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1.
Chem Biol Drug Des ; 103(4): e14520, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38570710

RESUMO

Quercetin, a bioactive natural compound renowned for its potent anti-inflammatory, antioxidant, and antiviral properties, has exhibited therapeutic potential in various diseases. Given that bronchopulmonary dysplasia (BPD) development is closely linked to inflammation and oxidative stress, and quercetin, a robust antioxidant known to activate NRF2 and influence the ferroptosis pathway, offers promise for a wide range of age groups. Nonetheless, the specific role of quercetin in BPD remains largely unexplored. This study aims to uncover the target role of quercetin in BPD through a combination of network pharmacology, molecular docking, computer analyses, and experimental evaluations.


Assuntos
Displasia Broncopulmonar , Ferroptose , Hiperóxia , Animais , Recém-Nascido , Humanos , Displasia Broncopulmonar/tratamento farmacológico , Displasia Broncopulmonar/metabolismo , Hiperóxia/tratamento farmacológico , Hiperóxia/metabolismo , Quercetina/farmacologia , Quercetina/uso terapêutico , Simulação de Acoplamento Molecular , Ciclo-Oxigenase 2 , Animais Recém-Nascidos , Antioxidantes , Farmacologia em Rede
3.
Cell Biol Toxicol ; 40(1): 20, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38578518

RESUMO

The epithelial-mesenchymal transition (EMT) and fibroblast activation are major events in idiopathic pulmonary fibrosis pathogenesis. Here, we investigated whether growth arrest-specific protein 6 (Gas6) plays a protective role in lung fibrosis via suppression of the EMT and fibroblast activation. rGas6 administration inhibited the EMT in isolated mouse ATII cells 14 days post-BLM treatment based on morphologic cellular alterations, changes in mRNA and protein expression profiles of EMT markers, and induction of EMT-activating transcription factors. BLM-induced increases in gene expression of fibroblast activation-related markers and the invasive capacity of primary lung fibroblasts in primary lung fibroblasts were reversed by rGas6 administration. Furthermore, the hydroxyproline content and collagen accumulation in interstitial areas with damaged alveolar structures in lung tissue were reduced by rGas6 administration. Targeting Gas6/Axl signaling events with specific inhibitors of Axl (BGB324), COX-2 (NS-398), EP1/EP2 receptor (AH-6809), or PGD2 DP2 receptor (BAY-u3405) reversed the inhibitory effects of rGas6 on EMT and fibroblast activation. Finally, we confirmed the antifibrotic effects of Gas6 using Gas6-/- mice. Therefore, Gas6/Axl signaling events play a potential role in inhibition of EMT process and fibroblast activation via COX-2-derived PGE2 and PGD2 production, ultimately preventing the development of pulmonary fibrosis.


Assuntos
Transição Epitelial-Mesenquimal , Fibroblastos , Peptídeos e Proteínas de Sinalização Intercelular , Animais , Camundongos , Ciclo-Oxigenase 2/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Pulmão/metabolismo
4.
Shanghai Kou Qiang Yi Xue ; 33(1): 85-89, 2024 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-38583031

RESUMO

PURPOSE: To study the relationship between the expression of prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2) and the osteogenic activity and oxygen level of alveolar bone. METHODS: The alveolar bones of 56 patients with chronic periodontitis who received dental treatment from March 2021 to March 2023 were collected as the experimental (periodontitis) group, and the healthy alveolar bones of 53 patients who received dental treatment during the same period were selected as the control group. The osteoblasts were cultured by tissue block culture, and modified Kaplow's alkaline phosphatase (ALP) staining was used to identify the cells. COX-2, PGE2 and osteoclastogenesis inhibitory factor (OPG) receptor activator of nuclear factor-κb ligand (RANKL) and other indicators were determined by ELISA. PGE2, COX-2, OPG, internal oxygen level, ALP, RANKL and their correlation were compared between the two groups. Statistical analysis was performed with SPSS 27.0 software package. RESULTS: PGE2, COX-2 and RANKL in periodontitis group were significantly higher than those in the control group, but OPG, internal oxygen level and ALP were significantly lower than those in the control group (P<0.05). PGE2 and COX2 were highly positively correlated with OPG, internal oxygen level and ALP, but were highly positively correlated with RANKL(P<0.05). CONCLUSIONS: The expression of PGE2 and COX-2 is highly negatively correlated with ALP and oxygen levels. Clinical treatment may consider increasing oxygen levels, increasing oxygen partial pressure, and regulating ALP levels by drugs, so as to change the inflammatory condition of periodontitis or other dental diseases.


