Search

Glycosylation is an important post-modification reaction in plant secondary metabolism, and contributes to structural diversity of bioactive natural products. In plants, glycosylation is usually catalyzed by UDP-glycosyltransferases. Flavonoid 2′- O -glycosides are rare glycosides. However, no UGTs have been reported, thus far, to specifically catalyze 2′- O -glycosylation of flavonoids. In this work, UGT71AP2 was identified from the medicinal plant Scutellaria baicalensis as the first flavonoid 2′- O -glycosyltransferase. It could preferentially transfer a glycosyl moiety to 2′-hydroxy of at least nine flavonoids to yield six new compounds. Some of the 2′- O -glycosides showed noticeable inhibitory activities against cyclooxygenase 2. The crystal structure of UGT71AP2 (2.15 Å) was solved, and mechanisms of its regio-selectivity was interpreted by p K a calculations, molecular docking, MD simulation, MM/GBSA binding free energy, QM/MM, and hydrogen‒deuterium exchange mass spectrometry analysis. Through structure-guided rational design, we obtained the L138T/V179D/M180T mutant with remarkably enhanced regio-selectivity (the ratio of 7- O -glycosylation byproducts decreased from 48% to 4%) and catalytic efficiency of 2′- O -glycosylation (k cat / K m , 0.23 L/(s·μmol), 12-fold higher than the native). Moreover, UGT71AP2 also possesses moderate UDP-dependent de-glycosylation activity, and is a dual function glycosyltransferase. This work provides an efficient biocatalyst and sets a good example for protein engineering to optimize enzyme catalytic features through rational design. This work reports a novel 2′- O -glycosyltransferase, unravels its regio-selectivity mechanism, and improves its catalytic function through protein engineering. [Display omitted] [ABSTRACT FROM AUTHOR]

Canine ovarian epithelial tumours (OETs) are currently divided into ovarian adenomas and carcinomas, which are further inconsistently subclassified as papillary or cystic, whereas in human medicine, OETs are subdivided into several subtypes. This study aimed to establish clear morphological features enabling more consistent distinction between benign OETs and ovarian carcinomas (OvCas) as well as defining different histopathological patterns of canine OvCas. Analysis revealed a mitotic count threshold of >2 as a potential criterion for differentiating OvCas from benign OETs. Alongside ovarian adenomas, ovarian borderline tumours were introduced as a distinct category among benign OETs. OvCas exhibited five different histopathological patterns, namely papillary, solid with tubular differentiation, micropapillary, cystic and sarcomatous. Since some OvCas can morphologically overlap with other ovarian tumours, the expression of cytokeratin 7, a cytokeratin expressed in ovarian epithelium, was assessed and proved helpful, although it was not expressed in all cases. Furthermore, we investigated the expression of 14-3-3σ and cyclooxygenase 2 (COX-2). Based on the frequent expression of 14-3-3σ, this marker appears to have a role in canine OETs since it is not expressed in normal canine ovaries. The infrequent expression of COX-2 suggests that it is a poor candidate as a potential therapeutic target in canine OvCas. [ABSTRACT FROM AUTHOR]

Objective: To assess the analgesic and anti-inflammatory effects of standardized extract of Cotinus coggygria (C. coggygria) in different animal models. Methods: C. coggygria extracts (25, 50, and 100 mg/kg) were administered to rats and mice (n=6) during hot plate, tail-flick, acetic acid-induced writhing, and formalin tests to determine its analgesic efficacy. The anti-inflammatory activity of C. coggygria extracts was evaluated by histamine and carrageenan-induced paw edema, cotton pellet-induced granuloma, and acetic acid-induced peritoneal capillary dye leakage tests. Results: C. coggygria extracts (50 and 100 mg/kg) significantly alleviated thermal and chemical-induced pain in rodents (P<0.05). It also demonstrated notable anti-inflammatory properties by mitigating histamine and carrageenan-induced paw edema, granuloma deposits, and vascular permeability (P<0.05). Moreover, C. coggygria extracts remarkably reduced TNF-α, IL-1β, IL-6, COX-2, and oxidative stress in rat paws (P<0.05). Carrageenan-induced histological aberrations in hind paw tissues were effectively (P<0.05) mitigated by treatment with C. coggygria extracts. Conclusions: C. coggygria Scop. extracts show analgesic and antiinflammatory effects via inhibition of COX-2 and inflammatory and oxidative mediators. [ABSTRACT FROM AUTHOR]

