Computational screening of potential anti-inflammatory leads from Jeevaneeya Rasayana plants targeting COX-2 and 5- LOX by molecular docking and dynamic simulation approaches.

Inflammation plays a pivotal role in various pathological processes, ranging from routine injuries and infections to cancer. Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) are two major enzymes involved in the formation of lipid mediators of inflammation, such as prostaglandins and leukotrienes, through the arachidonic acid pathway. Despite the frequent use of nonsteroidal anti-inflammatory drugs for managing inflammatory disorders by inhibiting these enzymes, there is a wide spectrum of adverse effects linked to their usage. Jeevaneeya Rasayana (JR), a polyherbal formulation traditionally used in India, is renowned for its anti-inflammatory properties. The present study aimed to identify the potential phytocompounds in JR plants against COX-2 and 5-LOX, utilizing molecular docking and dynamic simulations. Among the 429 identified phytocompounds retrieved from publicly available data sources, Terrestribisamide and 1-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine have shown potential binding affinity and favorable interactions with COX-2 and 5-LOX arachidonic acid binding sites. The physicochemical properties and ADMET profiles of these compounds determined their drug-likeness and pharmacokinetics features. Additional validation using molecular dynamics simulations, SASA, Rg, and MM-PBSA binding energy calculations affirmed the stability of the complex formed between those compounds with target proteins. Together, the study identified the effectual binding potential of those bioactive compounds against COX-2 and 5-LOX, providing a viable approach for the development of effective anti-inflammatory medications.

Phospholipid metabolic adaptation promotes survival of IDH2 mutant acute myeloid leukemia cells.

Genetic mutations in the isocitrate dehydrogenase (IDH) gene that result in a pathological enzymatic activity to produce oncometabolite have been detected in acute myeloid leukemia (AML) patients. While specific inhibitors that target mutant IDH enzymes and normalize intracellular oncometabolite level have been developed, refractoriness and resistance has been reported. Since acquisition of pathological enzymatic activity is accompanied by the abrogation of the crucial WT IDH enzymatic activity in IDH mutant cells, aberrant metabolism in IDH mutant cells can potentially persist even after the normalization of intracellular oncometabolite level. Comparisons of isogenic AML cell lines with and without IDH2 gene mutations revealed two mutually exclusive signalings for growth advantage of IDH2 mutant cells, STAT phosphorylation associated with intracellular oncometabolite level and phospholipid metabolic adaptation. The latter came to light after the oncometabolite normalization and increased the resistance of IDH2 mutant cells to arachidonic acid-mediated apoptosis. The release of this metabolic adaptation by FDA-approved anti-inflammatory drugs targeting the metabolism of arachidonic acid could sensitize IDH2 mutant cells to apoptosis, resulting in their eradication in vitro and in vivo. Our findings will contribute to the development of alternative therapeutic options for IDH2 mutant AML patients who do not tolerate currently available therapies.

[Theories of the pathogenesis of polypous rhinosinusitis and the asthmatic triad]. / Teorii patogeneza polipoznogo rinosinusita i astmaticheskoi triady.

Polypous rhinosinusitis (PRS) is a chronic inflammatory disease of the mucous membrane of the nasal cavity and paranasal sinuses, characterized by the formation and recurrent growth of polyps. Often, PRS is a manifestation of the most severe clinical symptom complex - the asthmatic triad (AT). AT is characterized by three main clinical manifestations: bronchial asthma (BA) itself, PRS, intolerance to acetylsalicylic acid, other nonsteroidal anti-inflammatory drugs (NSAIDs) and NA. However, not all three components of the triad are expressed equally, a variant of the dyad (BA with PRS) is possible. AT is one of the most severe variants of BA, it is more difficult to respond to conservative therapy and significantly reduces the ability of patients to work. In the world, PRS and AT are detected in 0.5-16% of the population, in Russia the number of patients is about 1.5 million people. MATERIAL AND METHODS: The analysis of the medical literature on this problem has been carried out. RESULTS: To date, there is no consensus on the etiology and pathogenesis of the polypous process in the nasal cavity and paranasal sinuses, therefore, many theories of the occurrence of this disease have been proposed, the main ones being: anatomical factors, osteitis, virological, bacterial, allergic, autoimmune theory and the theory of metabolic disorders of arachidonic acid. The key role in modern studies of the pathogenesis of AT is still given to the peculiarities of arachidonic acid metabolism. CONCLUSIONS: The low effectiveness of treatment and the severity of clinical manifestations encourage scientists to further investigate the etiopathogenesis of polypous rhinosinusitis and the asthmatic triad.