Assuntos
Dinoprostona , Periodontite , Humanos , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Dinoprostona/farmacologia , Osteoblastos/metabolismo , Osteogênese , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo
5.
Can Respir J ; 2024: 5554886, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38584671

RESUMO

Objective: To investigate the mechanism through which Astragalus and Panax notoginseng decoction (APD) facilitates the treatment of ferroptosis-mediated pulmonary fibrosis. Materials and Methods: First, the electromedical measurement systems were used to measure respiratory function in mice; the lungs were then collected for histological staining. Potential pharmacologic targets were predicted via network pharmacology. Finally, tests including immunohistochemistry, reverse transcription-quantitative polymerase chain reaction, and western blotting were used to evaluate the relative expression levels of collagen, transforming growth factor ß, α-smooth muscle actin, hydroxyproline, and ferroptosis-related genes (GPX4, SLC7A11, ACSL4, and PTGS2) and candidates involved in the mediation of pathways associated with ferroptosis (Hif-1α and EGFR). Results: APD prevented the occurrence of restrictive ventilation dysfunction induced by ferroptosis. Extracellular matrix and collagen fiber deposition were significantly reduced when the APD group compared with the model group; furthermore, ferroptosis was attenuated, expression of PTGS2 and ACSL4 increased, and expression of GPX4 and SLC7A11 decreased. In the APD group, the candidates related to the mediation of ferroptosis (Hif-1α and EGFR) decreased compared with the model group. Discussion and Conclusions. APD may ameliorate restrictive ventilatory dysfunction through the inhibition of ferroptosis. This was achieved through the attenuation of collagen deposition and inflammatory recruitment in pulmonary fibrosis. The underlying mechanisms might involve Hif-1α and EGFR.


Assuntos
Ferroptose , Panax notoginseng , Fibrose Pulmonar , Animais , Camundongos , Fibrose Pulmonar/tratamento farmacológico , Ciclo-Oxigenase 2 , Colágeno , Receptores ErbB
6.
Int J Nanomedicine ; 19: 3031-3044, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38562612

RESUMO

Purpose: Peripheral nerve damage lacks an appropriate diagnosis consistent with the patient's symptoms, despite expensive magnetic resonance imaging or electrodiagnostic assessments, which cause discomfort. Ultrasonography is valuable for diagnosing and treating nerve lesions; however, it is unsuitable for detecting small lesions. Poly(vanillin-oxalate) (PVO) nanoparticles are prepared from vanillin, a phytochemical with antioxidant and anti-inflammatory properties. Previously, PVO nanoparticles were cleaved by H2O2 to release vanillin, exert therapeutic efficacy, and generate CO2 to increase ultrasound contrast. However, the role of PVO nanoparticles in peripheral nerve lesion models is still unknown. Herein, we aimed to determine whether PVO nanoparticles can function as contrast and therapeutic agents for nerve lesions. Methods: To induce sciatic neuritis, rats were administered a perineural injection of carrageenan using a nerve stimulator under ultrasonographic guidance, and PVO nanoparticles were injected perineurally to evaluate ultrasonographic contrast and therapeutic effects. Reverse transcription-quantitative PCR was performed to detect mRNA levels of pro-inflammatory cytokines, ie, tumor necrosis factor-α, interleukin-6, and cyclooxygenase-2. Results: In the rat model of sciatic neuritis, PVO nanoparticles generated CO2 bubbles to increase ultrasonographic contrast, and a single perineural injection of PVO nanoparticles suppressed the expression of tumor necrosis factor-α, interleukin-6, and cyclooxygenase-2, reduced the expression of F4/80, and increased the expression of GAP43. Conclusion: The results of the current study suggest that PVO nanoparticles could be developed as ultrasonographic contrast agents and therapeutic agents for nerve lesions.


Assuntos
Benzaldeídos , Nanopartículas , Neuropatia Ciática , Ratos , Humanos , Animais , Peróxido de Hidrogênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Dióxido de Carbono , Ciclo-Oxigenase 2/metabolismo , Neuropatia Ciática/metabolismo , Neuropatia Ciática/patologia , Nanopartículas/química , Nervo Isquiático/diagnóstico por imagem , Nervo Isquiático/metabolismo
7.
J Ovarian Res ; 17(1): 77, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38594780

RESUMO

PURPOSE: Our explorative study assessed a panel of molecules for their association with epithelial ovarian carcinomas and their prognostic implications. The panel included tissue expression of VEGF-C, COX-2, Ki-67 and eNOS alongside plasma levels of VEGF-C and nitric oxide. METHODS: 130 cases were enrolled in the study. Plasma levels were quantified by ELISA and tissue expressions were scored by immunohistochemistry. The Chi square and Fischer's exact test were applied to examine the impact of markers on clinicopathological factors. Non-parametric Spearman's rank correlation test was applied to define the association among test factors. RESULTS: Plasma VEGF-C levels and COX-2 tissue expression strongly predicted recurrence and poor prognosis (< 0.001). Tissue Ki-67 was strongly indicative of late-stage disease (< 0.001). The aforementioned markers significantly associated with clinicopathological factors. Nuclear staining of VEGF-C was intriguing and was observed to correlate with high grade-stage malignancies, highly elevated plasma VEGF-C, and with recurrence. eNOS tissue expression showed no significant impact while nitric oxide associated positively with ascites levels. Tissue expression of VEGF-C did not associate significantly with poor prognosis although the expression was highly upregulated in most of the cases. CONCLUSION: Plasma VEGF-C holds immense promise as a prognostic marker and the nuclear staining of VEGF-C seems to have some significant implication in molecular carcinogenesis and is a novel finding that commands further robust scrutiny. We present a first such study that assesses a set of biomarkers for prognostic implications in clinical management of epithelial ovarian carcinomas in a pan-Indian (Asian) population.


