Cyclooxygenase Activity Research Articles

Quercetin decreases the antinociceptive effect of diclofenac in an arthritic gout-pain model in rats.

To analyse the antinociceptive interaction between quercetin (QUER) and diclofenac (DIC) in experimental arthritic gout-pain. The antinociceptive effect of DIC and QUER alone and in combination were evaluated using an arthritic gout-pain model. Pain was induced through intra-articular administration of uric acid in the rats and the treatments were administered 2 h later. Additionally, the cyclooxygenase (COX) activity was determined in rats treated with DIC, QUER and their combination. DIC induced a maximal effect of 69.7 ± 2.7% with 3.1 mg/kg; whereas QUER only produced 17.6 ± 2.6% with the maximal dose (316 mg/kg). Ten of twelve DIC + QUER combinations showed a lesser antinociceptive effect than DIC alone did (P < 0.05). Moreover, DIC reduced total-COX (70.4 ± 1.3 versus 52.4 ± 1.8 and 77.4 ± 9.0 versus 56.1 ± 1.3, P < 0.05) and COX-2 (60.1 ± 1.0 versus 42.4 ± 1.8 and 58.1 ± 2.4 versus 48.7 ± 1.3, P < 0.05) activity after 1 and 3 h, respectively. Nevertheless, only the COX-2 activity induced by DIC was prevented in the presence of QUER (63.2 ± 3.0 versus 60.1 ± 1.0 and 56.6 ± 1.3 versus 58.1 ± 2.4 at 1 and 3 h, respectively). All these data demonstrated that the simultaneous administration of QUER + DIC produces an unfavorable interaction on the antinociceptive effect of DIC. Therefore, this combination might not be recommendable to relieve arthritic gout-pain.

Pharmacological, Biochemical and Immunological Studies on Protective Effect of Mangiferin in 6-Hydroxydopamine (6-OHDA)-Induced Parkinson's Disease in Rats.

Background:Parkinson’s disease is a neurodegenerative disorder and is marked by inflammation and death of neurons in the striatum region of the midbrain. It has been reported that expression of NF-κB increases during Parkinson’s disease, which promotes oxidative stress, stimulates release of proinflammatory cytokines, and induces expression of nitric oxide. Therefore, in this study, we have used mangiferin a specific NF-κB inhibitor. Mangiferin is a polyphenolic compound traditionally used for its antioxidant and anti-inflammatory properties.Methods:The study utilized male Wistar rats weighing 200–250 g (56 rats; n = 8/group). On day “0,” stereotaxic surgery of rats was done to induce 6-hydroxydopamine lesioning in rats. Coordinates for substantia nigra were anteroposterior-2 mm, mediolateral-5 mm and dorsoventral-8.2 mm. After 14 days, those rats which show at least 210 contralateral rotations after administration of apomorphine (0.5 mg/kg S.C.) were selected for the study and were given treatment for 28 days. On day 28 of treatment, rats were subjected to behavioral studies to evaluate the effect of mangiferin and their brains were taken out after euthanasia to perform biochemical, molecular and immunological studies.Results:Treatment with mangiferin significantly improves the key parameters of locomotor activity and oxidative stress and reduces the parameters of inflammatory stress. Also, the activity of caspases was reduced. Significant decrease in activity of both cyclooxygenase 1 and 2 was also observed. Maximum improvement in all parameters was observed in rats treated with grouping of mangiferin 45 µg/kg and levodopa 10 mg/kg. Treatment with levodopa alone has no significant effect on biochemical and molecular parameters though it significantly improves behavioral parameters.Conclusion:Current treatment of Parkinson’s disease does not target progression of Parkinson’s disease. Results of this study suggest that mangiferin has protective effect in hemi-Parkinsonian rats. Therefore, the combination therapy of mangiferin and levodopa can be helpful in management of Parkinson’s disease.

The Role of Organic Small Molecules in Pain Management.

