PTGS2 as target of compound Huangbai liquid in the nursing of pressure ulcer.

OBJECTIVE: Pressure ulcer refers to ulceration and necrosis caused by local skin and cell tissues being compressed for a long time, continuous ischemia, hypoxia, and malnutrition. However, role of prostaglandin-endoperoxide synthase 2 (PTGS2) in the management of pressure ulcers in with compound Huangbai liquid is still unclear. METHODS: Traditional Chinese medicine components and related targets of compound Huangbai liquid were collected through traditional Chinese medicine systems pharmacology (TCMSP) and Batman-traditional Chinese medicine database. Disease-related targets were obtained using the Gene Cards database. The protein-protein interaction (PPI) network was constructed using the Search tool for retrieval of interacting genes (STRING) and analyzed by Cytoscape to obtain the core components. To evaluate the clinical efficacy of the compound Huangbai liquid in the treatment of pressure ulcers, 40 patients with pressure ulcers were selected and divided into an observation group and a control group, with 20 individuals in each group. The observation group received treatment with compound Huangbai liquid. RESULTS: Sixty-five components and 480 targets of compound Huangbai liquid were obtained from TCMSP and Batman - traditional Chinese medicine databases. Two hundred seventy-three pressure ulcer-related targets were obtained. Seventy-two potential targets of compound Huangbai pigment in treatment of pressure ulcer were obtained, and 2 unrelated targets were deleted. There were 70 nodes and 1167 edges in PPI network. Gene ontology (GO) function is involved in biological processes such as reactive oxygen species metabolism and cellular response to chemical stress. Cellular components such as platelet α granules lumen and membrane rafts were involved. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment results showed that compound Huangbai liquid in treatment of pressure ulcer. The clinical results indicate that the compound Huangbai liquid has a good therapeutic effect on pressure ulcers. CONCLUSION: PTGS2 may be a target for treatment of pressure ulcers with compound Huangbai liquid, providing a new direction for its treatment.

Selective COX-2 inhibitors as anticancer agents: a patent review (2018-2023).

INTRODUCTION: COX-2 is a crucial enzyme in the manufacture of prostaglandins. The enzyme's metabolites might have an important function as regulators of the inflammatory response and other medical conditions such as cancer. Selective COX-2 inhibitors are believed to enhance or reverse the response of cancer chemotherapeutics. AREAS COVERED: This study addresses the chemical structures as well as the antitumor activity of new COX-2 inhibitors produced in the recent five years, aiming to provide an insight into the mechanism of COX-2 induced PGE2 powerful signal in cancer development. EXPERT OPINION: The significance of selective COX-2 inhibitors as an efficient superfamily of compounds with anti-inflammatory, anti-Alzheimer's, anti-Parkinson's disease, and anticancer properties has piqued the passion of academics in the field of drug development. Long-term usage of selective COX-2 inhibitors, such as celecoxib has been proven in clinical trials to lower the incidence of several human malignancies. Furthermore, celecoxib has the potential to greatly increase the effectiveness of chemotherapy. Our extensive understanding of selective COX-2 inhibitor SAR may aid in the development of safer and more effective selective COX-2 inhibitors as cancer chemopreventive agents. This review focuses on the different structural classes of selective COX-2 inhibitors, with a particular emphasis on their SAR.

4-phenylbutyric acid improves sepsis-induced cardiac dysfunction by modulating amino acid metabolism and lipid metabolism via Comt/Ptgs2/Ppara.