Assuntos
Neoplasias Ovarianas , Humanos , Feminino , Carcinoma Epitelial do Ovário/patologia , Prognóstico , Neoplasias Ovarianas/patologia , Ciclo-Oxigenase 2/metabolismo , Fator C de Crescimento do Endotélio Vascular , Antígeno Ki-67 , Óxido Nítrico , Estadiamento de Neoplasias , Biomarcadores Tumorais/metabolismo
8.
J Obstet Gynaecol ; 44(1): 2337691, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38594870

RESUMO

BACKGROUND: Existing treatments for primary dysmenorrhoea (PD), such as NSAIDs, impart side effects. Ge-Gen decoction (GGD), a traditional Chinese medicine, has shown promise in treating PD, but its exact mechanisms remain unclear. Here, we aimed to investigate the efficiency of GGD in alleviating PD using a rat model to understand its precise mechanism of action. METHODS: We established a rat model of dysmenorrhoea induced by oestradiol and oxytocin. The PD rats were administered GGD or Ibuprofen (positive control) intragastrically once daily for seven consecutive days. Serum levels of prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2α), ß-endorphin (ß-EP), thromboxane B2 (TXB2), 6-keto-prostaglandin F1α (6-keto-PGF1α) were determined using an enzyme-linked immunosorbent assay (ELISA). The expression levels of oestrogen receptor alpha (ERα) and cyclooxygenase-2 (COX-2) in uterine tissue were measured using immunohistochemical assays, and those of phosphorylated and total extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) were assessed using western blot analysis. RESULTS: Treatment with GGD significantly reduced writhing behaviour, histopathological scores, and levels of COX-2, PGE2, and PGF2α in the serum of PD rats. Additionally, GGD increased ß-EP content and inhibited ERK1/2 activation and ERα expression in uterine tissues. CONCLUSIONS: The results of this study suggest that GGD alleviates PD in rats by suppressing the COX-2-mediated release of PGE2 and PGF2α, modulating the ERα/ERK1/2/COX-2 pathway, and increasing ß-EP content. These results provide insights into the potential mechanisms of GGD in treating PD and support its further investigation as an alternative therapy for this condition.


Ge-Gen decoction is commonly used to alleviate primary dysmenorrhoea. However, its anti-dysmenorrhoea mechanism remains elusive. In this study, using a rat model of primary dysmenorrhoea, we demonstrate that Ge-Gen decoction reduced the levels of cyclooxygenase-2, prostaglandin E2, and prostaglandin F2 alpha in serum and phosphorylated extracellular signal-regulated protein kinases 1 and 2 in the uterus. These results suggest that Ge-Gen decoction alleviates primary dysmenorrhoea via inactivation of the oestrogen receptor alpha/extracellular signal-regulated protein kinases 1 and 2/cyclooxygenase-2 pathway. This study enhances our understanding of the pathogenesis of primary dysmenorrhoea and may potentially inform the development of novel treatment approaches.


Assuntos
Dismenorreia , Receptor alfa de Estrogênio , Humanos , Feminino , Ratos , Animais , Dismenorreia/tratamento farmacológico , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/uso terapêutico , Dinoprostona , Dinoprosta/uso terapêutico
9.
J Diabetes Res ; 2024: 2920694, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38529047

RESUMO

Background: Diabetic keratopathy (DK) poses a significant challenge in diabetes mellitus, yet its molecular pathways and effective treatments remain elusive. The aim of our research was to explore the pyroptosis-related genes in the corneal epithelium of the streptozocin-induced diabetic rats. Methods: After sixteen weeks of streptozocin intraperitoneal injection, corneal epithelium from three diabetic rats and three normal groups underwent whole-transcriptome sequencing. An integrated bioinformatics pipeline, including differentially expressed gene (DEG) identification, enrichment analysis, protein-protein interaction (PPI) network, coexpression, drug prediction, and immune deconvolution analyses, identified hub genes and key drivers in DK pathogenesis. These hub genes were subsequently validated in vivo through RT-qPCR. Results: A total of 459 DEGs were screened out from the diabetic group and nondiabetic controls. Gene Set Enrichment Analysis highlighted significant enrichment of the NOD-like receptor, Toll-like receptor, and NF-kappa B signaling pathways. Intersection of DEGs and pyroptosis-related datasets showed 33 differentially expressed pyroptosis-related genes (DEPRGs) associated with pathways such as IL-17, NOD-like receptor, TNF, and Toll-like receptor signaling. A competing endogenous RNA network comprising 16 DEPRGs, 22 lncRNAs, 13 miRNAs, and 3 circRNAs was constructed. After PPI network, five hub genes (Nfkb1, Casp8, Traf6, Ptgs2, and Il18) were identified as upregulated in the diabetic group, and their expression was validated by RT-qPCR in streptozocin-induced rats. Immune infiltration characterization showed that diabetic corneas owned a higher proportion of resting mast cells, activated NK cells, and memory-resting CD4 T cells. Finally, several small compounds including all-trans-retinoic acid, Chaihu Shugan San, dexamethasone, and resveratrol were suggested as potential therapies targeting these hub genes for DK. Conclusions: The identified and validated hub genes, Nfkb1, Casp8, Traf6, Ptgs2, and Il18, may play crucial roles in DK pathogenesis and serve as therapeutic targets.


