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Fucoidans possess potent anti-inflammatory effects. In the present study, the anti-inflammatory effect of the fucoidan (SFF-PS-F5) isolated from fermented Sargassum fusiforme was evaluated in vitro in RAW 264.7 macrophages and in vivo in zebrafish. The in vitro test results demonstrate that SFF-PS-F5 effectively inhibited nitric oxide (NO) production induced by lipopolysaccharides (LPS) in RAW 264.7 cells. SFF-PS-F5 effectively and concentration-dependently improved the viability of LPS-stimulated RAW 264.7 cells, and reduced the level of prostaglandin E

Protein modulation is a process of changing protein structure which is either derived or deliberately induced. This leads to variation in protein activity during protein-protein interactions and can be utilized to understand disease mechanisms or to develop novel therapeutics. In this context, COX-2, iNOS and GST along with basic liver biochemistry were examined in experimentally injured rats and quercetin (QC) supplementation. Diethylnitrosamine (10 ml/kgbwt of 1%DEN) was used to generate liver injury in animals. Quercetin was administered at 60 mg/kgbwt daily in DEN-treated animals to investigate the effect. Hepatic AST/ALT/ALP/γGT, bilirubin, glycogen, LPO, CAT, SOD, GST, collagen levels, protein oxidation and nitrites were examined in all animals. Besides, histopathology and immunohistochemistry of COX-2 and iNOS was performed in tissue sections. Molecular docking of quercetin with human COX-2, iNOS and GST was performed by Autodock 4.2.6 software while drug likeliness and the properties of the ligand by SWISS-ADME and admetSAR and Molinspiration respectively. Our results demonstrate disturbed primary liver function concomitant with disconcert liver biochemistry and anatomy in DEN-treated animals (p 0.05). Immunohistochemistry exhibited up-regulation of COX-2 and iNOS during liver injury. Molecular docking showed quercetin as acceptable drug as it passes Lipinski rule and shows binding with GST, iNOS, COX-2. In conclusion, COX-2, iNOS and GST appears to be the dynamic molecular targets of Quercetin action to restore tissue biochemistry and anatomy during experimental liver injury.

Despite the extensive explorations of nanoscale metal-organic frameworks (nanoMOFs) in drug delivery, the intrinsic bioactivity of nanoMOFs, such as anticancer activity, is severely underestimated owing to the overlooked integration of the hierarchical components including nanosized MOFs and molecular-level organic ligands and metal-organic complexes. Herein, we propose a de novo design of multifunctional bioactive nanoMOFs ranging from molecular to nanoscale level, and demonstrate this proof-of-concept by a copper-olsalazine (Olsa, a clinically approved drug for inflammatory bowel disease, here as a bioactive linker and DNA hypomethylating agent) nanoMOF displaying a multifaceted anticancer mechanism: (1) Cu-Olsa nanoMOF-mediated redox dyshomeostasis for enhanced catalytic tumor therapy, (2) targeting downregulation of cyclooxygenase-2 by the organic complex of Cu

Cigarette smoke exposure represents a well-established ovotoxic exogenous stress, but the molecular mechanisms underlying of this effect are still unclear. Cigarette smoke upregulates inflammatory genes in the female reproductive organs, therefore an abnormal inflammation response may contribute to the impairment of female fertility. In this study we investigated for the first time the effect of cigarette smoke exposure on NOS and COX expression and activity and on their transcription factors (CREB and NF-kB) in human GCs and on the release of NO and PGE

Di-(2-ethylhexyl) phthalate (DEHP), a typical environmental endocrine disruptor (EED), can disrupt estrogen and androgen secretion and metabolism process, thus inducing dysfunctional reproduction such as impaired gonadal development and spermatogenesis disorder. Prostaglandin synthases (PGS) catalyze various prostaglandins biosynthesis, involved in inflammatory cascade and tumorigenesis. Yet, little is known about how PGS may impact prostatic hyperplasia development and progression. This study concentrates predominantly on the potential prostatic toxicity of DEHP exposure and the mediating role of PGS. In vivo study, adult male rats were administered via oral gavage 30 μg/kg/d, 90 μg/kg/d, 270 μg/kg/d, 810 μg/kg/d DEHP or vehicle for four weeks. The results elucidated that low-dose DEHP may cause the proliferation of the prostate with an increased PCNA/TUNEL ratio. Given the importance of estrogens and androgens in prostatic hyperplasia, our first objective was to evaluate the levels of sex hormones. DEHP improved the ratio of estradiol (E

Wilson's disease (WD) is an inherited disorder involving copper accumulation in the liver and brain. An important mechanism responsible for hepatocyte injury in WD is mitochondria destruction, although damage may also be caused by oxidative stress and lipid peroxidation.The study included 54 treated patients with WD without liver cirrhosis and 10 healthy controls. All patients had liver biopsy and immunohistochemical analysis of liver samples was performed using targeted staining for markers of mitochondrial injury (thioredoxin-2 [TRX2], cytochrome c oxidases subunit 2 [COX2], and cytochrome c oxidases complex IV subunit 4 isoform 1 [COX4-1]), of oxidative stress (peroxiredoxin-1 [PRDX1] and 8-hydroxyguanosine [8-OHdG]), and of lipid peroxidation (4-hydroxynonenal [4-HNE]).Expression, measured as mean strengths of intensity (SI) of immunohistochemical reactions per 5 fields of view, was significantly lower in patients with WD compared to controls for COX2 (2.9 vs 8.3), 8-OHdG (0.05 vs 3.8), TRX2 (4.9 vs 10.1), and PRDX1 (4.6 vs 10.1) (all P ​ ​10Negligible COX4-1 and low COX2 expression in liver specimens may serve as markers of inner mitochondrial membrane injury in treated patients with WD and early stages of liver fibrosis.

Vein wall hypoxia has long been suggested as a key factor for the development of varicose veins (VVs) and accumulating evidence has revealed the phenotypic transformation of vascular smooth muscle cells (VSMCs) under hypoxic conditions. However, the underlying molecular mechanisms of this process remain poorly understood. Our previous study revealed a positive correlation between c-fos expression and VSMC functional disturbance of VVs. This study aimed to further explore the role of c-fos in the phenotypic switching of VSMCs under hypoxic conditions.Human umbilical vein smooth muscle cells (HUVSMCs) were cultured under hypoxia or normoxia. PD0325901 (10 μmol/L) and pyrrolidine dithiocarbamate (PDTC) (10 μmol/L) were used to inhibit the extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-κ B (NF-κB) signaling pathways, respectively. HUVSMCs stably overexpressing c-fos were constructed to explore the underlying mechanism. The Western blot analysis was performed to detect the protein expression levels of c-fos, phosphorylated p65 (p-p65), interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), osteopontin (OPN), and α-smooth muscle actin (α-SMA). Cell proliferation and migration capacity were detected by a Cell Counting Kit 8 (CCK-8) assay and a wound-healing assay, respectively. The cell apoptotic rate was determined using the Annexin V-FITC Apoptosis Detection Kit.Hypoxic exposure increased the expression levels of indicators of the p-ERK1/2/c-fos and NF-κB signaling pathways, which was accompanied by altered levels of phenotypic biomarkers (α-SMA and OPN). Cells exposed to hypoxia were characterized by a greater proliferative and migratory ability. No significant differences were observed in the rate of cell apoptosis between the normal group and the hypoxic group. In addition, inhibition of the ERK1/2/c-fos signaling pathway by PD0325901 (10 μmol/L) reduced the expression of inflammatory cytokines and attenuated hypoxia-mediated phenotypic transformation. Furthermore, inhibition of the NF-κB signaling pathway by PDTC (10 μmol/L) downregulated the expression level of OPN and reduced the migration of HUVSMCs under hypoxia exposure. However, pretreatment with PDTC did not suppress the expression of c-fos or cell proliferation. Finally, the introduction of exogenous c-fos in HUVSMCs induced increased protein expression levels of p-p65, COX-2, and OPN, accompanied by a remarkable increase in HUVSMC proliferation and migration.Our research demonstrated that hypoxia could promote the phenotypic transformation of HUVSMCs partially through the ERK1/2/c-fos/NF-κB signaling pathway, which provided a novel insight into hypoxia-associated venous wall remodeling to further aid the development of a novel therapeutic target for the prevention or treatment of VVs.

