Action Of Anti-inflammatory Drugs Research Articles

Modulation of Phospholipase A2 Membrane Activity by Anti-inflammatory Drugs.

The phospholipase A2 (PLA2) superfamily consists of lipolytic enzymes that hydrolyze specific cell membrane phospholipids and have long been considered a central hub of biosynthetic pathways, where their lipid metabolites exert a variety of physiological roles. A misregulated PLA2 activity is associated with mainly inflammatory-derived pathologies and thus has shown relevant therapeutic potential. Many natural and synthetic anti-inflammatory drugs (AIDs) have been proposed as direct modulators of PLA2 activity. However, despite the specific chemical properties that these drugs share in common, little is known about the indirect modulation able to finely tune membrane structural changes at the precise lipid-binding site. Here, we use a novel experimental strategy based on differential scanning calorimetry to systematically study the structural properties of lipid membrane systems during PLA2 cleavage and under the influence of several AIDs. For a better understanding of the AIDs-membrane interaction, we present a comprehensive and comparative set of molecular dynamics (MD) simulations. Our thermodynamic results clearly demonstrate that PLA2 cleavage is hindered by those AIDs that significantly reduce the lipid membrane cooperativity, while the rest of the AIDs oppositely tend to catalyze PLA2 activity to different extents. On the other hand, our MD simulations support experimental results by providing atomistic details on the binding, insertion, and dynamics of each AID on a pure lipid system; the drug efficacy to impact membrane cooperativity is related to the lipid order perturbation. This work suggests a membrane-based mechanism of action for diverse AIDs against PLA2 activity and provides relevant clues that must be considered in its modulation.

Possible Participation of Adenine Nucleotide Translocase ANT1 in the Cytotoxic Action of Progestins, Glucocorticoids, and Diclofenac on Tumor Cells.

A comparative analysis of the cytostatic effects of progestins (gestobutanoyl, megestrol acetate, amol, dienogest, and medroxyprogesterone acetate), glucocorticoids (hydrocortisone, dexamethasone), and diclofenac on tumor cells was carried out in order to confirm their in silico predicted probabilities experimentally. The results showed the different sensitivity of HeLa, MCF-7, Hep-2, K-562, and Wi-38 cell lines to progestins, glucocorticoids, and diclofenac. The minimum IC50 was found for progestin gestobutanoyl (GB) as 18 µM for HeLa cells, and varied from 31 to 38 µM for MCF-7, Hep-2, and K-562. Glucocorticoids and diclofenac were much less cytotoxic in the HeLa, MCF-7, and Hep-2 cell lines than progestins, with IC50 values in the range of 150-3000 μM. Myelogenous leukemia K-562 cells were the least sensitive to the action of progestins and glucocorticoids but the most sensitive to diclofenac, which showed a pronounced cytotoxic effect with an IC50 of 31 μM. As we have shown earlier, progestins can uniquely modulate MPTP opening via the binding of adenine nucleotide translocase. On this basis, we evaluated the expression of adenylate nucleotide translocase ANT1 (SLC25 A4) as a possible participant in cytotoxic action in these cell lines after 48 h incubation with drugs. The results showed that progestins differently regulated ANT1 expression in different cell lines. Gestobutanoyl had the opposite effect on ANT1 expression in the HeLa, K562, and Wi-38 cells compared with the other progestins. It increased the ANT1 expression more than twofold in the HeLa and K562 cells but had no influence on the Wi-38 cells. Glucocorticoids and diclofenac increased ANT1 expression in the Wi-38 cells and decreased it in the K562, MCF-7, and Hep-2 cells. The modulation of ANT1 expression discovered in our study can be a new explanation of the cytotoxic and cytoprotective effects of hormones, which can vary depending on the cell type. ANT isoforms in normal and cancerous cells could be a new target for steroid hormone and anti-inflammatory drug action.

