Inflammatory mediators, oxidative stress and genetic disturbance in rheumatoid arthritis rats supported by alfalfa seeds metabolomic constituents via blocking interleukin-1receptor.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by aggressive cartilage and bone erosion. This work aimed to evaluate the metabolomic profile of Medicago sativa L. (MS) (alfalfa) seeds and explore its therapeutic impact against RA in rats. Arthritis was induced by complete Freund's adjuvant (CFA) and its severity was assessed by the arthritis index. Treatment with MS seeds butanol fraction and interlukin-1 receptor antagonist (IL-1RA) were evaluated through measuring interlukin-1 receptor (IL-1R) type 1 gene expression, interlukin-1 beta (IL-1ß), oxidative stress markers, C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), prostaglandin E2 (PGE2), caspase-3 (Cas-3), intracellular adhesion molecule-1 (ICAM-1), DNA fragmentation, and chromosomal damage. Total phenolics/ flavonoids content in the ethyl acetate, butanol fraction and crude extract of MS seeds were estimated. The major identified compounds were Quercetin, Trans-taxifolin, Gallic acid, 7,4'-Dihydroxyflavone, Cinnamic acid, Kudzusaponin SA4, Isorhamnetin 3-O-beta-D-2'',3'',4''-triacetylglucopyranoside, Apigenin, 5,7,4'-Trihydroxy-3'-methoxyflavone, Desmethylxanthohumol, Pantothenic acid, Soyasapogenol E, Malvidin, Helilandin B, Stigmasterol, and Wairol. Treatment with MS seeds butanol fraction and IL-1RA enhanced all the biochemical parameters and the histopathological features of the ankle joint. In conclusion, Trans-taxifolin was isolated for the first time from the genus Medicago. MS butanol fraction seeds extract and IL-1 RA were considered as anti-rheumatic agents.

A systematic review and dose-response meta-analysis of the effect of selenium supplementation on serum concentration of C-reactive protein.

BACKGROUND: Despite conducting new studies on the potential effect of selenium in reducing inflammation; results held contradictory weights and turns into an intriguing area of research. Concerns have been raised on this matter on hand to reach conclusive/consistent results. Therefore, this study seeks to address this scientific gap by assessing randomized controlled trials (RCTs) investigating the effect of selenium intake on C-reactive protein (CRP). METHOD AND MATERIALS: To find all the relevant English-language RCTs, databases including SCOPUS, Web of Science, Clinical Trials.gov, PubMed, and Cochrane Library were searched with no time limit (up to June 2022). Based on the mean changes for both comparison and intervention groups, the effect sizes were calculated. Further, DerSimonian and Laird random-effects model was performed to determine the summary of overall effects and their heterogeneity. RESULTS: Fifteen studies were selected for systematic review and thirteen studies were known to be eligible for meta-analysis. Meta-analysis results indicated a significant effect in serum CRP concentrations compared to the control group (weighted mean difference (WMD)= -0.22 mg/L 95 % confidence interval (CI): - 0.39, - 0.04; p = 0.014). CONCLUSION: In conclusion, our study confirms the downward effect of selenium on the serum concentration of CRP. On a wider level, further research is also needed to assess the selenium effect on other inflammatory mediators.

Ocimum sanctum L water extract: In-situ green synthesis of zinc oxide nanoparticles for treatment of rheumatoid arthritis: Preclinical study.