While the effects of delta-9-tetrahydrocannabinol (THC), the psychoactive component of cannabis, have been studied extensively in the central nervous system, there is limited knowledge about its effects on the female reproductive system. The aim of this study was to assess the effect of THC on the expression and secretion of the angiogenic factor vascular endothelial growth factor (VEGF) in the ovary, and to determine if these effects were mediated by prostaglandins. Spontaneously immortalized rat granulosa cells (SIGCs) were exposed to THC for 24 h. Gene expression, proliferation and TNFα-induced apoptosis were evaluated in the cells and concentrations of VEGF and prostaglandin E2 (PGE

Peroxisome proliferator-activated receptor α (PPARα) regulates fatty acid oxidation (FAO). Usually, very-long chain fatty acids are first activated by acyl-CoA synthetase (ACS) to generate acyl-CoA for oxidation by acyl-CoA oxidase (ACOX) in peroxisomes, and the resultant shorter chain fatty acids will be further oxidized in mitochondria. ACS long-chain family member 4 (ACSL4) preferentially uses arachidonic acid (AA) as substrates to synthesize arachidonoyl-CoA. Arachidonoyl-CoA is usually esterified into phospholipids. When AA is released by phospholipase A2 (PLA2) from phospholipids, it will be used for prostaglandin synthesis by cyclooxygenases (COX). In this study, when PPARα agonist WY-14,643 was mixed in liquid Lieber-DeCarli ethanol or control diets and fed to mice, liver PLA2, COX-2, and ACOX1 were induced but ACSL4 was inhibited, suggesting that AA released by PLA2 from phospholipid will be metabolized to prostaglandin via COX-2 instead of being synthesized into acyl-CoA by ACSL4. However, liver prostaglandin E2 (PGE2), a major component of prostaglandin, was not increased with the induced COX-2 but decreased by WY-14,643. ACOX1 specific inhibitor mixed in the liquid diets restored both the WY-14,643-suppressed liver TG and PGE2, but COX-2 specific inhibitor celecoxib mixed in the liquid diets reversed the WY-14,643-suppressed liver TG but not liver PGE2 contents. These results suggest that induction of PLA2, COX-2 and ACOX1 orchestrates to increase oxidation of AA/PGE2, which constitutes one new mechanism by which PPARα induces peroxisomal FAO and inhibits ethanol-induced liver fat accumulation.

To explore the therapeutic effect of chondroitin sulfate (CS) on Aspergillus fumigatus (A. fumigatus) keratitis.The nontoxic concentration of CS was determined using the Draize eye test and cell counting kit-8. Cell scratch test and cell proliferation test were evaluated the impact of CS on the proliferation and migration of human corneal epithelial cells (HCECs). Adherence assay and plate counting were used to detect fungal load in vivo and in vitro, respectively. Clinical score and hematoxylin-eosin (HE) staining were applied to assess the therapeutic effects of CS in an A. fumigatus keratitis mice model. The neutrophil infiltration and activity were detected by flow cytometry (FCM), immunofluorescence staining, and myeloperoxidase (MPO) assay. Toll-like receptor 4 (TLR-4) expression in RAW 264.7 cells and mouse cornea was detected by immunofluorescence staining. Real-time PCR (RT-PCR), western blot, and enzyme-linked immunosorbent assay (ELISA) were applied to examine the expression of inflammatory mediators.CS at 400 μg/mL (non-cytotoxic) significantly promoted proliferation and migration of HCECs. In an A. fumigatus keratitis mice model, CS treatment alleviated fungal keratitis (FK) severity by decreasing corneal fungal load and inhibiting neutrophil infiltration. In RAW 264.7 cells, the mRNA and protein levels of TLR-4, phosphorylated nuclear factor (NF)-κB (p-NF-κB), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-a (TNF-α), cyclooxygenase 2 (COX-2), and macrophage inflammatory protein-2 (MIP-2) were remarkably lower in the siTLR-4 treated group, while higher in rTLR-4 treated group than in the corresponding control group. CS treatment suppressed rTLR-4 induced the mRNA and protein expression of TLR-4, p-NF-κB, IL-1β, IL-6, COX-2, TNF-α, and MIP-2 in RAW cells.CS may ameliorate the prognosis of A. fumigatus keratitis by promoting corneal epithelial proliferation, inhibiting the recruitment and activity of neutrophils, and inhibiting the inflammatory response by down-regulation of the TLR-4/NF-κB signaling.

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.

Understanding the metabolic effects of fatty acids on fish intestine is critical to the substitution of fish oil with vegetable oils in aquaculture. In this study, the effects of eicosapentaenoic acid (EPA) and palmitic acid (PA) on fish intestine were evaluated in vitro and in vivo. As the first step for in vitro study, an intestinal cell line (SPIF) was established from silver pomfret (Pampus argenteus). Thereafter, the effects of EPA and PA on cell viability, prostaglandin E2 (PGE2) production, and the expression of genes related to heat shock response, inflammation, extracellular matrix (ECM) formation and degradation were examined in SPIF cells. Finally, these metabolic effects of EPA and PA on the intestine were examined in zebrafish (Danio rerio) larvae. Results showed that all tested fatty acids (PA, oleic acid, linoleic acid, α-linolenic acid, arachidonic acid, and docosahexaenoic acid) except EPA reduced SPIF viability to distinct degrees at the same concentrations. PA decreased SPIF viability accompanied by an increase in PGE2 level. Meanwhile, PA increased the expression of genes related to heat shock response (grp78, grp94, hsp70, and hsp90) and inflammation (nf-κb, il-1β, and cox2). Furthermore, PA reduced the expression of collagen type I (col1a1a and col1a1b) and extracellular matrix (ECM) degradation-related gene mmp2, while up-regulating timp2 mRNA expression. In vivo, PA also increased hsp70, il-1β, and cox2 mRNA levels and limited the expression of collagen type I in the larval zebrafish intestine. Interestingly, the combination of EPA and PA partially recovered the PA-induced changes in cell viability, PGE2 production, and mRNA expression in vitro and in vivo. These results suggest that PA may result in heat shock and inflammatory responses, as well as alter ECM formation and degradation in fish intestine, while EPA could at least partially mitigate these negative effects caused by PA.

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.

Excessive microglia activation occurred in many neurodegenerative diseases. Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1, ARFGEF1) is involved in cell migration and neurite growth. In the present study, we aimed to explore the effects and potential mechanisms of BIG1 in LPS-mediated neuro-inflammation and migration in BV2 cells. Loss-of-function and gain-of-function experiments were performed. Inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-10) mRNA levels and concentrations were analyzed by Quantitative Real-time PCR (RT-qPCR) and ELISA kits. The NO concentration was tested by ELISA kit. iNOS and COX-2 mRNA and protein levels were measured by RT-qPCR and western blot. Cell migration was determined by transwell assay. The results demonstrated that BIG1 silencing reduced TNF-α, IL-1β, and IL-6 expression, while increased IL-10 expression. The NO production, iNOS and COX-2 expression were clearly inhibited by BIG1 knockdown in the presence of LPS. Furthermore, ablation of BIG1 attenuated the migration capacity of BV2 cells. Overexpression of BIG1 displayed the opposite trends. Moreover, we found BIG1 suppression inhibited PI3K/Akt/NF-κB pathway activation. 740Y-P, an agonist of PI3K, abolished the roles of BIG1 silencing in neuro-inflammation and migration. Additionally, ChIP-qPCR and Dual-luciferase reporter assay determined that KLF4 binds to the promoter of BIG1, western blot analysis demonstrated that KLF4 could regulate BIG1 positively. In addition, we observed that BIG1 overexpression partly rescued the biological activities of KLF4 silencing in neuro-inflammation and migration in LPS-stimulated BV2 cells. Taken together, BIG1 was mediated by KLF4 regulated LPS-mediated neuro-inflammation and migration in BV2 cells via PI3K/Akt/NF-kB signaling pathway.