In this review, a timeline starting at the willow bark and ending in the latest discoveries of analgesic and anti-inflammatory drugs will be discussed. Furthermore, the chemical features of the different small organic molecules that have been used in pain management will be studied. Then, the mechanism of different types of pain will be assessed, including neuropathic pain, inflammatory pain, and the relationship found between oxidative stress and pain. This will include obtaining insights into the cyclooxygenase action mechanism of nonsteroidal anti-inflammatory drugs (NSAID) such as ibuprofen and etoricoxib and the structural difference between the two cyclooxygenase isoforms leading to a selective inhibition, the action mechanism of pregabalin and its use in chronic neuropathic pain, new theories and studies on the analgesic action mechanism of paracetamol and how changes in its structure can lead to better characteristics of this drug, and cannabinoid action mechanism in managing pain through a cannabinoid receptor mechanism. Finally, an overview of the different approaches science is taking to develop more efficient molecules for pain treatment will be presented.

Protective effect of (+)-catechin against lipopolysaccharide-induced inflammatory response in RAW 264.7 cells through downregulation of NF-κB and p38 MAPK.

Catechin, a flavonol belonging to the flavonoid group of polyphenols is present in many plant foods. The present study was done to evaluate the effect of catechin on various inflammatory mediators using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. The effect of catechin on total cyclooxygenase (COX) activity, 5-lipoxygenase (5-LOX), myeloperoxidase, nitrite and inducible nitric oxide synthase (iNOS) level, secretion of tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) were assessed in LPS-stimulated RAW 264.7 cells. The expression of COX-2, iNOS, TNF-α, nuclear factor-ĸB (NF-κB) and p38 mitogen-activated protein kinase (MAPK) genes were also investigated. The effect was further analyzed using human PBMCs by assessing the level of TNF-α and IL-10. The study demonstrated that the inflammatory mediators such as COX, 5-LOX, nitrite, iNOS, and TNF-α were significantly inhibited by catechin in a concentration-dependent manner whereas IL-10 production was up-regulated in RAW 264.7 cells. Moreover, catechin down-regulated the mRNA level expression of COX-2, iNOS, TNF-α, NF-κB and p38 MAPK. The current study ratifies the beneficial effect of catechin as a dietary component in plant foods to provide protection against inflammatory diseases.

Approaches to Potentiated Neuroprotective Treatment in the Rodent Model of Ischemic Optic Neuropathy.

Nonarteritic anterior ischemic optic neuropathy (NAION) commonly causes sudden optic nerve (ON)-related vision loss. The rodent NAION model (rAION) closely resembles NAION in presentation and physiological responses. We identified early rAION-associated optic nerve head (ONH) inflammatory gene expression responses and the anti-inflammatory prostaglandin PGJ2’s effects on those responses. We hypothesized that blocking pro-inflammatory prostaglandin (PGE2) production by inhibiting monoacylglycerol lipase or cyclooxygenase activity and co-administering PGJ2 would potentiate RGC survival following ischemic neuropathy. Deep sequencing was performed on vehicle- and PGJ2-treated ONHs 3d post-rAION induction. Results were compared against responses from a retinal ischemia model. Animals were treated with PGJ2 and MAGL inhibitor KML29, or PGJ2 + COX inhibitor meloxicam. RGC survival was quantified by stereology. Tissue PG levels were quantified by ELISA. Gene expression was confirmed by qPCR. PGJ2 treatment nonselectively reduced inflammatory gene expression post-rAION. KML29 did not reduce PGE2 1d post-induction and KML29 alone increased RGC loss after rAION. Combined treatments did not improve ONH edema and RGC survival better than reported with PGJ2 alone. KML29′s failure to suppress PGE2 ocular synthesis, despite its purported effects in other CNS tissues may result from alternative PG synthesis pathways. Neither KML29 nor meloxicam treatment significantly improved RGC survival compared with vehicle. While exogenous PGJ2 has been shown to be neuroprotective, treatments combining PGJ2 with these PG synthesis inhibitors do not enhance PGJ2’s neuroprotection.

