Cyclooxygenase-2 Levels Research Articles

The Potential of the Probiotic Isolate Lactobacillus plantarum SS18‐50 to Prevent Colitis in Mice

ABSTRACTThe objective of this study was to investigate the effect of the Lactobacillus plantarum (L. plantarum) SS18‐50 (an isolate with favorable probiotic properties following space traveling) on dextran sulfate sodium (DSS)‐induced colitis in mice. Male ICR mice were randomly assigned to one of six groups: a control group, a model group, and four intervention groups comprising the isolate (SS18‐50‐L and SS18‐50‐H) and the wild type (GS18‐L and GS18‐H) strains. The model group and the intervention groups were administered a 3.5% DSS (w/v) solution to induce acute enteritis. The four intervention groups were administered the corresponding bacterial suspensions, SS18‐50‐L (1.0 × 107 CFU/mL), SS18‐50‐H (1.0 × 109 CFU/mL), GS18‐L (1.0 × 107 CFU/mL), and GS18‐H (1.0 × 109 CFU/mL). The results demonstrated that the disease activity index (DAI) score of the SS18‐50‐H was markedly lower than that of the CON. Subsequently, the colon tissue of mice was analyzed to determine the levels of myeloperoxidase (MPO), superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA). The results demonstrated that all strains within the intervention groups exhibited good performance to prevent colitis. Particularly, the SS18‐50‐H strain exhibited a pronounced stimulative effect on GSH, an increase in SOD activity, and a decrease in MPO activity and MDA content. The SS18‐50‐H treatment resulted in a notable elevation in serum somatostatin (SS) levels and a concomitant reduction in endothelin (ET) and substance P (SP) levels, which approached normal ranges. The results of the RT‐qPCR analysis demonstrated that the mRNA expression levels of tumor necrosis factor (TNF‐α), cyclooxygenase (COX‐2), interleukin (IL‐10), and interleukin (IL‐6) in the SS18‐50‐H were significantly reduced to levels comparable to those observed in the CON. In conclusion, L. plantarum SS18‐50 has been demonstrated to inhibit the development of colitis in a dose‐dependent manner, thereby establishing it as a high‐quality lactic acid bacterium with a colitis inhibitory effect.

Correlation between serum levels of cyclooxygenase-2, aquaporin-1, pepsinogen I, gastrin-17 and pathological features of Laryngeal Cancer.

To explore the association between the levels of cyclooxygenase-2 (COX-2), aquaporin-1 (AQP1), pepsinogen I (PGI), and gastrin-17 (G17) and pathological features of laryngeal cancer (LC). Clinical data of 120 patients with LC, treated in Shanghai Jiao Tong University School of Medicine from May 2022 to May 2023, as well as 120 healthy individuals who underwent physical examinations during the same period, were retrospectively analyzed. Serum levels of COX-2, AQP1, PGI, and G17 of LC patients and the healthy cohort were compared, and their association with pathological features of LC was investigated. LC was associated with significantly higher serum levels of COX-2, AQP1, and G17 and lower of PGI compared to the control group (P<0.05). Levels of COX-2, AQP1, and G17 positively correlated with the tumor, node and metastasis (TNM) staging, infiltration depth, and the lymph node metastases, and negatively correlated with the degree of differentiation (P<0.05). There was a significant negative correlation between the level of PGI and TNM staging, infiltration depth, and lymph node metastases. PG1 also positively correlated with the degree of differentiation (P<0.05). Area under curve (AUC) of combined COX-2, AQP1, PG-I, and G17 was significantly higher than that of each index alone (P<0.05). Levels of COX-2, AQP1, PGI, and G17 showed significant association with specific pathological features of LC. Serum levels of COX-2, AQP1, PGI, and G17 have certain predictive value for LC, and the combined predictive value of these four indicators is higher than that of a single indicator.

Correlation analysis of LXR and its target genes COX2 and CETP with the severity of OSAHS in obese young rats.