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.

The COX/prostaglandin (COX/PG) pathway plays a role in cancer pathogenesis via the production of prostaglandin E2 (PGE2). In breast cancer, the expression patterns of the COX/PG pathway enzymes involved in PGE2 synthesis are not well defined.Using the Cancer Genome Atlas data, we analyzed the expression patterns of cyclooxygenases, COX1 (PTGS1) and COX2 (PTGS2), and four downstream enzymes of the COX/prostaglandin pathway - PTGS3 (PTGDS), PTGES1, PTGES2 and PTGES3 - in invasive breast cancer. The Clinical Proteomic Tumor Analysis Consortium database was used to determine the expression of these six genes at the protein level. Existing single-cell RNA sequencing data were used to evaluate the expression of the six COX/PG genes in luminal and basal epithelial cells from normal breast tissues. Cox regression Kaplan-Meier adjusted survival analyses were performed to evaluate the association of COX/PG pathway genes in overall survival using the TCGA data. Finally, we utilized the Tumor Immune Estimation Resource to correlate the expression of these six COX/PG genes with tumor infiltrating immune cell number.COX1, COX2 and PTGES3 were significantly upregulated at the protein level in breast cancer compared to normal tissues (P0.005). However, only PTGES3 expression was elevated at both the mRNA and protein level in breast cancer (P0.0005). PTGES3 is the most highly expressed enzymes within the COX/PG pathway in both luminal and basal epithelial cells in normal breast tissues. Using Cox Regression Kaplan-Meier survival analysis, PTGES3 expression had a significant inverse prognostic association with breast cancer survival [HR1.43, P = 0.0057]. Elevated PTGES3 expression within the tumor microenvironment significantly correlated with CD8+ T cell abundance, suggesting a possible immunomodulatory role of PTGES3 in the tumor microenvironment.PTGES3, a terminal synthetase in the COX/prostaglandin pathway, is a putative prognostic marker in breast cancer.

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.

Stimulation of the fish immune system using immunostimulants is an environmentally friendly strategy to minimize bacterial outbreaks in aquaculture. Different biological and synthetic immunostimulants can enhance non-specific innate immune responses by directly activating immune cells. An example are Bacillus spp., known for their immunostimulatory effects, although the exact mechanisms by which Bacillus spp. offer protection against diseases remains to be elucidated. Furthermore, most studies have focused on Bacillus spp. cells, while the immunostimulant effect of their extracellular metabolome, known to harbour biologically important metabolites, including antimicrobial molecules, has been scarcely evaluated. Here, we evaluated the in vitro immune-modulatory properties of extracellular extracts of three Bacillus spp. strains (B. subtilis FI314, B. vezelensis FI436 and B. pumilus FI464), previously isolated from fish-guts and characterized for their in vitro and in vivo antimicrobial activity against a wide range of fish pathogens. Bacillus spp. extracellular extracts did not affect immune cells viability, but remarkably increased pathogens' phagocytosis when seabream head-kidney leukocytes were challenged with Vibrio anguillarum and Edwardsiella tarda. All extracts significantly increased the engulfment of bacterial pathogens 1 h post-infection. Cells stimulated with the extracellular extracts showed an up-regulation of the expression of immune-relevant genes associated with inflammation, including IL-1β, IL-6, and COX-2. In cells challenged with E. tarda, FI314 extracellular extract significantly increased the expression of IL-1β, IL-6, and COX-2, while FI436 and FI464 significantly increased IL-6 expression. The results of this study revealed that the extracellular molecules from Bacillus spp. fish isolates improved the in vitro response of gilthead seabream immune cells and are thus promising candidates to act as immunostimulants, helping fish fight diseases.

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.

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.

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.

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.

Ultraviolet A (UVA) irradiation caused skin keratinocytes to accumulate reactive oxygen species (ROS) leading to the skin injury. Thymoquinone (TQ) was identified as the prominent bioactive ingredient in Nigella sativa seeds which was applied in therapying various human diseases. This study aimed to illustrate the role and mechanism of TQ in UVA-induced skin injury. We pre-treated HaCaT cells with TQ and irradiated them by UVA. MTT and Elisa assays were used to evaluate cell viability and apoptosis, as well as cytokine levels. To detect the related parameters of oxidative stress and mitochondrial function, colorimetry, spectrophotometry, bioluminescence, and dual-luciferase reporter methods were used. RT-qPCR and western blotting were performed for expressions of related mRNAs and proteins. TQ significantly improved the UVA-induced cytotoxicity on HaCaT cells. TQ treatment alleviated the oxidative stress and inflammation in UVA-irradiated keratinocytes. Besides, UVA irradiation promoted mitochondrial dysregulation in HaCaT cells leading to cell apoptosis, which could be reversed by TQ treatment. More importantly, NrF2/ARE pathway was activated in TQ-treated cells, while COX-2 was depressed, and inhibiting the pathway or activating COX-2 blocked the therapeutic effect of TQ on UVA-induced skin cell injury. Our study suggested that TQ treatment attenuated the UVA-induced oxidative and inflammatory responses, as well as mitochondrial apoptosis in keratinocytes by COX-2 inhibition via activating NrF2/ARE pathway. This might be a novel sight for preventing the solar radiation damage to the skin.

The crude polysaccharide was extracted from A. asphodeloides rhizomes and further purified to produce two fractions F1 (50.0%) and F2 (19.6%). The chemical constitutions of the polysaccharides were neutral sugars (51.4%–89.7%), uronic acids (1.0%–30.2%) and sulfate esters (3.4%–8.1%), with various ratios of monosaccharides including rhamnose (1.4%–6.1%), arabinose (7.1%–21.2%), xylose (0.2%–4.8%), mannose (39.9%–79.0%), glucose (6.0%–11.1%) and galactose (2.6%–22.0%). The molecular properties of the polysaccharides were investigated by the HPSEC-UV-MALLS-RI system, revealing the Mw 130.0 × 103–576.5 × 103 g/moL, Rg 87.6–382.6 nm and SVg 0.3–54.3 cm3/g. The polysaccharides stimulated RAW264.7 cells to produce considerable amounts of NO and up-regulate the expression of TNF-α, IL-1 and COX-2 genes. Polysaccharides exhibited the growth inhibitory effects on cancer cells lines of AGS, MKN-28 and MKN-45, in which F2 fraction exhibited prominent bioactivities. The AGS cells treated with F2 experienced condensed cytoplasm, shrinkage of nucleus and chromatin marginalization with the highest number of cells at early-stage apoptosis reaching 54.6%. The inhibitory effect of F2 polysaccharide on AGS cells was through MAPKs and STAT3 signaling pathways. The backbone of the F2 was mainly linked by (1 → 4)-linked mannopyranosyl and (1 → 3)-linked galactopyranosyl. Taken together, the polysaccharide from A. asphodeloides rhizomes could be utilized as medicinal, pharmacological and functional food ingredients.