Insights on the toxicity of selected rare earth elements in rainbow trout hepatocytes

The increasing extraction of rare earth elements (REEs) for technology applications raised concerns for contamination and toxicity in the environment. The purpose of this study was to examine the toxicity of the following REEs in primary cultures of rainbow trout hepatocytes: yttrium (Y), samarium (Sm), gadolinium (Gd), terbium (Tb) and lutetium (Lu). Hepatocytes were exposed to increasing concentrations of the above elements for 24 h at 15 °C and they were analyzed for viability, metallothioneins (MT), glutathione-S-transferase (GST) and arachidonate cyclooxygenase (COX) as markers of oxidative stress and inflammation. The results revealed that the cytoxicity of REEs were as follows in decreasing order: Y > Sm > Lu > Tb > Gd in concordance with published rainbow trout mortality data. While effects on GST and COX activities were marginal, MT levels were more strongly increased with the 2 most toxic REEs (Y and Sm) and Gd, while MT levels were decreased in the least toxic ones (Tb, Lu). While cell viability followed published trout mortality data, it also followed the redox potential and the glutathione affinity constant (log k). The capacity to induce/decrease MT levels was associated with ionic radius, log k (glutathione) and electronegativity. A proposed mechanism of toxicity for REEs is presented based on the chemical properties of REEs, namely the glutathione binding constant and ionic radius, in light of the observed effects in trout hepatocytes.

Mechanism of reactivation of the peroxidase catalytic activity of human cyclooxygenases by reducing cosubstrate quercetin

Our earlier studies show that the peroxidase activity of cyclooxygenase 1 and 2 (COX-1 and COX-2) can be reactivated in vitro and in vivo by the presence of certain naturally-occurring flavonoids such as quercetin and myricetin, which serve as reducing cosubstrates. These compounds can activate COX at nanomolar concentrations. In the present study, quercetin is used as a representative model compound to investigate the chemical mechanism by which the peroxidase activity of human COX-1 and COX-2 is reactivated after each catalytic cycle. Molecular docking and quantum mechanics calculations are carried out to probe the interactions of quercetin with the peroxidase sites of COX-1/2 and the reactivation mechanism. It is found that some of the partially-ionized states of quercetin can bind tightly and closely inside the peroxidase active sites of the COX enzymes and directly interact with heme Fe ion. While quercetin contains several phenolic hydroxyl groups, it is found that only the C-3′-OH group can effectively donate an electron for the reduction of heme because it not only can bind closely and tightly inside the peroxidase sites of COX-1/2, but it can also facilely donate an electron to heme Fe ion. This investigation provides a mechanistic explanation for the chemical process by which quercetin reactivates COX-1/2 peroxidases. This knowledge would aid in the rational design of drugs that can selectively target the peroxidase sites of COX-1/2 either as activators or inhibitors.

Cardioprotective effects of Oroxylum indicum extract against chemotherapeutics‐induced cardiotoxicity

Cancer chemotherapy, especially doxorubicin (DOX) and cyclophosphamide (CPS) is commonly associated with adverse effects such as myelosuppression and cardiotoxicity. At this time, little approved therapeutic options are available for the management of chemotherapy-associated cardiotoxicity. Thus, identification of novel therapeutics, with potent cardioprotective effects and minimal adverse effects are pertinent in chemotherapy-induced cardiotoxicity. Oroxylum indicum extract (OIE, Sabroxy®) is a natural product known to possess several biological functions including antioxidant, anti-inflammatory and cytoprotective effects. This study was designed to examine whether OIE extract confers protection against chemotherapy-induced cardiotoxicity, and explored potential mechanism involved. Adult male mice were treated with DOX and CPS, OIE or a combination of OIE and DOX & CPS. Swimming test was performed to assess cardiac function. Markers of oxidative stress were assessed by levels of reactive oxygen species (ROS), nitrite, hydrogen peroxide, catalase and glutathione content. Activity of interleukin converting enzyme and cyclooxygenase was determined as markers of inflammation. Mitochondrial function was assessed by measuring complex I activity. Apoptosis was assessed by caspase and protease activity. Mice treated with DOX and CPS exhibited reduced swim rate, increased oxidative stress markers, increased markers of inflammation and apoptosis. These effects were prevented by co-administration of OIE. Furthermore, computational molecular docking revealed potential binding of DOX and CPS to tyrosine hydroxylase and OIE as a potential protective agent. These data indicated that OIE counteracts chemotherapy-induced cardiotoxicity through inhibition of ROS-mediated apoptosis. Taken together, our findings suggested that OIE possesses potential as a means to counteract potentially fatal cardiac complications associated with chemotherapy treatment.

