Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 15, Issue 2, 2015

TLRs are very important players to regulate innate immune responses. TLR4 controls the host defense by sensing an exotic pathogen, such as lipopolysaccharides. At the same time, some endogenous proteins, including HMGB1 and S100A8, could also function to be a ligand to elicit inflammatory reactions. These facts make TLR4 signaling system very complicated. For instance, the application of TLR4 ligands in cancer therapies is desirable for enhancement of anti-tumor immunity in terms of its reparative nature, but undesirable for enhancement of metastatic growth of cancer cells. In this manuscript, in order to make a novel molecular design to disrupt an interaction between TLR4/MD-2 and endogenous ligands, we provide a potential binding style of the TLR4/MD-2 complex with HMGB1 by using their 3D structural data and docking simulations, and also discuss S100A8 binding to TLR4/MD-2.

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is commonly used as a spice, food additive or dietary pigment. Accumulating evidence suggests that curcumin has several pharmacologic effects, including anti-inflammatory, anti-oxidant and anti-cancer activities. The molecular mechanisms underlying the targets of curcumin are diverse and involve combinations of multiple signaling pathways, including NF-ΚB and STAT3 signaling. Thus, curcumin is one of the most promising phytochemicals that target various cancers and inflammation-mediated diseases. Clinical trials have been ongoing or completed for various cancers, including breast, pancreatic and colorectal cancers, and multiple myeloma. In this review, the molecular mechanisms and the issue of bioavailability are mainly discussed.

Upon tissue injury and infection both stressed and dying cells can release proteins that normally reside inside the cells. Some of the released proteins become ligands of various cell surface receptors expressed by local cells and such proteins are denoted as damage associated molecular patterns (DAMPs). Binding of some DAMPs to certain cell surface receptors induces signals emanating in the production of pro-inflammatory cytokines, ultimately leading to an inflammatory response. Our laboratory is interested in the S100A9 protein, a bona fide DAMP protein. This protein normally resides inside monocytes and neutrophils and in these cells it forms heterodimers with the S100A8 protein. The S100A8/A9 heterodimer is released in large amounts during several types of inflammatory disease and is currently used clinically as a biomarker in some diseases. The fact that several different proinflammatory functions have been ascribed to this protein makes it a potential target for the development of small molecule inhibitors. We have developed several such inhibitors, some of which are already in phase III clinical development. This review describes our efforts to investigate the biological functions of the S100A9 protein as well as our ongoing efforts of developing second-generation, more specific, small molecule inhibitors of its pro-inflammatory functions.

The role of chemokines and their receptors in controlling several physiological and pathological processes has only become evident in the last couple of years. From a sole function of chemo-attraction, our view on chemokine receptor activation has switched to the regulation of pleiotropic signaling pathways influencing numerous molecular and cellular processes. The large number of chemokines and receptors and hence possible combinations of chemokine-chemokine receptor interactions, as well as the expression profiles of chemokines and chemokine receptors within particular cell types, has contributed to the complexity of chemokine receptor signaling as we see it today. The chemokine CCL2 and its main chemokine receptor CCR2 have been implicated in the pathogenesis of several different disease processes, including vascular permeability and attraction of immune cells during metastasis, a number of different neurological disorders, autoimmune disease, obesity, and atherosclerosis. Here we review recent findings on the role of the CCL2-CCR2 axis in the regulation of these diseases. We believe that research has only gained a first glimpse of what chemokines can control and what the underlying mechanisms are. There is certainly more to be found that will - with high certainty - have strong implications for clinical applications in the near future.

Evidence to show that the Eph/ephrin system is involved in inflammation induced by infection, injury, inflammatory diseases, and atherosclerosis has been increased. Although the roles of the Eph/ephrin system in both neural and vascular development as well as cell motility are well documented, its involvement in inflammatory processes has not yet been elucidated in detail. Moreover, the soluble form of artificially oligomerized or dimerized Fc-fused ephrin-A1 has been widely used in in vitro and/or in vivo studies to activate the EphA receptors, whereas its physiological functions as a membrane-anchored protein remain largely unknown. Recent studies using clinical samples reported that the overexpression of Ephs and ephrins in some tumors such as hepatocellular carcinoma positively correlated with both malignancy of tumors and the poor prognosis of cancer patients. However, the molecular mechanisms underlying malignancy of tumors are not fully understood. The author herein summarizes the molecular mechanisms of the Eph/ephrin system involved in the immune system and inflammatory processes. Especially, the author focuses on inflammation-induced physiological changes in vascular endothelial cells leading to vascular hyper-permeability and described them in this review. The author also introduces those that contribute to ephrin-A1-mediated lung metastasis.

Anti-Tumor Necrosis Factor (TNF) agents were the first molecular targeting drugs developed for the treatment of rheumatoid arthritis (RA). Anti-TNF agents improve the clinical picture of severe RA patients, inhibit joint destruction and improve quality of life. In the 15 years since their introduction, they have become the preferred drug therapy for management of RA. The success of anti-TNF agents in the treatment of RA has resulted in the development of many drugs for other inflammatory diseases using the same molecular targeting concept. However, many unresolved issues surround the use of anti-TNF agents, including the risk for infection, primary non-responders, secondary loss of efficacy and pharmacoeconomical issues. This review focuses on the multifaceted impact of anti-TNF agents in the treatment of RA.

