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Background The paper is aimed at uncovering the mechanism of miR-204-5p in regulating inflammatory responses of human osteoarthritic synovial fibroblasts (SFs). Methods IL-1β-induced osteoarthritic SFs were established as an osteoarthritis (OA) cell model. The osteoarthritic SFs were accordingly transfected with mimics-miR-204-5p, inhibitors-miR-204-5 or FOXC1 siRNA. MTT tested the vitality of osteoarthritic SFs by analyzing the cell optical density. The expressions of miR-204-5p, FOXC1, TNF-α, IL-6, PGE2, MMP-1, MMP-13 and COX-2 in osteoarthritic SFs were measured by qRT-PCR, Western blotting and/or ELISA. The binding of miR-204-5p to FOXC1 was verified through luciferase reporter assay. The regulatory effect of miR-204-5p on FOXC1 was also tested in normal SFs. Results miR-204-5p was under-expressed and FOXC1 was over-expressed in osteoarthritic SFs. The expressions of FOXC1, TNF-α, IL-6, PGE2, MMP-1, MMP-13 and COX-2 were up-regulated in IL-1β-treated SFs. Up-regulation of miR-204-5p or down-regulation of FOXC1 suppressed the inflammatory responses of osteoarthritic SFs. miR-204-5p negatively regulated FOXC1 by being a sponge in osteoarthritic SFs as well as in normal SFs. Conclusion miR-204-5p down-regulates FOXC1 to ameliorate inflammation of SFs in OA.

Background: Colon cancers are among the top three causes of cancer-related deaths. This study is a continuation of previous research aiming to identify effective treatments. Objective: This study investigated the effects of Tarantula cubensis alcoholic extract (TCAE) and Nerium oleander (NO) distillate on the levels of midkine, transforming growth factor (TGF)-β, vascular endothelial growth factor (VEGF), alpha-fetoprotein (AFP), cyclooxygenase (COX)-2, insulin-like growth factor (IGF) and caspase-3 in the liver and colon tissues of rats with experimentally induced colon cancer. Method: The liver and colon tissues of rats were homogeneously divided into control, colon cancer (azoxymethane, AZM), AZM + TCAE, and AZM + NO distillate groups. The levels of midkine, TGF-β, VEGF, AFP, COX-2, IGF, and caspase-3 in the colon and liver tissues were measured by ELISA. Results: The levels of all parameters in colon and liver tissues in the AZM group were higher (p Conclusion: NO distillate and TCAE may prevent the studied markers from reaching specified levels observed in the colon in AZM-induced colon cancer. The increases in the levels of the parameters in the liver were not as severe as those in the colon; however, an 18-week study period may not be sufficient for liver metastasis formation. Future molecular studies should investigate the mechanisms and pathways of these treatments in greater detail.

Background: Chronic inflammation plays a crucial role in the initiation, promotion, and invasion of tumors, and thus the antiproliferative effects of numerous anti-inflammatory drugs have been frequently reported in the literature. Upregulation of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2) has been linked to various human cancers, including breast cancer. Objective: This research aims to investigate the antiproliferative activity of different Non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 selective and non-selective agents, against various breast cancer cell lines and to elucidate possible molecular pathways involved in their activity. Methods: The antiproliferative and combined effects of NSAIDs with raloxifene were evaluated by MTT assay. Cell migration was assessed using a wound-healing assay. The mechanism of cell death was determined using the Annexin V-FITC/ propidium iodide staining flow cytometry method. A mass spectrometry-based targeted metabolomics approach was used to profile the metabolomic changes induced in the T47d cells upon drug treatment. Results: Our results have demonstrated that celecoxib, a potent and selective COX-2 inhibitor, resulted in significant antiproliferative activity against all examined breast cancer cell lines with IC50 values of 95.44, 49.50. and 97.70 μM against MDA-MB-231, T47d, and MCF-7, respectively. Additionally, celecoxib exhibited a synergistic effect against T47d cells combined with raloxifene, a selective estrogen receptor modulator. Interestingly, celecoxib treatment increased cell apoptosis and resulted in substantial inhibition of cancer cell migration. In addition, the metabolomic analysis suggests that celecoxib may have affected metabolites (n = 43) that are involved in several pathways, including the tricarboxylic acid cycle, amino acids metabolism pathways, and energy production pathways in cancer cells. Conclusion: Celecoxib may possess potential therapeutic utility for breast cancer treatment as monotherapy or in combination therapy. The reported metabolic changes taking place upon celecoxib treatment may shed light on possible molecular targets mediating the antiproliferative activity of celecoxib in an independent manner of its COX-2 inhibition.

Odontogenic keratocysts (OKCs) and orthokeratinized odontogenic Cysts (OOCs) are distinct clinicopathological entities. OKC appears to behave in a way more similar to that of a neoplasm, such as ameloblastoma (AB). The aim of this study is to compare the influence of Ki-67, Cyclin D1 and COX-2 in the diagnosis and pathogenesis of OKC, OOC and AB.A cross-sectional observational study of 41 samples was organized into 3 groups: (1) OKC n=22; (2) AB n=13 and (3) OOC n=6. Paraffin blocks were sectioned and stained with hematoxylin and eosin (HE). Immunohistochemical study using Bond Polymer Refine Red Detection Kit, Leica, Wetzlar, Germany, was performed for the following antibodies: Ki-67, Cyclin D1 and COX-2. Double blind immunostaining was quantified subjectively. Staining: nuclear or cytoplasmic; nuclear (Ki-67 and Cyclin D15% positive) and cytoplasmic (COX-2; 1; 1-30 cytoplasm: 2; 31-60 cytoplasm; 3; 61-100 cytoplasm). Considering positive stained 61-100 cytoplasms.The expression of Ki-67 was higher in the OKC group than in the AB group (p0.05). Cyclin D1 showed a higher expression in OKC vs. OOC and OKC vs. AB (p0.05). Finally, expression of COX-2 was higher in OKC vs AB (p0.05).COX-2, Ki-67 and Cyclin D1 show statistically significant differences between the groups, suggesting that they could be useful tools in the differential diagnosis between OKCs and OOC and a predictive indicator for their biologic behaviour. The higher expressions of these 3 markers of OKC vs AB highlight once more the aggressive behaviour of this now re-considered cystic lesion. These markers could prove useful in the choice of more aggressive surgical treatment in OKCs as their behaviour appears to be similar to that of a neoplasm.

Patients with chronic obstructive pulmonary disease (COPD) are characterized by an imbalance between oxidant enzymes and antioxidant enzymes. In the present study, we explored the protective effect of vitamin E on COPD and the underlying mechanisms. Targets of vitamin E were predicted by bioinformatics analysis. After establishing cigarette smoke (CS)-induced COPD rats, the expression levels of epidermal growth factor receptor (EGFR), cyclooxygenase 2 (COX2), and transcriptional activity of signal transducer and activator of transcription 3 (STAT3) were measured. Additionally, the effects of vitamin E on CS-induced COPD were explored by assessing inflammation, the reactive oxygen species (ROS), the activity of superoxide dismutase (SOD) and the content of malondialdehyde (MDA), viability of human bronchial epithelioid (HBE) cells, and the expression of EGFR/MAPK pathway-related factors after loss- and gain- function assays. Vitamin E alleviated COPD. Vitamin E inhibited MAPK signaling pathway through decreasing EGFR expression. Additionally, vitamin E suppressed CS-induced HBE cell damage. Functionally, vitamin E attenuated CS-induced inflammation, apoptosis, and ROS by inhibiting the EGFR/MAPK axis, thereby inhibiting COX2-mediated p-STAT3 nuclear translocation. Moreover, overexpression of COX2 attenuated the protective effect of vitamin E on COPD rats. The present study shows that vitamin E inhibits the expression of COX2 by negatively regulating the EGFR/MAPK pathway, thereby inhibiting the translocation of phosphorylated STAT3 to the nucleus and relieving COPD.

