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Extensive research has been dedicated to develop compounds that can target multiple aspects of Alzheimer's disease (AD) treatment due to a growing understanding of AD's complex multifaceted nature and various interconnected pathological pathways. In the present study, a series of biological assays were performed to evaluate the potential of the tryptamine analogues synthesized earlier in our lab as multi-target-directed ligands (MTDLs) for AD. To assess the inhibitory effects of the compounds, various in vitro assays were employed. Three compounds, SR42, SR25, and SR10, displayed significant AChE inhibitory activity, with IC50 values of 0.70 µM, 0.17 µM, and 1.00 µM, respectively. These values superseded the standard drug donepezil (1.96 µM). In the MAO-B inhibition assay, SR42 (IC50 = 43.21 µM) demonstrated superior inhibitory effects as compared to tryptamine and other derivatives. Moreover, SR22 (84.08%), SR24 (79.30%), and SR42 (75.16%) exhibited notable percent inhibition against the COX-2 enzyme at a tested concentration of 100 µM. To gain insights into their binding mode and to validate the biological results, molecular docking studies were conducted. Overall, the results suggest that SR42, a 4,5 nitro-benzoyl derivative of tryptamine, exhibited significant potential as a MTDL and warrants further investigation for the development of anti-Alzheimer agents.
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Enfermedad de Alzheimer , Monoaminooxidasa , Humanos , Monoaminooxidasa/metabolismo , Enfermedad de Alzheimer/metabolismo , Inhibidores de la Monoaminooxidasa/química , Ciclooxigenasa 2/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Inhibidores de la Colinesterasa/química , Relación Estructura-Actividad , Triptaminas/farmacología , Acetilcolinesterasa/metabolismo , LigandosRESUMEN
High-frequency near-infrared (NIR) semiconductor laser-irradiation has an unclear effect on nociception in the compressed lateral periodontal ligament region, a peripheral nerve region. This study aimed to investigate the effects of NIR semiconductor laser irradiation, with a power of 120 J, on inflammatory pain markers and neuropeptides induced in the compressed lateral periodontal ligament area during ETM. A NIR semiconductor laser [910 nm wavelength, 45 W maximum output power, 300 mW average output power, 30 kHz frequency, and 200 ns pulse width (Lumix 2; Fisioline, Verduno, Italy)] was used. A nickel-titanium closed coil that generated a 50-g force was applied to the maxillary left-side first molars and incisors in 7-week-old Sprague-Dawley (280-300 g) rats to induce experimental tooth movement (ETM) for 24 h. Ten rats were divided into two groups (ETM + laser, n = 5; ETM, n = 5). The right side of the ETM group (i.e., the side without induced ETM) was evaluated as the untreated group. We performed immunofluorescent histochemistry analysis to quantify the interleukin (IL)-1ß, cyclooxygenase-2 (COX2), prostaglandin E2 (PGE2), and neuropeptide [calcitonin gene-related peptide (CGRP)] expression in the compressed region of the periodontal tissue. Post-hoc Tukey-Kramer tests were used to compare the groups. Compared with the ETM group, the ETM + laser group showed significant suppression in IL-1ß (176.2 ± 12.3 vs. 310.8 ± 29.5; P < 0.01), PGE2 (104.4 ± 14.34 vs. 329.6 ± 36.52; P < 0.01), and CGRP (36.8 ± 4.88 vs. 78.0 ± 7.13; P < 0.01) expression. High-frequency NIR semiconductor laser irradiation exerts significant effects on ETM-induced inflammation. High-frequency NIR semiconductor laser irradiation can reduce periodontal inflammation during orthodontic tooth movement.
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Péptido Relacionado con Gen de Calcitonina , Ligamento Periodontal , Ratas , Animales , Ratas Sprague-Dawley , Láseres de Semiconductores/uso terapéutico , Técnicas de Movimiento Dental , Dinoprostona , Dolor/radioterapia , Rayos InfrarrojosRESUMEN
Oxaliplatin (OXA) is a common chemotherapy drug for colorectal, gastric, and pancreatic cancers. The anticancer effect of OXA is often accompanied by neurotoxicity and acute and chronic neuropathy. The symptoms present as paresthesia and pain which adversely affect patients' quality of life. Herein, five consecutive intraperitoneal injections of OXA at a dose of 4 mg/kg were used to mimic chemotherapy. OXA administration induced mechanical allodynia, activated spinal astrocytes, and increased inflammatory response. To develop an effective therapeutic measure for OXA-induced neuropathic pain, emodin was intrathecally injected into OXA rats. Emodin developed an analgesic effect, as demonstrated by a significant increase in the paw withdrawal threshold of OXA rats. Moreover, emodin treatment reduced the pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-1ß) which upregulated in OXA rats. Furthermore, autodock data showed four hydrogen bonds were formed between emodin and cyclooxygenase-2 (COX2), and emodin treatment decreased COX2 expression in OXA rats. Cell research further proved that emodin suppressed nuclear factor κB (NF-κB)-mediated inflammatory signal and reactive oxygen species level. Taken together, emodin reduced spinal COX2/NF-κB mediated inflammatory signal and oxidative stress in the spinal cord of OXA rats which consequently relieved OXA-induced neuropathic pain.