Pathogenesis of Post-Traumatic Stress Disorder, Therapeutic Targets

Abstract—The review summarizes current literature information on the mechanisms of pathogenesis of severe stress-induced disease – post-traumatic stress disorder (PTSD). Hormonal, biochemical, genetic and morphofunctional changes in peripheral organs and in the central nervous system occurring in PTSD are characterized. It turned out that most researchers have formed an opinion about the leading role of chronic inflammation in PTSD. The data on the study of the action of anti-inflammatory drugs with a narrow biochemical orientation are presented. The review concludes with the presentation of the hypothesis that the pathogenesis of PTSD should be considered as an integrative inflammatory process of peripheral and central systems. The therapeutic agent in this case, most likely, should be a multifunctional drug. Judging by the results of the authors' experiments, it is most likely to be drugs of the pharmacological group of heparins.

Mechanism of Anti-Inflammatory Drugs in the Early Treatment of Oral Gingival Mucosa and Soft Tissue Trauma.

Traumatic tissue develops an uncontrolled inflammatory response that causes secondary damage to the injured tissue and other parts of the body. Therefore, preventing wound infection, reducing inflammatory response, and reducing secondary tissue damage are the keys to early treatment of tissue trauma. In the treatment of gingival soft tissue trauma, anti-inflammatory and analgesic drugs are reasonably selected according to the condition, which can effectively reduce inflammation, and they help periodontal tissue regeneration and healing. However, there are few studies on the mechanism of anti-inflammatory drugs in the early treatment of oral gingival mucosal soft tissue trauma, and the specific mechanism is unknown. Therefore, this paper explored the mechanism of anti-inflammatory drugs in the early treatment of oral gingival mucosa and soft tissue trauma through experiments, which provided theoretical support for the clinical treatment of gingival mucosa and soft tissue trauma repair. In this paper, two anti-inflammatory drugs, levofloxacin and metronidazole, were selected to measure their release properties in vitro and in vivo. Then, the white-eared rabbits were treated with gingival wound treatment experiments, and the physiological characteristics, intratissue pressure, tissue partial pressure of oxygen, IL-6 content, and PGE2 content were determined at each postinjury period, and the mechanism of action of anti-inflammatory drugs was determined. Research results have shown that anti-inflammatory drugs can significantly inhibit the content of IL-6 and PGE2 in gingival soft tissue after injury, reduce the local inflammatory response, and accelerate tissue healing.

Grossamide attenuates inflammation by balancing macrophage polarization through metabolic reprogramming of macrophages in mice

Macrophages exhibited different phenotypes in response to environmental cues. To meet the needs of rapid response to stimuli, M1-activated macrophages preferred glycolysis to oxidative phosphorylation (OXPHOS) in mitochondria to quickly produce energy and obtain ample raw materials to support cell activation at the same time. Activated macrophages produced free radicals and cytokines to eradicate pathogens but also induced oxidative damage and enhanced inflammation. Grossamide (GSE), a lignanamide from Polygonum multiflorum Thunb., exhibited notable anti-inflammatory effects.In this study, the potential of GSE on macrophage polarization was explored. GSE significantly down-regulated the levels of M1 macrophage biomarkers (Cd32a, Cd80 and Cd86) while increased the levels of M2 indicators (Cd163, Mrc1 and Socs1), showing its potential to inhibit LPS-induced M1 polarization of macrophages. This ability has close a link to its effect on metabolic reprogramming of macrophage. GSE shunted nitric oxide (NO) production from arginine by up-regulation of arginase and down-regulation of inducible nitric oxide synthase, thus attenuated the inhibition of NO on OXPHOS. LPS created three breakpoints in the tricarboxylic acid cycle (TCA) cycle of macrophage as evidenced by down-regulated isocitrate dehydrogenase, accumulation of succinate and the inhibited SDH activity, significantly decreased level of oxoglutarate dehydrogenase expression and its substrate α-ketoglutarate. Thus GSE reduced oxidative stress and amended fragmented TCA cycle. As a result, GSE maintained redox (NAD+/NADH) and energy (ATP/ADP) state, reduced extracellular acidification rate and enhanced the oxygen consumption rate. In addition, GSE decreased the release of inflammatory cytokines by inhibiting the activation of the LPS/TLR4/NF-κB pathway. These findings highlighted the central role of immunometabolism of macrophages in its functional plasticity, which invited future study of mode of action of anti-inflammatory drugs from viewpoint of metabolic reprogramming.

