Search Results (1,043)

There is an urgent need to develop new anti-inflammatory compounds due to the versatility of their applications and the side effects associated with currently used nonsteroidal anti-inflammatory drugs (NSAIDs). Compounds containing the 1,2-benzothiazine 1,1-dioxide moiety in their structure have demonstrated a broad range of pharmacological activities, among which the anti-inflammatory effect is the most well-documented. Numerous in vivo studies have confirmed the effectiveness of these compounds in alleviating pain and inflammation. In turn, in vitro studies have shown that 1,2-benzothiazine derivatives exhibit anti-inflammatory activity not only through the classical mechanism involving the inhibition of cyclooxygenase (COX) but also through modern, more complex mechanisms. These innovative mechanisms include inhibition of microsomal prostaglandin E₂ synthase-1 (mPGES-1) or 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), suppression of pro-inflammatory cytokines, and modulation of kinase activity involved in inflammatory processes. Importantly, many studies have shown that some new 1,2-benzothiazine 1,1-dioxide derivatives exhibit even stronger anti-inflammatory activity than traditional NSAIDs, making them promising candidates for new drugs targeting inflammation-related diseases. This paper presents a review of 1,2-benzothiazine 1,1-dioxide derivatives investigated for their anti-inflammatory activity in both in vivo and in vitro models, taking into account their various mechanisms of action and potential directions for further research. Full article

Chronic inflammation driven by Cyclooxygenase-2 (COX-2) overexpression plays a key role in lung cancer (LC) progression, making it a critical therapeutic target. This study explores thymoquinone (TQ), a potent bioactive phytochemical derived from Nigella sativa, known for its anti-inflammatory and anti-cancer effects, focusing on its ability to suppress lipopolysaccharide (LPS)-induced COX-2 expression via microRNA hsa-miR-199a-3p modulation in LC cells. Using A549 and SHP-77 LC cells, we tested the effect of TQ under LPS stimulation and miRNA inhibition. Advanced techniques like TaqMan qPCR, luciferase reporter gene constructs, and anti-miRNA transfection confirmed that miR-199a-3p directly silences COX-2. Western blot and ELISA assays revealed that TQ dramatically reduces COX-2 protein and PGE2 levels by boosting miRNA-199a-3p. Importantly, TQ also blocked MAPK (p38, JNK, ERK) and NF-κB activation, even when miR-199a-3p was suppressed, proving its multi-targeted action beyond miRNA regulation. These findings reveal a novel anti-inflammatory mechanism, where TQ curbs COX-2-driven inflammation by enhancing miR-199a-3p, simultaneously shutting down pro-cancer MAPK/NF-κB signaling pathways. Given the strong link between chronic inflammation and LC aggressiveness, this study positions TQ as a promising therapeutic candidate, especially for inflammation-mediated lung cancer progression. Its dual ability to modulate miRNA and key signaling cascades makes it a compelling option for future LC treatment strategies. Full article

Colorectal cancer (CRC) remains a major contributor to global cancer-related mortality, with rising incidence observed in several regions, including Saudi Arabia. This review compiles and critically analyzes recent preclinical research from Saudi-based institutions that investigates the anti-CRC potential of natural and synthetic compounds. Numerous natural products such as Nigella sativa, Moringa oleifera, Curcuma longa, and marine-derived metabolites have demonstrated cytotoxic effects through pathways involving apoptosis induction, reactive oxygen species (ROS) generation, and inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and cyclooxygenase-2 (COX-2). In parallel, synthetic and semi-synthetic agents, including C4–G4 (semi-synthetic hybrids designed from flavonoids and benzoxazole scaffolds that act as dual epidermal growth factor receptor (EGFR)/COX-2 inhibitors)), oxazole derivatives, and camptothecin-based nanocarriers, exhibit promising anti-tumor activity via molecular targeting of cyclin-dependent kinase 8 (CDK8), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and β-catenin pathways. Selected in vivo studies primarily utilizing xenograft and chemically induced rodent models have shown reductions in tumor volume and modulation of apoptotic and inflammatory biomarkers. Additionally, green-synthesized metallic nanoparticles (NPs) and polyethylene glycol (PEG)-modified carriers have been investigated to improve bioavailability and tumor targeting of lead compounds. While these findings are encouraging, the majority remain in preclinical phases. Limitations such as poor solubility, lack of pharmacokinetic data, and absence of clinical trials impede translational progress. This review highlights the need for standardized evaluation protocols, mechanistic validation, and region-specific clinical studies to assess efficacy and safety. Given Saudi Arabia’s rich biodiversity and growing research capacity under national strategies like Vision 2030, the country is well-positioned to contribute meaningfully to CRC drug discovery. By integrating bioactive natural products, rationally designed synthetics, and advanced delivery platforms, a pipeline of innovative CRC therapeutics tailored to local and global contexts may be realized. Full article

