Therapeutic potency of crocin in the treatment of inflammatory diseases: Current status and perspective

Crocin is the major component of saffron, which is used in phytomedicine for the treatment of several diseases including diabetes, fatty liver, depression, menstruation disorders, and, of special interest in this review, inflammatory diseases. Promising selective anti-inflammatory properties of this pharmacological active component have been observed in several studies. Saffron has been shown to exert anti-inflammatory properties against several inflammatory diseases and can be used as a novel therapeutic agent for the treatment of inflammatory diseases either alone or in combination with other standard anti-inflammatory agents. This review summarizes the protective role of saffron and its pharmacologically active constituents in the pathogenesis of inflammatory diseases including digestive diseases, dermatitis, asthma, atherosclerosis, and neurodegenerative diseases for a better understanding and hence a better management of these diseases.     

α7烟碱型乙酰胆碱受体在胆碱能抗炎通路中的作用机制及应用现状

胆碱能抗炎通路是一条神经-免疫调节通路,以中枢神经系统的迷走神经为起点,以神经递质乙酰胆碱为基础,以免疫细胞膜表面的α7烟碱型乙酰胆碱受体(α7 nicotinic acetylcholine receptor, α7 nAChR)为关键作用位点。其中,电信号与化学信号相互转化,激活JAK-STAT3、PI3K-Akt等信号通路,抑制NF-κB的核转位,进而抑制促炎因子的释放,促进抑炎因子的释放,调节和控制机体的炎症,具体的作用机制正在研究中。研究表明,可以通过使用药物激活α7 nAChR和电刺激迷走神经这2种方法,激活胆碱能抗炎通路。其中,激活α7 nAChR具有操作简便、创伤小和效果显著等优势。常用药物有选择性激动剂,例如PNU282987和GTS-21等,非选择性激动剂例如烟碱。多项研究显示,该方法在脓毒症、缺血再灌注、胃肠炎、骨关节炎和自身免疫病等外周器官炎性疾病治疗中都具有一定的效果。α7 nAChR作为胆碱能抗炎通路的关键作用位点,成为许多炎性疾病的潜在治疗靶点,本文对胆碱能抗炎通路中的α7 nAChR所涉及的抗炎机制、通路激活方式,以及其近年来在炎性疾病中的应用进行了综述,为未来研究其具体作用机制和新的治疗靶点提供参考。     

Dominance of the strongest: Inflammatory cytokines versus glucocorticoids

Pro-inflammatory cytokines are involved in the pathogenesis of many inflammatory diseases, and the excessive expression of many of them is normally counteracted by glucocorticoids (GCs), which are steroids that bind to the glucocorticoid receptor (GR). Hence, GCs are potent inhibitors of inflammation, and they are widely used to treat inflammatory diseases, such as asthma, rheumatoid arthritis and inflammatory bowel disease. However, despite the success of GC therapy, many patients show some degree of GC unresponsiveness, called GC resistance (GCR). This is a serious problem because it limits the full therapeutic exploitation of the anti-inflammatory power of GCs. Patients with reduced GC responses often have higher cytokine levels, and there is a complex interplay between GCs and cytokines: GCs downregulate pro-inflammatory cytokines while cytokines limit GC action. Treatment of inflammatory diseases with GCs is successful when GCs dominate. But when cytokines overrule the anti-inflammatory actions of GCs, patients become GC insensitive. New insights into the molecular mechanisms of GR-mediated actions and GCR are needed for the design of more effective GC-based therapies.     

Emerging roles of DP and CRTH2 in allergic inflammation

The lipid mediator prostaglandin D(2) (PGD(2)) has long been implicated in various inflammatory diseases including asthma. PGD(2) elicits biological responses by activating two seven-transmembrane (7TM) G-protein-coupled receptors, the D-prostanoid receptor DP and the chemoattractant receptor homologous-molecule expressed on T-helper-type-2 cells (CRTH2), which are linked to different signaling pathways. Understanding how immune cells integrate and coordinate signals that are triggered by the same ligand is crucial for the development of novel anti-inflammatory therapies. Here, we examine the roles of DP and CRTH2 in the orchestration of complex inflammatory processes, and discuss their importance as emerging targets for the treatment of asthma and inflammatory diseases.     