Background and objective Tumor microenvironment (TME) is one of the important factors in tumorigenesis and progression, in which tumor-associated macrophages (TAMs) play an important role in non-small cell lung cancer (NSCLC) progression. However, the mechanism of TAMs in NSCLC progression remains unclear, so this study aimed to investigate the role of TAMs in NSCLC progression and to find potential therapeutic targets. Methods Gene Expression Profiling Interactive Analysis (GEPIA) database was used to analyze the expression of prostaglandin E2 receptor 4 (EP4) mRNA in NSCLC and normal lung tissues; the protein expression levels of cyclooxygenase-2 (COX-2), EP4, cluster of differentiation 86 (CD86), CD163 and CD31 were detected by immunohistochemistry (IHC) in 120 NSCLC tissues and 24 paracancerous tissues specimens. The nude mouse lung adenocarcinoma cell A549 and macrophage RAW264.7 co-transplanted tumor model was established. And the samples were collected by gavage with EP4 inhibitor E7046, and then stained with hematoxylin-eosin (HE), IHC, and immunofluorescence (IF), and then detected by Western blot for the epithelial mesenchymal transformation (EMT) of the tumor tissues of the nude mice in each group. Western blot was used to detect the expressions of EMT related protiens in each group of nude mice; full-length transcriptome sequencing was used to screen the key genes causing liver metastasis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed. Results EP4 mRNA expression level in NSCLC tissues was generally lower than that in normal lung tissues (P<0.05); COX-2, EP4, CD163, CD31 proteins were differentially expressed in NSCLC tissues and adjacent tissues, and differences were observed in many clinicopathological parameters of NSCLC patients; RAW264.7 shortened the latency period of tumorigenesis of A549 and promoted the proliferation of tumors and liver metastasis of tumors, and E7046 could reduce tumor cell proliferation activity, tumor tissue vascular density and M2-type macrophage infiltration in nude mice; IF staining showed that macrophages were mainly distributed around the metastatic foci of tumors; Western blot results showed that compared with A549 alone transplantation group, the relative expression of E-cadherin protein in tumor tissues of mice in A549 and RAW264.7 co-transplantation group was significantly decreased, and the difference was statistically significant (P<0.05), while the relative expression of N-cadherin protein was up-regulated, but the difference was not statistically significant (P>0.05); the main pathways enriched in the differential genes of the full-length transcriptome were the PI3K-AKT and MAPK signaling pathways. Conclusion During NSCLC development, the COX-2/PGE2/EP4 axis may promote tumor progression by inducing macrophage functional activation, and EP4 may be a potential new target for tumor immunotherapy. This study provides new perspectives and ideas for in-depth exploration of the mechanisms of NSCLC development, as well as a theoretical basis for the development of new therapeutic strategies for NSCLC. [ABSTRACT FROM AUTHOR]

Bacterial infection was the major etiology for pulpal/root canal infection. This study aimed to investigate the activation of toll-like receptor-3 (TLR) on cyclooxygenase-2 (COX-2) expression and prostaglandin E 2 (PGE 2) and PGF 2α production of human dental pulp cells (HDPCs) and associated signaling. HDPCs were exposed to different concentrations of Poly (I:C) (a TLR3 activator). Cell viability was determined by 3- (4,5-Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay and alkaline phosphatase (ALP) activity was evaluated by ALP staining. Activation of extracellular signal-regulated kinase (ERK) and p38 by Poly (I:C) was determined by immunofluorescent staining. The COX-2 protein expression was analyzed by Western blot. PGE 2 and PGF 2α production was measured by enzyme-linked immunosorbent assay. The mRNA expression was studied by real-time polymerase-chain reaction. Moreover, HDPCs were exposed to Poly(I:C) with/without U0126 or SB203580 treatment and analysis of COX-2 expression and prostanoid production were conducted. Poly (I:C) showed little effect on ALP activity, but decreased viability of HDPCs. It stimulated COX-2 mRNA and protein expression. Poly (I:C) induced PGE 2 and PGF 2α production of HDPCs. Poly (I:C) activated p -ERK, and p-p38 protein expression. Treatment by U0126 (a mitogen-activated protein kinase kinase (MEK)/ERK inhibitor) and SB203580 (a p38 inhibitor) attenuated Poly (I:C)-induced COX-2 mRNA and protein expression as well as PGE 2 and PGF 2α production. TLR3 activation is involved in the infection and inflammatory responses of pulp tissues, via MEK/ERK , and p38 signaling to mediate COX-2 expression as well as PGE 2 and PGF 2α production, contributing to the pathogenesis and progression of pulpal/periapical diseases. [ABSTRACT FROM AUTHOR]