INTRODUCTION: Cardiac dysfunction after sepsis the most common and severe sepsis-related organ failure. The severity of cardiac damage in sepsis patients was positively associated to mortality. It is important to look for drugs targeting sepsis-induced cardiac damage. Our previous studies found that 4-phenylbutyric acid (PBA) was beneficial to septic shock by improving cardiovascular function and survival, while the specific mechanism is unclear. OBJECTIVES: We aimed to explore the specific mechanism and PBA for protecting cardiac function in sepsis. METHODS: The cecal ligation and puncture-induced septic shock models were used to observe the therapeutic effects of PBA on myocardial contractility and the serum levels of cardiac troponin-T. The mechanisms of PBA against sepsis were explored by metabolomics and network pharmacology. RESULTS: The results showed that PBA alleviated the sepsis-induced cardiac damage. The metabolomics results showed that there were 28 metabolites involving in the therapeutic effects of PBA against sepsis. According to network pharmacology, 11 hub genes were found that were involved in lipid metabolism and amino acid transport following PBA treatment. The further integrated analysis focused on 7 key targets, including Comt, Slc6a4, Maoa, Ppara, Pparg, Ptgs2 and Trpv1, as well as their core metabolites and pathways. In an in vitro assay, PBA effectively inhibited sepsis-induced reductions in Comt, Ptgs2 and Ppara after sepsis. CONCLUSIONS: PBA protects sepsis-induced cardiac injury by targeting Comt/Ptgs2/Ppara, which regulates amino acid metabolism and lipid metabolism. The study reveals the complicated mechanisms of PBA against sepsis.

A Standardized Extract of Cultured Lentinula edodes mycelia Up-regulates COX-2 in Inflammation-related Malignant Progressive Fibrosarcoma Cell Clone QRsP-11.

BACKGROUND/AIM: Cyclooxygenase is an enzyme that transforms arachidonic acid to prostaglandins. Cyclooxygenase-2 (COX-2) is an isoform of cyclooxygenase. There exist many reports on the expression levels of COX-2 in cancer tissues, and prognosis of cancer patients has been reported to be related to COX-2 up-regulation. In the present study we assessed the suppressive effect of AHCC® on the expression of COX-2 in QRsP-11cells. MATERIALS AND METHODS: QR-32 is a clone which was derived from murine fibrosarcoma BMT-11 cells by treatment with quercetin. These clone cells regress spontaneously after injection into C57BL/6 mice. QRsP-11 is a clone derived from QR-32, showing very aggressive tumorigenicity. AHCC® is a standardized extract of cultured Lentinula edodes mycelia and has been reported to exert suppressive effects on various tumor-associated proteins including HSP27. The protein levels of COX-2 in QR-32 and QRsP-11 cells were compared by using western blotting. Furthermore, the expression levels of COX-2 were assessed in QRsP-11 cells after AHCC®-treatment. RESULTS: Western blot analysis showed a significant up-regulation of COX-2 in QRsP-11 cells compared to QR-32 cells. In vitro AHCC®-treatment increased COX-2 expression levels in QRsP-11 cells contrary to expectations. CONCLUSION: When using AHCC® in cancer treatment, it might be important to decrease COX-2 expression by means of non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin. Further studies are required to clarify the mechanism of up-regulation of COX-2 through AHCC®-treatment.

The CTCF/LncRNA-PACERR complex recruits E1A binding protein p300 to induce pro-tumour macrophages in pancreatic ductal adenocarcinoma via directly regulating PTGS2 expression.

BACKGROUND: Tumour-associated macrophages (TAMs) play an important role in promoting the progression of pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to study the epigenetic mechanisms in regulating pro-tumour M2-polarised TAMs in the PDAC tumour microenvironment. METHODS: This study was conducted based on ex vivo TAMs isolated from PDAC tissues and in vitro THP1-derived TAM model. RNA-sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing and chromatin immunoprecipitation sequencing were performed to investigate gene expression, chromatin accessibility, transcription factor binding sites and histone modifications. Gene knockdown in THP1-derived TAMs was performed with lentivirus, and the impact of THP1-derived TAMs on invasion and metastasis ability of PDAC cells were investigated with in vitro and in vivo functional assays. RNA-chromatin interaction was analysed by chromatin isolation through RNA purification with sequencing. RNA-protein interaction was studied by RNA immunoprecipitation and RNA pull-down. RESULTS: Our data showed that the transcription factor CTCF (CCCTC-binding factor) was highly expressed in TAMs and predicted to be significantly enriched in hyper-accessible chromatin regions when compared to monocytes. High infiltration of CTCF+ TAMs was significantly associated with poor prognosis in PDAC patients. Knockdown of CTCF in THP1-derived TAMs led to the down-regulation of specific markers for M2-polarised TAMs, including CD206 and CD163. When THP1-derived TAMs with CTCF knockdown, they showed a decreased ability of invasion and metastasis. Further integrative analysis of multi-omics data revealed that prostaglandin-endoperoxide synthase 2 (PTGS2) and PTGS2 antisense NF-κB1 complex-mediated expression regulator RNA (PACERR) were critical downstream targets of CTCF and positively correlated with each other, which are closely situated on a chromosome. Knockdown of PACERR exhibited a similar phenotype as observed in CTCF knockdown THP1-derived TAMs. Moreover, PACERR could directly bind to CTCF and recruit histone acetyltransferase E1A binding protein p300 to the promoter regions of PACERR and PTGS2, thereby enhancing histone acetylation and gene transcription, promoting the M2 polarization of TAMs in PDAC. CONCLUSIONS: Our study demonstrated a novel epigenetic regulation mechanism of promoting pro-tumour M2-polarised TAMs in the PDAC tumour microenvironment.

