Inhibited Edema Formation Research Articles

Design, Synthesis, and In Vivo Evaluation of a New Series of Indole-Chalcone Hybrids as Analgesic and Anti-Inflammatory Agents.

Indole-chalcone hybrids have burst into prominence as potent weapons in the battle against pain and inflammation due to their unique features, allowing these ligands to form pivotal interactions with biological targets. In this context, the base-catalyzed Claisen-Schmidt condensation of 3',4'-(methylenedioxy)acetophenone with heteroaromatic aldehydes carrying an indole scaffold yielded new chalcones (1-7). The central and peripheral antinociceptive activities of all chalcones (compounds 1-7) at the dose of 10 mg/kg (i.p.) were evaluated by hot plate (supraspinal response), tail immersion (spinal response), and acetic acid-induced writhing tests in mice. The anti-inflammatory activities of compounds 1-7 were also investigated by means of a carrageenan-induced mouse paw edema model. The results revealed that compounds 1-7 extended the latency of response to thermal stimulus significantly in a hot-plate test similar to dipyrone (300 mg/kg; i.p.), the positive control drug. However, only compounds 2-7 were found to be significantly effective in the tail-immersion test. Compounds 1-7 also significantly showed analgesic effect by reducing the number of writhes and anti-inflammatory activity by inhibiting edema formation at different time intervals and levels. 1-(1,3-Benzodioxol-5-yl)-3-(1-methyl-1H-indol-2-yl)prop-2-en-1-one (4) drew attention by providing the highest efficacy results in both acute analgesia and inflammation models. Based on the in silico data acquired from the QikProp module, compound 4 was predicted to possess favorable oral bioavailability and drug-like properties. Taken together, it can be concluded that chalcones (1-7), especially compound 4, are outstanding candidates for further research to investigate their potential use in the management of pain and inflammation.

Combined effect of trifluoperazine and sodium cromoglycate on reducing acute edema and limiting lasting functional impairments after spinal cord injury in rats

Edema formation is one of the very first events to occur after spinal cord injury (SCI) leading to an increase of the intrathecal pressure and consequently to serious spinal tissue and functional impairments. Current edema treatments are still symptomatic and/or non-specific. Since edema formation mechanisms are mainly described as vasogenic and cytotoxic, it becomes crucial to understand the interplay between these two subtypes. Acting on key targets to inhibit edema formation may reduce secondary damage and related functional impairments. In this study, we characterize the edema kinetic after T9–10 spinal contusion. We use trifluoperazine (TFP) to block the expression and the functional subcellular localization of aquaporin-4 supposed to be implicated in the cytotoxic edema formation. We also use sodium cromoglycate (SCG) to deactivate mast cell degranulation known to be implicated in the vasogenic edema formation. Our results show a significant reduction of edema after TFP treatment and after TFP-SCG combined treatment compared to control. This reduction is correlated with limited onset of initial sensorimotor impairments particularly after combined treatment. Our results highlight the importance of potential synergetic targets in early edema therapy after SCI as part of tissue sparing strategies.

Efficacy of low-intensity pulsed ultrasound for the treatment of viral pneumonia: study protocol for a randomized controlled trial

BackgroundViral pneumonia has always been a problem faced by clinicians because of its insidious onset, strong infectivity, and lack of effective drugs. Patients with advanced age or underlying diseases may experience more severe symptoms and are prone to severe ventilation dysfunction. Reducing pulmonary inflammation and improving clinical symptoms is the focus of current treatment. Low-intensity pulsed ultrasound (LIPUS) can mitigate inflammation and inhibit edema formation. We aimed to investigate the efficacy of therapeutic LIPUS in improving lung inflammation in hospitalized patients with viral pneumonia.MethodsSixty eligible participants with clinically confirmed viral pneumonia will be assigned to either (1) intervention group (LIPUS stimulus), (2) control group (null stimulus), or (3) self-control group (LIPUS stimulated areas versus non-stimulated areas). The primary outcome will be the difference in the extent of absorption and dissipation of lung inflammation on computed tomography. Secondary outcomes include changes in lung inflammation on ultrasonography images, pulmonary function, blood gas analysis, fingertip arterial oxygen saturation, serum inflammatory factor levels, the sputum excretion volume, time to the disappearance of pulmonary rales, pneumonia status score, and course of pneumonia. Adverse events will be recorded.DiscussionThis study is the first clinical study of the efficacy of therapeutic LIPUS in the treatment of viral pneumonia. Given that the current clinical recovery mainly depends on the body’s self-limiting and conventional symptomatic treatment, LIPUS, as a new therapy method, might be a major advance in the treatment of viral pneumonia.Trial registrationChiCTR2200059550 Chinese Clinical Trial Registry, May 3, 2022.