Inhibitory effect of esculentoside A on tumour necrosis factor alpha production by human monocytes

Esculentoside A (EsA) is a saponin isolated from the roots of Phytolacca esculenta. Previous experiments have shown that it has strong anti-inflammatory effects. Tumour necrosis factor (TNF) is a very important inflammatory mediator. It is known that there are two types of TNF-TNFalpha is from macrophages/monocytes and TNFbeta is from activated lymphocytes. In order to study the mechanism of the anti-inflammatory effect of EsA, it was determined whether TNFalpha production from human peripheral monocytes was altered by EsA under lipopolysaccharide (LPS)-stimulated conditions. EsA was found to decrease TNFalpha production in a dose-dependent manner at concentrations higher than 1 mumol/l EsA. Recent studies have shown that EsA has a curative effect on chocolate cyst and other inflammatory diseases. Our previous studies have shown that EsA could reduce the release of platelet activating factor (PAF) from rat macrophages, and inhibit interleukin-1 and interleukin-6 production from routine macrophages. The reducing effects of EsA on the release of TNFalpha, IL-1, IL-6 and PAF may explain its anti-inflammatory effect.     

Curcumin as a natural regulator of monocyte chemoattractant protein-1

Monocyte chemoattractant/chemotactic protein-1 (MCP-1), a member of the CC chemokine family, is one of the key chemokines that regulate migration and tissue infiltration of monocytes/macrophages. Its role in the pathophysiology of several inflammatory diseases has been widely recognized, thus making MCP-1 a possible target for anti-inflammatory treatments. Curcumin (diferuloylmethane) is a natural polyphenol derived from the rhizomes of Curcuma Longa L. (turmeric). Anti-inflammatory action underlies numerous pharmacological effects of curcumin in the control and prevention of several diseases. The purpose of this review is to evaluate the effects of curcumin on the regulation of MCP-1 as a key mediator of chemotaxis and inflammation, and the biological consequences thereof. In vitro studies have shown that curcumin can decrease MCP-1 production in various cell lines. Animal studies have also revealed that curcumin can attenuate MCP-1 expression and improve a range of inflammatory diseases through multiple molecular targets and mechanisms of action. There is limited data from human clinical trials showing the decreasing effect of curcumin on MCP-1 concentrations and improvement of the course of inflammatory diseases. Most of the in vitro and animal studies confirm that curcumin exert its MCP-1-lowering and anti-inflammatory effects by down-regulating the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathway. As yet, there is limited data from human clinical trials showing the effect of curcumin on MCP-1 levels and improvement of the course of inflammatory diseases. More evidence, especially from human studies, is needed to better assess the effects of curcumin on circulating MCP-1 in different human diseases and the role of this modulatory effect in the putative anti-inflammatory properties of curcumin.     

模式识别受体介导炎症信号通路及人参属植物皂苷抗炎研究进展

炎症是一种非常常见而又十分重要的基本病理过程,临床表现为红、肿、痛,其伴随着疾病的发生而产生,同时又会加重疾病的发展,有些甚至会产生恶性肿瘤。在炎症分子机制的研究中,已发现多条重要的信号通路,其中模式识别受体介导的炎症信号通路在很多疾病中都扮演着重要的角色,基于这些重要的炎症信号通路中的关键分子筛选抗炎药物受到广泛关注。人参属植物是名贵的中药材,具有很高的药用价值。我国人参属植物主要包括:人参、三七、竹节参及其变种珠子参等。皂苷是人参属植物的主要活性成分之一,药理研究显示其具有良好的抗炎效果。本文就此将近年来模式识别受体介导的炎症信号通路及人参属植物皂苷抗炎的研究成果进行总结,为抗炎药物研究提供理论基础。     

Berberine as a promising natural compound for the treatment of periodontal disease: A focus on anti-inflammatory properties

Accumulating evidence during the last two decades has addressed the potential anti-inflammatory properties of berberine (BBR), a bioactive alkaloid compound isolated from Coptidis rhizoma, in controlling or treating several inflammatory diseases. Periodontitis is one of the most common chronic and serious inflammatory diseases, in which uncontrolled and unabated host immune responses against periodontopathic pathogens play critical and crucial roles in the disease pathogenesis. Hence, regulating inflammatory responses in periodontitis has a valuable approach and holds promise in treating periodontitis. For the first time, this paper reviews the evidence from in vitro and in vivo experimental models to explore the anti-inflammatory effects of BBR in periodontitis and exhibits that BBR has the high potency to exert anti-inflammatory effects by reducing expression and secretion of pro-inflammatory mediators including TNF-α, IL-1β, IL-17, RANKL, MMP-2, MMP-9 and MCP-1. The BBR-mediated anti-inflammatory actions could translate into the inhibition of the periodontal tissues and alveolar bone destruction and the control of the disease in vivo. As the second aim of this paper, we also paid attention to the therapeutic potential of BBR in treating human diseases regarding its anti-inflammatory properties.     

