cyclooxygenase-II Research Articles

The antioxidant, anti-inflammatory, and anti-apoptotic effects of sesamin against cisplatin-induced renal and testicular toxicity in rats

Purpose The present study investigated the nephron-testicular protective effects of sesamin against cisplatin (CP)-induced acute renal and testicular injuries. Methods Thirty-two male Wistar rats were allocated to receive carboxymethylcellulose (0.5%, as sesamin vehicle), CP (a single i.p. 5 mg/kg dose), CP plus sesamin at 10 or 20 mg/kg orally for 10 days. Results Data analysis showed significant increases in serum urea, creatinine, interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α), as well as renal and testicular tissue malondialdehyde and nitric-oxide concentrations in CP-intoxicated rats in comparison to control animals. On the contrary, rats treated with CP only exhibited significantly lower (p < .05) serum testosterone, tissue glutathione, and activities of endogenous antioxidant enzymes compared to control rats. Histopathologically examining CP-intoxicated rats’ tissues using H&E and PAS stains showed atrophied glomeruli, interstitial inflammatory cells, atypic tubular epithelium with focal apoptosis, and reduced mucopolysaccharide content. Further, immunohistochemical staining of the same group revealed an increase in p53 and cyclooxygenase-II (Cox-II) expression in renal and testicular tissues. Treatment with sesamin alleviated almost all the changes mentioned above in a dose-dependent manner, with the 20 mg/kg dose restoring several parameters’ concentrations to normal ranges. Conclusions In brief, sesamin could protect the kidneys and testes against CP toxicity through its antioxidant, anti-inflammatory, and anti-apoptotic effects.

HPLC and GC Characterization of Dicliptera bupleuroides Aerial Parts and Evaluation of Its Anti-Inflammatory Potential in Vitro, in silico and in Vivo Using Carrageenan and Formalin Induced Inflammation in Rat Models.

The current study aimed to evaluate the anti-inflammatory activity of Dicliptera bupleuroides Nees aerial parts methanol extract and its different fractions namely hexane, chloroform, ethyl acetate and butanol in vitro using cyclooxygenase inhibitory assay (COX-2). In vivo anti-inflammatory evaluation was performed using carrageenan and formalin induced inflammation in rat models followed by molecular docking. High performance liquid chromatography (HPLC) and gas chromatography coupled with mass chromatography (GC/MS) analyses were used for chemical analyses of the tested samples. The tested samples showed significant inhibition in COX-2 inhibitory assay where methanol extract (DBM) showed the highest inhibitory potential at 100 μg/mL estimated by 67.86 %. At a dose of 400 mg/kg, all of the examined samples showed pronounced results in carrageenan induced acute inflammation in rat model at 4th h interval with DBM showed the highest efficiency displaying 65.32 % inhibition as compared to the untreated rats. Formalin model was employed for seven days and DBM exhibited 65.33 % and 69.39 % inhibition at 200 and 400 mg/kg, respectively approaching that of the standard on the 7th day. HPLC revealed the presence of caffeic acid, gallic acid and sinapic acid, quercetin and myricetin in DBM. GC/MS analysis of its hexane fraction revealed the presence of 16 compounds belonging mainly to fatty acids and sterols that account for 85.26 % of the total detected compounds. Molecular docking showed that hexadecanoic acid followed by decanedioic acid and isopropyl myristate showed the best fitting within cyclooxygenase-II (COX-II) while nonacosane followed by hexatriacontane and isopropyl myristate revealed the most pronounced fitting within the 5-lipoxygenase (5-LOX) active sites. Absorption, metabolism, distribution and excretion and toxicity prediction (ADMET/ TOPKAT) concluded that most of the detected compounds showed reasonable pharmacokinetic, pharmacodynamic and toxicity properties that could be further modified to be more suitable for incorporation in pharmaceutical dosage forms combating inflammation and its undesirable consequences.

Crosstalk between diacylglycerol kinase and protein kinase A in the regulation of airway smooth muscle cell proliferation

BackgroundDiacylglycerol kinase (DGK) regulates intracellular signaling and functions by converting diacylglycerol (DAG) into phosphatidic acid. We previously demonstrated that DGK inhibition attenuates airway smooth muscle (ASM) cell proliferation, however, the mechanisms mediating this effect are not well established. Given the capacity of protein kinase A (PKA) to effect inhibition of ASM cells growth in response to mitogens, we employed multiple molecular and pharmacological approaches to examine the putative role of PKA in the inhibition of mitogen-induced ASM cell proliferation by the small molecular DGK inhibitor I (DGK I).MethodsWe assayed cell proliferation using CyQUANT™ NF assay, protein expression and phosphorylation using immunoblotting, and prostaglandin E2 (PGE2) secretion by ELISA. ASM cells stably expressing GFP or PKI-GFP (PKA inhibitory peptide-GFP chimera) were stimulated with platelet-derived growth factor (PDGF), or PDGF + DGK I, and cell proliferation was assessed.ResultsDGK inhibition reduced ASM cell proliferation in cells expressing GFP, but not in cells expressing PKI-GFP. DGK inhibition increased cyclooxygenase II (COXII) expression and PGE2 secretion over time to promote PKA activation as demonstrated by increased phosphorylation of (PKA substrates) VASP and CREB. COXII expression and PKA activation were significantly decreased in cells pre-treated with pan-PKC (Bis I), MEK (U0126), or ERK2 (Vx11e) inhibitors suggesting a role for PKC and ERK in the COXII-PGE2-mediated activation of PKA signaling by DGK inhibition.ConclusionsOur study provides insight into the molecular pathway (DAG-PKC/ERK-COXII-PGE2-PKA) regulated by DGK in ASM cells and identifies DGK as a potential therapeutic target for mitigating ASM cell proliferation that contributes to airway remodeling in asthma.