Mechanisms of the immune/inflammatory responses and production of reactive oxygen and nitrogen species in gingivitis and pharmacodynamics of anti-inflammatory drugs

Introduction: Gingivitis is characterized as an inflammation of the gum and can have different etiologies, however, most cases occur due to poor oral hygiene and accumulation of bacteria in dental plaque, causing periodontal disease, which can progress to tooth loss. Knowing the pathophysiology of gingivitis is necessary for an effective therapeutic intervention by the professional. This work aims to describe the pathophysiological process of gingivitis and discuss the mechanism of action of anti-inflammatory drugs. Methodology: This work is a literature review carried out on Google Scholar, PUBMED and SciELO platforms. Results and Discussion: Bacteria accumulated in the plaque are recognized by phagocytes, which are activated and induce immune and inflammatory responses, in addition to activating oxidative and nitrosative stress pathways, resulting in bacterial death and gingival necrosis. In the face of aggression, gingiva cells activate the arachidonic acid cascade, which gives rise to several pro-inflammatory mediators; Typical anti-inflammatory drugs block enzymes in this cascade, inhibiting the production of these chemical signals. Conclusion: Therefore, immune and inflammatory responses are important for the prognosis of gingivitis, however, in some cases, therapeutic interventions are necessary so that there is no great tissue and tooth loss.

Mechanisms of the immune/inflammatory responses and production of reactive oxygen and nitrogen species in gingivitis and pharmacodynamics of anti-inflammatory drugs

Introduction: Gingivitis is characterized as an inflammation of the gum and can have different etiologies, however, most cases occur due to poor oral hygiene and accumulation of bacteria in dental plaque, causing periodontal disease, which can progress to tooth loss. Knowing the pathophysiology of gingivitis is necessary for an effective therapeutic intervention by the professional. This work aims to describe the pathophysiological process of gingivitis and discuss the mechanism of action of anti-inflammatory drugs. Methodology: This work is a literature review carried out on Google Scholar, PUBMED and SciELO platforms. Results and Discussion: Bacteria accumulated in the plaque are recognized by phagocytes, which are activated and induce immune and inflammatory responses, in addition to activating oxidative and nitrosative stress pathways, resulting in bacterial death and gingival necrosis. In the face of aggression, gingiva cells activate the arachidonic acid cascade, which gives rise to several pro-inflammatory mediators; Typical anti-inflammatory drugs block enzymes in this cascade, inhibiting the production of these chemical signals. Conclusion: Therefore, immune and inflammatory responses are important for the prognosis of gingivitis, however, in some cases, therapeutic interventions are necessary so that there is no great tissue and tooth loss.

Sex-Related Differences in Drugs with Anti-Inflammatory Properties.

There is increasing evidence of sex differences in the action of anti-inflammatory drugs, with women being at significantly higher risk of adverse effects. Nevertheless, clinicians’ awareness of the implications of these sex differences on dosing and adverse event monitoring in routine practice is still in need of improvement. We reviewed the literature evaluating sex differences in terms of pharmacokinetics and pharmacodynamics of anti-inflammatory drugs. The anti-thrombotic activity of selective and non-selective COX-inhibitors tends to be stronger in men than women. Side effect profiles differ with regards to gastro-intestinal, renal and hepatic complications. Glucocorticosteroids were found to be more effective in men; women were more sensitive to corticosteroids when their oestradiol levels were high, a finding important for women taking hormonal contraception. TNF-alpha inhibitors have a longer half-life in men, leading to stronger immunosuppression and this a higher incidence of infections as side effects. Although research on sex differences in the effectiveness and safety of drugs is increasing, findings are often anecdotal and controversial. There is no systematic sex-differentiated reporting from clinical trials, and women are often under-represented. As personalized medicine is gaining in importance, sex, and gender aspects need to become integral parts of future research and policy making.