Suckling-evoked pulsatile release of oxytocin (OT) from the posterior pituitary plays a key role in breastfeeding, which relies on burst-like discharges of OT neurons. To explore cellular mechanisms regulating OT neuronal activity, using lactating rats with pup-deprivation (PD) during postpartum day 1-5, we observed the involvement of prostaglandin, cyclic AMP/protein kinase A (PKA) and hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) signaling pathway in OT neuronal activity. PD gradually reduced lactation efficiency. Intermittent PD (IPD) was largely reversed by intranasally-applied OT (IAO) but not by hypodermically-applied OT. IPD caused involution-like histological changes in the mammary glands, increased hypothalamic OT release but did not influence plasma OT concentrations. In the supraoptic nucleus, IPD increased OT receptor (OTR) expressions in OT neurons as well as Gαq subunit, Gβ subunit and cyclooxygenase 2 (Cox-2). These effects except that on Gβ subunit were reversed by IAO. Notably, IPD increased the expression of catalytic subunit of PKA in the SON, specifically in vasopressin neurons but not in OT neurons. In addition, IPD increased the expression of HCN3. IAO partially reversed these changes in the SON. Lastly, blocking HCN3 blocked excitation and burst firing in OT neurons-evoked by prostaglandin E2, a key mediator of OT-evoked burst firing; blocking Cox-2 or PKA reduced the molecular association between OTR and HCN3. Thus, there is a prostaglandin-cAMP/PKA-HCN3 pathway in the regulation of OT neuronal activity. PD disrupts lactation performance through uncoupling OTR and PKA-HCN3 signaling. The reversal effect of IAO highlights its therapeutic potential in PD-evoked hypogalactia.

Acetaminophen is one of the most common medications taken during pregnancy, considered safe for maternal health and fetal development. However, recent epidemiological studies have associated prenatal acetaminophen use with several developmental disorders in offspring. As acetaminophen can freely cross into and through the placenta, epidemiological associations with prenatal acetaminophen use may reflect direct actions on the fetus and/or the impact of altered placental functions. In the absence of rigorous mechanistic studies, our understanding of how prenatal acetaminophen exposure can cause long-term effects in offspring is limited. The objective of this study was to determine whether acetaminophen can alter key functions of a major placental cell type by utilizing immortalized human first trimester trophoblast cells. This study employed a comparative analysis with the nonsteroidal, anti-inflammatory drug aspirin, which has established effects in first trimester trophoblast cells. We report that immortalized trophoblast cells express the target proteins of acetaminophen and aspirin: cyclooxygenase (COX) -1 and -2. Unlike aspirin, acetaminophen significantly repressed the expression of angiogenesis and vascular remodeling genes in HTR-8/SVneo cells. Moreover, acetaminophen impaired trophoblast invasion by over 80%, while aspirin had no effect on invasion. Acetaminophen exposure reduced the expression of matrix metalloproteinase (MMP)-2 and -9 and increased the expression of tissue inhibitors of matrix metalloproteinases 2, leading to an imbalance in the ratio of proteolytic enzymes. Finally, a bioinformatic approach identified novel acetaminophen-responsive gene networks associated with key trophoblast functions and disease. Together these results suggest that prenatal acetaminophen use may interfere with critical trophoblast functions early in gestation, which may subsequently impact fetal development.

Background Cyclooxygenase 2 (COX-2) is a key enzyme in the synthesis of prostaglandins. Recent studies have shown that overexpression of COX-2 can reduce the antitumor effect of the immune system by inhibiting the proliferation of B and T lymphocytes. Programmed cell death ligand 1 (PD-L1) was the first functionally characterized ligand of programmed cell death protein 1. It plays an important role in maintaining peripheral and central immune tolerance by combining with programmed cell death protein 1. Arginase 1 (ARG1) can process L-arginine in the local microenvironment and affect the function of T cells, resulting in immune escape. In this study, COX-2, PD-L1, and ARG1 expression in human pituitary adenoma (PA) and their relationship were investigated, which provided an initial theoretic basis for further study of the immune escape mechanism in PA in cellular and animal experiments. Methods The protein expression of COX-2, PD-L1, and ARG1 in 55 PA samples was detected by immunohistochemistry, with 10 normal brain tissues as the control group. The location of COX-2, PD-L1, and ARG1 in PA cells was studied by double immunofluorescence colocalization. The results of immunohistochemistry were further verified by Western blot. Results The expression of COX-2, PD-L1, and ARG1 in PA was significantly higher than that in normal brain tissue. In functional PA (FPA) and nonfunctional PA (NFPA), there was no significant difference in the expression of COX-2 and PD-L1, whereas ARG1 was higher in NFPA. Moreover, the protein expression level of COX-2 was positively correlated with that of PD-L1 and ARG1, and the expression of PD-L1 was positively correlated with that of ARG1. Immunofluorescence confocal imaging showed that COX-2, PD-L1, and ARG1 were all expressed in the cytoplasm of PA cells, and the physical positions of COX-2, PD-L1, and ARG1 were partially coincident. Conclusions These findings indicate that overexpression of COX-2, PD-L1, and ARG1 may be involved in the pathogenesis of PA. ARG1 plays a more important role in the development of NFPA. By upregulating the expression of PD-L1, COX-2 may promote the expression of ARG1, forming the COX-2/PD-L1/ARG1 signal pathway in promoting the occurrence and development of PA. Perhaps further study of the pathogenesis of PA can start with the mechanism of immune escape.

Colchicine is a drug from the past with a bright shining future. It has gained much attention nowadays due to the newly explored therapeutic avenues that were opened by its application in serious ailments. Colchicine has been recently observed as a potential treatment for osteoarthritis (OA). OA is a widespread joint degenerative disease that causes extensive pain and disability. Colchicine has been discovered to affect bone turnover and to reduce different cytokines like interleukin 6 (IL6). Colchicine oral administration has several limitations including extensive first-pass effect, poor bioavailability, and severe GIT side effects. The transdermal route circumvents these limitations. However, colchicine transdermal delivery is challenging owing to its high aqueous solubility and hence poor skin permeation. In this study, novel colchicine transdermal delivery systems were developed to conquer such obstacles. Cellulose-based patches were primed, where mesoporous silica nanoparticles (MSNs) were prepared and used as colchicine encapsulators. The free colchicine or the encapsulated drug was embedded into self-healing hydrogel. The hydrogel was prepared by reacting carboxyethyl chitosan and oxidized pullulan. These composites were used to treat cotton fabric to produce easily applicable and extended-release transdermal patches. Nitrogen adsorption-desorption isotherms, DLS, TEM, and SEM were used to estimate surface area, pore-volume, size, zeta potential, and morphology of MSNs. The hydrogel was characterized using FTIR and TEM. The prepared cotton patch was tested for fabric stiffness. Ex vivo drug permeation study through isolated rat skin was conducted. In comparison to free drug aqueous solution, the patches revealed enhanced drug flux and amplified permeated drug levels which were sustained all over 24 h. Skin permeation was further validated via confocal laser microscopy using fluorescein. The therapeutic investigation of colchicine formulated patches in mono-iodoacetate (MIA)-induced rat osteoarthritis model depicted improved locomotor activity, glutathione blood level, and remarkable decline in levels of malondialdehyde, nitric oxide, TNF-α, and COX-2. Histopathology of rats knee joint supported the OA protective effect of the developed patches, The obtained results revealed significant potentiality of the developed colchicine mesoporous silica nanoparticles/hydrogel patches in the offering, efficient safe and patient convenient formulation for OA management.

Stress is a major risk factor for the development and exacerbation of mood and anxiety disorders, and recent studies have suggested inflammatory contributions to the pathogenesis of depression. Interestingly, pharmacological inhibition of cyclooxygenase-2 (COX-2) has shown promise in the treatment of affective disorders in small scale clinical studies; however, the mechanisms by which COX-2 inhibition affects behavioral domains relevant to affective disorders are not well understood. Here, we examined the effects of pharmacological inhibition of COX-2 with the highly selective inhibitor Lumiracoxib (LMX) on anxiety-like behavior and in vivo basolateral amygdala (BLA) neural activity in response to acute restraint stress exposure. In male mice, pretreatment with LMX prevented the increase in BLA calcium transients induced by restraint stress and prevented anxiogenic behavior seen after restraint stress exposure. Specifically, acute injection of LMX 5mg kg(−1) reduced anxiety-like behavior in the light-dark box (LD) and elevated-zero maze (EZM). In addition, in vivo fiber photometry studies showed that acute stress increased calcium transients and the predicted action potential frequency of BLA neurons, which was also normalized by acute LMX pretreatment. These findings indicate pharmacological inhibition of COX-2 can prevent acute stress-induced increase in BLA cellular activity and anxiety-like behavior and provides insights into the neural mechanisms by which COX-2 inhibition could affect anxiety domain symptoms in patients with affective disorders.