Assuntos
Diabetes Mellitus Experimental , Piroptose , Animais , Ratos , Biologia Computacional , Ciclo-Oxigenase 2 , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Interleucina-18 , Piroptose/genética , Estreptozocina , Fator 6 Associado a Receptor de TNF
10.
Int J Biol Macromol ; 264(Pt 1): 130510, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38447847

RESUMO

Pectin polysaccharides have demonstrated diverse biological activities, however, the inflammatory potential of pectin polysaccharides extracted from Cucurbita moschata Duch remains unexplored. This study aims to extract, characterize and evaluate the effects of pumpkin pectin polysaccharide on lipopolysaccharide (LPS)-induced inflammatory response in RAW264.7 cells and dextran sulfate sodium (DSS)-induced colitis in mice, along with its underlying mechanism of action. Initially, we extracted three fractions of pectin polysaccharides from pumpkin and screened them for anti-inflammatory activity in LPS-induced macrophages, identifying CMDP-3a as the most potent anti-inflammatory fraction. Subsequently, CMDP-3a underwent comprehensive characterization through chromatography and spectroscopic analysis, revealing CMDP-3a as an RG-I-HG type pectin polysaccharide with →4)-α-D-GalpA-(1 â†’ and →4)-α-D-GalpA-(1 â†’ 2,4)-α-L-Rhap-(1 â†’ as the main chain. Further, in the LPS-induced RAW264.7 cells model, treatment with CMDP-3a significantly down-regulated the mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and pro-inflammatory cytokines (IL-1ß, TNF-α, and IL-6) by inhibiting the MAPK and NF-κB signaling pathways. Finally, in a mouse colitis model, CMDP-3a administration obviously inhibited DSS-induced pathological alterations and reduced inflammatory cytokine expressions in the colonic tissues by down-regulating the TLR4/NF-κB and MAPK pathways. These findings provide a molecular basis for the potential application of CMDP-3a in reducing inflammatory responses.


Assuntos
Colite , Cucurbita , Animais , Camundongos , NF-kappa B/metabolismo , Lipopolissacarídeos/efeitos adversos , Pectinas/farmacologia , Pectinas/metabolismo , Anti-Inflamatórios/química , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Polissacarídeos/química , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia , Citocinas/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ciclo-Oxigenase 2/metabolismo
11.
J Transl Med ; 22(1): 241, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38443917

RESUMO

BACKGROUND: Tumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity. METHODS: Multiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy. Immune cells infiltrating melanoma lesions and inflamed normal tissues were subjected to gene expression profiling with multiplex qRT-PCR for 122 candidate genes. Subsequently, immunohistochemistry was conducted to assess the expression of 14 candidate markers of immune cell subsets and checkpoints. TCR-beta sequencing was used to explore T cell clonal repertoires across specimens. RESULTS: While genes involved in MHC I/II antigen presentation, IFN signaling, innate immunity and immunosuppression were abundantly expressed across specimens, irAE tissues over-expressed certain genes associated with immunosuppression (CSF1R, IL10RA, IL27/EBI3, FOXP3, KLRG1, SOCS1, TGFB1), including those in the COX-2/PGE2 pathway (IL1B, PTGER1/EP1 and PTGER4/EP4). Immunohistochemistry revealed similar proportions of immunosuppressive cell subsets and checkpoint molecules across samples. TCRseq did not indicate common TCR repertoires across tumor and inflammation sites, arguing against shared antigen recognition between anti-tumor and anti-self immunity in this patient. CONCLUSIONS: This comprehensive study of a single patient with melanoma experiencing both tumor regression and irAEs on ICB explores the immune landscape across these tissues, revealing similarities between anti-tumor and anti-self immunity. Further, it highlights expression of the COX-2/PGE2 pathway, which is known to be immunosuppressive and potentially mediates ICB resistance. Ongoing clinical trials of COX-2/PGE2 pathway inhibitors targeting the major COX-2 inducer IL-1B, COX-2 itself, or the PGE2 receptors EP2 and EP4 present new opportunities to promote anti-tumor activity, but may also have the potential to enhance the severity of ICB-induced irAEs.