To analyse the relationships between the expression levels of liver X receptor (LXR), cyclooxygenase-2(COX2) and cholesterol ester transfer protein (CETP) and the severity of obstructive sleep apnoea hypopnoea syndrome (OSAHS) in obese young rats, to obtain information for basic research on OSAHS in obese children. Twenty-four 3-4-week-old young rats were randomly assigned to the normal control group, obesity group, OSAHS group, obesity and OSAHS group. We used polysomnography to measure the obstructive apnoea hypopnoea index (OAHI) to assess the severity of OSAHS and western blotting to test the expression levels of LXRα, COX2, and CETP in the liver, heart, kidney, and brain tissues. LXR, COX2, and CETP expression levels in the remaining groups were considerably higher than those in the control group (P < 0.05). Compared with those in the obesity group, LXRα, COX2, and CETP expression levels in the obesity and OSAHS group were considerably greater in the liver, kidney, and heart tissues (P < 0.05); the brain tissues of the obesity and OSAHS group showed considerably higher expression levels of COX2 and CETP (P < 0.05). Compared with those in the OSAHS group, LXRα, COX2, and CETP expression levels in the obesity and OSAHS group were significantly greater in all tissues (P < 0.05). The expression levels of LXRα, COX2, and CETP and obesity increased with increasing OSAHS severity (r = 0.777, P < 0.01; r = 0.728, P < 0.01; r = 0.793, P < 0.01; r = 0.786, P < 0.01; and r = 0.698, P < 0.01), and the oxygen concentration increased with decreasing OSAHS severity(r=-0.576, P < 0.01). LXR, COX2, and CETP expression levels were significantly increased in the liver, kidney, heart, and brain tissues of young rats with obesity and OSAHS, and were positively correlated with the severity of OSAHS.

Hydroethanolic Extract of Polygonum aviculare L. Mediates the Anti-Inflammatory Activity in RAW 264.7 Murine Macrophages Through Induction of Heme Oxygenase-1 and Inhibition of Inducible Nitric Oxide Synthase

Polygonum aviculare L. (PAL), commonly known as knotgrass, has been utilized as a traditional folk medicine across Asian, African, Latin American and Middle Eastern countries to treat various inflammatory diseases, including arthritis and airway inflammation. Numerous medicinal herbs exert anti-inflammatory and antioxidative effects that are mediated through the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and the inhibition of nuclear factor kappa B (NF-κB). However, the underlying molecular mechanisms linking the antioxidative and anti-inflammatory effects remain poorly understood. Heme oxygenase-1 (HO-1) is an antioxidant enzyme that catalyzes heme degradation, ultimately leading to the production of carbon monoxide (CO). Elevated levels of CO have been correlated with the decreased level of inducible nitric oxide synthase (iNOS). In this study, we examined whether HO-1 plays a key role in the relationship between the antioxidative and anti-inflammatory properties of PAL. The anti-inflammatory and antioxidative activities of PAL in an in vitro system were evaluated by determining NF-κB activity, antioxidant response element (ARE) activity, pro-inflammatory cytokine and protein levels, as well as antioxidant protein levels. To examine whether HO-1 inhibition interfered with the anti-inflammatory effect of PAL, we measured nitrite, reactive oxygen species, iNOS, and HO-1 levels in RAW 264.7 murine macrophages pre-treated with Tin protoporphyrin (SnPP, an HO-1 inhibitor). Our results demonstrated that PAL increased ARE activity and the Nrf2-regulated HO-1 level, exerting antioxidative activities in RAW 264.7 macrophages. Additionally, PAL reduced cyclooxygenase-2 (COX-2) and iNOS protein levels by inactivating NF-κB in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Further investigation using the HO-1 inhibitor revealed that HO-1 inhibition promoted iNOS expression, subsequently elevating nitric oxide (NO) generation in LPS-activated RAW 264.7 macrophages treated with PAL compared to those in the macrophages without the HO-1 inhibitor. Overall, our findings suggest that HO-1 induction by PAL may exert anti-inflammatory effects through the reduction of the iNOS protein level. Hence, this study paves the way for further investigation to understand molecular mechanisms underlying the antioxidative and anti-inflammatory activities of medicinal herbs.

