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Background: Congenital cytomegalovirus (CMV) infections represent one leading cause of human neurodevelopmental disorders. Despite their high prevalence and severity, no satisfactory therapy is available and pathophysiology remains elusive. The pathogenic involvement of immune processes occurring in infected developing brains has been increasingly documented. Here, we have used our previously validated rat model of CMV infection of the fetal brain in utero to test whether the maternal administration of four different drugs with immunomodulatory properties would have an impact on the detrimental postnatal outcome of CMV infection. Methods: CMV infection of the rat fetal brain was done intracerebroventricularly. Each of the drugs, including acetylsalicylic acid (aspirin, ASA), a classical inhibitor of cyclooxygenases Cox-1 and Cox-2, the two key rate-limiting enzymes of the arachidonic acid-to-prostaglandins (PG) synthesis pathway, was administered to pregnant dams until delivery. ASA was selected for subsequent analyses based on the improvement in postnatal survival. A combination of qRT-PCR, mass spectrometry-based targeted lipidomics, immunohistochemistry experiments, monitoring of neurologic phenotypes and electrophysiological recordings was used to assess the impact of ASA in CMV-infected samples and pups. The postnatal consequences of CMV infection were also analyzed in rats knocked-out (KO) for Cox-1. Results: Increased PGE2 levels and increased proportions of Cox-1+ and Cox-2+ microglia were detected in CMV-infected developing brains. Maternal intake of ASA led to decreased proportion of Cox-1+ fetal, but not neonatal, microglia, while leaving the proportions of Cox-2+ microglia unchanged. Maternal intake of ASA also improved the key postnatal in vivo phenotypes caused by CMV infection and dramatically prevented against the spontaneous epileptiform activity recorded in neocortical slices from CMV-infected pups. In contrast with maternal intake of ASA, Cox-1 KO pups displayed no improvement in the in vivo phenotypes after CMV infection. However, as with ASA administration, the spontaneous epileptiform activity was dramatically inhibited in neocortical slices from CMV-infected, Cox-1 KO pups. Conclusion: Overall, our data indicate that, in the context of CMV infection of the fetal brain, maternal intake of ASA during pregnancy improved CMV-related neurodevelopmental alterations in the offspring, likely via both Cox-1 dependent and Cox-1 independent mechanisms, and provide proof-of-principle for the use of ASA against the detrimental outcomes of congenital CMV infections. [ABSTRACT FROM AUTHOR]

Summary: Vicuñas (Vicugna vicugna) are wild South American camelids (SACs) protected by law in Argentina, and information on pathogens that infect them is scarce. In this study, an adult vicuña found dead in the province of Salta was examined, and evidence of infection by Sarcocystis sp. protozoans was sought. Infection of skeletal muscles by S. aucheniae, with the production of macroscopic sarcocysts, a disease known as SAC sarcocystosis, has been described in the other three SACs - llamas, alpacas, and guanacos - but its occurrence in vicuñas has so far remained unknown. In the analyzed individual, many macroscopic cysts compatible with S. aucheniae were found upon necropsy in the muscular tissue of the neck and diaphragm. Analysis of 18 S rRNA and cytochrome c oxidase subunit 1 (cox-1) gene sequences by BLAST searches and construction of phylogenetic trees demonstrated that the etiological agent was S. aucheniae. Our results show for the first time that vicuñas act as intermediate hosts in the life cycle of this parasite. In addition, this study provides the first cox-1 sequences for S. aucheniae isolates from the four SAC species acting as intermediate hosts and suggests that this marker could be useful for genotypification of this parasite species. The impact of SAC sarcocystosis on the health, well-being, and fitness of vicuñas, and the relevance of vicuña infections in the epidemiology of S. auchaniae, remain to be elucidated. [ABSTRACT FROM AUTHOR]

Background: Ascaridia galli is pathogenic in chickens and causes substantially reduced growth rates, weight loss, low egg production and death in infected chickens. It is necessary to carry out research on the molecular identification of A. galli in chickens in traditional markets in Surabaya using the polymerase chain reaction (PCR) method with the COX-1 mtDNA gene primer. Methods: This research was carried out from April to July 2023. The number of samples used in this research was 100 chicken small intestines taken from traditional markets in Surabaya, Indonesia. A. galli worms obtained from worm collections were identified according to the morphology of the A. galli worms. DNA extraction was carried out followed by PCR laboratory procedure. The specific primers utilized were designed to target the COX-1 gene and the amplified products were visualized in 1.5% agarose. Result: The A. galli worm has a long body posture. Male A. galli worms measure 30-50 mm long; while, adult female A. galli worms measure 65-80 mm long. The results of electrophoresis with a 2% agarose gel run for 30 minutes at 100 Volts and visualized under ultraviolet light using a UV Transilluminator (Geldoc) showed the presence of a single band of the COX-1 mtDNA gene in the 533 base pair. Infection with A. galli worms often causes reduced growth rates and decreased body weight, which is associated with increased worm weight. [ABSTRACT FROM AUTHOR]

Sarcocystis infection in sheep has caused significant economic losses in the livestock industry, and the genetic similarity among Sarcocystis species highlights the need for precise diagnostic methods in sheep. This study developed a loop-mediated isothermal amplification (LAMP) method targeting COX-1 and 28S rRNA genes to detect Sarcocystis tenella and Sarcocystis gigantea, respectively. The LAMP method exhibited high specificity, selectively amplifying target DNA sequences without cross-reactivity with closely related protozoa, such as Toxoplasma gondii and Neospora caninum. Detection limits were determined as 3 × 105 copies/L for S. tenella and 6 × 104 copies/L for S. gigantea, enabling sensitive identification of low-level infections. Comparative analysis with conventional PCR on sheep cardiac tissues demonstrated a higher LAMP detection rate (80.0% vs 66.7%). In conclusion, the LAMP method offers superior sensitivity to conventional PCR, allows visual confirmation of results, and provides a rapid diagnostic tool for identifying S. tenella and S. gigantea infection in sheep. However, due to the limitation of sample availability, we were unable to assess all Sarcocystis species that use sheep as intermediate hosts, which warrants further research. [ABSTRACT FROM AUTHOR]

Abstract Background Congenital cytomegalovirus (CMV) infections represent one leading cause of human neurodevelopmental disorders. Despite their high prevalence and severity, no satisfactory therapy is available and pathophysiology remains elusive. The pathogenic involvement of immune processes occurring in infected developing brains has been increasingly documented. Here, we have used our previously validated rat model of CMV infection of the fetal brain in utero to test whether the maternal administration of four different drugs with immunomodulatory properties would have an impact on the detrimental postnatal outcome of CMV infection. Methods CMV infection of the rat fetal brain was done intracerebroventricularly. Each of the drugs, including acetylsalicylic acid (aspirin, ASA), a classical inhibitor of cyclooxygenases Cox-1 and Cox-2, the two key rate-limiting enzymes of the arachidonic acid-to-prostaglandins (PG) synthesis pathway, was administered to pregnant dams until delivery. ASA was selected for subsequent analyses based on the improvement in postnatal survival. A combination of qRT-PCR, mass spectrometry-based targeted lipidomics, immunohistochemistry experiments, monitoring of neurologic phenotypes and electrophysiological recordings was used to assess the impact of ASA in CMV-infected samples and pups. The postnatal consequences of CMV infection were also analyzed in rats knocked-out (KO) for Cox-1. Results Increased PGE2 levels and increased proportions of Cox-1+ and Cox-2+ microglia were detected in CMV-infected developing brains. Maternal intake of ASA led to decreased proportion of Cox-1+ fetal, but not neonatal, microglia, while leaving the proportions of Cox-2+ microglia unchanged. Maternal intake of ASA also improved the key postnatal in vivo phenotypes caused by CMV infection and dramatically prevented against the spontaneous epileptiform activity recorded in neocortical slices from CMV-infected pups. In contrast with maternal intake of ASA, Cox-1 KO pups displayed no improvement in the in vivo phenotypes after CMV infection. However, as with ASA administration, the spontaneous epileptiform activity was dramatically inhibited in neocortical slices from CMV-infected, Cox-1 KO pups. Conclusion Overall, our data indicate that, in the context of CMV infection of the fetal brain, maternal intake of ASA during pregnancy improved CMV-related neurodevelopmental alterations in the offspring, likely via both Cox-1 dependent and Cox-1 independent mechanisms, and provide proof-of-principle for the use of ASA against the detrimental outcomes of congenital CMV infections.