Capsaicin induces the reversible opening of tight junctions (TJs) and enhances the delivery of hydrophilic macromolecules through a paracellular route. We previously revealed that TRPA1 is involved in the capsaicin-induced Ca2+ influx and TJ permeability increase, although there are no reports that capsaicin directly activates TRPA1. In this study, we investigated the upstream factors of TRPA1 using RNA-seq analysis, and found that the cyclooxygenase 2 (COX2) gene was upregulated by capsaicin. Cyclooxygenase 2 converts arachidonic acid (AA), a metabolite by phospholipase A2 (PLA2), to prostaglandins. Prostaglandin E2 (PGE2) production was stimulated by capsaicin, and capsaicin-induced Ca2+ influx was effectively inhibited by PLA2 and COX2 inhibitors. The AA-induced TJ permeability increase was inhibited by a TRPA1 antagonist, but the capsaicin- and AA-induced TJ permeability increases were hardly inhibited by a COX2 inhibitor. These results suggest that capsaicin-induced PLA2 activation and AA production are the important steps for the TJ permeability increase. [ABSTRACT FROM AUTHOR]

Objective: To investigate the underlying mechanism of antiinflammatory action of coumarin and eugenol in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Methods: RAW 264.7 cells were treated with 2.5 µg/mL of LPS, 50 µM of coumarin, and 50 µM eugenol for 24 h. The viability of the cells was assessed using MTT assay. The production of nitric oxide was determined using Griess reagent and DCFH-DA was used to measure the production of reactive oxygen species. The protein expression of NLRP3, IL-1ß, NF-κB, and cyclooxygenase 2 was assessed using Western blot analysis. Results: Coumarin and eugenol showed anti-inflammatory effects against LPS-induced inflammatory response by ameliorating the expression of NLRP3 inflammasome and NF-κB, which further led to a subsequent reduction in IL-1ß, nitric oxide, and reactive oxygen species. Conclusions: Coumarin and eugenol exert their anti-inflammatory activities by modulating the NLRP3 inflammasome pathway and NF-κB. These compounds may have promising therapeutic applications for the treatment of various inflammatory diseases. [ABSTRACT FROM AUTHOR]

In preclinical research, etodolac, a non-steroidal anti-inflammatory drug, affected transient receptor potential ankyrin 1 (TRPA1) activation. Yet, whether the in vitro interaction between etodolac and TRPA1 translates to altered TRPA1 functionality in vivo in human remains to be investigated. A randomized, double-blinded, celecoxib-controlled study was conducted to assess the effect of etodolac on TRPA1-mediated dermal blood flow (DBF) changes on the forearm of 15 healthy, male volunteers aged between 18 and 45 years. Over four study visits, separated by at least five days wash-out, a single or four-fold dose of etodolac 200 mg or celecoxib 200 mg was administered orally. Two hours post-dose, TRPA1 functionality was evaluated by assessing cinnamaldehyde-induced DBF changes. DBF changes were quantified and expressed in Perfusion Units (PUs) using laser Doppler imaging during 60 min post-cinnamaldehyde application. The corresponding area under the curve (AUC0–60min) was calculated as summary measure. Statistical analysis was performed using Linear mixed models with post-hoc Dunnett. Neither the single dose of etodolac nor celecoxib inhibited the cinnamaldehyde-induced DBF changes compared to no treatment (AUC0–60min ± SEM of 17,751 ± 1,514 PUs*min and 17,532 ± 1,706 PUs*min vs. 19,274 ± 1,031 PUs*min, respectively, both p=1.00). Similarly, also a four-fold dose of both compounds failed to inhibit the cinnamaldehyde-induced DBF changes (19,235 ± 1,260 PUs*min and 19,367 ± 1,085 PUs*min vs. 19,274 ± 1,031 PUs*min, respectively, both p=1.00). Etodolac did not affect the cinnamaldehyde-induced DBF changes, suggesting that it does not alter TRPA1 functionality in vivo in human. [ABSTRACT FROM AUTHOR]