Impact of Tyrosine Kinase Inhibitors Applied for First-Line Chronic Myeloid Leukemia Treatment on Platelet Function in Whole Blood of Healthy Volunteers In Vitro.

The tyrosine kinase inhibitors (TKIs) imatinib, dasatinib, bosutinib, and nilotinib are established for first-line treatment of chronic myeloid leukemia (CML) but may cause side effects such as bleeding and thrombotic complications. We investigated the impact of TKIs on platelet function ex vivo in anticoagulated whole blood (WB) samples from healthy adults by lumiaggregometry and PFA-100 test. Samples (n = 15 per TKI) were incubated for 30 minutes with TKI at therapeutically relevant final concentrations. Aggregation and ATP release were induced by collagen (1 µg/mL), arachidonic acid (0.5 mmol/L), and thrombin (0.5 U/mL). Imatinib, bosutinib, and nilotinib significantly increased collagen-induced aggregation compared with controls. In addition, for bosutinib and nilotinib, a significant increase in aggregation after induction with arachidonic acid was detected. ATP-release and PFA-100 closure times were not influenced significantly by these three TKI. In contrast, dasatinib demonstrated a concentration-dependent inhibition of collagen-induced aggregation and ATP release and a significant prolongation of the PFA-100 closure time with the collagen/epinephrine cartridge. Aggregation and ATP release by other agonists as well as closure time with the collagen/ADP cartridge were not influenced significantly. In conclusion, we clearly show a concentration-dependent inhibition of collagen-induced platelet function in WB by dasatinib confirming prior results obtained in platelet-rich plasma. Bosutinib and nilotinib exerted no impairment of platelet activation. On the contrary, both TKI showed signs of platelet activation. When comparing our results with existing data, imatinib in therapeutic relevant concentrations does not impair platelet function.

ATF6α promotes prostate cancer progression by enhancing PLA2G4A-mediated arachidonic acid metabolism and protecting tumor cells against ferroptosis.

BACKGROUND: Despite the clinical success of androgen receptor (AR)-targeted therapies, prostate cancer (PCa) inevitably progresses to castration-resistant prostate cancer (CRPC). Transcription factor 6 α (ATF6α), an effector of the unfolded protein response (UPR) that modulates the cellular response to endoplasmic reticulum (ER) stress, has been linked to tumor development, metastasis, and relapse. However, the role of ATF6α in CRPC remains unclear. METHODS: The effect of ATF6α on the CRPC-like phenotype in PCa cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carb-Oxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS), 5-Bromo-2-deoxyUridine (BrdU) incorporation analysis, and cell death assay. Mechanistically, bioinformatic analysis was utilized to evaluate the potential of PLA2G4A as the target of ATF6α. Moreover, Western blot analysis, real-time polymerase chain reaction, chromatin immunoprecipitation, arachidonic acid (AA), and prostaglandin E2 (PGE2) assays were performed to identify the regulatory effect of ATF6α on PLA2G4A. RESULTS: In this study, we found that the increase of ATF6α expression in response to androgen deprivation generates PCa cells with a CRPC-like phenotype. PCa cells with high levels of ATF6α expression are resistant to ferroptosis, and genetic and pharmacological inhibition of ATF6α could, therefore, promote the ferroptotic death of tumor cells and delay PCa progression. Molecular analyses linked ATF6α regulation of ferroptosis to the PLA2G4A-mediated release of AA and the resulting increase in PGE2 production, the latter of which acts as an antiferroptotic factor. CONCLUSIONS: This study defines ATF6α as a novel antiferroptotic regulator that exacerbates PCa progression. In addition, our data establish ATF6α-PLA2G4A signaling as an important pathological pathway in PCa, and targeting this pathway may be a novel treatment strategy.