Aspirin and omega-3 fatty acid status interact in the prevention of cardiovascular diseases in Framingham Heart Study

BackgroundThe roles of omega-3 (n3) fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] and low-dose aspirin in the primary prevention of ischemic cardiovascular disease (CVD) are controversial. Since omega-3 (n3) fatty acids and aspirin affect cyclooxygenase activity in platelets, there could be a clinically-relevant effect of aspirin combined with a particular n3 fatty acid level present in each individual. MethodsRBC EPA+DHA, arachidonic acid (AA) and docosapentaenoic acid (DPA) were measured in 2500 participants without known CVD in the Framingham Heart Study. We then tested for interactions with reported aspirin use (1004 reported use and 1494 did not) on CVD outcomes. The median follow-up was 7.2 years. ResultsHaving RBC EPA+DHA in the second quintile (4.2–4.9% of total fatty acids) was associated with significantly reduced risk for future CVD events (relative to the first quintile, <4.2%) in those who did not take aspirin (HR 0.54 (0.30, 0.98)), but in those reporting aspirin use, risk was significantly increased (HR 2.16 (1.19, 3.92)) in this quintile. This interaction remained significant when adjusting for confounders. Significant interactions were also present for coronary heart disease and stroke outcomes using the same quintiles. Similar findings were present for EPA and DHA alone but not for DPA and AA. ConclusionsThere is a complex interaction between aspirin use and RBC EPA+DHA levels on CVD outcomes. This suggests that aspirin use may be beneficial in one omega-3 environment but harmful in another, implying that a personalized approach to both aspirin use and omega-3 supplementation may be needed.

Assessing the effectiveness of ketorolac in pain management of traumatic injuries in prehospital emergency care services

Objective: Pain is usually one of the most common symptoms among all traumatic injuries. One of the drugs that has recently entered the Iranian prehospital emergency system is ketorolac. Ketorolac is a non-steroidal anti-inflammatory drug (NSAID) that inhibits prostaglandin synthesis by inhibiting cyclooxygenase activity and reduces pain and inflammation. It can be considered as the strongest analgesic drug in this category. The aim of this study was to evaluate the effectiveness of ketorolac in pain management of traumatic injuries in a prehospital setting. Methods: This descriptive cross-sectional study was undertaken to evaluate the effectiveness of a treatment method in the pain management of traumatic injuries in the prehospital environment of Lorestan province in Iran. We included 134 injured patients from road emergency bases of Lorestan province. In order to control the pain of these injured patients, 30 mg of ketorolac was injected slowly intravenously in one minute. Pain was measured in the time interval of zero minutes (before injection), 15 minutes, 30 minutes, and 45 minutes by visual acuity scale (VAS). The analysis of the obtained data was performed by SPSS software version 23. Results: The mean age of participants was 37.42±23.6. There were 47 female injuries (35.1%) and 87 male injuries (64.9%). In terms of pain intensity, 49 patients (36.6%) had moderate pain (VAS=4-6) and 85 patients (63.4%) had severe pain (VAS=7-10). The average of pain relief in the injured group with severe and moderate pain 15 minutes after the injection was 0.471 and 0.878 (P=0.001), respectively. In addition, the mean of pain relief in the injured group with severe and moderate pain 30 minutes after the injection was 1.124 and 1.796, respectively (P=0.001). Pain reduction in the group of severely injured patients with moderate pain in the first 30 minutes was statistically significant. Conclusion: Findings revealed that ketorolac is a suitable drug in pain management for trauma patients with moderate and severe pain in trauma patients. On the other hand, due to the peak effect (more than 30 minutes), it is not an effective drug for trauma patients with severe pain in a short period transferred to the prehospital environment.

Biochemical characterization of the cyclooxygenase enzyme in penaeid shrimp.