Comparative antihyperglycemic, analgesic and anti-inflammatory potential of ethanolic aerial root extracts of Ceriops decandra and Ceriops tagal: Supported by molecular docking and ADMET analysis

Ceriops decandra (Griff.) (CD) and Ceriops tagal (Perr.) (CT) are two mangrove plants of the Sundarbans distributed along the coastal areas of South Asia and South Pacific Africa. Traditionally, these plants are used to treat diabetes, pain, angina, hemorrhage, and ulcer. In this study, we investigated the antioxidative, antihyperglycemic, analgesic, and anti-inflammatory potential of the aerial roots of CD and CT. At first, the antioxidative potential of CD and CT ethanolic extracts were investigated qualitatively and quantitatively by 2,2-diphenyl-1-picryl hydrazyl (DPPH) radical and hydrogen peroxide scavenging assays and by determining total antioxidant capacity. The total phenolic, flavonoid, tannin, and terpenoid contents of CD and CT were also estimated. The extracts' antihyperglycemic, analgesic, and anti-inflammatory potential were evaluated by oral glucose tolerance test, acetic acid-induced writhing test, and formaldehyde-induced paw-edema test, respectively. In vitro α-glucosidase and α-amylase enzyme inhibitory activities were also assessed. The CD and CT extracts were also analyzed using GCMS for the presence of phytochemicals. Then, molecular docking was carried out with α-glucosidase, α-amylase, cyclooxygenase-II (COX-II), 3-lipoxygenase (3-LOX) enzymes using the compounds found in GCMS analysis as well as the previously reported compounds from CD and CT. Finally, the pharmacokinetic and toxicological profiles of eight selected compounds were assessed with SwissADME and admetSAR server. In the antioxidative, antihyperglycemic, analgesic, and anti-inflammatory activity tests, CT extract showed a greater potential than CD extract. In addition, CT extract demonstrated higher α-glucosidase enzyme inhibitory activity in comparison to CD extract although CD extract exhibited better α-amylase enzyme inhibitory activity. Molecular docking studies revealed the presence of potentially bioactive compounds in both CD and CT. 2-(2-methylphenyl)-1-phenyl-(z)-1-propene of CD demonstrated good binding affinities for α-glucosidase, COX-II, and 3-LOX. In addition, 5S*,8S*,9S*,10R*,13S*)-18-hydroxy-16-nor-3-oxodolabr-4(18)-en-15-oic acid had high binding interactions for both α-glucosidase and α-amylase while 2′,5,5′-tetramethyl-1,1′-biphenyl, 2-methyl-4-(3′-phenylpropyl)piperidine and decandrin C had high binding interactions for both COX-II and 3-LOX. Finally, 5S*,8S*,9S*,10R*,13S*)-18-hydroxy-16-nor-3-oxodolabr-4(18)-en-15-oic acid, decandrin C, 2-(2-methylphenyl)-1-phenyl-(z)-1-propene and 2-methyl-4-(3′-phenylpropyl)piperidine demonstrated better pharmacokinetic and toxicological properties in the ADMET analysis compared to the others. Hence it can be concluded that the present study supports the traditional usage of CD and CT for diabetes and pain and reveals the presence of bioactive phytochemicals in both.

Browning plasticity of white adipose tissue in tree shrew during cold acclimation and rewarming

This study investigated the browning plasticity of white adipose tissue (WAT) in Tupaia belangeri during cold acclimation and rewarming in order to demonstrate the adaptation mechanism of tree shrews to environmental change. The experimental group was transferred to a cold temperature, 5 ± 1 °C, acclimated for 28 d, and then returned to 25 ± 1 °C for 28 d, while the control group was maintained at the acclimation temperature, 25 ± 1 °C, for 56 d. Body mass, food intake, resting metabolic rate (RMR), WAT mass, morphology and related gene expression in male T. belangeri were measured. The results showed that body mass, food intake and RMR increased significantly under cold acclimation. There was also a significant increase in WAT mass and expression of peroxisome proliferation receptor α (PPARα), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), cyclooxygenaseII (COXII), bone morphogenetic protein 7 (BMP7) and the PR domain containing 16 (PRDM16), all of which decreased to control levels after rewarming. Further, WAT cells showed more multilocule adipocytes during cold acclimation, which returned to control levels after rewarming. These results suggest that browning may appear in the WAT of T. belangeri during cold acclimation. The return to control levels of WAT cell characteristics and expression of the genes involved in WAT browning after rewarming demonstrates strong browning plasticity.