Background Inhibition of the microsomal prostaglandin (PG) E2 synthase (mPGES-1) introduces a promising anti-inflammatory treatment approach by specifically reducing PGE2 . The microvasculature is a central target organ for early manifestations of cardiovascular disease. Therefore, a better understanding of the prostaglandin system and characterising the effects of mPGES-1 inhibition in this vascular bed are of interest. Experimental approach The effects of mPGES-1 inhibition on constriction and relaxation of resistance arteries (O100-400μm) from patients with end stage kidney disease (ESKD) and controls (Non-ESKD) were studied using wire-myography in combination with immunological and mass-spectrometry based analyses. Key results Inhibition of mPGES-1 in arteries from ESKD patients and Non-ESKD controls significantly reduced adrenergic vasoconstriction, which was not affected by the COX-2 inhibitors NS-398 and Etoricoxib or the COX-1/COX-2 inhibitor Indomethacin, tested in Non-ESKD controls. Correspondingly, a significant increase of acetylcholine-induced dilatation was observed for mPGES-1 inhibition only. In IL-1β treated arteries, inhibition of mPGES-1 significantly reduced PGE2 levels while PGI2 levels remained unchanged. In contrast, COX-2 inhibition blocked the formation of both prostaglandins. Blockage of PGI2 signaling with an IP receptor antagonist did not restore the reduced constriction, neither did blocking of PGE2 -EP4 or signaling through PPARγ. A biphasic effect was observed for PGE2 , inducing dilatation at nmol and constriction at μmol concentrations. Immunohistochemistry demonstrated expression of mPGES-1, COX-1, PGIS, weak expression for COX-2 as well as receptor expression for PGE2 (EP1-4), thromboxane (TP) and PGI2 (IP) in ESKD and Non-ESKD. Conclusion Our study demonstrates vasodilating effects following mPGES-1 inhibition in human microvasculature and suggests that several pathways besides shunting to PGI2 may be involved.

Sorafenib-mediated chemotherapy is currently the first choice for hepatocellular carcinoma (HCC) that cannot be surgically excised, and can significantly improve the survival of patients. However, its poor water solubility restricts its bioavailability, and long-term single use of it does not achieve satisfactory HCC therapy effects. Herein, we report a novel cascaded copper-based metal-organic framework (MOF) therapeutic nanocatalyst using HKUST-1 by integrating cyclooxygenase-2 (COX-2) inhibitor meloxicam (Mel) and chemotherapeutic agent sorafenib (Sol) to amplify HCC therapy. This HKUST-1 nanocatalyst can be degraded by glutathione (GSH) into a Fenton-like agent to trigger chemodynamic therapy (CDT). CDT-mediated cytotoxic reactive oxygen species (ROS) can activate ferroptosis by accumulating lipid peroxides (LPO). Alternatively, GSH depletion not only deactivates glutathione peroxidase 4 (GPX4) to trigger ferroptosis, but also leads to oxidative stress amplification. Moreover, Sol can also activate ferroptosis by inhibiting system XC-, resulting in cascade-amplified ferroptosis mediated HCC therapy. Furthermore, the down-regulation of COX-2 can induce PINK1/Parkin-mediated mitophagy to further act synergistically with Sol-mediated chemotherapy. Therefore, this HKUST-1 nanocatalyst provides a novel strategy to regulate GSH and COX-2 levels for amplified chemo/chemodynamic and ferroptosis-mediated HCC therapy.

Huangqin decoction (HQD) is a Traditional Chinese Medicine formula for ulcerative colitis. However, the pharmacology and molecular mechanism of HQD on ulcerative colitis is still unclear. Combined microarray analysis, network pharmacology, and molecular docking for revealing the therapeutic targets and molecular mechanism of HQD against ulcerative colitis. TCMSP, DrugBank, Swiss Target Prediction were utilized to search the active components and effective targets of HQD. Ulcerative colitis effective targets were obtained by microarray data from the GEO database (GSE107499). Co-targets between HQD and ulcerative colitis are obtained by Draw Venn Diagram. PPI (Protein–protein interaction) network was constructed by the STRING database. To obtain the core target, topological analysis is exploited by Cytoscape 3.7.2. GO and KEGG enrichment pathway analysis was performed to Metascape platform, and molecular docking through Autodock Vina 1.1.2 finished. 161 active components with 486 effective targets of HQD were screened. 1542 ulcerative colitis effective targets were obtained with |Log2FC|> 1 and adjusted P-value

Granulocyte colony-stimulating factor (G-CSF) has been reported to exert a protective effect against secondary brain damage, but the underlying mechanisms remain unknown. We explored the ability of G-CSF to protect the brain from injury in a rat autologous blood-induced model of intracerebral hemorrhage (ICH), with a special focus on the anti-inflammation effect. An ICH was induced in 8-week-old male rats by an infusion of autologous blood, and the rats were then randomly assigned to five treatment groups: sham, ICH, and ICH+ low-dose (25 µg/kg), middle-dose (50 µg/kg), and high-dose (75 µg/kg) G-CSF. We then evaluated the levels of brain inflammation-related genes and proteins. The levels of tumor-necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) mRNA increased between days 1 and 14 post-ICH, with the highest expression on day 3. These changes were rectified by G-CSF in a dose-dependent manner. At day 3 post-injury, an elevation of the nuclear factor-kappa B (NF-κB) p65 protein level and a reduction of the inhibitor of NF-κB alpha (IκBα) protein level were observed; G-CSF treatment exerted a beneficial effect on both protein expressions. The expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins were increased; these changes were rectified by the highest dose of G-CSF. The brain-protecting effects of G-CSF are likely to be attributable, at least in part, to attenuation of the TNF-α, IL-6, iNOS, and COX-2 expressions induced by NF-κB activation in the brain tissues of this autologous blood-induced ICH rat model.

The protozoan parasite Trypanosoma brucei is the causative agent of the neglected tropical disease human African trypanosomiasis, otherwise known as sleeping sickness. Trypanosomes have evolved many immune-evasion mechanisms to facilitate their own survival, as well as prolonging host survival to ensure completion of the parasitic life cycle. A key feature of the bloodstream form of T. brucei is the secretion of aromatic keto acids, which are metabolized from tryptophan. In this study, we describe an immunomodulatory role for one of these keto acids, indole-3-pyruvate (I3P). We demonstrate that I3P inhibits the production of PGs in activated macrophages. We also show that, despite the reduction in downstream PGs, I3P augments the expression of cyclooxygenase (COX2). This increase in COX2 expression is mediated in part via inhibition of PGs relieving a negative-feedback loop on COX2. Activation of the aryl hydrocarbon receptor also participates in this effect. However, the increase in COX2 expression is of little functionality, as we also provide evidence to suggest that I3P targets COX activity. This study therefore details an evasion strategy by which a trypanosome-secreted metabolite potently inhibits macrophage-derived PGs, which might promote host and trypanosome survival.