Virtual Screening and Molecular Docking to Study the Mechanism of Chinese Medicines in the Treatment of Coronavirus Infection.

BACKGROUND Heat-clearing and detoxifying herbs (HDHs) play an important role in the prevention and treatment of coronavirus infection. However, their mechanism of action needs further study. This study aimed to explore the anti-coronavirus basis and mechanism of HDHs. MATERIAL AND METHODS Database mining was performed on 7 HDHs. Core ingredients and targets were screened according to ADME rules combined with Neighborhood, Co-occurrence, Co-expression, and other algorithms. GO enrichment and KEGG pathway analyses were performed using the R language. Finally, high-throughput molecular docking was used for verification. RESULTS HDHs mainly acts on NOS3, EGFR, IL-6, MAPK8, PTGS2, MAPK14, NFKB1, and CASP3 through quercetin, luteolin, wogonin, indirubin alkaloids, ß-sitosterol, and isolariciresinol. These targets are mainly involved in the regulation of biological processes such as inflammation, activation of MAPK activity, and positive regulation of NF-kappaB transcription factor activity. Pathway analysis further revealed that the pathways regulated by these targets mainly include: signaling pathways related to viral and bacterial infections such as tuberculosis, influenza A, Ras signaling pathways; inflammation-related pathways such as the TLR, TNF, MAPK, and HIF-1 signaling pathways; and immune-related pathways such as NOD receptor signaling pathways. These pathways play a synergistic role in inhibiting lung inflammation and regulating immunity and antiviral activity. CONCLUSIONS HDHs play a role in the treatment of coronavirus infection by regulating the body's immunity, fighting inflammation, and antiviral activities, suggesting a molecular basis and new strategies for the treatment of COVID-19 and a foundation for the screening of new antiviral drugs.

Evaluation of the therapeutic efficacy of human bone marrow mesenchymal stem cells with COX-2 silence and TGF-ß3 overexpression in rabbits with antigen-induced arthritis.