Objective Prolonged use of nonsteroidal anti-inflammatory drugs is associated with severe side effects and toxicity. Therefore, we studied the anti-inflammatory role of Calcarea carbonica which had minimal toxicity at the low doses. Methods THP-1 human mononuclear cells were treated with C. carbonica to evaluate the 50% cytotoxicity concentration (CC50) and 50% effective concentration (EC50). Cell survival was evaluated in lipopolysaccharide-stimulated C. carbonica-treated cells. Nitric oxide (NO) and tumor necrosis factor-α (TNF-α) were measured to evaluate the anti-inflammatory activity of C. carbonica. Cyclooxygenase-2 (COX-2) protein expression was determined by Western blotting analysis, and the interaction of C. carbonica with the COX-2 protein was evaluated using molecular docking simulation. Results The CC50 and EC50 of C. carbonica were found to be 43.26 and 11.99 µg/mL, respectively. The cell survival assay showed a 1.192-fold (P = 0.0129), 1.443-fold (P = 0.0009) and 1.605-fold (P = 0.0004) increase in cell survival at 24, 48 and 72 h after initiating C. carbonica treatment, respectively. C. carbonica-treated cells showed a reduction in NO levels by 2.355 folds (P = 0.0001), 2.181 folds (P = 0.0001) and 2.071 folds (P = 0.0001) at 24, 48 and 72 h, respectively. The treated cells also showed a reduction in TNF-α levels by 1.395 folds (P = 0.0013), 1.541 folds (P = 0.0005) and 1.550 folds (P = 0.0005) at 24, 48 and 72 h, respectively. In addition, a 1.193-fold reduction (P = 0.0126) in COX-2 protein expression was found in C. carbonica-treated cells. The molecular docking showed interaction of C. carbonica with the phenylalanine 367 residue present in active site of Cox-2. Conclusion C. carbonica exhibited anti-inflammatory properties in lipopolysaccharide-stimulated cells by significantly reducing NO production and TNF-α level through downregulation of the COX-2 protein. This effect is probably mediated through interaction of C. carbonica with the phenylalanine 367 residue present in active site of Cox-2.

The objectives of this study were to evaluate in horse testes the expression of kisspeptin (KiSS) and GnRH1 neuropeptides and their cognate receptors, KiSS1R and GnRH1R, as well as their action on testosterone, GnRH1, prostaglandin F2α (PGF2α), and PGE2 synthesis and cyclooxygenase 1 (COX1) and COX2 activity by Leydig cells in vitro. Testes were obtained from 9 sexually mature horses by surgical castration. Immunohistochemistry, evidenced the presence of KiSS, KiSS1R, GnRH, and GnRH1R in Leydig cells, whereas germinal and Sertoli cells were positive only for GnRH1. Transcripts for both neuropeptides and their cognate receptors were revealed in isolated Leydig cells by RT-PCR. Isolated and purified Leydig cells were in vitro cultured with agonists and antagonists of KiSS (KiSS-10 and KiSS-234, respectively) and GnRH1 (buserelin and antide, respectively). KiSS-10 and buserelin increased (P 0.01) COX1 activity and testosterone and PGF2α basal secretion, while decreased (P 0.01) that of PGE2. KiSS-10 and buserelin did not affect COX2 activity. GnRH1 basal production was increased (P 0.01) by KiSS-10, but not by buserelin. Antide counteracted the KiSS and GnRH1 effects, whereas KiSS-234 influence only those of KiSS. Summarizing, the KiSS/GnRH1 system is present in horse Leydig cells and modulates their endocrine activity. In particular, the endocrine effects of KiSS are mediated by GnRH1, so suggesting that hypothalamic-like interaction between KiSS and GnRH1 occurs also in Leydig cells.

Lipid mediators derived from omega (n)-3 and n-6 long-chain polyunsaturated fatty acids (LCPUFA) play key roles in bronchoconstriction, airway inflammation, and resolution processes in asthma. This study compared the effects of dietary supplementation with either a combination of LCPUFAs or eicosapentaenoic acid (EPA) alone to investigate whether the combination has superior beneficial effects on the outcome of asthmatic mice. Mice were sensitized with house dust mite (HDM) extract, and subsequently supplemented with either a combination of LCPUFAs or EPA alone in a recall asthma model. After the final HDM and LCPUFA administration, airway hyperresponsiveness (AHR), bronchoalveolar lavages, and lung histochemistry were examined. Lipid mediator profiles were determined by liquid chromatography coupled with tandem mass spectrometry (LC–MS–MS). The LCPUFA combination reduced AHR, eosinophilic inflammation, and inflammatory cytokines (IL-5, IFN-γ, and IL-6) in asthmatic mice, whereas EPA enhanced inflammation. The combination of LCPUFAs was more potent in downregulating EPA-derived LTB5 and LTC5 and in supporting DHA-derived RvD1 and RvD4 (2.22-fold and 2.58-fold higher levels) than EPA alone. Ex vivo experiments showed that LTB5 contributes to granulocytes’ migration and M1-polarization in monocytes. Consequently, the LCPUFA combination ameliorated airway inflammation by inhibiting adverse effects of EPA and promoting pro-resolving effects supporting the lipid mediator-dependent resolution program.

Chrysophyllum abidum fruit is a seasonal fruit commonly eaten as snacks with abundant health promoting phytochemicals in the fruit peels. The fruit peels have been reported to be rich in anti-inflammatory eleagnine, myricetin rhamnoside, quercetin, linoleic acid and oleic acid. We hypothesized that the anti-inflammatory effect of the peel extract involve suppression of pro-inflammatory cytokines, cyclooxygenase-2 and nuclear factor-kappa B (NF-κB). Hence, this study was designed to assess the anti-nociceptive and anti-inflammatory effects of fruit peel extract of Chrysophyllum albidum in animal models of nociception and inflammation. The anti-nociceptive activity of CAPEE (100 and 400 mg/kg) was evaluated in acetic acid-induced writhing and formalin-induced paw licking in mice. Formalin-induced paw edema and carrageenan-induced air pouch models of inflammation were used to evaluate the anti-inflammatory activity. CAPEE (100 and 400 mg/kg) significantly reduced abdominal writhing and paw licking in acetic acid and formalin tests in mice, respectively. CAPEE demonstrated significant inhibition of paw edema at 24 h (41.0% and 55.7%) and 72 h (52.3% and 86.6%) after formalin injection. CAPEE suppressed inflammatory responses in carrageenan-induced air pouch by reducing exudates, inflammatory cells infiltration, nitrites and myeloperoxidase activity. There was significant inhibition of tumor necrosis factor-alpha, interleukin-6 levels and reduced immunopositive expression of COX-2 and NF-κB. In conclusion, CAPEE has anti-nociceptive and anti-inflammatory potentials via mechanisms associated with inhibition of pro-inflammatory cytokines and cyclooxygenase-2 (COX-2) expression through suppression of nuclear factor kappa B (NF-κB) activation, and has potential as a functional food ingredient.