Background Alzheimer’s disease (AD) causes substantial medical and societal burden with no therapies ameliorating cognitive deficits. Centralized pathologies involving amyloids, neurofibrillary tangles, and neuroinflammatory pathways are being investigated to identify disease-modifying targets for AD. Cyclooxygenase-2 (COX-2) is one of the potential neuroinflammatory agents involved in AD progression. However, chronic use of COX-2 inhibitors in patients produced adverse cardiovascular effects. We asked whether inhibition of EP2 receptors, downstream of the COX-2 signaling pathway, can ameliorate neuroinflammation in AD brains in presence or absence of a secondary inflammatory stimuli. Methods We treated 5xFAD mice and their non-transgenic (nTg) littermates in presence or absence of lipopolysaccharide (LPS) with an EP2 antagonist (TG11-77.HCl). In cohort 1, nTg (no-hit) or 5xFAD (single-hit—genetic) mice were treated with vehicle or TG11-77.HCl for 12 weeks. In cohort 2, nTg (single-hit—environmental) and 5xFAD mice (two-hit) were administered LPS (0.5 mg/kg/week) and treated with vehicle or TG11-77.HCl for 8 weeks. Results Complete blood count analysis showed that LPS induced anemia of inflammation in both groups in cohort 2. There was no adverse effect of LPS or EP2 antagonist on body weight throughout the treatment. In the neocortex isolated from the two-hit cohort of females, but not males, the elevated mRNA levels of proinflammatory mediators (IL-1β, TNF, IL-6, CCL2, EP2), glial markers (IBA1, GFAP, CD11b, S110B), and glial proteins were significantly reduced by EP2 antagonist treatment. Intriguingly, the EP2 antagonist had no effect on either of the single-hit cohorts. There was a modest increase in amyloid–plaque deposition upon EP2 antagonist treatment in the two-hit female brains, but not in the single-hit genetic female cohort. Conclusion These results reveal a potential neuroinflammatory role for EP2 in the two-hit 5xFAD mouse model. A selective EP2 antagonist reduces inflammation only in female AD mice subjected to a second inflammatory insult.

Cancer remains a major public health problem worldwide and the latest statistics show that breast cancer (BC) is among the most frequent in women. MicroRNAs (miRNAs; miRs) and cyclooxygenase-2 (COX-2) are new diagnostic and therapeutic biomarkers for monitoring BC. COX-2 is a prominent tumor-associated inflammatory factor highly expressed in human tumor cells, including BC. Expression of COX-2 contributes to tumor growth, metastasis and recurrence. MiRs are a group of short (~22 nucleotides), noncoding regulatory RNAs that downregulate gene expression post-transcriptionally and play vital roles in regulating cancer development and progression. Interestingly, there are a group of miRNAs differentially expressed in breast tumor tissue. Understanding the pathway linking miRNAs to COX-2 can provide novel insight for suppressing COX-2 expression via gene silencing thereby leading to the development of selective miRNA inhibitors. Further research can also reveal key intermediate players and their potential as therapeutic targets. Given the association between different miRNAs and COX-2 expression in BC, this review presents a comprehensive overview of the current literature concerning how miRNAs and COX-2 signaling interact in BC progression.

Motivation. Skin tumor is one of the frequent occurring forms of cancer where 2-3 million instances are reported worldwide. The ultraviolet rays along with the environmental pollutants and other contaminants can be the potential factors of skin cancer. Cyclin D1 is a serious gene included in controlling the development through the G1 phase of the cell cycle. Ochratoxin A (OTA) is a naturally existing mycotoxin which majorly occurs in food like grains. It is responsible for producing the splitting of single-strand DNA and is identified to be cancer-causing. It is established as a critical risk factor towards reproductive health in both males and females. Methodology. A single dose of ochratoxin A was used for topical application for assessment of skin tumor promotion activity, hyperplasia, ornithine decarboxylase activity, and expression of cyclin D1 and COX-2 in mouse skin. Enhancement in the synthesis of DNA, activation of the epidermal growth factor receptor, and overexpression of cyclin D1 and COX-2 were noted. Primary murine keratinocyte cell culture was cultured with Waymouth’s medium. Western blot analysis and real-time polymerase chain reaction (RT-PCR) were used to detect the expression of cyclin D1 and COX-2. Chromatin immunoprecipitation (ChIP) assays were used to the association between AP-1 transcription and nuclear factor-kappaB (NF-κB) with COX-2 and cyclin D1 promoters. Results. The results found that cyclin D1 and COX-2 were responsible for stimulating OTA-induced PMK proliferation and hyperplasia. Implications. EGFR-mediated pathways were also responsible for tumor promotion due to OTA.

Microglial activation has been studied extensively in diabetic retinopathy. We have previously detected activation and migration of microglia in 8-week-old diabetic rat retinas. It is widely acknowledged that microglia-mediated inflammation contributes to the progression of diabetic retinopathy. However, existing cell models do not explore the role of activated microglia in vitro. In this study, microglia were subject to various conditions mimicking diabetic retinopathy, including high glucose, glyoxal, and hypoxia. Under high glucose or glyoxal treatment, microglia demonstrated only partially functional changes, while under hypoxia, microglia became fully activated showing enlarged cell bodies, enhanced migration and phagocytosis as well as increased production of pro-inflammatory factors such as cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), and inducible nitric oxide synthase (iNOS). The data indicate that hypoxia-treated microglia is an optimal in vitro model for exploration of microglia activation in diabetic retinopathy.

The effects of 3,5,3',4'-tetrahydroxystilbene (piceatannol) on azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colon cancer growth and changes in IL-1β, IL-6, tumor necrosis factor-α (cytokines), MCP-1, vascular endothelial growth factor, and PD-1 colon levels were investigated herein.AOM (10 mg/kg,In mice administered piceatannol (12.5 mg/kg), the tumor number, tumor area, and Ki-67-positive cell numbers decreased by 30.1%, 57.2%, and 89.1%, respectively, colon MCP-1 and PD-1 levels showed reductions of 43.8% and 70.9%, respectively, and COX-2-positive cell numbers declined by 60.2%.The inhibitory effects of piceatannol on AOM/DSS-induced colon tumor growth

The balance between endothelial nitric oxide (NO) synthase (eNOS) activation and production of reactive oxygen species (ROS) is very important for NO homeostasis in liver sinusoidal endothelial cells (LSECs). Overexpression of cyclooxygenase‐2 (COX‐2), a major intravascular source of ROS production, has been observed in LSECs of cirrhotic liver. However, the links between low NO bioavailability and COX‐2 overexpression in LSECs are unknown. This study has confirmed the link between low NO bioavailability and COX‐2 overexpression by COX‐2‐dependent PGE2‐EP2‐ERK1/2‐NOX1/NOX4 signalling pathway in LSECs in vivo and in vitro. In addition, the regulation of COX‐2‐independent LKB1‐AMPK‐NRF2‐HO‐1 signalling pathway on NO homeostasis in LSECs was also elucidated. The combinative effects of celecoxib on diminishment of ROS via COX‐2‐dependent and COX‐2‐independent signalling pathways greatly decreased NO scavenging. As a result, LSECs capillarisation was reduced, and endothelial dysfunction was corrected. Furthermore, portal hypertension of cirrhotic liver was ameliorated with substantial decreasing hepatic vascular resistance and great increase of portal blood flow. With the advance understanding of the mechanisms of LSECs protection, celecoxib may serve as a potential therapeutic candidate for patients with cirrhotic portal hypertension.