OBJECTIVE: Mesenchymal stem cells (MSCs), especially genetically modified MSCs, have become a promising therapeutic approach for the treatment of rheumatoid arthritis (RA) through modulating immune responses. However, most MSCs used in the treatment of RA are modified based on a single gene. In this study, we evaluated the therapeutic effects of human BMSCs (hBMSCs) with COX-2 silence and TGF-ß3 overexpression in the treatment of RA in a rabbit model. MATERIALS AND METHODS: hBMSCs were cotransfected with shCOX-2 and TGF-ß3 through lentiviral vector delivery. After SPIO-Molday ION Rhodamine-B™ (MIRB) labeling, lenti-shCOX2-TGF-ß3 hBMSCs, lenti-shCOX2 hBMSCs, lenti-TGF-ß3 hBMSCs, hBMSCs without genetic modification, or phosphate-buffered saline (PBS) were injected into the knee joint of rabbits with antigen-induced arthritis (AIA). The diameter of the knee joint and soft-tissue swelling score (STS) were recorded, and the levels of inflammatory mediators, including interleukin-1ß (IL-1ß), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and prostaglandin E2 (PGE2) were evaluated by ELISA. Clinical 3.0T MR imaging (MRI) was used to track the distribution and dynamic migration of hBMSCs in the joint. Histopathological and immunohistochemical assays were conducted to localize labeled hBMSCs and assess the alteration of synovial hyperplasia, inflammatory cell infiltration, and cartilage damage. RESULTS: COX-2 silencing and TGF-ß3 overexpression in hBMSCs were confirmed through real-time PCR and Western blot analyses. Reduced joint diameter, soft-tissue swelling (STS) score, and PGE2, IL-1ß, and TNF-α expression were detected 4 weeks after injection of MIRB-labeled lenti-shCOX2-TGF-ß3 hBMSCs into the joint in rabbits with AIA. Eight weeks after hBMSC injection, reduced inflammatory cell infiltration, improved hyperplasia of the synovial lining, recovered cartilage damage, and increased matrix staining were observed in joints injected with lenti-shCOX2-TGF-ß3 hBMSCs and lenti-shCOX2 hBMSCs. Slight synovial hyperplasia, no surface fibrillation, and strong positive expression of collagen II staining in chondrocytes and cartilage matrix were detected in the joints 12 weeks after injection of lenti-shCOX2-TGF-ß3 hBMSCs. In addition, hBMSCs were detected by MRI imaging throughout the process of hBMSC treatment. CONCLUSION: Intra-articular injection of hBMSCs with COX-2 silence and TGFß3 overexpression not only significantly inhibited joint inflammation and synovium hyperplasia, but also protected articular cartilage at the early stage. In addition, intra-articular injection of hBMSCs with COX-2 silence and TGFß3 overexpression promoted chondrocyte and matrix proliferation. This study provides an alternative therapeutic strategy for the treatment of RA using genetically modified hBMSCs.

Development of methylated cobalt-alkyne complexes with selective cytotoxicity against COX-positive cancer cell lines.

Derivatives of the cytotoxic cyclooxygenase (COX) inhibitor [(prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS) with a methyl group in the 3, 4, 5, or 6 position of the acetylsalicylic acid (ASS) scaffold were synthesized with the aim to achieve enhanced selectivity for COX-2. From this modification, a higher specificity for COX-2-expressing tumors is expected, preventing COX-1-mediated side effects. The cobalt-alkyne complexes were tested for their COX-inhibitory and antiproliferative properties as well as their cellular uptake. Methylation reduced the effects at the isolated COX-1, whereas those at the isolated COX-2 remained nearly constant compared to Co-ASS. In cellular systems, the new compounds showed superior cytotoxicity toward the COX-positive HT-29 colon carcinoma cells than cisplatin. The reduced growth-inhibitory potency in T-24 cells, which express distinctly fewer COX enzymes (COX-1/COX-2 = 50/1) than HT-29 cells (COX-1/COX-2 = 50/50), and the only marginal activity in COX-negative MCF-7 breast cancer cells point to an interference in the arachidonic acid cascade through COX-2 inhibition as part of the mode of action, especially as the cellular uptake was even higher in MCF-7 cells than in T-24 cells. These findings clearly demonstrate that the methylated cobalt-alkyne complexes possess promising potential for further development as reasonable alternatives to the limited platinum-based antitumor agents.

Amino acid derivatives of 2-Mercaptobenzimidazoles suppress cytokines at the site of inflammation and block gastric H+/K+ ATPase.