BACKGROUND AND OBJECTIVE: Rheumatoid arthritis is a chronic progressive autoimmune disorder, characterised by destruction of cartilage and under line bones. Though exact etiology of rheumatoid arthritis (RA) remains unknown. It is believed that alteration in control of cellular or molecular responses is involved in the chronic inflammation. Earlier in RA patients it was observed the circulating RA specific biomarkers and immunoglobulin deposits in the synovial joints. Zinc Oxide Nanoparticles (ZnO NPs) is used as an anti-inflammatory and anticancer agent, however there is nil/very less scientific data shows the anti-arthritic activity of green synthesis ZnO nanoparticles (Ocimum sanctum water extract in-situ synthesis of ZnO NPs having active compound Caffeic acid and Rosmerinic acid). Hence, the present activity was planned to assess the anti-arthritic activity of ZnO NPs in CIA rats. METHODS: Arthritis in rats were induced by subcutaneous injection of collagen type II (CII) (200 µl) at the base of tail on day 0 followed by booster dose on day 14. ZnO NPs were given (2 mg/kg b.wt./day) orally for 20 days. At the end of the study serum, joint homogenate was used to assess the level of biomarkers (RF, a-CCP, a-CII and CRP) and inflammatory mediators. In addition, m-RNA expression of various genes such as Nuclear factor-kB (NF-kB), inflammatory mediators like tumour necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) etc. were assayed in joint tissue. Finally all these biochemical and molecular results were confirmed by microscopic study of joint tissue. RESULTS: ZnO NPs, treated rats showed decrease in inflammation and clinical severity. This was related with decrease in the level of biomarkers (like RF, a-CCP and CRP), inflammatory mediators (TNF-α, COX-2) and activity of transcription factor NF-kB. All these findings were positively correlated with microscopic analysis of joint tissue that showed reduced inflammation and bone erosion in treated group. CONCLUSION: This study validates the anti-arthritic activity of ZnO NPs as it mitigates the arthritis related symptoms in CIA rats.

Medicinal Herbs and Their Derived Ingredients Protect against Cognitive Decline in In Vivo Models of Alzheimer's Disease.

Alzheimer's disease (AD) has pathological hallmarks including amyloid beta (Aß) plaque formation. Currently approved single-target drugs cannot effectively ameliorate AD. Medicinal herbs and their derived ingredients (MHDIs) have multitarget and multichannel properties, engendering exceptional AD treatment outcomes. This review delineates how in in vivo models MHDIs suppress Aß deposition by downregulating ß- and γ-secretase activities; inhibit oxidative stress by enhancing the antioxidant activities and reducing lipid peroxidation; prevent tau hyperphosphorylation by upregulating protein phosphatase 2A expression and downregulating glycogen synthase kinase-3ß expression; reduce inflammatory mediators partly by upregulating brain-derived neurotrophic factor/extracellular signal-regulated protein kinase 1/2-mediated signaling and downregulating p38 mitogen-activated protein kinase (p38 MAPK)/c-Jun N-terminal kinase (JNK)-mediated signaling; attenuate synaptic dysfunction by increasing presynaptic protein, postsynaptic protein, and acetylcholine levels and preventing acetylcholinesterase activity; and protect against neuronal apoptosis mainly by upregulating Akt/cyclic AMP response element-binding protein/B-cell lymphoma 2 (Bcl-2)-mediated anti-apoptotic signaling and downregulating p38 MAPK/JNK/Bcl-2-associated x protein (Bax)/caspase-3-, Bax/apoptosis-inducing factor-, C/EBP homologous protein/glucose-regulated protein 78-, and autophagy-mediated apoptotic signaling. Therefore, MHDIs listed in this review protect against Aß-induced cognitive decline by inhibiting Aß accumulation, oxidative stress, tau hyperphosphorylation, inflammation, synaptic damage, and neuronal apoptosis in the cortex and hippocampus during the early and late AD phases.

TamaFlex™-A novel nutraceutical blend improves lameness and joint functions in working horses.

