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The enzyme 5-lipoxygenase (5-LO) converts arachidonic acid to leukotrienes, which mediate inflammation. The enzyme is known to contribute to organ fibrosis, but how it contributes to renal fibrosis is unclear. Here, we reported that fibrotic kidneys expressed high levels of 5-LO, and deleting the 5-LO gene mitigated renal fibrosis in mice subjected to unilateral ureteral obstruction (UUO), based on assays of collagen deposition, injury and inflammation. Mechanistically, the exogenous leukotrienes B4 and C4, the downstream products of 5-LO, could induce the epithelial-mesenchymal transition (EMT) in kidney epithelial cell cultures, based on assays of E-cadherin, vimentin and snail expression. Studies in UUO mice confirmed that 5-LO deletion inhibited the EMT in the obstructed kidney. More importantly, 5-LO inhibitor zileuton loaded in CREKA-Lip, which could target to fibrotic kidney, markedly attenuated UUO-induced renal fibrosis and injury by inhibiting the EMT in the obstructed kidney. Our results suggested that 5-LO activity may contribute to renal fibrosis by promoting renal EMT, implying that the enzyme may be a useful therapeutic target.

• Co-infection HTLV-1/HIV impacted the biomarker profile of HTLV patients. • Increase in the inflammatory response is hallmarked in the presence of co-infection. • HAM(+) patients are characterized by higher levels of CXCL8, CCL2, CXCL-10 and TNF. The impact of HIV co-infection on the plasma immunological biomarker profile of HTLV-1 infected patients was evaluated. The plasma levels of leukotrienes and chemokines/cytokines were quantified by ELISA and Cytometric Bead Array. A total of 138 volunteers were enrolled and divided into two subgroups ("HTLV-1(+)HIV(-)" and "HTLV-1(+)(HIV(+)"), which were categorized according to the HTLV-1-associated neurological disease (AS, pHAM and HAM). Reference controls were BD and HIV mono-infected patients. HAM(+) exhibited higher CD4+ T-cell counts as compared to HIV+ mono-infected patients and lower HTLV-1 proviral load as compared to mono-infected HAM(-) patients. AS(+) exhibited higher levels of CysLT, CXCL8/IL-8 and lower levels of CCL5/RANTES as compared to AS(-). Increased levels of IL-6 and TNF with reduced levels of CXCL10/IP10 and CCL5/RANTES were observed in co-infected pHAM(+) as compared to mono-infected pHAM(-). HAM(+) patients revealed an increase in CXCL8/IL-8, CCL2/MCP-1, CXCL-10/IP-10, TNF and a decrease in IL-2 as compared to HAM(-) subgroup. [ABSTRACT FROM AUTHOR]

Arachidonic acid (ARA), an n-6 essential fatty acid, plays an important role in human and animal growth and development. The ARA presents in the membrane phospholipids can be released by phospholipase A2. These free arachidonic acid molecules are then used to produce eicosanoids through three different pathways. Previous studies have demonstrated that eicosanoids have a wide range of physiological functions. Although they are generally considered to be pro-inflammatory molecules, recent advances have elucidated they have an effect on innate immunity via regulating the development, and differentiation of innate immune cells and the function of the intestinal epithelial barrier. Here, we review eicosanoids generation in intestine and their role in intestinal innate immunity, focusing on intestinal epithelial barrier, innate immune cell in lamina propria (LP) and their crosstalk. [ABSTRACT FROM AUTHOR]

Bioactive lipid mediators play a major role in regulating inflammatory processes. Herein, early pro-inflammatory phases are characterized and regulated by prostanoids and leukotrienes, whereas specialized pro-resolving mediators (SPM), including lipoxins, resolvins, protectins, and maresins, dominate during the resolution phase. While pro-inflammatory properties of prostanoids have been studied extensively, their impact on later phases of the inflammatory process has been attributed mainly to their ability to initiate the lipid-mediator class switch towards SPM. Yet, there is accumulating evidence that prostanoids directly contribute to the resolution of inflammation and return to homeostasis. In this mini review, we summarize the current knowledge of the resolution-regulatory properties of prostanoids and discuss potential implications for anti-inflammatory, prostanoid-targeted therapeutic interventions. [ABSTRACT FROM AUTHOR]

Non-steroidal Anti-inflammatory drugs (NSAID)-exacerbated respiratory disease (N-ERD) is characterized by nasal polyposis, chronic rhinosinusitis, adult-onset asthma and hypersensitive reactions to cyclooxygenase-1 (COX-1) inhibitors. Among the available treatments for this disease, a combination of endoscopic sinus surgery followed by aspirin desensitization and aspirin maintenance therapy has been an effective approach. Studies have shown that long-term aspirin maintenance therapy can reduce the rate of nasal polyp recurrence in patients with N-ERD. However, the exact mechanism by which aspirin can both trigger and suppress airway disease in N-ERD remains poorly understood. In this review, we summarize current knowledge of aspirin effects in N-ERD, cardiovascular disease, and cancer, and consider potential mechanistic pathways accounting for the effects of aspirin in N-ERD. [ABSTRACT FROM AUTHOR]

Introduction: The leukotriene pathway may be implicated in the induction of virus-induced inflammation. Respiratory epithelial cells may express low levels of 5-lipoxygenase (5-LO) and release leukotrienes (LTs) C4, D4, and E4, upon exposure to viruses or other stimuli. Enhanced expression of 5-LO pathway proteins after rhinovirus (RV) infection has previously been described. We hypothesized that anti-leukotriene treatment of epithelial cells, with or without exposure to RV-infected peripheral blood mononuclear cells (PBMCs)-conditioned media, may inhibit RV-induced up-regulation of inflammatory cytokines. Methods: PBMCs from a healthy donor were exposed to RV1B and supernatants were harvested at 48 h post infection. BEAS-2B cells were infected with RV, with or without conditioning with the PBMC supernatant. Treatment with anti-LT agents was performed either on both PBMCs and BEAS-2B or at the bronchial epithelial level only, with varying concentrations of montelukast (CysLT receptor antagonist) or MK-886 [FLAP(5-lipoxygenase-activating-protein) inhibitor]. Evaluation of the inflammatory cytokines IL-8, RANTES, IL-11, IL-6, and IP-10 was performed using ELISA. Results: Our results show that anti-LT treatment of RV-infected bronchial epithelial cells suppresses epithelial RV-mediated cytokine production, independent of conditioning. Conclusions: This observation may represent an indirect mode of action of the anti-leukotrienes in virus-induced asthma. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) contains a conserved CX3C motif on the ectodomain of the G protein. The motif has been indicated as facilitating attachment of the virus to the host, initiating infection via the human CX3CR1 receptor. The natural CX3CR1 ligand, CX3CL1, has been shown to induce signaling pathways resulting in transcriptional changes in the host cells. We hypothesize that binding of RSV to CX3CR1 via CX3C leads to transcriptional changes in host epithelial cells. Using transcriptomic analysis, the effect of CX3CR1 engagement by RSV was investigated. Normal human bronchial epithelial (NHBE) cells were infected with RSV virus containing either wild-type (WT) G protein or a mutant virus containing a CX4C mutation in the G protein. RNA sequencing was performed on mock-infected and 4-days-postinfected cultures. NHBE cultures were also treated with purified recombinant wild-type A2 G protein. Here, we report that RSV infection resulted in significant changes in the levels of 766 transcripts. Many nuclearassociated proteins were upregulated in the WT group, including nucleolin. In contrast, cilium-associated genes, including CC2D2A and CFAP221 (PCDP1), were downregulated. The addition of recombinant G protein to the culture led to the suppression of ciliumrelated genes while also inducing nucleolin. Mutation of the CX3C motif (CX4C) reversed these effects on transcription, decreasing nucleolin induction and lessening the suppression of cilium-related transcripts in culture. Furthermore, immunohistochemical staining demonstrated decreases in ciliated cells and altered morphology. Therefore, it appears that engagement of CX3CR1 leads to induction of genes necessary for RSV entry as well as dysregulation of genes associated with the function of cilia. [ABSTRACT FROM AUTHOR]