The genus Lavandula represents one of the most valuable aromatic and medicinal plants, holding significant economic importance in the pharmaceutical, food, perfumery, and cosmetics industries. Among them, L. multifida is a traditionally used medicinal plant in the Mediterranean region. This work provides a comprehensive review of L. multifida, focusing on its traditional uses, phytochemistry, and pharmacological properties. Unlike conventional lavenders, its essential oil is dominated by phenolic monoterpenes, principally carvacrol, alongside significant concentrations of β-bisabolene, 1,8-cineole, and camphor. This distinct phytochemical profile is further complemented by a rich range of non-volatile constituents, including flavonoids, phenolic acids, and triterpenoids. Pharmacological investigations have validated its broad-spectrum antimicrobial activity, demonstrating efficacy against multidrug-resistant bacterial strains and fungal pathogens through mechanisms such as membrane disruption, metabolic interference, and quorum sensing inhibition. Furthermore, the species exhibits significant antioxidant and anti-inflammatory properties, mediated primarily through radical scavenging, cyclooxygenase inhibition, and cytokine modulation. Owing to its distinct chemistry, specific traditional uses for respiratory and digestive ailments, limited endemic habitat, and underexplored status, L. multifida presents a promising candidate for future research with high potential for novel drug discovery, particularly in antiparasitic and respiratory therapies. This review concludes by identifying key research priorities for L. multifida, including a detailed analysis of its non-volatile compounds, mechanistic elucidation, toxicological assessments, and standardization of extracts. Addressing these gaps is essential to validate its traditional applications and advance its development into evidence-based phytomedicines, adjuvant therapies, and natural agrochemicals. Full article

Snack bars are convenient, ready-to-eat foods with various natural ingredients and may serve as functional foods, offering bioactive phytochemicals. In this study, tomato-based snack bars enriched in plant proteins were evaluated for their antioxidant, antidiabetic, anti-obesity, and anti-inflammatory properties by in vitro test, comparing different protein sources (pea and RuBisCO) and drying methods (microwave vacuum and oven). The rubisco bars exhibited the highest levels of polyphenols (10.12 ± 0.27 mg GAE/g) and flavonoids (5.65 ± 0.47 mg CE/g), and demonstrated superior antioxidant capacity in DPPH, ORAC, and FRAP assays, particularly when microwaved. Rubisco bars also exhibited better inhibition activity of dipeptidyl-peptidase IV and pancreatic lipase, suggesting potential antidiabetic and anti-obesity effects. In contrast, pea bars displayed notable anti-inflammatory effects by reducing tumor necrosis factor (TNF)-α-induced cyclooxygenase-2 (COX-2) expression in intestinal cells. Both protein types were digestible, though rubisco bars released more peptides during simulated gastrointestinal digestion. While these in vitro findings provide insights into the functional potential of tomato-based snack bars, further studies, including in vivo investigations, are required to confirm their health-promoting effects and to evaluate physiologically relevant doses. Overall, these findings highlight the potential of tomato-based snack bars as sustainable, nutrient-rich functional foods with potential health-promoting properties. Full article