BACKGROUND: Lameness is one of the major causes of reduced physical performance and early retirement in working horses. TamaFlex™ (NXT15906F6) is a standardized synergistic anti-inflammatory botanical formulation containing Tamarindus indica seed extract and Curcuma longa rhizome extract at a 2:1 ratio. METHODS: We conducted a 12-week single-center, randomized, blinded, placebo-controlled trial demonstrating the efficacy of NXT15906F6 in horses with lameness grade 2-4 on the American Association of Equine Practitioners (AAEP) scale. Twenty-two lame horses were supplemented with NXT15906F6 (2.5 gram/day) or placebo over a period of 84 days. Improvement in lameness over placebo was the primary endpoint, and changes in the levels of rheumatoid factor (RF), anti-nuclear antibody (ANA), and anti-cyclic citrullinated peptide (ACC-peptide) in serum, and pro-inflammatory cytokines including interleukin (IL-1ß and IL-6), tumor necrosis factor-α (TNF-α) and prostaglandin-E2 (PGE2 ) in serum and synovial fluid were the secondary endpoints. RESULTS: NXT15906F6 exhibited significant relief from lameness in a time-dependent manner. NXT15906F6 also reduced levels of ANA, PGE2 , IL-1ß, TNF-α and IL-6. Moreover, NXT15906F6 supplementation is safe and tolerable in alleviating joint pain in lame horses, and protects the joints from further degradation by reducing pro-inflammatory mediators. CONCLUSION: NXT15906F6 significantly reduces the lameness during walking and trotting, leading to an improvement in their joint flexibility, health, and working performances.

Evaluation of antiobesity and hepatorenal protective activities of Salvia officinalis extracts pre-treatment in high-fat diet-induced obese rats.

The present study evaluated the effects of Hail Salvia officinalis total extract (SOTE) and its high flavonoid fraction (SOHFF) on the high-fat diet (HFD)-induced obesity and hepatorenal damage in rats. Salvia officinalis plants were collected from Hail region, Saudi Arabia. Rats were fed HFD and supplemented orally with SOTE (250 mg kg-1) or SOHFF (100 mg kg-1) or simvastatin (SVS; 10 mg kg-1) every day for 8 weeks. Compared to the controls, HFD-induced obesity led to significant increases in body weight, body weight gained, blood insulin, leptin, cardiac enzymes (LDH and CPK) activity, and atherogenic index (AI). HFD rats also showed higher levels of hepatic and renal function biomarkers (ALT, urea, and creatinine), as well as lower levels of PPARγ and Nrf2-gene expression and a disrupted lipid profile. Moreover, HFD rats had lower levels of hepatic and renal antioxidant biomarkers (CAT, GPx, SOD, GR, and GSH), accompanied by higher levels of hepatic and renal lipid peroxidation (LPO), nitric oxide (NO), and inflammatory mediators (interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α)). In addition, histological examination of hepatic and renal tissues revealed histopathological changes that validated the biochemical findings. Compared to HFD group, SOTE and SOHFF treatment led to marked amelioration of all the aforementioned parameters. Collectively, supplementation with SOTE and SOHFF effectively reversed HFD-induced alterations through its antioxidant, hypolipidemic, and anti-inflammatory properties. Hence, SOTE and SOHFF have therapeutic potential in controlling obesity and related pathologies.

Specialized pro-resolving mediators as modulators of immune responses.

Specialized pro-resolving mediators (SPMs) are endogenous small molecules produced mainly from dietary omega-3 polyunsaturated fatty acids by both structural cells and cells of the active and innate immune systems. Specialized pro-resolving mediators have been shown to both limit acute inflammation and promote resolution and return to homeostasis following infection or injury. There is growing evidence that chronic immune disorders are characterized by deficiencies in resolution and SPMs have significant potential as novel therapeutics to prevent and treat chronic inflammation and immune system disorders. This review focuses on important breakthroughs in understanding how SPMs are produced by, and act on, cells of the adaptive immune system, specifically macrophages, B cells and T cells. We also highlight recent evidence demonstrating the potential of SPMs as novel therapeutic agents in topics including immunization, autoimmune disease and transplantation.

Targeted treatment for osteoarthritis: drugs and delivery system.