Bufei Huoxue capsule (BHC) as a classic Chinese patent medicine formula, has the efficacy of tonifying the lungs and activating the blood. It has been extensively used in China for the treatment of chronic obstructive pulmonary disease (COPD) clinically. However, its mechanism is still unclear, which hampers the applications of BHC in treating COPD. The purpose of the present study was to demonstrate the protective efficacy and mechanism of BHC on COPD model rats by integrating serum metabolomics analysis and network pharmacology study. A COPD rat model was established by cigarette fumigation combined with lipopolysaccharide (LPS) airway drip for 90 consecutive days. After oral administration for 30 days, the rats were placed in the body tracing box of the EMKA Small Animal Noninvasive Lung Function Test System to determine lung function related indexes. Histopathological alteration was observed by H&E staining and Masson staining. The serum levels of inflammatory cytokine , matrix metalloprotein 9, and laminin were determined by ELISA kits. Oxidative stress levels were tested by biochemical methods. UHPLC-Q-TOF/MS analysis of serum metabolomics and network pharmacology were performed to reveal the bioactive metabolites, key components and pathways for BHC treating COPD. WB and ELISA kits were used to verify the effects of BHC on key pathway. BHC could improve lung function, immunity, lung histopathological changes and collagen deposition in COPD model rats. It also could significantly reduce inflammatory response in vivo, regulate oxidative stress level, reduce laminin content, and regulate protease-antiprotease balance. Metabolomics analysis found 46 biomarkers of COPD, of which BHC significantly improved the levels of 23 differential metabolites including arachidonic acid, leukotriene B4 and prostaglandin E2. Combined with the results of network pharmacology, the components of BHC, such as calycosin, oxypaeoniflora, (S)-bavachin and neobavaisoflavone could play therapeutic roles through the arachidonic acid pathway. In addition, the results of WB and ELISA indicated that BHC could suppress the expressions of COX2 and 5-LOX in lung tissues and inhibit the generation of AA and its metabolites in serum samples. Regulation of arachidonic acid metabolic pathway may be the crucial mechanism for BHC treating COPD. In summary, the studies indicated that BHC exhibited the protective effect on COPD model rats by anti-inflammatory and anti-oxidative properties through arachidonic acid metabolism pathway. This study provided beneficial support for the applications of BHC in treating COPD. [Display omitted] • BHC exhibits the protective effect on COPD model rats. • Anti-Inflammatory and anti-oxidant properties are exhibited by BHC. • BHC alleviates COPD by arachidonic acid metabolism pathway. [ABSTRACT FROM AUTHOR]

There is limited knowledge regarding the blockade of cysteinyl leukotriene receptors (CysLTRs) and their effects in teleost fish. The present study investigated the effects of Zafirlukast, antagonist of CysLTR 1 receptor, on the foreign body inflammatory reaction in Nile tilapia (Oreochromis niloticus). Zafirlukast-treated tilapia demonstrated a decrease in the formation of multinucleated foreign body giant cells and Langhans cells on the round glass coverslips implanted in the subcutaneous tissue, along with a significant reduction in white blood cell counts and decreased production of reactive oxygen species. There was an increase in serum levels of α2-macroglobulins, as well as a decrease in ceruloplasmin and haptoglobin. Zafirlukast treatment led to a significant decrease in the area of splenic melanomacrophage centers and a reduction in the presence of lipofuscin. These findings highlight the potential anti-inflammatory effects of zafirlukast treatment in tilapia and indicate its action on CysLTR 1 receptor, modulating the innate immune response of tilapia during the foreign body reaction. The comprehension of chronic inflammation mechanisms in fish has become increasingly relevant, especially concerning the utilization of biomaterials for vaccine and drug delivery. [Display omitted] • Zafirlukast treatment resulted in an anti-inflammatory effect on tilapia. • Tilapia treated with zafirlukast shows decreased in the formation of foreign body giant cells and Langhans. • Zafirlukast treated-tilapia demonstrated a decreased in leukocyte counts and ROS production. • Tilapia treated with zafirlukast shows decreased in splenic MMCs and the presence of lipofuscin. • Our findings suggest the involvement of CysLTRs in the foreign body reaction of tilapia. [ABSTRACT FROM AUTHOR]

5-Lipoxygenase (5-LOX) reacts with arachidonic acid (AA) to first generate 5(S)-hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid [5(S)-HpETE] and then an epoxide from 5(S)-HpETE to form leukotriene A4, from a single polyunsaturated fatty acid. This work investigates the kinetic mechanism of these two processes and the role of ATP in their activation. Specifically, it was determined that epoxidation of 5(S)-HpETE (dehydration of the hydroperoxide) has a rate of substrate capture (Vmax/Km) significantly lower than that of AA hydroperoxidation (oxidation of AA to form the hydroperoxide); however, hyperbolic kinetic parameters for ATP activation indicate a similar activation for AA and 5(S)-HpETE. Solvent isotope effect results for both hydroperoxidation and epoxidation indicate that a specific step in its molecular mechanism is changed, possibly because of a lowering of the dependence of the rate-limiting step on hydrogen atom abstraction and an increase in the dependency on hydrogen bond rearrangement. Therefore, changes in ATP concentration in the cell could affect the production of 5-LOX products, such as leukotrienes and lipoxins, and thus have wide implications for the regulation of cellular inflammation.

Eicosanoids are lipid-mediator molecules with key roles in inflammatory skin diseases, such as psoriasis. Eicosanoids are released close to the source of inflammation, where they elicit local pleiotropic effects and dysregulations. Monitoring inflammatory mediators directly in skin lesions could provide new insights and therapeutic possibilities. Here, we analyzed dermal interstitial fluid samples obtained by dermal open-flow microperfusion in a rat model of skin inflammation. We developed a solid-phase extraction ultra-HPLC/MS/MS method to reliably and precisely analyze small-volume samples and quantified 11 eicosanoids [thromboxane B2, prostaglandin (PG) E2, PGD2, PGF2α, leukotriene B4, 15-HETE, 12-HETE, 5-HETE, 12-hydroxyeicosapentaenoic acid, 13-HODE, and 17-hydroxydocosahexaenoic acid]. Our method achieved a median intraday precision of approximately 5% and interday precision of approximately 8%. All calibration curves showed excellent linearity between 0.01 and 50 ng/ml (R2 > 0.980). In the rat model, eicosanoids were significantly increased in imiquimod-treated inflamed skin sites compared with untreated control sites. Oral treatment with an anti-inflammatory glucocorticoid decreased eicosanoid concentrations. These results show that a combination of tissue-specific sampling with LC/MS analytics is well suited for analyzing small sample volumes from minimally invasive sampling methods such as open-flow microperfusion or microdialysis to study local inflammation and the effect of treatments in skin diseases.