Age-related disorders, such as Alzheimer’s disease (AD) and age-related macular degeneration (AMD) share common features such as amyloid-β (Aβ) protein accumulation. Retinal deposition of Aβ aggregates in AMD patients has suggested a potential link between AMD and AD. In the present study, we analyzed the expression pattern of a focused set of miRNAs, previously found to be involved in both AD and AMD, in the retina of a triple transgenic mouse model of AD (3xTg-AD) at different time-points. Several miRNAs were differentially expressed in the retina of 3xTg-AD mice, compared to the retina of age-matched wild-type (WT) mice. In particular, bioinformatic analysis revealed that miR-155 had a central role in miRNA-gene network stability, regulating several pathways, including apoptotic and inflammatory signaling pathways modulated by TNF-related apoptosis-inducing ligand (TNFSF10). We showed that chronic treatment of 3xTg-AD mice with an anti-TNFSF10 monoclonal antibody was able to inhibit the retinal expression of miR-155, which inversely correlated with the expression of its molecular target SOCS-1. Moreover, the fine-tuned mechanism related to TNFSF10 immunoneutralization was tightly linked to modulation of TNFSF10 itself and its death receptor TNFRSF10B, along with cytokine production by microglia, reactive gliosis, and specific AD-related neuropathological hallmarks (i.e., Aβ deposition and Tau phosphorylation) in the retina of 3xTg-AD mice. In conclusion, immunoneutralization of TNFSF10 significantly preserved the retinal tissue in 3xTg-AD mice, suggesting its potential therapeutic application in retinal degenerative disorders.

BACKGROUND: Penile cancer (PeCa) is a rare disease, but its incidence has increased worldwide, mostly in HPV+ patients. Nevertheless, there is still no targeted treatment for this carcinoma. OBJECTIVE: To predict the main signaling pathways involved in penile tumorigenesis and its potential drug targets. METHODS: Genome-wide copy number profiling was performed in 28 PeCa. Integration analysis of CNAs and miRNAs and mRNA targets was performed by DIANA-TarBase v.8. The potential impact of the miRNAs/target genes on biological pathways was assessed by DIANA-miRPath v.3.0. For each miRNA, KEGG pathways were generated based on the tarbase and microT-CDS algorithms. Pharmaco-miR was used to identify associations between miRNAs and their target genes to predict druggable targets. RESULTS: 269 miRNAs and 2,395 genes were mapped in cytobands with CNAs. The comparison of the miRNAs mapped at these cytobands and the miRNAs that were predicted to regulate the genes also mapped in these regions, resulted in a set of common 35 miRNAs and 292 genes. Enrichment pathway revealed their involvement in five top signaling pathways. EGFR and COX2 were identified as potential druggable targets. CONCLUSION: Our data indicate the potential use of EGFR and COX2 inhibitors as a target treatment for PeCa patients.

Background: Osteoarthritis (OA) is degenerative joint disorder mainly characterized by long-term pain with limited activity of joints, the disease has no effective preventative therapy. Rutin (RUT) is a flavonoid compound, present naturally. The flavonoid shows range of biological activities such as anti-inflammatory and anti-cancer effect. We screened RUT for its activity against osteoarthritis with in vivo and in vitro models of osteoarthritis. Methods: Animal model of OA was developed using C57BL/6 mice by surgical destabilization of medial meniscus. For in vitro studies the human articular cartilage tissues were used which were collected from osteoarthritis patients and were processed to isolate chondrocytes. The chondrocytes were submitted to advanced glycation end products (AGEs) for inducing osteoarthritis in vitro. Cell viability was done by CCK-8 assay, ELISA analysis for MMP13, collage II, PGE2, IL-6, TNF-α, ADAMTS-5 and MMP-13. Western blot analysis was done for expression of proteins and in silico analysis was done by docking studies. Results: Pretreatment of RT showed no cytotoxic effect and also ameliorated the AGE mediated inflammatory reaction on human chondrocytes in vitro. Treatment of RT inhibited the levels of COX-2 and iNOS in AGE exposed chondrocytes. RT decreased the AGE mediated up-regulation of IL-6, NO, TNF-α and PGE-2 in a dose dependent manner. Pretreatment of RT decreased the extracellular matrix degradation, inhibited expression of TRAF-6 and BCL-2 the NF-κB/MAPK pathway proteins. The treatment of RT in mice prevented the calcification of cartilage tissues, loss of proteoglycans and also halted the narrowing of joint space is mice subjected to osteoarthritis. The in-silico analysis suggested potential binding affinity of RT with TRAF-6 and BCL-2. Conclusion: In brief RT inhibited AGE-induced inflammatory reaction and also degradation of ECM via targeting the NF-κB/MAPK pathway proteins BCL-2 and TRAF-6. RT can be a potential molecule in treating OA.

The identification of Ultra-High Risk (UHR) individuals is thought to be useful for early intervention to improve psychosis outcomes. However, transition rates vary widely, and there is an effort to make these criteria more specific and accurate. Neuroinflammation has been discussed in the pathophysiology of psychosis. The metabolism of eicosanoids is a key process in inflammatory states. Therefore, we investigated whether the study of the inflammatory COX-2 pathway through the quantification of the eicosanoid levels can be a useful approach for the characterisation of UHR individuals.One hundred and twenty-two individuals were included in this study (67 UHR and 55 controls) based on performance on the Prodromal Questionnaire. UHR status was assessed by Structured Interview for Prodromal Syndromes (SIPS). We determined the levels of Prostaglandin FConcentrations of PGEOur findings suggest that overactivation of the COX-2 pathway may be related to an increased risk for psychosis. However, our data do not allow us to draw conclusions related to the cause-effect mechanisms. Future studies should determine whether the levels of the eicosanoids have a predictive value for the transition of UHR to frank psychosis.