The management of osteoarthritis (OA) is a clinical challenge due to the particular avascular, dense, and occluded tissue structure. Despite numerous clinical reports and animal studies, the pathogenesis and progression of OA are still not fully understood. On the basis of traditional drugs, a large number of new drugs have been continuously developed. Intra-articular (IA) administration for OA hastens the development of targeted drug delivery systems (DDS). OA drugs modification and the synthesis of bioadaptive carriers contribute to a qualitative leap in the efficacy of IA treatment. Nanoparticles (NPs) are demonstrated credible improvement of drug penetration and retention in OA. Targeted nanomaterial delivery systems show the prominent biocompatibility and drug loading-release ability. This article reviews different drugs and nanomaterial delivery systems for IA treatment of OA, in an attempt to resolve the inconsonance between in vitro and in vivo release, and explore more interactions between drugs and nanocarriers, so as to open up new horizons for the treatment of OA.

Palmitoylethanolamide: A Natural Compound for Health Management.

All nations which have undergone a nutrition transition have experienced increased frequency and falling latency of chronic degenerative diseases, which are largely driven by chronic inflammatory stress. Dietary supplementation is a valid strategy to reduce the risk and severity of such disorders. Palmitoylethanolamide (PEA) is an endocannabinoid-like lipid mediator with extensively documented anti-inflammatory, analgesic, antimicrobial, immunomodulatory and neuroprotective effects. It is well tolerated and devoid of side effects in animals and humans. PEA's actions on multiple molecular targets while modulating multiple inflammatory mediators provide therapeutic benefits in many applications, including immunity, brain health, allergy, pain modulation, joint health, sleep and recovery. PEA's poor oral bioavailability, a major obstacle in early research, has been overcome by advanced delivery systems now licensed as food supplements. This review summarizes the functionality of PEA, supporting its use as an important dietary supplement for lifestyle management.

Resolution-Based Therapies: The Potential of Lipoxins to Treat Human Diseases.

Inflammation is an a physiological response instead an essential response of the organism to injury and its adequate resolution is essential to restore homeostasis. However, defective resolution can be the precursor of severe forms of chronic inflammation and fibrosis. Nowadays, it is known that an excessive inflammatory response underlies the most prevalent human pathologies worldwide. Therefore, great biomedical research efforts have been driven toward discovering new strategies to promote the resolution of inflammation with fewer side-effects and more specificity than the available anti-inflammatory treatments. In this line, the use of endogenous specialized pro-resolving mediators (SPMs) has gained a prominent interest. Among the different SPMs described, lipoxins stand out as one of the most studied and their deficiency has been widely associated with a wide range of pathologies. In this review, we examined the current knowledge on the therapeutic potential of lipoxins to treat diseases characterized by a severe inflammatory background affecting main physiological systems, paying special attention to the signaling pathways involved. Altogether, we provide an updated overview of the evidence suggesting that increasing endogenously generated lipoxins may emerge as a new therapeutic approach to prevent and treat many of the most prevalent diseases underpinned by an increased inflammatory response.

Jasmonates from Chinese acorns (Quercus serrata var. brevipetiolata) exert pronounced anti-neuroinflammatory activities.

Chinese oak (Quercus serrata var. brevipetiolata) belongs to the genus Quercus in Fagaceae family. Its seed, called as Chinese acorn, has been served as a traditional medicine and foodstuff in China. In this study, ten jasmonates were isolated and purified from Chinese acorn, including five new (1-5) and five known jasmonates (6-10). The new jasmonates were identified as butyl (1R,2R)-2-[(2'Z)-5'-hydroxy-penten-2'-enyl]-3-oxo-cyclopentane acetate (1), methyl {2-[4'-(ß-d-glucopyranosyloxy)-pentyl}-3-oxo-cyclopentane acetate (2), methyl {(1R,2R)-2-[(2'Z,4'R)-4'-(ß-d-glucopyransyloxy)-pent-2'-enyl]}-3-oxo-cyclopentane acetate (3), methyl {(1R,2R)-2-[(2'E,4'S)-4'-(ß-d-glucopyransyloxy)-pent-2'-enyl]}-3-oxo-cyclopentane acetate (4), and methyl {(1R,2R)-2-[(2'S,3'E)-2'-(ß-D-glucopyransyloxy)-pent-3'-enyl]}-3-oxo-cyclopentane acetate (5), respectively. The isolated jasmonates were evaluated for anti-neuroinflammatory activity, and some showed pronounced inhibitory effects on the production of nitric oxide (NO) induced by lipopolysaccharide (LPS) in BV-2 microglia cells. Some jasmonates could dose-dependently reduce the expression of LPS-induced pro-inflammatory factors (iNOS and COX-2) and could block NF-κB nuclear translocation. This study suggested that Chinese acorns could be served as a healthy product for neuroinflammatory related diseases, such as Alzheimer's disease.