Objective(s): The current study was designed to investigate the therapeutic and protective effects of montelukast (ML) against doxorubicin (DOX)-induced acute kidney damage in rats.Materials and Methods: Thirty-five Wistar albino female rats were randomly divided into 5 groups as follows: Group I: Control; Group II: Control+ML; Group III: DOX; Group IV: DOX+ML; Group V: ML+DOX. At the end of the experiment, the kidney tissues of rats were collected. Thiobarbituric acid reactive substance (TBARS), reduced glutathione, superoxide dismutase (SOD), and catalase levels were determined from the kidney tissues. In addition, the kidney tissues were examined histologically.Results: DOX induced a significant increase in the kidney TBARS levels, whereas SOD contents significantly decreased when compared with the control group. On the other hand, ML administration before and after DOX injection caused significant decreases in TBARS production and also increases in SOD levels. Histologically, the most remarkable damage was glomerulosclerosis and tubular changes in the DOX group. Moreover, marked tubular necrosis and swelling in tubular epithelial cells were observed in this group. Contrarily, although glomerulosclerosis was recognized as alleviated also in both DOX+ML and ML+DOX groups, the lesions did not completely ameliorate. However, treatment with ML after DOX injection was more effective than treatment with ML before DOX injection with respect to the protection of tubular structures. Conclusion: It was determined that ML treatment after DOX injection caused therapeutic effects against DOX-induced kidney damage. Thence, ML treatment is of some clinical properties for oxidative stress damage in kidney tissues.

Leukotrienes (LTs) are autacoids derived from the precursor arachidonic acid (AA) via the action of five-lipoxygenase (5-LO). When inflammatory cells are activated, 5-LO translocates to the nuclear membrane to initiate oxygenation of AA released by cytosolic phospholipase A2 (cPLA2) into leukotriene A4 (LTA4). LTA4 can also be exported from an activated donor cell into an acceptor cell by the process of transcellular biosynthesis. When thimerosal is added to cells, the level of free AA increases by inhibition of lysophospholipid acyltransferases of the Lands pathway of phospholipid remodeling. Another arachidonate phospholipid cycle involves phosphatidylinositol (PI) in the plasma membrane that undoubtedly intersects with the Lands pathway of phospholipid remodeling. The highest abundance of PI occurs between the ER and the plasma membrane and is probably a result of the importance of the PI signaling cascade in cellular biochemistry. Because transport proteins mediate the rapid intracellular movement of phospholipids, largely as result of physical membrane contact, 5-LO-dependent production of LTA4 could be mediated by the disappearance of free AA from the nuclear membrane, transfer to the ER for Lands cycle reesterification into PI, and population of PI(18:0/20:4) for cell membrane signaling.

The studies in the organism adaptation for the conditions of technogenic environmental changes, especially in child population, will allow to design a set of diagnostic markers for assessing the health status and early detection of pathological trends for development of hypersensitivity to environmental substances and improve efficiency of therapeutic and preventive measures. Metals are capable to alter functional activity of immune system by producing both immunostimulating and suppressive effects on immune reactivity, dependent on the properties of the given metal, its environmental concentration, source and duration of exposure. The aim of the present study was to investigate the features of hypersensitivity markers in children under the conditions of external exposure to aluminum. We have conducted a survey of the schoolchildren aged from 7 to 11 y.o. (a mean of 8.82±0.11 years), permanently inhabiting the territory of active industrial exposure associated with environmental contamination with aluminum compounds. The comparison group consisted of children from a “conventionally clean” area, with acceptable parameters of environmental quality. Specific features of sensitization developing to aluminum were evaluated, including both reactive and alternative mediator mechanisms (leukotrienes and prostaglandins), as well as participation of the cytokines in evolving sensitivity to the metal in the ex vivo experiments. We have shown a 1.43-fold increased level of metal in peripheral blood of the observation group, than in comparison group (respectively, observation group, 0.020±0.005 μg/ml; comparison group 0.014±0.003 μg/ml). Enhanced levels of IgE antibodies were found to be 2.13-fold higher compared to the reference values (213.55±88.10 IU/ml against normal rates of < 100.0 IU/ml) accompanied by increased specific IgG antibodies to aluminum (1.55-fold relative to the controls, i.e., 0.157±0.054 cu in observation group versus 0.101±0.041 cu for the comparison group), as well as a 2.09-fold increased spontaneous production of leukotrienes C4/D4/E4 (80.60±19.44 pg/ml for observation group; 38.51±2.40 pg/ml in the comparison group), which was 1.67-fold enhanced by experimental aluminum stimulation. Prostaglandin F2α levels among the children from observation group were increased 1.9-fold (observation group, 892.62±97.20 pg/ml; comparison group, 457.11±132.99 pg/ml, p < 0.05). Under the ex vivo experimental conditions, we observed mostly suppressive effects of aluminum upon the cytokine production. E.g., IL-4 production was inhibited by 2.13-fold, as compared with control values (observation group, 0.64±0.23 pg/ml; comparison group, 1.36±0.09 pg/ml); the suppression for IL-17 was 1.90 times (observation group, 1.08±0.27 pg/ ml; comparison group, 2.05±0.37 pg/ml, p < 0.05). The parameters studied may be used as aluminum hypersensitivity markers and used for monitoring and predictions in public health care.

Increasing environmental distress is associated with a growing asthma incidence; no treatments are available but montelukast (MTK)—an antagonist of the cysteinyl leukotrienes receptor 1—is widely used in the management of symptoms among adults and children. Recently, new molecular targets have been identified and MTK has been proposed for repurposing in other therapeutic applications, with several ongoing clinical trials. The proposed applications include neuroinflammation control, which could be explored in some neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases (AD and PD). However, this drug has been associated with an increasing number of reported neuropsychiatric adverse drug reactions (ADRs). Besides, and despite being on the market since 1998, MTK metabolism is still poorly understood and the mechanisms underlying neuropsychiatric ADRs remain unknown. We review the role of MTK as a modulator of leukotriene pathways and systematize the current knowledge about MTK metabolism. Known toxic effects of MTK are discussed, and repurposing applications are presented comprehensively, with a focus on AD and PD.