Chloropicrin (CP), a warfare agent now majorly used as a soil pesticide, is a strong irritating and lacrimating compound with devastating toxic effects. To elucidate the mechanism of its ocular toxicity, toxic effects of CP (0-100 μM) were studied in primary human corneal epithelial (HCE) cells. CP exposure resulted in reduced HCE cell viability and increased apoptotic cell death with an up-regulation of cleaved caspase-3 and poly ADP ribose polymerase indicating their contribution in CP-induced apoptotic cell death. Following CP exposure, cells exhibited increased expression of heme oxygenase-1, and phosphorylation of H2A.X and p53 as well as 4-hydroxynonenal adduct formation, suggesting oxidative stress, DNA damage and lipid peroxidation. CP also caused increases in mitogen activated protein kinase-c-Jun N-terminal kinase and inflammatory mediator cyclooxygenase-2. Proteomic analysis revealed an increase in the carbonylation of 179 proteins and enrichment of pathways (including proteasome pathway and catabolic process) in HCE cells following CP exposure. CP-induced oxidative stress and lipid peroxidation can enhance protein carbonylation, prompting alterations in corneal epithelial proteins as well as perturbing signaling pathways resulting in toxic effects. Pathways and major processes identified following CP exposure could be lead-hit targets for further biochemical and molecular characterization as well as therapeutic intervention.

pH-sensitive polyethylene glycol-conjugated urokinase nanogels (PEG-UK) is a new form of urokinase (UK) nanogels that could release UK at certain pH values. In our former study, we demonstrated that the pH value in the infarcted brain significantly declined to the level that could trigger the delivery of UK from PEG-UK. Thrombolysis is recommended as the first choice for ischemic stroke within the time window. However, it is common for the patients to miss the thrombolysis time window, which is one of the major causes of bad prognosis from ischemic stroke. It remains promising for seeking therapeutic approaches for ischemic stroke by investigating potential protective reagents delivered out of the usually thrombolysis time window. In this study, the protective effect of administration of PEG-UK outside the usual time window and the underlying mechanisms were investigated. PEG-UK was administrated 2 h and a half after ischemic stroke Delayed administration of PEG-UK significantly ameliorated the severity of neurological deficits of permanent middle cerebral occlusion (pMCAO) rats and reduced the infiltration of inflammatory cells and the concentration of interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the brain tissues. The content of water and the leakage of Evans Blue (EB) in the PEG-UK group were also decreased. Maintenance of the expression of platelet-derived growth factor-C (PDGF-C) and inhibition of the upregulation of metalloproteinase proteins, low-density lipoprotein receptor-related protein (LRP), nuclear factor κB (NF-κB) p65 and cyclooxygenase-2 (Cox-2) were observed through western blotting and realtime PCR in the PEG-UK group. Besides, delayed administration of PEG-UK attenuated the up regulation of Caspase8 and Caspase9 and the cleavage of Caspase3 and poly (ADP-ribose) polymerase 1 (PARP1) in ischemic lesion sites. Moreover, PEG-UK treatment also inhibited the upregulation and phosphorylation of N-methyl-D-aspartic acid receptors (NMDARs), which has been revealed to play a vital role in mediating excito-neurotoxicity in ischemic stroke. In conclusion, through the inhibition of LRP/NF-κB/Cox-2 pathway, the Caspase cascade and activation of NMDARs, administration of PEG-UK outside the usual time window could still exert protective effects in pMCAO rats through the maintenance of the integrity of BBB and the inhibition of apoptosis and excito-neurotoxicity.

Background and aim Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling, which is mainly caused by inflammation. Inhibiting inflammation can relieve PAH. Grape seed procyanidin (GSP) possesses remarkable anti-inflammatory property and vascular protective function. In this experiment, we verified the anti-inflammatory property of GSP in cigarette smoke-exposed PAH rats and revealed its molecular mechanism. Methods and results In vivo, 45 Sprague Dawley (SD) rats were divided into 5 groups randomly, treated with normoxia/cigarette smoke (CS)/GSP + CS/CS + solvent/GSP. After GSP + CS administration, a decrease in mPAP, PVR, RVHI, WT%, and WA% was detected in the rats as compared to those treated with CS. In vitro, the proliferation of pulmonary arterial smooth muscle cells (PASMCs) caused by cigarette smoke extract (CSE) was effectively attenuated with GSP + CSE administration. Furthermore, GSP significantly increased the expression of peroxisome proliferator-activated receptor γ (PPAR-γ) together with the lowered expression level of cyclooxygenase 2 (COX-2) in PASMCs co-incubated with CSE. Conclusion These findings indicate that GSP ameliorates inflammation by the PPAR-γ/COX-2 pathway and finally inhibits the proliferation of PASMCs, which leads to pulmonary vascular remodeling.

The long-term effects of cyclooxygenase 1 and 2 (COX-1/2) inhibitors are usually tested in terms of the periphery of the organism. Therefore, we studied the effects of SC560 (selective COX-1 inhibitor) and celecoxib (selective COX-2 inhibitor) on the activity of brain monoaminergic systems and animal behaviour. Additionally, we tested the effect of these inhibitors during inflammation. We have observed that long-term administration of celecoxib reduces the activity of the noradrenergic system, increases the activity of dopaminergic and serotonergic systems, increases locomotor activity, and enhances the exploratory behaviour of rats. Administration of SC560 also increases the activity of dopaminergic and serotonergic systems but reduces locomotor activity and impairs the exploratory behaviour of rats. The mechanism responsible for decreased activity of the noradrenergic system may be related to the weakening of activity of the positive feedback loop between the paraventricular nucleus and coeruleus locus. We suggest that the effect of used inhibitors on the dopaminergic system is associated with a possible increase in anandamide concentration and its effect on dopamine reuptake in synaptic clefts. It also appears that cyclooxygenase peroxidase activity may play a role in this process. In turn, changes in the activity of the serotonergic system may be related to the activity of indoleamine-2,3-dioxygenase, which decreases because of the decreased concentration of pro-inflammatory compounds. We believe that behavioural changes induced by COX inhibitors are the result of the modified activity of monoaminergic CNS systems in the brainstem, hypothalamus, and medial prefrontal cortex.

Cognitive comorbidities can substantially reduce quality of life in people with epilepsy. Inflammation is a component of all chronic diseases including epilepsy, as well as acute events like status epilepticus (SE). Neuroinflammation is the consequence of several broad signaling cascades including cyclooxygenase-2 (COX-2)-associated pathways. Activation of the EP2 receptor for prostaglandin E2 appears responsible for blood-brain barrier leakage and much of the inflammatory reaction, neuronal injury and cognitive deficit that follows seizure-provoked COX-2 induction in brain. Here we show that brief exposure of mice to TG11-77, a potent, selective, orally available and brain permeant EP2 antagonist, eliminates the profound cognitive deficit in Y-maze performance after SE and reduces delayed mortality and microgliosis, with a minimum effective i.p. dose (as free base) of 8.8 mg/kg. All in vitro studies required to submit an investigational new drug (IND) application for TG11-77 have been completed, and non-GLP dose range-finding toxicology in the rat identified no overt, organ or histopathology signs of toxicity after 7 days of oral administration at 1000 mg/kg/day. Plasma exposure in the rat was dose-linear between 15 and 1000 mg/kg dosing. TG11-77 thus appears poised to continue development towards the initial clinical test of the hypothesis that EP2 receptor modulation after SE can provide the first preventive treatment for one of the chief comorbidities of epilepsy.