The effects of garlic (Allium sativum) supplementation on inflammatory biomarkers, fatigue, and clinical symptoms in patients with active rheumatoid arthritis: A randomized, double-blind, placebo-controlled trial.

Based on the antiinflammatory properties of garlic, current study was conducted to evaluate the garlic supplement effects on serum levels of some inflammatory biomarkers, clinical symptoms, and fatigue in women with active rheumatoid arthritis. In this randomized, double-blind, placebo-controlled trial study, 70 women with RA were randomly divided into two groups: The intervention group was supplemented with 1,000 mg of garlic, and the control group received placebo for 8 weeks. At baseline and at the end of the study, clinical symptoms, fatigue, serum level of C-reactive protein (CRP), tumor necrosis factor-a (TNF-a), and erythrocyte sedimentation rate (ESR) were determined. After intervention, serum levels of CRP (p = .018) and TNF-a (p < .001) decreased significantly in the garlic group as compared with the placebo group. Also, pain intensity, tender joint count, disease activity score (DAS-28), and fatigue were significantly decreased in the intervention group compared with the control group (p < .001; for all). Swollen joint count was significantly decreased in the garlic group (p < .001), but not in the placebo group (p = .123). No significant changes were observed for ESR. Garlic supplementation by improving inflammatory mediators and clinical symptoms can be considered as a potential adjunct treatment in patients with RA. However, further studies with larger duration are needed.

The effect of green tea on inflammatory mediators: A systematic review and meta-analysis of randomized clinical trials.

Catechin in green tea might be able to reduce inflammatory mediators; therefore, in this study, we aimed to indicate green tea effects on inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), and interleukin-6 (IL-6). The advanced search methods of electronic databases were used to find randomized clinical trials that assessed green tea effect on inflammatory mediators among adult population. Google Scholar, PubMed/Medline, EMBASE, SCOPUS, and ISI Web of Science were searched until January 2019. Delphi checklist was used for assessing the quality of included articles. Mean changes in serum inflammatory biomarkers were calculated by subtracting endpoint values from the baseline in each study arm. Then the effect size for each selected study was estimated as the difference between mean changes in the intervention and control groups. We included 16 articles in our meta-analysis and 17 articles in systematic review. Our results indicated that green tea could not significantly decrease serum CRP levels and significantly increased IL-6 and significantly decreased TNF-α levels. In conclusion, green tea might not be able to change inflammatory mediators especially in diseases with low inflammation, but scientists who want to assess green tea effect on inflammatory mediators should perform their study on patients with high inflammation. Studies exclusive on male or female and considering nutrients intake as a confounding factor are a necessity.

Can Specialized Pro-resolving Mediators Deliver Benefit Originally Expected from Fish Oil?