Background: Aspirin-exacerbated respiratory disease (AERD) is characterized by eosinophilic rhinosinusitis, nasal polyposis, and bronchial asthma, along with the onset of respiratory reactions after the ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid (ASA). In addition to the therapeutic routines and surgical options available, a low dietary intake of food salicylate has been suggested as adjunctive therapy for this condition. This study aimed to assess the influence of a short-term low salicylate diet on inflammatory markers in patients with AERD and whether that would result in symptomatic improvement. Methods: Prospective study with randomization to either a high or low salicylate diet for 1 week, followed by cross-over to the other study arm. Participants were asked to record their dietary salicylate for each week of the study. Urinary creatinine, salicylate and leukotriene levels were measured at the time of recruitment, end of week one and end of week two and the SNOT-22 questionnaire was filled out at the same time points. Results: A total of seven participants completed the study. There was no statistical difference in the urinary salicylate and leukotriene levels between the two diets; nevertheless, participants on low salicylate diet reported improved SNOT-22 symptoms scores (p = 0.04), mainly in the rhinologic, ear/facial, and sleep dysfunction symptom domains. In addition, these last two domains outcomes were more significant than the minimal clinically important difference. Conclusions: A short-term low salicylate diet may not result in biochemical outcomes changes but seems to provide significant symptomatic relief for patients with AERD. Trial registration: NCT01778465 (www.clinicaltrials.gov) [ABSTRACT FROM AUTHOR]

Sepsis rapidly contributed to multiorgan failure affecting most commonly of the cardiovascular and respiratory systems and yet there were no effective therapies. The current study aimed at providing evidence on the cardioprotection of suppression of 5-Lipoxygenase (5-Lox) and identifying the possible mechanism in the mouse model of sepsis. The cecal ligation-perforation (CLP) model was applied to C57BL/6 wild-type (WT) and 5-Lox deficient (5-Lox−/−) mice to induce sepsis. 5-Lox expression was up-regulated in mouse myocardium and leukotriene B4 (LTB4) level was increased in serum after sepsis. Subsequently, we utilized a recombinant adenoviral expression vector (rAAV9) to overexpress Alox5 gene in adult mice. Compared to WT mice, 5-Lox overexpression accelerated CLP-induced myocardial injury and cardiac dysfunction. Oppositely, 5-Lox deficiency offered protection against myocardial injury in a mouse model of sepsis and attenuated sepsis-mediated inflammation, oxidative stress and apoptosis in the mouse heart. Mechanically, 5-Lox promoted LTB4 production, which in turn contributed to the activation of leukotriene B4 receptor 1 (BLT1)/interleukin-12p35 (IL-12p35) pathway and enhanced M1 macrophage polarization. However, the suppression of BLT1 by either gene mutation or antagonist U75302 significantly inhibited the adverse effect of 5-Lox in sepsis. Further study demonstrated that pharmacological inhibition of 5-Lox prevented CLP-induced septic cardiomyopathy (SCM). Our study identified 5-Lox exacerbated sepsis-associated myocardial injury through activation of LTB4 production and promoting BLT1/IL-12p35 pathway. Hence, inhibition of 5-Lox may be a potential candidate strategy for septic cardiac dysfunction treatment. An illustrative summary. Following CLP, 5-Lox promotes the activation of LTB4-BLT1-IL-12p35 pathway in heart. Genetic and pharmacological inhibition of 5-Lox blunt the cardiac inflammatory responses (inflammatory cells infiltration and cytokine expression), improve survival and preserve cardiac function (higher LVEF at 24 h post-CLP). Blockage of BLT1 abolishes 5-Lox mediated myocardial injury.▪ •.Inhibition of 5-lipoxygenase (5-Lox) alleviated septic cardiomyopathy (SCM). • 5-Lox promoted activation of BLT1/IL-12p3. • 5-Lox may become a potential target for pharmacological or dietary interventions to decrease sepsis-related cardiac injury. [ABSTRACT FROM AUTHOR]

The participation of arachidonic acid metabolism products – prostaglandins and leukotrienes – in the process of inflammation is a common pathogenetic link of cold injury and epilepsy. Montelukast is widely used for the treatment of bronchial asthma and allergic rhinitis as a leukotriene receptor blocker. However, the mechanism of action of the drug suggests a wider range of its pharmacological properties and the corresponding scope of application. This study is aimed to determine the effectiveness of montelukast as a potential frigoprotective and anticonvulsant drug. Experiments were performed on 73 white mice weighing 20-22 g on models of acute general cooling and pentylenetetrazol convulsions. Frigoprotective properties were studied at a temperature of –18°C, recording the lifetime. Montelukast ("Singular", 2 mg/kg), acetylsalicylic acid ("Aspirin", 50 mg/kg), celecoxib ("Celebrex", 74 mg/kg), diclofenac sodium ("Voltaren", 14 mg/kg) were administered intragastrically as a suspension in a prophylactic mode, 30 minutes before the cold injury. In the study of anticonvulsant activity, montelukast ("Singular", 4 mg/kg) and sodium valproate ("Depakin", 300 mg/kg) were administered intragastrically 30 minutes before stimulating convulsions by subcutaneous administration of pentylenetetrazole (90 mg/kg). The latent period of convulsions, the number of convulsions per 1 animal, % of mice with clonic and tonic paroxysms, the severity of convulsions in points, the duration of the convulsive period, the lifetime of animals and lethality were recorded for an hour. On the model of acute general cooling, montelukast showed a dose-dependent frigoprotective effect at a dose of 2 mg/kg surpassing drugs with proven frigoprotective properties – acetylsalicylic acid and celecoxib. On the model of pentylenetetrazole-induced convulsions, montelukast statistically significantly reduced the integral indicator of anticonvulsant activity – lethality – by 2.57 times. Thus, the experiment proved the significant role of leukotrienes in the pathogenesis of cold injury and epilepsy and justified the feasibility of further study of the frigoprotective and anticonvulsant properties of montelukast – leukotriene receptor blocker a drug as for adjuvant therapy, especially when these pathologies are combined with bronchial asthma and allergic rhinitis. [ABSTRACT FROM AUTHOR]