Assuntos
Antígenos de Grupos Sanguíneos , Melanoma , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Inibidores de Checkpoint Imunológico , Ciclo-Oxigenase 2 , Dinoprostona , Inibidores de Ciclo-Oxigenase 2 , Inflamação , Receptores de Antígenos de Linfócitos T
12.
Cell Mol Biol (Noisy-le-grand) ; 70(2): 161-168, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38430026

RESUMO

CircRNAs can regulate ferroptosis and affect cancer development and are promising biomarkers and therapeutic targets in lung cancer. circSCUBE3 is expressed in lung adenocarcinoma (LUAD) tissues. In this study, our purpose was to study the role and regulatory mechanism of circSCUBE3 in LUAD ferroptosis. circSCUBE3 was identified to be significantly downregulated in LUAD samples and cell lines. The expression of biomarkers related to lipid oxidation (4-HNE) and ferroptosis (Ptgs2) was both downregulated in LUAD tissues, suggesting the ferroptosis resistance in LUAD. Erastin, a ferroptosis inducer, was used to stimulate the LUAD cells for 48 h. The cell viability, 4-HNE and Ptgs2 level of LUAD cells were decreased by exposure to erastin while the expression of circSCUBE3 was not significantly altered. We then overexpressed circSCUBE3 in LUAD cells and found it decreased the GSH level and GSH/GSSG ratio in LUAD cells. CircSCUBE3 might serve as an independent factor of ferroptosis and may induce ferroptosis in LUAD by inhibiting GSH synthesis. The loss-of-function experiments were conducted, and circSCUBE3 deficiency reversed the erastin-induced reduction in cell viability, GSH level, GSH/GSSG ratio, mitochondrial membrane potential and elevation in MDA content, Ptgs2, 4-HNE expression as well as lipid ROS production. CircSCUBE3 negatively regulated GPX4 expression in LUAD cells, and the silencing of GPX4 counteracted the impact of circSCUBE3 deficiency on LUAD cell viability as well as ferroptosis, suggesting that circSCUBE3 regulated the GPX4-mediated GSH synthesis in LUAD. CircSCUBE3 was to bind to CREB, which activated the transcription of GPX4. CircSCUBE3 negatively regulated GPX4 expression by competitively interacting with CREB. In the tumor-bearing mouse models, circSCUBE3 silencing promoted tumor growth and reversed the erastin treatment-induced inhibition on tumorigenesis in vivo. In conclusion, circSCUBE3 inhibited LUAD development by promoting ferroptosis via the CREB/GPX4/GSH axis, which might provide a novel option for the LUAD targeted therapy.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Ferroptose , Neoplasias Pulmonares , Animais , Camundongos , Ciclo-Oxigenase 2/genética , Ferroptose/genética , Dissulfeto de Glutationa , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Biomarcadores , Lipídeos
13.
Cancer Med ; 13(3): e6986, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38426619

RESUMO

BACKGROUND: PTGS2 encodes cyclooxygenase-2 (COX-2), which catalyses the committed step in prostaglandin synthesis. Various in vivo and in vitro data suggest that COX-2 mediates the VEGF signalling pathway. In silico analysis performed in TCGA, PanCancer Atlas for head and neck cancers, demonstrated significant expression and co-expression of PTGS2 and genes that regulate VEGF signalling. This study was designed to elucidate the expression pattern of PTGS2 and genes regulating VEGF signalling in patients with locally advanced oral squamous cell carcinoma (OSCC). METHODOLOGY: Tumour and normal tissue samples were collected from patients with locally advanced OSCC. RNA was isolated from tissue samples, followed by cDNA synthesis. The cDNA was used for gene expression analysis (RT-PCR) using target-specific primers. The results obtained were compared with the in silico gene expression of the target genes in the TCGA datasets. Co-expression analysis was performed to establish an association between PTGS2 and VEGF signalling genes. RESULTS: Tumour and normal tissue samples were collected from 24 OSCC patients. Significant upregulation of PTGS2 expression was observed. Furthermore, VEGFA, KDR, CXCR1 and CXCR2 were significantly upregulated in tumour samples compared with paired normal samples, except for VEGFB, whose expression was not statistically significant. A similar expression pattern was observed in silico, except for CXCR2 which was highly expressed in the normal samples. Co-expression analysis showed a significant positive correlation between PTGS2 and VEGF signalling genes, except for VEGFB which showed a negative correlation. CONCLUSION: PTGS2 and VEGF signalling genes are upregulated in OSCC, which has a profound impact on clinical outcomes.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/patologia , Ciclo-Oxigenase 2/genética , Fator A de Crescimento do Endotélio Vascular/genética , DNA Complementar
14.
Sci Rep ; 14(1): 7559, 2024 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-38555391