Antinociceptive effect and identification of berberine alkaloid in Berberis ruscifolia extracts

Ethnopharmacological relevanceAerial parts (leaves and stems) of Berberis ruscifolia Lam. are a usual preparation as an analgesic, anti-inflammatory, antimalarial, antibacterial, and digestive in folk medicine. However, there were no previous studies of its chemical composition and biological activity related to analgesic effects. The objective of the studyThe evaluation of the anti-nociception of the infusion (I), the decoction (D), and the ethanolic extract (EE) obtained from aerial parts of B. ruscifolia and its main chemical constituent in them, in mouse models. Material and methodsThe chemical constituent of B. ruscifolia extracts was evaluated and quantified by LC-MS and HPLC methodology. The inhibition of nociception in mice was analyzed by formalin and acetic acid-induced contortions tests. Also, when the formalin test was performed to evaluate the antinociceptive activity, the inhibition of edema formation and the antipyretic effect of each extract were simultaneously evaluated in the same experiment. For the oral administration in the in vivo assays, doses ranging from 10 to 1000 mg/kg and 10–30 mg/kg were used for extract and the chemical compound, respectively. ResultsThe presence of berberine (Berb) was identified in the three evaluated extracts where the EE showed the highest content of this compound getting a yield of 2%, while in the I and D, Berb is present at 0.2%. The three extracts promoted a reduction of the contortions induced by acetic acid, being observed in EE the highest activity with 63 ± 6% of significant inhibition of the nociceptive behavior at a dose of 300 mg/kg, while D significantly inhibited 32 ± 12% at the same dose and for I at a dose of 1000 mg/kg an inhibition of 44 ± 8% was observed. Likewise, in the formalin trial, I and EE reduced nociception at a dose of 1000 (31 ± 5%) and 300 (35 ± 3%) mg/kg, respectively in the neurogenic phase, while in the second phase of the experiment, all the extracts evaluated showed an antinociceptive effect, with significant inhibition of I of 54 ± 6% and D of 44 ± 5% at a dose of 1000 mg/kg and for EE showed a 63 ± 2% inhibition at a dose of 300 mg/kg being the one with the highest antinociceptive activity. These extracts showed no inhibition in temperature and formalin-injected paw edema formation when compared to the control. As for Berb, at a 30 mg/kg dose, it showed significant inhibition of 70 ± 5% in the acetic acid-induced contortion test. ConclusionAltogether, the present results evidenced the analgesic properties of B. ruscifolia, scientific information presented for the first time, and also provided important knowledge not reported so far about the chemical composition of its extracts, by identifying the presence of Berb in them. Finally, we were able to conclude that the analgesic effect demonstrated by this medicinal plant is partly due to the presence of Berb.

Anti-inflammatory activity and metabolites profiling of aqueous stem bark extract of Ficus vogelii (Moraceae) in rats

IntroductionFicus vogelii is a terrestrial tree, used in Cameroonian pharmacopeia to treat various inflammatory diseases such as rheumatism. Accordingly, the present work aimed at evaluating anti-inflammatory potential of Ficus vogelii aqueous extract and identified phytochemicals of interest. MethodsThe characterization of the phytochemicals was carried out by HPLC-ESI-MSn. The anti-inflammatory potential of the aqueous extract of Ficus vogelii (100, 200, 400 and 600 mg/kg) was investigated using acute inflammatory models induced by chemicals, and chronic inflammatory models induced by formalin and Complete Freund Adjuvant (CFA) in rats. ResultsFicus vogelii significantly (p < 0.001) inhibited carrageenan-induced rat paw edema with maximum inhibitions of 75.86% (0.5 h), 82.41% (3 h) and 90.18% (6 h) at 100 mg/kg. This extract significantly (p < 0.001) reduced paw edema induced by histamine (54.10%), serotonin (54.06%), dextran (38.90%) and arachidonic acid (56.95%) respectively up to 1 h. Similarly, the extract significantly (p < 0.001) inhibited edema formation on the left paws of rats from day 2 up to 7 days post formalin injection, and significantly (p < 0.001) decreased paw edema of CFA-treated rats with the highest effect of 67.85% and 77.07% obtained on day 13 and day 21. Furthermore, the extract showed an antioxidant potential by improving the tissue levels of malondialdehyde, nitrites, superoxide dismutase and catalase. Phytochemicals analysis showed several compounds with isocitric acid (19%), trihydroxy-octadecenoic acid (18%), followed by dihydroxybenzoic acid, chlorogenic acid and vicenin-2 (8–9%). Oxylipins represented approximately 25% of the extract, thus being some of the compounds responsible for the observed activity. ConclusionThese results suggest that Ficus vogelii have anti-inflammatory effects on acute and chronic inflammation conditions.