GCMN is a sporadic disease with an incidence ranging from 1/20,000 to 1/500000. So far, several studies have found that GCMN is related to somatic mutations, but most of them have focused on known pathogenic genes, and transcriptome sequencing based on large datasets is relatively uncommon. At present, the use of next-generation sequencing technologies and bioinformatics platforms makes genomic information study more comprehensive and efficient. In this study, the transcriptome differences between GCMN lesions and surrounding normal skin tissues were investigated using high-throughput transcriptome sequencing, and hub genes and pathways related to pathogenesis were identified, providing a theoretical foundation for further research into the pathogenesis of GCMN.Pathological skin tissue and surrounding normal skin tissue from GCMN patients, namely the pathological group (PG) and the control group (CG), were obtained. 1. All specimens were stained with HE to ensure that the samples met the experimental requirements. 2. Ten pairs of specimens were selected for high-throughput transcriptome sequencing, and the differentially expressed genes (DEGs) between the PG and the CG were obtained. The DEGs were analyzed by clusterProfiler R software for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The function of the subnetwork was analyzed and the hub genes were identified by the STRING database and Cytoscape software. 3. The expression differences of hub genes PTGS2, EGF, and SOX10 in pathological skin tissues and normal skin tissues were verified by qRT-PCR and immunofluorescence staining.1. HE staining revealed a lot of melanocytes in the dermis and subcutaneous tissues. They were found around the hair follicles, sweat glands, sebaceous glands, and blood vessel walls, or in a specific pattern. 2. The screening threshold was set at p 0.01 and |log2fc|1, and a total of 1163 DEGs were discovered between the PG and CG, with 519 genes up-regulated and 644 genes down-regulated in the pathological tissues. According to the GO functional analysis, 29 biological processes, 18 cell compositions, and 17 molecular functions were significantly enriched, with the majority of them being related to keratinocytes and the extracellular matrix. There were 779 nodes and 2359 interactions in the protein interaction network. Using the MCODE plug-in, the network was divided into 25 functional clusters. According to ClueGO results, Cluster5 was involved in melanin biosynthesis and melanocyte proliferation. Using 11 operation methods in the Cytohubba plug-in, PTGS2, EGF, and SOX10 in Cluster5 were chosen as hub genes. 3. qRT-PCR and immunofluorescent staining revealed that compared to normal skin tissue, the expression of SOX10 was significantly up-regulated, and the expression of PTGS2 and EGF was significantly down-regulated in pathological skin tissue(P 0.001).In GCMN, keratinocytes and extracellular matrix may directly and indirectly affect melanocyte activity. PTGS2, EGF, and SOX10 are important genes and significantly differentially expressed in pathological and normal skin tissues. These findings may serve as a springboard for future research.

Commelina benghalensis Linn is a perennial plant with upright stems reaching a height of 1 m. Its stem is commonly used to induce abortion in traditional medicine. However, there are insignificant scientific data to evaluate such a claim.The study was conducted to determine the abortifacient and toxicological potential of ethanol extract of Commelina benghalensis Linn stem (EECBS) via selected proinflammatory and oxidative stress biomarkers in pregnant Wistar rats.To determine the phytochemicals responsible for EECBS's toxicity and abortifacient effects, high-performance liquid chromatography-photodiode array detection (HPLC-PDA) and gas chromatography-mass spectrometry (GC-MS) was used. The abortion rate was determined by monitoring the markers of reproductive system failure in the experimental model. To assess rat hepatotoxicity, biochemical markers and immunohistopathological parameters were used.Results demonstrated the presence of isomeric benzene-mesitylene compounds in EECBS. Also, EECBS significantly altered the markers of liver function and oxidative damage while eliciting a significantly reduced (P 0.05) number of live fetuses, number of corpora lutea, progesterone, estradiol, and luteinizing hormone, whereas the number of dead fetuses percentage vaginal opening, and post-implantation loss increased significantly (P 0.05). Estrogenicity studies indicated a significant (P 0.05) increase in uterine weight, uterine glucose, and ALP dose-dependently. Moreover, EECBS also caused a vaginal hemorrhage preceding the parturition. Also, EECBS treatment significantly increased levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and significantly elevated the expression of COX-2 protein in the liver.The current investigation established Commelina benghalensis Linn stem's abortifacient activity. Continuous use, on the other hand, may cause liver damage in pregnant rats by disrupting antioxidant defense mechanisms, promoting the production of pro-inflammatory cytokines, and increasing COX-2 expression. Hence, caution should be excised while consuming this plant's stem for medication purposes, especially during the gestational period.

Cousinia thomsonii is traditionally known for treating various diseases including joint pain, swelling, body ache, asthma, dermatitis, cough and arthritis.This study employs lipopolysaccharide induced inflammatory wistar-rat model to evaluate efficacy of Cousinia thomsonii active-extracts on the expression of crucial inflammatory markers viz. iNOS, PPAR-γ, Rel-A, COX-2 and serum analysis of CRP.Methanol and aqueous extracts were administered orally at 25, 50, 100 mg/kg doses for 21 days. Serum was collected on 22nd day and rats were sacrificed to extract paw tissues. Dexamethasone (0.5 mg/kg) served as positive control. Immunoblotting and qPCR was used for expression analysis of iNOS, PPAR-γ, Rel-A, COX-2 respectively. ELISA was employed for evaluating CRP levels. Discovery-studio and Auto-Dock-Vina were used to check docking interactions of various identified compounds.Both extracts caused dose-dependent decline in iNOS, Rel-A, COX-2 and CRP levels, while there was a dose-dependent increase in PPAR-γ expression. Methanol extract dominated immunomodulatory potential as compared with the aqueous extract. The results of the GCMS revealed the presence of ten compounds. Some of these compounds include 1-Octacosanol, Ethyl Linoleate, 1-Heptacosanol, 1-Hexadecanol, 1-Dodecanol and Behenic alcohol having strong anti-inflammatory, antimicrobial, anti-acne and anti-viral activities. Molecular Docking scores were calculated between each target protein and selected compounds. The best affinity/interactions were observed between 1-Octacosanol towards iNOS, PPAR-γ, Rel-A, COX-2 and CRP with binding energy of -10.4, -11.1, -8.6, -9.9 and -7.9 (kcal/mol) respectively. These compounds may act as strong inhibitors for iNOS, Rel-A, COX-2 and CRP or as agonists for PPAR-γ; thereby inducing anti-inflammatory/immuno-modulatory activities.The results indicate that Cousinia thomsonii contains therapeutically active compounds and thus could serve as potential therapeutic regimen against diverse inflammatory diseases.

Angiotensin-converting enzyme (ACE) affects blood pressure. In addition, ACE overexpression in myeloid cells increases their immune function. Using MS and chemical analysis, we identified marked changes of intermediate metabolites in ACE-overexpressing macrophages and neutrophils, with increased cellular ATP (1.7–3.0-fold) and Krebs cycle intermediates, including citrate, isocitrate, succinate, and malate (1.4–3.9-fold). Increased ATP is due to ACE C-domain catalytic activity; it is reversed by an ACE inhibitor but not by an angiotensin II AT1 receptor antagonist. In contrast, macrophages from ACE knockout (null) mice averaged only 28% of the ATP levels found in WT mice. ACE overexpression does not change cell or mitochondrial size or number. However, expression levels of the electron transport chain proteins NDUFB8 (complex I), ATP5A, and ATP5β (complex V) are significantly increased in macrophages and neutrophils, and COX1 and COX2 (complex IV) are increased in macrophages overexpressing ACE. Macrophages overexpressing ACE have increased mitochondrial membrane potential (24% higher), ATP production rates (29% higher), and maximal respiratory rates (37% higher) compared with WT cells. Increased cellular ATP underpins increased myeloid cell superoxide production and phagocytosis associated with increased ACE expression. Myeloid cells overexpressing ACE indicate the existence of a novel pathway in which myeloid cell function can be enhanced, with a key feature being increased cellular ATP.

Our understanding of the relationship between stress-derived epinephrine and early pregnancy failure remains incomplete. Here, we explored the effect of epinephrine exposure on early pregnancy and pseudopregnancy in mice. Increased expression of adrenergic receptors Adra1b, Adra2b and Adrb2 was observed during decidualization and post-implantation embryogenesis was delayed or survival impaired. Epinephrine treatment also impaired decidualization in both the gravid and pseudopregnant uterus, suggesting the effect on decidualization was independent of the conceptus. This included a suppression of endometrial stroma cell proliferation and of key decidualization regulators, including COX2, BMP2 and WNT4. Collectively, these data demonstrate that maternal epinephrine exposure during early pregnancy impairs uterine decidualization and embryo development, underlying early pregnancy failure.

