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Lung cancer (LC) is the leading cause of cancer‐related death worldwide, with non‐small cell lung cancer (NSCLC) comprising 85% of all cases. COX‐2, an enzyme induced significantly under stress conditions, catalyzes the conversion of free arachidonic acid into prostaglandins. It exhibits high expression in various tumors and is closely linked to LC progression. COX‐2 functions as a pivotal driver in cancer pathogenesis by promoting prostaglandin E2 synthesis and facilitating tumor cell occurrence and development. Furthermore, COX‐2 holds potential as a predictive marker for early‐stage NSCLC, guiding targeted therapy in patients with early COX‐2 overexpression. Additionally, combining COX‐2 inhibitors with diverse treatment modalities enhances tumor therapeutic efficacy, minimizes adverse effects on healthy tissues, and improves overall patient survival rates posttreatment. In conclusion, combined therapy targeting COX‐2 presents a promising novel strategy for NSCLC treatment, offering avenues for improving prognosis and effective tumor treatment. This review provides novel insights and ideas for developing new treatment strategies to improve the prognosis of NSCLC. COX‐2 functions in the tumor microenvironment. Key points COX‐2 cross‐interacts with a variety of signaling molecules, participating in multiple signaling pathways and in the development of tumors. Targeted COX‐2 therapy can effectively inhibit the occurrence and development of non‐small cell lung cancer. Potential future drug development, limitations, and prospects for targeted COX‐2 therapy.

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.

Since colorectal cancer is one of the world’s most common cancers, studies on its prevention and early diagnosis are an emerging area of clinical oncology these days. For this study, a review of randomized controlled, double-blind clinical trials of selected NSAIDs (aspirin, sulindac and celecoxib) in chemoprevention of colorectal cancer was conducted. The main molecular anticancer activity of NSAIDs is thought to be a suppression of prostaglandin E2 synthesis via cyclooxygenase-2 inhibition, which causes a decrease in tumor cell proliferation, angiogenesis, and increases apoptosis. The lower incidence of colorectal cancer in the NSAID patients suggests the long-lasting chemopreventive effect of drugs studied. This new approach to therapy of colorectal cancer may transform the disease from a terminal to a chronic one that can be taken under control.

The cyclooxygenase (COX) pathway regulates vascular tone and, therefore, local O2 delivery‐utilization matching. The two main isoforms, COX‐1 and COX‐2, may promote opposing effects on contracting muscle O2 transport in health by inducing vasoconstriction and vasodilatation, respectively. Whether COX‐2 and its main vasodilatory product (prostacyclin, PGI2) modulate microvascular O2 transport to skeletal muscle and thus exercise tolerance is unknown. We tested the hypothesis that acute selective COX‐2 inhibition (SC2I) would impair cardiorespiratory and skeletal muscle microvascular responses from rest to exercise, thereby reducing exercise tolerance in healthy adults. Twelve individuals participated in a randomized, double‐blind, crossover study to receive SC2I (200 mg celecoxib) or placebo (control, CON). Moderate and severe intensity cycling were performed with measurements of heart rate, arterial blood pressure, pulmonary oxygen uptake (V̇O2 ${\\dot V_{{{\\mathrm{O}}_2}}}$ ), leg muscle microvascular oxygenation (StO2 ${S_{{\\mathrm{t}}{{\\mathrm{O}}_2}}}$ ; near‐infrared spectroscopy) and time to exhaustion. Leg muscle StO2 ${S_{{\\mathrm{t}}{{\\mathrm{O}}_2}}}$was also assessed during cuff occlusion protocols. SC2I decreased the plasma concentration of the stable PGI2 metabolite 6‐keto prostaglandin F1α (CON: 203 (54) pg/mL; SC2I: 108 (54) pg/mL; P = 0.002). There was no difference in exercise tolerance (CON: 278 (55) s; SC2I: 298 (75) s), arterial blood pressure, heart rate, pulmonary V̇O2 ${\\dot V_{{{\\mathrm{O}}_2}}}$or leg muscle StO2 ${S_{{\\mathrm{t}}{{\\mathrm{O}}_2}}}$from rest to moderate or severe exercise between conditions (P > 0.05 for all). Moreover, there was no significant difference in StO2 ${S_{{\\mathrm{t}}{{\\mathrm{O}}_2}}}$during cuff occlusion protocols between conditions. Contrary to our hypothesis, these data indicate that COX‐2 is not obligatory for the regulation of skeletal muscle microvascular oxygenation at rest or during moderate or severe intensity exercise, and therefore does not modulate exercise tolerance in healthy adults. What is the central question of this study? What are the effects of acute selective cyclooxygenase‐2 (COX‐2) inhibition via oral celecoxib on cardiorespiratory and skeletal muscle microvascular function at rest and during moderate and severe intensity exercise in healthy young individuals? What is the main finding and its importance? Selective COX‐2 inhibition reduced plasma prostacyclin metabolites but had no effect on central or peripheral determinants of oxygen transport, peak oxygen uptake or exercise tolerance. These findings indicate that COX‐2 is not obligatory for skeletal muscle oxygen delivery–utilization matching at rest or during contractions in healthy adults.