Pharmacotherapeutic potential of pratensein to avert metribuzin instigated hepatotoxicity via regulating TGF-β1, PI3K/Akt, Nrf-2/Keap-1 and NF-κB pathway

Metribuzin (MBN) is a selective herbicide that adversely damages the vital organs of the body including the liver. Pratensein (PTN) is a novel flavonoid that exhibits marvelous medicinal properties. This experimental trial commenced to elucidate the pharmacotherapeutic strength of PTN to counteract MBN provoked liver toxicity in rats. Thirty-six male albino rats (Rattus norvegicus) were categorized into four groups i.e., the control, MBN (133.33 mg/kg), MBN (133.33 mg/kg) + PTN (20 mg/kg) and PTN (20 mg/kg) alone treated group. Our findings revealed that MBN exposure promoted the expressions of Keap-1 as well as concentrations of ROS and MDA while reducing the gene expressions of Nrf-2 as well as activities of catalase (CAT), glutathione Peroxidase (GPx), glutathione reductase (GSR), heme oxygenase-1 (HO-1), superoxide dismutase (SOD) and glutathione (GSH) contents. The levels of albumin and total proteins were reduced whereas the levels of alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were enhanced following the MBN administration. Moreover, the gene expression of transforming growth Factor–β1 (TGF-β1), matrix metallopeptidase-2 (MMP-2), matrix metallopeptidase-9 (MMP-9), collagen, type I, alpha 1 and type-3 alpha were escalated in response to MBN intoxication. Furthermore, MBN administration cause a sudden upregulation in the levels of NF-κB, IL-1β, TNF-α, IL-6 & COX-2. Besides, MBN exposure enhanced the gene expression of Bax and Caspase-3 while reducing the gene expression of PI3K, Akt and Bcl-2. Additionally, MBN exposure dysregulated the normal histology of liver. However, PTN treatment notably protected the hepatic tissues via regulating abovementioned dysregulations due to its marvelous ROS scavenging potential.

Metabolic processes of prostaglandin metabolism in women at 28–30 weeks of gestation with COVID-19

Background. COVID-19 negatively impacts pregnancy progression and outcomes. However, data regarding pregnancy complications related to prostaglandin activity during COVID-19 remain insufficient.The aim. To assess markers of metabolic processes related to prostaglandin metabolism in the blood of pregnant women depending on the severity of COVID-19 and to explore associations with the development of pregnancy complications.Methods. The study included 109 pregnant women in their third trimester (28–30 weeks), 36 of whom had mild COVID-19, 38 had moderate COVID-19, and 35 were not infected with SARS-CoV-2. The concentration of prostaglandins E2 and F2α, phospholipase A2 (PLA2), cyclooxygenase 2 (COX2), and arachidonic acid (AA) were measured in the blood using enzyme-linked immunosorbent assays and gasliquid chromatography for AA.Results. Comparative analysis showed that pregnant women with moderate COVID-19 had significantly higher levels of AA, COX2, PLA2, prostaglandins E2 and F2α (p &lt; 0.0001) compared to those with mild disease. These women also experienced more frequent complications, such as chronic placental insufficiency, preterm labor, and premature rupture of membranes. Regression analysis revealed associations between chronic placental insufficiency and prostaglandin E2 levels (p &lt; 0.0001), preterm labor, AA (p = 0.001) and COX2 (p = 0.001); premature rupture of membranes and PLA2 (p = 0.025), COX2 (p &lt; 0.001), AA (p &lt; 0.001).Conclusion. Moderate COVID-19 during the third trimester of pregnancy is associated with increased levels of AA, COX2, PLA2, and prostaglandins E2 and F2α in the blood. The most significant factors increasing the risk of pregnancy complications in women with moderate COVID-19 were elevated levels of AA, COX2, and prostaglandin E2 in the blood.

Effects of Exosomes from Menstrual Blood-derived Stem Cells and Ginger on Endometriotic Stem Cells.