Rosmarinus officinalis extract-loaded emulgel prevents UVB irradiation damage to the skin

UVB-irradiation increases the risk of various skin disorders, therefore leading to inflammation and oxidative stress. In this sense, antioxidant-rich herbs such as Rosmarinus officinalis may be useful in minimizing the damage promoted by reactive oxygen species. In this work, we report the efficacy of a R. officinalis hydroethanolic extract (ROe)-loaded emulgel in preventing UVB-related skin damage. Total phenols were determined using Folin-Ciocalteu assay, and the main phytocomponents in the extract were identified by UHPLC-HRMS. Moreover, in vitro sun protection factor (SPF) value of ROe was also assessed, and we investigated the in vivo protective effect of an emulgel containing ROe against UVB-induced damage in an animal model. The ROe exhibited commercially viable SPF activity (7.56 ± 0.16) and remarkable polyphenolic content (24.15 ± 0.11 mg (Eq.GA)/g). HPLC-MS and UHPLC-HRMS results showcased that the main compounds in ROe were: rosmarinic acid, carnosic acid and carnosol. The evaluation of the in vitro antioxidant activity demonstrated a dose-dependent effect of ROe against several radicals and the capacity to reduce iron. Therefore, we demonstrated that topical application of the formulation containing ROe inhibited edema formation, myeloperoxidase activity, GSH depletion and maintained ferric reducing (FRAP) and ABTS scavenging abilities of the skin after UVB exposure.

Antidiarrheal and Cardio-Depressant Effects of Himalaiella heteromalla (D.Don) Raab-Straube: In Vitro, In Vivo, and In Silico Studies.

Himalaiella heteromalla (D.Don) Raab-Straube is a commonly used remedy against various diseases. Crude extract and fractions of H. heteromalla were investigated for a gastrointestinal, bronchodilator, cardiovascular, and anti-inflammatory activities. H. heteromalla crude extract (Hh.Cr) relaxed spontaneous contractions and K+ (80 mM)-induced contraction in jejunum tissue dose-dependently. The relaxation of K+ (80 mM) indicates the presence of Ca++ channel blocking (CCB) effect, which was further confirmed by constructing calcium response curves (CRCs) as they caused rightward parallel shift of CRCs in a manner comparable to verapamil, so the spasmolytic effect of Hh.Cr was due to its CCB activity. Application of Hh.Cr on CCh (1 µM) and K+ (80 mM)-induced contraction in tracheal preparation resulted in complete relaxation, showing its bronchodilator effect mediated through Ca++ channels and cholinergic antagonist activity. Application of Hh.Cr on aortic preparations exhibited vasorelaxant activity through angiotensin and α-adrenergic receptors blockage. It also showed the cardio suppressant effect with negative chronotropic and inotropic response in paired atrium preparation. Similar effects were observed in in vivo models, i.e., decreased propulsive movement, wet feces, and inhibition of edema formation.

Anti-inflammatory secondary metabolites from Scrophularia kotschyana.

The species belonging to Scrophularia genus grow mainly in Irano-Turanian and Mediterranean regions and have been used as folk remedy for inflammatory-related diseases since ancient times. The present study was aimed to evaluate the anti-inflammatory activity of the extracts of Scrophularia kotschyana as well as the isolated compounds. The aerial parts and the roots of the plant were separately extracted with methanol. Anti-inflammatory activities of both extracts were evaluated with formalin test in mice. As the methanolic extract of the aerial parts significantly (p < .05) inhibited inflammation, it was then submitted to successive solvent extractions with n-hexane, dichloromethane, ethyl acetate and n-butanol to yield subextracts. Anti-inflammatory activities of the subextracts were evaluated within the same test system. Among the subextracts tested, the n-butanol subextract produced a significant (p < .05) anti-inflammatory activity at all doses (5, 10, and 30mg/kg, ip.). Sequential chromatographic separation of the n-butanol subextract yielded 8-O-acetyl-4'-O-(E)-p-coumaroylharpagide, 8-O-acetyl-4'-O-(Z)-p-coumaroylharpagide, β-sitosterol 3-O-β-glucopyranoside, apigenin 7-O-β-glucopyranoside, apigenin 7-O-rutinoside, luteolin 7-O-β-glucopyranoside and luteolin 7-O-rutinoside. The anti-inflammatory activities of the isolates were evaluated at 5mg/kg dose. Luteolin 7-O-β-glucopyranoside and apigenin 7-O-rutinoside caused a significant (p < .05) inhibition of oedema formation.