Background: Blast-induced spinal cord injuries (bSCI) account for 75% of all combat-related spinal trauma and are associated with long-term functional impairments. However, limited studies have evaluated the neuropathological outcomes in the spinal cord following blast exposure. Objectives In this study, we aimed to determine the acute and sub-acute neuropathological changes in the spinal cord of ferrets after blast exposure. Methods: An advanced blast simulator was used to expose ferrets to tightly coupled repeated blasts. The Catwalk XT system was used to detect gait performances in ferrets at 24 h and 1 month post-blast exposure. After euthanasia, the cervical spinal cord samples were collected at 24 h or 1 month post-blast. A quantitative real-time polymerase chain reaction was performed to evaluate changes in the gene expression of multiple Toll-like Receptors (TLR), Cyclooxygenase (COX-1 and COX-2) enzymes and cytokines. Western blotting was performed to investigate markers of axonal injury (Phosphorylated-Tau, pTau; Phosphorylated Neurofilament Heavy Chain, pNFH; and Neurofilament Light Chain present in degenerating neurons, NFL-degen) and neuroinflammation (Glial Fibrillary Acidic Protein, GFAP; and Ionized Calcium Binding Adaptor Molecule, Iba-1). Results: Blast exposure significantly affected the gait performances in ferrets, especially at 24 h post-blast. Multiple TLRs, COX-2, Interleukin-1-beta (IL-1β), Interleukin-6 (IL-6), and Tumor Necrosis Factor-α (TNF-α) were significantly upregulated in the spinal cord at 24 h after blast exposure. Although only TLR3 was significantly upregulated at 1 month, non-significant increases in TLR1 and TLR2 were observed in the spinal cord at 1 month post-blast. Phosphorylation of Tau at serine (Ser396 and Ser404) and threonine (Thr205) increased in the spinal cord at 24 h and 1 month post-blast exposure. The increased expression of pNFH and NFL-degen proteins was evident at both time points. The expression of GFAP, but not Iba-1, significantly increased at 24 h and 1 month following blast exposure. Conclusions: Our results indicate that blast exposure causes acute and sub-acute neuroinflammation and associated axonal injury in the cervical spinal cord. These data further suggest that inhibition of TLRs and/or COX-2 enzyme might offer protection against blast-induced injuries to the spinal cord. Full article

The primary mechanism of non-steroidal anti-inflammatory drugs (NSAIDs) is inhibition of prostaglandin production mediated by cyclooxygenase. Given the possible association of cyclooxygenase-2, but not cyclooxygenase-1, with membrane lipid rafts, we assessed whether the lipid raft membrane interactivity of NSAIDs correlates with cyclooxygenase-2 selectivity. Lipid raft model membranes and reference membranes were prepared with 1,2-dioleoylphosphatidylcholine/sphingomyelin/cholesterol and 1,2-dipalmitoylphosphatidylcholine, respectively. After treating the membranes with 2–50 μM NSAIDs at pH 7.4, 6.5, and 5.5, fluorescence polarization was measured to determine their membrane interactivity. Conventional NSAIDs (diclofenac, ibuprofen, indomethacin, aspirin, and flurbiprofen) and Coxibs (lumiracoxib, etoricoxib, celecoxib, valdecoxib, and rofecoxib) decreased membrane fluidity, whereas Oxicams (meloxicam, piroxicam, tenoxicam, and lornoxicam) increased. Membrane effects of NSAIDs were so dependent on medium pH that they significantly increased with reducing pH from 7.4 to 5.5. Under inflammatory acidic conditions, the lipid raft membrane interactivity of NSAIDs was more likely to correlate with cyclooxygenase-2 selectivity than the reference membrane interactivity. It is hypothesized that NSAIDs may interact with lipid raft membranes to induce membrane fluidity changes with the potency corresponding to cyclooxygenase-2 inhibition, disrupting the structural and functional integrity of lipid rafts to affect the activity of cyclooxygenase-2 localized in lipid rafts, resulting in cyclooxygenase-2 selective inhibition. Full article