Pinitol attenuates LPS-induced pneumonia in experimental animals: Possible role via inhibition of the TLR-4 and NF-κB/IκBα signaling cascade pathway.

Pneumonia is a chronic disorder of the respiratory system associated with worsening quality of life and a significant economic burden. Pinitol, a plant cyclic polyol, has been documented for immune-inflammatory potential. The aim of present investigation was to evaluate the potential and possible mechanism of action of pinitol against lipopolysaccharide (LPS)-induced pneumonia in the experimental animal model. Pneumonia was induced in Sprague-Dawley rats by intratracheal administration of LPS (2 mg/kg). Animals were treated with either vehicle or dexamethasone or pinitol (5 or 10 or 20 mg/kg). Potential of pinitol against LPS-induced pulmonary insult was assessed based on behavioral, biochemical, molecular, and ultrastructural studies. Intratracheal instillation of LPS induced significant (P < .05) inflammatory infiltration inbronchoalveolar lavage fluid (BALF) and lung tissue reflected by elevated pleural effusion volume, lung edema, BALF polymorphonuclear leukocytes count and lung myeloperoxidase levels, which was attenuated by pinitol (10 and 20 mg/kg) administration. Pinitol also markedly (P < .05) inhibited LPS-induced alterations in electrocardiographic, hemodynamic changes, right ventricular, and lung function tests. The LPS-induced downregulated nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1), whereas upregulated transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), and inducible nitric oxide synthase (iNOs) lung messenger RNA expressions were significantly (P < .05) inhibited by pinitol. Western blot analysis suggested pinitol markedly (P < .05) decreased nuclear factor-κB (NF-κB), inhibitor of nuclear factor κB (IkBα), toll-like receptor 4 (TLR-4), and cyclooxygenase-II (COX-II) protein expressions in the lung. These findings were further supported by histological and ultrastructural analyses of lung tissue that showpinitol significantly (P < .05) ameliorates LPS-induced aberrations in lung tissue. In conclusion, pinitol attenuated LPS-induced pneumonia via inhibition of TLR-4 to downregulate the NF-κB/IκBα signaling cascade and thus ameliorated the production of proinflammatory cytokines (TNF-α, ILs, NLRP3, and TGF-β), inflammatory mediators (COX-II and iNOs) and elevated oxidative stress (Nrf-2 and HO-1).

Effects of troxerutin on vascular inflammatory mediators and expression of microRNA-146a/NF-κB signaling pathway in aorta of healthy and diabetic rats

This study has investigated the effect of a potent bioflavonoid, troxerutin, on diabetes-induced changes in pro-inflammatory mediators and expression of microRNA-146a and nuclear factor-kappa-B (NF-κB) signaling pathway in aortic tissue of type-I diabetic rats. Male Wistar rats were randomly divided into four groups (n = 6/each): healthy, healthy-troxerutin, diabetic, and diabetic-troxerutin. Diabetes was induced by streptozotocin injection (60 mg/kg; intraperitoneally) and lasted 10 weeks. Troxerutin (150 mg/kg/day) was administered orally for last month of experiment. Inflammatory cytokines IL-1β, IL-6, and TNF-α, as well as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM), cyclooxygenase-II (COX-II), and inducible-nitric oxide synthase (iNOS) were measured on aortic samples by enzyme-linked immunosorbent assay. Gene expressions for transcription factor NF-κB, interleukin-1 receptor-associated kinase-1 (IRAK-1), TNF receptor-associated factor-6 (TRAF-6), and microRNA-146a were determined using real-time polymerase chain reaction. Ten-week diabetes significantly increased mRNA levels of IRAK-1, TRAF-6, NF-κB, and protein levels of cytokines IL-1β, IL-6, TNF-α, adhesion molecules ICAM-1, VCAM, and iNOS, COX-II, and decreased expression of microRNA-146a as compared with healthy rats (p < 0.05 to p < 0.01). However, one month treatment of diabetic rats with troxerutin restored glucose and insulin levels, significantly decreased expression of inflammatory genes and pro-inflammatory mediators and increased microRNA level in comparison to diabetic group (p < 0.05 to p < 0.01). In healthy rats, troxerutin had significant reducing effect only on NF-κB, TNF-α and COX-II levels (p < 0.05). Beside slight improvement of hyperglycemia, troxerutin prevented the activation of NF-κB-dependent inflammatory signaling in the aorta of diabetic rats, and this response may be regulated by microRNA-146a.

A Novel Approach to Refractory Epilepsy by Targeting Pgp Peripherally and Centrally: Therapeutic Targets and Future Perspectives.

