Potent Inhibitor Of Inflammation Research Articles

Therapeutic Effects of IL-1RA against Acute Bacterial Infections, including Antibiotic-Resistant Strains.

Innate immunity is essential for the anti-microbial defense, but excessive immune activation may cause severe disease. In this study, immunotherapy was shown to prevent excessive innate immune activation and restore the anti-bacterial defense. E. coli-infected Asc-/- mice develop severe acute cystitis, defined by IL-1 hyper-activation, high bacterial counts, and extensive tissue pathology. Here, the interleukin-1 receptor antagonist (IL-1RA), which inhibits IL-1 hyper-activation in acute cystitis, was identified as a more potent inhibitor of inflammation and NK1R- and substance P-dependent pain than cefotaxime. Furthermore, IL-1RA treatment inhibited the excessive innate immune activation in the kidneys of infected Irf3-/- mice and restored tissue integrity. Unexpectedly, IL-1RA also accelerated bacterial clearance from infected bladders and kidneys, including antibiotic-resistant E. coli, where cefotaxime treatment was inefficient. The results suggest that by targeting the IL-1 response, control of the innate immune response to infection may be regained, with highly favorable treatment outcomes, including infections caused by antibiotic-resistant strains.

Effect of Intralesional Steroid Injection in Bilateral Benign Vocal Fold Lesions

Abstract Background Corticosteroids are one of the most potent inhibitors of inflammation and wound repair. Local injection of steroid gives the option of administration of a potent drug locally, thereby avoiding the systemic side effects of them. They have been used in the last decade in managing benign vocal fold lesions as intralesional steroid injection has the advantages of rapid subsidence of the inflammation and edema with rapid improvement of voice postoperatively Ailil of the work This study is designed to show clinical ancl encloscopic voice Iinprovelnent of microlaryngeal surgery alone versus microlaryngeal surgery of the prilnary lesion combined with steroid injection in the opposing lesion in patients with bilateral vocal fold benign lesions. Patients and methods 40 patients with bilateral benign vocal fold lesions with Inoclerate to severe dysphonia are divided into two groups, one group underwent microlaryngo-surgery with excision of the primary lesion and injection of steroids into the contralateral lesions. The second group underwent microlaryngo-surgery with excision of the primary lesion only. Each subject was evaluated, preoperatively and postoperatively through a protocol including auditory perceptual assessment, laryngoscopic picture and self-rating by the patient using VHI. Results Comparing pre and post therapy results for each group, there was statistically significant improvcmcnt (reduction) in the size of thc contralatcral lesion and significant improvement in the quality of voice quality resulting in overall improvement in VHI. Conclusion Intralesional steroid injection in the contralateral lesion in bilateral benign vocal fold lesions is effective in improving voice quality postoperatively

DhHP-6 alleviates inflammation and reduces vascular permeability by eliminating reactive oxygen species

Inflammation is a defensive immune response to external stimuli. However, uncontrolled inflammation may cause potential damage to the host. Therefore, timely control of uncontrolled inflammation is particularly important. Previous studies have found that small molecules with antioxidant activity, such as peroxidase mimic enzymes, can inhibit the development of inflammation. DhHP-6 is a new peptide mimic of peroxidase previously designed by our laboratory. Here, we explored its anti-inflammatory activity in vitro and in vivo. Our results showed that treatment with DhHP-6 significantly reduced the production of reactive oxygen species (ROS), NO, IL-6, and TNF-α in RAW264.7 cells induced by lipopolysaccharides (LPS); in addition, it also blocked the phosphorylation of extracellularly regulated kinase 1 and 2 (ERK1/2) and ribosomal s6 kinase 1 (RSK1), thereby blocking the phosphorylation and degradation of IκBα, and inhibiting the nuclear translocation of p65. Interestingly, treatment with DhHP-6 blocked the phosphorylation of ERK1/2 and myosin light chain kinase (MLCK) in HUVECs induced by LPS. Finally, we found that DhHP-6 treatment significantly reduced the infiltration of immune cells in balloon model rats. Therefore, we believe that DhHP-6 is a potent inhibitor of inflammation.

Topical phenylbutyrate antagonizes NF-κB signaling and resolves corneal inflammation.