Gynostemma pentaphyllum (GP) is a medicinal plant that has long been used as drug for the treatment of rheumatism, liver disease, and diabetes. In this study, GP was extracted with 50% ethanol extract, and then the extract was heat-processed under high pressure to analyze the anti-inflammatory potential of these extract (named actiponin (AP)) and its derived components, damulin A and damulin B, in RAW264.7 cells and carrageenan-induced rat models. Ap had no effect on RAW264.7 cells up to 180 μg/mL, but DA and DB showed cytotoxicity from 18 μM. Pretreatment with AP significantly suppressed the LPS-induced increase in nitric oxide (NO) and inducible nitric oxide synthase (iNOS) protein expression via griess reagent and Western blot analysis, and these effects were similar to those of DA and DB. AP, DA, and DB also significantly suppressed the expression of prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2) protein, which were increased by LPS, in a concentration-dependent manner. In addition, AP, DA, and DB inhibited the LPS-induced increase in pro-inflammatory cytokines, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 in RAW264.7 cells. The anti-inflammatory activities of AP, DA, and DB are mediated by the suppression of the nuclear factor (NF)-κB and phosphorylation of mitogen-activated protein kinases (MAPKs) signaling pathways. Oral administration of 30, 50, 100, or 200 mg/kg (AP) suppressed carrageenan-induced edema in a concentration-dependent manner. Collectively, these results suggest that AP exerts potential anti-inflammatory activity by suppressing the inflammatory-mediators and pro-inflammatory cytokines via the NF-κB and MAPK pathways in vitro and by reducing the thickness of carrageenan-induced paw edema in vivo. Full article

Ehrlich ascites tumor (EAT) is a rapidly growing, angiogenesis-dependent tumor characterized by high levels of vascular endothelial growth factor (VEGF). VEGF contributes to ascites formation, which supports tumor cell growth and the accumulation of tumor-associated macrophages (TAMs), primarily of the immunosuppressive M2 phenotype. M2 macrophages promote tumor progression by secreting angiogenic and immunomodulatory factors such as VEGF, matrix metalloproteinases (MMPs), and cyclooxygenase-2 (COX-2). This study investigated the effects of tannic acid (TA) on tumor growth and angiogenesis in EAT-bearing mice, focusing on TAM–tumor cell interactions. We evaluated ascites volume, cell counts, macrophage activity, peritoneal angiogenesis and blood vessel density, concentrations of VEGF, COX-2, and MMP-2/-9, blood biomarkers, and DNA damage using the comet assay. TA treatment significantly reduced tumor growth and angiogenesis by modulating TAM function. Specifically, TA inhibited VEGF, COX-2, and MMP-2/-9 expression, decreased M2 macrophage numbers, and enhanced the antitumor immune response, as shown by increased lymphocyte activation and favorable shifts in lymphocyte-to-monocyte (LMR) and neutrophil-to-lymphocyte (NLR) ratios. Additionally, TA induced DNA fragmentation in tumor and blood cells, indicating cytotoxicity and potential induction of apoptosis. These findings suggest that TA’s inhibition of TAMs may be a promising strategy for treating tumors and other angiogenesis-related conditions. Full article

In the present study, we investigated the mechanisms underlying the anti-inflammatory effects of rosmarinosin A in (LPS)-stimulated RAW 264.7 macrophages. The cells were pretreated with various concentrations of rosmarinosin A, and then stimulated with LPS. Rosmarinosin A reduced the production of nitric oxide (NO) and prostaglandin E₂ (PGE₂), possibly through the modulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, respectively. Additionally, it inhibited the production of pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin (IL) 1β, and IL-6. The molecular mechanisms of rosmarinosin A involved the suppression of nuclear factor κB (NF-κB) p65 translocation into the nucleus. Furthermore, rosmarinosin A exhibited anti-inflammatory properties by suppressing the mitogen-activated protein kinase (MAPK) signaling pathway. These findings suggest that rosmarinosin A may exert its anti-inflammatory effects, at least in part, through the modulation of NF-κB and MAPK pathways in LPS-activated macrophages, offering the potential for therapeutic development. Full article