Based on translational and epidemiological evidence, perioperative inhibition of beta-adrenergic and COX2 signaling can reduce the risk for post-surgical metastatic disease. Here we aimed to assess in a pilot study the impact of a perioperative combined COX-2 and beta-adrenergic blockade on long-term cancer outcomes in colorectal cancer patients undergoing curative surgery. Thirty-four newly diagnosed colorectal cancer patients without evidence of metastases enrolled in this double-blinded placebo-controlled randomized clinical trial (treatment, n = 16; placebo, n = 18). A 20-day oral treatment of propranolol and etodolac regimen was initiated 5 days before surgery. Beneficial effects on short-term molecular biomarkers of cancer progression were reported earlier. Here we present outcomes of five postoperative years of disease-free-survival and overall survival. Adverse event rates were equivalent between the two groups. Intent-to-treat analyses of 5-year follow-up showed that 2/16 (12.5%) vs 9/18 (50%) patients exhibited recurrence in treatment vs placebo groups, respectively (p = 0.033), and 2/16 (12.5%) vs 4/18 (22%) died (p = 0.467). In protocol compliant patients 0/11 (0%) vs. 8/17 (47%) exhibited recurrence in treatment vs. placebo groups, respectively (p = 0.007), and 0/11 (0%) and 3/17 (17.6%) died (p = 0.151). In this pilot clinical trial, a combined perioperative treatment with propranolol and etodolac significantly improved 5-year disease-free-survival. The small sample size and a single center study design merits caution in interpreting these results, specifically in estimating the effect-size. Larger studies in colorectal cancer are warranted and needed. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a condition which causes inflammation in synovialjoints. Patients experience pain, stiffness and swelling commonly in their hands and feet, but it can also be a systemic disease which affects the heart, lungs and eyes in some patients. It is more common in women than men, and the peak age for diagnosis is around 70 years; however, it can affect all ages. Early diagnosis and treatment should be prompt to reduce the chance of permanent damage to thejoints, as this will cause functional impairment and affect quality of life, and work/leisure activities (Heidari, 2011). A treat-to-target strategy aims to achieve remission or low disease activity by up-titrating medication from the point of diagnosis, thus minimising the impact of the disease (National Institute for Health and Care Excellence [NICE], 2018).This strategy only works if patients take the prescribed medication. The nurse's role is vital in supporting patients' understanding of the medications and advising on how to manage side-effects. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between single nucleotide polymorphisms in the COX2 gene (rs689466 and rs5275) and local and systemic signs and symptoms of teething. Material and Methods: Forty-four pairs of mothers-babies/toddlers were included. Erupted primary teeth were evaluated during clinical examination. Local and systemic signs and symptoms of teething were obtained from mothers' reporting via anamnesis. Samples of buccal cells were retrieved for DNA genotyping using real-time PCR. The T-test, Chi-square test, logistic regression, and haplotype analyses were applied. Results: Almost all mothers (95.5%) reported at least one local or systemic sign and symptom of teething. The most common was increased salivation (79.5%), diarrhea (72.3 %), and fever (70.5 %). The mean number of signs and symptoms per child was higher in boys than girls (mean = 5.1; SD= 1.5; p=0.008). Sleep disturbance (p=0.03) and loss of appetite (p=0.05) were more reported in boys. The rs689466 and rs5275 were not associated with signs and symptoms of teething (p>0.05). Conclusion: The single nucleotide polymorphisms in the COX2 gene (rs689466 and rs5275) were not associated with local and systemic signs and symptoms of teething. [ABSTRACT FROM AUTHOR]