Heart failure is one of the diseases with the highest mortality in the world, and inflammation is the main cause for its occurrence and development. The stilbene skeleton of resveratrol has been shown to have excellent anti-inflammatory and antioxidant activities. In order to continue our research on dihydropyrazole derivatives, a series of novel (E)-4-methyl-2-(3-phenyl-5-(4-styrylphenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazole derivatives were designed and synthesized according to the principle of molecular hybridization for evaluation their anti-inflammatory and antioxidation activities. We screened their anti-inflammatory abilities in RAW264.7 cells and analyzed the preliminary structure-activity relationship, and explored the related molecular mechanisms. We further used doxorubicin (DOX)-induced heart failure model to explore the protective role of our compound in vivo. Our results showed that compound F5 exhibited the most potent activity and was superior to the positive control. It reversed the expression of lipopolysaccharide (LPS)-regulated inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and superoxide dismutase 1 (SOD1) in RAW264.7 cells. In addition, compound F5 also inhibited DOX-induced inflammation and reactive oxygen species by modulating the p38/nuclear factor kappa B (NF-κB) signaling pathway in H9C2 cells. In vivo results showed that compound F5 ameliorated DOX-caused damage, such as reduced left ventricular ejection fraction, severe inflammation, fibrosis and oxidative stress in heart. In conclusion, compound F5 could be used as a promising agent for the treatment of heart failure through attenuating oxidative stress and inflammation.

Uncontrolled inflammation predisposes to pleiotropic effects leading to cancer development thanks to promoting all stages of tumorigenesis. Therefore, cancer-associated inflammation has been delegated as the seventh hallmark of cancer. Thus, raging the war against both inflammation and cancer via the innovation of bioactive agents with dual anti-inflammatory and anticancer activities is a necessity. Herein, a novel series of pyrazole-chalcone analogs of Lonazolac (7a-g and 8a-g) have been synthesized and investigated for their in vitro anticancer activity against four cancer cell lines using the MTT assay method. Among all, hybrid 8g was the most potent against three cancer cell lines, HeLa, HCT-116, and RPMI-822 with ICsub50/subvalues of 2.41, 2.41, and 3.34 µM, respectively. In contrast, hybrid 8g showed moderate inhibitory activity against MCF-7 with ICsub50/sub28.93 μM and with a selectivity profile against MCF-10A (non-cancer cells). Mechanistically, hybrid 8g was the most potent inhibitor against tubulin polymerization (ICsub50/sub = 4.77 µM), suggesting tubulin as a molecular target and explaining the observed cytotoxicity of hybrid 8g. This was mirrored by the detected potent pre-G1 apoptosis induction and G2/M cell cycle arrest. Moreover, hybrid8gexhibited selectivity against COX-2 (ICsub50/sub = 5.13 µM) more than COX-1 (ICsub50/sub = 33.46 µM), indicating that 8g may have lower cardiovascular side effects, but is still not potent as celecoxib (COX-2 ICsub50/sub = 0.204 µM, COX-1 = 35.8 µM). Notably, hybrid 8g showed promising inhibitory activity towards 5-LOX (ICsub50/sub = 5.88 µM). Finally, the anti-inflammatory activity of hybrid8 g was confirmed by high iNOS and PGE2 inhibitory activities in LPS-stimulated RAW cells with ICsub50/subvalues of4.93 µM and 10.98 µM, respectively, that accompanied by showingthe most potent inhibition of NO release (70.61 % inhibition rate). Molecular docking studies of hybrid 8g confirmed good correlations with the executed biological results. Furthermore, hybrid 8g had good drug-likeness and suitable physicochemical properties. Taken together, the combined results suggested hybrid8gas a promising orally administered candidate in the journey of repurposing NSAIDs for cancer chemopreventionand treatment.

This study is to investigate the role of 12-Epi-Napelline, a new alkaloid isolated from aconitum, in promoting the paracrine of Bone Mesenchymal Stem Cells (BMSCs) and the synergistic therapeutic effects on osteoarthritis.We tested the cytotoxicity and optimization of 12-Epi-Napelline, and then simulated the osteoarthritis model in vitro damaging the chondrocytes by lipopolysaccharide (LPS) and RT-qPCR, Western blot and Immunofluorescence were used to detect the inflammatory factor IL-1β, COX-2, TNF-α, MMP-13 and anabolic cytokines of Col-2, BMP-2, TGF-β1 and Sox9 expression in chondrocytes after 12-Epi-Napelline treatment. Under the treatment of different time, Col-2, BMP-2, TGF-β1 and Sox9 expression in BMSCs were detected by RT-qPCR, Western blot, and Immunofluorescence. By establishing an osteoarthritis model in vivo, the anti-osteoarthritis effect of 12-Epi-Napelline or BMSCs was evaluated.The results showed the expressions of IL-1β, COX-2, TNF-α, and MMP-13 were down-regulated in chondrocytes after 12-Epi-Napelline treatment, while the expression of Col-2, BMP-2, TGF-β1 and Sox9 were increased to normal chondrocytes. These increased expression also occurred in BMSCs. BMSCs had the trend of transforming into chondrocytes by regulating TGF-β signaling pathway under the treatment of 12-Epi-Napelline.This study could confirm that 12-Epi-Napelline is not only effective in the treatment of osteoarthritis, but also can induce BMSCs to secrete growth factors that promote chondrocyte repair to help repair the damage caused by osteoarthritis.

Asiatic acid (AA), a triterpenoid compound isolated from Centella asiatica, has anti-inflammatory, antioxidant and anticancer biological characteristics. To explore the effect of AA on LPS-induced acute kidney injury (AKI) in broilers, a total of 60 one-day-old broilers were randomly divided into 6 groups, including the normal group, AKI model group, AKI + AA 15 mg/kg group, AKI + AA 30 mg/kg group, AKI + AA 60 mg/kg group and normal + AA 60 mg/kg group. Hematoxylin-eosin staining was used to observe the histopathology in kidney tissue, and the mRNA and protein expressions related to oxidative stress and ferroptosis were tested by qPCR and western blotting respectively. AA mitigated vacuolar degeneration and enlarged glomerular space caused by LPS in kidney tissue. Additionally, AA significantly increased the mRNA levels of Nrf2, HO-1, NQO1, GCLC, GCLM, GPX4, SLC7A11 and FTH1, and decreased the mRNA levels of Keap1 and PTGS2 in LPS-induced AKI. Likewise, AA significantly upregulated the protein expressions of Nrf2, HO-1, NQO1, GPX4, SLC7A11 and FTH1, and downregulated the protein expressions of Keap1 and PTGS2 in LPS-induced AKI. These results suggested that AA alleviated LPS-induced AKI by inhibiting oxidative stress and ferroptosis through targeting regulation of the Nrf2 pathway in broilers.

Metabolic syndrome (MetS) is a public health problem and a risk of developing cardiometabolic and neurodegenerative diseases. The biochemical-inflammatory impairment in brain areas related to learning and memory has not been differentiated between MetS models. We aimed to compare the effect of the MetS generated by consuming high-fat (HFD) or -carbohydrate diets (HCD) on the hippocampus and frontal cortex, related to astrocyte-neuron metabolism and neuroinflammation origin. Sixty male Wistar rats were separated into three groups: 1) control group, 2) HCD group, and 3) HFD group. After 3 months, we evaluated zoometry, a serum bioclinical profile, and in the hippocampus and frontal cortex, we performed biochemical assays (concentration of lactate, glutamate, fatty acids, and ASAT, ALAT, and LDH activity), immunoreactivity tests (GFAP, COX2, CD36, and BDNF), and immunoassays (TNF-α, IL-1β, IL-6, and PGE2). The bioclinical parameters showed that both diets induce MetS. At the brain level, it is noteworthy that the HCD group had an increase in lactate and glutamate concentration, reactive astrogliosis, immunoreactive COX2 neurons in the CA1 subfield hippocampus and frontal cortex, and high levels of PGE2, TNF-α, IL-1β, and IL-6, and low BDNF immunoreactivity. Meanwhile, the HFD is highlighted by increased fatty acid levels and CD36 expression in the hippocampus and frontal cortex, strong reactive astrogliosis and COX2 immunoreactivity, and the greatest inflammation with the lowest BDNF immunoreactivity. In conclusion, MetS induction by an HFD or HCD generates different biochemical, cellular, and inflammatory patterns in the hippocampus and frontal cortex.