Routinely used anti-inflammatory drugs are associated with off-target effects such as cyclooxygenase (COX)-1 inhibition and gastric ulcers. The aim of this study is to examine the anti-inflammatory potential and gastroprotective effects of synthetic amino acid derivatives of 2-mercaptobenzimidazole (MBAA1, MBAA2, MBAA3, MBAA4 and MBAA5). The results showed that compound MBAA5 possess a potential anti-inflammatory action by inhibition of 15-LOX and COX-2. MBAA5 also attenuated the pro-inflammatory cytokines and mediators (TNF-α, IL-1ß and COX-2) in rat hind paw in carrageenan-induced inflammatory model of rat. 2-mercaptobenzimidazole derivative, MBAA5 also inhibited gastric H+/K+ ATPase and demonstrated a better selectivity index for COX-2 (SI 27.17) in comparison to celecoxib (SI 41.43). Molecular docking studies predicted the binding interactions of the synthesized compounds with retrieved target proteins of H+/K+ ATPase, COX-1, COX-2, and 15-LOX. The results of in silico and molecular docking analysis of amino acid derivatives of 2-mercaptobenzimidazoles further explained their pharmacological activities. Moreover, these compounds presented better antimicrobial activity against three clinical isolates of Helicobacter pylori. Together, our findings suggested that these synthetic 2-mercaptobenzimidazole derivatives are safer therapeutic candidates for inflammation.

Atorvastatin inhibits proliferation and promotes apoptosis of colon cancer cells via COX-2/PGE2/ß-Catenin Pathway.

PURPOSE: To explore the effects of atorvastatin (ATST) on the proliferation and apoptosis of colon cancer cells through the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2)/ß-catenin pathway. METHODS: HCT116 cells were cultured and transfected, and they were treated with ATST at different concentrations for different time. The association between the expressions of COX-2 and PGE2 and the survival time of patients with colon cancer was analyzed via Kaplan-Meier survival analysis. Then the protein expressions of COX-2, ß-catenin and apoptosis-related molecules in HCT116 cells were determined using Western blotting, and the proliferation of HCT116 cells was detected via cell counting kit-8 (CCK-8) assay. RESULTS: There was a significant difference in the survival rate between HCT116 cells treated with 30 µM ATST and those treated with 0 µM ATST. The survival time was obviously longer in patients with low expressions of COX-2 and PGE2 than that those with high expressions of COX-2 and PGE2. Low expressions of COX-2 and PGE2 in colon cancer tissues indicate a longer survival time. Moreover, a positive correlation was found between HCT116 cell density and COX-2 level, HCT116 cell density and PGE2 level, and COX-2 and PGE2 levels. ATST could down-regulate COX-2 and ß-catenin, and knocking down COX-2 could lower ß-catenin. After treatment with ATST and ATST + anti-COX-2, the activity of cleaved caspase-9, caspase-3 and PARP was remarkably enhanced, suggesting that ATST and ATST + anti-COX-2 can promote apoptosis of HCT116 cells. It was found that ATST and ATST + anti-COX-2 could also inhibit the proliferation of HCT116 cells.

Betulinic acid exerts antigenotoxic and anticarcinogenic activities via inhibition of COX-2 and PCNA in rodents.

Phytochemicals have been suggested as an effective strategy for cancer prevention. Within this context, triterpene betulinic acid (BA) exhibits several biological properties but its chemopreventive effect has not been fully demonstrated. The present study investigated the antigenotoxic potential of BA against doxorubicin (DXR)-induced genotoxicity using the mouse peripheral blood micronucleus assay, as well as its anticarcinogenic activity against 1,2dimethylhydrazine (DMH)-induced colorectal lesions in rats. Micronuclei (MN) assay and aberrant crypt foci assay were used to assess the antigenotoxic and the anticarcinogenic potential, respectively. The molecular mechanisms underlying the anticarcinogenic activity of BA were evaluated by assessing anti-inflammatory (COX-2) and antiproliferative (PCNA) pathways. The results demonstrated that BA at the dose of 0.5 mg/kg bodyweight exerted antigenotoxic effects against DXR, with a reduction of 70.2% in the frequencies of chromosomal damage. Animals treated with BA showed a 64% reduction in the number of preneoplastic lesions when compared to those treated with the carcinogen alone. The levels of COX-2 and PCNA expression in the colon were significantly lower in animals treated with BA and DMH compared to those treated with the carcinogen alone. The chemopreventive effect of BA is related, at least in part, to its antiproliferative and anti-inflammatory activity, indicating a promising potential of this triterpene in anticancer therapies, especially for colorectal cancer.

Chronic mercury exposure induces oxidative stress in female rats by endothelial nitric oxide synthase uncoupling and cyclooxygenase-2 activation, without affecting oestrogen receptor function.

