COX-2 downregulation via G-quadruplex structure induction in the PTGS2-promoter region by mononuclear octahedral cobalt(III) Schiff base complex [CoL3] in colorectal cancer cells.

Ferrostatin-1 attenuates sepsis-induced lung injury by inhibiting ferroptosis via activation of the SLC7A11/GSH/GPX4 signaling pathway.

Transforming growth factor (TGF)-β1 is a pro-fibrotic cytokine that affects extracellular matrix (ECM) deposition and fibroblast activity. 17β-Estradiol (E2), the dominant ovarian steroid during the follicular phase (FLP) of the estrous cycle, can also influence ECM remodeling and fibrosis, through prostaglandin (PG) synthesis. PGs have opposing roles in fibrosis, with PGE₂ showing anti-fibrotic effects and PGF₂α promoting fibrosis. Equine endometrosis, whose main pathological feature is fibrosis, is marked by chronic inflammation and ECM accumulation, and may involve mediators like TGF-β1, PGs, and E2. This study aimed to assess how TGF-β1, E2, and their combination affect PG synthase and receptors transcription (qPCR) and PG concentrations (ELISA) in equine endometrial explants during the FLP, after 24 and 48 h. Prostaglandin-endoperoxide synthase 2 (PTGS-2) mRNA was reduced with TGF-β1 and combination treatments at 24 h. Estradiol and combined treatments downregulated microsomal prostaglandin E synthase1 (PGES) mRNA at 24 h, while prostaglandin F synthase (PGFS) mRNA reduced with TGF-β1 at 24 h and with E2 at 48 h. The PGE₂ concentration was lower in TGF-β1 +E2 group than in controls and TGF-β1 alone at 48 h. In contrast, PGF₂α concentration increased with E2 at 24 h and TGF-β1 and TGF-β1 +E2 treatments at 48 h. Prostaglandin E receptor (EP)2 and 4 mRNA upregulated with the combination treatment, while prostaglandin F receptor (FP) mRNA decreased in all treated groups. These findings suggest that TGF-β1 and E2 interact to regulate PG pathways, with potential to drive fibrotic changes in the equine endometrium, by shifting the balance between anti- and pro-fibrotic mediators like PGE₂ and PGF₂α.

Cyclometalated iridium complex as a PD-L1 inhibitor: Suppressing expression via COX-2 blockade.

Thiophene-based styrene derivative improves colitis symptoms in DSS-induced BALB/C mice through AhR-mediated gut barrier function and inflammatory responses.

Recent advances in understanding the pathogenesis, diagnosis, and treatment of tuberous sclerosis complex (TSC)-associated Lymphangioleiomyomatosis.

An indoloquinolinone 3a alleviates lipopolysaccharide-induced acute lung injury by modulating the NF-κB and AMPK/Nrf2 signaling pathways.

In 2019, a number of patients were hospitalized after the use of electronic cigarettes and displayed acute lung injuries. Such injury was categorized as e-cigarette or vaping associated lung injury (EVALI). Among these patients, Vitamin E acetate (VEA) was detected in most used electronic cigarette cartridges as well as the patients' bronchoalveolar lavage fluid, suggesting VEA to be a culprit of causing lung injury. Although further experiments verified the potential of VEA aerosol to cause cytotoxicity and lung injury, mechanisms of VEA aerosol toxicity are not well understood. In this study, we tested the toxicity of VEA, and its aerosol using a human macrophage model. VEA aerosols significantly induced oxidative stress as well as proinflammatory responses. In addition, the aerosol activated the aryl hydrocarbon receptor (AhR) signaling pathway, inducing CYP1A1 expression in human U937 monocyte-derived macrophages. Additionally, non-aerosolized VEA and VEA aerosol induce the expression of inflammatory markers such as interleukin (IL)-8 and cyclooxygenase (COX)-2 in an AhR-dependent manner as shown in CRISPR-cas9 AhR-knockout U937-derived human macrophages. These results suggest that VEA is an agonist for AhR and provide new potential mechanisms for lung injury induced by VEA aerosol inhalation via AhR activation in addition to the generation of oxidative stress.