The vascular endothelial growth factor (VEGF)-VEGF receptor (R) system is deeply involved in angiogenesis and lymphangiogenesis. VEGFR1/ Fms-like tyrosine kinase-1 (Flt-1) and VEGFR2 are significantly expressed in vascular endothelial cells, where they transfer proangiogenic signals. Particularly, VEGFR2 has strong tyrosine kinase activity; thus, the major and direct angiogenic signals are generated from VEGFR2. VEGFR3 is specifically expressed in lymphatic endothelial cells, generating the main signal for lymphangiogenesis. In addition, VEGFR1 is wellexpressed on the membrane of macrophage lineage cells such as monocytes, transducing an important signal for the migration and cytokine/chemokine production of these cells. This VEGFR1–macrophage axis stimulates seemingly non-inflammatory and inflammatory responses in various tissues and promotes a variety of diseases such as tumor growth via proangiogenesis, tumor metastasis, lymphangiogenesis, arthritis, and atherosclerosis. This axis is also important for the physiological recovery systems like bone marrow reconstitution and wound healing. VEGFR1 expresses two forms of mRNA: one for the full-length VEGFR1/Flt-1 receptor with tyrosine kinase; the other for a soluble form carrying only the ligand-binding region (sFlt-1/soluble VEGFR1) that functions as a decoy receptor by trapping its ligands VEGF-A, PlGF, and VEGF-B. Therefore, the VEGFR1-dependent inflammatory and non-inflammatory reactions are also regulated by a balance of gene expression between full-length and soluble forms of VEGFR1/Flt-1. Taken together, these findings suggest that VEGF-VEGFR signal is an important target for suppressing various diseases including inflammation.

Accumulating evidence indicates that low grade inflammation is closely associated with obesity-related disorders including type 2 diabetes, hypertension and atherosclerosis. Adiponectin is a fat-derived plasma protein with anti-inflammatory functions. Circulating levels of adiponectin are decreased in obese states, and these conditions are broadly associated with various obesity-related diseases. Furthermore, adiponectin has direct protective functions against cardiovascular disease, cerebrovascular disease, non-alcoholic steatohepatitis (NASH) and chronic kidney disease (CKD). In this review, we will focus on the protective functions of adiponectin against these obesity-related diseases from the view point of its anti-inflammatory properties.

Introduction: Immunosuppressant agents modulate the activity of the immune system and control adipose tissue inflammatory responses associated with obesity. Controlling adipose tissue inflammation represents an interesting option for inhibiting the low-grade inflammatory state in obese subjects and for preventing obesity-associated pathologies. In this work, we assessed the effects of thalidomide on the inflammatory response in adipose tissue as well as on systemic inflammatory marker expression in the well-established high-fat diet-induced obesity mouse model. Methods: Swiss male mice were fed a high-fat diet (60% kcal from fat) for 12 weeks and received thalidomide for the last 10 days (100 mg.kg-1). Adipokine levels were measured in serum and adipose tissue by EIA and real-time quantitative PCR, respectively. Adipose tissue infiltrating macrophages were identified by immunohistochemistry and western blot analysis of F4/80 marker expression. Other inflammatory markers, such as c-Jun N-terminal kinase (JNK) phosphorylation and monocyte chemoattractant protein-1 (MCP-1) production, were also evaluated by western blot analysis. In vitro assays using 3T3-L1 adipocytes were also conducted to evaluated adipokine release. Results: In obese mice, thalidomide administration induced a reduction in adiposity accompanied by a reduction of tumor necrosis factor-α (TNF-α), leptin and MCP-1 adipose tissue production, macrophage infiltration and JNK activation. TNF-α and leptin serum levels were also reduced by thalidomide treatment in obese mice. In vitro, the release of basal TNF-α and lipopolysaccharide (LPS)-induced MCP-1 was inhibited in 3T3-L1 cells. Significance: Our results suggest that drugs that can modulate the inflammatory status as well as control adipose tissue expansion could represent an interesting approach in the management of obesity, highlighting the need for further development of such compounds.

Natural killer (NK) cells are innate lymphoid cells which act against a variety of pathogens and tumours. Phenotypically they are characterized by surface markers named cluster designation (CD) antigens. CD56 and CD16 are recognized as specific NK markers in the dogs as well as in humans. Surgical interventions suppress NK cells both in rats and humans. In this direction, it has been shown that an antibiotic regimen (amoxicillin, benzylpenicillin/dihydrostreptomycin, sulfametazine/sulfamerazine/ sulfathiazole, enrofloxacin, lincomycin/spectinomycin) administered only twice is effective in preventing infections after laparatomic ovariectomy, in the bitch. On these grounds, this research will show that the administration of a fluoroquinolone (5 mg/kg of enrofloxacin, Baytril®, Bayer, Milan, Italy) one hour before and at the end of ovariectomy is able to increase CD56 and CD16 expression levels. Moreover, the antibiotic administration modifies the relative expression levels of the two CD; thus suggesting that the fluoroquinolone employed enhances the activation of a specific subset of NK cells mainly involved in body recovering during the post operative period as already observed in humans.