Background: Since 2020, peoples' lifestyles have been largely changed due to the COVID-19 pandemic worldwide. In the medical field, although many patients prefer remote medical care, this prevents the physician from examining the patient directly; thus, it is important for patients to accurately convey their condition to the physician. Accordingly, remote medical care should be implemented and adaptable home medical devices are required. However, only a few highly accurate home medical devices are available for automatic wheeze detection as an exacerbation sign. Objective: We developed a new handy home medical device with an automatic wheeze recognition algorithm, which is available for clinical use in noisy environments such as a pediatric consultation room or at home. Moreover, the examination time is only 30 seconds, since young children cannot endure a long examination time without crying or moving. The aim of this study was to validate the developed automatic wheeze recognition algorithm as a clinical medical device in children at different institutions. Methods: A total of 374 children aged 4-107 months in pediatric consultation rooms of 10 institutions were enrolled in this study. All participants aged =6 years were diagnosed with bronchial asthma and patients =5 years had reported at least three episodes of wheezes. Wheezes were detected by auscultation with a stethoscope and recorded for 30 seconds using the wheeze recognition algorithm device (HWZ-1000T) developed based on wheeze characteristics following the Computerized Respiratory Sound Analysis guideline, where the dominant frequency and duration of a wheeze were >100 Hz and >100 ms, respectively. Files containing recorded lung sounds were assessed by each specialist physician and divided into two groups: 177 designated as "wheeze" files and 197 as "no-wheeze" files. Wheeze recognitions were compared between specialist physicians who recorded lung sounds and those recorded using the wheeze recognition algorithm. We calculated the sensitivity, specificity, positive predictive value, and negative predictive value for all recorded sound files, and evaluated the influence of age and sex on the wheeze detection sensitivity. Results: Detection of wheezes was not influenced by age and sex. In all files, wheezes were differentiated from noise using the wheeze recognition algorithm. The sensitivity, specificity, positive predictive value, and negative predictive value of the wheeze recognition algorithm were 96.6%, 98.5%, 98.3%, and 97.0%, respectively. Wheezes were automatically detected, and heartbeat sounds, voices, and crying were automatically identified as no-wheeze sounds by the wheeze recognition algorithm. Conclusions: The wheeze recognition algorithm was verified to identify wheezing with high accuracy; therefore, it might be useful in the practical implementation of asthma management at home. Only a few home medical devices are available for automatic wheeze detection. The wheeze recognition algorithm was verified to identify wheezing with high accuracy and will be useful for wheezing management at home and in remote medical care. [ABSTRACT FROM AUTHOR]

Leukotrienes, together with the prostaglandins and other related compounds, are derived from 20 carbon (eicosa) fatty acids that contain double bonds (enoic). Hence this group of substances is called the eicosanoids. The name leukotriene derives from the original discovery of these substances in white blood cells (polymorphonuclear leucocytes) and the fact that they all have in common 4 double bonds (hence the 4 subscript), 3 of which are in a conjugated triene structure. Leukotrienes do not exist preformed in cells. They are formed from the breakdown of arachidonic acid, a polyunsaturated 20 carbon fatty acid. In its esterified form, arachidonic acid is bound to the phospholipids of the cell membranes. Both immunological and non-immunological stimuli can release arachidonic acid from membrane phospholipids by activating phospholipase A2. The glucocorticosteroid drugs can inhibit phospholipase A2 and thereby decrease the production of all the leukotrienes and hence leukotriene-mediated responses. Generally, inflammation leads to vasodilation, vascular hyperpermeability, increased blood flow and recruitment of leukocytes to inflamed sites. These events cause enhanced production of cytokines, chemokines, chemical mediators and lipid mediators such as LTs and prostaglandins. Acute inflammation occurs over a short time (seconds, minutes and hours). In contrast, chronic inflammation is a long-lasting inflammatory and immune response that occurs over months to years and results in diverse diseases including asthma, allergies, atherosclerosis, arthritis, obesity, cancer and other age-related diseases such as AMD. In this review article we aimed to highlight the evidence that implicates LTs in physiological function and also in disease processes. [ABSTRACT FROM AUTHOR]

A proposed beneficial impact of highly unsaturated “fish oil” fatty acids is their conversion by lipoxygenase (LOX) enzymes to specialized proresolving lipid mediators, including 12/15-LOX products from EPA and DHA. The transformations of DHA include formation of docosatrienes, named for the distinctive conjugated triene of the double bonds. To further the understanding of biosynthetic pathways and mechanisms, herein we meld together biosynthesis and NMR characterization of the unstable leukotriene A (LTA)-related epoxide intermediates formed by recombinant human 15-LOX-1, along with identification of the stable enzymatic products, and extend the findings into the 12/15-LOX metabolism in resident murine peritoneal macrophages. Oxygenation of EPA by 15-LOX-1 converts the initial 15S-hydroperoxide to 14S,15S-trans-epoxy-5Z,8Z,10E,12E,17Z-EPA (appearing as its 8,15-diol hydrolysis products) and mixtures of dihydroperoxy fatty acids, while mainly the epoxide hydrolysis products are evident in the murine cells. DHA also undergoes transformations to epoxides and dihydroperoxides by 15-LOX-1, resulting in a mixture of 10,17-dihydro(pero)xy derivatives (docosatrienes) and minor 7S,17S- and 14,17S-dihydroperoxides. The 10,17S-dihydroxy hydrolysis products of the LTA-related epoxide intermediate dominate the product profile in mouse macrophages, whereas (neuro)protectin D1, the leukotriene B4-related derivative with trans,trans,cis conjugated triene, was undetectable. In this study, we emphasize the utility of UV spectral characteristics for product identification, being diagnostic of the different double bond configurations and hydroxy fatty acid functionality versus hydroperoxide. LC-MS is not definitive for configurational isomers. Secure identification is based on chromatographic retention times, comparison with authentic standards, and the highly distinctive UV spectra.

Leukotrienes (LTs) and sphingolipids are critical lipid mediators participating in numerous cellular signal transduction events and developing various disorders, such as bronchial hyperactivity leading to asthma. Enzymatic reactions initiating production of these lipid mediators involve 5-lipoxygenase (5-LO)-mediated conversion of arachidonic acid to LTs and serine palmitoyltransferase (SPT)-mediated de novo synthesis of sphingolipids. Previous studies have shown that endoplasmic reticulum membrane protein ORM1-like protein 3 (ORMDL3) inhibits the activity of SPT and subsequent sphingolipid synthesis. However, the role of ORMDL3 in the synthesis of LTs is not known. In this study, we used peritoneal-derived mast cells isolated from ORMDL3 KO or control mice and examined their calcium mobilization, degranulation, NF-κB inhibitor-α phosphorylation, and TNF-α production. We found that peritoneal-derived mast cells with ORMDL3 KO exhibited increased responsiveness to antigen. Detailed lipid analysis showed that compared with WT cells, ORMDL3-deficient cells exhibited not only enhanced production of sphingolipids but also of LT signaling mediators LTB4, 6t-LTB4, LTC4, LTB5, and 6t-LTB5. The crosstalk between ORMDL3 and 5-LO metabolic pathways was supported by the finding that endogenous ORMDL3 and 5-LO are localized in similar endoplasmic reticulum domains in human mast cells and that ORMDL3 physically interacts with 5-LO. Further experiments showed that 5-LO also interacts with the long-chain 1 and long-chain 2 subunits of SPT. In agreement with these findings, 5-LO knockdown increased ceramide levels, and silencing of SPTLC1 decreased arachidonic acid metabolism to LTs to levels observed upon 5-LO knockdown. These results demonstrate functional crosstalk between the LT and sphingolipid metabolic pathways, leading to the production of lipid signaling mediators.