Chronic inflammation of the immune privileged cornea originating from viral or nonviral conditions results in significant vision loss. Topical corticosteroids are the common treatments for corneal inflammation, but the drugs cause serious and potentially blinding side effects in the long term. Therefore, new standalone and/or synergistic anti-inflammatory therapies with lower side effects are desperately needed. Here, we show that the aromatic fatty acid phenylbutyrate (PBA) acts as a potent inhibitor of inflammation in preclinical ocular-inflammation models. PBA prevents the transcription as well as translation of pro-inflammatory cytokines by LPS and poly(I:C) via persistent inhibition of NF-κB signaling. PBA quickens the resolution of ocular inflammation in mice by decreasing corneal thickness and immune cell infiltration. More importantly, PBA can synergize with the dexamethasone to antagonize NF-κB signaling at lower drug concentrations. Our results demonstrate that PBA therapy exerts previously unreported anti-inflammatory effects in the eye and facilitates corneal healing during persistent inflammation.

Phenanthroindolizidine Alkaloids Isolated from Tylophora ovata as Potent Inhibitors of Inflammation, Spheroid Growth, and Invasion of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC), representing the most aggressive form of breast cancer with currently no targeted therapy available, is characterized by an inflammatory and hypoxic tumor microenvironment. To date, a broad spectrum of anti-tumor activities has been reported for phenanthroindolizidine alkaloids (PAs), however, their mode of action in TNBC remains elusive. Thus, we investigated six naturally occurring PAs extracted from the plant Tylophora ovata: O-methyltylophorinidine (1) and its five derivatives tylophorinidine (2), tylophoridicine E (3), 2-demethoxytylophorine (4), tylophoridicine D (5), and anhydrodehydrotylophorinidine (6). In comparison to natural (1) and for more-in depth studies, we also utilized a sample of synthetic O-methyltylophorinidine (1s). Our results indicate a remarkably effective blockade of nuclear factor kappa B (NFκB) within 2 h for compounds (1) and (1s) (IC50 = 17.1 ± 2.0 nM and 3.3 ± 0.2 nM) that is different from its effect on cell viability within 24 h (IC50 = 13.6 ± 0.4 nM and 4.2 ± 1 nM). Furthermore, NFκB inhibition data for the additional five analogues indicate a structure–activity relationship (SAR). Mechanistically, NFκB is significantly blocked through the stabilization of its inhibitor protein kappa B alpha (IκBα) under normoxic as well as hypoxic conditions. To better mimic the TNBC microenvironment in vitro, we established a 3D co-culture by combining the human TNBC cell line MDA-MB-231 with primary murine cancer-associated fibroblasts (CAF) and type I collagen. Compound (1) demonstrates superiority against the therapeutic gold standard paclitaxel by diminishing spheroid growth by 40% at 100 nM. The anti-proliferative effect of (1s) is distinct from paclitaxel in that it arrests the cell cycle at the G0/G1 state, thereby mediating a time-dependent delay in cell cycle progression. Furthermore, (1s) inhibited invasion of TNBC monoculture spheroids into a matrigel®-based environment at 10 nM. In conclusion, PAs serve as promising agents with presumably multiple target sites to combat inflammatory and hypoxia-driven cancer, such as TNBC, with a different mode of action than the currently applied chemotherapeutic drugs.

Design and synthesis of adamantyl-substituted flavonoid derivatives as anti-inflammatory Nur77 modulators: Compound B7 targets Nur77 and improves LPS-induced inflammation in vitro and in vivo

In continuing our study on discovering new Nur77-targeting anti-inflammatory agents with natural skeletons, we combined adamantyl group and hydroxamic acid moiety with flavonoid nucleus, synthesized three series of flavonoid derivatives with a similar structure like CD437, and evaluated their activities against LPS-induced inflammation. Compound B7 was found to be an excellent Nur77 binder (Kd = 3.55 × 10-7 M) and a potent inhibitor of inflammation, which significantly decreased the production of cytokines in vitro, such as NO, IL-6, IL-1β, and TNF-α, at concentrations of 1.25, 2.5, and 5 μM. Mechanistically, B7 modulated the colocalization of Nur77 at mitochondria and inhibited the lipopolysaccharides (LPS)-induced inflammation via the blockade of NF-κB activation in a Nur77-dependent manner. Additionally, B7 showed in vivo anti-inflammatory activity in the LPS-induced mice model of acute lung injury (ALI). These data suggest that the Nur77-targeting flavonoid derivatives can be particularly useful for further pharmaceutical development for the treatment of inflammatory diseases such as ALI.

