly protected hippocampal neuronal cell death and reduced astrocytes and microglia activation. These findings indicate that transduced Tat-Trx1 might be a potential therapeutic agent for treating ischemic injury.     

Immunomodulatory role of thymulin in lung diseases

Importance of the field: Inflammation is a hallmark of lung diseases. The available treatment options are unsatisfactory because they are not efficacious or induce major side effects. Alternative approaches need to be developed. Thymulin is a peptide exclusively produced in the thymus with several anti-inflammatory properties.

Areas covered in this review: The physiological features of thymulin and data that support its potential as an anti-inflammatory treatment for lung diseases are reviewed.

What the reader will gain: Thymulin has consistent beneficial effects in experimental models of lung diseases. It has a broad inhibitory effect on pro-inflammatory cytokines, suppresses p38 (a MAPK family member) and inhibits the activation of the NF-κB signal pathway. It is an attractive peptide for lung gene therapy because has no toxicity even at high doses and when expressed by adenoviral vectors reduces immune response against viral proteins.

Take home message: Thymulin has a selective immunomodulatory effect, enhancing anti-inflammatory and inhibiting pro-inflammatory cytokines. It suppresses p38 (implicated in glucocorticoid-resistance) and inhibits NF-κB activation, which has an important pathogenic role in several lung diseases. The broad spectrum of anti-inflammatory effects of this peptide in several animal models of lung disease makes thymulin a good candidate for future clinical trials.     

Mitochondrial thioredoxin-2 has a key role in determining tumor necrosis factor-alpha-induced reactive oxygen species generation, NF-kappaB activation, and apoptosis.

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that is involved in numerous pathologies, in part through stimulation of the mitochondrial production of reactive oxygen species (ROS). Previous studies show that in addition to mitochondrial superoxide dismutase- and glutathione-dependent systems, mitochondria also contain thioredoxin-2 (Trx2), an antioxidant protein that can detoxify ROS. The purpose of this study was to determine whether Trx2 protects against oxidative damage triggered by TNF-alpha. After a 30-min treatment in HeLa cells, TNF-alpha (5-40 ng/ml) oxidized Trx2 but not cytoplasmic Trx1. Preferential, significant Trx2 oxidation occurred within 10 min of TNF-alpha treatment. Moreover, overexpression of Trx2, but not Trx1, decreased TNF-alpha-induced ROS generation, suggesting mitochondrial compartmentation of ROS production and subsequent specific detoxification by Trx2, not Trx1. Overexpression of Trx2 or the active-site mutant C93S Trx2 was used to evaluate their downstream effects following TNF-alpha stimulation. Results showed that nuclear translocation of NF-kappaB was inhibited with Trx2 overexpression but not with the dominant negative active-site mutant C93S Trx2. Moreover, when cotransfected with a NF-kappaB-luciferase reporter and then treated with TNF-alpha, NF-kappaB activity was significantly attenuated with Trx2 overexpression but not with C93S Trx2 expression. Trx2 overexpression, but not C93S Trx2, significantly inhibited TNF-alpha-induced apoptosis as measured by terminal dUTP nick-end labeling assay. These findings support the interpretation that mitochondrial-generated ROS is a principal component in TNF-alpha-induced effects and that Trx2 blocks TNF-alpha-induced ROS generation and downstream NF-kappaB activation and apoptosis.     

Some aspects of the inhibitory activity of hypolaetin-8-glucoside in acute inflammation

Hypolaetin-8-glucoside (H-8-G) has been examined for its mode of action in several models of acute inflammation. Its anti-inflammatory activity in carrageenan-induced inflammation of the rat hind-paw is not affected either by adrenalectomy or by phentolamine given with propranolol. H-8-G and its aglycone, hypolaetin, did not antagonize the actions of histamine, 5-hydroxytryptamine (5-HT), bradykinin or prostaglandin E2 (PGE2) on various smooth muscle preparations in-vitro, but protected erythrocytes from heat-induced lysis. The glycoside was more potent than troxerutin on capillary permeability increased by histamine and exerted inhibitory effects on protein exudation, leucocyte migration and beta-glucuronidase activity in the carrageenan air pouch, thereby showing some difference from indomethacin. These results are discussed in relation to the features of non-steroidal anti-inflammatory drugs (NSAID) and flavonoid anti-inflammatory actions.     