Menstrual blood-derived stem cells from endometriosis patients (E-MenSCs) have different gene expression patterns than those from healthy nonendometriotic females (NE-MenSCs). Exosomes extracted from mesenchymal stem cells and plants are considered for the treatment of various diseases. This study aimed to compare the effects of exosomes derived from NE-MenSCs (C-exos) and those from the roots of ginger (P-exos) on E-MenSCs. E-MenSCs at the third passage were used, and after evaluating the effective dosage with MTT, C-exos (200 µg/mL) or P-exos (100 µg/mL) were added to treat them. Following a 72-h incubation, the cells were analyzed with annexin V/PI test to evaluate the apoptosis rate. Also, genes related to inflammation (IL-6, IL-8, IL-1β, NF-κB, COX2), cell cycle (Cyclin D1), the steroid pathway (ESR1), migration and invasion (MMP-2, MMP-9, VEGF), and the apoptosis pathway (BAX, BCL2) were detected by real-time PCR. Apoptosis was increased in both the P- and C-exos groups. The expression levels of IL-6 and IL-1β were significantly lower in the P-exos group than in the E-MenSCs group. The expression levels of IL-8, NF-κB, COX-2, and MMP-9 were significantly decreased in both the P-exos group and the C-exos group. The expression level of VEGF was significantly lower in the P-exos group than in the E-MenSCs group. The BAX/BCL2 ratio was much lower in the P-exos group than in the E-MenSCs group. In this study, we established the feasibility of using a novel natural nontoxic material to target endometriotic mesenchymal stem cells to modify their gene expression and function toward healthy cells. Both C-exos and P-exos showed positive effects on the gene expression and function of endometriotic cells. Considering that plant exosomes are easier to access and less expensive, they can be considered for clinical use in improving the symptoms of endometriosis patients.

Inhibition of pro-inflammatory cytokines by homalolide A and homalomenol A isolated from rhizomes of Homalomena pendula.

Inflammation, a natural process of the innate immune system, involves elevated levels of various proinflammatory mediators, such as, nitric oxide (NO) and prostaglandin (PGE2), cytokines such as interleukin 6 (IL-6), interleukin 10 (IL-10) and tumor necrosis factor alpha (TNF-α), and enzymes including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). This study investigated the anti-inflammatory effects of homalolide A (1) and homalomenol A (2), two sesquiterpenoids isolated from the rhizome of Homalomena pendula, on lipopolysaccharide (LPS)- stimulated macrophage cells. The results demonstrated that both 1 and 2 dose-dependently inhibited the production of PGE2, TNF-α and IL-6 in RAW 264.7 macrophages. Furthermore, 2 also stimulated IL-10 production in RAW 264.7 cells. Consistent with these findings, these compounds suppressed the LPS-stimulated protein levels of iNOS and COX-2 in RAW 264.7 cells. These results suggested that 1 and 2 could be effective candidates for ameliorating inflammatory-associated complications.

Potential role of the antimicrobial peptide Tachyplesin III in regulating nontypeable Haemophilus influenzae-induced inflammation in airway epithelial cells.

The respiratory bacterium nontypeable (non-encapsulated) Haemophilus influenzae (NTHi) is a key pathogen driving exacerbations in chronic obstructive pulmonary disease (COPD), and is associated with an excessive airway inflammation. Increasing issues with tolerance and unwanted side effects of existing pharmaceuticals present an urgent need for new, effective and minimally toxic therapeutic options. This study aimed to investigate the potential role of Tachyplesin III, an antimicrobial peptide derived from the hemolysates of Southeast Asian horseshoe crabs, in regulating NTHi-induced airway inflammation. The results revealed that Tachyplesin III effectively inhibited the production of IL-1β in NTHi-stimulated human lung epithelial cells (A549), without causing cytotoxic effects. Additionally, Tachyplesin III significantly reduced TNF-α, PGE2 and NO production in NTHi-stimulated A549 cells. Moreover, this peptide inhibited the nuclear translocation of the NF-κB p65 subunit in NTHi-stimulated lung epithelial cells. It also reduced transcriptional activation of NF-κB target genes, as shown by lower mRNA levels of IL-1β, TNF-α, COX-2 and iNOS, which correlated with corresponding decreases in their protein expression. Tachyplesin III peptide also inhibited pro-IL-1β and NLRP3 protein expression and prevented NTHi-induced caspase-1 cleavage and IL-1β maturation. Together, our findings demonstrate that Tachyplesin III effectively reduced NTHi-mediated inflammation via the NF-κB/NLRP3 inflammasome signaling pathway, highlighting its important anti-inflammatory activity. Complementing these findings, in silico analysis revealed key pharmacokinetic and toxicological attributes, establishing a foundational understanding of Tachyplesin III as a promising therapeutic agent for managing NTHi-associated inflammation.

Association between the variations in metabolic pathways and oral cancer risk: results from a Pakistani case-control study.