Cyclooxygenase-2 (COX-2) is overexpressed in various cancers and has emerged as a promising target in oncological pharmacotherapy. This study investigates the in vitro antitumor properties and mechanism of action of novel vicinal diaryl-substituted heterocyclic COX-2 inhibitors, with a focus on VA1213, in comparison to celecoxib, a widely marketed COX-2 inhibitor known for its off-target effects. We assessed cytotoxicity, apoptosis induction, cell-cycle distribution, antimetastatic activity, and alterations in key signaling pathways in HT-29 colorectal carcinoma and MDA-MB-231 breast carcinoma cell lines. Among the novel compounds, VA1213 exhibited the most potent growth-inhibitory activity, demonstrating time-dependent cytotoxicity with a lower IC50 after 48-72 h of treatment compared to VA692 and VA694, and consistent with that observed for celecoxib. Unlike celecoxib, which produced rapid cytotoxic effects, VA1213 required prolonged exposure, suggesting a distinct mechanism of action. VA1213 induced G₀/G₁ phase cell cycle arrest and apoptosis via caspase-3 activation. Furthermore, it impaired EGFR downstream signaling by reducing ERK1/2 and AKT phosphorylation, without directly inhibiting EGFR itself. At sub-cytotoxic concentrations, VA1213 was more effective than celecoxib in inhibiting cell migration and demonstrated a comparable reduction in clonogenic potential. These findings highlight VA1213 as a COX-2 inhibitor with noteworthy in vitro antitumor efficacy, comparable to that of celecoxib. Its ability to interfere with multiple cancer-associated signaling pathways and reduce tumor cell aggressiveness underscores its potential as a promising therapeutic candidate. Further in vivo studies are warranted to confirm its efficacy and assess potential off-target effects.

Sodium cyclamate alters cardiac homeostasis via immunoinflammatory signaling modulation: A multi-biomarkers and in-silico evaluation.

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are widely available and inexpensive agents with proposed antitumor activity, particularly in tumors harboring PIK3CA mutations. This meta-analysis of randomized controlled trials (RCTs) evaluated whether adjuvant NSAID therapy improves outcomes in patients with resected PIK3CA-mutated colorectal cancer (CRC). PubMed, Embase, and the Cochrane Library were systematically searched for RCTs assessing NSAID use following curative-intent resection of CRC in patients with confirmed PIK3CA mutations. Pooled hazard ratios (HRs) with corresponding 95 % confidence intervals (CIs) were calculated for disease-free survival (DFS) and overall survival (OS) using both fixed and random-effects models. Sensitivity analyses excluded participants with low-dose aspirin exposure concomitant with cyclooxygenase-2 (COX-2) inhibitors. Among 477 records screened, four RCTs met eligibility criteria, comprising 426 patients assigned to NSAIDs (aspirin or COX-2 inhibitors) and 363 receiving placebo. Adjuvant NSAID therapy improves DFS (HR 0.65; 95 % CI, 0.46-0.90). In sensitivity analyses excluding concomitant aspirin exposure, a similar magnitude of effect was observed (HR 0.57; 95 % CI, 0.39-0.83). The pooled OS analysis was not statistically significant (HR 0.78; 95 % CI, 0.39-1.57). Exclusion of low-dose aspirin users was associated with lower mortality risk (HR 0.54; 95 % CI, 0.30-0.99), although these findings should be interpreted cautiously. Adjuvant NSAID therapy is associated with improved DFS in patients with PIK3CA-mutated CRC. OS benefit remains uncertain, and findings from sensitivity analyses are exploratory. These findings support consideration of NSAIDs as a biomarker-informed adjuvant strategy in selected patients while underscoring the need for confirmatory evidence from ongoing randomized trials.

Objective: This study aimed to systematically investigate lipopolysaccharide (LPS)-induced activation of BV2 microglial cells and to evaluate the effects of different exposure durations on cellular activation, cytokine release, and polarization status, thereby clarifying the role of LPS in microglial activation and defining an optimal stimulation window for model establishment. Methods: BV2 microglial cells treated with LPS for different time intervals were analyzed using ELISA kits, quantitative PCR (qPCR), and Western blotting. Specifically, morphological changes were documented by inverted microscopy by recording cell size, the number of processes, and cytoplasmic granularity; the expression levels of pro-inflammatory cytokines (IL-6, IL-1β) and anti-inflammatory cytokines (IL-10) were measured; and the mRNA and protein expression of the polarization-related marker cyclooxygenase-2 (COX-2) were determined. Results: LPS induced time-dependent microglial activation with coordinated shifts in polarization markers and cytokine profiles. After 6 h, the anti-inflammatory marker CD206 was significantly downregulated (P < 0.05), whereas the M1-associated marker COX-2 was markedly upregulated (P < 0.01), accompanied by increased pro-inflammatory cytokines including IL-6 and IL-1β (P < 0.01) and a reduction in IL-10. These changes became more pronounced at 12 and 24 h, with further elevations of pro-inflammatory indices and continued decreases of anti-inflammatory indicators, consistent with a progressive shift toward an M1-like phenotype under sustained stimulation. Conclusion: LPS effectively induces inflammatory activation of BV2 microglia and drives a shift toward an M1-like pro-inflammatory phenotype. Integrating morphological changes, cytokine profiles, and polarization marker expression, 12 h appears to represent a robust and relatively stable time window for model establishment.