Modified Xiaoqinglong decoction alleviates lipopolysaccharide-induced acute lung injury in mice by regulating arachidonic acid metabolism and exerting anti-apoptotic and anti-inflammatory effects.

Effective therapeutics are not available for acute lung injury (ALI) and acute respiratory distress syndrome. Modified Xiaoqinglong decoction (M-XQL) is reported to effectively treat pneumonia, but the underlying mechanisms are unclear. In this study, the therapeutic effect and mechanism of M-XQL were examined using a lipopolysaccharide (LPS)-induced ALI mouse model. The effects of M-XQL on lung injury, inflammatory responses, and cell apoptosis were analyzed. Additionally, high-throughput sequencing was performed to evaluate the therapeutic mechanism of M-XQL. Pretreatment with M-XQL significantly and dose-dependently mitigated the pathological changes and upregulation of pulmonary, nitric oxide content and cell apoptosis and serum tumor necrosis factor-alpha contents in the LPS-induced ALI mouse model. RNA sequencing analysis revealed that the expression of several arachidonic acid metabolism-associated genes in the LPS + high-dose M-XQL group differed from that in the LPS group. In particular, the Cbr2, Cyp4f18, and Cyp2e1 levels were upregulated, whereas the Alox12, Ptges, and Ptges2 levels were downregulated in the LPS + high-dose M-XQL group. These results suggest that M-XQL exerts therapeutic effects in ALI mice by regulating arachidonic acid metabolism and exerting anti-apoptotic and anti-inflammatory effects. Thus, M-XQL is a potential agent for the clinical treatment of ALI.

Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma.

Background High resistance to therapy and poor prognosis characterizes malignant pleural mesothelioma (MPM). In fact, the current lines of treatment, based on platinum and pemetrexed, have limited impact on the survival of MPM patients. Adaptive response to therapy-induced stress involves complex rearrangements of the MPM secretome, mediated by the acquisition of a senescence-associated-secretory-phenotype (SASP). This fuels the emergence of chemoresistant cell subpopulations, with specific gene expression traits and protumorigenic features. The SASP-driven rearrangement of MPM secretome takes days to weeks to occur. Thus, we have searched for early mediators of such adaptive process and focused on metabolites differentially released in mesothelioma vs mesothelial cell culture media, after treatment with pemetrexed. METHODS: Mass spectrometry-based (LC/MS and GC/MS) identification of extracellular metabolites and unbiased statistical analysis were performed on the spent media of mesothelial and mesothelioma cell lines, at steady state and after a pulse with pharmacologically relevant doses of the drug. ELISA based evaluation of arachidonic acid (AA) levels and enzyme inhibition assays were used to explore the role of cPLA2 in AA release and that of LOX/COX-mediated processing of AA. QRT-PCR, flow cytometry analysis of ALDH expressing cells and 3D spheroid growth assays were employed to assess the role of AA at mediating chemoresistance features of MPM. ELISA based detection of p65 and IkBalpha were used to interrogate the NFkB pathway activation in AA-treated cells. RESULTS: We first validated what is known or expected from the mechanism of action of the antifolate. Further, we found increased levels of PUFAs and, more specifically, arachidonic acid (AA), in the transformed cell lines treated with pemetrexed. We showed that pharmacologically relevant doses of AA tightly recapitulated the rearrangement of cell subpopulations and the gene expression changes happening in pemetrexed -treated cultures and related to chemoresistance. Further, we showed that release of AA following pemetrexed treatment was due to cPLA2 and that AA signaling impinged on NFkB activation and largely affected anchorage-independent, 3D growth and the resistance of the MPM 3D cultures to the drug. CONCLUSIONS: AA is an early mediator of the adaptive response to pem in chemoresistant MPM and, possibly, other malignancies.

Effect of Enteral Lipid Supplement on Severe Retinopathy of Prematurity: A Randomized Clinical Trial.