Oral cancer (OC) is a significant global health concern, with Pakistan ranking 5th worldwide in OC incidence. Given the poor prognosis, early detection of at-risk individuals is crucial. Genetic factors, particularly single nucleotide polymorphisms (SNPs) in metabolic genes, may influence OC susceptibility. This study investigated the association between SNPs in CYP1A1, COX2, SOD2, and HIF1a genes and OC risk in the Pakistani population. A prospective study was conducted from October 2019 to March 2022, enrolling 215 newly diagnosed OC patients and 410 controls. Genetic variations were analyzed using High-Resolution Melting (HRM)analysis and Sanger sequencing, with protein expression evaluated by ELISA. No significant associations were found between the studied SNPs and OC risk. However, a non-significant trend was observed for the SOD2 variant (rs4880), where the G allele was associated with a higher OC risk than the A allele (p = 0.20). Elevated COX2 and HIF1α levels (p-values of 0.014 and <0.001, respectively) and reduced SOD2 levels (p < 0.0001) were observed in OC patients, while CYP1A1 levels remained similar in both controls and cases. Although SNPs in CYP1A1, COX2, SOD2, and HIF1α were not significantly associated with OC risk in the Pakistani population, altered protein expression levels of COX2, HIF1α and SOD2 suggest additional regulatory mechanisms. Further investigation into post-transcriptional modifications and epigenetic factors could lead to novel biomarkers and therapeutic targets for OC in Pakistan.

Relative protective activities of avenanthramide A, B, and C against H2O2-induced endothelial dysfunction in EA.hy926 cells.

This study compared the antihypertensive effects of avenanthramides A, B, and C, with a focus on their antioxidant and anti-inflammatory properties. Treatment with avenanthramides A, B, and C (50μM) significantly enhanced cell viability and nitric oxide production in H2O2-induced endothelial dysfunction in EA.hy926 cells. Avenanthramides notably increased the levels of antioxidant enzymes and glutathione while reducing malondialdehyde and reactive oxygen species. Moreover, avenanthramides promoted the Nrf2 translocation to nucleus, enhancing the expression of antioxidant enzymes. Furthermore, avenanthramides inhibited the protein levels of iNOS and COX-2, as well as the phosphorylation of IkBα and translocation of p65, thereby mitigating endothelial inflammation. Molecular docking analysis revealed that avenanthramide A exhibited the strongest binding affinity for HO-1 and iNOS, which was correlated with its superior biological activity. Overall, by upregulating Nrf2/HO-1 pathways and downregulating NF-kB pathways, avenanthramides show potential as therapeutic agents for the treatment of endothelial dysfunction.

Anti-inflammatory and antioxidative effects of bioactive peptides IKW and RIY in spontaneously hypertensive rats and angiotensin II-stimulated vascular smooth muscle cells

The chicken muscle-derived peptide IKW and the rapeseed-derived peptide RIY are two previously identified anti-hypertensive peptides that up-regulate angiotensin-converting enzyme 2 (ACE2). Given the interplay between hypertension and vascular inflammation and oxidation, this study investigated the potential anti-inflammatory and antioxidative activities of IKW and RIY in the aorta of spontaneously hypertensive rats (SHRs) and angiotensin II (Ang II)-stimulated vascular smooth muscle cells (VSMCs). SHRs were orally administered 15 mg peptides/kg body weight for 7 days, leading to reduced vascular inflammation and oxidative stress through the modulation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways, decreased aortic nitrotyrosine and intracellular calcium levels, and shifts in the oxylipin profile towards anti-inflammatory species. Meanwhile, VSMCs treated with peptides (50 μM), with or without suramin (10 μM), under Ang II stimulation (1 μM or 10 nM), showed reduced levels of reactive oxygen species, intracellular calcium, interleukin-1β, and cyclooxygenase 2 (COX2). The inhibitory effects on COX2 were partially mediated by ACE2 and sirtuin-1 (SIRT1) upregulation, with SIRT1 contributing to ACE2 expression, as knocking down ACE2 or blocking SIRT1 attenuated these effects. Overall, our results confirm that peptides IKW and RIY exhibit anti-inflammatory and antioxidative effects in the vasculature of SHRs and in Ang II stimulated VSMCs.