RESUMO

Chronic rhinosinusitis (CRS) can be traditionally classified as CRSwNP [with nasal polyps (NPs)] and CRSsNP (without NPs) based on the clinical phenotypes but recently suggested to be classified by the endotypes. We have identified overexpression of the cyclooxygenase-2 (COX-2) gene in NP tissues of Taiwanese CRSwNP patients. Therefore, in this study, we sought to investigate its protein expression/location/distribution in NP specimens and explore its roles in nasal polyposis. The COX-2 protein and mRNA expression was found higher in NPs than that in the control and CRSsNP patients' nasal tissues, mainly located at the epithelium and subepithelial stroma. Consistently, the CRS-related peptidoglycan (PGN) and bradykinin provoked COX-2 mRNA and protein upregulation in the human NP-derived fibroblasts and caused PGE2, thromboxane A2 (TXA2), and interleukin (IL-6) secretion in culture medium. Further analysis revealed that the PI3K/Akt activation and COX-2 induction were necessarily required for PGN-induced IL-6 production/secretion and the induced PGE2, but not TXA2, was speculated to affect IL-6 protein trafficking and production. Finally, the IL-6 increase observed in vitro could also be detected in NP tissues. Collectively, we demonstrated here that COX-2 protein and IL-6 are overexpressed in human NP tissues. In response to PGN challenge, the PI3K/Akt activation and COX-2-mediated PGE2 autacoid correlates with extracellular IL-6 protein trafficking/production in NP-derived fibroblasts, which can additionally contribute to the production of Th17-related cytokines such as IL-17 and TNF-α. This study also suggests COX-2 as a special biomarker for CRSwNP endotyping and may highlight the importance of COX-2 inhibitors in treating CRSwNP.


Assuntos
Pólipos Nasais , Rinite , Humanos , Doença Crônica , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/uso terapêutico , Fibroblastos/metabolismo , Interleucina-6/metabolismo , Pólipos Nasais/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rinite/genética , RNA Mensageiro/metabolismo , Regulação para Cima
15.
J Ethnopharmacol ; 327: 117997, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38442805

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Yataprasen is a topical Thai herbal remedy for the treatment of musculoskeletal pain and is included in Kumpe Thart Phra Narai, the first Thai textbook of traditional medicine. The herbal preparation is made from a hydroethanolic extract of a mixture of 13 medicinal plants, of which Putranjiva roxburghii Wall. leaves are the major ingredient. AIM OF THE STUDY: In this study, we investigated the underlying mechanism of action for the anti-inflammatory effects of the Yataprasen remedy, its main ingredients, and the phytochemicals isolated from P. roxburghii leaves. MATERIALS AND METHODS: The anti-inflammatory effects of the Yataprasen remedy, along with its main ingredients, including the leaves of Baliospermum solanifolium (Burm.) Suresh, Melia azedarach L., P. roxburghii, Senna siamea (Lam.) Irwin & Barneby, and Tamarindus indica L. were determined by measuring prostaglandin E2 (PGE2) secretion, nitric oxide (NO) production, and the synthesis of inflammatory biomarkers in lipopolysaccharide (LPS)-treated RAW264.7 macrophage cells. The active ingredients of the P. roxburghii leaves were separated by chromatography and spectroscopic measurements were used to identify their chemical structures. RESULTS: Ethanol extracts of the Yataprasen remedy and some of its ingredients significantly suppressed LPS-induced PGE2 secretion and NO production in a dose-dependent manner. Treatment of RAW264.7 cells with ethanolic extracts of the Yataprasen remedy (50 µg/mL) significantly inhibited LPS-induced mRNA expression of TNF-α, COX-2, iNOS, and NF-κB. Among the plant ingredient extracts, P. roxburghii leaf extract exhibited the highest inhibitory effects on LPS-induced TNF-α and iNOS expression. Moreover, T. indica leaf extract showed the highest activity on the inhibition of LPS-induced COX-2 and NF-κB expression. Putraflavone, podocarpusflavone A, and amentoflavone were isolated biflavonoids from P. roxburghii leaf extract and showed the inhibitory effects on LPS-induced PGE2 secretion and NO synthesis in RAW264.7 cells. Of the isolated biflavonoids, amentoflavone exhibited the strongest anti-inflammatory activity by inhibiting the expression of TNF-α, COX-2, and iNOS. CONCLUSION: The results support reported the anti-inflammatory effects of the Yataprasen remedy, which are associated with the downregulation of proinflammatory mediators. P. roxburghii, along with its biflavonoids, are the impact components that contribute to the anti-inflammatory effects of the herbal remedy.


Assuntos
Biflavonoides , NF-kappa B , NF-kappa B/metabolismo , Biflavonoides/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Lipopolissacarídeos/farmacologia , Ciclo-Oxigenase 2/metabolismo , Tailândia , Linhagem Celular , Macrófagos , Extratos Vegetais/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Etanol/farmacologia , Óxido Nítrico/metabolismo
16.
J Alzheimers Dis ; 98(2): 699-713, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427490