Anti-tumour and Anti-inflammatory Effects of Fractions of Annona muricata leaf-extract on dimethylbenzanthracene-induced mammary tumours in Wistar rats

The major challenge concerning tumours and cancers is that they currently do not have a cure. The side effects from the available treatment options have made research gravitate towards phytotherapy. Annona muricata is one of the highly recommended plants due to its usage albeit in crude form in treating several diseases especially, tumours and cancer inclusive. However, the fraction of its extracts responsible for these effects, is still unknown. This study was designed to investigate the anti-tumour and anti-inflammatory effects of Hexane, ethyl-acetate, butanol and aqueous fractions of A. muricata leaves in dimethylbenzanthracene-induced (DMBA) mammary tumours. Forty-two female Wistar rats were divided into 7 groups of 6 animals each. Group 1 was Control and were on basal diet; Groups 2 to 7 were tumour-induced with 0.05mg/g DMBA subcutaneously with soy oil as vehicle. Group 2 was untreated; Group 3 was treated with doxorubicin (0.0125mg/g); Groups 4 to 7 were treated orally with the four fractions respectively at 12.5mg/g for 14 days. Data obtained were subjected to Analysis of Variance using Bonferroni post-hoc test. P<0.05 was taken as statistically significant. Annona muricata fractions reduced the TNF-α and CRP concentrations which were elevated in response to tumour induction, with the butanol fraction having the highest reduction potential, with a value of 0.02 ± 0.08 and 0.15 ± 0.04 respectively. However, these reductions were not statistically significant across all treatment groups. This study shows that all four fractions of A. muricata are potent inhibitors of inflammation, particularly in DMBA-induced mammary tumours. However, the butanol fraction proves to be the most potent in altering the process of inflammation via the TNF-α and the CRP signalling pathways. Key words: Tumour, Cancer, Annona muricata, dimethylbenzanthracene, doxorubicin.

Neuroprotective Effects of Celastrol on Transient Global Cerebral Ischemia Rats via Regulating HMGB1/NF-κB Signaling Pathway.

Cerebral ischemia is a major cause of brain dysfunction, neuroinflammation and oxidative stress have been implicated in the pathophysiological process of cerebral ischemia/reperfusion injury. Celastrol is a potent inhibitor of inflammation and oxidative stress that has little toxicity. The present study was designed to evaluate whether celastrol has neuroprotective effects through anti-inflammatory and antioxidant actions, and to elucidate the possible involved mechanisms in transient global cerebral ischemia reperfusion (tGCI/R) rats. Celastrol (1, 2, or 4 mg/kg) was administrated intraperitoneally immediately after reperfusion and the effect of celastrol on reverting spatial learning and memory impairment was determined by Morris water maze (MWM) task. Inflammatory response and oxidative stress, hippocampal neuronal damage and glial activation, and HMGB1/NF-κB signaling pathway proteins were also examined. Our results indicated that celastrol dose-dependently reduced hippocampal and serum concentration of pro-inflammatory markers (TNF-α, IL-1β, and IL-6) and oxidative stress marker (MDA), whereas the anti-inflammatory marker IL-10 and antioxidant markers (GSH, SOD, and CAT) were increased significantly in celastrol treated tGCI/R rats. Celastrol alleviated apoptotic neuronal death, inhibited reactive glial activation and proliferation and improved ischemia-induced neurological deficits. Simultaneously, we found that mechanisms responsible for the neuroprotective effect of celastrol could be attributed to its anti-inflammatory and antioxidant actions via inhibiting HMGB1/NF-κB signaling pathway. These findings provide a proof of concept for the further validation that celastrol may be a superior candidate for the treatment of severe cerebral ischemic patients in clinical practice in the future.

Evaluation of Anti-inflammatory and Regenerative Efficiency of Naringin and Naringenin in Degenerated Human Nucleus Pulposus Cells: Biological and Molecular Modeling Studies.