This study investigates the protective effect of opuntiol, a naturally occurring flavonoid, against lipopolysaccharide (LPS)-induced acute kidney injury in mice. Acute kidney injury (AKI) is a serious clinical complication characterized by inflammation, oxidative stress, and apoptosis, often resulting in high morbidity and mortality. Male mice were divided into six groups and administered opuntiol (25, 50 and 100 mg/kg b. wt.) intraperitoneally prior to LPS (10 mg/kg b. wt.) administration. The most effective dose was 50 mg/kg b. wt., as indicated in the dose-finding study. Kidney function markers (urea, creatinine, blood urea nitrogen (BUN), uric acid), antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), inflammatory cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB), cyclooxygenase-2 (COX-2), and gene expression levels (pro-inflammatory, apoptotic, and antioxidant genes) were analyzed using biochemical assays and qRT-PCR. Opuntiol significantly reduced elevated levels of serum urea, creatinine, BUN, and uric acid compared to the LPS group. Further, opuntiol restored antioxidant enzyme activities and MDA levels were significantly decreased. Opuntiol also downregulated inflammatory markers and gene expressions (TNF-alpha, NF-kappaB, TLR4, Bax, Caspase-3, etc.) while upregulating anti-apoptotic (Bcl-2) and antioxidant (Nrf-2) genes. Opuntiol offers significant protection against LPS-induced AKI by mitigating oxidative damage, inflammation, and apoptotic signaling. It enhances renal function and promotes antioxidant defense. These findings support the therapeutic potential of opuntiol as a novel nephroprotective agent in managing sepsis-associated kidney injury and encourage further preclinical and clinical investigations. Key words Opuntiol " Acute kidney injury " Lipopolysaccharide " Oxidative stress " Inflammation " Apoptosis.

Structural characterization and in vitro antioxidant and immunomodulatory activities of a water-soluble polysaccharide from Angelica sinensis (ASP-4).

Neuroprotective potentials of alpha-lipoic acid against multi-walled carbon nanotubes-induced neurotoxicity and behavioral deficits in male albino rats: Role of antioxidant and anti-apoptotic pathways.

Abnormal accumulation of prostaglandin E2 (PGE2) is a secondary effect of the presence of bacterial infection, and usually causes overproduction of proinflammatory cytokines, thereby leading to infiltration of neutrophils, serving as a key etiology of endometritis linking to infertility. Metastasis-associated protein 1 (MTA1), functioning as a master transcriptional coregulator, is increasingly recognized as an important influencer of inflammation, but its functional roles in endometritis, if any, remain unexplored. Herein, by investigating clinical correlations, in vitro assays, and uterus-specific Mta1 knockouts, we show that MTA1 expression was significantly downregulated in endometrial biopsies from patients with chronic endometritis (CE) and in human endometrial stromal cells (HESCs) challenged with clinically relevant pathogenic dosage of lipopolysaccharide (LPS). MTA1 deletion augmented endometrial neutrophil infiltration, exacerbated inflammatory phenotype and negatively affected the outcome of LPS-induced endometritis through modulation of PGE2 secretion. We have also identified cyclooxygenase-2 (COX2) as the key rate-limiting enzyme responsible for the deregulated PGE2 synthesis in MTA1 deficiency-exacerbated endometritis. Mechanistically, MTA1 negatively regulated the transcription of Cox2, likely in collaboration with HDAC2 (histone deacetylase 2), in LPS-challenged endometrial stromal cells (ESCs). In summary, MTA1 signaling may govern appropriate inflammatory response in ESCs against the pathogenesis of endometritis.

Marek's disease (MD), caused by the oncogenic Marek's disease virus (MDV), is a highly contagious avian infection that induces lymphoproliferative tumors. The RNA-binding protein ELAVL1 is known to regulate tumor cell proliferation and apoptosis, but its role in MDV-induced oncogenesis remains unclear. This study investigated whether ELAVL1 modulates proliferation and apoptosis in the MDV-transformed MSB1 cell line and whether its effects involve the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway. MSB1 cells were transiently transfected with ELAVL1-overexpressing plasmids (pEGFP-C-ELAVL1) or ELAVL1-specific siRNA, with expression confirmed by real-time PCR (qRT-PCR). Cell proliferation was assessed using the CCK-8 assay, while cell cycle distribution and apoptosis rates were analyzed by flow cytometry. COX-2 and PGE2 expression levels were determined by qRT-PCR, Western blotting, and ELISA. Overexpression of ELAVL1 significantly promoted the proliferation of MSB1 cells, decreased transition into the G1 phase, increased the proportions of S and G2 phase cells, and suppressed apoptosis. Correspondingly, both mRNA and protein levels of COX-2 and PGE2 were significantly elevated. Conversely, ELAVL1 knockdown significantly inhibited proliferation, induced G1 phase arrest, decreased S phase cells, and significantly decreased COX-2 and PGE2 expression. These findings indicate that ELAVL1 promotes proliferation and inhibits apoptosis in MDV-transformed MSB1 cells, potentially via the COX-2/PGE2 signaling pathway.