Enhancement of Dissolution Rate of Quercetin Using Solid Dispersion Approach: In Vitro and In Vivo Evaluation

Objective: The objective of present study was to enhance the potential activities of Quercetin by improving its solubility and dissolution profiles through solid dispersion approach. Method: A three level full factorial design (32) was adopted to study the possible combinations of polyethylene glycol (PEG) 6000 & pluronic F 127 (PF 127). The solid dispersions were prepared by solvent evaporation method and evaluated for percentage yield, drug content, aqueous solubility and drug release. For in vivo evaluations SD4 was incorporated into Carbopol base gel and subjected to anti-inflammatory activity using carrageenan-induced rat paw edema method. Results: SD4 batch with drug to carrier ratio 1:1 showed release of 82.96 ± 1.76 % in 240 min following Higuchi’s model. It was 5.54 fold increment in solubility as compared to quercetin. SD4 batch was further evaluated by FTIR, DSC, PXRD and SEM. The crystallinity was significantly reduced and drug was homogeneously dispersed in the carrier as shown by the results of DSC, PXRD and SEM. The DPPH scavenging assay showed significance in the IC50 value of SD4 as compared to pure quercetin and ascorbic acid when subjected to one way ANOVA at 0.05 level of significance (P<0.0001). In vivo anti-inflammatory study showed 78.17 ± 0.156 % inhibition of edema by SD4 and 58.64 ± 0.640 % by pure quercetin which is significantly lower (P<0.05). Conclusion: These findings demonstrate that the solid dispersion of quercetin shows increased solubility, dissolution profile, drug release and significant potential in enhancing the antiinflammatory activity of drug.

NSAIDs and heart failure: A dangerous relationship.

One of the potential cardiotoxic action of anti-inflammatory drugs is the occurrence of heart failure (HF), due to their effects on fluid retention and blood pressure. The risk of hospitalization for HF is roughly doubled for both Coxibs, cyclooxygenase-1 (COX-1) and cyclooxygenase- 2 (COX-2) inhibitors, and all the conventional nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs are also associated with a risk of vascular thrombosis, which for NSAIDs is different in relation to their different ability to inhibit COX-1 and COX-2. The cardiovascular toxicity of these drugs in the direction of HF follow different pathways respect to their related vascular thrombosis toxicity and involves, in particular, the renal prostaglandins, PGE2 and prostacyclin, mostly synthesized by COX-2. In the kidneys the PGs perform a direct vasodilatory action, e.g. by means of non-contrasting angiotensin mechanisms, and for this reason nimesulide effects on renal microcirculation are independent from the prevalence of intrarenal renin angiotensin aldosterone system (RAAS) activity. Conversely, nimesulide reduces sodium tubular urinary flow only in presence of intrarenal RAAS.

Systems Biology of Immunomodulation for Post-Stroke Neuroplasticity: Multimodal Implications of Pharmacotherapy and Neurorehabilitation.

Recent studies indicate that anti-inflammatory drugs, act as a double-edged sword, not only exacerbating secondary brain injury but also contributing to neurological recovery after stroke. Our aim is to explore whether there is a beneficial role for neuroprotection and functional recovery using anti-inflammatory drug along with neurorehabilitation therapy using transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), so as to improve functional recovery after ischemic stroke. We develop a computational systems biology approach from preclinical data, using ordinary differential equations, to study the behavior of both phenotypes of microglia, such as M1 type (pro-inflammatory) vis-à-vis M2 type (anti-inflammatory) under anti-inflammatory drug action (minocycline). We explore whether pharmacological treatment along with cerebral stimulation using tDCS and rTMS is beneficial or not. We utilize the systems pathway analysis of minocycline in nuclear factor kappa beta (NF-κB) signaling and neurorehabilitation therapy using tDCS and rTMS that act through brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) signaling pathways. We demarcate the role of neuroinflammation and immunomodulation in post-stroke recovery, under minocycline activated-microglia and neuroprotection together with improved neurogenesis, synaptogenesis, and functional recovery under the action of rTMS or tDCS. We elucidate the feasibility of utilizing rTMS/tDCS to increase neuroprotection across the reperfusion stage during minocycline administration. We delineate that the signaling pathways of minocycline by modulation of inflammatory genes in NF-κB and proteins activated by tDCS and rTMS through BDNF, TrkB, and calmodulin kinase (CaMK) signaling. Utilizing systems biology approach, we show that the activation pathways for pharmacotherapy (minocycline) and neurorehabilitation (rTMS applied to ipsilesional cortex and tDCS) results into increased neuronal and synaptic activity that commonly occur through activation of N-methyl-d-aspartate receptors. We construe that considerable additive neuroprotection effect would be obtained and delayed reperfusion injury can be remedied, if one uses multimodal intervention of minocycline together with tDCS and rTMS. Additive beneficial effect is, thus, noticed for pharmacotherapy along with neurorehabilitation therapy, by maneuvering the dynamics of immunomodulation using anti-inflammatory drug and cerebral stimulation for augmenting the functional recovery after stroke, which may engender clinical applicability for enhancing plasticity, rehabilitation, and neurorestoration.