Study DesignDevelopment of an in vitro model for assessing the anti-inflammatory efficacies of naringin (Nar) and naringenin (NG).PurposeTo evaluate the efficacy of natural flavonoids as therapeutic drugs against anti-inflammatory processes in the nucleus pulposus (NP) cells using in-vitro and in-silico methods.Overview of LiteratureIntervertebral disc (IVD) disease is a common cause of low back pain. Chronic inflammation and degeneration play a significant role in its etiopathology. Thus, a better understanding of anti-inflammatory agents and their role in IVD degeneration and pro-inflammatory cytokines expression is necessary for pain management and regeneration in IVD.MethodsWe performed primary cell culture of NP cells; immunocytochemistry; gene expression studies of cytokines, metalloproteases, extracellular proteins, and apoptotic markers using quantitative polymerase chain reaction and reverse transcription-polymerase chain reaction (RT-PCR); cytotoxicity assay (MTT); and molecular docking studies using AutoDock 4.2 software (Molecular Graphics Laboratory, La Jolla, CA, USA) to confirm the binding mode of proteins and synthesized complexes. We calculated the mean±standard deviation values and performed analysis of variance and t-test using SPSS ver. 17.0 (SPSS, Inc., Chicago, IL, USA).ResultsMolecular docking showed that both Nar and NG bind to the selected genes of interest. Semi-quantitative RT-PCR analysis reveals differential gene expression of collagen (COL)9A1, COL9A2, COL9A3, COL11A2, COMT (catechol-O-methyltransferase), and THBS2 (thrombospondin 2); up regulation of ACAN (aggrecan), COL1A1, COL11A1, interleukin (IL)6, IL10, IL18R1, IL18RAP, metalloprotease (MMP)2, MMP3, MMP9, ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5), IGF1R (insulin-like growth factor type 1 receptor), SPARC (secreted protein acidic and cysteine rich), PARK2 (parkin), VDR (vitamin D receptor), and BCL2 (B-cell lymphoma 2); down regulation of IL1A, CASP3 (caspase 3), and nine genes with predetermined concentrations of Nar and NG.ConclusionsThe present study evaluated the anti-inflammatory and regenerative efficiencies of Nar and NG in degenerated human NP cells. Altered gene expressions of cytokines, metalloproteases, extracellular proteins, apoptotic genes were dose responsive. The molecular docking (in silico) studies showed effective binding of these native ligands (Nar and NG) with genes identified as potent inhibitors of inflammation. Thus, these natural flavonoids could serve as anti-inflammatory agents in the treatment of low back pain and sciatica.

SUN-095 Attenuation of Inflammation by a Novel Small Molecule Prevents High Fat Diet-Induced Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of both metabolic and inflammatory diseases, and it has become pervasive worldwide. Inflammation, including inflammation resulting from free fatty acid (FFA) activation of toll-like receptor (TLR) signaling, has been suggested to be an essential component of the pathophysiology of both insulin resistance and NAFLD. High fat (HF) diets promote an increased uptake and storage of FFAs and triglycerides in hepatocytes, which initiates inflammation and steatosis that induces lipotoxicity and an exacerbation of inflammation. In previous studies, we have established the efficacy of phenylmethimazole, a TLR3/4 inhibitor, to prevent and reverse HF diet-induced NAFLD, inflammation, and insulin resistance. A new library of small molecule compounds, including COB-214, was generated to identify even more potent inhibitors of inflammation. The objectives of this study were to evaluate the efficacy of COB-214 to delay and/or prevent hepatic steatosis, inflammation, and insulin resistance in a HF diet-induced model of NAFLD. C57BL/6J male mice were fed a HF diet (60 % fat, 20% protein, 70% carbohydrate) and divided into 3 groups (N=8 for each group): sham injection (stress control), DMSO (vehicle control), COB-214. Each treatment was administered once daily at a dosage of 1mg/kg for 16 weeks. Histological examination of liver sections from these mice using hematoxylin and eosin (H&E) revealed less hepatic lipid accumulation in mice treated with COB-214 when compared to mice in the sham- and DMSO-treated groups. Transcription of pro-inflammatory cytokines was down-regulated in both liver and mesenteric adipose tissue isolated from COB-214-treated mice when compared to sham- and DMSO-treated mice. Treatment with COB-214 prevented HF diet-induced insulin resistance measured by a 3-hour intraperitoneal glucose tolerance test (IPGTT) and 1.5-hour intraperitoneal insulin tolerance test (IPITT). Future directions include determining the efficacy of COB-214 to reverse HF diet-induced NAFLD, inflammation, and insulin resistance. At the conclusion of this study, we hope to have established the role of a novel class of small molecule inhibitors of inflammation in the treatment and prevention of NAFLD.