RESUMO

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease and symptoms develop gradually over many years. The current direction for medication development in AD is focused on neuro-inflammation and oxidative stress. Amyloid-ß (Aß) deposition activates microglia leading to neuro-inflammation and neurodegeneration induced by activation of COX-2 via NFκB p50 in glioblastoma cells. Objective: The study aimed to evaluate the concentration of COX-2 and NFκB p50 in serum of AD, mild cognitive impairment (MCI), and geriatric control (GC) and to establish a blood-based biomarker for early diagnosis and its therapeutic implications. Methods: Proteins and their mRNA level in blood of study groups were measured by surface plasmon resonance (SPR) and quantitative polymerase chain reaction (qPCR), respectively. The level of protein was further validated by western blot. The binding study of designed peptide against COX-2 by molecular docking was verified by SPR. The rescue of neurotoxicity by peptide was also checked by MTT assay on SH-SY5Y cells (neuroblastoma cell line). Results: Proteins and mRNA were highly expressed in AD and MCI compared to GC. However, COX-2 decreases with disease duration. The peptide showed binding affinity with COX-2 with low dissociation constant in SPR and rescued the neurotoxicity of SH-SY5Y cells by decreasing the level of Aß, tau, and pTau proteins. Conclusions: It can be concluded that COX-2 protein can serve as a potential blood-based biomarker for early detection and can be a good platform for therapeutic intervention for AD.


Assuntos
Doença de Alzheimer , Neuroblastoma , Doenças Neurodegenerativas , Humanos , Idoso , Doença de Alzheimer/genética , Ciclo-Oxigenase 2 , Simulação de Acoplamento Molecular , Peptídeos beta-Amiloides/metabolismo , Inflamação/metabolismo , Biomarcadores , Diagnóstico Precoce , RNA Mensageiro , Proteínas tau/metabolismo , Fragmentos de Peptídeos/uso terapêutico
17.
BMC Res Notes ; 17(1): 82, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38504371

RESUMO

OBJECTIVE: Tristetraprolin (TTP/ZFP36) family proteins exhibit antiinflammatory effects by destabilizing proinflammatory mRNAs. Previous studies showed that bacterial endotoxin lipopolysaccharides (LPS) stimulated TTP and tumor necrosis factor (TNF) gene expression, but less was known about LPS effects on TTP homologues and other proinflammatory gene expression in macrophages. The objective was to investigate LPS regulation of TTP family gene and TTP-targeted gene expression in mouse RAW264.7 macrophages using much higher concentrations of LPS and much longer treatment time than previous studies. RESULTS: MTT assay showed that LPS was not toxic to the cells under LPS treatment up to 1000 ng/mL for 2-24 h. LPS mildly affected the soluble protein content in the cells. qPCR assay showed that LPS stimulated TTP mRNA rapidly but not sustainably with 40, 10, and 3 fold of the DMSO control after 2, 8 and 24 h treatment, respectively. Immunoblotting confirmed qPCR results on LPS stimulation of TTP gene expression in the mouse macrophages. LPS exhibited minimal effects on ZFP36L1, ZFP36L2 and ZFP36L3 mRNA levels. LPS increased mRNA levels of TNF, COX2, GM-CSF, INFγ and IL12b up to 311, 418, 11, 9 and 4 fold, respectively. This study demonstrated that LPS did not affect macrophage viability, dramatically increased antiinflammatory TTP gene expression as well as proinflammatory TNF and COX2 gene expression but had only mild effects on TTP homologues and other proinflammatory cytokine gene expression in the mouse macrophages.


Assuntos
Lipopolissacarídeos , Tristetraprolina , Camundongos , Animais , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , Tristetraprolina/genética , Tristetraprolina/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Macrófagos/metabolismo , Anti-Inflamatórios/farmacologia , Expressão Gênica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação da Expressão Gênica
18.
Biomed Pharmacother ; 173: 116340, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38428308

RESUMO

The current study investigated the ameliorating impact of GA water extract (GAE) on CCl4-induced nephrotoxicity in renal cells and tissue by comparing its effectiveness with the Ketosteril (Ks) drug in restoring oxidative stress and necroinflammation. The cell morphology, necrosis, and redox state were evaluated in Vero cells. The influence of GAE on CCl4-induced oxidative stress, inflammation, and necrosis was examined in rats. The predicted inhibitory mechanism of GAE phenolic constituents against COX-2 and iNOS was also studied. The results revealed that GAE contains crucial types of phenolic acids, which are associated with its antiradical activities. GAE improved CCl4-induced Vero cell damage and restored renal architecture damage, total antioxidant capacity, ROS, TBARS, NO, GSH, GPX, SOD, and MPO in rats. GAE downregulated the gene expression of renal NF-κB, TNF-α, iNOS, and COX-2, as well as kidney injury molecule-1 (KIM-1) in rats. The GAE improved blood urea, creatinine, cholesterol, and reducing power. The computational analysis revealed the competitive inhibitory mechanism of selected phenolic composites of GAE on COX-2 and iNOS activities. The GAE exhibited higher potency than Ks in most of the studied parameters, as observed by the heatmap plots. Thus, GAE is a promising extract for the treatment of kidney toxicity.