Ascaridia species are the most common nematodes infecting pigeons. The current study investigated specific identity of nematode parasites collected from domestic pigeons (Columba livia domestica) in Al-Qassim Region, Saudi Arabia. Out of 354 pigeons, 13.3 % were infected with nematode parasites. The morphological structure and genetic relationship of nematode worms were studied using conventional methods (Light and scanning electron microscopes) coupled with the newly introduced molecular method. Microscopical and ultrastructure observations showed that the present nematode worms belong to the genus Ascaridia and have all the characteristic features of Ascaridia columbae. Moreover, Random Amplifier morphometric (RAPD) PCR analysis revealed that the present A. columbae had a close identity of up to 98.3 % to Ascaridia columbae JX624729 for Cox-1 gene regions, and up to 98.3 % to Ascaridia nymphii LC057210, and Ascaridia galli EF180058 for ITS1-5.8s- ITS2 rDNA gene regions. Phylogenetic analysis supported the placement of this Ascaridia species within Ascaridiidae family with close relationships to other nematode species obtained from GenBank. Finally, our study recommends using molecular analysis in helminths identification as the main methodology for correct identification especially in closely related species.

Some microorganisms known as endophytes live in symbiotic relationships in the living tissues of plants without posing a health risk. As a result, they synthesize many metabolites which are helpful for the plants in many ways. So, these metabolites are known to exhibit many biological properties like antioxidant, antidiabetic anti-inflammatory, etc. Currently, many drugs are used to control inflammatory diseases like arthritis and, irritable bowel disease; however, they pose a lot of side effects. The present study was taken up to explore the anti-inflammatory properties along with the phytochemicals present, its quantification, and other in vitro biological activities of the less reported Aspergillus melleus, an endophytic fungus, isolated from Premna serratifolia L., a medicinal plant. The results of the investigation demonstrated the presence of alkaloids, phenols, terpenoids, flavonoids, tannins, cardiac glycosides and amino acids in the methanolic extract of endophytic fungus. It yielded 25.28 µg GAE/g and 19.465 µg GAE/g of total phenolic and flavonoid content, respectively. The results of anti-inflammatory activity showed 84.69+0.82% protein inhibition by BSA and also showed IC50 values of 68.53 µg/mL and 43.34 µg/mL for COX1 and COX 2, respectively. It exhibited 63.91+0.08% of radical scavenging activity by DPPH. The IC50 values of 181.41 µg/mL and 190.62 µg/mL were found for the in vitro antidiabetic activity. This study shows that the endophytic fungus A. melleus has exhibited considerably good results with respect to its in vitro biological activities. Yet, there is a scope for future researchers to isolate the bioactive metabolites to explore for future needs.

It has been reported that aspirin and P2Y inhibitors have emerged as the preferred therapeutic agents for managing vaso-occlusive illness due to their anti-thrombotic properties. However, complaints about the side effects of these drugs are still being reported. Ongoing research is being conducted on the design and development of novel antithrombotic agents to obtain good health and well-being. ortho-Coumaric acid derivates were designed using the ChemDraw program, while a physicochemical prediction study was carried out by the Swiss ADME program, and the MOE platform was operated to predict the activity of the ortho-Coumaric derivates against cyclooxygenase-1. The structural modification of carboxylic acid and phenolic moieties generated ester and thiourea derivatives, thereby increasing the S score of these derivatives, was compared to ortho-coumaric acid. All derivatives have adequate oral absorption (55-85%). Microwave-assisted nucleophilic acyl substitution was operated to produce thiourea derivatives of ortho-coumaric acid using ortho-methoxy cinnamic acid, one of the ortho-coumaric acid derivates, as the starting material for reacting with substituted aniline. This method produced novel compounds in yields of 60-70 percent, depending on the substituent of the aniline compound. The structure of all product reactions was confirmed by UV & IR spectrophotometer, ¹HNMR, 13CNMR, and HR-ESI-MS spectrometer. The thiourea moiety of ortho-coumaric derivates interacts similarly with aspirin. The majority of ortho-coumaric derivates have a higher level of interaction with cyclooxygenase-1 compared to ortho-coumaric acid. All of the derivatives exhibited favorable characteristics for oral absorption. Therefore, it may be inferred that these derivatives possess potential as agents with anti-thrombotic properties. [ABSTRACT FROM AUTHOR]

Selective COX-1 inhibitors are preferential therapeutic targets for platelet aggregation and clotting responses. In this study, we examined the selective COX-1-inhibitory activities of four newly synthesized compounds, 10–13, along with their abilities to inhibit platelet aggregation against ADP and collagen. The target compounds 10–13 were synthesized using the conventional method, sonication, and microwave-assisted methods. Microanalytical and spectral data were utilized to elucidate the structures of the new compounds 10–13. Additionally, a spectral NMR experiment [NOESY] was conducted to emphasize the configuration around the double bond of the imine group C=N. The obtained results revealed no observed correlation between any of the neighboring protons, suggesting that the configuration at the C=N double bond is E. Biological results revealed that all the screened compounds 10–13 might serve as selective COX-1 inhibitors. They showed IC50 values ranging from 0.71 μM to 4.82 μM against COX-1 and IC50 values ranging from 9.26 μM to 15.24 μM against COX-2. Their COX-1 selectivity indices ranged between 2.87 and 18.69. These compounds show promise as promising anti-platelet aggregation agents. They effectively prevented platelet aggregation induced by ADP with IC50 values ranging from 0.11 μM to 0.37 μM, surpassing the standard aspirin with an IC50 value of 0.49 μM. Additionally, they inhibited the platelet aggregation induced by collagen with IC50 values ranging from 0.12 μM to 1.03 μM, demonstrating superior efficacy compared to aspirin, which has an IC50 value of 0.51 μM. In silico molecular modeling was performed for all the target compounds within the active sites of COX-1 and COX-2 to rationalize their selective inhibitory activities towards COX-1. It was found that the binding interactions of the designed compounds within the COX-1 active site had remained unaffected by the presence of celecoxib. Molecular modeling and DFT calculations using the B3LYP/6-31+G (d,p) level were performed to study the stability of E-forms with respect to Z-forms for the investigated compounds. A strong correlation was observed between the experimental observations and the quantum chemical descriptors. [ABSTRACT FROM AUTHOR]

Some microorganisms known as endophytes live in symbiotic relationships in the living tissues of plants without posing a health risk. As a result, they synthesize many metabolites which are helpful for the plants in many ways. So, these metabolites are known to exhibit many biological properties like antioxidant, antidiabetic anti-inflammatory, etc. Currently, many drugs are used to control inflammatory diseases like arthritis and, irritable bowel disease; however, they pose a lot of side effects. The present study was taken up to explore the anti-inflammatory properties along with the phytochemicals present, its quantification, and other in vitro biological activities of the less reported Aspergillus melleus, an endophytic fungus, isolated from Premna serratifolia L., a medicinal plant. The results of the investigation demonstrated the presence of alkaloids, phenols, terpenoids, flavonoids, tannins, cardiac glycosides and amino acids in the methanolic extract of endophytic fungus. It yielded 25.28 µg GAE/g and 19.465 µg GAE/g of total phenolic and flavonoid content, respectively. The results of anti-inflammatory activity showed 84.69+0.82% protein inhibition by BSA and also showed IC50 values of 68.53 µg/mL and 43.34 µg/mL for COX1 and COX 2, respectively. It exhibited 63.91+0.08% of radical scavenging activity by DPPH. The IC50 values of 181.41 µg/mL and 190.62 µg/mL were found for the in vitro antidiabetic activity. This study shows that the endophytic fungus A. melleus has exhibited considerably good results with respect to its in vitro biological activities. Yet, there is a scope for future researchers to isolate the bioactive metabolites to explore for future needs. [ABSTRACT FROM AUTHOR]

