El tratamiento con resiniferatoxina exhibe propiedades antiinflamatorias en un modelo murino de inflamación inducida por lipopolisacárido

Introducción. La inflamación es una respuesta fisiológica protectora del sistema inmunológico frente a diversos estímulos, tales como la infección o daño celular, la cual, al no resolverse de manera adecuada, puede ser perjudicial para le hospedero. En la búsqueda de nuevas lternativas terapéuticas que inhiban la respuesta inflamatoria, diversos estudios han reportado el uso de varias moléculas, tales como la resiniferatoxina (RTX), un potente agonista del receptor de potencial transitorio vanilloide (TRPV)-1. Objetivo. Evaluar si el tratamiento con RTX exhibe propiedades antiinflamatorias, utilizando un modelo murino de inflamación inducida por lipopolisacárido (LPS). Material y métodos. Se estimularon ratones BALB/c con LPS y posteriormente fueron tratados con dexametasona (DEX), capsaicina (CAP), Bay 11-7082, capsazepina (CPZ) y RTX. Además, otros grupos de ratones fueron estimulados con LPS y luego tratados con Bay 11-7082 y CPZ más RTX. Después del tratamiento, se determinaron cuantitativamente los niveles plasmáticos de prostaglandina (PG)-E2, óxido nítrico (NO), interleucina (IL)-1β y factor de necrosis tumoral (TNF)-α utilizando kits de EnzymeLinked ImmunoSorbent Assay ELISA. Resultados. El tratamiento con RTX disminuyó de manera significativa los niveles plasmáticos de PGE2, NO, IL-1β y TNF-α. Así mismo, se observó que los tratamientos con Bay 11-7082 y CPZ más RTX mostraron un efecto antiinflamatorio sinérgico, observándose una disminución significativa más pronunciada en los niveles plasmáticos de TNF-α y PGE2. Conclusión. Estos hallazgos sugieren que el tratamiento con RTX muestra propiedades antiinflamatorias, aparentemente asociadas con la vía de señalización factor nuclear (NF)-κB, independiente de los receptores TRPV1, colocando a la RTX como un fármaco potencial en el tratamiento de enfermedades inflamatorias.

Lingonberry Fruit Ethanol Extract Ameliorates DSS-Induced Ulcerative Colitis In Vivo and In Vitro

Ulcerative colitis (UC) is an inflammatory chronic intestinal disease with pathological characteristics, including imbalanced immune function and the overexpression of inflammatory cytokines and mediators. Inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6) were oversecreted in UC condition. Cyclooxygenase (COX)-2 and prostaglandin (PG)E2 were also overexpressed in colon tissue. Lingonberry (LB) (Vaccinium vitis-idaea L.) possesses pharmacological activities, including anti-oxidant, anti-cancer, and anti-obesity effects. To explore LB’s effects on UC, BALB/c mice were administered with 3% (w/v) dextran sulphate sodium (DSS) and LB extract (70% ethanol) orally for nine days. The severity of UC was measured by the change in body weight and colon length. To evaluate LB’s regulatory effect on inflammatory cytokines, the enzyme-linked immunosorbent assay (ELISA) kit was used to measure the inflammatory cytokines in mouse serum. Mouse peritoneal microphages were used to detect LB’s anti-inflammatory effect. The results showed that LB treatment ameliorated less weight loss and longer colon length compared to the DSS-treated group. LB treatment also ameliorated the secretion of inflammatory cytokines. These results indicated that LB has potential as an herbal medicine to treat UC.