Importance: Lack of arachidonic acid (AA) and docosahexaenoic acid (DHA) after extremely preterm birth may contribute to preterm morbidity, including retinopathy of prematurity (ROP). Objective: To determine whether enteral supplementation with fatty acids from birth to 40 weeks' postmenstrual age reduces ROP in extremely preterm infants. Design, Setting, and Participants: The Mega Donna Mega trial, a randomized clinical trial, was a multicenter study performed at 3 university hospitals in Sweden from December 15, 2016, to December 15, 2019. The screening pediatric ophthalmologists were masked to patient groupings. A total of 209 infants born at less than 28 weeks' gestation were tested for eligibility, and 206 infants were included. Efficacy analyses were performed on as-randomized groups on the intention-to-treat population and on the per-protocol population using as-treated groups. Statistical analyses were performed from February to April 2020. Interventions: Infants received either supplementation with an enteral oil providing AA (100 mg/kg/d) and DHA (50 mg/kg/d) (AA:DHA group) or no supplementation within 3 days after birth until 40 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was severe ROP (stage 3 and/or type 1). The secondary outcomes were AA and DHA serum levels and rates of other complications of preterm birth. Results: A total of 101 infants (58 boys [57.4%]; mean [SD] gestational age, 25.5 [1.5] weeks) were included in the AA:DHA group, and 105 infants (59 boys [56.2%]; mean [SD] gestational age, 25.5 [1.4] weeks) were included in the control group. Treatment with AA and DHA reduced severe ROP compared with the standard of care (16 of 101 [15.8%] in the AA:DHA group vs 35 of 105 [33.3%] in the control group; adjusted relative risk, 0.50 [95% CI, 0.28-0.91]; P = .02). The AA:DHA group had significantly higher fractions of AA and DHA in serum phospholipids compared with controls (overall mean difference in AA:DHA group, 0.82 mol% [95% CI, 0.46-1.18 mol%]; P < .001; overall mean difference in control group, 0.13 mol% [95% CI, 0.01-0.24 mol%]; P = .03). There were no significant differences between the AA:DHA group and the control group in the rates of bronchopulmonary dysplasia (48 of 101 [47.5%] vs 48 of 105 [45.7%]) and of any grade of intraventricular hemorrhage (43 of 101 [42.6%] vs 42 of 105 [40.0%]). In the AA:DHA group and control group, respectively, sepsis occurred in 42 of 101 infants (41.6%) and 53 of 105 infants (50.5%), serious adverse events occurred in 26 of 101 infants (25.7%) and 26 of 105 infants (24.8%), and 16 of 101 infants (15.8%) and 13 of 106 infants (12.3%) died. Conclusions and Relevance: This study found that, compared with standard of care, enteral AA:DHA supplementation lowered the risk of severe ROP by 50% and showed overall higher serum levels of both AA and DHA. Enteral lipid supplementation with AA:DHA is a novel preventive strategy to decrease severe ROP in extremely preterm infants. Trial Registration: ClinicalTrials.gov Identifier: NCT03201588.

Effects and mechanism of arachidonic acid against TNF-α induced apoptosis of endothelial cells.

This study aimed to investigate the effects of arachidonic acid metabolite epoxyeicosatrienoic acid (EETs) in the apoptosis of endothelial cells induced by tumor necrosis factor-alpha (TNF-α). After human umbilical vein endothelial cells were cultured, TNF-α/ActD, 14, 15-EET, and HMR-1098 were added, respectively, into the culture medium. The apoptosis level of endothelial cells was detected by flow cytometry. After TNF-α/ActD induced endothelial cell apoptosis, flow cytometry staining showed that endothelial cell apoptosis increased significantly, and the apoptotic cells were significantly reduced after the addition of 14, 15-EET. However, the apoptotic cells significantly increased after the addition of HMR-1098. Western Blot results showed that the phosphorylation levels of LC3-II and AMPK were increased after TNF-α/ActD induction, and the increase was noticeable after the addition of 14, 15-EET. However, the phosphorylation levels of LC3-II and AMPK significantly decreased after the addition of HMR-1098. The activity of Caspase-8 and -9 decreased significantly after the addition of 14, 15-EET but increased after the addition of HMR-1098. Arachidonic acid can inhibit TNF-α induced endothelial cell apoptosis by upregulating autophagy.