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications, but their use can be associated with a number of adverse reactions, including upper gastrointestinal lesions. The aim of the study was to identify clinical and pharmacogenetic factors associated with upper gastrointestinal lesions, including those linked to NSAIDs, in patients at a multidisciplinary hospital. The study included 92 patients (mean age 59.4±16.5 years; 47 women), who underwent esophagogastroduodenoscopy during inpatient treatment. Patients' intake of NSAIDs and gastroprotectors during the year before hospitalization was considered. Demographic, clinical, laboratory data of patients were compared between groups, including genotyping for CYP2C9*2 rs179985, CYP2C9*3 rs1057910, CYP2C8*3 rs11572080, CYP2C8*3 rs10509681, PTGS-1 rs10306135, PTGS-1 rs12353214, and PTGS-2 rs20417 using real-time PCR. In NSAIDs+ patients, PTGS1 rs10306135 AT+TT genotypes increased the chance of developing gastrointestinal complications by 5.4 times (95 % CI=1.30–22.27). In total sample, smoking (OR=3.12, 95 % CI=1.15–8.46), and alcohol intake (OR=4.09, 95 % CI=1.05–15.87) increased odds of gastrointestinal damage. In NSAIDs+ patients omeprazole, famotidine and both famotidine and omeprazole during the last year were as ineffective as not taking gastroprotectors; in total sample famotidine (OR=0.19, 95 % CI=0.04–0.93) and two gastroprotectors (OR=0.13, 95 % CI=0.02–0.75) reduced the chance of upper gastrointestinal lesions. Pharmacogenetic features of patients may significantly contribute to the development NSAIDs-induced upper gastrointestinal injuries. [ABSTRACT FROM AUTHOR]

Abstract Background Taeniasis, is a worldwide foodborne zoonotic disease caused by two principal species; Taenia saginata and Taenia solium. The tapeworm infects the intestine causing taeniasis in humans. Taeniasis is a very rare parasitic infection in Palestine with very few annual cases of unknown species. The infection rate and the disease status are not clear due to the lack of reports about the actual number of patients. Case presentation Two Palestinian patients; one male of 22 years old from Hebron and the other is female of 33 years old from Ramallah were referred to Palestinian Health Services in the West Bank, Palestine, complained of weight loss, abdominal pain and presence of motile segments of creamy color in the their stool. Microscopic analysis of the stool samples from infected cases revealed Taenia eggs and proglottids, confirmed taeniasis infection. The parasite species was identified as T. saginata by polymerase chain reaction (PCR) amplification and sequencing of the cytochrome oxidase -1 (COX-1) gene. Conclusion Taeniasis is an unusual parasitic infection in Palestine, there is a growing concern that the actual numbers of infected individuals are much higher and the occurrence of human taeniasis is principally due to people’s eating habits in consumption of raw or undercooked beef meat. This report highlighted for the first time the existence of taeniasis infection in the country; which necessitates the need to conduct further research and surveillance to reveal the actual infection rate and the available Taenia species.

AbstractContext Dolichos trilobus Linn (Leguminosae) is often used in Yi ethnic medicine to treat pain, fracture, and rheumatism.Objective To explore the therapeutic potential of doliroside B (DB) from D. trilobus and its disodium salt (DBDS) and the underlying mechanism in pain.Materials and methods In the writhing test, Kunming mice were orally treated with DB and DBDS at doses of 0.31, 0.62, 1.25, 2.5, and 5 mg/kg. Vehicle, morphine, indomethacin, and acetylsalicylic acid were used as negative and positive control on the nociception-induced models, respectively. In the hot plate test, mice were orally treated with DB and DBDS at doses of 2.5, 5, 10, and 20 mg/kg. In the formalin test, mice were orally treated with DB and DBDS at doses of 2.5, 5, 10, and 20 mg/kg. In the meanwhile, lipopolysaccharide-induced inflammatory model in RAW264.7 macrophages was adopted to study the mechanism of pain alleviation for DBDS.Results DBDS (5 mg/kg) inhibited the writhing number by 80.2%, which exhibited the highest antinociceptive activity in pain models. DBDS could selectively inhibite the activity of COX-1. Meanwhile, it also reduced the production of NO, iNOS, and IL-6 by 55.8%, 69.0%, and 49.9% inhibition, respectively. It was found that DBDS also positively modulated the function of GABAA1 receptor.Discussion and conclusions DBDS displayed antinociceptive activity by acting on both the peripheral and central nervous systems, which may act on multitargets. Further work is warranted for developing DBDS into a potential drug for the treatment of pain.

Background: Taeniasis, is a worldwide foodborne zoonotic disease caused by two principal species; Taenia saginata and Taenia solium. The tapeworm infects the intestine causing taeniasis in humans. Taeniasis is a very rare parasitic infection in Palestine with very few annual cases of unknown species. The infection rate and the disease status are not clear due to the lack of reports about the actual number of patients. Case presentation: Two Palestinian patients; one male of 22 years old from Hebron and the other is female of 33 years old from Ramallah were referred to Palestinian Health Services in the West Bank, Palestine, complained of weight loss, abdominal pain and presence of motile segments of creamy color in the their stool. Microscopic analysis of the stool samples from infected cases revealed Taenia eggs and proglottids, confirmed taeniasis infection. The parasite species was identified as T. saginata by polymerase chain reaction (PCR) amplification and sequencing of the cytochrome oxidase -1 (COX-1) gene. Conclusion: Taeniasis is an unusual parasitic infection in Palestine, there is a growing concern that the actual numbers of infected individuals are much higher and the occurrence of human taeniasis is principally due to people's eating habits in consumption of raw or undercooked beef meat. This report highlighted for the first time the existence of taeniasis infection in the country; which necessitates the need to conduct further research and surveillance to reveal the actual infection rate and the available Taenia species. [ABSTRACT FROM AUTHOR]

Drug repurposing is a promising approach that has the potential to revolutionize the drug discovery and development process. By leveraging existing drugs, we can bring new treatments to patients more quickly and affordably. Anti-inflammatory drugs have been shown to target multiple pathways involved in cancer development and progression. This suggests that they may be more effective in treating cancer than drugs that target a single pathway. Cell viability was measured using the MTT assay. The expression of genes related to inflammation (TNFa, IL1b, COX-1, COX-2, and 5-LOX) was measured in HepG2, MCF7, and THLE-2 cells using qPCR. The levels of TNFα, IL1b, COX-1, COX-2, and 5-LOX were also measured in these cells using an ELISA kit. An enzyme binding assay revealed that sulfadiazine expressed weaker inhibitory activity against COX-2 (IC50 = 5.27 μM) in comparison with the COX-2 selective reference inhibitor celecoxib (COX-2 IC50 = 1.94 μM). However, a more balanced inhibitory effect was revealed for sulfadiazine against the COX/LOX pathway with greater affinity towards 5-LOX (IC50 = 19.1 μM) versus COX-1 (IC50 = 18.4 μM) as compared to celecoxib (5-LOX IC50 = 16.7 μM, and COX-1 IC50 = 5.9 μM). MTT assays revealed the IC50 values of 245.69 ± 4.1 µM and 215.68 ± 3.8 µM on HepG2 and MCF7 cell lines, respectively, compared to the standard drug cisplatin (66.92 ± 1.8 µM and 46.83 ± 1.3 µM, respectively). The anti-inflammatory effect of sulfadiazine was also depicted through its effect on the levels of inflammatory markers and inflammation-related genes (TNFα, IL1b, COX-1, COX-2, 5-LOX). Molecular simulation studies revealed key binding interactions that explain the difference in the activity profiles of sulfadiazine compared to celecoxib. The results suggest that sulfadiazine exhibited balanced inhibitory activity against the 5-LOX/COX-1 enzymes compared to the selective COX-2 inhibitor, celecoxib. These findings highlight the potential of sulfadiazine as a potential anticancer agent through balanced inhibitory activity against the COX/LOX pathway and reduction in the expression of inflammatory genes. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the influence of bee pollen supplementation on the levels of enzymes important for gastric mucosal homeostasis, namely cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and a biomarker—asymmetric dimethylarginine (ADMA)—in the gastric mucosa of Wistar rats. The experimental phase divided the rats into four groups: two control groups, sedentary and active, both not supplemented, and two experimental groups, sedentary and active, supplemented with bee pollen. The results indicated that bee pollen supplementation reduced the levels of COX-1 and elevated iNOS levels, while showing no significant impact on COX-2 levels. These findings do not conclusively support the gastroprotective and anti-inflammatory effects of bee pollen on gastric mucosa. However, the supplementation could have resulted in reduced ADMA levels in the physically active supplemented group. Our study does not unequivocally demonstrate the positive effects of bee pollen supplementation on the gastric mucosa, which may be attributed to the specific metabolism and bioavailability of substances within unprocessed, dried bee pollen. Further research should explore the topic of potential therapeutic applications of bee pollen in gastrointestinal health and its interactions with ADMA signaling pathways. [ABSTRACT FROM AUTHOR]