BACKGROUND Cyclooxygenase-2 protein is a critically important mediator in inflammation that influences proliferation, apoptosis, angiogenesis and metastasis. Previous works showed a relationship between cyclooxygenase-2 and tumourigenesis in humans and animal models. In epithelial odontogenic tumours and cysts, increased cell proliferation and survival have been linked to its pathogenesis and tumour development. The aim of the present study was to analyse the immunohistochemical expression of cyclooxygenase-2 in solid ameloblastoma and odontogenic keratocyst and its association with proteins related to cell proliferation and apoptosis. METHODS This study was conducted on 40 cases from the Pathological Anatomy Service, University of Chile. The cases were diagnosed as solid ameloblastoma (n = 21) and odontogenic keratocyst (n = 19) according to WHO 2017. Slides prepared from paraffin-embedded sections were immunohistochemically stained for cyclooxygenase-2, cyclin D1, Ki-67, p63 and Bcl-2. Statistical evaluation was performed by the Shapiro-Wilk test, ANOVA Mann-Whitney test and Spearman's correlation coefficient (p

Hydroxysafflor yellow A (HSYA) from safflower (Carthamus tinctorius L.) possesses several medicinal properties. However, it is unknown whether HSYA is effective in the treatment of rheumatoid arthritis (RA). Hence, we investigated the effects of HSYA on the inflammation and synovial damage in rats with collagen-induced arthritis (CIA) by subjecting them to treatment with different doses of HSYA. Our results revealed that HSYA could significantly reduce paw swelling, pathological manifestations, and serum cytokine levels in rats with CIA. The HSYA-treated groups showed increased antioxidant enzyme activity in the serum and decreased expression of inflammatory mediators in the synovial tissues. Furthermore, HSYA treatment inhibited extracellular signal-regulated kinase (ERK) signalling pathway activation. Notably, the highest dose of HSYA (20 mg/kg) exhibited the best effects against RA symptoms. Therefore, our findings suggest that HSYA alleviates the inflammatory response and synovial damage in rats with CIA by inhibiting the ERK signalling pathway.

Over one hundred clinical trials since 2005 have failed to significantly improve the prognosis of glioblastoma. Since 2005, the standard of care has been maximal resection followed by 60Gy irradiation over six weeks with daily temozolomide. With this, a median survival of 2 years can be expected. This short paper reviewed how the pharmacodynamic attributes of an EMA/FDA approved, cheap, generic drug to treat pain, celecoxib, intersect with pathophysiological elements driving glioblastoma growth, such that growth drive inhibition can be expected from celecoxib. The two main attributes of celecoxib are carbonic anhydrase inhibition and cyclooxygenase-2 inhibition. Both attributes individually have been in active study as adjuncts during current cancer treatment, including that of glioblastoma. That research is briefly reviewed here. This paper concludes from the collected data, that starting celecoxib, 600 to 800mg twice daily before surgery and continuing it through the chemoirradiation phase of treatment would be a low-risk intervention with sound rationale.

A successful pregnancy requires sufficient decidualization of endometrial stromal cells (ESCs). CD82, a metastasis suppressor, is a critical regulator for trophoblast invasion but the effect in decidualization was largely unknown. Here we reported that there was a high level of CD82 in DSC by the immunohistochemistry staining and flow cytometer analysis. Stimulation with prostaglandin E2 (PGE2) elevated the expression of CD82 in ESCs. In contrast, celecoxib, a selective COX-2 inhibitor, significantly downregulated the expression of CD82 in decidual stromal cells (DSCs). Bioinformatics analysis and further research showed that recombinant human interleukin (IL)-1β protein (rhIL-1β) upregulated CD82 in ESCs. Of note, blocking IL-1β signaling with anti-human IL-1β neutralizing antibody could reverse the stimulatory effect of PGE2 on CD82 in ESCs. Silencing CD82 resulted in the decease of the decidualization markers PRL and IGFBP1 mRNA levels in DSCs. More importantly, we observed rhIL-1β also upregulated the expression of COX-2, and the upregulation of PRL and IGFBP1 induced by rhIL-1β could be abolished by celecoxib in ESCs or CD82 deficiency in DSCs. This study suggests that CD82 should be a novel promotor for decidualization under a positive regulation of the COX-2/PGE2/IL-1β positive feedback loop.

Age-related cardiovascular disease is the leading cause of death in elderly populations. Coxibs, including celecoxib, valdecoxib, etoricoxib, parecoxib, lumiracoxib, and rofecoxib, are selective cyclooxygenase-2 (COX-2) inhibitors used to treat osteoarthritis and rheumatoid arthritis. However, many coxibs have been discontinued due to adverse cardiovascular events. COX-2 contains cyclooxygenase (COX) and peroxidase (POX) sites. COX-2 inhibitors block COX activity without affecting POX activity. Recently, quercetin-like flavonoid compounds with OH groups in their B-rings have been found to serve as activators of COX-2 by binding the POX site. Galangin-like flavonol compounds serve as inhibitors of COX-2. Interestingly, nabumetone, flurbiprofen axetil, piketoprofen-amide, and nepafenac are ester prodrugs that inhibit COX-2. The combination of galangin-like flavonol compounds with these prodrug metabolites may lead to the development of novel COX-2 inhibitors. This review focuses on the most compelling evidence regarding the role and mechanism of COX-2 in cardiovascular diseases and demonstrates that quercetin-like compounds exert potential cardioprotective effects by serving as cofactors of COX-2.

Cyclooxygenase 2 (COX2) has been associated with the development of inflammatory bowel disease (IBD), but the nature of this association has remained unclear. I demonstrate that mice that lack COX2 lose tolerance to pathogen associated molecular patterns. Thus, challenge with dietary cholate—an environmental trigger that I show impairs intestinal barrier function—induces severe intestinal inflammation in COX2 knock-out mice. COX2 knock-out within the myeloid compartment is sufficient to drive disease upon cholate challenge, while also altering upon disease the balance between pro-inflammatory and inflammation resolving mediators towards a pro-inflammatory phenotype. ApoA-I mimetic peptides including 4F have been investigated as potential anti-inflammatory therapies. I show that 4F targets the small intestine, where it is transported into the intestinal lumen in a cholesterol-dependent manner. In turn, 4F can increase trans-intestinal cholesterol efflux, a secondary cholesterol efflux pathways whose modulation is of therapeutic import. 4F therapy abrogates disease in the myeloid COX2 knock-out and cholate model of IBD, while rescuing the elevated levels of pro-inflammatory mediators in macrophages, intestinal tissue, and plasma. 4F can directly clear lipid pro-inflammatory mediators from tissue and plasma, strongly suggesting a causative role for changes in the levels of these mediator in both the protective mechanism of 4F and the pathogenic mechanism of COX2-mediated IBD. Further investigation into the protective mechanism of 4F identified a novel trans-intestinal lipid transport clearance pathway for inflammatory mediators, which pathway may be involved in 4F’s protective mechanism. These findings are vivid examples of the synergy that can result from simultaneously investigating both pathogenic and protective mechanisms in genetic mouse models of disease.

The biocide chlorpyrifos (CPF) was described to increase breast cancer risk in humans, to produce breast cancer in animals, and to induce cell proliferation in MCF-7 and MDA-MB-231 cells after 1 and 14 days of treatment. The entire mechanisms related to these CPF actions remain unknown. CPF induced cell proliferation in MCF-7 and MDA-MB-231 cells after 1 and 14 days of treatment by AhR activation through the PGE2/Wnt/β-catenin pathway and HSP90 and HSP70 overexpression. Our results reveal new information on CPF toxic mechanisms induced in human breast cancer cell lines, which could assist in elucidating its involvement in breast cancer.