Copyright of Arquivos de Neuro-Psiquiatria is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Coffee leaf extract (CLE) has the potential to inhibit intestinal inflammation and protect against dysfunction; however, the mechanisms for these bioactivities remain to be fully elucidated. This study investigated the capacity of fractions derived from CLE, prepared by solvent precipitation and liquid-liquid extraction, to mitigate intestinal barrier dysfunction induced by lipopolysaccharide using the Caco-2/U937 co-culture model. The results showed that water-soluble proteins and polysaccharides recovered from CLE were the primary contributors to triggering inflammation. Among the 11 fractions recovered, the ethyl acetate fraction (WEAC) showed the highest nitric oxide inhibitory activity (half-maximal inhibitory concentration (IC 50) = 155.08 ± 2.60 μg/mL). High-performance liquid chromatography analysis exhibited that WEAC contained the highest concentrations of phenolic compounds, including 3,5-dicaffeoylquinic acid, epicatechin, isoquercitrin, and phloridzin. WEAC significantly increased transepithelial electrical resistance values and inhibited the secretion of lactate dehydrogenase, tumor necrosis factor-α, and interleukin-8 in Caco-2/U937 co-culture cells (p < 0.05). Additionally, WEAC improved the expression of zonula occludens 1 and claudin 1 in apical Caco-2 cells, while reducing the expression of cyclooxygenase 2 in basolateral U937 cells. Molecular docking analysis revealed that 3,5-diCQA, isoquercetin, mangiferin, and epicatechin involved in regulating membrane permeability and anti-inflammatory biomarkers. Our results suggested that a phenolic-enriched WEAC fraction recovered from coffee leaves was a potential resource for preparation of nutraceuticals or functional foods designed to ameliorate intestinal barrier dysfunction and inflammation. [Display omitted] [ABSTRACT FROM AUTHOR]

BACKGROUND: Nonsteroidal anti-inflammatory drugs are an effective nonopiate option for pain control. However, the antiplatelet aggregation of cyclooxygenase-1 (COX-1) inhibitors presents a concern in that they may exacerbate bleeding in patients with solid organ injuries. OBJECTIVE: The aim of the study is to evaluate the impact of nonsteroidal anti-inflammatory drugs on blunt solid organ injury. We hypothesized that nonsteroidal anti-inflammatory drugs would not contribute to intra-abdominal bleed progression. METHODS: This is a retrospective cohort study of blunt solid organ injury evaluated from June 1, 2015, to June 30, 2019, at an urban midwestern Level I trauma center. Patients receiving and those not receiving nonsterioidal anti-inflammatory drugs were compared on intra-abdominal bleeding progression as assessed by surgical intervention, angioembolization, and blood transfusions. RESULTS: We analyzed 706 patients, of whom 206 were given nonsteroidal anti-inflammatory drugs during their hospital course. Compared with those who were not given nonsteroidal anti-inflammatory drugs, patients given nonsteroidal anti-inflammatory drugs were less likely to have an operation (odds ratio, OR 0.46, 95% confidence interval, CI [0.25, 0.85], p =.012) and were less likely to have an embolization (OR 0.27, 95% CI [0.11, 0.70], p =.004). There was no difference in the need for packed red blood cell transfusion between the nonsteroidal anti-inflammatory drug and non- nonsteroidal anti-inflammatory drug groups (95% CI [0.91, 1.99], p =.13). CONCLUSION: Patients given nonsteroidal anti-inflammatory drugs had a decreased likelihood of receiving an organ-specific procedure or needing a blood transfusion and had no difference in mortality. Our findings indicate that nonsteroidal anti-inflammatory drugs in patients with blunt solid organ injuries were not associated with an increased risk of adverse events related to intra-abdominal bleeding. [ABSTRACT FROM AUTHOR]

The expression of epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) has been reported in human nasopharyngeal and canine nasal carcinomas. The present study measured EGFR and COX-2 expression and calculated correlations between these proteins and clinical variables and outcomes in dogs with nasal carcinoma treated with radiation therapy. Before treatment, the immunohistochemistry of EGFR and COX-2 was performed in 67 biopsied tissues from canine nasal carcinomas. The correlations between these protein levels, clinical variables, and outcomes were evaluated. EGFR and COX-2 were detected in 88.1% and 82.1% of our samples, respectively. Neither EGFR nor COX-2 was associated with T stage and cribriform plate destruction. Dogs with low EGFR levels had a significantly longer survival time than dogs with high EGFR expression (P=0.043). The COX-2 expression level was not significantly associated with survival times after radiation therapy (P=0.653). Overexpression of EGFR is negatively correlated with survival in dogs with nasal carcinoma. Future studies should identify tumor biomarkers to develop therapeutic targets for effective treatments for canine nasal carcinomas. [ABSTRACT FROM AUTHOR]