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Emodina , Neuralgia , Ratas , Animales , Oxaliplatino/efectos adversos , FN-kappa B/metabolismo , Ciclooxigenasa 2 , Emodina/efectos adversos , Calidad de Vida , Ratas Sprague-Dawley , Neuralgia/inducido químicamente , Neuralgia/tratamiento farmacológico , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológicoRESUMEN
Chronic activation of microglia is a driving factor in the progression of neuroinflammatory diseases, and mechanisms that regulate microglial inflammatory signaling are potential targets for novel therapeutics. Regulator of G protein Signaling 10 is the most abundant RGS protein in microglia, where it suppresses inflammatory gene expression and reduces microglia-mediated neurotoxicity. In particular, microglial RGS10 downregulates the expression of pro-inflammatory mediators including cyclooxygenase 2 (COX-2) following stimulation with lipopolysaccharide (LPS). However, the mechanism by which RGS10 affects inflammatory signaling is unknown and is independent of its canonical G protein targeted mechanism. Here, we sought to identify non-canonical RGS10 interacting partners that mediate its anti-inflammatory mechanism. Through RGS10 co-immunoprecipitation coupled with mass spectrometry, we identified STIM2, an endoplasmic reticulum (ER) localized calcium sensor and a component of the store-operated calcium entry (SOCE) machinery, as a novel RGS10 interacting protein in microglia. Direct immunoprecipitation experiments confirmed RGS10-STIM2 interaction in multiple microglia and macrophage cell lines, as well as in primary cells, with no interaction observed with the homologue STIM1. We further determined that STIM2, Orai channels, and the calcium-dependent phosphatase calcineurin are essential for LPS-induced COX-2 production in microglia, and this pathway is required for the inhibitory effect of RGS10 on COX-2. Additionally, our data demonstrated that RGS10 suppresses SOCE triggered by ER calcium depletion and that ER calcium depletion, which induces SOCE, amplifies pro-inflammatory genes. In addition to COX-2, we also show that RGS10 suppresses the expression of pro-inflammatory cytokines in microglia in response to thrombin and LPS stimulation, and all of these effects require SOCE. Collectively, the physical and functional links between RGS10 and STIM2 suggest a complex regulatory network connecting RGS10, SOCE, and pro-inflammatory gene expression in microglia, with broad implications in the pathogenesis and treatment of chronic neuroinflammation.
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Canales de Calcio/metabolismo , Señalización del Calcio , Calcio/metabolismo , Regulación de la Expresión Génica , Microglía/metabolismo , Proteínas RGS/metabolismo , Molécula de Interacción Estromal 2/metabolismo , Animales , Canales de Calcio/genética , Inflamación/genética , Inflamación/metabolismo , Ratones , Células RAW 264.7 , Proteínas RGS/genética , Molécula de Interacción Estromal 2/genéticaRESUMEN
BACKGROUND AND OBJECTIVE: TLR is known to regulate the immune system in cancer. TLR-7 and TLR-9 can enhance the antitumor immune system in many types of solid tumors. Cyclooxygenase-2 (COX-2) is a biomarker of inflammation. This study aimed to investigate the effect of papaya leaves extract on immune response (TLR 7, TLR 9) and inflammation (COX-2) in rats induced DMBA. MATERIALS AND METHODS: This experimental study used Sprague dawley female rats of age more less 50 days. Rats were divided into 4 groups: Negative Control (NC), Positive Control (PC), Cancer Drug Doxorubicin (DOXO) and Papaya Leaves Extract (PLE). The study was conducted for 13 weeks. DMBA induction performed for 5 weeks with administration of 2 times per week. RESULTS: the expression of TLR-7 of PLE and DOXO was higher than PC groups significantly different (p<0.05). The expression of TLR-9 of PLE was higher than NC, PC and DOXO groups but not significantly different (p>0.05) while the expression of COX-2 of PLE and DOXO groups was lower than NC and PC groups but not significantly different (p>0.05). CONCLUSION: It can be concluded that papaya leaves extract can improve the immune system and reduce inflammation. It shows that papaya leaves extract has potent as anti-cancer.