Arachidonic Acid Is a Safe and Efficacious Schistosomicide, and an Endoschistosomicide in Natural and Experimental Infections, and Cysteine Peptidase Vaccinated Hosts.

Blood flukes of the genus Schistosoma are covered by a protective heptalaminated, double lipid bilayer surface membrane. Large amounts of sphingomyelin (SM) in the outer leaflet form with surrounding water molecules a tight hydrogen bond barrier, which allows entry of nutrients and prevents access of host immune effectors. Excessive hydrolysis of SM to phosphoryl choline and ceramide via activation of the parasite tegument-associated neutral sphingomyelinase (nSMase) with the polyunsaturated fatty acid, arachidonic acid (ARA) leads to parasite death, via allowing exposure of apical membrane antigens to antibody-dependent cell-mediated cytotoxicity (ADCC), and accumulation of the pro-apoptotic ceramide. Surface membrane nSMase represents, thus, a worm Achilles heel, and ARA a valid schistosomicide. Several experiments conducted in vitro using larval, juvenile, and adult Schistosoma mansoni and Schistosoma haematobium documented ARA schistosomicidal potential. Arachidonic acid schistosomicidal action was shown to be safe and efficacious in mice and hamsters infected with S. mansoni and S. haematobium, respectively, and in children with light S. mansoni infection. A combination of praziquantel and ARA led to outstanding cure rates in children with heavy S. mansoni infection. Additionally, ample evidence was obtained for the powerful ARA ovocidal potential in vivo and in vitro against S. mansoni and S. haematobium liver and intestine eggs. Studies documented ARA as an endogenous schistosomicide in the final mammalian and intermediate snail hosts, and in mice and hamsters, immunized with the cysteine peptidase-based vaccine. These findings together support our advocating the nutrient ARA as the safe and efficacious schistosomicide of the future.

Can Bioactive Lipid Arachidonic Acid Prevent and Ameliorate COVID-19?

It is proposed that the bioactive lipid, arachidonic acid (AA, 20:4 n-6), can inactivate severe acute respiratory syndrome(SARS-CoV-2), facilitate M1 and M2 macrophage generation, suppress inflammation, prevent vascular endothelial cell damage, and regulate inflammation resolution processes based on the timely formation of prostaglandin E2 (PGE2) and lipoxin A4 (LXA4) based on the context. Thus, AA may be useful both to prevent and manage coronavrus disease-2019(COVID-19).

Arachidonic acid inhibits inflammatory responses by binding to myeloid differentiation factor-2 (MD2) and preventing MD2/toll-like receptor 4 signaling activation.

Arachidonic acid (AA) plays a fundamental role in the function of all cells. Metabolites of AA contribute to inflammation as well as for resolving inflammation. Although AA-derived metabolites exhibit well-substantiated bioactivity, it is not known whether AA regulates inflammatory responses independent of its metabolites. With the recent discovery that saturated fatty acids activate toll-like receptor-4 (TLR4), we tested the hypothesis that AA directly regulates inflammatory responses through modulating the activity of TLR4. In cultured cardiomyocytes and macrophages, we found that AA prevents saturated fatty acid-induced TLR4 complex formation with accessory proteins and the induction of proinflammatory cytokines. We discovered that AA directly binds to TLR4 co-receptor, myeloid differentiation factor 2 (MD2) and prevents saturated fatty acids from activating TLR4 pro-inflammatory signaling pathway. Similarly, AA reduced lipopolysaccharide (LPS)-induced inflammation in macrophages and septic death in mice through binding to MD2. In high-fat diet mouse model of obesity and LPS-induced model of acute lung injury, both mediating inflammatory responses through TLR4, treatment with AA prevented MD2/TLR4 dimerization, induction of inflammatory factors, and tissue injuries. In summary, we have discovered that AA interacts with MD2 and disrupts TLR4 activation by LPS and saturated fatty acids. These findings provide experimental evidence for a direct mechanism of AA-induced regulation of inflammation.