Cyclooxygenase (COX) is a two-step enzyme that converts arachidonic acid into prostaglandin H2, a labile intermediate used in the production of prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α). In vertebrates and corals, COX must be N-glycosylated on at least two asparagine residues in the N-(X)-S/T motif to be catalytically active. Although COX glycosylation requirement is well-characterized in many species, whether crustacean COXs require N-glycosylation for their enzymatic function have not been investigated. In this study, a 1,842-base pair cox gene was obtained from ovarian cDNA of the black tiger shrimp Penaeus monodon. Sequence analysis revealed that essential catalytic residues and putative catalytic domains of P. monodon COX (PmCOX) were well-conserved in relation to other vertebrate and crustacean COXs. Expression of PmCOX in 293T cells increased levels of secreted PGE2 and PGF2α up to 60- and 77-fold, respectively, compared to control cells. Incubation of purified PmCOX with endoglycosidase H, which cleaves oligosaccharides from N-linked glycoproteins, reduced the molecular mass of PmCOX. Similarly, addition of tunicamycin, which inhibits N-linked glycosylation, in PmCOX-expressing cells resulted in PmCOX protein with lower molecular mass than those obtained from untreated cells, suggesting that PmCOX was N-glycosylated. Three potential glycosylation sites of PmCOX were identified at N79, N170 and N424. Mutational analysis revealed that although all three residues were glycosylated, only mutations at N170 and N424 completely abolished catalytic function. Inhibition of COX activity by ibuprofen treatment also decreased the levels of PGE2 in shrimp haemolymph. This study not only establishes the presence of the COX enzyme in penaeid shrimp, but also reveals that N-glycosylation sites are highly conserved and required for COX function in crustaceans.

Intrinsic exercise capacity induces divergent vascular plasticity via arachidonic acid-mediated inflammatory pathways in female rats

Metabolic syndrome prevalence has increased among US adults, particularly among non-hispanic white and black women. Sedentary behavior often leads to chronic inflammation, a triggering factor of metabolic syndrome. Given that intrinsic exercise capacity is genetically inherited, we questioned if low-grade chronic inflammation would be present in a female rat model of low intrinsic exercise capacity-induced metabolic syndrome, while beneficial increase of resolution of inflammation would be present in a female rat model of high intrinsic exercise capacity. In the vascular system, two primary markers for inflammation and resolution of inflammation are cyclooxygenase (COX) and lipoxygenase (LOX), respectively. Our study focused on the novel hypothesis that untrained, inherited exercise capacity induces divergent vascular plasticity via changes in the delicate balance between COX and LOX inflammatory mediators.We used divergent rat strains with low (LCR) and high (HCR) aerobic running capacity. By using animals with contrasting intrinsic exercise capacities, it is possible to determine the exact triggers that lead to inherited vascular plasticity in female rats. We observed that female LCR displayed increased periovarian fat pad and body weight, which is congruent with their obesity-presenting phenotype. Furthermore, LCR presented with vascular hypocontractility and increased COX and LOX-derived pro-inflammatory factors. On the other hand, HCR presented with a “shutdown” of COX-induced vasoconstriction and enhanced resolution of inflammation to maintain vascular tone and homeostasis. In conclusion, LCR display low-grade chronic inflammation via increased COX activity. These results provide mechanistic clues as to why lower intrinsic aerobic capacity correlates with a predisposition to risk of vascular disease. Conversely, being born with higher intrinsic aerobic capacity is a significant factor for improved vascular physiology in female rats.

Farrerol ameliorate adjuvant‐induced ankle injury via alteration of PPAR‐γ signal pathway