Synthesis and structure anti-inflammatory activity relationships studies of andrographolide derivatives

Andrographolide is a main bioactive diterpene lactone in A. paniculata with anti-inflammatory activity. In this study, a series of andrographolide derivatives were synthesized and evaluated for their structure-anti-inflammatory activity relationships in vivo. Among all compounds, isoandrographolide and 14-deoxyandrographolide showed stronger anti-inflammatory activity than andrographolide. The results indicated that the introduction of tetrahydrofuran ring and cyclic olefinic bond plays an important role in enhancing the anti-inflammatory activity of andrographolide derivatives. Isoandrographolide and 14-deoxyandrographolide are potent inhibitor of inflammation.

Assessment of Novel Curcumin Derivatives as Potent Inhibitors of Inflammation and Amyloid-β Aggregation in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting the elderly population worldwide. Brain inflammation plays a key role in the progression of AD. Deposition of senile plaques in the brain stimulates an inflammatory response with the overexpression of pro-inflammatory mediators, such as the neuroinflammatory cytokine. interleukin-6. Curcumin has been revealed to be a potential agent for treating AD following different neuroprotective mechanisms, such as inhibition of aggregation and decrease in brain inflammation. We synthesized new curcumin derivatives with the aim of providing good anti-aggregation capacity but also improved anti-inflammatory activity. Nine curcumin derivatives were synthesized by etherification and esterification of the aromatic region. From these derivatives, compound 8 exhibited an anti-inflammatory effect similar to curcumin, while compounds 3, 4, and 10 were more potent. Moreover, when the anti-aggregation activity is considered, compounds 3, 4, 5, 6, and 10 showed biological activity in vitro. Compound 4 exhibited a strong anti-aggregation effect higher than curcumin. Monofunctionalized curcumin derivatives showed better bioactivity than difunctionalized compounds. Moreover, the presence of bulky groups in the chemical structure of curcumin derivatives decreased bioactivity.

Pigment Epithelium-Derived Factor (PEDF) Prevents Hepatic Fat Storage, Inflammation, and Fibrosis in Dietary Steatohepatitis of Mice.

Pigment epithelium-derived factor (PEDF) has been shown to be a potent inhibitor of inflammation through its anti-oxidative property. Since oxidative response is considered to play the pivotal role of the development and progression of nonalcoholic steatohepatitis (NASH), it is conceivable that PEDF may play a protective role against NASH. In this study, we examined whether administration of PEDF slowed the progression of NASH in mice models. Mice were fed methionine- and choline-deficient (MCD) diet with or without intramuscular administration of adenovirus-expressing PEDF (Ad-PEDF). Effects of PEDF administration on NASH were histologically and biochemically evaluated. Administration of Ad-PEDF significantly decreased hepatic fat storage as well as serum levels of ALT in MCD diet-fed mice. Dihydroethidium staining showed that MCD diet-triggered oxidative stress was reduced in the liver of Ad-PEDF-administered mice compared to that of PBS- or Ad-LacZ-administered mice. Activation of Kupffer cells and hepatic fibrosis was also inhibited by Ad-PEDF administration. Quantitative real-time RT-PCR revealed that MCD diet up-regulated expressions of TNF-α, IL-1β, IL-6, TGF-β, collagen-1, and collagen-3 mRNA, which were also attenuated with Ad-PEDF administration, whereas MCD diet-induced down-regulation of expressions of PPAR-γ mRNA was restored with Ad-PEDF administration. Furthermore, immunoblotting analysis showed that MCD diet-induced up-regulation of NADPH oxidase components was significantly decreased in Ad-PEDF-administered mice. The present results demonstrated for the first time that PEDF could slow the development and progression of steatohepatitis through the suppression of steatosis and inflammatory response in MCD diet-fed mice. Our study suggests that PEDF supplementation may be a novel therapeutic strategy for the treatment of NASH.