Paeonol ameliorates postmenopausal hyperlipidemia by inhibiting COX-2 to suppress GRP78-mediated endoplasmic reticulum stress.

Abstract Turmeric ( Curcuma longa ), a medicinal plant, has maintained its cultural and therapeutic significance over centuries in Ayurveda, Unani, and Traditional Chinese Medicine. However, novel formulations and delivery methods are being developed to address these challenges. Curcumin exhibits potent antioxidant properties by scavenging free radicals and modulating oxidative pathways to mitigate diseases associated with oxidative stress. Its anti‐inflammatory effects involve the inhibition of key signaling pathways, such as those involving nuclear factor kappa‐B (NF‐kB) and cyclooxygenase‐2 (COX‐2). Curcumin has exhibited considerable potential in cancer treatment, neuroprotection, cardiovascular health, metabolic and autoimmune disease moderation, and gastrointestinal and skin health. Although generally regarded as safe, high doses or prolonged use may result in toxic side effects, necessitating a careful evaluation. Research gaps concerning curcumin include standardization, formulation development, and large‐scale clinical validation. Future directions may involve the application of nanotechnology, therapeutic strategies, and enhanced bioavailability approaches to improve the treatment outcomes. Overall, turmeric and curcumin are natural bioactive compounds with multifunctional properties and hold potential for integration into modern preventive and therapeutic medicine.

Ethanol-induced gastric ulcer is categorized via acute mucosal injury mediated by oxidative stress, inflammation, and disruption of gastric barrier. Notoginsenoside R1 (NR) is a saponin that has shown the anti-inflammatory and anti-oxidative effects; however, its gastroprotective effect and mechanisms remain unclear. In this experimental study, we evaluate the gastroprotective effect of notoginsenoside R1 (NR) against ethanol-induced gastric ulcers and evaluate the underlying mechanism. Orally administration of ethanol (5mL/kg) was used for induction of the gastric ulcers in the rats. Rats were pretreated with NR prior to ethanol exposure. Gastric damage was assessed via lesion score, ulcer index, pH, gastric juice volume, and total acidity. Biochemical analyses included hepatic, antioxidant, non-hepatic, inflammatory cytokines, apoptosis, and inflammatory parameters that were analyzed. Key signaling genes were further evaluated at the mRNA level. NR treatment significantly (p < 0.001) improved body weight and altered organ weights (stomach and liver) as well as relative organ weight. NR pretreatment remarkably ameliorates ethanol-induced gastric injury, as evidenced by decreased ulcer index, lesion score, gastric juice, total acidity, and restoration of gastric pH. NR altered the levels of myeloperoxidase (MPO), nitric oxide (NO), heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2 (Nrf2), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). Notoginsenoside R1 treatment group rats significantly (p < 0.001) altered the levels of hepatic parameters such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP); non-hepatic parameters like total bilirubin, total protein, albumin, and A/G ratio; antioxidant parameters viz., malonaldehyde (MDA), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH); inflammatory cytokines include tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), and interleukin-18 (IL-18); apoptosis parameters such as Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), caspase-3, cleaved caspase-3, and Bax/Bcl-2 ratio; inflammatory parameters such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), inducible nitric oxide synthase (iNOS), prostaglandin E₂ (PGE₂), and transforming growth factor-β (TGF-β). Notoginsenoside R1 treatment significantly (p < 0.001) altered the mRNA expression of COX-2, iNOS, PGE2 synthase, NF-κB (p65), Bax, Bcl-2, caspase-3, extracellular signal-regulated kinase 1 (ERK1), toll-like receptor 2 (TLR-2), and myeloid differentiation primary response 88 (MyD88). Notoginsenoside R1 exerts the gastroprotective effect against ethanol-induced gastric ulcers via attenuation of oxidative stress, apoptosis, and inflammation, primarily via alteration of HO-1/Nrf2, VEGFR2/ERK, and NF-κB/TLR-2/Myd88 signaling pathway.