Refractory epilepsy is a type of epilepsy involving seizures uncontrolled by first or second- line anticonvulsant drugs at a regular therapeutic dose. Despite considerable growth in epileptic pharmacotherapy, one-third of the patients are resistant to current therapies. In this, the mechanisms responsible for resistant epilepsy are either increased expulsion of antiepileptic drugs (AEDs) by multidrug resistance (MDR) transporters from the epileptogenic tissue or reduced sensitivity of drug in epileptogenic brain tissue. The difficulty to treat refractory epilepsy is because of drug resistance due to cellular drug efflux, use of drug monotherapy, and subtherapeutic dose administration. Increased expression of Pgp is also responsible for resistance epilepsy or refractory epilepsy. Increased glutamate expression via inhibition of cyclooxygenase-II (COX-II) enzyme also upregulate P-glycoprotein (Pgp) expression and augment instance of recurrent seizures. Peripheral and central inhibition of Pgp is a powerful tool to control this drug resistant epilepsy. Drug resistance primarily involves multidrug resistance (MDR1) gene responsible for encoding P-glycoprotein (Pg- P1 or MDR1). Currently, there is no drug under clinical practice which inhibits MDR1. The present review cites some drugs like Calcium Channel Blockers (CCBs), COX-II inhibitors, and glutamate receptors antagonists that inhibit P-gp. The exploitation of these targets may emerge as a beneficial approach for patients with drug-resistant epilepsy. The present review further highlights the mechanistic role of Pgp in drug-resistant epilepsy, glutamate role in drug efflux, and management approach.

Urban Particulate Matter Enhances ROS/IL-6/COX-II Production by Inhibiting MicroRNA-137 in Synovial Fibroblast of Rheumatoid Arthritis.

Background: Rheumatoid arthritis (RA) has been associated with air pollution, possibly due to the augmentation of inflammatory effects. In this study, we aimed to determine the roles of inflammatory pathways and microRNA involved in the pathogenesis of RA fibroblast-like synoviocytes (FLS) inflammation induced by particulate matter. Methods: The inflammatory mediators, messenger RNAs, microRNAs and their interrelationships were investigated using western blotting, QPCR, ELISA and immunohistochemistry. Results: Particulate matter (PMs) induced an increase in the expression of interleukin-6 (IL-6) and cyclooxygenase-II (COX-II) in RA-FLS and microRNA-137 was found definitely to mediate the inflammatory pathways. PMs-induced generation of reactive oxygen species (ROS) in RA-FLS was attenuated by pretreatment with antioxidants. Nox-dependent ROS generation led to phosphorylation of ERK1/2, p38 and JNK, followed by downregulation of microRNA-137. In vivo studies, the joints of rats exposed to PMs revealed synovial fibroblast inflammation under pathologic examination and the expressions of IL-6 and COX-II were obviously increased. PMs exposure results in activated ROS-mediated mitogen-activated protein kinase (MAPK) signaling pathways and cause increased IL-6 and COX-II through downregulation of hsa-miRNA-137, which lead to inflammation and RA exacerbation. Conclusions: microRNA-137 plays an important role in PMs-induced RA acute exacerbation through MAPK signaling pathways and IL-6/COX-II activation. Targeting these mechanisms can potentially be used to develop new therapeutic strategies and prevention of RA inflammation in the future.

Exploring the Anti-Acne Potential of Impepho [Helichrysum odoratissimum (L.) Sweet] to Combat Cutibacterium acnes Virulence.

The Gram-positive bacterium Cutibacterium acnes (previously Propionibacterium acnes), plays an important role in the pathogenesis and progression of the dermatological skin disorder acne vulgaris. The methanolic extract of Helichrysum odoratissimum (L.) Sweet (HO-MeOH) was investigated for its ability to target bacterial growth and pathogenic virulence factors associated with acne progression. The gas chromatography–mass spectrometry (GC-MS) analysis of HO-MeOH identified α-humulene (3.94%), α-curcumene (3.74%), and caryophyllene (8.12%) as major constituents, which correlated with previous reports of other Helichrysum species. The HO-MeOH extract exhibited potent antimicrobial activity against C. acnes (ATCC 6919) with a minimum inhibitory concentration (MIC) of 7.81 µg/ml. It enhanced the antimicrobial activity of benzoyl peroxide (BPO). The extract showed high specificity against C. acnes cell aggregation at sub-inhibitory concentrations, preventing biofilm formation. Mature C. acnes biofilms were disrupted at a sub-inhibitory concentration of 3.91 µg/ml. At 100 µg/ml, HO-MeOH reduced interleukin-1α (IL-1α) cytokine levels in C. acnes-induced human keratinocytes (HaCaT) by 11.08%, highlighting its potential as a comedolytic agent for the treatment of comedonal acne. The extract exhibited a 50% inhibitory concentration (IC50) of 157.50 µg/ml against lipase enzyme activity, an enzyme responsible for sebum degradation, ultimately causing inflammation. The extract’s anti-inflammatory activity was tested against various targets associated with inflammatory activation by the bacterium. The extract inhibited pro-inflammatory cytokine levels of IL-8 by 48.31% when compared to C. acnes-induced HaCaT cells at 7.81 µg/ml. It exhibited cyclooxygenase-II (COX-II) enzyme inhibition with an IC50 of 22.87 µg/ml. Intracellular nitric oxide (NO) was inhibited by 40.39% at 7.81 µg/ml when compared with NO production in lipopolysaccharide (LPS)-induced RAW264.7 cells. The intracellular NO inhibition was potentially due to the 2.14 fold reduction of inducible nitric oxide synthase (iNOS) gene expression. The HO-MeOH extract exhibited an IC50 of 145.45 µg/ml against virulent hyaluronidase enzyme activity, which is responsible for hyaluronan degradation and scar formation. This study provides scientific validation for the traditional use of H. odoratissimum as an ointment for pimples, not only due to its ability to control C. acnes proliferation but also due to its inhibitory activity on various targets associated with bacterial virulence leading to acne progression.