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Antiinflamatorios/farmacología , Carica , Ciclooxigenasa 2/sangre , Inflamación/prevención & control , Extractos Vegetales/farmacología , Hojas de la Planta , Receptor Toll-Like 7/sangre , Receptor Toll-Like 9/sangre , 9,10-Dimetil-1,2-benzantraceno , Inmunidad Adaptativa/efectos de los fármacos , Animales , Antiinflamatorios/aislamiento & purificación , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Biomarcadores/sangre , Carica/química , Doxorrubicina/farmacología , Femenino , Inflamación/sangre , Inflamación/inducido químicamente , Neoplasias/sangre , Neoplasias/inducido químicamente , Neoplasias/prevención & control , Extractos Vegetales/aislamiento & purificación , Hojas de la Planta/química , Ratas WistarRESUMEN
Hyaluronic acid (HA), a major glycosaminoglycan of the extracellular matrix, has cell signaling functions that are dependent on its molecular weight. Anti-inflammatory effects for high-molecular-weight (HMW) HA and pro-inflammatory effects for low-molecular-weight (LMW) HA effects were found for various myeloid cells, including microglia. Astrocytes are cells of ectodermal origin that play a pivotal role in brain inflammation, but the link between HA with different molecular weights and an inflammatory response in these cells is not clear. We tested the effects of LMW and HMW HA in rat primary astrocytes, stimulated with Poly:IC (PIC, TLR3 agonist) and lipopolysaccharide (LPS, TLR4 agonist). Oxylipin profiles were measured by the UPLC-MS/MS analysis and metabolites HDoHEs (from docosahexaenoic acid), -HETEs, prostaglandins (from arachidonic acid), DiHOMEs and HODEs (from linoleic acid) were detected. Both, HMW and LMW HA downregulated the cyclooxygenase-mediated polyunsaturated fatty acids metabolism, LMW also reduced lipoxygenase-mediated fatty acid metabolism. Taken together, the data show that both LMW and HMW (i) influence themselves on cytokines (TNFα, IL-6, IL-10), enzymes iNOS, COX-2, and oxylipin levels in extracellular medium of cultured astrocytes, (ii) induced cellular adaptations in long-term applications, (iii) modulate TLR4- and TLR3-signaling pathways. The effects of HMW and LMW HA are predominantly revealed in TLR4- and TLR3- mediated responses, respectively.
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Astrocitos/inmunología , Ácido Hialurónico/inmunología , Inflamación/inmunología , Oxilipinas/inmunología , Animales , Células Cultivadas , Ciclooxigenasa 2/inmunología , Femenino , Ácido Hialurónico/química , Interleucina-10/inmunología , Lipopolisacáridos/inmunología , Masculino , Peso Molecular , Ratas , Ratas Wistar , Receptores Toll-Like/inmunologíaRESUMEN
Curcumin is a natural herbal product that has been popularly used to treat autoimmune diseases in China; however, its effects on rheumatoid arthritis and its mechanism are not clear. The main purposes of this study are to explore the therapeutic effects of curcumin on collagen-induced arthritis (CIA) rats and the pharmacological mechanism. In the present study, CIA rats were established by injecting bovine type II collagen. Curcumin and methotrexate were then orally administered daily, and the swelling degree of the hind limb joints was scored every two days. Histopathological changes were observed by hematoxylin-eosin staining. The levels of cytokines (TNF-α, IL-1ß, IL-17 and TGF-ß) were detected by radioimmunoassay, while the expression of IκBα and COX-2 was detected by Western blot. In addition, cell viability was detected by CCK-8 assay, and the effect of curcumin on macrophage apoptosis was detected by flow cytometry and TUNEL assay. The results indicated that in vivo curcumin attenuated the degree of joint swelling of rats and the further development of joint histopathology. Moreover, it downregulated the levels of cytokines. In vitro curcumin inhibited the degradation of IκBα and reduced the production of COX-2 in LPS-induced inflammatory RAW264.7 cells. Importantly, curcumin significantly induced macrophage apoptosis. In conclusion, in this study, we have demonstrated that curcumin exerts therapeutic effects on arthritis in CIA rats and has a strong pharmacological activity on reducing the inflammatory response in macrophages. Its mechanism may be related to the inhibition of the NF-κB signaling pathway and the promotion of macrophage apoptosis.