Mercury has been shown to be a significant health risk factor and is positively associated with cardiovascular diseases. Evidence reveals that men are more likely to develop cardiovascular diseases than women during reproductive age. However, the effects of mercury in females remain poorly investigated, despite the finding that female hormones demonstrate a cardioprotective role. In the present study, we evaluated whether chronic mercury chloride exposure could alter blood pressure and vascular function of the female rat aorta. Ten-week-old female Wistar rats were divided into two groups: control (vehicle) and mercury treated (first dose of 4.6 µg/kg, subsequent daily doses of 0.07 µg/kg), im. Mercury treatment did not modify systolic blood pressure (SBP) but increased vascular reactivity due to the reduction of nitric oxide bioavailability associated with the increase in reactive oxygen species from endothelial nitric oxide synthase (eNOS) uncoupling. Furthermore, increased participation of the cyclooxygenase-2 pathway occurred through an imbalance in thromboxane 2 and prostacyclin 2. However, the oestrogen signalling pathway was not altered in either group. These results demonstrated that chronic exposure to mercury in females induced endothelial dysfunction and, consequently, increased aortic vascular reactivity, causing vascular damage to the female rat aorta and representing a risk of cardiovascular diseases.

Comparative Anti-Inflammatory Effects of Salix Cortex Extracts and Acetylsalicylic Acid in SARS-CoV-2 Peptide and LPS-Activated Human In Vitro Systems.

The usefulness of anti-inflammatory drugs as an adjunct therapy to improve outcomes in COVID-19 patients is intensely discussed in this paper. Willow bark (Salix cortex) has been used for centuries to relieve pain, inflammation, and fever. Its main active ingredient, salicin, is metabolized in the human body into salicylic acid, the precursor of the commonly used pain drug acetylsalicylic acid (ASA). Here, we report on the in vitro anti-inflammatory efficacy of two methanolic Salix extracts, standardized to phenolic compounds, in comparison to ASA in the context of a SARS-CoV-2 peptide challenge. Using SARS-CoV-2 peptide/IL-1ß- or LPS-activated human PBMCs and an inflammatory intestinal Caco-2/HT29-MTX co-culture, Salix extracts, and ASA concentration-dependently suppressed prostaglandin E2 (PGE2), a principal mediator of inflammation. The inhibition of COX-2 enzyme activity, but not protein expression was observed for ASA and one Salix extract. In activated PBMCs, the suppression of relevant cytokines (i.e., IL-6, IL-1ß, and IL-10) was seen for both Salix extracts. The anti-inflammatory capacity of Salix extracts was still retained after transepithelial passage and liver cell metabolism in an advanced co-culture model system consisting of intestinal Caco-2/HT29-MTX cells and differentiated hepatocyte-like HepaRG cells. Taken together, our in vitro data suggest that Salix extracts might present an additional anti-inflammatory treatment option in the context of SARS-CoV-2 peptides challenge; however, more confirmatory data are needed.

CD147 receptor is essential for TFF3-mediated signaling regulating colorectal cancer progression.

Major gaps in understanding the molecular mechanisms of colorectal cancer (CRC) progression and intestinal mucosal repair have hampered therapeutic development for gastrointestinal disorders. Trefoil factor 3 (TFF3) has been reported to be involved in CRC progression and intestinal mucosal repair; however, how TFF3 drives tumors to become more aggressive or metastatic and how TFF3 promotes intestinal mucosal repair are still poorly understood. Here, we found that the upregulated TFF3 in CRC predicted a worse overall survival rate. TFF3 deficiency impaired mucosal restitution and adenocarcinogenesis. CD147, a membrane protein, was identified as a binding partner for TFF3. Via binding to CD147, TFF3 enhanced CD147-CD44s interaction, resulting in signal transducer and activator of transcription 3 (STAT3) activation and prostaglandin G/H synthase 2 (PTGS2) expression, which were indispensable for TFF3-induced migration, proliferation, and invasion. PTGS2-derived PGE2 bound to prostaglandin E2 receptor EP4 subtype (PTGER4) and contributed to TFF3-stimulated CRC progression. Solution NMR studies of the TFF3-CD147 interaction revealed the key residues critical for TFF3 binding and the induction of PTGS2 expression. The ability of TFF3 to enhance mucosal restitution was weakened by a PTGS2 inhibitor. Blockade of TFF3-CD147 signaling using competitive inhibitory antibodies or a PTGS2 inhibitor reduced CRC lung metastasis in mice. Our findings bring strong evidence that CD147 is a novel receptor for TFF3 and PTGS2 signaling is critical for TFF3-induced mucosal restitution and CRC progression, which widens and deepens the understanding of the molecular function of trefoil factors.