Nitric esters are among the compounds that can liberate nitrogen monoxide (NO) in the organism. Due to the vasodilatation caused by nitrogen monoxide, NO-donors have been shown to protect endothelial function, acting as vasodilators, promoting efficient oxygen supply to tissues, to lower blood pressure, and to inhibit platelet aggregation. Incorporation of a NO-liberating moiety in the structure of non-steroidal anti-inflammatory drugs results in anti-inflammatory agents that are safer for the gastrointestinal system. In this research, ibuprofen and naproxen, two commonly applied non-steroidal anti-inflammatory drugs (NSAID), non-selective inhibitors of cyclooxygenases, were used to design novel anti-inflammatory agents able to release NO in the organism. Thus, the NSAIDs were amidated with beta-alanine and L-proline, which were able to incorporate the 2-nitro-oxyethyl moiety as the NO donor. The resulting compounds were anti-inflammatory agents, found to be more potent than the mother drugs, demonstrating remarkable inhibition of cyclooxygenase-2 over cyclooxygenase-1 and the ability to release NO in vitro. Furthermore, two of the most active anti-inflammatory compounds proved to be effective hypolipidemic agents, decreasing plasma total cholesterol, triglycerides, and LDL-cholesterol in hyperlipidemic rats significantly. The most effective compound in all the above tests was the ibuprofen derivative 5, which inhibited COX-2 by 95%, decreased inflammation by 73%, and reduced all lipidemic indices by more than 50%. Furthermore, docking experiments of compound 5 on the active sites of COX-1 and COX-2 showed that it interacts intensely with the binding site of COX-2, and the binding energy is equivalent to that of the relevant to celecoxib selective COX-2 inhibitor 4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide (SC-5580). In conclusion, the performed structural modifications resulted not only in the improvement of the anti-inflammatory activity, compared with the parent NSAID, but also acquired strong hypolipidemic activity. Thus, the combination of structural characteristics resulting in a decrease in lipidemia, with possible inhibition of atherosclerosis, due to their anti-inflammatory activity and vasodilatation ability, via the liberated NO, may constitute a useful rationale for new compounds. Full article

Objectives: Our study aimed to examine the antioxidative and anti-inflammatory potential of the lyophilized aqueous leaf extract of Vitis vinifera. Methods: The antioxidant capacity of the extract was evaluated using the DPPH and FRAP assays. The in vivo phase of the study included 40 male Wistar albino rats. One half of the animals were used to induce the carrageenan model of acute inflammation, while the other half were used for examination of the extract effect on the redox state. Rats from the experimental group drank tap water containing 150 mg/kg Vitis vinifera extract for 14 days, while control animals received saline at the same volume. The molecular docking studies of polyphenols present in the leaf extract were conducted in AutoDock Vina. Results: In vitro assessment of the antioxidative capacity of the applied extract revealed significant free radical scavenging activity (IC₅₀ value 11.63 µg/mL), along with a pronounced ferric reducing ability (0.143 at 700 nm). Moreover, animal treatment with the extract led to significant paw edema inhibition (30.34%, 35.06%, and 41.54% in the second, third, and fourth hours, respectively) and to pro-oxidative marker reduction. Additionally, Vitis vinifera extract significantly increased catalase activity and glutathione levels. The in silico results showed that rutin binds to cyclooxygenase 1 (−8.2 kcal/mol) and 2 (−8.3 kcal/mol), as well as to antioxidant enzymes (catalase: −8.6 kcal/mol, SOD: −7.4 kcal/mol), indicating its key role in mediating the biological activity of the tested extract. Conclusions: This study highlights the significant antioxidant and anti-inflammatory potential of V. vinifera lyophilized aqueous leaf extract from the Serbian market, supported by both in vivo and in silico analyses. Full article