Estudo dos anti-inflamatórios e analgésicos utilizados pelos idosos da Estratégia Saúde da Família de Porto Alegre

Background: The high prevalence of anti-inflammatory and analgesic drug use by the elderly has been widely discussed in the literature because polymedication increases the risk of adverse effects and iatrogenic and drug interactions. Anti-inflammatory and analgesic drugs are primarily used to treat pain in the elderly, who are subject to high rates of arthrosis, arthritis and rheumatism. The prescription of anti-inflammatories and analgesics in the elderly should be individualized because the pharmacokinetics and pharmacodynamics of these drugs are altered in the elderly, which can cause numerous adverse effects. However, many studies have indicated a possible antioxidant action of anti-inflammatory drugs. Some studies have suggested that anti-inflammatory drugs induce the generation of reactive oxygen species, while other studies have demonstrated that they also have antioxidant activity. Aims: We report the findings of a transversal study of the use of anti inflammatory and analgesic drugs among a random sample of elderly patients at the Family Health Strategy (FHS) in Porto Alegre, Rio Grande do Sul, Brazil. Methods: This study is part of the “The multidimensional study of the elderly in the Family Health Strategy in Porto Alegre, Brazil (EMI-SUS)” conducted over the period of March 2011 to December 2012. Data collection was performed by community health workers at the subjects’ homes using a general questionnaire and included sociodemographic data, life conditions and habits, chronic diseases and drug use. For this study, the focus was on drugs classified as anti-inflammatory or analgesic drugs according to the Anatomical Therapeutic Chemical classification system recommended by the World Health Organization. Blood was subsequently collected by the project team at the healthcare unit where the elderly patients were registered. The plasma levels of oxidative and inflammatory markers such as insulin, homeostatic model assessmentinsulin resistance (HOMA-IR), malondialdehyde (MDA), ferric reducing ability of plasma (FRAP), advanced oxidation protein products (AOPP), interleukin-6 (IL-6) and ultra-sensitivity C-reactive protein (PCR_US) were determined. Anthropometric data were measured, but only body mass index (BMI) was used in this study. Results: Among the 758 elderly patients included in this study, between 60 and 111 years old, with the prevalence of anti inflammatory and analgesic drug use was 28.8%. Paracetamol (67.9%) and ibuprofen (31.7%) were the most commonly used drugs. Women used anti inflammatory and analgesic drugs (P=0.022) more frequently than men. Self rated health was related to the use of anti-inflammatory and analgesic drugs, i.e., the worse the reported health, the greater the use of these drugs (P<0.001). Of the conditions described by the elderly, hepatic disease (P=0.004) and arthrosis/arthritis/rheumatism were associated with the use of anti-inflammatory and analgesic drugs. In addition, we observed that the higher the usage of medicines in general, the greater the use of anti-inflammatory and analgesic drugs (P<0.001). Gastric problems reported by this elderly cohort may be associated with chronic or occasional use of NSAIDs (P=0.042). There was no statistically significant association between the use of NSAIDs and oxidative or inflammatory markers. Conclusion: This study demonstrates the moderate use of anti-inflammatory and analgesic drugs by elderly patients at the FHS in Porto Alegre. Although these medications are important for the management of pain and inflammation, they may interfere with the improvement of the quality of life of the elderly. Thus, anti-inflammatory and analgesic drugs should be prescribed very carefully and individually in the elderly. With regard to inflammatory and oxidative markers, it is important to emphasize that the physiological effects of NSAIDs on markers of inflammation and oxidative metabolism are poorly characterized and controversial. This is the first study to demonstrate a lack of association between NSAID use and plasma levels of oxidative, antioxidant and inflammatory markers or the HOMA-IR value.