Metabolomic evidence for the therapeutic effect of gentiopicroside in a corticosterone-induced model of depression.

BACKGROUND: Depression is a disease that seriously threatens the quality of human life. To explore the effect of gentiopicroside on depression, this study investigated the therapeutic effect of gentiopicroside on corticosterone-induced depressionin vivo and in vitro by using metabolomic methods. METHODS: A total of 36 rats were randomly assigned to three groups: a normal group, model group (depression), and treatment group (depression + gentiopicroside). Corticosterone was administrated to induce depression-like model rats. Morris water maze test was used to validated the behavior performance. The hippocampus of rats was obtained for metabolomic detection. Metabolites that were differentially expressed between the groups were extracted for Heatmap, Go, and pathway enrichment analyses. Finally, neuronal cells were cultured and examined to validated the effect of gentiopicroside. RESULTS: Corticosterone injured rats learning capacity, and decreased the levels of 5-HT, and reversed by gentiopicroside delivery. Metabolites obtained from the hippocampus of rats in the three groups were subjected to a principal component analysis (PCA). Go and pathway enrichment analyses revealed the involvement of sphingolipid metabolism et al. Gentiopicroside could inhibit apoptosis caused by corticosterone, and also decrease neuronal cell proliferation and BDNF levels in vitro. Arachidonic acid (ARA) reversed the protective effect of gentiopicroside on neuronal cells. CONCLUSION: These findings suggest that gentiopicroside reduces apoptosis and increases the proliferation of hippocampus cells in depressed animals by regulating metabolites. Moreover, our study provides a new basis for the clinical treatment of depression and demonstrates the potential efficacy of gentiopicroside in this area of pathology.

Ginsenoside Rb1 inhibits autophagy through regulation of Rho/ROCK and PI3K/mTOR pathways in a pressure-overload heart failure rat model.

OBJECTIVE: This study was designed to explore the relationship between ginsenoside Rb1 (Grb1) and high-load heart failure (HF) in rats. METHODS: The parameters of cardiac systolic function (left ventricular posterior wall thickness (LVPWT), left ventricular internal diastolic diameter (LVID), fraction shortening (FS) and mitral valves (MVs)) of rat hearts in each group were inspected by echocardiogram. The expressions of rat myocardial contractile proteins, autophagy-related proteins and the activation of Rho/ROCK and PI3K/mTOR pathways were detected by Western blot. KEY FINDINGS: LVPWT, FS, MVs and the expression of myocardial contractile proteins α-MHC, apoptosis-related proteins Bcl-2 and signalling pathway involved proteins pAkt and mTOR were significantly reduced in the HF, HF+5 mg/kg Grb1 (HF+Grb1-5) and HF+Grb1+arachidonic acid (AA) groups with LVID, ß-MHC, cell apoptosis, cell autophagy and Rho/ROCK significantly increased compared with the control group, of which the tendency was contrary to the HF+20 mg/kg Grb1 (HF+Grb1-20) group compared with the HF group (P < 0.05). In the HF+Grb1+AA group, there was no significant change in the above indexes compared with the HF group. CONCLUSIONS: The results indicated that Grb1 can exert anti-HF function by inhibiting cardiomyocyte autophagy of rats through regulation of Rho/ROCK and PI3K/mTOR pathways.

Adequate Platelet Function Inhibition Confirmed by Two Inductive Agents Predicts Lower Recurrence of Ischemic Stroke/Transient Ischemic Attack.

BACKGROUND: The correlation between platelet function and recurrent ischemic stroke or TIA remains uncertain. OBJECTIVE: To investigate two inductive agents to detect platelet functions and assess associations with recurrent ischemic stroke/TIA. METHOD: The study included 738 ischemic stroke/TIA patients. On days 0, 3, and 9 after antiplatelet therapy, platelet function tests were determined by maximum aggregation rate (MAR) using a PL-11 platelet function analyzer and phase matching reagents. Two induction agents were used: arachidonic acid (AA) and adenosine diphosphate (ADP). At 3-month follow-up, recurrence of stroke/TIA was recorded. RESULT: Cut-off values of adequate platelet function inhibition were MARADP < 35% and MARAA < 35%. Data showed that antiplatelet therapy could reduce the maximum aggregation rate. More importantly, adequate platelet function inhibition of either MARADP or MARAA was not associated with the recurrence of stroke/TIA, but adequate platelet function inhibition of not only MARADP but also MARAA predicts lower recurrence (0/121 (0.00%) versus 18/459 (3.92%), P = 0.0188). CONCLUSION: The platelet function tested by PL-11 demonstrated that adequate inhibition of both MARADP and MARAA could predict lower risk of ischemic stroke/TIA recurrence.