Edaravone acts as a potential therapeutic drug against pentylenetetrazole-induced epilepsy in male albino rats by downregulating cyclooxygenase-II.

IntroductionThe effects of edaravone against pentylenetetrazole (PTZ)‐induced epilepsy in male albino rats were investigated. Edaravone is a well‐known commercial drug used in the treatment of strokes and amyotrophic lateral sclerosis (ALS). Antioxidant and free radical scavenging activities of edaravone have been reported in patients with ALS.MethodsIn this study, the experimental groups were as follows: sham, control, 5 mg/kg edaravone, and 10 mg/kg edaravone. Behavioral assessment, determination of biochemical markers, apoptosis, nitric oxide (NO), and mRNA and protein expression of cyclooxygenase‐II (COX‐II) were carried out. Seizure incidence, including generalized tonic–clonic seizure (GTCS) and minimal clonic seizure (MCS), was directly associated with PTZ administration in rats.ResultsEdaravone supplementation substantially increased MCS and GTCS latency in rats, and biochemical markers were significantly altered in the brain tissue of PTZ‐treated rats. Edaravone treatment normalized altered biochemical markers compared with the untreated control. Apoptosis and NO levels were significantly reduced by more than 50% compared to their respective controls. COX‐II mRNA was increased by 130% in PTZ‐treated rats, while edaravone supplementation reduced mRNA and protein expression of COX‐II by more than 20% and 40%, respectively. Immunohistochemistry indicated that COX‐II protein expression was reduced by 13.2% and 33.7% following supplementation with 5 and 10 mg/kg edaravone, respectively.ConclusionTaken together, our results suggest that edaravone functions by downregulating the levels of COX‐II and NO and is a potential candidate for the treatment of PTZ‐induced epilepsy.

Verification of the anti-inflammatory activity of the polyphenolic-rich fraction of Araucaria bidwillii Hook. using phytohaemagglutinin-stimulated human peripheral blood mononuclear cells and virtual screening

Ethnopharmacological relevanceAraucaria bidwillii Hook., the bunya pine, is an evergreen plant belonging to family Araucariaceae. Traditionally, its leaves and oleoresins have been used as herbal remedies to alleviate pain and inflammation. Based upon the frequent adverse effects accompanying synthetic anti-inflammatory drugs, this study will assess the anti-inflammatory activity of both the total methanol extract and the polyphenolic-rich fraction of A. bidwillii leaves. Materials and methodsThe anti-inflammatory activity was assessed in vitro using phytohaemagglutinin-stimulated human peripheral blood mononuclear cells (PBMCs). Isolation of the major compounds was conducted using various chromatographic techniques. Molecular modelling studies are performed on tumor necrosis factor-α (TNF-α), cyclooxygenase-II (COX-II) and 5-lipooxygenase (5-LOX). ResultsBoth the total methanol extract of Araucaria bidwillii leaves and its fraction revealed a dose-dependent manner in lowering the levels of IL-1β, IL-6 and TNF-α with an equivalent activity to that of indomethacin. In addition, the phytochemical investigation of the polyphenolic-rich fraction results in identification of agathisflavone-4′,7''-dimethyl ether (1), 7-O-methyl-6-hydroxyapigenin (2) and 4′,4′-di-O-methylamentoflavone (3) as the main components. In silico molecular modelling showed that agathisflavone-4′,7''-dimethyl ether (1) exhibited the fittest binding in TNF-α active sites, while 7-O-methyl-6-hydroxyapigenin (2) showed the highest inhibition in COX-II whereas 4′,4′-di-O-methylamentoflavone (3) is the most potent 5-LOX inhibitor. ConclusionThus, the leaves of Araucaria bidwillii could afford a potent anti-inflammatory agent that effectively ameliorates inflammation and its related hazards. This in turn consolidates the fact of using the leaves of Araucaria bidwillii to sooth inflammation in traditional medicine.