Sertraline as a Multi-Target Modulator of AChE, COX-2, BACE-1, and GSK-3β: Computational and In Vivo Studies.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with the dysregulation of several key enzymes, including acetylcholinesterase (AChE), cyclooxygenase-2 (COX-2), glycogen synthase kinase 3β (GSK-3β), β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), and caspase-3. In this study, machine learning algorithms such as Random Forest (RF), Gradient Boost (GB), and Extreme Gradient Boost (XGB) were employed to screen US-FDA approved drugs from the ZINC15 database to identify potential dual inhibitors of COX-2 and AChE. The models were trained using molecules obtained from the ChEMBL database, with 5039 molecules for AChE and 3689 molecules for COX-2. Specifically, 1248 and 3791 molecules were classified as active and inactive for AChE, respectively, while 858 and 2831 molecules were classified as active and inactive for COX-2. The three machine learning models achieved prediction accuracies ranging from 92% to 95% for both AChE and COX-2. Virtual screening of US-FDA drugs from the ZINC15 database identified sertraline (SETL) as a potential dual inhibitor of AChE and COX-2. Further docking studies of SETL in the active sites of AChE and COX-2, as well as BACE-1, GSK-3β, and caspase-3, revealed strong binding affinities for all five proteins. In vivo validation was conducted using a lipopolysaccharide (LPS)-induced rat model pretreated with SETL for 30 days. The results demonstrated a significant decrease in the levels of AChE (p < 0.001), BACE-1 (p < 0.01), GSK-3β (p < 0.05), and COX-2 (p < 0.05). Additionally, the downstream effects were evaluated, showing significant decreases in the apoptosis marker caspase-3 (p < 0.05) and the oxidative stress marker malondialdehyde (MDA) (p < 0.001), indicating that SETL is clinically localized in its effectiveness, mitigating both enzymatic activity and the associated pathological changes of cognitive impairment and AD.

Hua-Zhuo-Jie-Du Decoction Combined with Cisplatin Inhibits the Development of Gastric Cancer Cells by Regulating Immune and Autophagy Signaling.

Host immunity and autophagy of cancer cells markedly impact the development of gastric cancer. Hua-Zhuo-Jie-Du decoction (TDP) has been used in gastritis clinically. This study aimed to evaluate the effects of TDP combined with cisplatin (DDP) on gastric cancer and explore the molecular mechanism. A total of 16 BALB/c nude mice were used to model the SGC7901 cells xenograft and treated with TDP and DDP or both, with the model group as the control. Hematoxylin-Eosin (H&E) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining were performed, and the expression levels of CD31 and Ki-67 were quantified by immunohistochemistry staining. Additionally, cyclooxygenase (COX)-2, matrix metalloproteinas (MMP)-2, and MMP-9 expression levels were quantified using quantitative real-time PCR (qRT-PCR) and Western blotting (WB). WB was used to determine Cleaved-caspase3, Beclin-1, LC3B, and p-p62 levels. Lastly, flow cytometry was employed to evaluate immune responses in mice. TDP and DDP significantly decreased tumor weight and nuclear division, resulting in loosely distributed cells. Besides, TDP and DDP down-regulated the protein expression levels of Ki-67, CD31, COX-2, MMP-2, and MMP-9, as well as decreased the number of CD4+ IL-17+ cells. Conversely, TDP and DDP up-regulated Cleaved-caspase3 expression and the proportion of CD3+/CD4+ and CD8+/CD3+ cells. Notably, optimal effects were achieved using the combination of DDP and TDP. Furthermore, DDP increased the LCII/LCI ratio and the Beclin-1 levels while down-regulating p62 levels. However, TDP alleviated these effects. These results collectively indicated that the combination of TDP with DDP can inhibit the development of gastric cancer cells by mediating the immune and autophagy signaling pathways.

The role of COX2 deficiency attenuates cardiac damage in acute myocardial infarction

Cardiac cell damage frequently occurs as a consequence of acute myocardial infarction (AMI), a critical complication of coronary atherosclerotic heart disease. There is an escalating recognition of the association between COX2 and myocardial damage induced by ischemia. The objective of this study is to investigate the inhibitory effect of the COX2 on cardiomyocyte damage in the context of AMI. To create an AMI model, mice with the genetic background of wild-type C57BL6/J (WT) and COX2-/- mice were utilized. The left anterior descending (LAD) coronary artery in their hearts was obstructed, and subsequent assessment of hemodynamic parameters and heart function was conducted. Notably, increased levels of COX2 were observed in AMI mice. Through correlational analysis between COX2 expression and cardiac function following AMI, it was revealed that COX2 knockout mice had smaller infarct sizes, better cardiac performance, and suppressed levels of reactive oxygen species (ROS) compared to WT mice. Additionally, we discovered that COX2 knockout mice exhibited significantly higher mRNA levels of smooth muscle actin, collagen I, and collagen III than normal mice with AMI. Conversely, the levels of superoxide dismutase (SOD), malondialdehyde (MDA) were higher but iron content was decreased in COX2 knockout mice compared to normal mice with AMI.In summary, our research demonstrates that the downregulation of COX2 enhances cardiac tissue recovery in the context of AMI.