From plant extract to molecular panacea: a commentary on Stone (1763) 'An account of the success of the bark of the willow in the cure of the agues'.

The application of aspirin-like drugs in modern medicine is very broad, encompassing the treatment of inflammation, pain and a variety of cardiovascular conditions. Although anecdotal accounts of willow bark extract as an anti-inflammatory drug have occurred since written records began (for example by Hippocrates), the first convincing demonstration of a potent anti-pyretic effect of willow bark containing salicylates was made by the English cleric Edward Stone in the late eighteenth century. Here, we discuss the route to optimizing and understanding the mechanism of action of anti-inflammatory drugs that have their origins in Stone's seminal study, ‘An account of the success of the bark of the willow in the cure of agues’. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society.

A Role for Glutathione Transferase Omega 1 (GSTO1-1) in the Glutathionylation Cycle

The glutathionylation of intracellular protein thiols can protect against irreversible oxidation and can act as a redox switch regulating metabolic pathways. In this study we discovered that the Omega class glutathione transferase GSTO1-1 plays a significant role in the glutathionylation cycle. The catalytic activity of GSTO1-1 was determined in vitro by assaying the deglutathionylation of a synthetic peptide by tryptophan fluorescence quenching and in T47-D epithelial breast cancer cells by both immunoblotting and the direct determination of total glutathionylation. Mutating the active site cysteine residue (Cys-32) ablated the deglutathionylating activity of GSTO1-1. Furthermore, we demonstrate that the expression of GSTO1-1 in T47-D cells that are devoid of endogenous GSTO1-1 resulted in a 50% reduction in total glutathionylation levels. Mass spectrometry and immunoprecipitation identified β-actin as a protein that is specifically deglutathionylated by GSTO1-1 in T47-D cells. In contrast to the deglutathionylation activity, we also found that GSTO1-1 is associated with the rapid glutathionylation of cellular proteins when the cells are exposed to S-nitrosoglutathione. The common A140D genetic polymorphism in GSTO1 was found to have significant effects on the kinetics of both the deglutathionylation and glutathionylation reactions. Genetic variation in GSTO1-1 has been associated with a range of diseases, and the discovery that a frequent GSTO1-1 polymorphism affects glutathionylation cycle reactions reveals a common mechanism where it can act on multiple proteins and pathways.

Letter: The action of anti-inflammatory drugs in two models of inflammation.

Letter: The action of anti-inflammatory drugs in two models of inflammation.

Anti-inflammatory action of drugs that raise adenosine-3',5'-cyclic monophosphate and putrescine levels in-vivo.

Isoprenaline and salbutamol, two beta-adrenoceptor agonist drugs, and 3-isobutyl-methyl xanthine and thioacetamide have been shown to be anti-inflammatory. Their mode of action is probably due to an increase in the levels of the three endogenous substances adenosine-3',5'-cyclic monophosphate and putrescine and spermidine in-vivo.

The action of anti-inflammatory drugs on the permeability of mesenteric mesothelium to plasma protein.

Journal Article The Action of Anti-inflammatory Drugs on the Permeability of Mesenteric Mesothelium to Plasma Protein Get access B J Northover B J Northover Department of Pharmacy, Christian Medical College, Vellore, South India Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 15, Issue 1, September 1963, Pages 153–154, https://doi.org/10.1111/j.2042-7158.1963.tb12762.x Published: 12 April 2011 Article history Received: 07 December 1962 Published: 12 April 2011

Expression, regulation and functional activities of aminopeptidase N (EC 3.4.11.2; APN; CD13) on murine macrophage J774 cell line