Nonsteroidal Anti-Inflammatory Drugs: Exploiting Bivalent COXIB/ TP Antagonists for the Control of Cardiovascular Risk.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are some of the most widely prescribed or dispensed over the counter analgesics and antipyretics that act by inhibiting prostaglandins and thromboxane synthesis. After the identification of a second isoform of COX, the pharmaceutical research focused on developing COX-2- selective drugs (COXIBs) considered as second generation NSAIDs that would retain the anti-inflammatory and analgesic activities of traditional NSAID without blunting the gastrointestinal cytoprotection sustained by COX1-derived products such as PGE2. However, while several clinical trials confirmed a gastrointestinal safer profile of COXIBs vs unselective COX inhibitors, increasing evidence for potential cardiovascular risk associated with COXIBs rapidly emerged. Today, there are no really safe NSAIDs to be used in chronic pain and anti-inflammatory treatments, as an adequate therapy associated with a minimal gastrointestinal damage and cardiovascular toxicity is yet to be developed. OBJECTIVE: Here, we present evidences that combining the anti-aggregating and antiatherotrombotic activities of a thromboxane receptor antagonist with the antiinflammatory activity of a COXIB we could obtain a new multitarget drug providing protection against the harmful activities mediated by the COXIB component, yet exploiting its recognized therapeutic advantages as a gastrointestinal-safer anti-inflammatory drug. We also summarize recent progress achieved in this field of research and possible new strategies to obtain a new bivalent compound. CONCLUSION: This possible third-generation NSAID with a safer pharmacological profile, will have all the pharmacological characteristics for the long-term therapy of chronic disorders such as inflammatory diseases or selected forms of cancer.

Protective Effects of Arachidonic Acid Against Paraquat-Induced Pulmonary Injury.

In this study, we aimed to study the effects of arachidonic acid (AA) on acute lung injury (ALI) caused by paraquat (PQ) in mice. Male Kunming mice were randomly divided into three groups: control group, PQ group, and PQ + AA group (n = 24). The mice in the PQ and PQ + AA groups received a single oral dose of 20 mg/kg bodyweight PQ, and the mice of the PQ + AA group were challenged by 500 mg/kg bodyweight AA posttreatment 2 h after PQ administration. The results indicated that the administration of AA significantly increased the activity of superoxide dismutase (SOD), decreased the activity of myeloperoxidase (MPO), the content of malondialdehyde (MDA), and the level of lactate dehydrogenase (LDH). Pathological examination also revealed that AA effectively alleviated PQ-induced histological damage. Furthermore, AA significantly reduced PQ-induced upregulations of inflammatory mediators such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-8. These results demonstrated that AA had effective protection against PQ-induced ALI.

Efficacy and safety of arachidonic acid for treatment of school-age children in Schistosoma mansoni high-endemicity regions.

Arachidonic acid (ARA), an omega-6 fatty acid, is a potent schistosomicide that displayed significant and safe therapeutic effects in Schistosoma mansoni-infected schoolchildren in S. mansoni low-prevalence regions. We here report on ARA efficacy and safety in treatment of schoolchildren in S. mansoni high-endemicity areas of Kafr El Sheikh, Egypt. The study was registered with ClinicalTrials.gov (NCT02144389). In total, 268 schoolchildren with light, moderate, or heavy S. mansoni infection were assigned to three study arms of 87, 91, and 90 children and received a single dose of 40 mg/kg praziquantel (PZQ), ARA (10 mg/kg per day for 15 days), or PZQ combined with ARA, respectively. The children were examined before and after treatment for stool parasite egg counts and blood biochemical, hematological, and immunological parameters. ARA, like PZQ, induced moderate cure rates (50% and 60%, respectively) in schoolchildren with light infection and modest cure rates (21% and 20%, respectively) in schoolchildren with high infection. PZQ and ARA combined elicited 83% and 78% cure rates in children with light and heavy infection, respectively. Biochemical and immunological profiles were either unchanged or ameliorated after ARA therapy. Combination of PZQ and ARA might be useful for treatment of children with schistosomiasis in high-endemicity regions.