PURPOSE: The enzyme Cyclooxygenases (COX-1 and COX-2) catalyze the formation of prostaglandin, a mediator of the inflammatory pathway. Inflammation related pathological conditions may be alleviated by targeting the Cox enzymes.COX-2 inhibitors that are currently available in the market causes undesirable side effects. Our present study focuses on the in-silico inhibition of COX -2 enzyme by the phytocompounds from Albizia amara and Phyla nodiflora. METHODS: The phytochemicals present in Albizia amara and Phyla nodiflora were analyzed for their COX-2 inhibition potential. Eight compounds from Albizia amara and eleven compounds from Phyla nodiflora obtained from GC–MS analysis was used for the current study. Molecular docking was performed using AutoDock vina. The crystal structure of COX-2 (PDB ID: 5IKR) was obtained from Protein data bank. PyMol was used to remove any solvent, organic and inorganic molecules. Energy minimization of the protein was carried out using SPDBV software. Geometrical optimizations of the ligands were performed using Avogadro software. Celecoxib was used as the positive control. ADMET properties of the compounds were analyzed using SwissADME and ProtoxII online servers. Molecular mechanics/generalized born surface area (MM/GBSA) calculations were performed to evaluate the binding efficiency. Molecular dynamics of the protein and protein–ligand complex was studied for about 100 ns using Desmond package of Schrodinger suite. RESULTS: Among the eighteen compounds, Squalene present in both the plants showed a better binding energy of -7.7 kcal/mol, when compare to other phytocompounds present in the extract. The control celecoxib showed a binding energy of about – 9.4 kcal/mol. The toxicity and ADMET properties of squalene indicated that it is non-toxic and followed Lipinski’s rule. Molecular Dynamics (MD) analysis showed that the binding of squalene to the enzyme was stable. CONCLUSION: Squalene could potentially inhibit COX2 and o wing to its properties, squalene can be formulated in gels/creams and could be possibly used for external edema and inflammation GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40199-021-00408-6.

Unlike in normal cells, ursodeoxycholic acid (UDCA) causes apoptosis rather than protection in cancer cells. Aim of this study was to demonstrate whether UDCA actually inhibits proliferation and induces apoptosis in bile duct cancer cells; the effect of UDCA on the expression of COX-2, PI3K/AKT, ERK, and EGFR; how UDCA affects cancer cell invasiveness and metastasis, since these effects are not established in bile duct cancer cells. SNU-245 cells (human extrahepatic bile duct cancer cells) were cultured. MTT assays were performed to evaluate the effect of UDCA on the cell proliferation. A cell death detection enzyme-linked immunosorbent assay and a caspase-3 activity assay were used to determine apoptosis. Western blot analysis measured expression levels of various proteins. The invasiveness of the cancer cells was evaluated by invasion assay. In cultured bile duct cancer cells, UDCA suppressed cell proliferation in bile duct cancer cells by inducing apoptosis and p53 activation, blocking deoxycholic acid (DCA)-induced activated EGFR-ERK signaling and COX-2, inhibiting DCA-induced activated PI3K-AKT signaling, and suppressing the invasiveness of bile duct cancer cells. In addition, a MEK inhibitor impaired UDCA-induced apoptosis in bile duct cancer cells. UDCA has antineoplastic and apoptotic effects in bile duct cancer cells. Thus, UDCA could be a chemopreventive agent in patients with a high risk of cancer, and/or a therapeutic option that enhances other chemotherapeutics.

Purpose Reactive microglia are an important hallmark of neuroinflammation. Reactive microglia release various inflammatory mediators, such as cytokines, chemokines, and prostaglandins, which are produced by enzymes like cyclooxygenases (COX). The inducible COX-2 subtype has been associated with inflammation, whereas the constitutively expressed COX-1 subtype is generally considered as a housekeeping enzyme. However, recent evidence suggests that COX-1 can also be upregulated and may play a prominent role in the brain during neuroinflammation. In this review, we summarize the evidence that supports this involvement of COX-1. Methods Five databases were used to retrieve relevant studies that addressed COX-1 in the context of neuroinflammation. The search resulted in 32 articles, describing in vitro, in vivo, post mortem, and in vivo imaging studies that specifically investigated the COX-1 isoform under such conditions. Results Reviewed literature generally indicated that the overexpression of COX-1 was induced by an inflammatory stimulus, which resulted in an increased production of prostaglandin E2. The pharmacological inhibition of COX-1 was shown to suppress the induction of inflammatory mediators like prostaglandin E2. Positron emission tomography (PET) imaging studies in animal models confirmed the overexpression of COX-1 during neuroinflammation. The same imaging method, however, could not detect any upregulation of COX-1 in patients with Alzheimer's disease. Conclusion Taken together, studies in cultured cells and living rodents suggest that COX-1 is involved in neuroinflammation. Most postmortem studies on human brains indicate that the concentration of COX-1-expressing microglial cells is increased near sites of inflammation. However, evidence for the involvement of COX-1 in neuroinflammation in the living human brain is still largely lacking.

Carbon tetrachloride (CCl4) is an abundant environmental pollutant that can generate free radicals and induce oxidative stress in different human and animal organs like the kidney, lung, brain, and spleen, causing toxicity. The present study evaluated the alleviative mechanism of the isolated polyphenolic fraction from seedless (pulp and skin) black Vitis vinifera (VVPF) on systemic oxidative and necroinflammatory stress in CCl4-intoxicated rats. Here, we found that the administration of VVPF to CCl4-intoxicated rats for ten days was obviously ameliorated the CCl4-induced systemic elevation in ROS, NO and TBARS levels, as well as MPO activity. Also, it upregulated the cellular activities of the enzymatic (SOD, and GPx) and non-enzymatic (TAC and GSH) antioxidants. Furthermore, the gene expression of the ROS-related necroinflammatory mediators (NF-κB, iNOS, COX-2, and TNF-α) in the kidney, brain, and spleen, as well as IL-1β, and IL-8 in the lung were greatly restored. The histopathological studies confirmed these biochemical results and showed a noticeable enhancing effect in the architecture of the studied organs after VVPF intake. Thus, this study indicated that VVPF had an alleviative effect on CCl4-induced necroinflammation and oxidative stress in rat kidney, lung, brain, and spleen via controlling the ROS/NF-κB pathway.

Inflammation is a form of innate immune response of living organisms to harmful stimuli. In marine bivalves, inflammation is a common defense mechanism. Several studies have investigated the morphological features of inflammation in bivalves, such as hemocyte infiltration. However, the molecular and biochemical responses associated with inflammation in marine bivalves remain unexplored. Here, we investigated changes in nitric oxide (NO) levels, cyclooxygenase 2 (COX-2) activity, and allograft inflammatory factor-1 (AIF-1) gene expression levels in hemolymph samples collected from Manila clam (Ruditapes philippinarum) exposed to pro- and anti-inflammatory substances. These included the pro-inflammatory agent lipopolysaccharide (LPS), and the nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen and diclofenac, all widely used in vertebrates. Our study showed that NO levels, COX-2 activity, and AIF-1 expression increased in response to the treatments with LPS and decreased in response to the treatments with NSAIDs in a concentration-dependent manner. These results suggest that the mechanism of inflammatory responses in bivalves is very similar to that of vertebrates, and we propose that inflammatory responses can be quantified using these techniques and used to determine the physiological status of marine bivalves exposed to biotic or abiotic stresses.