Protective Effects Induced by a Hydroalcoholic Allium sativum Extract in Isolated Mouse Heart

The aim of the present study was to investigate the possible protective effects of a garlic hydroalcoholic extract on the burden of oxidative stress and inflammation occurring on mouse heart specimens exposed to E. coli lipopolysaccharide (LPS), which is a well-established inflammatory stimulus. Headspace solid-phase microextraction combined with the gas chromatography–mass spectrometry (HS-SPME/GC–MS) technique was applied to determine the volatile fraction of the garlic powder, and the HS-SPME conditions were optimized for each of the most representative classes of compounds. CIEL*a*b* colorimetric analyses were performed on the powder sample at the time of delivery, after four and after eight months of storage at room temperature in the dark, to evaluate the color changing. Freshly prepared hydroalcoholic extract was also evaluated in its color character. Furthermore, the hydroalcoholic extract was analyzed through GC–MS. The extract was found to be able to significantly inhibit LPS-induced prostaglandin (PG) E2 and 8-iso-PGF2α levels, as well as mRNA levels of cyclooxygenase (COX)-2, interleukin (IL)-6, and nuclear factor-kB (NF-kB), in heart specimens. Concluding, our findings showed that the garlic hydroalcoholic extract exhibited cardioprotective effects on multiple inflammatory and oxidative stress pathways.

Caffeic Acid Modulates Processes Associated with Intestinal Inflammation

Caffeic acid is one of the most abundant hydroxycinnamic acids in fruits, vegetables, and beverages. This phenolic compound reaches relevant concentrations in the colon (up to 126 µM) where it could come into contact with the intestinal cells and exert its anti-inflammatory effects. The aim of this investigation was to study the capacity of caffeic acid, at plausible concentrations from an in vivo point of view, to modulate mechanisms related to intestinal inflammation. Consequently, we tested the effects of caffeic acid (50–10 µM) on cyclooxygenase (COX)-2 expression and prostaglandin (PG)E2, cytokines, and chemokines (IL-8, monocyte chemoattractant protein-1 -MCP-1-, and IL-6) biosynthesis in IL-1β-treated human myofibroblasts of the colon, CCD-18Co. Furthermore, the capacity of caffeic acid to inhibit the angiotensin-converting enzyme (ACE) activity, to hinder advanced glycation end product (AGE) formation, as well as its antioxidant, reducing, and chelating activity were also investigated. Our results showed that (i) caffeic acid targets COX-2 and its product PGE2 as well as the biosynthesis of IL-8 in the IL-1β-treated cells and (ii) inhibits AGE formation, which could be related to (iii) the high chelating activity exerted. Low anti-ACE, antioxidant, and reducing capacity of caffeic acid was also observed. These effects of caffeic acid expands our knowledge on anti-inflammatory mechanisms against intestinal inflammation.

Mechanical Stress Induce PG-E2 in Murine Synovial Fibroblasts Originating from the Temporomandibular Joint

Genetic predisposition, traumatic events, or excessive mechanical exposure provoke arthritic changes in the temporomandibular joint (TMJ). We analysed the impact of mechanical stress that might be involved in the development and progression of TMJ osteoarthritis (OA) on murine synovial fibroblasts (SFs) of temporomandibular origin. SFs were subjected to different protocols of mechanical stress, either to a high-frequency tensile strain for 4 h or to a tensile strain of varying magnitude for 48 h. The TMJ OA induction was evaluated based on the gene and protein secretion of inflammatory factors (Icam-1, Cxcl-1, Cxcl-2, Il-1ß, Il-1ra, Il-6, Ptgs-2, PG-E2), subchondral bone remodelling (Rankl, Opg), and extracellular matrix components (Col1a2, Has-1, collagen and hyaluronic acid deposition) using RT-qPCR, ELISA, and HPLC. A short high-frequency tensile strain had only minor effects on inflammatory factors and no effects on the subchondral bone remodelling induction or matrix constituent production. A prolonged tensile strain of moderate and advanced magnitude increased the expression of inflammatory factors. An advanced tensile strain enhanced the Ptgs-2 and PG-E2 expression, while the expression of further inflammatory factors were decreased. The tensile strain protocols had no effects on the RANKL/OPG expression, while the advanced tensile strain significantly reduced the deposition of matrix constituent contents of collagen and hyaluronic acid. The data indicates that the application of prolonged advanced mechanical stress on SFs promote PG-E2 protein secretion, while the deposition of extracellular matrix components is decreased.