Aminopeptidase N (APN; CD13) is a ubiquitous membrane-bound enzyme. Expressed on haematopoietic cells APN participates in inflammatory and immune responses by regulating local concentration of chemotactic peptides and by fine-tuning antigen presentation. The data of this study have shown for the first time that cells of murine macrophage line, J774, often used as a model cell line, express CD13 both at transcriptional level and at the level of membrane protein with aminopeptidase N (APN) activity. The level of transcriptional expression of CD13/APN on J774 cells was compared to that found on normal cells participating in immune responses. The highest CD13/APN level was found in peritoneal macrophages, followed by J774 cells and splenocytes, whereas lymph node, thymus and bone-marrow cells expressed low level of CD13/APN mRNA. Further, the CD13 (mRNA, protein and APN) on J774 cells could be up-regulated by pro-inflammatory IFN-γ which is in agreement with the known role of CD13/APN in inflammatory responses. Co-regulation of CD13 with MHC-II and CD86 is in line with the reported role of APN expressed on human cells in antigen presentation. CD13 on J774 cells co-localize with mannose receptors (MR), and co-internalize upon MR ligation by ovalbumin, suggesting a new function of CD13 in MR-mediated phagocytosis. That function of CD13 is independent of APN enzyme activity. Anti-inflammatory drug dexamethasone diminished the IFN-γ-induced increase of CD13. The observed down-regulation of CD13 on J774 cells by dexamethasone might be relevant as a possible mechanism involved in action of anti-inflammatory drugs on normal macrophages.

QSAR of anti-inflammatory drugs

The computer analysis of relations between molecular structures and their biological activity using fragment-based methods is very useful to draw conclusions for the understanding of drug action and for the development of more efficient non-toxic drug candidates. We used the computer system SARD-21 (Structure Activity Relationship & Design) to investigate common structural features (fragments and substituents) typical for high- and low-effective non-steroid anti-inflammatory drugs (NSAIDs) succesfully. This derived information has been used for the model for prediction of anti-inflammatory effectiveness of medicines with 76% and 81% level of recognition by two methods. This information could be used for creating new highly effective NSAIDs, and for increasing effectiveness of already known components. In a second part of this paper the interrelation between structure and efficacy for anti-inflammatory drug action is carried out using traditional QSAR with descriptors from topology and from quantum-mechanical calculations followed by regression models from modelling. The aim of this paper is to compare both molecular approaches of molecular design of drugs.

Gender Medicine and Frankincense: Novel Findings in Inflammation Research

Detailed insights into the pathobiochemical mechanisms of the inflammatory process and the molecular actions of anti-inflammatory drugs are determinants for successful intervention with inflammatory diseases. Gender differences regarding susceptibility to inflammatory diseases are well known, for example rheumatoid arthritis and systemic lupus erythematosus more often affect women. In asthma, sex differences are apparent with a male predominance in childhood, whereas after puberty females predominate, due to a drop in males, reflecting a protective function of androgens. However, the biochemical mechanisms underlying these gender disparities are not understood. Leukotrienes, generated by the 5-lipoxygenase (5-LO) pathway, are involved in inflammatory and allergic disorders, and leukotriene receptor antagonists are used in asthma therapy. We found that leukotriene formation is substantially higher in females versus males, accompanied by different 5-LO trafficking, due to male-specific activation of extracellular signal-regulated kinases (ERKs). The differences are directly related to male/female testosterone levels. Our data suggest that gender issues should be considered in the use of anti-leukotrienes as therapeutics to optimize pharmacological therapy, in men and women. The anti-inflammatory properties of frankincense, the gum resin derived from Boswellia species, are well-recognized. Boswellic acids (BAs) are major ingredients of frankincense that were shown to inhibit 5-LO in vitro, but recent data question the pharmacological relevance of such interference in vivo. We report about the identification of human cathepsin G as pharmacologically relevant target of BAs. In particular, the major naturally occurring β-BA, reaching pharmacological relevant plasma levels (6.5–10 μM) after oral intake of medical frankincense preparations, potently inhibits cathepsin G in vitro and ex vivo, and exhibits high efficacy in animal models of inflammation, supporting an anti-inflammatory efficacy of frankincense in patients.