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen have shown initial promise in producing antidepressant effects. This is perhaps due to these drugs being peroxisome proliferator-activated receptor gamma (PPARγ) agonists, in addition to their inhibition of cyclooxygenase enzymes. Some, albeit mixed, evidence suggests that PPARγ agonists have antidepressant effects in humans and animals. This double-blind, placebo-controlled, pharmacologic functional magnetic resonance imaging (ph-fMRI) study aimed to elucidate the impact of ibuprofen on emotion-related neural activity and determine whether observed effects were due to changes in PPARγ gene expression. Twenty healthy volunteers completed an emotional face matching task during three fMRI sessions, conducted one week apart. Placebo, 200 mg, or 600 mg ibuprofen was administered 1 h prior to each scan in a pseudo-randomized order. Peripheral blood mononuclear cells were collected at each session to isolate RNA for PPARγ gene expression. At the doses used, ibuprofen did not significantly change PPARγ gene expression. Ibuprofen dose was associated with decreased blood oxygen level-dependent (BOLD) activation in the dorsolateral prefrontal cortex and fusiform gyrus during emotional face processing (faces-shapes). Additionally, PPARγ gene expression was associated with increased BOLD activation in the insula and transverse and superior temporal gyri (faces-shapes). No interaction effects between ibuprofen dose and PPARγ gene expression on BOLD activation were observed. Thus, results suggest that ibuprofen and PPARγ may have independent effects on emotional neurocircuitry. Future studies are needed to further delineate the roles of ibuprofen and PPARγ in exerting antidepressant effects in healthy as well as clinical populations.

Maternal immune adaptation to accommodate pregnancy depends on sufficient availability of regulatory T (Treg) cells to enable embryo implantation. Toll-like receptor 4 is implicated as a key upstream driver of a controlled inflammatory response, elicited by signals in male partner seminal fluid, to initiate expansion of the maternal Treg cell pool after mating. Here, we report that mice with null mutation in Tlr4 (Tlr4−/−) exhibit impaired reproductive outcomes after allogeneic mating, with reduced pregnancy rate, elevated mid-gestation fetal loss, and fetal growth restriction, compared to Tlr4+/+ wild-type controls. To investigate the effects of TLR4 deficiency on early events of maternal immune adaptation, TLR4-regulated cytokines and immune regulatory microRNAs were measured in the uterus at 8 h post-mating by qPCR, and Treg cells in uterus-draining lymph nodes were evaluated by flow cytometry on day 3.5 post-coitum. Ptgs2 encoding prostaglandin-endoperoxide synthase 2, cytokines Csf2, Il6, Lif, and Tnf, chemokines Ccl2, Cxcl1, Cxcl2, and Cxcl10, and microRNAs miR-155, miR-146a, and miR-223 were induced by mating in wild-type mice, but not, or to a lesser extent, in Tlr4−/− mice. CD4+ T cells were expanded after mating in Tlr4+/+ but not Tlr4−/− mice, with failure to expand peripheral CD25+FOXP3+ NRP1− or thymic CD25+FOXP3+ NRP1+ Treg cell populations, and fewer Treg cells expressed Ki67 proliferation marker and suppressive function marker CTLA4. We conclude that TLR4 is an essential mediator of the inflammation-like response in the pre-implantation uterus that induces generation of Treg cells to support robust pregnancy tolerance and ensure optimal fetal growth and survival.

NOD-like receptor family caspase recruitment domain family domain containing 5 (NLRC5) has been found to be a critical mediator of inflammatory response. However, the role of NLRC5 in osteoarthritis (OA) has not been reported. Our results showed that NLRC5 was down-regulated by IL-1β induction in chondrocytes. Overexpression of NLRC5 in chondrocytes significantly suppressed IL-1β-induced inflammatory response through inhibiting the production of multiple inflammatory mediators including inducible nitric oxide synthases (iNOS), and cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), NO, TNF-α and IL-6, as well matrix metalloproteinase 3 (MMP-3) and MMP-13. Consistently, NLRC5 knockdown exhibited opposite effects on the production of these inflammatory mediators in IL-1β-induced chondrocytes. Furthermore, overexpression of NLRC5 increased the IĸBα expression, while decreased the p-p65 expression, indicating that NLRC5 inhibited the activation of NF-κB signaling. Additionally, inhibition of NF-κB by PDTC mitigated the si-NLRC5-mediated promotion of IL-1β-induced inflammatory injury in chondrocytes. Finally, NLRC5 treatment ameliorated cartilage degeneration in an OA model in rats. Taken together, these findings revealed that NLRC5 attenuated IL-1β-induced inflammatory injury in chondrocytes through regulating the NF-κB signaling.

Degeneration of motor neurons, glial cell reactivity, and vascular alterations in the CNS are important neuropathological features of amyotrophic lateral sclerosis (ALS). Immune cells trafficking from the blood also infiltrate the affected CNS parenchyma and contribute to neuroinflammation. Mast cells (MCs) are hematopoietic-derived immune cells whose precursors differentiate upon migration into tissues. Upon activation, MCs undergo degranulation with the ability to increase vascular permeability, orchestrate neuroinflammation and modulate the neuroimmune response. However, the prevalence, pathological significance, and pharmacology of MCs in the CNS of ALS patients remain largely unknown. In autopsy ALS spinal cords, we identified for the first time that MCs express c-Kit together with chymase, tryptase, and Cox-2 and display granular or degranulating morphology, as compared with scarce MCs in control cords. In ALS, MCs were mainly found in the niche between spinal motor neuron somas and nearby microvascular elements, and they displayed remarkable pathological abnormalities. Similarly, MCs accumulated in the motor neuron-vascular niche of ALS murine models, in the vicinity of astrocytes and motor neurons expressing the c-Kit ligand stem cell factor (SCF), suggesting an SCF/c-Kit-dependent mechanism of MC differentiation from precursors. Mechanistically, we provide evidence that fully differentiated MCs in cell cultures can be generated from the murine ALS spinal cord tissue, further supporting the presence of c-Kit+ MC precursors. Moreover, intravenous administration of bone marrow-derived c-Kit+ MC precursors infiltrated the spinal cord in ALS mice but not in controls, consistent with aberrant trafficking through a defective microvasculature. Pharmacological inhibition of c-Kit with masitinib in ALS mice reduced the MC number and the influx of MC precursors from the periphery. Our results suggest a previously unknown pathogenic mechanism triggered by MCs in the ALS motor neuron-vascular niche that might be targeted pharmacologically. Supplementary Information The online version contains supplementary material available at 10.1186/s40478-021-01241-3.

Photothermal therapy allows spatiotemporal control of the treatment effect only at the site of the disease and provides promising opportunities for imaging-guided precision therapy. However, the development of photothermal transduction agents (PTAs) for tumor-specific accumulation and precision imaging, avoiding toxicity to the surrounding healthy tissue, is still challenging. Herein, a cyclooxygenase-2-specific small-organic-molecule-based PTA (Cy7-TCF-IMC) is developed, which can self-assemble into nanosaucers having unique photothermal and photoacoustic properties. Specifically, the self-assembling nature of Cy7-TCF-IMC affords preferential accumulation in tumors arising from synergistic passive enhanced permeability and retention effects and active targeting for precision theranostics. Antitumor therapy results show that these Cy7-TCF-IMC nanosaucers are highly photoacoustic imaging-guided PTAs for tumor ablation. These findings suggest the self-assembled Cy7-TCF-IMC nanosaucer represents a new paradigm as a single-component supramolecular medicine that can synergistically optimize passive and active targeting, thereby improving the therapeutic index of cancer and future clinical outcomes.