TRPV1 Blocker HCRG21 Suppresses TNF-α Production and Prevents the Development of Edema and Hypersensitivity in Carrageenan-Induced Acute Local Inflammation.

Currently the TRPV1 (transient receptor potential vanilloid type 1) channel is considered to be one of the main targets for pro-inflammatory mediators including TNF-α. Similarly, the inhibition of TRPV1 activity in the peripheral nervous system affects pro-inflammatory mediator production and enhances analgesia in total. In this study, the analgesic and anti-inflammatory effects of HCRG21, the first peptide blocker of TRPV1, were demonstrated in a mice model of carrageenan-induced paw edema. HCRG21 in doses of 0.1 and 1 mg/kg inhibited edema formation compared to the control, demonstrated complete edema disappearance in 24 h in a dose of 1 mg/kg, and effectively reduced the productionof TNF-α in both doses examined. ELISA analysis of blood taken 24 h after carrageenan administration showed a dramatic cytokine value decrease to 25 pg/mL by HCRG21 versus 100 pg/mL in the negative control group, which was less than the TNF-α level in the intact group (40 pg/mL). The HCRG21 demonstrated potent analgesic effects on the models of mechanical and thermal hyperalgesia in carrageenan-induced paw edema. The HCRG21 relief effect was comparable to that of indomethacin taken orally in a dose of 5 mg/kg, but was superior to this nonsteroidal anti-inflammatory drug (NSAID) in duration (which lasted 24 h) in the mechanical sensitivity experiment. The results confirm the existence of a close relationship between TRPV1 activity and TNF-α production once again, and prove the superior pharmacological potential of TRPV1 blockers and the HCRG21 peptide in particular.

Gastro-protective actions of Aloe barbadensis Miller mitigate ethanol-induced gastric injury in rats

Purpose: To investigate the gastroprotective effect of leaf extract of Aloe barbadensis on ethanolinduced gastric ulcer in rats.Methods: Healthy male Wistar rats (n = 30) weighing 180 - 220 g (mean weight = 200 ± 20 g) were randomly assigned to 6 groups (5 rats/group): control group, gastric ulcer group, two Aloe barbadensis extract groups (250 and 500 mg/kg), cimetidine group and indomethacin group. Gastric ulcer was induced via oral injection of absolute ethanol at a dose of 1 mL/kg after a 24-h fast. Gross evaluation, determination of gastric juice acidity and histological examination of gastric tissue were carried out.Results: Treatment of gastric ulcer rats with Aloe barbadensis extract significantly reduced ulcerated area (UA), ulcer index (UI), and acidity of gastric juice (p &lt; 0.05). Injection of 1 % carrageenan into rat hind paw led to a time-dependent increase in paw volume which peaked 3 h after injection. However, the Aloe barbadensis extract significantly and dose-dependently reduced the volume of inflamed paw, and inhibited edema formation (p &lt; 0.05). It also markedly reduced or completely eliminated edema and leucocyte infiltration. Moreover, treatment of gastric ulcer rats with Aloe barbadensis leaf extract led to significant and dose-dependent reduction in gastric tissue MDA level (p &lt; 0.05). Histological examination of the gastric wall showed that control rats had severe injury in gastric mucosa,accompanied by edema and leucocytes infiltration, relative to rats pretreated with extract which showed marked gastric protection and inhibition of edema and leucocytes infiltration. Moreover, the extract treatment protected the gastric surface against ulceration as indicated by reduced lesions in the treated rat model.Conclusion: These results show that Aloe barbadensis mitigates ethanol-induced gastric injury in rats via inhibition of lipid peroxidation and inflammation. Thus, the extract has potentials for development into a therapeutic agent for the management of gastric ulcer.&#x0D; Keywords: Aloe barbadensis, Gastric ulcer, Gastric mucosa, Inflammation, Lipid peroxidation

5,6-dihydroxy-8Z,11Z,14Z,17Z-eicosatetraenoic acid accelerates the healing of colitis by inhibiting transient receptor potential vanilloid 4-mediated signaling.