The present study aims to explore the potential function of ketorolac tromethamine in treating osteoarthritis by examining its effects on interleukin-1 β (IL-1 β) -triggered cellular senescence in chondrocytes. More β-galactosidase (SA-β-Gal) positively stained cells, promoted cell fraction in the G0/G1 phase, increased release of matrix metalloproteinase (MMP) -3 and MMP-13, and upregulated cellular senescence-related genes (p21 and p53) were observed in IL-1 β-challenged HC-A cells, all of which were significantly reversed by 25 and 50 mg/mL ketorolac tromethamine. Furthermore, the upregulated cyclooxygenase-2 (COX-2) and elevated release of prostaglandin E2 in IL-1 β-challenged HC-A cells were dramatically repressed by ketorolac tromethamine. Lastly, the inhibitory effects of ketorolac tromethamine on the activation of SA-β-Gal and the upregulation of p21 and p53 were greatly abolished by the overexpression of COX-2. Collectively, ketorolac tromethamine repressed cellular senescence in aging articular chondrocytes by inhibiting COX-2. [ABSTRACT FROM AUTHOR]

Cyclooxygenase-2 (COX-2), a member of the Cyclooxygenase family, initiates the biosynthesis of prostanoids that regulates various cellular functions. Our pilot attempt revealed that the administration of etoricoxib, an inhibitor specific for COX-2, induces abnormal looping in the chicken heart. The present study attempts to reveal the mechanistic details of etoricoxib-induced abnormal cardiac looping. The activity of COX-2 was inhibited by administering 3.5 μg of etoricoxib into the egg's air cell on day zero of incubation. The gene and protein expression patterns of key mediators of heart development were then analyzed on day 2 (HH12) and day 3 (HH20). Reduced COX-2 activity altered the expressions of upstream regulators of organogenesis like Wnt11, BMP4, and SHH in the etoricoxib-exposed embryos. The observed expression shifts in the downstream regulators of myocardial patterning (MYOCD, HAND2, GATA4, GATA5, and GATA6) in the treated embryos corroborate the above results. In addition, the reduction in COX-2 activity hampered cardiomyocyte proliferation with a concomitant increase in the apoptosis rate. In conclusion, the collective effect of altered expression of signaling molecules of myocardial patterning and compromised cardiomyocyte turnover rate could be the reason behind the looping defects observed in the heart of etoricoxib-treated chick embryos. [ABSTRACT FROM AUTHOR]

Cyclooxygenases play a vital role in inflammation and are responsible for the production of prostaglandins. Two cyclooxygenases are described, the constitutive cyclooxygenase-1 and the inducible cyclooxygenase-2, for which the target inhibitors are the non-steroidal anti-inflammatory drugs (NSAIDs). Prostaglandins are a class of lipid compounds that mediate acute and chronic inflammation. NSAIDs are the most frequent choices for treatment of inflammation. Nevertheless, currently used anti-inflammatory drugs have become associated with a variety of adverse effects which lead to diminished output even market withdrawal. Recently, more studies have been carried out on searching novel selective COX-2 inhibitors with safety profiles. In this review, we highlight the various structural classes of organic and natural scaffolds with efficient COX-2 inhibitory activity reported during 2011–2021. It will be valuable for pharmaceutical scientists to read up on the current chemicals to pave the way for subsequent research. As a crucial enzyme for catalyzing the synthesis of prostaglandins, cyclooxygenase-2 (COX-2) was identified as a promising target for inflammation treatment. This review highlights the current progress of developing COX-2 inhibitors with various synthetic and natural structures as NSAIDs candidates. [Display omitted] [ABSTRACT FROM AUTHOR]