A REAL WORLD MANAGEMENT OF OSTEOARTHRITIS (OA) KNEE PATIENTS WHO UNDERGO TOTAL KNEE REPLACEMENT – A RETROSPECTIVE STUDY IN THAILAND. (ARMOR STUDY)

Background: In Thailand. Total knee replacement (TKA) is a common clinical intervention to manage patients with OA (osteoarthritis). Public and private hospitals tend to exhibit different patients of TKA use. Hence, knowledge with regard to TKA practice patterns, use and treatment outcomes in different hospitals in Thailand will improve the understanding of clinical management of OA and patient care. Objectives: The primary objective of the study was to examine the patterns of pain management during pre-operative, hospital admission for TKA, and postoperative periods (surgery to 3 months after discharge) for patients receiving TKA in public and private hospitals. The data were collected from various hospitals and subjected to analysis. Methods: This retrospective observational multi-center chart review study was conducted in public (n=2) and private (n=2) hospital in Thailand. A total of 220 patients diagnosed with knee OA (ICD-10 code, M17.0 and 17.1) who had undergone TKA were included in the study. The estimated ratio of patients from public and private hospitals was 1:1. Patient medical charts were accessed with the Ethics Committee’s approval. De-identified patient data were extracted from the chart and entered into a paper Case Report Form (CRF). Patients with history of major cardiovascular events and bilateral total knee replacement were excluded from the study. Results: At clinical baseline, cyclooxygenase-II (COX-II) inhibitors followed by traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) were the preferred drug classes for pain management irrespective of hospital type or age group. At operation, use of pain control drugs was comparable between public and private hospitals. The use of concomitant drugs such as antithrombotic agents was observed to be frequent in both the hospital types and different age groups. After surgery, use of opioids was the highest among other drug classes followed by COX-II inhibitors and tNSAIDs; however, the use of opioids decreased faster daily compared with COX-II inhibitors which remained constant until 4 days after surgery. Among discharge pain control medications, analgesics and opiods were used extensively followed by COX-II inhibitors; however, the use of NSAIDs was very limited because of associated complications. During the follow-up period, opiods were the most commonly prescriped drug class in both hospital types; use of COX-II inhibitors was significantly higher in private hospitals The same trend of drug use was observed by age group (both &gt; 70 and &lt; 70 years of age). The proportion of patients with complications was observed more in public hospitals as compared with private settings. In the present study, patients receiving COX-II-inhibitors combined with other pain control medications reported lower pain scored than average after surgery. The clinical outcome distribution among patients receiving multiple pain control drugs during discharge was observed to be better compared with other combined regimens or analgesics alone. Conclusion: Pain management is one of the most important and challenging aspects of TKA. The patterns of pain management during pre-operative, during operation and postoperative stages differed. The use of COX-II inhibitors followed by NSAIDs was observed to be higher in the pre-operative stage, while use of opioids was higher after surgery and follow-up period compared with COX-II inhibitors

Changes in PGE2 signaling after submandibulectomy alter post-tooth extraction socket healing.

Saliva is very important to oral health, and a salivary deficit has been shown to bring serious problems to oral health. There is scant information about the mechanisms through which salivary glands participate in post-tooth extraction socket healing. Therefore, the aim of the present study was to investigate the effect of submandibulectomy (SMx), consisting of the ablation of submandibular and sublingual glands (SMG and SLG, respectively), on PGE2 signaling and other bone regulatory molecules, such as OPG and RANKL, involved in tooth extraction socket healing. Male Wistar rats, 70 g body weight, were assigned to an experimental (subjected to SMx) or a control group (sham operated). One week later, the animals in both groups underwent bilateral extraction of the first mandibular molars. The effect of SMx on different stages of socket healing after tooth extraction (7, 14, and 30 days) was studied by evaluating some parameters of inflammation, including PGE2 and its receptors, and of bone metabolism, as well as by performing bone biomechanical studies. SMx increased TNFα and PGE2 content as well as cyclooxygenase-II (COX-II) expression in tooth socket tissue at almost all the studied time points. SMx also had an effect on mRNA expression of PGE2 receptors at the different time points, but did not significantly alter osteoprotegerin (OPG) and RANKL mRNA expression at any of the studied time points. In addition, an increase in bone mass density was observed in SMx rats compared with matched controls, and the structural and mechanical bone properties of the mandibular socket bone were also affected by SMx. Our results suggest that the SMG/SLG complex regulates cellular activation and differentiation by modulating the production of molecules intervening in tooth extraction socket repair, including the PGE2 signaling system, which would therefore account for the higher density and resistance of the newly formed bone in SMx rat.