5,6-dihydroxy-8Z,11Z,14Z,17Z-eicosatetraenoic acid (5,6-DiHETE) is an eicosapentaenoic acid-derived lipid metabolite, which we previously detected in inflamed mouse colon. In this study, we investigated the pathophysiological roles of 5,6-DiHETE in murine colitis and its underlying mechanisms of action, focusing on the effects on transient receptor potential vanilloid (TRPV) channel activity. Oral administration of dextran sodium sulfate (DSS, 2%, for 4days) caused colon inflammation, which peaked on day 7 and gradually declined by day 18. 5,6-DiHETE concentration in colon tissue was significantly increased during the healing phase of colitis (days 9 to 18). In vitro study showed that pretreatment with 5,6-DiHETE (0.1-1μM, 30minutes) significantly inhibited endothelial barrier disruption induced by a TRPV4 agonist (GSK1016790A, 50nM). Intracellular Ca2+ imaging also showed that pretreatment with 5,6-DiHETE (1μM, 10minutes) reduced GSK1016790A-induced intracellular Ca2+ increase in HEK293T cells overexpressing TRPV4. In vivo, intraperitoneal administration of 5,6-DiHETE (50µgkg-1 day-1 ) during the healing phase accelerated the recovery from DSS-induced colitis. Pathological studies showed that the administration of 5,6-DiHETE inhibited edema formation and leukocyte infiltration in inflamed colon tissue. In conclusion, we identified 5,6-DiHETE as a novel endogenous TRPV4 antagonist, and we also demonstrated that its administration promotes the healing of colitis by inhibiting inflammatory responses.

Pinus thunbergii Parl. Extracts Reduce Acute Inflammation by Targeting Oxidative Stress

Pinus thunbergii Parl. (PTP) has traditionally been used for edible and medicinal purposes to treat several disorders, including diabetes and neuralgia. Therefore, this study sought to evaluate the inhibitory effects of PTP leaf ethanol extracts on acute inflammation. Moreover, the reactive oxygen species (ROS) scavenging activity, superoxide dismutase (SOD) activity, lipopolysaccharide (LPS)-induced nitric oxide (NO) generation, and H2O2-induced lipid peroxidation capacity of PTP were assessed in vitro in RAW 264.7 macrophages. Our results suggest that PTP prevents cell damage caused by oxidative free radicals and downregulates the expression of LPS-induced inflammation-associated factors including inducible nitric oxidase synthetase (iNOS), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2). PTP inhibited NO production by 53.5% (P < 0.05) and iNOS expression by 71.5% (P < 0.01) at 100 µg/mL. PTP at 100 µg/mL also inhibited ROS generation by 58.2% (P < 0.01) and SOD activity by 29.3%, as well as COX-2 expression by 83.3% (P < 0.01) and PGE2 expression by 98.6% (P < 0.01). The anti-inflammatory effects of PTP were confirmed in vivo using an arachidonic acid (AA)-induced ear edema mouse model. Ear thickness and myeloperoxidase (MPO) activity were evaluated as indicators of inflammation. PTP inhibited edema formation by 64.5% (P < 0.05) at 1.0 mg/ear. A total of 16 metabolites were identified in PTP extracts and categorized into subgroups, including two phenolic acids (mainly quinic acid), seven flavonoids, five lignans, one sesquiterpenoid, and one long-chain fatty acid. Therefore, our results suggest that PTP possesses anti-inflammatory properties.

Chymase inhibition: A key factor in the anti-inflammatory activity of ethanolic extracts and spilanthol isolated from Acmella oleracea

Ethnopharmacological relevanceAcmella oleracea (L.) R. K. Jansen (Asteraceae), known as jambú in Brazil, is used in traditional medicine as analgesic and for inflammatory conditions, characterized by the presence of N-alkylamides, mainly spilanthol. This bioactive compound is responsible for the above-described pharmacological properties, including sialagogue and anesthetic. Aim of the studyThis study aimed to characterize the anti-inflammatory effects of A. oleracea leaves (AOEE-L) and flowers (AOEE-F) extracts, including an isolated alkylamide (spilanthol), using in vitro and in vivo models. The mechanism underlying this effect was also investigated. Materials and methodsExtracts were analyzed by HPLC-ESI-MS/MS in order to characterize the N-alkylamides content. AOEE-L, AOEE-F (25–100 μg/mL) and spilanthol (50–200 μM) were tested in vitro on VSMC after stimulation with hyperglycemic medium (25 mM glucose). Their effects over nitric oxide (NO) generation, chymase inhibition and expression, catalase (CAT), superoxide anion (SOD) radical activity were evaluated. After an acute administration of extracts (10–100 mg/mL) and spilanthol (6.2 mg/mL), the anti-inflammatory effects were evaluated by applying the formalin test in rats. Blood was collected to measure serum aminotransferases activities, NO activity, creatinine and urea. ResultsA number of distinct N-alkylamides were detected and quantified in AOEE-L and AOEE-F. Spilanthol was identified in both extracts and selected for experimental tests. Hyperglycemic stimulation in VSMC promoted the expression of inflammatory parameters, including chymase, NO, CAT and SOD activity and chymase expression, all of them attenuated by the presence of the extracts and spilanthol. The administration of extracts or spilanthol significantly inhibited edema formation, NO production and cell tissue infiltration in the formalin test, without causing kidney and liver toxicity. ConclusionTaken together, these results provide evidence for the anti-inflammatory activity of leaves and flowers extracts of jambú associated distinctly with their chemical profile. The effects appear to be associated with the inhibition of chymase activity, suppression of the proinflammatory cytokine NO and antioxidant activities.