Drug-induced taste disorders are a serious problem in an aging society. This study investigated the mechanisms underlying taste disturbances induced by diclofenac, a non-steroidal anti-inflammatory drug that reduces pain and inflammation by inhibiting the synthesis of prostaglandins by cyclooxygenase enzymes (COX-1 and COX-2). RT-PCR analyses demonstrated the expression of genes encoding arachidonic acid pathway components such as COX-1, COX-2 and prostaglandin synthases in a subset of mouse taste bud cells. Double-staining immunohistochemistry revealed that COX-1 and cytosolic prostaglandin E synthase (cPGES) were co-expressed with taste receptor type-1 member-3 (T1R3), a sweet/umami receptor component, or gustducin, a bitter/sweet/umami-related G protein, in a subset of taste bud cells. Long-term administration of diclofenac reduced the expression of genes encoding COX-1, gustducin and cPGES in mouse taste buds and suppressed both the behavioral and taste nerve responses to sweet and umami taste stimuli but not to other tastants. Furthermore, diclofenac also suppressed the responses of both mouse and human sweet taste receptors (T1R2/T1R3, expressed in HEK293 cells) to sweet taste stimuli. These results suggest that diclofenac may suppress the activation of sweet and umami taste cells acutely via a direct action on T1R2/T1R3 and chronically via inhibition of the COX/prostaglandin synthase pathway inducing down-regulated expression of sweet/umami responsive components. This dual inhibition mechanism may underlie diclofenac-induced taste alterations in humans. [ABSTRACT FROM AUTHOR]

We performed a parasitological examination of the gastrointestinal tract of farmed ring-necked pheasants (Phasianus colchicus karpowi) on two farms in Ehime, Japan. Fecal examination through flotation and sedimentation methods (43, 103, and 50 samples in three consecutive years from 2020, respectively) detected coccidian oocysts (5–58%), or capillarid (40–56%) and heterakid eggs (45–72%). Following artificial sporology, most sporulated coccidian oocysts were ellipsoidal without micropyle nor residuum, but with 1–3 polar refractile granules, morphologically reminiscent of Eimeria phasiani (Apicomplexa: Eucoccidiorida: Eimeriidae). Intensive sequencing of mitochondrial cytochrome c oxidase subunit I gene (cox-1) using pan-eimerian primers and multiple oocyst samples from different pheasants indicated a single species. We characterized, for the first time, the cox-1 sequence of E. phasiani, known to be prevalent in wild and captive ring-necked pheasants worldwide. Worm recovery under a dissection microscope revealed two capillariid and one heterakid nematode species: Eucoleus perforans (Nematoda: Trichocephalida: Capillariidae) in the esophageal epithelium (prevalence, 8–73%), Capillaria phasianina (Capillariidae) in the cecal mucosa (10–87%), and Heterakis gallinarum (Nematoda: Ascaridida: Heterakidae) in the cecal lumen (69–88%). The small subunit ribosomal RNA gene (SSU rDNA) of E. perforans was perfectly identical to that in a previous isolate from farmed Japanese green pheasants (Phasianus colchicus versicolor) at a distant locality in Japan. The SSU rDNA of C. phasianina was characterized, for the first time, demonstrating a sister relationship with Capillaria anatis, parasites found in the ceca of domestic ducks, geese, and various wild anatid birds. [ABSTRACT FROM AUTHOR]

Dolichos trilobus Linn (Leguminosae) is often used in Yi ethnic medicine to treat pain, fracture, and rheumatism. To explore the therapeutic potential of doliroside B (DB) from D. trilobus and its disodium salt (DBDS) and the underlying mechanism in pain. In the writhing test, Kunming mice were orally treated with DB and DBDS at doses of 0.31, 0.62, 1.25, 2.5, and 5 mg/kg. Vehicle, morphine, indomethacin, and acetylsalicylic acid were used as negative and positive control on the nociception-induced models, respectively. In the hot plate test, mice were orally treated with DB and DBDS at doses of 2.5, 5, 10, and 20 mg/kg. In the formalin test, mice were orally treated with DB and DBDS at doses of 2.5, 5, 10, and 20 mg/kg. In the meanwhile, lipopolysaccharide-induced inflammatory model in RAW264.7 macrophages was adopted to study the mechanism of pain alleviation for DBDS. DBDS (5 mg/kg) inhibited the writhing number by 80.2%, which exhibited the highest antinociceptive activity in pain models. DBDS could selectively inhibite the activity of COX-1. Meanwhile, it also reduced the production of NO, iNOS, and IL-6 by 55.8%, 69.0%, and 49.9% inhibition, respectively. It was found that DBDS also positively modulated the function of GABAA1 receptor. DBDS displayed antinociceptive activity by acting on both the peripheral and central nervous systems, which may act on multitargets. Further work is warranted for developing DBDS into a potential drug for the treatment of pain. [ABSTRACT FROM AUTHOR]

Gazella subgutturosa, a vulnerable species, is threatened by illegal hunting for meat and sport. The mitochondrial cytochrome c oxidase subunit 1 gene (cox-1) is used as a DNA marker to distinguish mammalian species for the investigation of illegal hunting. In this study, we sequenced a part of the cox-1 gene (709 bp) of six Mongolian G. subgutturosa individuals. Our DNA sequences were clustered in a clade of Gazella which is distinct from other clades of mammalian species in the phylogenetic tree. Our findings suggest that DNA sequences can be useful in the investigation of illegal hunting.

Simple Summary: This study illustrates so far under-reported canine gallbladder erosion/ulcer. Based on the clinicopathological information in addition to the COX-1 and COX-2 IHC results, canine gallbladder erosion/ulcer is possibly related to decreased cytoprotection physiologically provided by arachidonic acid. (1) Background: Gallbladder mucosal erosion and/or ulceration are illnesses associated with unexpected gallbladder intra-cystic bleeding (hemocholecyst), an under-reported problem in dogs. (2) Methods: Clinicopathological characteristics of 14 dogs with gallbladder erosion/ulcer were investigated in this single-center retrospective study using clinical data and archived gallbladder tissues of client-owned dogs. (3) Results: Canine gallbladder erosion/ulcer tends to occur in older, neutered dogs of various breeds. Vomiting, lethargy, and anorexia are common. Concurrent gallbladder rupture occurred in 5/14 cases (35.7%), while rupture was absent in 6/14 cases (42.8%) and undetermined in 3/14 (21.4%) cases. Histologically, the gallbladder wall was markedly thickened due to mucosal hyperplasia, inflammatory infiltrates, fibrosis, edema, hemorrhage, and smooth muscle hyperplasia/hypertrophy. Twelve out of fourteen cases (85.7%) had concurrent cholecystitis of varying severity. Bacteria were detected by Giemsa or Warthin–Starry stain in 8/14 (57.1%) cases. Bacterial rods immunoreactive to the anti-Helicobacter antibody were present in one case. Mucosal epithelial cells of the gallbladder erosion/ulcer cohort were immunopositive for the cyclooxygenases COX-1 or COX-2 in only 5/14 (35.7%) cases. In contrast, COX-1 and COX-2 were more frequently expressed in a reference pool of cases of gallbladder mucocele (n = 5) and chronic cholecystitis (n = 5). COX-1 was expressed in 9/10 cases (90.0%) of gallbladder mucocele and chronic cholecystitis and in 10/10 cases (100%) for COX-2. (4) Conclusions: Canine gallbladder erosion/ulcer is an under-reported condition which requires active clinical intervention. Based on the clinicopathological information reported in this study in addition to the COX-1 and COX-2 IHC results, we suggest that canine gallbladder erosion/ulcer may be related to decreased cytoprotection physiologically provided by arachidonic acid, but which is decreased or absent due to reduced COX expression because of yet undetermined etiologies. [ABSTRACT FROM AUTHOR]