6-Gingerol inhibits ROS and iNOS through the suppression of PKC-α and NF-κB pathways in lipopolysaccharide-stimulated mouse macrophages

Inflammation is involved in numerous diseases, including chronic inflammatory diseases and the development of cancer. Many plants possess a variety of biological activities, including antifungal, antibacterial and anti-inflammatory activities. However, our understanding of the anti-inflammatory effects of 6-gingerol is very limited. We used lipopolysaccharide (LPS)-stimulated macrophages as a model of inflammation to investigate the anti-inflammatory effects of 6-gingerol, which contains phenolic structure. We found that 6-gingerol exhibited an anti-inflammatory effect. 6-Gingerol could decrease inducible nitric oxide synthase and TNF-α expression through suppression of I-κBα phosphorylation, NF-κB nuclear activation and PKC-α translocation, which in turn inhibits Ca²⁺ mobilization and disruption of mitochondrial membrane potential in LPS-stimulated macrophages. Here, we demonstrate that 6-gingerol acts as an anti-inflammatory agent by blocking NF-κB and PKC signaling, and may be developed as a useful agent for the chemoprevention of cancer or inflammatory diseases.     

Inhibition of TNF-alpha synthesis in LPS-stimulated primary human monocytes by Harpagophytum extract SteiHap 69.

Harpagophytum procumbens (Devil's Claw) is often used in the supportive treatment of inflammatory and degenerative diseases of the skeletal system. Here we studied the anti-inflammatory properties of the Harpagophytum extract SteiHap 69 (Steiner Harpagophytum procumbens extract 69) on primary human monocytes, a useful model of peripheral inflammation. After eliminating lipopolysaccharides of bacterial origin, SteiHap 69 prevented the LPS-induced synthesis of tumour necrosis factor alpha (TNFalpha) in stimulated primary human monocytes in a dose-dependent manner. Harpagide and harpagoside had no effect on LPS-induced TNFalpha-release. Our data provides evidence that the Harpagophytum extract SteiHap 69 has anti-inflammatory properties. Further studies are required in order to elucidate the molecular mechanism of Devil's claw anti-inflammatory effects.     

Inhibition of Immune Complex-Induced Inflammation by A small Molecular Weight Selectin Antagonist

The anti-inflammatory effect of a small molecular weight antagonist of P- and E-selectin-dependent cell adhesion was examined. The glycolipid sulphatide was shown to block the adherence of thrombin-activated rat platelets to HL-60 cells. This interaction is known to be dependent on P-selectin. The rat dermal reverse passive Arthus reaction was used to assess the effect of sulphatide on a neutrophil dependent inflammatory response. Sulphatide dosedependently blocked both the vascular permeability increase and cell infiltration after intraperitoneal administration. These results show that a small molecular weight compound which blocks P- and E-selectin dependent adhesion in vitro can effectively block the inflammation due to immune complex deposition. A compound with this type of profile may have therapeutic potential in the treatment of immune complex mediated diseases.     

Glycyrrhizin inhibits the lytic pathway of complement--possible mechanism of its anti-inflammatory effect on liver cells in viral hepatitis

Glycyrrhizin, an aqueous extract of licorice root, has anti-inflammatory activity and has been used for the treatment of chronic viral hepatitis. In the present study we describe the mechanism by which glycyrrhizin inhibits complement. Glycyrrhizin inhibited the cytolytic activity of complement via the activation of both the classical and alternative pathways, while it had no effect on immune adherence, suggesting that it blocks C5 or a later stage of the complement cascade. Further analysis revealed that glycyrrhizin inhibits the lytic pathway in which the membrane attack complex (MAC) is formed. This mechanism suggests that glycyrrhizin may prevent tissue injury caused by MAC not only in chronic hepatitis but in many autoimmune and inflammatory diseases.     