Abstract 6364: LFA-9, a dual mPGES-1 and 5-LOX inhibitor, suppresses colon cancer stemness and inflammogen-induced inflammatory response

Abstract Chronic inflammation triggers tumorigenesis of the colorectum; hence several non-steroidal anti-inflammatory drugs (NSAIDs) have been explored for prevention and treatment of inflammatory diseases, including colorectal cancer (CRC). Although traditional NSAIDs and COX-2 inhibitors are effective chemopreventive agents for CRC, unwanted side effects (gastrointestinal and renal) hinder their use. Mechanistic studies suggest that the side effects are in part due to a COX-2 inhibition-associated increase in 5-lipoxygenase (5-LOX) metabolites and reduced PGI2 levels. Hence, agents targeting microsomal prostaglandin synthase-1 (mPGES-1) and 5-LOX inhibitors may prove to be more effective and safer agents for chemoprevention. LFA-9 was designed based on the pharmacophore of licofelone by adding 2-aminoethanoic acid (Glycine) at its carboxylic end to enhance renal clearance and selectivity towards dual mPGES-1 and 5-LOX inhibition. Here we characterized LFA-9 in detail for its mPGES1/5-LOX selectivity over COX-1/2 using in silico molecular modelling, in vitro enzyme activity assays, and ex vivo inhibition studies with human/mouse/rat mPGES-1 and 5-LOX enzymes to facilitate pre-clinical experimentation and clinical translation. In silico, LFA-9 showed strong binding affinity against 5-LOX (binding energies -199.85 and -215.3 Kcal/mol) and mPGES-1 (binding energies -238.27 and -257.76 Kcal/mol), but not against COX-1/2. LFA-9 substantially inhibited mPGES-1 (IC50 0.52 - 1.40 µM) and 5-LOX (IC50 0.89 - 2.75 µM) but not COX-1/2 (IC50&amp;gt;1mM) in cell-free assays. Ex-vivo, LFA-9 inhibited PGE2 (IC50 0.47 - 0.78 µM) and LTB4 (IC50 0.66 - 1.24 µM) production and spared PGI2 (IC50&amp;gt;1 mM) and TXB2 (IC50&amp;gt;1 mM) production in LPS-stimulated human/mouse/rat macrophages and whole blood (cell-based system). Circular dichroism and isothermal calorimetric-based studies demonstrated that LFA-9 strongly binds and induces changes in the secondary structure of human mPGES-1 and 5-LOX enzymes, thereby inhibiting their activities. Since PGE2 from mPGES1 activity promotes colon tumor stemness, LFA-9 was evaluated on colonic cancer organoids (spheroids) derived from PIRC (Polyposis in Rat Colon) rats that replicate human familial adenomatous polyposis. LFA-9 significantly inhibited the growth of colonic spheroids at 25 µM as compared to that of untreated as well as licofelone-treated spheroids. Anti-inflammatory properties of LFA-9 were evaluated in vivo using an inflammogen (carrageenan)-induced rat paw edema model. Dietary LFA-9 inhibited edema formation after carrageenan injection. In summary, LFA-9 showed anti-inflammatory and anti-tumor properties through mPGES1/5-LOX inhibition. Our data supports LFA-9, a novel mPGES-1 and 5-LOX inhibitor, as a safer drug candidate for prevention and therapy of colorectal cancer. (Supported by R01CA 213987, NIH/NCI HHSN261201500024I and VA merit). Citation Format: Nagendra Sastri Yarla, Gopal Pathuri, Hariprasad Gali, Venkateshwar Madka, Janani Panneerselvam, Parthasarathy Chandrakesan, Courtney W. Houchen, Elizabeth R. Glaze, Jennifer Fox, David McCormick, Chinthalapally V. Rao. LFA-9, a dual mPGES-1 and 5-LOX inhibitor, suppresses colon cancer stemness and inflammogen-induced inflammatory response [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6364.