Platelet function monitoring guided antiplatelet therapy in patients receiving high-risk coronary interventions.

BACKGROUND: Large-scale clinical trials have shown that routine monitoring of the platelet function in patients after percutanous coronary intervention (PCI) is not necessary. However, it is still unclear whether patients received high-risk PCI would benefit from a therapy which is guided by a selective platelet function monitoring. This explanatory study sought to assess the benefit of a therapy guided by platelet function monitoring for these patients. METHODS: Acute coronary syndrome (ACS) patients (n = 384) who received high-risk, complex PCI were randomized into two groups. PCI in the two types of lesions described below was defined as high-risk, complex PCI: lesions that could result in severe clinical outcomes if stent thrombosis occurred or lesions at high risk for stent thrombosis. The patients in the conventionally treated group received standard dual antiplatelet therapy. The patients in the platelet function monitoring guided group received an antiplated therapy guided by a modified thromboelastography (TEG) platelet mapping: If inhibition of platelet aggregation (IPA) induced by arachidonic acid (AA) was less than 50% the aspirin dosage was raised to 200 mg/d; if IPA induced by adenosine diphosphate (ADP) was less than 30% the clopidogrel dosage was raised to 150 mg/d, for three months. The primary efficacy endpoint was a composite of myocardial infarction, emergency target vessel revascularization (eTVR), stent thrombosis, and death in six months. RESULTS: This study included 384 patients; 191 and 193 in the conventionally treated group and platelet function monitoring guided group, respectively. No significant differences were observed in the baseline clinical characteristics and interventional data between the two groups. In the platelet function monitoring guided group, the mean IPA induced by AA and ADP were (69.2 ± 24.5)% (range, 4.8% to 100.0%) and (51.4 ± 29.8)% (range, 0.2% to 100.0%), respectively. The AA-induced IPA of forty-three (22.2%) patients was less than 50% and the ADP-induced IPA of fifty-seven (29.5%) patients was less than 30%; therefore, their drug dosages were adjusted. The TEG was rechecked one to four weeks after PCI, and the results indicated that the IPAs had significantly improved (P < 0.01). However, no significant differences were found in the rates of the primary efficacy endpoint. Rates in the conventionally treated group and platelet function monitoring guided group were 4.7% and 5.2%, respectively (hazard ratio: 1.13; P = 0.79). CONCLUSION: An antiplatelet therapy guided by TEG monitored platelet function could not improve clinical efficacy even in ACS patients treated with high-risk complex PCI.

Efficacy and safety of arachidonic acid for treatment of Schistosoma mansoni-infected children in Menoufiya, Egypt.

Arachidonic acid (ARA), an omega-6 fatty acid, kills juvenile and adult schistosomes in vitro and displays highly significant and safe therapeutic effects in mice and hamsters infected with Schistosoma mansoni or S. haematobium. This study aims to examine the efficacy and safety of ARA in treatment of school-age children infected with S. mansoni. In total, 66 S. mansoni-infected schoolchildren (20-23 children/study arm) received a single dose of 40 mg/kg praziquantel (PZQ), ARA (10 mg/kg per day for 15 days), or PZQ combined with ARA. The children were examined before and after treatment for worm egg counts in stool and blood biochemical and immunological parameters. ARA proved to be as efficacious as PZQ in treatment of schoolchildren with low infection intensity (78% and 85% cure rates, respectively). For moderate-intensity infection, the ARA and PZQ combination led to 100% cure rate. Biochemical, hematological, and immunological parameters were either unchanged or ameliorated after ARA therapy.