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Antiinflamatorios/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Curcumina/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Artritis Experimental/inmunología , Artritis Experimental/patología , Supervivencia Celular/efectos de los fármacos , Citocinas/inmunología , Articulaciones/efectos de los fármacos , Articulaciones/inmunología , Articulaciones/patología , Masculino , Ratones , Células RAW 264.7 , Ratas Sprague-DawleyRESUMEN
@#Background: Although the association of single nucleotide polymorphisms (SNPs) of cyclooxygenase (COX) genes and the risk of aspirin resistance (AR) has been extensively studied, the results remain conflicting. The majority of studies have focused on the role of rs20417 (COX-2 -G765C) in AR. To derive a more comprehensive and accurate evaluation of this association, we performed a meta-analysis including the most recent studies. Methods: Relevant studies published up to October 2018 were identified by searching the PubMed, EMBASE, Web of Science, Cochrane, China Nation Knowledge Infrastructure Platform, Wanfang, and VIP databases, and by manual searching reference lists of the retrieved articles. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to assess the strength of associations. Sensitivity and subgroup analyses were performed to explore the stability of results and between-study heterogeneity, respectively. Results: A total of 18 studies on rs20417 were pooled into the meta-analysis. Rs20417 was found to be associated with an increased risk of AR (C vs. G: OR = 1.43, 95% CI = 1.10–1.86, p < 0.05; GC+CC vs. GG: OR = 1.54, 95% CI =1.15–2.05, p < 0.05). These associations were stronger in Chinese participants and in patients with ischemic stroke in subgroup analyses. Conclusion: The presence of rs20417 indicates an increased risk of AR, especially in Chinese participants and patients with ischemic stroke. This association could help to improve personalized medicine and initiate appropriate treatment as necessary. Further large-scale studies are warranted to confirm our findings.
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AIM: This study aimed to observe the cyclooxygenase-2 expression and its correlation with tumour size and lymph node involvement in nasopharyngeal carcinoma. METHODS: This study was cross-sectional, that enrolled 126 samples diagnosed with nasopharyngeal carcinoma in Haji Adam Malik General Hospital, Medan, Indonesia which fulfilled the inclusion criteria. RESULTS: Based on this study, we found that the age peak incidence of nasopharyngeal carcinoma patients about a 41-60-year-old group (57.1%), dominated by men (71.4%). Through histopathological examination, non-keratinizing squamous cell carcinoma is the most predominant type (79.4%). We also found T3 is the most prevalent primary tumour size (32.5%) with prominent lymph node involvement N3 (45.2%), and stage IV (54.8%). Cyclooxygenase-2 overexpression is prevalent among nonkeratinizing squamous cell carcinoma (81.1%), T3 primary tumour size (41.1%), N3 node involvement (60.0%), and IV clinical stage (71.6%). In addition, we found a significant relationship between cyclooxygenase-2 expressions towards tumor size (p < 0.001) and lymph node involvement (p < 0.001) in nasopharyngeal carcinoma. CONCLUSION: It is proved that the overexpression of cyclooxygenase-2 will increase the susceptibility of nasopharyngeal carcinoma patients having advanced primary tumour size and lymph node involvement.
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Juniperonic acid (JPA; Δ5,11,14,17-20:4), originally identified in certain gymnosperm seeds, is a rare n-3 polyunsaturated fatty acid (PUFA) with lipid-modulating effects on rats and anti-proliferative effects on fibroblast cell proliferation. However, little is known how JPA exerted its immunosuppressive effect. The objective of this study was to investigate whether JPA inhibited the production of inflammatory mediators through the modulation of cellular phospholipid fatty acid compositions. Using standard lipid chemistry techniques in conjunction with argentated column chromatography, high-purity JPA (> 98%) was extracted, isolated, and purified from Biota kernels. When murine RAW264.7 macrophages were incubated with increasing concentrations of JPA, amounts of cellular phospholipid total PUFA, JPA, and Δ7-docosatetraenoic acid (Δ7-DTA; elongation product of JPA) increased in a dose-dependent manner; however, the proportions of total monounsaturated fatty acid (MUFA) and arachidonic acid (AA) decreased. JPA suppressed the production of nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) and the expression of inducible nitric oxide synthase (iNOS) up to 21, 75, 30, and 44%, respectively. The induction of cyclooxygenase-2 (COX-2) over-expression by JPA could account for the doubling of the PGE2 level. Furthermore, JPA suppressed the expression of phosphorylated mitogen-activated protein kinases (MAPK). In a separate study using the mouse ear edema model, we demonstrated that JPA also significantly suppressed inflammation, as measured by ear thickness and biopsy weight. The anti-inflammatory properties of JPA could be due, in part, to the incorporation of JPA into cellular phospholipids with subsequent modulation of membrane-mediated MAPK signaling.