Inflammatory responses, while essential for host defence, can precipitate chronic pathologies when sustained. The polyphenolic entity xanthone is distinguished by its capacity to modulate inflammation, notably via the inhibition of the COX‐2 enzyme and associated inflammatory pathways. Additionally, heterocyclic frameworks such as pyrazole, triazole, and imidazole are recognised for their anti‐inflammatory attributes. This investigation was conducted to engineer and synthesise a series of novel hybrid‐xanthone molecules with enhanced anti‐inflammatory capabilities. Utilising computational docking strategies, these hybrid‐xanthone variants were virtually screened against the COX‐2 enzyme structure (PDB ID:1CX2), and the 10 leading candidates were identified based on their binding affinities. These selected entities were synthesised through an optimised three‐stage synthetic route. Subsequent in vitro assessments were performed using the Egg albumin denaturation assay at incremental concentrations. Complementary in vivo experiments involved the Carrageenan‐induced paw edema protocol in Wistar rats, administered at 200 mg/kg to evaluate the anti‐inflammatory response over a period of 6 h. The best percentage inhibition was shown by compound A127(3‐(5′(1,2,4‐Triazole)‐pentyloxy)‐1,6,8‐trihydroxy xanthone), A11(3‐(1′‐(1,2,4‐Triazole)‐methyloxy)‐1,6,8‐trihydroxy xanthone) and A119(3‐(1′‐(1,2,4‐Triazole)‐methyloxy)‐1,6,8‐trihydroxy xanthone) as 60 ± 0.31, 58.57 ± 0.023, and 57.14 ± 0.21 respectively. Spectroscopic characterisation of the compounds was achieved through UV, IR, NMR, and Mass spectrometry techniques. The investigation revealed that out of the synthesised cohort, nine compounds exhibited favourable in silico profiles, and half of these manifested substantial anti‐inflammatory efficacy in both in vitro and in vivo models, outperforming the reference standard. These hybrid‐xanthone molecules demonstrated precise COX‐2 inhibition and maintained an acceptable safety margin in vivo, underscoring their therapeutic promise as anti‐inflammatory agents.

Acute or repetitive exposure to ultraviolet (UV) cause disruptions to the skin barrier and subsequent inflammatory skin disease. 4‐phenylpyridine (4‐PP) is a constituent of Brassica campestris L. ssp. Pekinensis and its effect on skin inflammation and molecular target remain unclear. The purpose of this study is to confirm the anti‐inflammatory efficacy of 4‐PP on UVB‐induced skin inflammation in human keratinocytes HaCaT and mouse skin and validation of its molecular target. 4‐PP also attenuated UVB‐induced phosphorylation of p38/mitogen‐activated protein kinase kinase (MKK) 3/6, c‐Jun N‐terminal kinase 1/2, MKK 4/7, extracellular‐signal‐regulated kinase 1/2, mitogen‐activated protein kinase 1/2. Additionally, 4‐PP inhibited UVB‐induced phosphorylation of epidermal growth factor receptor (EGFR) Y1068, Y1045 and 854 residues but not the proto‐oncogene tyrosine‐protein kinase c‐Src. Drug affinity responsive target stability assay revealed that 4‐PP directly binds to c‐Src and inhibits pronase c‐proteolysis. Knockdown of c‐Src inhibited UVB‐induced COX‐2 expression and phosphorylation of MAPKs and EGFR in HaCaT cells. Dorsal treatment of 4‐PP prevented UVB (0.5 J/cm2)‐induced skin thickness, phosphorylation of EGFR and COX‐2 expression in mouse skin. Our findings suggest that 4‐PP can be used as anti‐inflammatory agent with an effect of skin inflammation by inhibiting the COX‐2 expression via suppressing the c‐Src/EGFR/MAPKs signalling pathway.