Protective effects of phloridzin against methotrexate-induced liver toxicity in rats

BackgroundLiver is the largest internal organ concerning with metabolism, hormonal balance and clarifying of the toxins. One of the main complications of methotrexate (MTX) therapy was the hepatic injury. ObjectiveThis study was conducted to elucidate the possible protective effects of phloridzin (PHL) against MTX-induced hepatotoxicity as compared to standard agent N-acetylcysteine (NAC). Materials and methodsRats were randomly divided into a normal control group, a respective group (PHL 40mg/kg/day orally (p.o.) for 10 consecutive days), a hepatotoxicity control group (MTX 20mg/kg, i.p., once), and three treated groups received NAC (150mg/kg/day; a reference standard), PHL (40mg/kg/day) and PHL (80mg/kg/day) p.o. for 10 consecutive days, at the end of the day 3 of the experiment rats were administered MTX. Assessed biomarkers included serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) as liver function parameters, serum tumor necrosis factor-α (TNF-α) and cyclooxygenase-II (COX-II), as inflammatory biomarkers, hepatic total antioxidant capacity (TAC), thiobarbituric acid reactive substances (TBARS), glutathione reduced (GSH), nitrite (NO2−), catalase (CAT), glutathione-S-transferase (GST) and superoxide dismutase (SOD) as oxidative stress biomarkers. Furthermore, hepatic caspase-3 expression was assessed. Biochemical and molecular estimations reinforced by histopathological findings. ResultsRats pre-treated with PHL significantly reduced hepatic injury, evidenced by significant reductions in ALT, AST and LDH, TNF-α and COX-II levels, significant reductions in hepatic NO2− and TBARS levels, and significant elevations in hepatic TAC, GSH, GST, CAT and SOD levels. Additionally, downregulation of hepatic caspase-3 expression. Finally, histopathological results consistent with our previous findings. ConclusionPHL protects against hepatic injury in rats mainly through mitigation of oxidative stress, inflammation and apoptosis in hepatic tissues and may be promising to alleviate and early treatment of MTX-induced hepatoxicity in man.

Therapeutic effects of Laser and L-carnitine against amiodarone-induced pulmonary toxicity in adult male rats

Purpose: To compare the effects of laser and/or L-carnitine (LC) on amiodarone (AM)-induced lung toxicity in adult male rats. Methods: Lung toxicity was induced in 50 healthy male albino rats (150-180 g) by AM for 8 weeks. The rats were divided into 4 groups (7 per group): AM recovery, LC, laser, and laser + LC. After a 4-week exposure to laser and/or LC, key antioxidant enzymes, nitric oxide (NO), angiotensin II, cyclooxygenase-II (COX-II) and lipoxygenase (LOX) as well as oxidative stress and inflammation parameters were determined. Results: Administration of LC and/or laser exposure led to significant increases in reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and angiotensin II; and significant decreases in nitric oxide (NO) level and glutathione-S-transferase (GST) activity in the AM-treated rats when compared with the AM recovery group ( p ˂ 0.05). The LC and/or laser exposure also significantly inhibited COX II and LOX activities in the lungs, and brought about significant reduction in levels of TNF-α and lipid peroxidation (LPO), and significant increases in cytochrome levels ( p ˂ 0.05). Conclusion: These results indicate that AM induced pulmonary fibrosis in rats. However, AM withdrawal and treatment by LC and/or exposure to laser exerted mitigating effects against the AMinduced fibrosis. Keywords: Amiodarone, Lung toxicity, Laser; L-carnitine

Renoprotective effect of Hypericum perforatum against diabetic nephropathy in rats: Insights in the underlying mechanisms.

Oxidative stress and inflammation play a key role in the initiation and progression of diabetic nephropathy (DN). The present study aimed to investigate the possible protective effect of hypericum perforatum (HP) against DN. Rats were allocated into six groups: control, received normal saline; diabetic untreated (DM), received single dose of streptozotocin (STZ) after injection of nicotinamide (NA); gliclazide, received STZ,NA+gliclazide (10mg/kg); DM+HP50, DM+HP100, DM+HP200, received STZ,NA and HP 50, 100, 200mg/kg, respectively. Gliclazide and HP were administered daily via gavage for 8weeks. Serum glucose, insulin, kidney function and histopathological picture were assessed. Furthermore, oxidative/nitrosative stress, inflammatory cytokines, apoptotic and fibrotic markers were measured. Diabetic untreated group showed increase in serum glucose, urea, creatinine with albuminurea. Renal expression of protein for nuclear factor kappa-B (NF-кB), renal expression of inducible nitric oxide synthase (iNOS), cyclooxygenase II (COXII), collagen IV, fibronectin were elevated. Malondialdehyde (MDA), nitric oxide (NO), tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), intracellular adhesion molecule (ICAM-1), monocellular chemoattractant protein-1 (MCP-1), tumour growth factor- β (TGF-β), caspase-3 and cytochrome c contents were also increased consequently with decline of serum insulin, expression of peroxisome proliferator-activated receptor (PPARγ), renal reduced glutathione (GSH) content and superoxide dismutase (SOD) activity. Treatment with either gliclazide or HP mitigated the deleterious effects of STZ on the tested parameters. These findings indicate for the first time that HP may have a renoprotective effect against DN through reduction of oxidative/nitrosative stress, enhancement of antioxidant defense mechanisms, decline of inflammatory cytokines, antifibrotic, antiapoptotic and blood glucose lowering properties.