Assuntos
NF-kappa B , Insuficiência Renal , Chlorocebus aethiops , Ratos , Animais , NF-kappa B/metabolismo , Tetracloreto de Carbono/toxicidade , Goma Arábica , Células Vero , Ciclo-Oxigenase 2/metabolismo , Antioxidantes/farmacologia , Estresse Oxidativo , Insuficiência Renal/metabolismo , Oxirredução , Rim/metabolismo , Necrose/metabolismo
19.
Bioorg Chem ; 145: 107244, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38428284

RESUMO

Complications of the worldwide use of non-steroidal anti-inflammatory drugs (NSAIDs) sparked scientists to design novel harmless alternatives as an urgent need. So, a unique hybridization tactic of quinoline/pyrazole/thioamide (4a-c) has been rationalized and synthesized as potential COX-2/15-LOX dual inhibitors, utilizing relevant reported studies on these pharmacophores. Moreover, we extended these preceding hybrids into more varied functionality, bearing crucial thiazole scaffolds(5a-l). All the synthesized hybrids were evaluatedin vitroas COX-2/15-LOX dual inhibitors. Initially, series4a-cexhibited significant potency towards 15-LOX inhibition (IC50 = 5.454-4.509 µM) compared to meclofenamate sodium (IC50 = 3.837 µM). Moreover, they revealed reasonable inhibitory activities against the COX-2 enzyme in comparison to celecoxib.Otherwise, conjugates 5a-ldisclosed marked inhibitory activity against 15-LOX and strong inhibitory to COX-2. In particular, hybrids5d(IC50 = 0.239 µM, SI = 8.95), 5h(IC50 = 0.234 µM, SI = 20.35) and 5l (IC50 = 0.201 µM, SI = 14.42) revealed more potency and selectivity outperforming celecoxib (IC50 = 0.512 µM, SI = 4.28). In addition, the most potentcompounds, 4a, 5d, 5h, and 5l have been elected for further in vivoevaluation and displayed potent inhibition of edema in the carrageenan-induced rat paw edema test that surpassed indomethacin. Further, compounds5d, 5h, and 5l decreased serum inflammatory markers including oxidative biomarkersiNO, and pro-inflammatory mediators cytokines like TNF-α, IL-6, and PGE. Ulcerogenic liability for tested compounds demonstrated obvious gastric mucosal safety. Furthermore, a histopathological study for compound 5l suggested a confirmatory comprehensive safety profile for stomach, kidney, and heart tissues. Docking and drug-likeness studies offered a good convention with the obtained biological investigation.


Assuntos
Inibidores de Ciclo-Oxigenase 2 , Quinolinas , Ratos , Animais , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Celecoxib/uso terapêutico , Ciclo-Oxigenase 1/metabolismo , Inibidores de Lipoxigenase/farmacologia , Inibidores de Lipoxigenase/uso terapêutico , Simulação de Acoplamento Molecular , Anti-Inflamatórios não Esteroides , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Edema/induzido quimicamente , Edema/tratamento farmacológico , Relação Estrutura-Atividade , Estrutura Molecular
20.
J Zoo Wildl Med ; 55(1): 73-85, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38453490

RESUMO

Firocoxib is a COX-2-selective nonsteroidal anti-inflammatory drug (NSAID) with limited effects on COX-1, which means it likely has fewer side effects than typically associated with other NSAIDs. This study determined possible doses of firocoxib based on single- and multidose pharmacokinetic trials conducted in 10 Asian elephants (Elephas maximus). Initially, two single oral dose trials (0.01 and 0.1 mg/kg) of a commercially available tablet (n = 6) and paste (n = 4) formulation were used to determine a preferred dose. The 0.1 mg/kg dose was further evaluated via IV single dose (n = 3) and oral multidose trials (tablets n = 6; paste n = 4). Serum peak and trough firocoxib concentrations were also evaluated in Asian elephants (n = 4) that had been being treated for a minimum of 90 consecutive days. Key pharmacokinetic parameters for the 0.1 mg/kg single-dose trials included mean peak serum concentrations of 49 ± 3.3 ng/ml for tablets and 62 ± 14.8 ng/ml for paste, area under the curve (AUC) of 1,332 ± 878 h*mg/ml for tablets and 1,455 ± 634 h*mg/ml for paste, and half-life (T1/2) of 34.3 ± 30.3 h for tablets and 19.9 ± 12.8 h for paste. After 8 d of dosing at 0.1 mg/kg every 24 h, pharmacokinetic parameters stabilized to an AUC of 6,341 ± 3,003 h*mg/ml for tablets and 5,613 ± 2,262 for paste, and T1/2 of 84.4 ± 32.2 h for tablets and 62.9 ± 2.3 h for paste. Serum COX inhibition was evaluated in vitro and ex vivo in untreated elephant plasma, where firocoxib demonstrated preferential inhibition of COX-2. No adverse effects from firocoxib administration were identified in this study. Results suggest administering firocoxib to Asian elephants at a dose of 0.1 mg/kg orally, using either tablet or paste formulations, every 24 h.


Assuntos
4-Butirolactona/análogos & derivados , Elefantes , Sulfonas , Animais , Ciclo-Oxigenase 2 , Monitoramento de Medicamentos , Administração Oral , Anti-Inflamatórios não Esteroides , Comprimidos , Área Sob a Curva , Estudos Cross-Over , Meia-Vida
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