A novel synthetic derivative of squamosamide FLZ inhibits the high mobility group box 1 protein-mediated neuroinflammatory responses in murine BV2 microglial cells

High mobility group box 1 (HMGB1) is a critical pro-inflammatory cytokine that contributes to the pathogenesis of various human diseases. FLZ, a squamosamide derivative, has been demonstrated to have neuroprotective effects in Parkinson’s disease models and shows strong anti-inflammatory activity, while the precise mechanism remains unclear. Here, we investigated the anti-inflammatory mechanism of FLZ on HMGB1-mediated inflammatory responses. The effects of FLZ on HMGB1 release from microglial cells induced by lipopolysaccharide were first explored by Western blot assay and ELISA. Then, co-immunoprecipition was used to study FLZ’s effect on the interaction between HMGB1 and its receptor TLR4. Finally, we employed HMGB1 to simulate pro-inflammatory responses and then studied the inhibitory effects of FLZ on its bioactivity. FLZ has a significant inhibitory effect on HMGB1 release while it exerts no inhibitory effect on the binding between HMGB1 and TLR4. After the recognition of HMGB1 by TLR4, NF-κB signaling pathway is activated. FLZ could efficaciously alleviate HMGB1-induced inflammatory responses via the suppression of TLR4/MyD88/NF-κB signaling pathway. FLZ could inhibit HMGB1 release as well as HMGB1-induced inflammatory responses, HMGB1 might be one of the FLZ anti-inflammatory targets, and interfering at this inflammatory mediator may have benefit effects on neurodegenerative disorders, such as Parkinson’s disease.

     

Cannabinoids and neuroinflammation

Growing evidence suggests that a major physiological function of the cannabinoid signaling system is to modulate neuroinflammation. This review discusses the anti-inflammatory properties of cannabinoid compounds at molecular, cellular and whole animal levels, first by examining the evidence for anti-inflammatory effects of cannabinoids obtained using in vivo animal models of clinical neuroinflammatory conditions, specifically rodent models of multiple sclerosis, and second by describing the endogenous cannabinoid (endocannabinoid) system components in immune cells. Our aim is to identify immune functions modulated by cannabinoids that could account for their anti-inflammatory effects in these animal models.     

Effects of alminoprofen on the allergic reactions

The effects of alminoprofen, a nonsteroidal anti-inflammatory agent, on the experimental animal models of allergic reactions were examined and compared with those of ibuprofen. Alminoprofen at 30 mg/kg given intraduodenally significantly suppressed passive anaphylactic bronchoconstrictions, while ibuprofen did not at the same doses. In vitro studies revealed that alminoprofen, in contrast to ibuprofen, exerted an inhibitory effect on arachidonate 5-lipoxygenase activity which initiates the bio-synthesis of leukotrienes. Alminoprofen inhibited arachidonic acid-induced ear edema in mice and homologous passive cutaneous anaphylaxis in rats at high doses, while ibuprofen did not at the high doses. From its characteristic feature of inhibitory effects on 5-lipoxygenase activity and the experimental model of type I allergic reaction, it is suggested that alminoprofen is a new type of nonsteroidal anti-inflammatory agent.     

显臣粉刺净酊抗炎作用的研究

目的　观察显臣粉刺净酊的抗炎作用。方法　应用二甲苯致鼠耳肿胀和角叉菜胶致大鼠足爪肿胀炎症模型。结果　0 .3、0 .5 ml显臣粉刺净酊对鼠耳肿胀度的抑制率显著高于对照组 (P<0 .0 1) ,0 .9、1.5 m l显臣粉刺净酊可明显提高大鼠足肿胀度的抑制率 (P<0 .0 1)。结论　显臣粉刺净酊具有较好的抗炎作用 ,并呈现良好的量效关系     