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Ácidos Grasos Insaturados/metabolismo , Macrófagos/metabolismo , Fosfolípidos/metabolismo , Animales , Ciclooxigenasa 2/metabolismo , Edema/tratamiento farmacológico , Ácidos Grasos Monoinsaturados/metabolismo , Inflamación/tratamiento farmacológico , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Células RAW 264.7RESUMEN
BACKGROUND: Selective cyclooxygenase (COX)-2 inhibitors are commonly used analgesics that provide similar analgesia as that of other analgesics but with fewer adverse effects. However, few prospective studies have performed comparative analyses in this regard. PURPOSE: To evaluate the efficacy of a selective COX-2 inhibitor in early postoperative pain control, satisfaction with pain management, and incidence of systemic adverse effects in patients undergoing arthroscopic rotator cuff repair. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: This study included 180 patients who underwent arthroscopic rotator cuff repair between September 2011 and August 2012. The patients were randomly assigned to receive celecoxib, ibuprofen, or tramadol (n = 60 each). Visual analog scale (VAS) scores for pain intensity and satisfaction with medication, incidence of adverse effects, and use of rescue medication were recorded and compared between the 3 groups at 3 days and 2 weeks after surgery. Magnetic resonance and ultrasonography images of 82 patients were retrospectively reviewed at least 24 months after surgery, along with the range of motion and pain VAS and functional scores. RESULTS: There were no significant differences among the 3 groups in terms of pain intensity, incidence of adverse effects, or dosage of rescue medication at 3 days or 2 weeks after surgery. Pain VAS and functional scores at the final follow-up were also comparable among the 3 groups. However, the retear rate in the celecoxib group (11/30 [37%]) was significantly higher than those in the ibuprofen (2/27 [7%]) and tramadol (1/25 [4%]) groups ( P = .009). CONCLUSION: Despite having similar postoperative analgesic effects as other nonsteroidal anti-inflammatory drugs and opioids, selective COX-2 inhibitors should not be used for postoperative analgesia because they might negatively affect tendon-to-bone healing after surgical repair. Registration: NCT02850211 ( ClinicalTrials.gov identifier).
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Analgésicos/uso terapéutico , Artroscopía , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Manejo del Dolor , Lesiones del Manguito de los Rotadores/cirugía , Anciano , Analgesia , Analgésicos Opioides/uso terapéutico , Antiinflamatorios no Esteroideos , Artroplastia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor/etiología , Dimensión del Dolor , Periodo Posoperatorio , Rango del Movimiento Articular , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Glycolic acid (GA), commonly present in fruits, has been used to treat dermatological diseases. Extensive exposure to solar ultraviolet B (UVB) irradiation plays a crucial role in the induction of skin inflammation. The development of photo prevention from natural materials represents an effective strategy for skin keratinocytes. OBJECTIVE: The aim of this study was to investigate the molecular mechanisms underlying the glycolic acid (GA)-induced reduction of UVB-mediated inflammatory responses. METHODS: We determined the effects of different concentrations of GA on the inflammatory response of human keratinocytes HaCaT cells and C57BL/6J mice dorsal skin. After GA was topically applied, HaCaT and mice skin were exposed to UVB irradiation. RESULTS: GA reduced the production of UVB-induced nuclear factor kappa B (NF-κB)-dependent inflammatory mediators [interleukin (IL)-1ß, IL-6, IL-8, cyclooxygenase (COX)-2, tumor necrosis factor-α, and monocyte chemoattractant protein (MCP-1)] at both mRNA and protein levels. GA inhibited the UVB-induced promoter activity of NF-κB in HaCaT cells. GA attenuated the elevation of senescence associated with ß-galactosidase activity but did not affect the wound migration ability. The topical application of GA inhibited the genes expression of IL-1ß, IL-6, IL-8, COX-2, and MCP-1 in UVB-exposed mouse skin. The mice to UVB irradiation after GA was topically applied for 9 consecutive days and reported that 1-1.5% of GA exerted anti-inflammatory effects on mouse skin. CONCLUSION: We clarified the molecular mechanism of GA protection against UVB-induced inflammation by modulating NF-κB signaling pathways and determined the optimal concentration of GA in mice skin exposed to UVB irradiation.