A research on the mechanism of NSAID-related gastric ulcer treated by jia wei wu qi san based on the p38mapk signal pathway.

This study aims to explore the mechanism of NSAID-related gastric ulcer treated by JIA WEI WU QI SAN. Clean-grade SD rats were randomly divided into four groups. Group A was assigned as the control group. Groups B, C and D were intragastrically administered with 2.5mg/kg of indomethacin solution QD after 48 hours. After 15 days of treatment, group B was administered with 0.9% sodium chloride, group C was given rabeprazole (2mg/kg), and group D was administered with JIA WEI WU QI SAN (2g/kg). Abdominal aorta sampling was performed, and gastric tissues were isolated on the 29th day. The protein expression of p-P38MAPK and COX-2 were detected by western blot, while the concentration of PGE2 and IL-1 were determined by ELISA. (1) The expression of IL-1ingroup B dramatically declined in group D (P<0.01). (2)The expression of PGE-2dramatically increased in group D(P<0.01). (3) The expression of COX-2 increased in group D (P<0.05). (4) The expression of p-P38MAPK decreased in group D (P<0.05). JIA WEI WU QI SAN has multiple functions, including the activation of the p-P38MAPK signaling pathway, which promote the activation of COX-2, induce the arachidonic acid to increase the level of PG, and decrease the concentration of IL-1, thereby inducing an inflammatory reaction, and promote gastric mucosa repair.

GC-MS analysis, anticancer and anti-inflammatory activities of Saussurea hypoleuca spreng. Root.

Study has been premeditated to appraise the anticancer and anti-inflammatory activities of a native medicinal plant Saussurea hypoleuca Spreng root. Anticancer assays including MTT, Alamar Blue (AB), Neutral Red (NR) & LDH were employed on root methanolic extract (RME) and all fractions to calculate % age of cell viability and cell cytotoxicity. All fractions of plant root were tested for in vitro as well as in vivo anti-inflammatory assays by reported methods. GC-MS analysis of n-hexane: chloroform fractions in column chromatography has shown isopropyl myristate, hexadecanoic acid, 11-octadecenoic acid, Di-n-octyl phthalate, dioctyl ether, decanedioic acid, 1H-3a,7-Methanoazulene, 3,4-hexanedione and Tetracosapentaene. Percentage of cell viability in anticancer assays was significantly high in all fractions. However, whole results were momentous with ethyl acetate and aqueous fractions owning to excellent profile in evaluating cytotoxicity in each assay. COX-2 inhibition was calculated which was high in RME (68.69%), ethyl acetate (56.52%), aqueous (55.21%) and chloroform fraction (53.47%). Carrageenan and formalin models were developed on rats to investigate in vivo anti-inflammatory activity. RME (56.19%, 71.09%, 66.4%, 67.99%) and ethyl acetate (51.36%, 64.97%, 55.63% & 61.01%) produced significant % age inhibition in dose dependent manner at 200 and 400 mg/kg doses respectively. All above findings direct that plant root holds strong anticancer and anti-inflammatory activities.

Potential therapeutic effects of avenanthramide-C against lung toxicity caused by silver nanoparticles injection in rats.