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Selective COX-1 inhibitors are preferential therapeutic targets for platelet aggregation and clotting responses. In this study, we examined the selective COX-1-inhibitory activities of four newly synthesized compounds, 10–13, along with their abilities to inhibit platelet aggregation against ADP and collagen. The target compounds 10–13 were synthesized using the conventional method, sonication, and microwave-assisted methods. Microanalytical and spectral data were utilized to elucidate the structures of the new compounds 10–13. Additionally, a spectral NMR experiment [NOESY] was conducted to emphasize the configuration around the double bond of the imine group C=N. The obtained results revealed no observed correlation between any of the neighboring protons, suggesting that the configuration at the C=N double bond is E. Biological results revealed that all the screened compounds 10–13 might serve as selective COX-1 inhibitors. They showed IC50 values ranging from 0.71 μM to 4.82 μM against COX-1 and IC50 values ranging from 9.26 μM to 15.24 μM against COX-2. Their COX-1 selectivity indices ranged between 2.87 and 18.69. These compounds show promise as promising anti-platelet aggregation agents. They effectively prevented platelet aggregation induced by ADP with IC50 values ranging from 0.11 μM to 0.37 μM, surpassing the standard aspirin with an IC50 value of 0.49 μM. Additionally, they inhibited the platelet aggregation induced by collagen with IC50 values ranging from 0.12 μM to 1.03 μM, demonstrating superior efficacy compared to aspirin, which has an IC50 value of 0.51 μM. In silico molecular modeling was performed for all the target compounds within the active sites of COX-1 and COX-2 to rationalize their selective inhibitory activities towards COX-1. It was found that the binding interactions of the designed compounds within the COX-1 active site had remained unaffected by the presence of celecoxib. Molecular modeling and DFT calculations using the B3LYP/6-31+G (d,p) level were performed to study the stability of E-forms with respect to Z-forms for the investigated compounds. A strong correlation was observed between the experimental observations and the quantum chemical descriptors.

Clinically, indobufen is widely used for the treatment of antiplatelet aggregation and anticoagulation. Prior studies have discovered that abnormal platelet function can be promptly restored to normal when the drug is stopped. Herein, through the study of the enzyme reaction kinetics, we demonstrated that the inhibitory effect of indobufen on cyclooxygenase-1 (COX-1) was reversible and non-competitive. Specifically, the cyclooxygenase inhibition experiment showed that the level of 6-keto-PGF1α in the gastric mucosa of the indobufen-treated groups was significantly higher than that of the aspirin group (###p < 0.001), indicating a higher level of PGI2 in and a better physiological state of the gastric mucosa. Moreover, the rat gastric ulcer index and mucosal section experiments further confirmed the relief of gastrointestinal irritation and the adverse reaction rate of the indobufen-treated group compared to those of the aspirin group. Furthermore, indobufen was verified to exert reversible inhibitory activity on the heme group of COX-1 and thus reversibly inhibit COX-1 activity. In general, compared with aspirin, the long-term oral administration of indobufen yields a lower risk of gastrointestinal symptoms, such as ulcers. [ABSTRACT FROM AUTHOR]

Aluminum (Al) is a ubiquitous xenobiotic with known toxicity for both humans and animals. Our study was conducted to investigate the protective role of febuxostat (Feb) against aluminum chloride (AlCl3)-induced hepatorenal injury in rats. Hepatorenal injury was induced by oral administration of AlCl3 (40 mg/kg b.w.), for 2 months. Twenty-four male Sprague–Dawley rats were randomly allocated into four groups (six rats/group). The first group received the vehicle thought the experiment. The second group was considered as a control positive group. The third and fourth groups received oral treatment of Feb (10 mg/kg.b.w.) and (15 mg/kg.b.w.), respectively with AlCl3, concurrently for 2 months. Twenty-four hours, after the last treatment, serum biochemical, molecular, histopathology, and immunohistochemical studies were evaluated. Our findings showed that rats intoxicated with Alcl3 had disturbed biochemical picture. In addition, intoxication with AlCl3 increased oxidative stress and apoptosis, as demonstrated by an increase in malodialdeyde (MDA), carnitine o-acetyltransferase (Crat), and carbonic anhydrase (Car3) with a decrease in glutathione (GSH), MAP kinase-interacting serine/threonine kinase (MNK) and nuclear factor-erythroid 2-related factor 2 (Nrf2) mRNA expression. Furthermore, the levels of tumor necrosis factor-alpha (TNF-α) and the levels of caspase-3 were elevated with sever hepatic and renal pathological changes. Conversely, Feb (15 mg/kg.b.w.) could improve the serum biochemical indices and repressed MDA, Crat, and Car3 levels, whereas it increased GSH, MNK, and Nrf2 levels. Feb inhibited the apoptotic effect of AlCl3 in the liver and kidney by decreasing caspase-3 and TNF-α expression. The protective effect of Feb against AlCl3 toxicity was confirmed by histopathological findings. Moreover, molecular docking studies supported the anti-inflammatory effect of Feb due to its significant binding interactions with cyclooxygenase-1 (COX-1), NF-kappa-B-inducing kinase (NIK), and mitogen-activated protein kinases-p38 (MAPK-p38). The findings suggest that Feb system Feb can avert Alcl3-induced hepatotoxicity and nephrotoxicity by enhancing the antioxidant defense system, and inhibiting the inflammatory cascade and apoptosis. [ABSTRACT FROM AUTHOR]

Total synthesis of taiwanin C was realised efficiently in a global yield of 52%. Taiwanin C in aggregation assays inhibited platelet aggregation in a concentration-dependent manner with an IC50 of 0.46 μM after exposure of human platelet to AA. Similarly, to AA, taiwanin C inhibited significantly TRAP-6-induced platelet aggregation with IC50 of 0.56 μM. Molecular docking studies were carried out using the molecular target the COX-1, COX-2 and PAR-1 proteins. These studies suggest that taiwanin inhibits COX-1 more strongly than COX-2. Taiwanin C showed better antiplatelet action in the presence of TRAP-6 than indomethacin and molecular docking studies suggest different mechanisms of action for the two compounds on PAR-1. These results demonstrate that taiwanin C acts very efficiently in two different signaling pathways of platelet aggregation. Although preliminary, these results indicate that taiwanin C has potential for further studies on its use for the development of new antiplatelet. [ABSTRACT FROM AUTHOR]

Aim. The role of cyclooxygenases (COX-1 and/or COX-2), transcription nuclear factor NF-B, anti-inflammatory cytokines TGF1b, IL-4, IL-10 and pro-inflammatory cytokines IL-1, IL-6 were studied to substantiate the expediency of antiviral agent enisamium iodide (Nobazit) using to regulate key inflammatory components in acute respiratory infections, IL-8, TNF-alpha in the realization of the pharmacological activity of this drug. Materials and methods. Gene expression was determined by real-time RT-PCR, the concentration of interleukins was determined by ELISA, and the viability of peripheral blood mononuclear cells (PBMC) was assessed by the MTT spectrophotometric method. The chemiluminescence method was used to assess PBMC oxidant activity. Results. Enisamium iodide (10 M) reduced mRNA levels of COX-1, COX-2, NF-B, TGF1b, IL-1, IL-6 in stimulated PBMC of healthy donors by an average of 48% (p0.05). At 5 times higher concentration, 50 M, enisamium iodide suppressed the expression of these genes by an average of 43% (p0.05). At a concentration of 100 M, enisamium iodide reduced the expression of COX-2, TGF1b, IL-1, IL-6 by an average of 47% (p0.05). At a concentration of 10 M, enisamium iodide stimulated the secretion of IL-10 by mononuclear cells by 1.2 times, p0.05. The tested drug at a concentration of 50 M did not affected on the concentration of IL-1, IL-4, IL-8 and TNF-alpha, but significantly stimulated the production of IL-10 by 1.5 times, p0.05. The chemiluminescence method revealed that enisamium iodide in the entire concentration range (10100 M) does not reduce the viability of macrophages, but inhibits their oxidative activity (maximum value of CL intensity) by an average of 55% (p0.05). Conclusion. The anti-inflammatory effect of enisamium iodide at a concentration of 10 M may be associated with inhibition of the expression of COX-1, 2, NF-B, IL-1, IL-6, TGF1b and an increase in the expression and production of IL-10. An additional contribution to the anti-inflammatory activity of enisamium iodide is made by its antioxidant and antiradical activity. The absence of the effect of enisamium iodide (10100 M) on the viability of PBMC indicates its safety for the cells of the immune system and the expediency of using it to suppress inflammatory reactions in acute respiratory infections, restore the quality of life of patients and the possibility of using Nobazit as an effective agent for treatment of these infections of various etiologies.