Oral squamous cell carcinoma (OSCC) is a highly aggressive malignancy with limited effective treatment options. This study aimed to explore the therapeutic potential of novel pyrazole N-aryl sulfonate derivatives (compounds 4b, 4d, and 5f) as selective cyclooxygenase-2 (COX-2; prostaglandin-endoperoxide synthase 2, PTGS2) inhibitors in OSCC. Using CCK-8 and Transwell assays, we evaluated the anti-proliferative and anti-migratory effects of these compounds on CAL-27 and SAS cell lines, while apoptosis was assessed by Hoechst 33342 staining and flow cytometry. Molecular mechanisms were investigated through RT-qPCR, Western blot, and ELISA, focusing on COX-2, MMP2, MMP9, BCL2, BAX, and the JAK/STAT3 pathway. The results demonstrated that compounds 4b, 4d, and 5f significantly inhibited cell proliferation and migration, induced apoptosis, and downregulated the expression of COX-2 and its downstream targets. Notably, these compounds exhibited lower cytotoxicity in VERO cells, indicating favorable biological safety. In conclusion, our findings suggest that pyrazole N-aryl sulfonate derivatives effectively suppress OSCC cell growth and migration by targeting COX-2 and the JAK/STAT3 pathway, highlighting their promise as potential targeted therapeutics for OSCC. Full article

This study investigated the potential of astaxanthin (AST), a natural carotenoid, to mitigate inflammation-induced hyperexcitability in the spinal trigeminal nucleus caudalis (SpVc) and the associated hyperalgesia. The efficacy of systemic AST application was compared to that of celecoxib (CEL). Inflammation was induced by injecting Complete Freund’s adjuvant into the whisker pads of rats. The mechanical escape threshold was then assessed by delivering mechanical stimuli to the orofacial region. Although inflamed rats exhibited a significantly lower mechanical threshold compared to naïve rats, this threshold was restored to normal levels two days after treatment with AST, CEL, and the 1/2 CEL + 1/2 AST combination. The activity of SpVc wide-dynamic range (WDR) neurons was measured using extracellular single-unit recordings in response to mechanical stimulation of the orofacial area under anesthesia. In inflamed rats, AST, CEL, and 1/2 CEL + 1/2 AST administration significantly reduced the average firing rate of these neurons elicited by both non-noxious and noxious mechanical stimuli. In addition, all three treatments significantly decreased the heightened average spontaneous activity of SpVc neurons and normalized the increased average receptive field size in inflamed rats. This study provides evidence that systemic AST administration attenuates inflammatory mechanical hyperalgesia. This action is associated with the suppression of hyperexcitability in nociceptive SpVc WDR neurons, likely through the inhibition of the cyclooxygenase-2 signaling pathway. These findings support the potential of AST as a therapeutic agent for complementary and alternative medicine. It may provide a valuable alternative to non-steroidal anti-inflammatory drugs for the prevention of trigeminal inflammatory mechanical hyperalgesia. Full article

Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and post-stroke cognitive impairment (PSCI), represent an escalating global health and economic challenge. In the quest for disease-modifying interventions, natural polyphenols—most notably curcumin, the principal bioactive compound of Curcuma longa—have attracted considerable interest due to their pleiotropic neuroprotective effects. This narrative review critically synthesizes findings from a selection of peer-reviewed articles published between 2000 and 2025, chosen for their relevance to curcumin’s molecular mechanisms and translational potential. Curcumin’s complex chemical structure confers antioxidant, anti-inflammatory, and epigenetic modulatory properties; however, its clinical application is limited by poor oral bioavailability. Mechanistically, curcumin attenuates oxidative stress and suppresses key inflammatory mediators, including nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Additionally, it modulates apoptosis, inhibits amyloid-beta aggregation, and enhances cellular quality control processes such as autophagy and mitophagy, while upregulating neurotrophic factors such as brain-derived neurotrophic factor (BDNF). Preclinical studies employing rodent models of AD, PD, and ischemic stroke have demonstrated curcumin’s dose-dependent neuroprotective efficacy, with improved outcomes observed using nanoparticle-based delivery systems. Early-phase clinical trials further support curcumin’s favorable safety profile and potential cognitive benefits, although challenges remain regarding pharmacokinetics, formulation standardization, and therapeutic reproducibility. Future directions include the development of advanced drug delivery platforms, combinatory therapeutic regimens, and personalized medicine approaches integrating curcumin within multifaceted neurotherapeutic strategies. Collectively, this narrative review highlights curcumin as a promising multi-targeted candidate for combating neurodegenerative diseases, while emphasizing the need for further translational and clinical validation. Full article