The emergence and global impact of COVID-19 has focused the scientific and medical community on the pivotal influential role of respiratory viruses as causes of severe pneumonia, on the understanding of the underlying pathomechanisms, and on potential treatment for COVID-19. The latter concentrates on four different strategies: (i) antiviral treatments to limit the entry of the virus into the cell and its propagation, (ii) anti-inflammatory treatment to reduce the impact of COVID-19 associated inflammation and cytokine storm, (iii) treatment using cardiovascular medication to reduce COVID-19 associated thrombosis and vascular damage, and (iv) treatment to reduce the COVID-19 associated lung injury. Ideally, effective COVID-19 treatment should target as many of these mechanisms as possible arguing for the search of common denominators as potential drug targets. Leukotrienes and their receptors qualify as such targets: they are lipid mediators of inflammation and tissue damage and well-established targets in respiratory diseases like asthma. Besides their role in inflammation, they are involved in various other aspects of lung pathologies like vascular damage, thrombosis, and fibrotic response, in brain and retinal damages, and in cardiovascular disease. In consequence, leukotriene receptor antagonists might be potential candidates for COVID-19 therapeutics. This review summarizes the current knowledge on the potential involvement of leukotrienes in COVID-19, and the rational for the use of the leukotriene receptor antagonist montelukast as a COVID-19 therapeutic.

5-Lipoxygenase (5-LOX) converts arachidonic acid to lipidic inflammatory mediators such as leukotrienes (LTs). In diseases such as asthma, LTs contribute to a physiopathology that could be reverted by blocking 5-LOX. Natural products with anti-inflammatory potential such as ginger have been used as nutraceuticals since ancient times. 6-Gingerol and 6-shogaol are the most abundant compounds in the ginger rhizome; they possess anti-inflammatory, antioxidant, and chemopreventive properties. In the present study, 6-gingerol and 6-shogaol structures were analyzed and compared with two commercial 5-LOX inhibitors (zileuton and atreleuton) and with other inhibitor candidates (3f, NDGA, CP 209, caffeic acid, and caffeic acid phenethyl ester (CAPE)). The pharmacokinetics and toxicological properties of 6-gingerol, 6-shogaol, and the other compounds were evaluated. Targeted molecular coupling was performed to identify the optimal catalytic pocket for 5-LOX inhibition. The results showed that 6-gingerol and 6-shogaol follow all of the recommended pharmacokinetic parameters. These compounds could be inhibitors of 5-LOX because they present specific interactions with the residues involved in molecular inhibition. The current study demonstrated the potential of 6-gingerol and 6-shogaol as anti-inflammatory agents that inhibit 5-LOX, as they present a high level of performance in the toxicological analysis and could be catabolized by the cytochrome p450 enzymatic complex; however, 6-gingerol was superior in safety compared to 6-shogaol.

Background. Diabetes mellitus (DM) aggravates symptoms and prognosis of acute ischemic stroke (AIS), and inflammation plays an important role therein. Resolvin D2 (RvD2) is one of the specialized pro-resolving mediators (SPMs), while leukotriene B4 (LTB4) is a classic proinflammatory mediator. The ratio of RvD2 to LTB4 is an index of pro-resolving/proinflammatory balance. We aim to explore the role of RvD2/LTB4 ratio in ischemic stroke complicated with DM. Methods. The plasma levels of RvD2 and LTB4 were analyzed by enzyme immunoassay in stroke patients with DM (DM + AIS group) or without DM (nonDM+AIS group). Patients were followed up at 90 days after stroke onset, and modified Rankin Score (mRS) was assessed. The association of RvD2/LTB4 ratio with stroke severity and prognosis was also analyzed. Results. The plasma levels of RvD2 were positively correlated to LTB4. The RvD2/LTB4 ratio in DM + AIS group was lower than that in the nonDM+AIS group. No correlation was found between the RvD2/LTB4 ratio and infarct size or NIHSS score. The RvD2/LTB4 ratio at baseline was significantly lower in the poor prognosis group (mRS ≥ 3) than that in the good prognosis group (mRS ≤ 2). Conclusions. Our study indicated that the balance between pro-resolving and proinflammatory mediators was impaired by diabetes in ischemic stroke. The RvD2/LTB4 ratio may serve as a biomarker of prognosis for ischemic stroke. [ABSTRACT FROM AUTHOR]

The article presents the discussion on investigating the effect of shufengzhitong decoction combining with four cervical needles on cervical spondylotic radiculopathy (CSR) and leukotriene and inflammatory factors. Topics include focusing on conservative treatments for CSR containing traction, massage, acupuncture, and medication; and damaging the subtle brain spinal cord or meridian circulation and paralysis.

Background: Vascular leak is a hallmark of severe dengue, and high leukotriene levels have been observed in dengue mouse models, suggesting a role in disease pathogenesis. We sought to explore their role in acute dengue, by assessing levels of urinary LTE4 and urinary histamine in patients with varying severity of acute dengue. Methods: Urinary LTE4, histamine and creatinine were measured by a quantitative ELISA, in healthy individuals (n = 19), patients with dengue fever (DF = 72) and dengue haemorrhagic fever DHF (n = 48). The kinetics of LTE4 and histamine and diurnal variations were assessed in a subset of patients. Results: Urinary LTE4 levels were significantly higher (p = 0.004) in patients who proceed to develop DHF when compared to patients with DF during early illness (≤ 4 days) and during the critical phase (p = 0.02), which continued to rise in patients who developed DHF during the course of illness. However, LTE4 is unlikely to be a good biomarker as ROCs gave an AUC value of 0.67 (95% CI 0.57 and 0.76), which was nevertheless significant (p = 0.002). Urinary LTE4 levels did not associate with the degree of viraemia, infecting virus serotype and was not different in those with primary vs secondary dengue. Urinary histamine levels were significantly high in patients with acute dengue although no difference was observed between patients with DF and DHF and again did not associate with the viraemia. Interestingly, LTE4, histamine and the viral loads showed a marked diurnal variation in both patients with DF and DHF. Conclusions: Our data suggest that LTE4 could play a role in disease pathogenesis and since there are safe and effective cysteinyl leukotriene receptor blockers, it would be important to assess their efficacy in reducing dengue disease severity. [ABSTRACT FROM AUTHOR]

Air pollution is associated with early declines in lung function and increased levels of asthma-related cysteinyl leukotrienes (CysLT) but a biological pathway linking this rapid response has not been delineated. In this randomized controlled diesel exhaust (DE) challenge study of 16 adult asthmatics, increased exposure-attributable urinary leukotriene E4 (uLTE4, a biomarker of cysteinyl leukotriene production) was correlated (p = 0.04) with declines in forced expiratory volume in 1-second (FEV1) within 6 hours of exposure. Exposure-attributable uLTE4 increases were correlated (p = 0.02) with increased CysLT receptor 1 (CysLTR1) methylation in peripheral blood mononuclear cells which, in turn, was marginally correlated (p = 0.06) with decreased CysLTR1 expression. Decreased CysLTR1 expression was, in turn, correlated (p = 0.0007) with FEV1 declines. During the same time period, increased methylation of GPR17 (a negative regulator of CysLTR1) was observed after DE exposure (p = 0.02); this methylation increase was correlated (p = 0.001) with decreased CysLTR1 methylation which, in turn, was marginally correlated (p = 0.06) with increased CysLTR1 expression; increased CysLTR1 expression was correlated (p = 0.0007) with FEV1 increases. Collectively, these data delineate a potential mechanistic pathway linking increased DE exposure-attributable CysLT levels to lung function declines through changes in CysLTR1-related methylation and gene expression. [ABSTRACT FROM AUTHOR]