Adenosine modulation: a novel approach to analgesia and inflammation

Adenosine (ADO) is an endogenous purine nucleoside that functions as an extracellular signalling molecule. It is released locally at sites of cellular trauma, and acts on specific cell-surface purinergic receptors (termed P1 receptors) near its site of release to exert its effects. Four subtypes of the P1 family of G-protein-coupled receptors have been identified and cloned: A1, A2A, A2B and A3. A considerable body of evidence, including experimental animal data and preliminary clinical reports, indicates that ADO is involved in modulating endogenous antinociceptive processes in the brain and spinal cord. ADO analogues provide analgesic activity after systemic or spinal administration in a broad spectrum of animal pain models. In addition, iv. ADO infusion has shown benefit in human pain states. The spinal cord is a key site for ADO-mediated modulation of nociception. ADO is well known to act as an inhibitory neuromodulator in the central and peripheral nervous system, and it may act to control N-methyl-D-aspartate (NMDA)- and substance P-mediated events in nociception and central sensitisation at the spinal level. ADO is also released at sites of inflammation and it exerts anti-inflammatory effects via multiple mechanisms involving several cell types. These include effects on neutrophil function, endothelial cell permeability, in vivo and in vitro release of tumour necrosis factor (TNF-alpha and collagenase expression in synoviocytes. Accordingly, ADO analogues are effective in several animal models of inflammation, including the rat adjuvant arthritis model. Several therapeutic approaches to pain and inflammation, based on mimicking or modulating the effects of endogenous ADO, are currently under preclinical and clinical investigation. These include the use of ADO itself, the use of direct-acting ADO receptor agonists and the use of agents designed to modulate the levels and, therefore, the actions of ADO in the extracellular space (ADO kinase (AK) inhibitors). Data emerging in the next several years should indicate whether these strategies represent a therapeutically useful new approach to analgesia and inflammation.     

The anti-inflammatory effects of sanguinarine and its modulation of inflammatory mediators from peritoneal macrophages

The quaternary ammonium salt, sanguinarine (SANG), is of great practical and research interest because of its pronounced, widespread physiological effects, which promote anti-microbial and anti-inflammatory responses in experimental animals. Sanguinarine was originally shown to possess anti-inflammatory properties and it has been used to treat various inflammatory diseases. To gain insight into the anti-inflammatory effect of sanguinarine and its mechanisms of action, we used animal models of acute and chronic inflammation and lipopolysaccharide (LPS)-induced murine peritoneal macrophages to examine the anti-inflammatory function of sanguinarine. Sanguinarine displayed significant anti-inflammatory effects both in vitro and in vivo. Our findings further demonstrated that sanguinarine potently inhibited the expression of inflammatory mediators and inflammation in general. Additionally, our results demonstrated that sanguinarine inhibited the activation of mitogen-activated protein kinase (MAPK), which altered inflammatory mediator synthesis and release in vitro. This study extends our understanding of the anti-inflammatory activity of sanguinarine in acute and chronic inflammation. Furthermore, our findings provide clarification of the molecular mechanisms underlying the anti-inflammatory activity of sanguinarine, supporting the naturopathic use of sanguinarine for the treatment of various human inflammatory diseases.     

Increased mitochondrial thioredoxin 2 potentiates N-ethylmaleimide-induced cytotoxicity

Thioredoxin 2 (Trx2) is a mitochondrially localized antioxidant and antiapoptotic protein, whose functions are mainly dependent on the conserved cysteines at its redox active center. In the current study, we showed by mass spectrometry that a thiol alkylating agent, N-ethylmaleimide (NEM), alkylated a single cysteine residue in the active center of Trx2. The interaction between NEM and Trx2 in intact cells was confirmed by redox Western analysis. Overexpression of Trx2 in cultured 143B osteosarcoma cells caused increased sensitivity to NEM. Covalent modification by NEM resulted in a dominant-negative effect and increased the interaction between Trx2 and peroxiredoxin 3 (Prx3). Our data suggest that the alkylation of the essential thiol(s) of Trx2 has profound impact on the mitochondrial redox circuitry and that such effects are distinct from the responses to agents causing reversible disulfide bond formation between the vicinal dithiols in the active center.     

硫氧还蛋白的生物学及其与阿尔茨海默病和帕金森病的关系

硫氧还蛋白(thioredoxin，Trx)是一种具有氧化还原活性的小分子蛋白质，具有抗氧化、抗凋亡、调节转录因子活性等功能，在氧化还原调节和细胞信号转导中发挥重要作用。本文对哺乳动物的Trx及其与阿尔茨海默病(AD)和帕金森病(PD)的关系的研究进展进行综述。基于Trx的神经保护活性，增加Trx的表达可望成为AD和PD防治的新靶点。