This study evaluated the anti-inflammatory activity against lipopolysaccharide (LPS)-mediated mouse macrophages (in vitro) and assessed the protective effect of farrerol on arthritis caused by complete freund adjuvant (CFA) in rats. For the evaluation of the pharmacological effect of farrerol on the activity of nitric oxide (NO) and cyclooxygenase, pro-inflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β, RAW 264.7 cells were used. A 0.1ml CFA was injected subcutaneously for the induction of arthritis. The paw volume, body weight and arthritic score were estimated at regular intervals. Pro-inflammatory cytokines, inflammatory mediators, and antioxidant parameters were also estimated. Farrerol suppressed NO production and COX-catalyzed prostaglandin (PGE2 ) in RAW 264.7. Farrerol also downregulated the p-p65, p-IκBα expression and upregulated the PPAR-γ expression in RAW 264.7 cells. Treatment of farrerol increased body weight substantially, and reduced paw edema and arthritic score. Farrerol treatment also significantly improved the level of hemoglobin (Hb), count of red blood cells (RBC), and decreased the rate of erythrocyte sedimentation (ESR), white blood cell (WBC) parameters, while the generation of pro-inflammatory cytokines inhibited. Together, farrerol also suppressed the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β. Obtained results directed that the farrerol exerted its therapeutic effect against CFA-induced arthritic rats through anti-inflammatory mechanism by regulation of the PPAR-γ. PRACTICAL APPLICATIONS: Increase the arthritis disease worldwide day-by-day. The current research study showed the anti-arthritic effect of farrerol (flavonoid phytoconstituent) of Rhododendron dauricum Linn. In this study, farrerol considerably inhibited the NF-κB to show the anti-arthritic effect. The finding showed the potential effect against acute and chronic inflammation via inhibition of inflammatory mediators and oxidative stress. The result suggests the anti-inflammatory and antioxidant effect of farrerol. On the basis of result, we can say that farrerol can be the beneficial drug to treat the arthritis.

Microbiome Profile and Molecular Pathways Alterations in Gastrointestinal Tract by Hydrogen Sulfide-Releasing Nonsteroidal Anti-Inflammatory Drug (ATB-352): Insight into Possible Safer Polypharmacy.

Aims: Nonsteroidal anti-inflammatory drugs, including ketoprofen, induce adverse effects within the gastrointestinal (GI)-tract. Hydrogen sulfide (H2S) is an antioxidative gaseous mediator contributing to GI-protection. We aimed to evaluate the GI safety of a novel H2S-releasing derivative of ketoprofen (ATB-352) versus classic ketoprofen and the molecular mechanisms of their activity after chronic treatment in experimental animal models. Results: Ketoprofen (10 mg/kg/day) administered intragastrically for 7 days in contrast with ATB-352 (14 mg/kg/day) reduced mucosal H2S content inducing GI damage with significantly increased injury score, altered intestinal microbiome profile, and modulation of more than 50% of 36 investigated molecular sensors (e.g., mammalian target of rapamycin or suppressor of cytokine signaling 3 [SOCS3]). Polypharmacy with aspirin (10 mg/kg/day) enhanced ketoprofen toxicity not affecting GI safety of ATB-352. Omeprazole (20 mg/kg/day) decreased ketoprofen-induced injury to the level of ATB-352 alone. Both compounds combined or not with aspirin or omeprazole maintained the ability to inhibit cyclooxygenase (COX) activity manifested by decreased prostaglandin production. Innovation and Conclusions: Ketoprofen-induced H2S-production decrease and intestinal microbiome profile alterations lead to GI toxicity observed on macro-/microscopic and molecular levels. Ketoprofen but not ATB-352 requires concomitant treatment with omeprazole to eliminate GI adverse effects. ATB-352 applied alone or in a polypharmacy setting with aspirin effectively inhibited COX and maintained GI safety due to H2S-release. Neither compound affected DNA oxidation in the GI mucosa, but ATB-352 had lower impact on molecular oxidative/inflammatory response pathways and intestinal microbiome. The GI safety of ATB-352 could be due to the involvement of heme oxygenase 1 and SOCS3 pathway activation. Antioxid. Redox Signal. 36, 189-210.

Elevated CO2 improves the nutritive value, antibacterial, anti-inflammatory, antioxidant and hypocholestecolemic activities of lemongrass sprouts

Sprouts have been regarded as a big store for bioactive compounds with a wide range of biological activities. Elevated CO2 (eCO2, 620 μmol mol−1)was employed to enhance the nutritive and health promoting values of sprouts of two species of lemongrass, i.e. Cymbopogon citratus and Cymbopogon proximus. eCO2 improved the biomass production of sprouts, and their levels of primary metabolites e.g., amino acids and oils and active secondary metabolites e.g., phenolic compounds. As a result, eCO2 increased total antioxidant capacity, cytotoxicity against several human cancer cell lines, and antibacterial activities of Cymbopogon sprouts. We also recorded a significant increase in hypocholesterolaemic potential and anti-inflammatory activities of eCO2-treated sprouts, as indicated by inhibition of cholesterol micellar solubility and pancreatic lipase activity, as well as lipoxygenase and cyclooxygenase activities, respectively. Thus, the present investigation supports the use of eCO2 as a promising approach to produce lemongrass sprouts with effective phytochemicals and enhanced biological activities.