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Antiinflamatorios/administración & dosificación , Quimiocina CCL2/metabolismo , Ciclooxigenasa 2/metabolismo , Glicolatos/administración & dosificación , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/efectos de la radiación , FN-kappa B/metabolismo , Piel/efectos de los fármacos , Piel/efectos de la radiación , Rayos Ultravioleta , Administración Cutánea , Animales , Línea Celular , Movimiento Celular/efectos de los fármacos , Movimiento Celular/efectos de la radiación , Senescencia Celular/efectos de los fármacos , Senescencia Celular/efectos de la radiación , Quimiocina CCL2/genética , Quimiocina CCL2/inmunología , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/inmunología , Relación Dosis-Respuesta a Droga , Humanos , Interleucina-6/genética , Interleucina-6/inmunología , Interleucina-8/genética , Interleucina-8/inmunología , Queratinocitos/enzimología , Queratinocitos/inmunología , Masculino , Ratones Endogámicos C57BL , FN-kappa B/genética , FN-kappa B/inmunología , Regiones Promotoras Genéticas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/efectos de la radiación , Piel/enzimología , Piel/inmunología , Factores de Tiempo , TransfecciónRESUMEN
BACKGROUND: Lymphatic metastasis, facilitated by lymphangiogenesis is a common occurrence in breast cancer, the molecular mechanisms remaining incompletely understood. We had earlier shown that cyclooxygenase (COX)-2 expression by human or murine breast cancer cells promoted lymphangiogenesis and lymphatic metastasis by upregulating VEGF-C/D production by tumor cells or tumor-associated macrophages primarily due to activation of the prostaglandin receptor EP4 by endogenous PGE2. It is not clear whether tumor or host-derived PGE2 has any direct effect on lymphangiogenesis, and if so, whether EP4 receptors on lymphatic endothelial cells (LEC) play any role. METHODS: Here, we address these questions employing in vitro studies with a COX-2-expressing and VEGF-C/D-producing murine breast cancer cell line C3L5 and a rat mesenteric (RM) LEC line and in vivo studies in nude mice. RESULTS: RMLEC responded to PGE2, an EP4 agonist PGE1OH, or C3L5 cell-conditioned media (C3L5-CM) by increased proliferation, migration and accelerated tube formation on growth factor reduced Matrigel. Native tube formation by RMLEC on Matrigel was abrogated in the presence of a selective COX-2 inhibitor or an EP4 antagonist. Addition of PGE2 or EP4 agonist, or C3L5-CM individually in the presence of COX-2 inhibitor, or EP4 antagonist, restored tube formation, reinforcing the role of EP4 on RMLEC in tubulogenesis. These results were partially duplicated with a human dermal LEC (HMVEC-dLyAd) and a COX-2 expressing human breast cancer cell line MDA-MB-231. Knocking down EP4 with shRNA in RMLEC abrogated their tube forming capacity on Matrigel in the absence or presence of PGE2, EP4 agonist, or C3L5-CM. RMLEC tubulogenesis following EP4 activation by agonist treatment was dependent on PI3K/Akt and Erk signaling pathways and VEGFR-3 stimulation. Finally in a directed in vivo lymphangiogenesis assay (DIVLA) we demonstrated the lymphangiogenic as well as angiogenic capacity of PGE2 and EP4 agonist in vivo. DISCUSSION/CONCLUSIONS: These results demonstrate the roles of tumor as well as host-derived PGE2 in inducing lymphangiogenesis, at least in part, by activating EP4 and VEGFR-3 on LEC. EP4 being a common target on both tumor and host cells contributing to tumor-associated lymphangiogenesis reaffirms the therapeutic value of EP4 antagonists in the intervention of lymphatic metastasis in breast cancer.
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Dinoprostona/metabolismo , Células Endoteliales/metabolismo , Linfangiogénesis/fisiología , Neoplasias Mamarias Experimentales/patología , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Animales , Western Blotting , Línea Celular Tumoral , Células Endoteliales/patología , Ensayo de Inmunoadsorción Enzimática , Femenino , Ratones , Ratones Desnudos , Ratas , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
BACKGROUND: The purpose of this study was to present our assessment of the significance of myeloid-derived suppressor cells (MDSCs) in head and neck squamous cell carcinoma (HNSCC). METHODS: We examined the percentage of MDSCs in the peripheral blood of patients with HNSCC. The relationship among MDSC recruitment, tumor progression, and cyclooxygenase (COX)-2 inhibition was also evaluated by animal models. RESULTS: Circulating MDSCs were significantly increased in patients with HNSCC compared with healthy people, and this was associated with the clinical tumor burden. In immunocompetent 4-nitroquinoline-1-oxide (4-NQO)-induced oral tumor and immunocompromised tumor implantation animal models, MDSC recruitment was associated with the duration of 4-NQO treatment and tumor progression. The responsible mechanisms included the suppressive ability of T-cell proliferation and augmenting angiogenesis by MDSC. Blockade of COX-2 attenuated the induction and function of MDSCs and subsequently inhibited tumor growth. CONCLUSION: The levels of MDSC are linked with tumor progression in HNSCC. Moreover, targeting COX-2 could be a promising strategy for the treatment of HNSCC. © 2016 Wiley Periodicals, Inc. Head Neck 39: 347-355, 2017.
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Biomarcadores de Tumor/sangre , Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/patología , Huésped Inmunocomprometido/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Animales , Biopsia con Aguja , Carcinoma de Células Escamosas/sangre , Ciclooxigenasa 2/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Neoplasias de Cabeza y Cuello/sangre , Humanos , Inmunohistoquímica , Inflamación/inmunología , Inflamación/fisiopatología , Ratones , Ratones Endogámicos C57BL , Células Supresoras de Origen Mieloide/inmunología , Sensibilidad y Especificidad , Carcinoma de Células Escamosas de Cabeza y Cuello , Carga Tumoral/inmunología , Carga Tumoral/fisiologíaRESUMEN
Pain is one of the most disabling symptoms of rheumatoid diseases. Patients with pain secondary to osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis (AS) or gout require effective analgesic treatment, and the physician's task is to select a drug that is best suited for an individual patient. The choice of pharmacotherapy should be based both on drug potency and clinical efficacy, and its safety profile, particularly in the elderly population, as the number of comorbidities (and hence the risk of treatment complications and drug interactions) rises with age. In cases involving a high risk of gastrointestinal complications or concerns about hepatotoxicity, with a low cardiovascular risk, the first-line nonsteroidal anti-inflammatory drugs to consider should be coxibs including etoricoxib.