The Potential Therapeutic Application of Peptides and Peptidomimetics in Cardiovascular Disease.

Cardiovascular disease (CVD) remains a leading cause of mortality and morbidity worldwide. Numerous therapies are currently under investigation to improve pathological cardiovascular complications, but yet, there have been very few new medications approved for intervention/treatment. Therefore, new approaches to treat CVD are urgently required. Attempts to prevent vascular complications usually involve amelioration of contributing risk factors and underlying processes such as inflammation, obesity, hyperglycaemia, or hypercholesterolemia. Historically, the development of peptides as therapeutic agents has been avoided by the Pharmaceutical industry due to their low stability, size, rate of degradation, and poor delivery. However, more recently, resurgence has taken place in developing peptides and their mimetics for therapeutic intervention. As a result, increased attention has been placed upon using peptides that mimic the function of mediators involved in pathologic processes during vascular damage. This review will provide an overview on novel targets and experimental therapeutic approaches based on peptidomimetics for modulation in CVD. We aim to specifically examine apolipoprotein A-I (apoA-I) and apoE mimetic peptides and their role in cholesterol transport during atherosclerosis, suppressors of cytokine signaling (SOCS)1-derived peptides and annexin-A1 as potent inhibitors of inflammation, incretin mimetics and their function in glucose-insulin tolerance, among others. With improvements in technology and synthesis platforms the future looks promising for the development of novel peptides and mimetics for therapeutic use. However, within the area of CVD much more work is required to identify and improve our understanding of peptide structure, interaction, and function in order to select the best targets to take forward for treatment.

SOCS1 in cancer: An oncogene and a tumor suppressor

The Suppressor Of Cytokine Signaling 1 (SOCS1) has been extensively investigated in immune cells where it works as a potent inhibitor of inflammation by negative feedback regulation of the cytokine-activated JAK–STAT signaling pathways. SOCS1 is also recognized as a tumor suppressor in numerous cancers and its critical functional relevance in non-immune cells, including epithelial cells, has just begun to emerge. Most notably, conflicting results from clinical and experimental studies suggest that SOCS1 may function as either a tumor suppressor or a tumor promoter, in a cell context-dependent manner. Here, we present an overview of the mechanisms underlying SOCS1 function as a tumor suppressor and discuss the emerging evidences of SOCS1 activity as an oncogene.

THU0127 Pharmacodynamics of A Novel JAK1 Selective Inhibitor in Rat Arthritis and Anemia Models and in Healthy Human Subjects

BackgroundAnti-cytokine therapies have become the mainstay of treatment for rheumatoid arthritis (RA) disease symptoms and can arrest disease progression. Despite numerous treatment options there are still many RA patients who...

Omega-3 fatty acid-derived mediator, Resolvin E1, ameliorates 2,4-dinitrofluorobenzene-induced atopic dermatitis in NC/Nga mice

Atopic dermatitis (AD) is a common inflammatory skin disease for which few effective treatments are available. Resolvin E1 (RvE1; 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid) is an endogenous lipid mediator derived from omega-3 fatty eicosapentaenoic acid, which is a potent inhibitor of inflammation. AD-like skin lesion was induced by repetitive skin contact with DNFB in NC/Nga mice and the effects of RvE1 were evaluated on the basis of histopathological findings of skin, ear swelling and cytokine production of CD4+ T cells. Intraperitoneal injection of RvE1 for one week after DNFB challenge significantly lowered ear swelling and improved back skin lesions. In addition, RvE1 significantly suppressed production of interferon-gamma (IFN-γ) and interleukin-4 (IL-4) by activated CD4+ T cells and serum IgE level. Furthermore, RvE1 reduced DNFB-induced infiltration of eosinophils, mast cells, CD4+ T cells, and CD8+ T cells in skin lesions.Therefore, RvE1 may suppress the development of AD-like skin lesions in DNFB-treated NC/Nga mice by reducing IL-4 and IFN-γ of activated CD4+ T cells and serum IgE levels and infiltration of immune cells to skin lesion.