Artemisinin emulgel ameliorates cartilage degradation in knee osteoarthritis: in vitro and in vivo studies.

Aim: Laboratory scale-up of artemisinin-loaded emulgel (ART-emulgel) was carried out and characterized for therapeutic performance in osteoarthritis (OA).Materials & methods: The solubility of ART in various oils, surfactants and co-surfactants were screened for construction of pseudo ternary phase diagram (TPD), followed by scale-up of artemisinin loaded nanoemulsion (ART-NE). ART-NE was amalgamated with Carbopol Ultrez 10-NF to prepare ART-emulgel that was later characterized invitro and invivo to analyze therapeutic efficacy in monosodium-iodoacetate (MIA) induced knee OA.Results: The droplet diameter of ART-NE was estimated to be 104.3±2.593nm with a polydispersity index of 0.245±0.019 in addition to ζ-potential of 0.434±0.028mV. Steady-state flux and permeability coefficient for ART-emulgel were estimated to be 0.651±0.031 µg.cm2/h and 0.245±0.011cm/h, respectively. ART-emulgel demonstrated 43.18% reduction in COX-2 level; 52.28% drop in IL-1β, and 88.78% alleviation of Tumor Necrosis Factor-α (TNF-α) level when compared with monosodium-iodoacetate induced OA rats. ART-emulgel and injectable ART (intra-articular; I.A) portrayed minor synovial erosion compared with blank and diclofenac emulgel. Histopathological evidences indicated restoration of cartilage integrity followed by reduction of OARSI scores in ART-emulgel when compared with disease control animals.Conclusion: ART-emulgel is a potential dosage form for translating into a clinically viable product for the management of OA.

Anticancer activity of EMD37 against human head and neck cancer: Impact on apoptotic and inflammatory machineries

Accumulating evidence emphasizes the tumorigenic role of epidermal growth factor receptor (EGFR) in head and neck cancer (HNC). Although cetuximab is the sole anti-EGFR approved by the Food and Drug Administration for treating HNC patients.its response rates are modest. Thus, novel effective and tolerable therapeutic strategies are urged. We previously reported the capability of oxadiazole derivatives to degrade tyrosine kinase receptors including EGFR and exhibit potent anticancer activities against NCI-60 panel which does not include HNC. The aim of this study was to investigate the potential anticancer activity of EMD37, a novel 1,2,4-oxadiazole derivative, against human HNC cells and if effective, to examine the effect of EMD37 on apoptotic and inflammation mediators. Indeed, EMD37 exhibited potent cytotoxicity against patient-derived HNC cell lines (HNO-97, HN-9 and FaDu). Delving deeper, EMD37 triggered intrinsic and extrinsic apoptosis in HNC cells as evidenced by increased levels of caspase-8, caspase-9, caspase-3, caspase-7, caspase-6, TP53BP1 tumor suppressor and Bax, and downregulated anti-apoptotic Bcl-2 protein. EMD37 also significantly abrogated the levels of pro-inflammatory interleukin-1β, interleukin-6, cyclooxygenase-2 and matrix metalloproteinases (MMP-2 and MMP-9) which are heightened in HNC. Bioinformatic analysis revealed that BCL2low, IL6low and MMP9low HNC biospecimens are enriched with epithelial cell differentiation gene set, and CASP8high cohort is enriched with extrinsic apoptosis. Altogether, this study emphasizes the therapeutic potential of targeting the apoptotic and inflammatory machineries in HNC using EMD37.

Effect of Different Concentrations of PRP on the Expression of Factors Involved in the Endometrial Receptivity in the Human Endometrial Cells from RIF Patients Compared to the Controls.