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AIMS: There is growing evidence of an increased prevalence of osteoarthritis (OA) among people with diabetes. Synovial inflammation and increased expression of cyclooxygenase-2 (COX-2) are two key features of patients with OA. Methylglyoxal (MGO) is a common intermediate in the formation of advanced glycation end-products, and its concentration is also typically higher in diabetes. In this study, we investigated the effects of the treatment of different MGO concentrations to rabbit HIG-82 synovial cells on COX-2 expression. MAIN METHODS: The MGO induced COX-2 mRNA expression was detected by quantitative polymerase chain reaction. The MGO induced COX-2 protein production and its signaling pathways were detected by western blotting. The nuclear factor-kappa B (NF-κB) nuclear translocation by MGO was examined by immunofluorescence. KEY FINDINGS: In the present study, we find that MGO has no toxic effects on rabbit synovial cells under the experimental conditions. Our analysis demonstrates that MGO induced COX-2 mRNA and protein production. Moreover, MGO induces p38-dependent COX-2 protein expression as well as the phosphorylations of extracellular signal-regulated kinase, c-Jun N-terminal kinase (JNK), and Akt/mammalian target of rapamycin (mTOR)/p70S6K; however, inhibition of JNK and Akt/mTOR/p70S6K phosphorylations further activates COX-2 protein expression. Furthermore, MGO is shown to activate of nuclear factor-kappa B (NF-κB) nuclear translocation. SIGNIFICANCE: Our results suggest that MGO can induce COX-2 expression via a p38-dependent pathway and activate NF-κB nuclear translocation in synovial cells. These results provide insight into the pathogenesis of the synovial inflammation under the diabetic condition associated with higher MGO levels.
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Ciclooxigenasa 2/biosíntesis , Sistema de Señalización de MAP Quinasas/fisiología , FN-kappa B/metabolismo , Piruvaldehído/farmacología , Membrana Sinovial/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/biosíntesis , Animales , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Regulación Enzimológica de la Expresión Génica , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Conejos , Membrana Sinovial/efectos de los fármacosRESUMEN
Brominated diphenyl ether (BDE)-47 is a prevalent flame retardant chemical found in human tissues and is linked to adverse pregnancy outcomes in humans. Because dysregulation of the prostaglandin pathway is implicated in adverse pregnancy outcomes, the present study investigates BDE-47 induction of prostaglandin synthesis in a human extravillous trophoblast cell line, HTR-8/SVneo, examining the hypothesis that BDE-47 increases generation of reactive oxygen species (ROS) to stimulate the prostaglandin response. Treatment with 20 µM BDE-47 significantly increased mRNA expression of prostaglandin-endoperoxide synthase 2 (PTGS2) at 4, 12 and 24 h, and 24-h treatment significantly increased cyclooxygenase (COX)-2 cellular protein expression and prostaglandin E2 (PGE2) concentration in culture medium. The BDE-47-stimulated PGE2 release was inhibited by the COX inhibitors indomethacin and NS398, implicating COX activity. Exposure to 20 µM BDE-47 significantly increased ROS generation as measured by carboxydichlorofluorescein fluorescence, and this response was blocked by cotreatment with the peroxyl radical scavenger (±)-α-tocopherol. (±)-α-Tocopherol cotreatment suppressed BDE-47-stimulated increases of PGE2 release without significant effects on COX-2 mRNA and protein expression, implicating a role for ROS in post-translational regulation of COX activity. Because prostaglandins regulate trophoblast functions necessary for placentation and pregnancy, further investigation is warranted of BDE-47 impacts on trophoblast responses.