Andrographolide Activates Keap1/Nrf2/ARE/HO-1 Pathway in HT22 Cells and Suppresses Microglial Activation by Aβ42 through Nrf2-Related Inflammatory Response.

Therapeutic approach of Alzheimer's disease (AD) has been gradually diversified. We examined the therapeutic and preventive potential of andrographolide, which is a lactone diterpenoid from Andrographis paniculata, and focused on the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated heme oxygenase (HO)-1-inducing effects and the inhibitory activity of amyloid beta (Aβ)42-induced microglial activation related to Nrf2 and nuclear factor κB (NF-κB)-mediated inflammatory responses. Andrographolide induced the expression and translocation of Nrf2 from the cytoplasm to the nucleus, thereby activating antioxidant response element (ARE) gene transcription and HO-1 expression in murine hippocampal HT22 cells. Andrographolide eliminated intracellular Aβ42 in BV-2 cells and decreased the production of interleukin (IL)-6, IL-1β, prostaglandin (PG)E2, and nitric oxide (NO) because of artificial phagocytic Aβ42. It decreased pNF-κB accumulation in the nucleus and the expression of inducible nitric oxide synthase (i-NOS) and cyclooxygenase II (COX-II) in the microglial BV-2 cell line. In summary, andrographolide activates Nrf2-mediated HO-1 expression and inhibits Aβ42-overexpressed microglial BV-2 cell activation. These results suggested that andrographolide might have the potential for further examination of the therapeutics of AD.

Ameliorated Chemotherapeutic Potential of Diverse Dose Flouropyrimidine Therapy By Etodolac via NF-?B Pathway, PPAR-? Expression and COX-II Inhibition in DMH Induced Colon Cancer Rats

Background: 5-Flurorouracil (5-FU) chemotherapy has been one of the extensively employed standard therapies for the treatment of colon cancer. Various molecular interventions and dose modulations in the form of adjuvant therapies has been exploited for better therapeutic efficacy and low adverse effects to improve overall survival rate in advanced colorectal cancer. Non-steroidal anti-inflammatory drugs (NSAIDs) have shown huge potential to supplement the classical chemotherapeutic regimens in order to achieve better cytotoxic potency against cancer cells and specifically through targeting of multi apoptotic pathways and inflammatory markers. Methods: The present investigation was carried out to study the effect of etodolac (ETD) on the therapeutic spectrum of 5-FU in colon cancer in order to regress the dose related adverse potential by modulating the 5-FU dose in 1,2 dimethylhydrazine (DMH) induced colon cancer rats and to explore the molecular apoptotic pathways involved. Results: Diverse dose combination therapy of 5-FU plus ETD (FEC1; high dose combination of 5-FU and ETD in ratio of 4:1), FEC2; medium dose combination of 5-FU and ETD in ratio of 3:1) and (FEC3; low dose combination of 5-FU and ETD in ratio of 2:1) showed significant decrease in the tumor burden in a dose dependent manner (i.e. FEC1>FEC2>FEC3) in comparison to monotherapy. Further, the combination therapy also showed significantly enhanced apoptosis in DMH induced colon cancer rats in comparison to monotherapy. Conclusions: ETD could be a useful intervention as adjuvant therapy for increasing the cytotoxic potential of 5-FU at lower therapeutic dose. The present study showed the immense application and future role of ETD as an adjuvant agent in fluorouracil based combination strategy to widen therapeutic spectrum and increased apoptosis in cancer cells. To best of our knowledge, this report for the first time elucidates the enhanced therapeutic efficacy of low dose 5-FU in combination with ETD via nuclear factor kappa-B (NF-κB), peroxisome proliferator activator receptor-gamma (PPAR-γ), tumor necrosis factoralpha (TNF-α) and cyclooxygenase–II (COX-II) pathway in DMH induced colon cancer rats. Keywords: Colon cancer, DMH, ETD, 5-FU, COX-II inhibitor.

LPS로 자극한 RAW264.7 대식세포에서 보리순 에탄올 추출물의 항염증 효과

This study investigated the anti-inflammatory activity of barley leaf extract in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and hairless mice. Pre-treatment with barley leaf extract significantly inhibited the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-II (COX-II) in a dose-dependent manner in LPS-stimulated RAW264.7 cells. Barley leaf extract also significantly inhibited the secretion of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Moreover, phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear translocation of nuclear factor-kappa B (NF-κB) were strongly suppressed by barley leaf extract in LPS-stimulated cells. In hairless mice, barley extract significantly decreased the pathological phenotypes of contact dermatitis, such as erythema, edema, and scabs. These results indicate that barley leaf extract has an anti-inflammatory effect and therefore a possible role in the treatment of inflammatory diseases or in functional cosmetics.