In this article, we present the first detailed analysis of the hydro-distilled essential oil (HDEO) of the inflorescence heads of Echinops polyceras Boiss. (Asteraceae) from the flora of Jordan, offering observations at different growth (pre-flowering, full-flowering and post-flowering) stages. Additionally, we investigated the methanolic extract obtained from the aerial parts of the plant material at the full flowering stage in order to determine its inhibitory activity in terms of COX and protein denaturation and evaluate its antimicrobial effects against S. aureus (Gram-positive) and E. coli (Gram-negative) bacteria. Performing GC/MS analysis of HDEO, obtained from the fresh inflorescence heads at the different growth stages, resulted in the identification of 192 constituents. The main class of compounds detected in these three stages comprised aliphatic hydrocarbons and their derivatives, which amounted to 50.04% (pre-flower), 40.28% (full-flower) and 41.34% (post-flower) of the total composition. The oils also contained appreciable amounts of oxygenated terpenoids, primarily sesquiterpenoids and diterpenoids. The pre-flowering stage was dominated by (2E)-hexenal (8.03%) in addition to the oxygenated diterpene (6E,10E)-pseudo phytol (7.54%). The full-flowering stage primarily contained (6E,10E)-pseudo phytol (7.84%), β-bisabolene (7.53%, SH) and the diterpene hydrocarbon dolabradiene (5.50%). The major constituents detected in the HDEO obtained at the post-flowering stage included the oxygenated sesquiterpenoid intermedeol (5.53%), the sesquiterpene hydrocarbon (E)-caryophyllene (5.01%) and (6E,10E)-pseudo phytol (4.47%). The methanolic extract obtained from air-dried aerial parts of E. polyceras displayed more COX-2 inhibition than COX-1 inhibition at a concentration level of 200 µg/mL. The extract exhibited a capacity to inhibit protein denaturation that was comparable with respect to the activity of diclofenac sodium and displayed moderate levels of antimicrobial activity against both bacterial species. The current results demonstrate the need to perform further detailed phytochemical investigations to isolate and characterize active constituents. [ABSTRACT FROM AUTHOR]

Drug repurposing is a promising approach that has the potential to revolutionize the drug discovery and development process. By leveraging existing drugs, we can bring new treatments to patients more quickly and affordably. Anti-inflammatory drugs have been shown to target multiple pathways involved in cancer development and progression. This suggests that they may be more effective in treating cancer than drugs that target a single pathway. Cell viability was measured using the MTT assay. The expression of genes related to inflammation (TNFa, IL1b, COX-1, COX-2, and 5-LOX) was measured in HepG2, MCF7, and THLE-2 cells using qPCR. The levels of TNFα, IL1b, COX-1, COX-2, and 5-LOX were also measured in these cells using an ELISA kit. An enzyme binding assay revealed that sulfadiazine expressed weaker inhibitory activity against COX-2 (IC50 = 5.27 μM) in comparison with the COX-2 selective reference inhibitor celecoxib (COX-2 IC50 = 1.94 μM). However, a more balanced inhibitory effect was revealed for sulfadiazine against the COX/LOX pathway with greater affinity towards 5-LOX (IC50 = 19.1 μM) versus COX-1 (IC50 = 18.4 μM) as compared to celecoxib (5-LOX IC50 = 16.7 μM, and COX-1 IC50 = 5.9 μM). MTT assays revealed the IC50 values of 245.69 ± 4.1 µM and 215.68 ± 3.8 µM on HepG2 and MCF7 cell lines, respectively, compared to the standard drug cisplatin (66.92 ± 1.8 µM and 46.83 ± 1.3 µM, respectively). The anti-inflammatory effect of sulfadiazine was also depicted through its effect on the levels of inflammatory markers and inflammation-related genes (TNFα, IL1b, COX-1, COX-2, 5-LOX). Molecular simulation studies revealed key binding interactions that explain the difference in the activity profiles of sulfadiazine compared to celecoxib. The results suggest that sulfadiazine exhibited balanced inhibitory activity against the 5-LOX/COX-1 enzymes compared to the selective COX-2 inhibitor, celecoxib. These findings highlight the potential of sulfadiazine as a potential anticancer agent through balanced inhibitory activity against the COX/LOX pathway and reduction in the expression of inflammatory genes.

Background: Coronary Heart Disease (CHD), commonly known as the silent killer, impacted the severity of COVID-19 patients during the pandemic era. Thrombosis or blood clots create the buildup of plaque on the coronary artery walls of the heart, which leads to coronary heart disease. Cyclooxygenase 1 (COX-1) is involved in the production of prostacyclin by systemic arteries; hence, inhibiting the COX-1 enzyme can prevent platelet reactivity mediated by prostacyclin. To obtain good health and well-being, the research of discovery of new drugs for anti-thrombotic still continue. Objective: This study aims to predict the potential of 17 compounds owned by the vanillin analog to COX-1 receptor using in silico. Methods: This research employed a molecular docking analysis using Toshiba hardware and AutoDock Tools version 1.5.7, ChemDraw Professional 16.0, Discovery Studio, UCSF Chimera software, SWISSADME and pKCSM, a native ligand from COX- 1 (PDB ID: 1CQE) was validated. Results: The validation result indicated that the RMSD was 2 Å. The 4-formyl-2-methoxyphenyl benzoate compound had the lowest binding energy in COX-1 inhibition with a value of -7.70 Å. All vanillin derivatives show good intestinal absorption, and the predicted toxicity indicated that they were non-hepatotoxic. All these compounds have the potential to be effective antithrombotic treatments when consumed orally. Conclusion: In comparison to other vanillin derivative compounds, 4-formyl-2-methoxyphenyl benzoate has the lowest binding energy value; hence, this analog can continue to be synthesized and its potential as an antithrombotic agent might be confirmed by in vivo studies.

Targeted therapies have come into prominence in the ongoing battle against non-small cell lung cancer (NSCLC) because of the shortcomings of traditional chemotherapy. In this context, indole-based small molecules, which were synthesized efficiently, were subjected to an in vitro colorimetric assay to evaluate their cyclooxygenase (COX) inhibitory profiles. Compounds 3b and 4a were found to be the most selective COX-1 inhibitors in this series with IC50 values of 8.90 µM and 10.00 µM, respectively. In vitro and in vivo assays were performed to evaluate their anti-NSCLC and anti-inflammatory action, respectively. 2-(1H-Indol-3-yl)-N′-(4-morpholinobenzylidene)acetohydrazide (3b) showed selective cytotoxic activity against A549 human lung adenocarcinoma cells through apoptosis induction and Akt inhibition. The in vivo experimental data revealed that compound 3b decreased the serum myeloperoxidase and nitric oxide levels, pointing out its anti-inflammatory action. Moreover, compound 3b diminished the serum aminotransferase (particularly aspartate aminotransferase) levels. Based on the in vitro and in vivo experimental data, compound 3b stands out as a lead anti-NSCLC agent endowed with in vivo anti-inflammatory action, acting as a dual COX-1 and Akt inhibitor. [ABSTRACT FROM AUTHOR]

A series of previously synthesized 5-benzyliden-2-(5-methylthiazole-2-ylimino)thiazoli- din-4-one were evaluated for their anti-inflammatory activity on the basis of PASS predictive outcomes. The predictive compounds were found to demonstrate moderate to good anti-inflammatory activity, and some of them displayed better activity than indomethacin used as the reference drug. Structure–activity relationships revealed that the activity of compounds depends not only on the nature of the substituent but also on its position in the benzene ring. The most active compounds were selected to investigate their possible mechanism of action. COX and LOX activity were determined and found that the title compounds were active only to COX-1 enzymes with an inhibitory effect superior to the reference drug naproxen. As for LOX inhibitory activity, the derivatives failed to show remarkable LOX inhibition. Therefore, COX-1 has been identified as the main molecular target for the anti-inflammatory activity of our compounds. The docking study against COX-1 active site revealed that the residue Arg 120 was found to be responsible for activity. In summary, the 5-thiazol-based thiazolidinone derivatives have been identified as a novel class of selective COX-1 inhibitors. [ABSTRACT FROM AUTHOR]