Asunto(s)
Retardadores de Llama/toxicidad , Éteres Difenilos Halogenados/toxicidad , Sustancias Protectoras/farmacología , Trofoblastos/efectos de los fármacos , alfa-Tocoferol/farmacología , Línea Celular , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Humanos , Hidroxiprostaglandina Deshidrogenasas/genética , Oxidorreductasas Intramoleculares/genética , Prostaglandina-E Sintasas , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Trofoblastos/metabolismoRESUMEN
Several recent studies have reported that alloxan-treated rats with long-term hyperglycemia can develop naturally occurring periodontal disease (PD). Our previous studies detected dental caries in the same model. Therefore, these two lesions of different etiologies are expected to occur concurrently. In this study, we evaluated the use of diabetic rats as a PD model by employing a selective COX-2 inhibitor reported to be effective against PD. Six-week-old female F344 rats were divided into 3 groups: intact rats (control), alloxan-induced diabetic rats fed a standard diet (AL) and alloxan-induced diabetic rats fed a diet containing 0.01% etodolac (AL+Et). The animals were euthanized at 26 weeks of age, and their oral tissues were examined histopathologically. Gingivitis, marginal periodontitis and alveolar bone resorption were markedly enhanced along with dental caries in the AL group compared with the control group. However, the COX-2 inhibitor had no effect on periodontal inflammation in the AL+Et group. In addition, in the AL group, periodontitis was notably nonexistent around the normal molars, and gingivitis was scarcely worse than that in the control group. In the diabetic rats, the progression of periodontal inflammation was closely correlated with the severity of adjacent dental caries, and marginal periodontitis was frequently continuous with apical periodontitis. In conclusion, an alloxan-induced diabetic rat is not a model of PD but of dental caries. It is probable that in this model, hyperglycemia may enable crown caries to progress to apical periodontitis, while the associated inflammation may rostrally expand to surrounding periodontal tissue.
RESUMEN
AIM OF THE STUDY: FaDu human squamous cell carcinoma (FaDu-hSCC) demonstrated accelerated tumor repopulation during fractionated irradiation with pathological validation in a xenograft model system. Previous studies showed that the selective cyclooxygenase (COX)-2 inhibitor celecoxib can enhance the tumor response to radiotherapy. So we aimed to explore the effect of celecoxib in inducing apoptosis and inhibiting repopulation of FaDu tumors in nude mice during fractionated radiotherapy. MATERIAL AND METHODS: FaDu-hSCC was transplanted into the right hind leg of BALB/C nude mice. Mice were treated with celecoxib and/or fractionated irradiation. Celecoxib (100 mg/kg/day) was administered by daily gavage. Irradiation was delivered with 12 to 18 fractions of 3.0 Gy daily or every second day based on Petersen's repopulation model. At different time points, tumors were excised for immunohistochemistry staining. RESULTS: Significant tumor repopulation occurred after about 18 days of radiotherapy. On average, Ki-67 and bromodeoxyuridine (BrdUrd) labeling indices (LI) decreased with daily irradiation (both p < 0.05) and increased with every-second-day irradiation (both p > 0.05), suggesting accelerated repopulation. Ki-67 LI decreased in celecoxib concurrent with radiotherapy for 12 fractions in 24 days and 18 fractions in 36 days compared with irradiated alone (p = 0.004 and 0.042, respectively). BrdUrd LI values were lower in the concurrent groups than irradiated alone (p = 0.001 and 0.006, respectively). Epithelial growth factor receptor (EGFR) expression score decreased in the concurrent groups than irradiated alone (p = 0.037 and 0.031, respectively). Caspase-3 expression scores were higher in the concurrent groups than irradiated alone (p = 0.05 and 0.006, respectively). CONCLUSIONS: Celecoxib concurrent radiotherapy could inhibit tumor repopulation and increase tumor apoptosis during the treatment in FaDu squamous cell carcinoma.
RESUMEN
Δ7-Eicosatrienoic acid (Δ7-ETrA; Δ7,11,14-20:3), an elongation metabolite of pinolenic acid (PNA; Δ5,9,12-18:3), is a rare polyunsaturated fatty acid (PUFA) originally from pine seeds. Incorporation of PNA and Δ7-ETrA into murine macrophages inhibited lipopolysaccharide (LPS)-stimulated prostaglandin E2 (PGE2) production. Due to the lack of availability of the naturally-occurring fatty acid, we synthesized Δ7-ETrA and demonstrated it was capable of suppressing PGE2 production. Using laboratory synthetic techniques involving 2-carbon elongation and argentated column chromatography, Δ7-ETrA was synthesized and isolated. Its identity and purity (>98%) were confirmed by gas chromatography (GC)/GC-mass spectroscopy. Incubation of murine RAW264.7 cells or rat primary peritoneal macrophages with Δ7-ETrA reduced PGE2 production by up to 84%, but slightly down-regulated type-2 cyclooxygenase (COX-2) expression. Δ7-ETrA blocked nuclear factor-kappa B (NF-κB) translocation into nucleus and inactivated mitogen-activated protein kinases (MAPK), however, these results might not directly account for its inhibitory effect. Furthermore, PGE2 production reduced by Δ7-ETrA was highly correlated with the extent of Δ7-ETrA incorporation into cellular phospholipids and appeared to be the result of competition between this unusual fatty acid and arachidonic acid (AA) for COX-2. In conclusion, Δ7-ETrA incorporation suppresses PGE2 production by macrophages through competition between Δ7-ETrA and AA for COX-2.