Genus Ziziphus for the treatment of chronic inflammatory diseases

Natural products and traditional medicine are rich sources for developing therapeutics for chronic inflammatory diseases. However, the way from natural products/traditional medicines to Western pharmaceutical practices is not always straightforward. According to the World Health Organization (WHO), chronic diseases are the greatest threat to human health. 3 of 5 people die due to chronic inflammatory disorders worldwide like chronic respiratory diseases, stroke, cardiovascular diseases, cancer, diabetes, and obesity. Various nonsteroidal anti-inflammatory drugs (NSAIDs) are used to reduce inflammation and pain, but there are many side effects of these drugs' administration. Medicinal plants have therapeutic anti-inflammatory effects with low or no side effects. Ziziphus plant species are generally safe and not toxic to humans. Many studies on the Ziziphus species have shown that their therapeutic properties are attributed to the roots, leaves and fruits. Unfortunately, Ziziphus species from different regions worldwide with anti-inflammatory properties have not been documented in a single review paper. Therefore, it is crucial to establish ethnobotanical knowledge and applications of Ziziphus species against chronic inflammatory diseases. The current article exhaustively reviews phytochemical profile, pharmacological studies, toxicological effects, and ethnobotanical uses of Genus Ziziphus in chronic anti-inflammatory diseases. The present review article also highlights the most promising experimental data on Ziziphus extracts and pure compounds active in clinical trials and animal models of chronic inflammatory diseases. This review would be a valuable resource for contemporary researchers in the field to understand the promising role of the Ziziphus genus in chronic inflammatory disorders.     

Microglia Activation and Anti-inflammatory Regulation in Alzheimer’s Disease

Inflammatory regulators, including endogenous anti-inflammatory systems, can down-regulate inflammation thus providing negative feedback. Chronic inflammation can result from imbalance between levels of inflammatory mediators and regulators during immune responses. As a consequence, there are heightened inflammatory responses and irreversible tissue damage associated with many age-related chronic diseases. Alzheimer’s disease (AD) brain is marked by prominent inflammatory features, in which microglial activation is the driving force for the elaboration of an inflammatory cascade. How the regulation of inflammation loses its effectiveness during AD pathogenesis remains largely unclear. In this article, we will first review current knowledge of microglial activation and its association with AD pathology. We then discuss four examples of anti-inflammatory systems that could play a role in regulating microglial activation: CD200/CD200 receptor, vitamin D receptor, peroxisome proliferator-activated receptors, and soluble receptor for advanced glycation end products. Through this, we hope to illustrate the diverse aspects of inflammatory regulatory systems in brain and neurodegenerative diseases such as AD. We also propose the importance of neuronal defense systems, because they are part of the integral inflammatory and anti-inflammatory systems. Augmenting the anti-inflammatory defenses of neurons can be included in the strategy for restoration of balanced immune responses during aging and neurodegenerative diseases.     

Human umbilical cord mesenchymal stem cell-derived mitochondria (PN-101) attenuate LPS-induced inflammatory responses by inhibiting NFκB signaling pathway

Inflammation is one of the body’s natural responses to injury and illness as part of the healing process. However, persistent inflammation can lead to chronic inflammatory diseases and multi-organ failure. Altered mitochondrial function has been implicated in several acute and chronic inflammatory diseases by inducing an abnormal inflammatory response. Therefore, treating inflammatory diseases by recovering mitochondrial function may be a potential therapeutic approach. Recently, mitochondrial transplantation has been proven to be beneficial in hyperinflammatory animal models. However, it is unclear how mitochondrial transplantation attenuates inflammatory responses induced by external stimuli. Here, we isolated mitochondria from umbilical cord-derived mesenchymal stem cells, referred as to PN-101. We found that PN-101 could signifi-cantly reduce LPS-induced mortality in mice. In addition, in phorbol 12-myristate 13-acetate (PMA)-treated THP-1 macrophages, PN-101 attenuated LPS-induced increase production of pro-inflammatory cytokines. Furthermore, the anti-inflammatory effect of PN-101 was mediated by blockade of phosphorylation, nuclear translocation, and trans-activity of NFκB. Taken together, our results demonstrate that PN-101 has therapeutic potential to attenuate pathological inflammatory responses.     

Research update on the association between SFRP5, an anti-inflammatory adipokine,with obesity,type 2 diabetes mellitus and coronary heart disease

Secreted frizzled-related protein 5 (SFRP5), an anti-inflammatory adipokine secreted by adipocytes, has been demonstrated to exert its anti-inflammatory effect via antagonizing the non-canonical wingless-type family member 5A (WNT5A) signalling pathways. The WNT5A protein, as a potent pro-inflammatory signalling molecule, is strongly involved in a variety of inflammatory disorders such as obesity, type 2 diabetes mellitus (T2DM) and atherosclerosis. In this review, we systematically outlined the current understanding on the roles of SFRP5 in the pathogenesis of three inflammatory diseases including obesity, T2DM and coronary heart disease (CHD). Our review might stimulate future research using SFRP5 as a promising novel therapeutic target for the treatment of obesity, T2DM and CHD.