PURPOSE OF THE REVIEW: Fish oil (FO) supplementation has historically been used by individuals suffering from cardiovascular disease and other inflammatory processes. However, a meta-analysis of several large randomized control trials (RCTs) suggested FO conferred no benefit in reducing cardiovascular risk. Skeptics surmised that the lack of benefit was related to FO dose or drug interactions; therefore, the widely accepted practice of FO consumption was brought into question. RECENT FINDINGS: Thereafter, Serhan et al. identified specialized pro-resolving mediators (SPMs) to be one of the bioactive components and mechanisms of action of FO. SPMs are thought to enhance resolution of inflammation, as opposed to classic anti-inflammatory agents which inhibit inflammatory pathways. Numerous diseases, including persistent Inflammation, immunosuppression, and catabolic syndrome (PICS), are rooted in a burden of chronic inflammation. SPMs are gaining traction as potential therapeutic agents used to resolve inflammation in cardiovascular disorders, inflammatory bowel disease, sepsis, pancreatitis, and acute respiratory distress syndrome (ARDS). This narrative reviews the history of FO and the various studies that made the health benefits of FO inconclusive, as well as an overview of SPMs and their use in specific disease states.

Futuro de los tratamientos biológicos en la EPOC / The Future of Biological Therapies in COPD

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Resolution of vascular injury: Specialized lipid mediators and their evolving therapeutic implications.

Acute vascular injury occurs in a number of important clinical contexts, including spontaneous disease-related events (e.g. plaque rupture, thrombosis) and therapeutic interventions such as angioplasty, stenting, or bypass surgery. Endothelial cell (EC) disruption exposes the underlying matrix, leading to a rapid deposition of platelets, coagulation proteins, and leukocytes. A thrombo-inflammatory response ensues characterized by leukocyte recruitment, vascular smooth muscle cell (VSMC) activation, and the elaboration of cytokines, reactive oxygen species and growth factors within the vessel wall. A resolution phase of vascular injury may be described in which leukocyte efflux, clearance of debris, and re-endothelialization occurs. VSMC migration and proliferation leads to the development of a thickened neointima that may lead to lumen compromise. Subsequent remodeling involves matrix protein deposition, and return of EC and VSMC to quiescence. Recent studies suggest that specialized pro-resolving lipid mediators (SPM) modulate key aspects of this response, and may constitute an endogenous homeostatic pathway in the vasculature. SPM exert direct effects on vascular cells that counteract inflammatory signals, reduce leukocyte adhesion, and inhibit VSMC migration and proliferation. These effects appear to be largely G-protein coupled receptor-dependent. Across a range of animal models of vascular injury, including balloon angioplasty, bypass grafting, and experimental aneurysm formation, SPM accelerate repair and reduce lesion formation. With bioactivity in the pM-nM range, a lack of discernible cytotoxicity, and a spectrum of vasculo-protective properties, SPM represent a novel class of vascular therapeutics. This review summarizes current research in this field, including a consideration of critical next steps and challenges in translation.

Actions of SPM in regulating host responses in arthritis.

The discovery and identification of omega-3 fatty acid derived specialized pro-resolving mediators (SPM) provides a molecular mechanism for the beneficial effects of fish oil supplementation in patients suffering from arthritis. Here we review the plethora of bioactions of SPM in the context of joint diseases, focusing on both cellular targets and molecular mechanisms. Whenever possible, a parallel to clinical and preclinical data produced with fish oil supplementation is made to strengthen the mechanistic link between omega-3 fatty acids and SPM biosynthesis. SPM can modulate the reactivity of many cells that are pivotal to the development and/or maintenance of joint disease. Whereas work has so far focused on the actions of SPM on immune cells and therefore, within this context, macrophages, neutrophils, mast cells and T cells, we reason that more work needs to focus on the effects that these bioactive lipid mediators may have on the structural cell component of the joint, this encompassing synovial fibroblasts, chondrocytes, osteoclasts and osteoblasts. Full definition of the properties that SPM may exert on these cells can help in unveiling their ability to promote tissue restoration and regeneration, a prerequisite to repair joint damage, and as such promote the development of innovative therapeutic strategies based on the science of SPM and resolution.

Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors.