Anti-inflammatory Activity of Neuropathic Pain Reducing Herbal Medicine Based on Edema Inhibition of CARR-induced Sprague Dawley Paws

Neuropathic pain is nerve pain whose treatment still has side effects when used for the long term. Regulation and modulation of the immune system is needed to reduce the inflammatory reaction that triggers of the pain. Increasing neural tension may induced with nerve inflammation which producing compounds responsible for signalling pain, fever and heat. Ginger (Zingiber officinale Roscoe), cloves (Syzygium aromaticum L.) and nutmeg (Myristica fragrans Houtt) have been known to contain phenolic compounds that are efficacious as anti-inflammatory agents. This study aims to prove the anti-inflammatory activity of neuropathic pain reducing herbs consisting of a combination of the three ingredients. Result from herbs formulation and reflux extraction then analysed for anti-inflammatory activity using in vivo & Winter method with Sprague-Dawley white male rats (Rattus norvegicus) and quantitative phenol content. Anti-inflammatory analysis done by 6 groups of rats, which is normal control, negative control, positive control, dosage I (given herbal extract 1.125 mL/200 g BW), dosage II (given herbal extract 2.25 mL/200 g BW) and dosage III (given herbal extract 4,5 mL/200 g BW). Anti-inflammatory of 10 g herbs extract in 250 mL solvent then observed through the inhibition of oedema formation on rats’ paw along the time. Dosage III group has the higher inhibition percentage as in 75.76%, which almost equivalent as normal control group (82.28%).

Evaluation of two medicinal plants used for arthritis in northern Nigeria with focus on Terminalia avicennioides Guill. & Perr. and its mechanism of action

Chronic inflammation underlying non-communicable diseases continues to impose serious economic and public health burden globally. Exploring medicinal plants presents a valid approach to sourcing new anti-inflammatory therapies. This study was performed to evaluate Cassia sieberiana root and Terminalia avicennioides stem bark extracts in pain and inflammation, in order to identify an active extract and its mechanism of action. Aqueous and 70% v/v ethanol extracts of C. sieberiana root (CSA and CSE) and T. avicennioides stem bark extracts (TAA and TAE) were prepared. Acute toxicity, phenolic content and antioxidant activity of the extracts were determined. Graded doses of each extract were tested against acetic acid-induced nociception and acute formalin-induced paw inflammation. T. avicennioides stem bark ethanol extract was further tested in chronic paw inflammation and its effects on edematous response and nitric oxide in inflammed tissue were measured. All the extracts were acutely safe following oral administration of doses up to 2000 mg/kg. Comparatively, T. avicennioides aqueous extract (TAA) showed the highest phenolic content and displayed the highest antioxidant potency among the extracts. T. avicennioides and C. sieberiana ethanol extracts produced comparable inhibition of acetic acid-induced pain. Only T. avicennioides ethanol extract significantly (p < 0.001) ameliorated acute formalin-induced nociception in phase 1 of the test compared with other extracts. It was also the most effective in inhibiting edema formation during the inflammatory phase. In chronic paw inflammation, 300 and 900 mg/kg TAE significantly (p < 0.01) lowered post-treatment edema and reduced the relative paw index of the inflammed paw. At these doses, nitric oxide levels were also reduced compared to the control group. T. avicennioides and C. sieberiana extracts possess beneficial effects against pain, but T. avicennioides has a comparatively higher acute anti-inflammatory effect, concentrated in its ethanol extract. Inhibition of nitric oxide and prostaglandin activity may contribute to the anti-inflammatory effect of T. avicennioides ethanol extract in chronic inflammation.

NF-κB Phosphorylation Inhibition Prevents Articular Cartilage Degradation in Osteoarthritis Rats via 2-Aminoquinoline.

BackgroundOsteoarthritis is a chronic degenerative disease of the joints that is common in older people worldwide. The characteristic features of osteoarthritis include cartilage degradation, synovitis, and remodelling of subchondral bone. The present study investigated the effect of 2-aminoquinoline on knee articular cartilage degradation in an osteoarthritis rat model.Material/MethodsThe rat model of osteoarthritis was established in Wistar rats by intra-articular injection of monosodium iodoacetate. The rats were randomly divided into 6 groups of 10 rats each: a normal control group, an untreated group, and 4 (5, 10, 15 and 20 mg/kg) treatment groups. The rats in treatment groups received 5, 10, 15, or 20 mg/kg doses of 2-aminoquinoline on day 2 of monosodium iodoacetate injection.ResultsThe 2-aminoquinoline treatment of monosodium iodoacetate-injected rats markedly decreased weight-bearing asymmetry, inhibited edema formation, and improved paw withdrawal thresholds. The expression of inflammatory cytokines was markedly higher in the osteoarthritis rats. Treatment with 2-aminoquinoline led to a significant reduction in inflammatory cytokine expression in osteoarthritis rats in a dose-dependent manner. In osteoarthritis rats, the expressions of prostaglandin E2 (PGE2), matrix metalloproteinase-13 (MMP-13), and substance P were also higher in comparison to the control group. The 2-aminoquinoline treatment supressed PGE2, MMP-13, and substance P levels in osteoarthritis rats. Moreover, the expression of phosphorylated nuclear factor kappaB (p-NF-κB) was markedly higher in the untreated rats. However, activation of NF-κB was downregulated in the osteoarthritis rats by treatment with 2-aminoquinoline.ConclusionsThe present study demonstrated that 2-aminoquinoline prevents articular cartilage damage in osteoarthritis rats through inhibition of inflammatory factors and downregulation of NF-κB activation, suggesting that 2-aminoquinoline would be effective in treatment of osteoarthritis.