Cyclooxygenase-2 (COX-2) is up-regulated by redox imbalance and is considered a target for cancer therapy. The rationale of the COX-2 inhibitor lies in suppressing COX-2 catalyzed peroxidation of omega-6 polyunsaturated fatty acids (PUFAs), which are essential and pervasive in our daily diet. However, COX-2 inhibitors fail to improve cancer patients' survival and may lead to severe side effects. Here, instead of directly inhibiting COX-2, we utilize a small molecule, iminodibenzyl, which could reprogram the COX-2 catalyzed omega-6 PUFAs peroxidation in lung cancer by inhibiting delta-5-desaturase (D5D) activity. Iminodibenzyl breaks the conversion from dihomo-γ-linolenic acid (DGLA) to arachidonic acid, resulting in the formation of a distinct byproduct, 8-hydroxyoctanoic acid, in lung cancer cells and solid tumors. By utilizing COX-2 overexpression in cancer, the combination of DGLA supplementation and iminodibenzyl suppressed YAP1/TAZ pathway, decreasing the tumor size and lung metastasis in nude mice and C57BL/6 mice. This D5D inhibition-based strategy selectively damaged lung cancer cells with a high COX-2 level, whereas it could avoid harassing normal lung epithelial cells. This finding challenged the COX-2 redox basis in cancer, providing a new direction for developing omega-6 (DGLA)-based diet/regimen in lung cancer therapy.

Background: Oxidative stress and inflammation are the predominant cause of chronic diseases, including multiple forms of cancers. Prevention of oxidative stress and inflammation is considered to be a target for preventing these disorders due to their significant roles in various degenerative diseases. Various natural products and plant extracts prevent the process of free radical- induced damages. Objectives: The present study evaluated the biological properties of Thottea siliquosa, belonging to the family Aristolochiaceae, which is a traditionally used Ayurvedic plant. Methods: Antioxidant assays carried out were DPPH, FRAP, hydrogen peroxide scavenging, and hemolysis inhibition assay; nitric oxide and lipoxygenase inhibition assays were used for anti-inflammatory studies. Anticancer activity was evaluated using human endometrial and breast cancer cells by MTT assay. Bioactive compounds present in T. siliquosa were identified by LCMS and each was docked with various cancer targets, including EGFR, VEGFR, GST, COX2, and Lipooxygenase. Results: The results of the present study showed antioxidant properties of the methanolic crude extract of T. siliquosa as DPPH radical scavenging (110.40 ± 4.5 μg/mL), FRAP capacity (41.1 ± 6.2), and peroxide scavenging (233.4 ± 14.2 μg/mL). Besides, anti-inflammatory properties were also evident in terms of nitric oxide radical scavenging (28.76± 3.9 μg/mL) and lipoxygenase inhibition (39.2 ± 3.2 μg/mL) assays. In silico analysis confirmed the inhibitory potential of the bioactive compounds of T. siliquosa against cancer drug targets such as EGFR, VEGFR, and inflammatory enzymes cyclooxygenase as well as lipooxygenase. Further, the anticancer activity of the extract has been identified against human endometrial and breast cancer cells. The possible mechanism of anticancer action of the extract is mediated through the apoptosis induction mechanism acting through increased caspase and APAF-1 expressions. Conclusion: The study thus concludes that T. siliquosa showed significant antioxidant, anti-inflammatory and anticancer properties. Further studies together with a bioassay-guided fractionation may identify possible bioactive compounds.

Background: According to the special physiological and pharmacological activities of natural compounds, many drugs with special therapeutic effects have been developed. The Triptolide (TP) is a natural anti-tumor drug with a world patent, but its target and mechanism are yet unknown. Objective: The study aims to explore and predict the target and mechanism of TP on Non-Small Cell Lung Cancer (NSCLC), Pancreatic Cancer (PC) and Colorectal Cancer (CC) through network pharmacology technology. Methods: We screened the core targets of TP with NSCLC, PC and CC, respectively, and carried out network analysis, enrichment analysis and ligand-receptor docking to clarify its potential pharmacological mechanism. Results: By screening the core genes between TP with NSCLC, PC and CC, respectively, it was found that PTGS2 was the common target gene in the three cancers. NSCLC, CCL2, IL6, HMOX1 and COL1A1 are the specific target genes, while MMP2, JUN, and CXCL8 are the specific target genes in PC. In CC, the specific target genes includeERBB2, VEGFA, STAT1 and MAPK8. In enrichment analysis, it was found that the NF- κB, toll-like receptors and IL-17 signaling pathway were mainly involved in TP for these cancers. The binding energy of TP to the core target is less than that of cyclophosphamide. Conclusions: This study preliminarily revealed that TP may prevent and treat cancers\ through multiple targets and pathways. The possible mechanisms of TP include regulating immune and inflammatory responses, promoting apoptosis and inhibiting tumor development. It shows that TP may have potential in treating kinds of tumors.

Gastric cancer accounts for the majority cancer-related deaths worldwide. Although various methods have considerably improved the screening, diagnosis, and treatment of gastric cancer, its incidence is still high in Asia, and the 5-year survival rate of advanced gastric cancer patients is only 10%-20%. Therefore, more effective drugs and better screening strategies are needed for reducing the incidence and mortality of gastric cancer. Cyclooxygenase-2 (COX-2) is considered to be the key inducible enzyme in prostaglandins (PGs) synthesis, which is involved in multiple pathways in the inflammatory response. For example, inflammatory cytokines stimulate innate immune responses via Toll-like receptors and nuclear factor-kappa B to induce COX-2/PGE2 pathway. In these processes, the production of an inflammatory microenvironment promotes the occurrence of gastric cancer. Epidemiological studies have also indicated that non-steroidal anti-inflammatory drugs can reduce the risk of malignant tumors of the digestive system by blocking the effect of COX-2. However, clinical use of COX-2 inhibitors to prevent or treat gastric cancer may be limited because of potential side effects, especially in the cardiovascular system. Given these side effects and low treatment efficacy, new therapeutic approaches and early screening strategies are urgently needed. Some studies have shown that genetic variation in COX-2 also play an important role in carcinogenesis. However, the genetic variation analysis in these studies is incomplete and isolated, pointing out only a few single nucleotide polymorphisms (SNPs) and the risk of gastric cancer, and no comprehensive study covering the whole gene region has been carried out. In addition, copy number variation (CNV) is not mentioned. In this review, we summarize the SNPs in the whole COX-2 gene sequence, including exons, introns, and both the 5’ and 3’ untranslated regions. Results suggest that COX-2 does not increase its expression through the CNV and the SNPs in COX-2 may serve as the potential marker to establish risk stratification in the general population. This review synthesizes emerging insights of COX-2 as a biomarker in multiple studies, summarizes the association between whole COX-2 sequence variation and susceptibility to gastric cancer, and discusses the future prospect of therapeutic intervention, which will be helpful for early screening and further research to find new approaches to gastric cancer treatment.