The acute inflammatory response is host-protective to contain foreign invaders. Many of today's pharmacopeia that block pro-inflammatory chemical mediators can cause serious unwanted side effects such as immune suppression. Uncontrolled inflammation is now considered a pathophysiologic basis associated with many widely occurring diseases such as cardiovascular disease, neurodegenerative diseases, diabetes, obesity and asthma, as well as the classic inflammatory diseases, e.g. arthritis, periodontal diseases. The inflammatory response is designated to be a self-limited process that produces a superfamily of chemical mediators that stimulate resolution of inflammatory responses. Specialized proresolving mediators (SPM) uncovered in recent years are endogenous mediators that include omega-3-derived families resolvins, protectins and maresins, as well as arachidonic acid-derived (n-6) lipoxins that stimulate and promote resolution of inflammation, clearance of microbes, reduce pain and promote tissue regeneration via novel mechanisms. Here, we review recent evidence from human and preclinical animal studies, together with the structural and functional elucidation of SPM indicating the SPM as physiologic mediators and pharmacologic agonists that stimulate resolution of inflammation and infection. These results suggest that it is time to develop immunoresolvents as agonists for testing resolution pharmacology in nutrition and health as well as in human diseases and during surgery.

Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms.

Practitioners of ancient societies from the time of Hippocrates and earlier recognized and treated the signs of inflammation, heat, redness, swelling, and pain with agents that block or inhibit proinflammatory chemical mediators. More selective drugs are available today, but this therapeutic concept has not changed. Because the acute inflammatory response is host protective to contain foreign invaders, much of today's pharmacopeia can cause serious unwanted side effects, such as immune suppression. Uncontrolled inflammation is now considered pathophysiologic and is associated with many widely occurring diseases such as cardiovascular disease, neurodegenerative diseases, diabetes, obesity, and asthma, as well as classic inflammatory diseases (e.g., arthritis and periodontal diseases). The inflammatory response, when self-limited, produces a superfamily of chemical mediators that stimulate resolution of the response. Specialized proresolving mediators (SPMs), identified in recent years, are endogenous mediators that include the n-3-derived families resolvins, protectins, and maresins, as well as arachidonic acid-derived (n-6) lipoxins, which promote resolution of inflammation, clearance of microbes, reduction of pain, and promotion of tissue regeneration via novel mechanisms. Aspirin and statins have a positive impact on these resolution pathways, producing epimeric forms of specific SPMs, whereas other drugs can disrupt timely resolution. In this article, evidence from recent human and preclinical animal studies is reviewed, indicating that SPMs are physiologic mediators and pharmacologic agonists that stimulate resolution of inflammation and infection. The findings suggest that it is time to challenge current treatment practices-namely, using inhibitors and antagonists alone-and to develop immunoresolvents as agonists to test resolution pharmacology and their role in catabasis for their therapeutic potential.-Serhan, C. N. Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms.

Dual Role of GM-CSF as a Pro-Inflammatory and a Regulatory Cytokine: Implications for Immune Therapy.

Granulocyte macrophage colony stimulating factor (GM-CSF) is generally recognized as an inflammatory cytokine. Its inflammatory activity is primarily due its role as a growth and differentiation factor for granulocyte and macrophage populations. In this capacity, among other clinical applications, it has been used to bolster anti-tumor immune responses. GM-CSF-mediated inflammation has also been implicated in certain types of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. Thus, agents that can block GM-CSF or its receptor have been used as anti-inflammatory therapies. However, a review of literature reveals that in many situations GM-CSF can act as an anti-inflammatory/regulatory cytokine. We and others have shown that GM-CSF can modulate dendritic cell differentiation to render them "tolerogenic," which, in turn, can increase regulatory T-cell numbers and function. Therefore, the pro-inflammatory and regulatory effects of GM-CSF appear to depend on the dose and the presence of other relevant cytokines in the context of an immune response. A thorough understanding of the various immunomodulatory effects of GM-CSF will facilitate more appropriate use and thus further enhance its clinical utility.