• Paracetamol during pregnancy may disrupt the developing sexual brain. • It inhibits the enzyme cyclooxygenase 2 and 3 (COX-2,3) to reduce pain and inflammation. • COX-2 is required for prenatal masculinization of the mPOA in the brain. • Paracetamol during brain development may cause iatrogenic sexual diversity and accompanying affective states. Although paracetamol is considered a safe medication during pregnancy at therapeutic doses, and despite animal studies showing no negative effects or reporting no adverse effects during pregnancy, there are no well-controlled clinical studies demonstrating the safety for both the mother and fetus. Therefore, its use in this situation depends on the physician's discretion. Its mechanism involves the inhibition of the enzymes cyclooxygenase 2 and 3 (COX-2,3), which modulate pain and inflammation by reducing prostaglandins. However, COX-2 and prostaglandins are also part of the molecular cascade organizing the brain towards a male direction during the prenatal period, and potentially during other periods as well. Herein, we hypothesize that paracetamol, a common medication used to treat fever and pain, may have long-term effects as a neuroendocrine disruptor of the sexual brain when administered during critical periods of development such as pregnancy, and to a lesser extent, during the neonatal, infancy, and puberty periods. Throughout this manuscript, we discuss the effects of COX-2,3 inhibition on the organization of the brain and sexual partner preference, particularly affecting masculinization of the medial preoptic area. We argue how administration of paracetamol in critical periods of plasticity might have an enduring effect on sexual behavior and other motivated behaviors. Impairments in each of these processes can directly impact individuals' sexual and mental health. We also discuss how sexual experience in adulthood ameliorated the impaired sexual preference of paracetamol-treated males, indicating an interaction between biological and environmental mechanisms. This manuscript is meant to warn professionals that although paracetamol is a very effective and safe drug, it is likely to disorganize the developing sexual brain, probably contributing to what we call iatrogenic sexual diversity. [ABSTRACT FROM AUTHOR]

Background: Thailand have developed a list of potentially inappropriate medications for patients with heart failure (PIMHF). However, its association with clinical outcomes has not been evaluated in real-world clinical practice. Objective: To examine the association between the prescription of any PIMHF and hospitalization from heart failure (HF). Methods: A 1:1 matched case-control study was conducted. Data on HF patients visiting the study hospitals during 2017-2019 were obtained from the electronic medical record database. Patients with a history of first hospitalization due to HF and those with a history of outpatient department visits or non-HF hospitalization were defined as cases and controls, respectively. The association of hospitalization from HF with the prescription of any PIMHF was expressed as the adjusted odds ratio (aOR) and 95% confidence interval (95%CI), calculated using a conditional logistic regression (CLR) model. Results: After matching, 1,603 pairs of case and control were generated for the analysis. In total, 21 of 47 PIMHF were found to have been prescribed. Compared with the reference group of patients not prescribed any of the 21 PIMHF, those who had been prescribed a PIMHF had an aOR of 1.47 [95%CI 1.02:2.13]. NSAIDs/COX-2 inhibitors, oral short-acting beta-2 agonists, medications that promote fluid overload, and medications that elevate blood pressure were the four medication classes associated with the increased risk of hospitalization from HF (aOR = 2.64, [95%CI 1.30:5.38], aOR = 4.87, [95%CI 1.17:20.29], aOR = 1.50, [95%CI 1.01:2.22], and aOR = 2.51, [95%CI 1.26:4.99], respectively). Conclusions: The prescription of any of the 21 PIMHF found to have been prescribed in this study may increase the risk of hospitalization from HF. The Thai PIMHF list may be used in pharmacy practice as an assessment tool for the appropriate use of medication in HF patients. [ABSTRACT FROM AUTHOR]

Xiaoer-Feire-Kechuan (XFK) is an 11-herb Chinese medicine formula to treat cough and pulmonary inflammation. The complicated composition rendered its chemical analysis and effective-component elucidation. In this study, we combined quantitative analysis and bioactivity test to reveal the anti-inflammatory constituents of XFK. First, UPLC-DAD and UHPLC/Q-Orbitrap-MS methods were established and validated to quantify 35 analytes (covering 9 out of 11 herbs) in different XFK formulations. Parallel reaction monitoring mode built in Q-Orbitrap-MS was used to improve the sensitivity and selectivity. Then, anti-inflammatory activities of the 35 analytes were analyzed using in vitro COX-2 inhibition assay. Finally, major analytes forsythosides H, I, A (8 – 10), and baicalin (15) (total contents varied from 21.79 to 91.20 mg/dose in different formulations) with significant activities (inhibitory rate ≥ 80%) were proposed as the anti-inflammatory constituents of XFK. The present study provided an effective strategy to discover effective constituents of multi-herb formulas. [Display omitted] ∙ Effective components were elucidated for XFK, a 11-herb formula. ∙Contents of 35 compounds were determined using UPLC-DAD and UHPLC/Q-Orbitrap-MS. ∙Parallel Reaction Monitoring mode was used to improve the sensitivity. ∙COX-2 inhibition assay was used to evaluate the bioactivity of 35 compounds. ∙Five major compounds were proposed as anti-inflammatory constituents for XFK. [ABSTRACT FROM AUTHOR]