Ponatinib (Iclusig) is an oral tyrosine kinase BCR-ABL inhibitor for treating patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML) who are resistant to the therapies with other tyrosine kinase inhibitors. However, adverse cardiovascular events caused by Ponatinib are a serious issue that affects patients' survival rates. Thus, it is necessary to search for candidate drugs to reduce the cardiovascular toxicity of Ponatinib. To investigate the effects of Aspirin on Ponatinib-induced cardiovascular toxicity in zebrafish. AB strain of wild type zebrafish (Danio rerio), Tg (cmlc2: GFP) transgenic zebrafish, and Tg (gata1: dsRed) transgenic zebrafish were used as in vivo models to assess survival, blood flow, cardiac morphology, and function. Thrombus formation was detected using O-dianisidine staining. The transcriptome of zebrafish larvae treated with Ponatinib was assessed using RNA sequencing. Ponatinib not only reduced survival rate but also caused cardiovascular toxic events such as pericardial edema, abnormal heart structure, low heart rate, and thrombosis. In addition, whole-body transcriptome analysis showed that Ponatinib up-regulated the expression of cyclooxygenase-1 (COX-1). Compared with other antithrombotic drugs, a COX-1 inhibitor Aspirin more effectively reduced ponatinib-induced cardiovascular toxicity events and improved the survival rate of zebrafish larvae. Our findings suggest that Aspirin exhibits the potential to reduce Ponatinib-induced cardiovascular toxicity. [ABSTRACT FROM AUTHOR]

Barley (Hordeum vulgare L.) stands out for its special nutritional value compared to other cereals, garnering significant attention in recent years. In this study, a comprehensive chemical and biological evaluation of different barley cultivars extracted with different solvents was performed. Ultra-high performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-ESI-QTOF-MS/MS) was used in the phytochemical study. The molecular docking with absorption, distribution, metabolism, excretion, and toxicity (ADMET) study and multivariate analysis alongside the quantification of total phenolic contents (TPC) were performed. Furthermore, the anti-inflammatory action was in vitro assessed by measuring COX-1, COX-2, and 5-LOX inhibition. This study seeks to establish a suitable solvent for extracting anti-inflammatory properties from diverse barley cultivars. The methanol extract obtained from the G.131 cultivar, followed by the 80% methanol extract from the G.136 cultivar, exhibited the most favorable IC 50 values in comparison to the reference drugs indomethacin and celecoxib. The phytochemical profile revealed more than 60 compounds that belonged to nitrogen-containing compounds, phenolic compounds, organic acids, flavonoids, and their glycosides, hordatines, and other classes. The TPC and COX-2 inhibition was positively correlated with isoscoparin, coumaroyle–OH–eagmatine, isoorientin, isovitexin 7- O -rhamnosylglucoside, isoscoparin 7- O -glucoside, and isoorientin-7- O -[6-feruloyl]-glucoside. These findings along with their pharmacodynamics study suggested a potential synergistic and significant contribution of these compounds with the anti-inflammatory activity. [Display omitted] [ABSTRACT FROM AUTHOR]

(1) Background: Gallbladder mucosal erosion and/or ulceration are illnesses associated with unexpected gallbladder intra-cystic bleeding (hemocholecyst), an under-reported problem in dogs. (2) Methods: Clinicopathological characteristics of 14 dogs with gallbladder erosion/ulcer were investigated in this single-center retrospective study using clinical data and archived gallbladder tissues of client-owned dogs. (3) Results: Canine gallbladder erosion/ulcer tends to occur in older, neutered dogs of various breeds. Vomiting, lethargy, and anorexia are common. Concurrent gallbladder rupture occurred in 5/14 cases (35.7%), while rupture was absent in 6/14 cases (42.8%) and undetermined in 3/14 (21.4%) cases. Histologically, the gallbladder wall was markedly thickened due to mucosal hyperplasia, inflammatory infiltrates, fibrosis, edema, hemorrhage, and smooth muscle hyperplasia/hypertrophy. Twelve out of fourteen cases (85.7%) had concurrent cholecystitis of varying severity. Bacteria were detected by Giemsa or Warthin–Starry stain in 8/14 (57.1%) cases. Bacterial rods immunoreactive to the anti-Helicobacter antibody were present in one case. Mucosal epithelial cells of the gallbladder erosion/ulcer cohort were immunopositive for the cyclooxygenases COX-1 or COX-2 in only 5/14 (35.7%) cases. In contrast, COX-1 and COX-2 were more frequently expressed in a reference pool of cases of gallbladder mucocele (n = 5) and chronic cholecystitis (n = 5). COX-1 was expressed in 9/10 cases (90.0%) of gallbladder mucocele and chronic cholecystitis and in 10/10 cases (100%) for COX-2. (4) Conclusions: Canine gallbladder erosion/ulcer is an under-reported condition which requires active clinical intervention. Based on the clinicopathological information reported in this study in addition to the COX-1 and COX-2 IHC results, we suggest that canine gallbladder erosion/ulcer may be related to decreased cytoprotection physiologically provided by arachidonic acid, but which is decreased or absent due to reduced COX expression because of yet undetermined etiologies.

Ketoprofen can relieve pain and inflammation associated with many diseases but, it may cause unwanted side effects especially in kidneys. Curcumin nanoparticles (CurNPs) have a protective effect related to their anti-inflammatory and antioxidant properties. The present study examined the protective role of cyclooxygenase- 1 (COX-1) in kidney induced by CurNPs against Ketoprofen-induced nephropathic injury. Twenty adults male Wistar rats were randomly assigned into four groups (n=5); Ketoprofen administered group, Ketoprofen and CurNPs- treated group, CurNPs treated group and control group. Animals were sacrificed 6 weeks post-administration. Blood serum samples were used for evaluation of urea, creatinine, lipid peroxidation (MDA) and total antioxidant capacity (TAC) levels. Kidney specimens were collected for histopathology and COX-1 expression was studied as well. The histopathological results of kidney in Ketoprofen administrated group showed focal segmental and global glomerulosclerosis, periglomerular fibrosis, intratubular casts and lytic necrosis of renal tubular epithelium. The pathological lesions were decreased to be mild changes in kidney of Ketoprofen and CurNPs- treated group. Immunhistochemical examination of COX-1 showed negative expression in Ketoprofen group which was attenuated in Ketoprofen and CurNPs- treated group. The biochemical examination revealed that animals in Ketoprofen administrated group showed significant increase in urea, creatinine, and MDA while TAC levels were numerically decreased. These results were attenuated in Ketoprofen and CurNPs- treated group. Co-administration of CurNPs with Ketoprofen caused reduction in kidney parameters and MDA with numerical improvement in TAC. In the present study, CurNPs have obvious protective effects on nephropathic lesions induced by Ketoprofen. [ABSTRACT FROM AUTHOR]

Ionic liquids (ILs) are a potential solution to the general problem of low solubility, polymorphism and low bioavailability of active pharmaceutical ingredients (APIs). In this work, we report on the synthesis of three pharmaceutically active ILs (API-ILs) based on ibuprofen, one of the most commonly available over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs), with imidazolium cations ([C2C1Im][Ibu] and [C2(OH)C1Im][Ibu]) and a cholinium cation ([N1112(OH)][Ibu]). An upgrade to the aqueous solubility (water and biological simulated fluids) for the ibuprofen-based ILs relative to the ibuprofen's neutral and salt form (sodium ibuprofen) was verified. The cytotoxic profiles of the synthesized API-ILs were characterized using two human cells lines, Caco-2 colon carcinoma cells and HepG-2 hepatocellular carcinoma cells, up to ibuprofen's maximum plasma concentration (Cmax) without impairing their cytotoxicity response. Additionally, the EC50 in the Caco-2 cell line revealed similar results for both parent APIs and API-ILs. The biocompatibility of the ibuprofen-based ILs was also evaluated through a hemolytic activity assay, and the results showed that all the ILs were hemocompatible at concentrations higher than the ibuprofen Cmax. Moreover, the anti-inflammatory properties of the API-ILs were assessed through the inhibition of bovine serum albumin (BSA) denaturation and inhibition of cyclooxygenases (COX-1 and COX-2). The results showed that [C2C1Im][Ibu], [C2(OH)C1Im][Ibu] and [N1112(OH)][Ibu] maintained their anti-inflammatory response to ibuprofen, with improved selectivity towards COX-2, allowing the development of safer NSAIDs and the recognition of new avenues for selective COX-2 inhibitors in cancer chemotherapy and neurological diseases such as Alzheimer's and Parkinson's. [ABSTRACT FROM AUTHOR]