Bioactive Potential of Several Actinobacteria Isolated from Microbiologically Barely Explored Desert Habitat, Saudi Arabia.

Simple SummaryBioactive natural products have been regarded as promising tools for treatment of various ailments. Among natural sources, actinomycetes have been widely explored for their potential bioactivity. In this regard, the present study has focused on the phytochemical content and biological activities of several actinobacteria isolates, which were investigated for their phenolic and flavonoid content, as well as their antioxidant, antibacterial and antiprotozoal activities. The most active isolates were further investigated for their antileukemic activity, where such isolates were shown to exert cytotoxic activity against the tested cell lines, following a mechanism that might be due to the ability of the active isolate extracts to reduce cyclooxygenase and lipoxygenase activities. Overall, isolation and characterization of the active molecule from the potential actinomycetes strains will pave the way for the development of drugs against human diseases such as blood cancer.Biomolecules from natural sources, including microbes, have been the basis of treatment of human diseases since the ancient times. Therefore, this study aimed to investigate the potential bioactivity of several actinobacteria isolates form Al-Jouf Desert, Saudi Arabia. Twenty-one actinobacterial isolates were tested for their antioxidant (flavonoids, phenolics, tocopherols and carotenoids) content, and biological activities, namely FRAP, DPPH, ABTS, SOS and XO inhibition, anti-hemolytic and anti-lipid peroxidation as well as their antibacterial and antiprotozoal activities. Accordingly, five isolates (i.e., Act 2, 12, 15, 19 and 21) were selected and their 90% ethanolic extracts were used. The phylogenetic analysis of the 16S rRNA sequences indicated that the most active isolates belong to genus Streptomyces. The genus Streptomyces has been documented as a prolific producer of biologically active secondary metabolites against different cancer types. Thus, the anti-blood cancer activity and the possible molecular mechanisms by which several Streptomyces species extracts inhibited the growth of different leukemia cells, i.e., HL-60, K562 and THP-1, were investigated. In general, the five active isolates showed cytotoxic activity against the tested cell lines in a dose dependent manner. Among the potent isolates, isolate Act 12 significantly decreased the cell viability and showed maximum cytotoxic activities against both HL-60 and K562 cells, while isolate Act 15 exhibited maximum cytotoxic activity against THP-1 cells. Moreover, Act 2 and Act 12 reduced cyclooxygenase (COX-2) and lipoxygenase (LOX) activity, which is involved in the proliferation and differentiation of cancer cells and may represent a possible molecular mechanism underlying leukemia growth inhibition. The bioactive antioxidant extracts of the selected Streptomyces species inhibited leukemia cell growth by reducing the COX-2 and LOX activity. Overall, our study not only introduced a promising natural alternative source for anticancer agents, but it also sheds light on the mechanism underlying the anticancer activity of isolated actinomycetes.

Cyclooxygenase inhibition attenuates brain angiogenesis and independently decreases mouse survival under hypoxia.