Most clinical investigations about the impact of nanoparticles on cells and tissues show that nanoparticles may enter the human body by means of respiratory tracts. Humans, animals, plants and environments are continually presented to a wide scope of business items containing silver nanoparticles (Ag NPs) in their piece. Ag NPs, utilized in various consumer products as room showers, surface cleaners, wound dressings, food storage containers and many textiles. The current examination planned to explore the defensive role of Avenanthramide-C (Avns) contrary to the lung toxicity initiated by Ag NPs injection in rats. 40 male Wistar rats were separated into 4 groups (Gp1, control; Gp2, Avns; Gp3, Ag NPs; Gp4, Ag NPs+Avns). Current results revealed that; Ag NPs induced a significant depletion in RBCs count, hemoglobin, platelets counts and a significant increase in total WBCs, lung injury, cyclooxygenase-2 (COX2) and TNFα expressions as compared to control. Treatments of Ag NPs with Avenanthramide-C extract (Ag NPs+Avns) improved the lung structure and blood complete pictures as compared to Ag NPs group.

Activation of alpha7 nicotinic acetylcholine receptor protects bovine endometrial tissue against LPS-induced inflammatory injury via JAK2/STAT3 pathway and COX-2 derived prostaglandin E2.

Bovine endometritis is one of the major postpartum diseases associated with infertility and subfertility, decreasing the benefit of dairy industry. It is important to develop alternate therapies for endometritis in the context of drug residues in the milk and hormone disorder in the estrous cycle. α7 nicotine acetylcholine receptor has been identified as the core of 'cholinergic anti-inflammatory pathway (CAP)', which is a potential drug target to inflammatory diseases. However, there has been still no study on its anti-inflammatory effects and mechanism on lipopolysaccharide (LPS)-induced bovine endometritis. This study aimed to demonstrate the underlying anti-inflammatory effects and mechanism of α7-nACh receptor on LPS-induced inflammation in bovine endometrial tissues cultured in vitro. The results suggested that activation of α7-nACh receptor significantly suppressed the mRNA expression levels of interleukin 1ß (IL-1ß), IL-6, IL-8, and tumor necrosis factor alpha (TNF-α) in bovine endometrial tissues. Western blot and enzyme-linked immunosorbent assay (ELISA) detection results showed that activation of α7-nACh receptor inhibited LPS-induced phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Moreover, α7-nACh receptor agonist decreased the expression of cyclooxygenase 2 (COX-2) and microsomal prostaglandin E synthase-1(mPGES-1), as well as prostaglandin E2 (PGE2) secretion. Interestingly, in COX-2 inhibition experiment, activation of α7-nACh receptor increased COX-2 expression and PGE2 production, compared with COX-2 inhibitor treatment. In conclusion, activation of the cholinergic system through α7-nACh receptor agonist has suppressed inflammation of bovine endometrial tissues via JAK2/STAT3 pathway and potential COX-2-derived PGE2.

Olea europaea Suppresses Inflammation by Targeting TAK1-Mediated MAP Kinase Activation.

Possessing a variety of medicinal functions, Olea europaea L. is widely cultivated across the world. However, the anti-inflammatory mechanism of Olea europaea is not yet fully elucidated. In this study, how the methanol extract of the leaves of Olea europaea (Oe-ME) can suppress in vitro inflammatory responses was examined in terms of the identification of the target protein. RAW264.7 and HEK293T cells were used to study macrophage-mediated inflammatory responses and to validate the target protein using PCR, immunoblotting, nuclear fraction, overexpression, and cellular thermal shift assay (CETSA) under fixed conditions. Oe-ME treatment inhibited the mRNA expression levels of cyclooxygenase (COX)-2, matrix metallopeptidase (MMP)-9, and intercellular adhesion molecule-1 (ICAM-1) in activated RAW264.7 cells. Oe-ME diminished the activation of activator protein (AP)-1 and the phosphorylation of its upstream signaling cascades, including extracellular signal regulated kinase (ERK), mitogen-activated protein kinase kinase 1/2 (MEK1/2), c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase kinase 3/6 (MKK3/6), p38, MKK7, and transforming growth factor-ß-activated kinase 1 (TAK1), in stimulated-RAW264.7 cells. Overexpression and CETSA were carried out to verify that TAK1 is the target of Oe-ME. Our results suggest that the anti-inflammatory effect of Oe-ME could be attributed to its control of posttranslational modification and transcription of TAK1.