The Extraction Solvent Influences the Anti-Inflammatory Effects of Jakyakgamcho-Tang in Lipopolysaccharide-Stimulated Macrophages and Mice with Gouty Arthritis

Jakyakgamcho-Tang (JGT) is a traditional medicine used to treat muscular tension, spasm, and pain. Several studies have reported its clinical use as an anti-inflammatory and in gynaecological treatment. This study aimed to compare the anti-inflammatory effects of JGT according to extraction solvent, water (JGTW) and 30% EtOH (JGTE) on lipopolysaccharide (LPS)—stimulated macrophages and in mice with monosodium urate (MSU)—induced gouty arthritis. We evaluated the production of inflammatory mediators and cytokines and the expression of inducible nitric oxide (iNOS) and cyclooxygenase-2 (COX-2) in RAW 264.7 cells. We also examined oedema, pain, and inflammation in MSU-induced mice by measuring affected hind paw swelling, weight-bearing, pro-inflammatory cytokines levels, and myeloperoxidase (MPO) activity. In LPS-stimulated RAW264.7 cells, JGTW and JGTE significantly decreased prostaglandin (PG) E2(PGE2) production via suppressing COX-2 expression and cytokines interleukin-1β and interleukin-6. Only JGTE reduced the production of NO and cytokines and the mRNA levels of iNOS and cytokines. In MSU-induced mice, JGTE and JGTW efficiently decreased paw swelling and attenuated joint pain. JGTE (200 and 300 mg/kg) effectively suppressed inflammation by downregulating pro-inflammatory cytokines (tumour necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6) and MPO activity, which were only slightly reduced by JGTW. Our data demonstrate the anti-inflammatory activity of JGT in macrophage and gouty arthritis animal models and show that JGTE is more effective than JGTW at lower concentrations.

Use of selective PGE2 receptor antagonists on human endometriotic stromal cells and peritoneal macrophages

Non-hormonal therapeutic strategies for endometriosis are needed. The aim of this study was to characterize the effects of prostaglandin (PG)E2 receptor inhibitors to explore their potential as novel therapeutic strategies for endometriosis. The expression of PGE2 receptors (EP2 and EP4) in donated tissues from human ovarian endometriosis, adenomyosis and peritoneal endometriosis was examined using immunohistochemistry. Human endometriotic stromal cells (ESC) isolated from ovarian endometriotic tissue and peritoneal macrophages were treated with EP2 and EP4 antagonists. cAMP accumulation and the effect of EP antagonists was measured using cAMP assays. DNA synthesis in ESC was detected using bromodeoxyuridine incorporation analysis. IL-6 and IL-8 protein levels in ESC supernatants were measured using ELISAs. mRNA expression level for aromatase by ESC, and selected cytokines by peritoneal macrophages was measured using RT-PCR. EP2 and EP4 receptors were expressed in cells derived from control and diseased tissue, ovarian endometriotic, adenomyotic, and peritoneal lesions. A selective EP2 antagonist reduced DNA synthesis, cAMP accumulation and IL-1β-induced pro-inflammatory cytokine secretion and aromatase expression. A selective EP4 antagonist negated IL-1β-induced IL-6 secretion and aromatase expression. In peritoneal macrophages, EP expression was elevated in endometriosis samples but the EP4 antagonist reduced cAMP levels and expression of VEGF, CXCL2 and CXCL3 mRNA. EP2 and EP4 are functioning in endometriosis lesions and peritoneal macrophages, and their selective antagonists can reduce EP-mediated actions, therefore, the EP antagonists are potential therapeutic agents for controlling endometriosis.