Although cyclooxygenase (COX) role in cancer angiogenesis has been studied, little is known about its role in brain angioplasticity. In the present study, we chronically infused mice with ketorolac, a non‐specific COX inhibitor that does not cross the blood–brain barrier (BBB), under normoxia or 50% isobaric hypoxia (10% O2 by volume). Ketorolac increased mortality rate under hypoxia in a dose‐dependent manner. Using in vivo multiphoton microscopy, we demonstrated that chronic COX inhibition completely attenuated brain angiogenic response to hypoxia. Alterations in a number of angiogenic factors that were reported to be COX‐dependent in other models were assayed at 24‐hr and 10‐day hypoxia. Intriguingly, hypoxia‐inducible factor 1 was unaffected under COX inhibition, and vascular endothelial growth factor receptor type 2 (VEGFR2) and C‐X‐C chemokine receptor type 4 (CXCR4) were significantly but slightly decreased. However, a number of mitogen‐activated protein kinases (MAPKs) were significantly reduced upon COX inhibition. We conclude that additional, angiogenic factor‐independent mechanism might contribute to COX role in brain angioplasticity, probably including mitogenic COX effect on endothelium. Our data indicate that COX activity is critical for systemic adaptation to chronic hypoxia, and BBB COX is essential for hypoxia‐induced brain angioplasticity. These data also indicate a potential risk for using COX inhibitors under hypoxia conditions in clinics. Further studies are required to elucidate a complete mechanism for brain long‐term angiogenesis regulation through COX activity.

Comparative biomarker responses to urban pollution in three polychaete species: Perinereis cultrifera, Diopatra neapolitana, and Marphysa sanguinea from the lagoon of Tunis

Coastal lagoons are among the most vulnerable ecosystems as they are often exposed to different anthropogenic activities. The Polychaetes, which are dominant components in macrobenthic community, are particularly exposed to contamination. The current study was designed to assess and compare the sensitivity of different polychaetes species towards urban pollution. To do this, three polychaete species: Perinereis cultrifera, Diopatra neapolitana, and Marphysa sanguinea, were collected from the Tunis South Lagoon during summer 2013. A set of biomarkers indicative of genotoxicity (DNA damage), biotransformation, and oxidative stress (glutathione S-transferase, GST) as well as immune response (cyclooxygenase activity (COX), lysozyme activity, and nitric oxide level (NOx)), was used. The results revealed that D. neapolitana and P. cultrifera exhibited higher genetic alteration and GST activity and more prominent immune response when compared with M. sanguinea. These findings denote of the higher sensitivity of D. neapolitana and P. cultrifera to urban pollution and suggest their possible use in environmental biomonitoring programs.

Inhibition of cyclooxygenase activity by diclofenac attenuates varicose remodeling of mouse veins

Vessel Plus is an open acccess journal, which publishes articles related to vascular diseases, including acute respiratory distress syndrome, aneurysm, atherosclerosis, hypertension, stroke, peripheral vascular or pulmonary vascular diseases, etc.

Toxicity of representative mixture of five rare earth elements in juvenile rainbow trout (Oncorhynchus mykiss) juveniles

Rare earth elements (REEs) are contaminants of increasing interest due to intense mining activities for commercial purposes and ultimately released in the environment. We exposed juvenile rainbow trout (Oncorhynchus mykiss) to a representative mixture of the five most abundant REEs for 96 h at concentrations similar found in lakes contaminated by mining activities at 0.1, 1, 10, and 100X whereas the 1x mixture contained cerium (Ce, 280 μg/L), lanthanum (La, 140 μg/L), neodymium (Nd, 120 μg/L), praseodymium (Pr, 28 μg/L), and samarium (Sm, 23 μg/L). We investigated the expression of 14 genes involved in oxidative stress, DNA repair, tissue growth/proliferation, protein chaperoning, xenobiotic biotransformation, and ammonia metabolism in the liver. In addition, DNA damage, oxidative stress (lipid peroxidation or LPO), inflammation (cyclooxygenase or COX activity), detoxification mechanisms (glutathione-S-transferase activity or GST), and labile zinc were determined in gills. The data revealed that genes involved in oxidative stress-catalase (cat), heat shock proteins 70 (hsp70), and glutamate dehydrogenase (glud) were upregulated while glutathione S-transferase (gst) and metallothionein (mt) gene expressions were downregulated. The mixture was genotoxic and increased labile Zn in gills of exposed trout. These changes occurred at concentrations 600 times lower than the LC50 for this mixture indicating effects below the 1X concentration. Based on principal component analysis and concentration-dependent reponses, the following sublethal effects were considered the most important/significant: DNA strand breaks (genotoxicity), labile Zn, cat, gst, hsp70, sparc, mt, and glud. These effects of fish juveniles are likely to occur in environments under the influence of mining activities.