Eicosanoids are biologically active lipid mediators, comprising prostaglandins, leukotrienes, thromboxanes, and lipoxins, involved in several pathophysiological processes relevant to asthma, allergies, and allied diseases. Prostaglandins and leukotrienes are the most studied eicosanoids and established inducers of airway pathophysiology including bronchoconstriction and airway inflammation. Drugs inhibiting the synthesis of lipid mediators or their effects, such as leukotriene synthesis inhibitors, leukotriene receptors antagonists, and more recently prostaglandin D2 receptor antagonists, have been shown to modulate features of asthma and allergic diseases. This review, produced by an European Academy of Allergy and Clinical Immunology (EAACI) task force, highlights our current understanding of eicosanoid biology and its role in mediating human pathology, with a focus on new findings relevant for clinical practice, development of novel therapeutics, and future research opportunities. [ABSTRACT FROM AUTHOR]

Rationale: New approaches are needed to guide personalized treatment of asthma.Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping.Methods: Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma.Measurement and Main Results: Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE2 pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE2 metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE4 and the PGD2 metabolite 2,3-dinor-11β-PGF2α. High concentrations of LTE4 and PGD2 metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOPRED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers.Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma.Clinical trial registered with www.clinicaltrials.gov (NCT01976767). [ABSTRACT FROM AUTHOR]

Rationale: New approaches are needed to guide personalized treatment of asthma. Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping. Methods: Urinarymetabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the PredictionofRespiratoryDiseasesOutcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validationwas performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma. Measurement and Main Results:Metabolite concentrations in healthy control participantswere unrelated to age, body mass index, and sex, except for the PGE2 pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE2 metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthmawho adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE4 and the PGD2metabolite 2,3-dinor-11b-PGF2a. High concentrations of LTE4 and PGD2 metaboliteswere associatedwith lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOPRED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers. Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma. [ABSTRACT FROM AUTHOR]

Glaucoma is a complex neurodegenerative disease characterized by optic nerve damage and visual field loss, and remains a leading cause of irreversible blindness. Elevated intraocular pressure (IOP) is a critical risk factor that requires effective management. Emerging research underscores dual roles of bioactive lipid mediators in both IOP regulation, and the modulation of neurodegeneration and neuroinflammation in glaucoma. Bioactive lipids, encompassing eicosanoids, specialized pro-resolving mediators (SPMs), sphingolipids, and endocannabinoids, have emerged as crucial players in these processes, orchestrating inflammation and diverse effects on aqueous humor dynamics and tissue remodeling. Perturbations in these lipid mediators contribute to retinal ganglion cell loss, vascular dysfunction, oxidative stress, and neuroinflammation. Glaucoma management primarily targets IOP reduction via pharmacological agents and surgical interventions, with prostaglandin analogues at the forefront. Intriguingly, additional lipid mediators offer promise in attenuating inflammation and providing neuroprotection. Here we explore these pathways to shed light on their intricate roles, and to unveil novel therapeutic avenues for glaucoma management., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Oxazolidinone hydroxamic acid derivatives were synthesised and evaluated for inhibitory activity against leukotriene (LT) biosynthesis in three in vitro cell-based test systems and on direct inhibition of recombinant human 5-lipoxygenase (5-LO). Thirteen of the 19 compounds synthesised were considered active ((50% inhibitory concentration (IC50) ≤ 10 µM in two or more test systems)). Increasing alkyl chain length on the hydroxamic acid moiety enhanced activity and morpholinyl-containing derivatives were more active than N-acetyl-piperizinyl derivatives. The IC50 values in cell-based assay systems were comparable to those obtained by direct inhibition of 5-LO activity, confirming that the compounds are direct inhibitors of 5-LO. Particularly, compounds PH-249 and PH-251 had outstanding potencies (IC50 < 1 µM), comparable to that of the prototype 5-LO inhibitor, zileuton. Pronounced in vivo activity was demonstrated in zymosan-induced peritonitis in mice. These novel oxazolidinone hydroxamic acid derivatives are, therefore, potent 5-LO inhibitors with potential application as anti-allergic and anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

Trichomonas vaginalis, a flagellated extracellular protozoan parasite that infects the human genitourinary tract, is usually transmitted by sexual contact. Our previous study showed that the leukotriene B4 (LTB4), a T vaginalis‐secreted lipid mediator, induces interleukin (IL)‐8 production and promotes mast cell degranulation and migration via BLT1 in human. In this study, we investigated whether T vaginalis produces another leukotrienes and whether it causes increased MCP‐1 production, mast cell migration and degranulation by activating mast cells. We found that cysteinyl leukotrienes (CysLTs) were contained in T vaginalis‐derived secretory product (TvSP) by ELISA. The TvSP‐stimulated human mast cell line (HMC‐1) exhibited significantly increased monocyte chemoattractant protein‐1 (MCP‐1) secretion compared to the unstimulated cells. Inhibition of NOX2 activation of cells by treatment of NOX inhibitor or NOX2 siRNA reduced TvSP‐stimulated MCP‐1 production in HMC‐1 cells. It was also confirmed that the receptor for CysLTs is expressed in mast cells. The CysLT receptor (CysLTR) antagonist inhibited TvSP‐stimulated MCP‐1 production of mast cells, as well as ROS production, migration and degranulation of mast cells, and reduced phospho‐NF‐kB expression. These results suggest that T vaginalis‐secreted CysLTs promote migration, degranulation and MCP‐1 production in human mast cells through CysLT receptor‐mediated NOX2 activation. [ABSTRACT FROM AUTHOR]

Eicosanoids modulate both innate and adaptive immune responses in Mycobacterium tuberculosis (Mtb) infection and have been suggested as possible Host Directed Therapy (HDT) targets, but more knowledge of eicosanoid dynamics in Mtb infection is required. We investigated the levels and ratios of eicosanoid mediators and their cellular sources, monocyte subsets and CD4 T cells in Tuberculosis (TB) patients with various clinical states of Mtb infection. Patients consenting to prospective enrolment in a TB quality registry and biorepository, 16 with pulmonary TB (before and at-end-of treatment), 14 with extrapulmonary TB and 17 latently infected (LTBI) were included. Plasma levels of Prostaglandin E2 (PGE2), Lipoxin A4 (LXA4), and Leukotriene B4 (LTB4) were measured by enzyme-linked immunosorbent assay. Monocyte subsets and CD4 T cells and their expression of Cyclooxygenase-2 (COX-2), Prostaglandin receptor EP2 (EP2), and 5-Lipoxygenase (5-LOX) were analyzed by flow cytometry with and without Purified Protein Derivate (PPD)-stimulation. Pulmonary TB patients had elevated levels of the anti-inflammatory mediator LXA4 at diagnosis compared to LTBI (p < 0.01), while levels of PGE2 and LTB4 showed no difference between clinical states of Mtb infection. LTB4 was the only mediator to be reduced upon treatment (p < 0.05), along with the ratio LTB4/LXA4 (p < 0.01). Pulmonary TB patients had higher levels of total monocytes at diagnosis compared to end-of-treatment and LTBI (both p < 0.05), and a relative increase in the classical monocyte subset. All monocyte subsets had low basal expression of COX-2 and 5-LOX, which were markedly increased upon PPD stimulation. By contrast, the expression of EP2 was reduced upon stimulation. CD4 T cells expressed low basal COX-2 activity that increased modestly upon stimulation, whereas their basal expression of 5-LOX was considerable. In conclusion, the level of eicosanoids in plasma seem to vary between clinical states of Mtb infection. Mediators in the eicosanoid system are present in monocytes and CD4 T cells. The expression of eicosanoids in monocytes are responsive to mycobacterial stimulation independent of Mtb disease state, but subsets are heterogeneous with regard to eicosanoid-mediator expression. Further exploration of eicosanoid mediators as targets for HDT in TB are warranted.