Platelet-rich plasma (PRP) has been suggested for the improvement of endometrial growth and receptivity in the patients with recurrent implantation failure (RIF). The aim of present study was to investigate the impact of different concentration of PRP on the expression of genes involved in the endometrial receptivity in the human endometrial cells from RIF and controls with thin and normal endometrium in vitro. In this cross-sectional study, endometrial biopsies were obtained from 14 healthy fertile women and 14 women with RIF. Endometrial cells from 4 different group (RIF and control with endometrial thickness < 7mm and > 7mm) were cultured with three different concentration of PRP 3%, 5% and 10%. Expression of leukemia inhibitory factor (LIF), COX2 and P53, estrogen receptors (ERs) and progesterone receptors (PRs) genes were measured using quantitative real-time polymerase chain reaction (PCR). Protein expression levels of LIF, COX2 and p53 were evaluated using Western Blot method (WB). There was a significant decrease in the expression of PROA/b, ER2/b, LIF/b, COX2/b and P53/b genes in the RIF groups compared to the controls. Treatment with 5% and 10% PRP caused a significant increase in the gene expression of PRs, ERs, LIF/b, COX2/b and p53 in the RIF groups. Moreover, protein expression of COX2/b, LIF/b and p53/b increased following treatment with PRP in the RIF group with the endometrium thickness < 7mm. PRP enhances expression of LIF, COX2, p53, ERs and PRs in the RIF patients with thin endometrium which may improve endometrium receptivity.

LncRNA Taurine Up-Regulated 1 Knockout Provides Neuroprotection in Ischemic Stroke Rats by Inhibiting Nuclear-Cytoplasmic Shuttling of HuR.

Background: Long non-coding RNA taurine-upregulated gene 1 (TUG1) is involved in various cellular processes, but its role in cerebral ischemia-reperfusion injury remains unclear. This study investigated TUG1's role in regulating the nucleocytoplasmic shuttling of human antigen R (HuR), a key apoptosis regulator under ischemic conditions. Methods: CRISPR-Cas9 technology was used to generate TUG1 knockout Sprague Dawley rats to assess TUG1's impact on ischemic injury. The infarct area and neuronal apoptosis were evaluated using TUNEL, hematoxylin and eosin (HE), and TTC staining, while behavioral functions were assessed. Immunofluorescence staining with confocal microscopy was employed to examine TUG1-mediated HuR translocation and expression changes in the apoptosis-related proteins COX-2 and Bax. Results: TUG1 knockout rats showed significantly reduced cerebral infarct areas, decreased neuronal apoptosis, and improved neurological functions compared to controls. Immunofluorescence staining revealed that HuR translocation from the nucleus to the cytoplasm was inhibited, leading to decreased COX-2 and Bax expression levels. Conclusions: TUG1 knockout reduces ischemic damage and neuronal apoptosis by inhibiting HuR nucleocytoplasmic shuttling, making TUG1 a potential therapeutic target for ischemic stroke.

Reduced microvascular flow-mediated dilation in Syrian hamsters lacking d-sarcoglycan is caused by increased oxidative stress.

d-sarcoglycan mutation reduces mechanotransduction and induces dilated cardiomyopathy with aging. We hypothesized that in young hamsters with d-sarcoglycan mutation, which do not show cardiomyopathy, flow mechanotransduction might be affected in resistance arteries as the control of local blood flow. Flow-mediated-dilation (FMD) was measured in isolated mesenteric resistance arteries, using 3-months old hamsters carrying a mutation in the d-sarcoglycan gene (CH-147) and their control littermates. The FMD was significantly reduced in the CHF-147 group. Nevertheless, passive arterial diameter, vascular structure and endothelium-independent dilation to sodium nitroprusside were not modified. Contraction induced by KCl was not modified, whereas contraction due to phenylephrine was increased. The basal NO production and total eNOS expression levels were not altered. Nevertheless, eNOS phosphorylation, FAKs and RhoA expression were reduced in CH-147. In contrast, p47phox, COX2, iNOS and reactive oxygen species levels were higher in the endothelium of CHF-147 hamsters. Reducing ROS levels using the superoxide dismutase analog Tempol significantly restored the flow-mediated dilation (FMD) levels in CHF-147 hamsters. However, treatment with the COX-2 inhibitor NS-398 showed a non-significant improvement in FMD.