The Effect of Different Water Extracts from Platycodon grandiflorum on Selected Factors Associated with Pathogenesis of Chronic Bronchitis in Rats

The aim of this study was to assess the activity of extracts from Platycodon grandiflorum A. DC (PG) in a model of chronic bronchitis in rats. The research was carried out on three water extracts: E1 – from roots of field cultivated PG; E2 – from biotransformed roots of PG; E3 – from callus of PG. The extracts differed in saponins and inulin levels—the highest was measured in E3 and the lowest in E1. Identification of secondary metabolites was performed using two complementary LC-MS systems. Chronic bronchitis was induced by sodium metabisulfite (a source of SO2). Animals were treated with extracts for three weeks (100 mg/kg, intragastrically) and endothelial growth factor (VEGF), transforming growth factors (TGF-β1, -β2, -β3), and mucin 5AC (MUC5AC) levels were determined in bronchoalveolar lavage fluid, whereas C reactive protein (CRP) level was measured in serum. Moreover, mRNA expression were assessed in bronchi and lungs. In SO2-exposed rats, an elevation of the CRP, TGF-β1, TGF-β2, VEGF, and mucin was found, but the extracts’ administration mostly reversed this phenomenon, leading to control values. The results showed a strong anti-inflammatory effect of the extracts from PG.

Aryl Hydrocarbon Receptor Role in Co-Ordinating SARS-CoV-2 Entry and Symptomatology: Linking Cytotoxicity Changes in COVID-19 and Cancers; Modulation by Racial Discrimination Stress

There is an under-recognized role of the aryl hydrocarbon receptor (AhR) in co-ordinating the entry and pathophysiology of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) that underpins the COVID-19 pandemic. The rise in pro-inflammatory cytokines during the ‘cytokine storm’ induce indoleamine 2,3-dioxygenase (IDO), leading to an increase in kynurenine that activates the AhR, thereby heightening the initial pro-inflammatory cytokine phase and suppressing the endogenous anti-viral response. Such AhR-driven changes underpin the heightened severity and fatality associated with pre-existent high-risk medical conditions, such as type II diabetes, as well as to how racial discrimination stress contributes to the raised severity/fatality in people from the Black Asian and Minority Ethnic (BAME) communities. The AhR is pivotal in modulating mitochondrial metabolism and co-ordinating specialized, pro-resolving mediators (SPMs), the melatonergic pathways, acetyl-coenzyme A, and the cyclooxygenase (COX) 2-prostaglandin (PG) E2 pathway that underpin ‘exhaustion’ in the endogenous anti-viral cells, paralleling similar metabolic suppression in cytolytic immune cells that is evident across all cancers. The pro-inflammatory cytokine induced gut permeability/dysbiosis and suppression of pineal melatonin are aspects of the wider pathophysiological underpinnings regulated by the AhR. This has a number of prophylactic and treatment implications for SARS-CoV-2 infection and cancers and future research directions that better investigate the biological underpinnings of social processes and how these may drive health disparities.

Comparative study of oral mifepristone and endocervical prostaglandin-E2 gel as pre-induction cervical ripening agents in parturition

Background: Intracervical instillation of prostaglandin E2 is a well-known and widely practiced method of pre-induction cervical ripening. Mifepristone, due to its anti-progesterone action has been found to be a potential cervical ripening agent. This study was conducted to compare the safety, efficacy and outcome of these two drugs in pre-induction cervical ripening.Methods: One hundred antenatal women were recruited for the study; 50 in mifepristone arm and 50 in PG-E2 gel arm. Any singleton term pregnancy in vertex presentation with intact membranes and bishop’s score of <4 was included in the study. Any contraindication for vaginal delivery and any contraindication for mifepristone or PG-E2 were considered as exclusion criteria. Participants in the mifepristone arm were given tablet mifepristone 200 mg orally and those in PG-E2 gel group received endocervical instillation of PGE2 gel 0.5 mg, two doses 6 hours apart (if necessary). Induction of labour was considered successful if the parturient delivered within 48 hours of administration of mifepristone or first dose of PG-E2 gel, with or without labour augmentation with oxytocin. Delivery after 48 hours and caesarean delivery were considered unsuccessful induction.Results: There was a significant improvement in bishop’s score in mifepristone group 5.0±1.55 as compared to PG-E2 gel group 3.64±2.14; p value 0.001.Conclusions: Oral administration of 200 mg mifepristone is a safe, effective and convenient alternative to intracervical instillation of prostaglandin-E2 gel for pre-induction cervical ripening.