Little is known about the impact of ticks on livestock and humans in Cameroon. This study aimed to determine the prevalence, seasonal variation, and genetic diversity of hard ticks in the country. Ticks were collected during a cross‐sectional survey on domestic livestock in two markets of Yaoundé in 2019 and 2020 and identified using morphological keys, 16S ribosomal DNA, (16S rDNA), and the cytochrome c oxidase subunit 1 (Cox1) genes. The infestation rates were 39.18%, 11.53%, and 2.74% in cattle, sheep, and goats respectively. Three genera of ticks were identified, Rhipicephalus, Amblyomma, and Hyalomma comprising eleven tick species. The main species were Rhipicephalus decoloratus (30.25%), R. microplus (24.43%), and Amblyomma variegatum (12.96%). Rhipicephalus spp. (81.31%) and Amblyomma variegatum (51.54%) were abundant during the rainy season, while Hyalomma spp. (83.86%) during the dry season (p‐value <0.00001). Cox1 and 16S rDNA analysis showed a high level of genetic diversity among tick species with sequences close to those observed across Africa. Phylogenetic analysis revealed that our R. microplus belong to clade A and we identified R. sanguineus s.l. as R. linnea. This study shows a high tick infestation rate in cattle, while low in small ruminants with an extensive diversity of tick species, including several known vectors of important tick‐borne diseases. [ABSTRACT FROM AUTHOR]

Our laboratory recently developed [ 11 C]PS13 as a PET radioligand to selectively measure cyclooxygenase-1 (COX-1). The cyclooxygenase enzyme family converts arachidonic acid into prostaglandins and thromboxanes, which mediate inflammation. The total brain uptake of [ 11 C]PS13, which is composed of both specific binding and background uptake, can be accurately quantified with gold standard methods of compartmental modeling. This study sought to quantify the specific binding of [ 11 C]PS13 to COX-1 in healthy human brain using scans performed with arterial input function at baseline and after blockade by the COX-1-selective inhibitor ketoprofen. Methods: Eight healthy volunteers underwent two 90-min [ 11 C]PS13 PET scans with radiometabolite-corrected arterial input function, at baseline and about 2 h after oral administration of ketoprofen (75 mg). Results: Two-tissue compartment modeling effectively identified the total uptake of radioactivity in the brain (as distribution volume), showing the highest densities in the hippocampus, the occipital cortex, and the banks of the central sulcus. All brain regions exhibited displaceable and specific binding, and thus none could be used as a reference region. Ketoprofen blocked approximately 84% of the binding sites on COX-1 in the whole brain. After full occupancy was extrapolated, the average whole-brain values of [ 11 C]PS13 were 1.6 ± 0.8 mL·cm -3 for specific uptake, 1.7 ± 0.6 mL·cm -3 for background uptake, and 1.1 ± 0.5 for the specific-to-background ratio. The hippocampus had the highest specific-to-background ratio value of 2.7 ± 0.9. Conclusion: [ 11 C]PS13 exhibited high specific binding to COX-1 in the human brain, but its quantification requires arterial blood sampling., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Our lab has identified that transcripts and proteins of the cyclooxygenase (COX-1 and COX-2) isoenzymes are expressed during the early stages of vertebrate embryonic development, and that global COX-1/2 inhibition disrupts neural crest (NC) cell maturation in Ambystoma mexicanum (axolotl) embryos, with intriguing implications for tissue regeneration and healing. NC cells are embryonic stem cells that differentiate into various adult tissues including craniofacial cartilage, bone, and neurons in the peripheral and enteric nervous systems. Naproxen (NPX), a common non-steroidal anti-inflammatory drug (NSAID) used to relieve pain and inflammation, exerts its effects through COX-1 and COX-2 inhibition. Embryonic exposures to NSAIDs have been linked to preterm birth, neural tube closure defects, abnormal enteric innervation, and craniofacial malformations, potentially due to disrupted neural tube or NC cell development. To investigate the phenotypic and molecular effects of NPX exposure on NC development and differentiation, we exposed late neurula and early tailbud stage axolotl embryos to various concentrations of NPX and performed immunohistochemistry (IHC) for markers of migratory and differentiating NC cells. Our results reveal that NPX exposure impairs the migration of SOX9+ NC cells, leading to abnormal development of craniofacial cartilage structures, including Meckel's cartilage in the jaw. NPX exposure also alters the expression of markers associated with peripheral and central nervous system (PNS and CNS) development, suggesting concurrent neurodevelopmental changes.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world. The widespread use of NSAIDs is associated with a number of serious side effects and complications observed for both selective and non-selective COX inhibitors. Therefore, the search for new COX inhibitors, which along with their effectiveness will have minimal side effects, is a very important and urgent task. Methods: This work studied the synthesis of new 1,4,5,6-tetrahydropyrimidine-2-carboxamides based on the reaction of 2-morpholin-4-yl-N-(het)aryl-2-thioxoacetamides with 1,3-diaminopropane. All obtained compounds were tested for anti-inflammatory activity in vitro and in silico conditions. All synthesized 1,4,5,6-tetrahydropyrimidine-2-carboxamides were tested for influence on the course of the exudative phase of the inflammatory process based on the carrageenan model of paw edema of laboratory nonlinear heterosexual white rats weighing 220-250 g, using Diclofenac as a reference. Optimization of the geometry of the studied structures and molecular docking was carried out using the ArgusLab 4.0.1 software package. Results: The target products were obtained with yields of 71-98% and easily isolated from the reaction mixture. The best anti-inflammatory activity was found in N-(4-chlorophenyl)-1,4,5,6-tetrahydropyrimidine-2-carboxamide and in N-[4-chloro-3-(trifluoromethyl)phenyl]-1,4,5,6-tetrahydropyrimidine-2-carboxamide, suppression of the inflammatory response was 46.7 and 46.4%, respectively. The results of molecular docking with COX-1 and COX-2 enzymes were in good agreement with the experimental data, R2 ˃ 0.92 and R2 ˃ 0.83, respectively. Conclusion: The compounds under study were shown to be promising as potential anti-inflammatory agents.

Clinically, indobufen is widely used for the treatment of antiplatelet aggregation and anticoagulation. Prior studies have discovered that abnormal platelet function can be promptly restored to normal when the drug is stopped. Herein, through the study of the enzyme reaction kinetics, we demonstrated that the inhibitory effect of indobufen on cyclooxygenase-1 (COX-1) was reversible and non-competitive. Specifically, the cyclooxygenase inhibition experiment showed that the level of 6-keto-PGF1α in the gastric mucosa of the indobufen-treated groups was significantly higher than that of the aspirin group (###p < 0.001), indicating a higher level of PGI2 in and a better physiological state of the gastric mucosa. Moreover, the rat gastric ulcer index and mucosal section experiments further confirmed the relief of gastrointestinal irritation and the adverse reaction rate of the indobufen-treated group compared to those of the aspirin group. Furthermore, indobufen was verified to exert reversible inhibitory activity on the heme group of COX-1 and thus reversibly inhibit COX-1 activity. In general, compared with aspirin, the long-term oral administration of indobufen yields a lower risk of gastrointestinal symptoms, such as ulcers.

Gastric issues that accompany the use of NSAIDs (Non-steroid anti-inflammatory drugs) are always a serious global concern. The inhibition of the Cycloxygenase enzyme (COX) limits the prostaglandin synthesis and thereby facilitates the control of pains, inflammation etc. But this creates gastric issues due to the reduction of mucin formation in the stomach. The present work was performed to create a modification in the structure of NSAID drug Diflunisal, to reduce the gastric effect of acidic moiety in the structure and elevate the overall biological properties. The drug Tromethamine, a base used in acidosis treatment was substituted to reduce the acidic issues. The heterocyclic compound pyrrole was substituted to elevate the properties. Neutral, salt, amide and ester combinations of Tromethamine-Diflunisal were designed, optimized and docked to the crystal structures of COX-1 (PDB ID: 6Y3C) and COX-2 (PDB ID: 5IKR) enzymes, using PyRx software. The combinations with lower COX-1 and COX-2 binding energies relative to Diflunisal were noted. It was analysed if the combinations of Diflunisal, Tromethamine and pyrrole lowers drug-properties or induce toxicities. Pyrrole substitution at position R4 was not found favourable for COX binding. Among the favourable combinations, DF19 is the Diflunisal-Pyrrole-Tromethamine combination, equally favourable for binding to COX targets. [ABSTRACT FROM AUTHOR]