CCR3 antagonist impairs estradiol-induced eosinophil migration to the uterus in ovariectomized mice.

Eosinophils are abundant in the reproductive tract, contributing to the remodeling and successful implantation of the embryo. However, the mechanisms by which eosinophils migrate into the uterus and their relationship to edema are still not entirely clear, since there are a variety of chemotactic factors that can cause migration of these cells. Therefore, to evaluate the role of CCR3 in eosinophil migration, ovariectomized C57BL/6 mice were treated with CCR3 antagonist SB 328437 and 17β-estradiol. The hypothesis that the CCR3 receptor plays an important role in eosinophil migration to the mouse uterus was confirmed, because we observed reduction in eosinophil peroxidase activity in these antagonist-treated uteruses. The antagonist also influenced uterine hypertrophy, inhibiting edema formation. Finally, histological analysis of the orcein-stained uteruses showed that the antagonist reduced eosinophil migration together with edema. These data showed that the CCR3 receptor is an important target for studies that seek to clarify the functions of these cells in uterine physiology.

Regulation of murine arthritis by systemic, spinal, and intra-articular adrenoceptors.

The regulation of the immune system by the sympathetic nervous system is allowing the design of novel treatments for inflammatory disorders such as arthritis. In this study, we have analyzed the effects of α- and β-adrenoceptor agonists injected subcutaneously, intrathecally, or intra-articularly in zymosan-induced arthritis. Murine arthritis was induced by intra-articular (knee joint) injection of zymosan. α1 (phenylephrine), α2 (clonidine), β1 (dobutamine), or β2 (salbutamol)-adrenoceptor agonists were injected subcutaneously (sc), intrathecally (it), or intra-articularly (ia) to activate peripheral, spinal, or intra-articular adrenoceptors and to study their effects on articular edema formation and neutrophil migration into the synovial cavity. Treatments with phenylephrine did not affect the edema formation, but it increased neutrophil migration when injected subcutaneously (155.3%) or intra-articularly (187.7%). Treatments with clonidine inhibited neutrophil migration (59.9% sc, 68.7% it, 42.8% ia) regardless of the route of administration, but it inhibited edema formation only when injected intrathecally (66.7%) or intra-articularly (36%) but not subcutaneously. Treatments with dobutamine inhibited both edema (42.0% sc, 69.5% it, 61.6% ia) and neutrophil migration (28.4% sc, 70.3% it, 82.4% ia) in a concentration dependent manner. Likewise, all the treatments with salbutamol also inhibited edema formation (89.9% sc, 62.4% it, 69.8% ia) and neutrophil migration (76.6% sc, 39.1% it, 71.7% ia). Whereas the β-adrenoceptor agonists induced anti-inflammatory effects regardless of their route of administration, α1- and α2-adrenoceptor agonists induced either pro- and anti-inflammatory effects, respectively.

Escin: a review of its anti-edematous, anti-inflammatory, and venotonic properties.

This review discusses historical and recent pharmacological and clinical data on the anti-edematous, anti-inflammatory, and venotonic properties of escin (Reparil®). Escin, the active component of Aesculus hippocastanum, or horse chestnut, is available as orally absorbable dragées and as a transdermal gel. The anti-inflammatory and anti-edematous effects of escin have been studied over many years in pre-clinical models. More recent data confirm the anti-inflammatory properties of escin in reducing vascular permeability in inflamed tissues, thereby inhibiting edema formation. The venotonic effects of escin have been demonstrated primarily by in vitro studies of isolated human saphenous veins. The ability of escin to prevent hypoxia-induced disruption to the normal expression and distribution of platelet endothelial cell-adhesion molecule-1 may help explain its protective effect on blood vessel permeability. Escin oral dragées and transdermal gel have both demonstrated efficacy in blunt trauma injuries and in chronic venous insufficiency. Both oral escin and the transdermal gel are well tolerated.