Patients with coronary artery disease remain at increased risk of recurrent life-threatening cardiovascular events even after adequate guideline-based treatment of conventional risk factors, including blood lipid levels. Inflammation is a critical pathway in the pathogenesis of atherosclerosis and is independently associated with risk of recurrent cardiovascular events. Leukotrienes are potent pro-inflammatory and vasoactive mediators synthesized by leukocytes in atherosclerotic lesions. AZD5718 is a novel antagonist of 5-lipoxygenase activating protein that suppresses leukotriene biosynthesis.FLAVOUR is a phase IIa efficacy and safety study of AZD5718 in patients with myocardial infarction 1–4 weeks before randomization. Stenosis of the left anterior descending coronary artery after percutaneous intervention must be

SARS-CoV-2 causing coronavirus disease 2019 (COVID-19) has wreaked havoc during the global pandemic of 2020 infecting millions and leaving over a half million dead. As a new virus, not previously in the human population, but with similarities to other coronaviruses causing severe acute respiratory distress syndrome (SARS/ARDS), and no known treatments, the race to re-purpose existing drugs and to enlist novel therapeutics is underway. In the half-year since the first cases, we have acquired substantial knowledge of this virus and the clinical course of COVID-19 progression. Results from early clinical trials have revealed two treatments (remdesivir, dexamethasone) that mitigate disease progression but clearly, there is much room for improvement. Initial case reports indicated many succumb to COVID-19 of hypoxic respiratory failure due to ARDS. However, ensuing studies revealed an atypical, immune cell-sequestered, vasculature-inflamed state leading to multiorgan thrombotic complications and end organ failure likely due to hyperinflammatory host responses. This Perspective focuses on a potential mechanism for a key COVID-19 disease progression turning point related to vascular and airway inflammation. The leukotriene lipid mediators have been overlooked with discussion centering on cytokine storms unleashing the deadly form of COVID-19. Leukotrienes possess some of the most potent known activities on immune cell trafficking and vascular leakage. We offer a simple treatment paradigm using two generic drugs targeting the hyperinflammatory response that characterizes the turning point from mild to severe/critical COVID-19 by targeting leukotriene biosynthesis with zileuton (Zyflo® controlled release formulation) and antagonism of the cysteinyl leukotriene 1 receptor with montelukast (Singulair®).

Leukotrienes are biologically active eicosanoid lipid mediators that originate from oxidative metabolism of arachidonic acid. Biosynthesis of leukotrienes involves a set of soluble and membrane-bound enzymes that constitute a machinery complex primarily expressed by cells of myeloid origin. Leukotrienes and their synthetic enzymes are critical immune modulators for leukocyte migration. Increased concentrations of leukotrienes are implicated in a number of inflammatory disorders. More recent work indicates that leukotrienes may also interact with a variety of tissue cells, contributing to the low-grade inflammation of cardiovascular, neurodegenerative, and metabolic conditions, as well as that of cancer. Leukotriene signaling contributes to the active tumor microenvironment, promoting tumor growth and resistance to immunotherapy. This review summarizes recent insights into the intricate roles of leukotrienes in promoting tumor growth and metastasis through shaping the tumor microenvironment. The emerging possibilities for pharmacological targeting of leukotriene signaling in tumor metastasis are considered.

Nonsteroidal antiinflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is characterized by moderate-to-severe asthma and a higher prevalence of chronic rhinosinusitis/nasal polyps, but is a highly heterogeneous disorder with various clinical manifestations. Two major pathogenic mechanisms are: (1) overproduction of cysteinyl leukotrienes with dysregulation of arachidonic acid metabolism and (2) increased type 2 eosinophilic inflammation affected by genetic mechanisms. Aspirin challenge is the gold standard to diagnose NERD, whereas reliable in vitro biomarkers have yet not been identified. Therapeutic approaches have been done on the basis of disease severity with the avoidance of culprit and cross-reacting NSAIDs, and when indicated, aspirin desensitization is an effective treatment option. Biologic approaches targeting Type 2 cytokines are emerging as potential therapeutic options. Here, we summarize the up-to-date evidence of pathophysiologic mechanisms and diagnosis/management approaches to the patients with NERD with its phenotypic classification.

The lifetime prevalence of asthma in California is nearly 20%, and better therapies are needed to manage this common chronic disease. Fish oils containing omega-3 fatty acids are considered a potential therapy for asthma and other inflammatory diseases. Fish oil inhibits the production of arachidonic acid 5-lipoxygenase (ALOX5), an enzyme that exacerbates the lung inflammation that causes asthma. We discuss the genetics of asthma and our preliminary results using a strategy to identify the subgroup of patients who may respond well to treatment with fish oil. These findings, and others, suggest that certain gene polymorphisms of the ALOX5 gene predispose patients to the increased production of inflammatory leukotrienes. Our clinical trials will test the hypothesis that patients with moderate to severe asthma, and with specific high-risk ALOX5 gene sequence variations, will have fewer asthma symptoms when treated with fish oil. The strategy is to decrease the total burden of leukotriene production by supplementing with omega-3 polyunsaturated fatty acids. These studies will also help determine whether genotyping or metabolic profiling (for example, with exhaled breath condensate) can help establish “personalized medicine” for asthma.

Albeit showing abrogated airway tuft cell expansion in I Ltc4s i SP -/- sp mice ([8]), the authors' previous work does not provide direct proof for airway tuft cells as the source of CysLTs during I Alternaria i -induced type 2 airway inflammation. N. brasiliensis infection causes tuft cell hyperplasia, whereas H. polygyrus products reverse tuft cell expansion. Although tuft cell-derived CysLTs are implicated in early innate type 2 immune responses, it is unclear what the relative contribution of tuft cell CysLTs in chronic type 2 inflammation is, e.g., in allergic asthma or nasal polyposis. A lack of CysLT synthesis in tuft cells abrogates allergen-induced tuft cell expansion and attenuates ILC2 and eosinophil responses, demonstrating both autocrine and paracrine functions of tuft cell-derived CysLTs. [Extracted from the article]

An editorial is presented on a possible explanation for the contrasting results of REDUCE-IT vs. STRENGTH: cohort study mimicking trial designs. Topics include reducing biomarkers of chronic inflammation such as C-reactive protein (CRP), tumour necrosis factor-a, and proinflammatory eicosanoids and leukotrienes; and estimate effects of the observed changes in circulating levels of three biomarkers.