Although Hif‐2α is a master regulator of catabolic factor expression in osteoarthritis development, Hif‐2α inhibitors remain undeveloped. The aim of this study was to determine whether Cirsium japonicum var. maackii (CJM) extract and one of its constituents, apigenin, could attenuate the Hif‐2α‐induced cartilage destruction implicated in osteoarthritis progression. In vitro and in vivo studies demonstrated that CJM reduced the IL‐1β‐, IL‐6, IL‐17‐ and TNF‐α‐induced up‐regulation of MMP3, MMP13, ADAMTS4, ADAMTS5 and COX‐2 and blocked osteoarthritis development in a destabilization of the medial meniscus mouse model. Activation of Hif‐2α, which directly up‐regulates MMP3, MMP13, ADAMTS4, IL‐6 and COX‐2 expression, is inhibited by CJM extract. Although cirsimarin, cirsimaritin and apigenin are components of CJM and can reduce inflammation, only apigenin effectively reduced Hif‐2α expression and inhibited Hif‐2α‐induced MMP3, MMP13, ADAMTS4, IL‐6 and COX‐2 expression in articular chondrocytes. IL‐1β induction of JNK phosphorylation and IκB degradation, representing a critical pathway for Hif‐2α expression, was completely blocked by apigenin in a concentration‐dependent manner. Collectively, these effects indicate that CJM and one of its most potent constituents, apigenin, can lead to the development of therapeutic agents for blocking osteoarthritis development as novel Hif‐2α inhibitors.

Glioblastoma (GBM) is an aggressive and highly malignant primary brain tumour, accounting for a significant proportion of adult brain tumours. It is associated with a poor prognosis and high recurrence rates. Although temozolomide (TMZ) remains the standard first‐line chemotherapy for GBM, its clinical efficacy is often limited by the development of drug resistance and toxic effects on normal tissues. Melatonin (Mel), a natural indoleamine synthesised by the pineal gland, has demonstrated synergistic anti‐tumour effects when combined with various chemotherapy agents in multiple studies. This study investigates the synergistic potential of Mel to enhance TMZ's therapeutic efficacy against GBM. The results demonstrate that the combination of Mel and TMZ significantly inhibits glioblastoma cell proliferation, migration, and invasion. Mechanistically, this synergistic effect is mediated through the NF‐κB/COX‐2 signalling pathway. Mel enhances TMZ's anti‐tumour activity by inhibiting IκBα phosphorylation, suppressing NF‐κB activation, and downregulating COX‐2 expression. Additionally, the combination treatment induced apoptosis via activation of the Caspase‐3 pathway. These results suggest that Mel can potentiate the therapeutic efficacy of TMZ in glioblastoma treatment, offering a promising strategy to overcome TMZ resistance while reducing its associated toxicity.

Obesity is a world‐wide problem, especially the child obesity, with the complication of various metabolic diseases. Child obesity can be developed as early as the age between 2 and 6. The expansion of fat mass in child age includes both hyperplasia and hypertrophy of adipose tissue, suggesting the importance of proliferation and adipogenesis of preadipocytes. The changed composition of gut microbiota is associated with obesity, revealing the roles of lipopolysaccharide (LPS) on manipulating adipose tissue development. Studies suggest that LPS enters the circulation and acts as a pro‐inflammatory regulator to facilitate pathologies. Nevertheless, the underlying mechanisms behind LPS‐modulated obesity are yet clearly elucidated. This study showed that LPS enhanced the expression of cyclooxygenase‐2 (COX‐2), an inflammatory regulator of obesity, in preadipocytes. Pretreating preadipocytes with the scavenger of reactive oxygen species (ROS) or the inhibitors of NADPH oxidase or p42/p44 MAPK markedly decreased LPS‐stimulated gene expression of COX‐2 together with the phosphorylation of p47phox and p42/p44 MAPK, separately. LPS activated p42/p44 MAPK via NADPH oxidase‐dependent ROS accumulation in preadipocytes. Reduction of intracellular ROS or attenuation of p42/p44 MAPK activation both reduced LPS‐mediated COX‐2 expression and preadipocyte proliferation. Moreover, LPS‐induced preadipocyte proliferation and adipogenesis were abolished by the inhibition of COX‐2 or PEG2 receptors. Taken together, our results suggested that LPS enhanced the proliferation and adipogenesis of preadipocytes via NADPH oxidase/ROS/p42/p44 MAPK‐dependent COX‐2 expression.

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.