Honaucins A−C, Potent Inhibitors of Inflammation and Bacterial Quorum Sensing: Synthetic Derivatives and Structure-Activity Relationships

Honaucins A-C were isolated from the cyanobacterium Leptolyngbya crossbyana which was found overgrowing corals on the Hawaiian coast. Honaucin A consists of (S)-3-hydroxy-γ-butyrolactone and 4-chlorocrotonic acid, which are connected via an ester linkage. Honaucin A and its two natural analogs exhibit potent inhibition of both bioluminescence, a quorum-sensing-dependent phenotype, in Vibrio harveyi BB120 and lipopolysaccharide-stimulated nitric oxide production in the murine macrophage cell line RAW264.7. The decrease in nitric oxide production was accompanied by a decrease in the transcripts of several proinflammatory cytokines, most dramatically interleukin-1β. Synthesis of honaucin A, as well as a number of analogs, and subsequent evaluation in anti-inflammation and quorum-sensing inhibition bioassays revealed the essential structural features for activity in this chemical class and provided analogs with greater potency in both assays.

CD4+CD25+Foxp3+ regulatory T cells suppress cardiac fibrosis in the hypertensive heart

CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs) are potent inhibitors of inflammation and autoimmune diseases. Because inflammation has been associated with development of cardiac fibrosis in experimental hypertension, here we investigated whether adoptively transferred Tregs would inhibit development of cardiac fibrosis initiated by elevating blood pressure. Cardiac fibrosis was induced in mice by constricting the aorta between the two carotid arteries. Immediately after the operation mice received either vehicle or purified, cultured Tregs (1.5 × 10⁶). Fourteen days later we assessed effects on developing left ventricular fibrosis, blood pressure, inflammation, myofibroblasts and the transforming growth factor-beta1 (TGF-β1) system. Fourteen days after aortic constriction, marked left-ventricular fibrosis was apparent and this was greatly reduced in mice receiving adoptively transferred Tregs. This reduction in fibrosis was associated with attenuated inflammatory cell numbers, reduced interstitial myofibroblast numbers and attenuated activity of the TGF-β1 system, indicated by reductions in the expression of TGF-β1 and its receptors activin-like kinase-5 and type II TGF-β receptor. Adoptively transferred Tregs did not affect blood pressure and exerted only a small effect on left-ventricular hypertrophy. These data indicate that Tregs attenuate cardiac fibrosis associated with hypertensive heart disease by suppressing inflammation.

Extracellular purine metabolism and signaling of CD73-derived adenosine in murine Treg and Teff cells

CD73-derived adenosine acts as potent inhibitor of inflammation, and regulatory T cells (Treg) have been shown to express CD73 as a novel marker. This study explored the role of endogenously formed adenosine in modulating NF-κB activity and cytokine/chemokine release from murine Treg and effector T cells (Teff) including key enzymes/purinergic receptors of extracellular ATP catabolism. Stimulating murine splenocytes and CD4(+) T cells with anti-CD3/anti-CD28 significantly upregulated activated NF-κB in CD73(-/-) T cells (wild type: 4.36 ± 0.21; CD73(-/-): 6.58 ± 0.75; n = 4; P = 0.029). This was associated with an augmented release of proinflammatory cytokines IL-2, TNF-α, and IFN-γ. Similar changes were observed with the CD73 inhibitor APCP (50 μM) on NF-κB and IFN-γ in wild-type CD4(+) T-cells. Treatment of stimulated CD4(+) T-cells with adenosine (25 μM) potently reduced IFN-γ release which is mediated by adenosine A2a receptors (A2aR). AMP (50 μM) also reduced cytokine release which was not inhibited by APCP. In Teff, A2aR activation (CGS21680) potently inhibited the release of IL-1, IL-2, IL-3, IL-4, IL-12, IL-13, IFN-γ, TNF-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), CCL3, and CCL4. However, in Treg, CGS21680 did not alter cytokine/chemokine release. In summary, CD73-derived adenosine tonically inhibits active NF-κB in CD4(+) T-cells, thereby modulating the release of a broad spectrum of proinflammatory cytokines and chemokines. Downregulation of P2X7 and upregulation of CD73 in Treg after antigenic stimulation may be an important mechanism to maintain the ability of Treg to generate immunosuppressive adenosine.