It is estimated that over 80% of adults will have difficulty with low back pain during their lifetime. Back pain is generally described as acute, subacute, and chronic based on the duration of symptoms. Although most back pain complaints are self-resolved and not considered emergent, some do hold an increased level of urgency. Recognizing red flags early in the evaluation is crucial to expedite appropriate treatment. In the absence of red flags routine imaging should be avoided. A single standard of care for patients with low back pain has not been established. The myriad of diagnoses and treatment choices makes it difficult to develop a single algorithm for management. Nonspecific low back pain is a prevalent complaint in primary care and acute care settings. Most patients with acute/subacute low back pain will resolve regardless of the modality used or not used. [ABSTRACT FROM AUTHOR]

Mefenamic acid (MEF) is a non-steroidal anti-inflammatory drug (NSAID) which it is most often used for treating pain of some inflammation diseases in the short term as well as mild to moderate pain. Interestingly, mefenamic acid is known to have anti proliferative activity against various human cancers. In the present study, induction of apoptosis in oral malignant Burkitt's lymphoma (Raji) cell through caspase-3 and -9 pathways was examinated. The pure laboratory experimental with posttest only control group design was carried out in this study. The colorimetric assay caspase-3 and - 9 were used to know the apoptosis induction proofed by increasing the proteolytic activity. Double staining (AO-EB) was confirmed to detect cell apoptosis. To know the level protein of Cox-2 in the treated cells was analized by Western blotting. The doses of mefenamic acid were set as 0, 5, 10, 20 and 40 µg/mL. Results revealed the proteolytic activity of caspase-3 and -9 was markedly increased in cell treated with MEF at doses 10-40 µg/mL. Induction of apoptosis was also increased in double staining analysis at the same doses. However, down regulation of Cox-2 and overexpression of p27Kip-1 were detected in cells treatment. In conclusion, MEF induces apoptosis in oral malignant Burkitt's lymphoma through increased the proteolytic activity of caspase-3 and -9 followed by down regulation of Cox-2 and up regulation of p27Kip-1 targeting this molecule could represent a promising new therapeutic approach for this type of cancer. [ABSTRACT FROM AUTHOR]

Effective regulation of the inflammatory process is essential for pulp repair and regeneration. Meloxicam has anti-inflammatory activity in systemic administration. The purpose of this study is to observe effects of topically applied meloxicam on inflamed pulp and to explore its potential value in the treatment of pulpitis. The coronal pulp tissues of rat molars were stimulated with 10 mg/mL lipopolysaccharide (LPS group) and then treated with 500 μmol/L meloxicam (meloxicam group). The untreated pulp tissues were used as the control group. After 3 h of incubation in vitro , the gene expression of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) in each group was detected by real-time RT-PCR. The pulp tissues of each group were randomly subcutaneously implanted into nude mice, and 500 μmol/L meloxicam was injected into the subcutaneous pocket of the meloxicam group. Haematoxylin eosin staining, Masson staining and immunohistochemical staining were performed on samples after 3 days and 4 weeks retrieval, respectively. Compared with the LPS group, the mRNA expression levels of TNF-α and IL-6 of the meloxicam group were significantly reduced in vitro. The inflammatory response and cyclooxygenase-2 expression of the meloxicam group were decreased, and osteodentin-like tissue was generated in the pulp cross section of the meloxicam group in vivo. The topical application of meloxicam inhibits the inflammatory response of inflamed pulp and further promotes the formation of osteodentin-like tissues but fails to induce the formation of the pulp–dentin complex. Topically applied meloxicam has the potential to regulate pulp inflammation. [ABSTRACT FROM AUTHOR]