t-0070907 and Inflammation

Icariin (ICA) might be a potential anti-inflammatory medication in a variety of diseases including COPD, and previous studies showed that ICA could attenuate cigarette smoke (CS)-induced inflammation by inhibiting nuclear factor (NF)-κB. Peroxisome proliferator-activated receptor (PPAR) γ, a nuclear hormone receptor, has been reported to play a critical role in the inflammatory process in COPD. Whether PPAR-γ is involved in the anti-inflammatory effect of icariin on COPD has scarcely been explored. This study aimed at investigating the role of ICA in PPAR-γ expression in the CS-induced model, and then elucidating the therapeutic effects of ICA on COPD based on the PPARγ-NF-κB signaling pathway. The Beas-2B cells and H292 cells were induced with cigarette smoke extract (CSE) for 8 h after treatment with ICA for 16 h. The PPARγ expression and NF-κB pathway-related indicators were detected by western blotting, cellular immunofluorescence, and Real-time PCR. The PPARγ knock down or T0070907-treated Beas-2B cells were constructed to further investigate the relationship between the inhibition of NF-κB by ICA and PPARγ. A COPD model was established by CS exposure for 6 months, and ICA (40 mg/kg) was administrated by gastric perfusion. Then, the pulmonary function, lung histology, inflammatory cytokine levels, and protein expressions were detected. We found ICA up-regulated PPARγ protein expression in both Beas-2B cells and H292 cells, and it improved CSE-induced PPARγ down regulation and NF-κB activation. Furthermore, the inhibition of NF-κB pathway by ICA was partially dependent on PPARγ in the PPARγ knock down or T0070907-treated Beas-2B cells, suggesting that ICA attenuated CSE-induced inflammatory responses were associated with modulating the PPARγ-NF-κB pathway. Moreover, ICA showed similar effects on PPARγ and NF-κB expressions in the COPD model, and it effectively ameliorated the pulmonary function and lung inflammatory infiltration in the COPD rat model. Conclusively, the therapeutic effect of ICA on COPD was indirectly achieved by reducing airway inflammation, which was partially associated with modulating the PPARγ-NF-κB signaling pathway.

Topics: Animals; Anti-Inflammatory Agents; Cigarette Smoking; Inflammation; NF-kappa B; PPAR gamma; Pulmonary Disease, Chronic Obstructive; Rats; Up-Regulation

Female fertility depends greatly on the capacity of the uterus to recognize and eliminate microbial infections, a major reason of inflammation in the endometrium in many species. This study aimed to determine the in vitro effect of peroxisome proliferator-activated receptor gamma (PPARγ) ligands on the transcriptome genes expression and alternative splicing in the porcine endometrium in the mid-luteal phase of the estrous cycle during LPS-stimulated inflammation using RNA-seq technology. The endometrial slices were incubated in vitro in the presence of LPS and PPARγ agonists-PGJ2 or pioglitazone and antagonist-T0070907. We identified 222, 3, 4, and 62 differentially expressed genes after LPS, PGJ2, pioglitazone, or T0070907 treatment, respectively. In addition, we detected differentially alternative spliced events: after treatment with LPS-78, PGJ2-60, pioglitazone-52, or T0070907-134. These results should become a basis for further studies explaining the mechanism of PPARγ action in the reproductive system in pigs.

Topics: Alternative Splicing; Animals; Benzamides; Endometrium; Female; Gene Expression Profiling; Inflammation; Lipopolysaccharides; Pioglitazone; PPAR gamma; Prostaglandin D2; Pyridines; Swine

Endocrine disrupting chemicals, such as bisphenol A (BPA), have been linked to obesity. However, the direct effect of BPA on the hypothalamic pro-opiomelanocortin (POMC) neurons, which regulate energy homeostasis, remains unexplored. We define the effect of BPA on functionally characterized, POMC-expressing cell models, mHypoA-POMC/GFP-2 and mHypoE-43/5. Exposure to BPA significantly induced the mRNA levels of Pomc in both primary culture and the cell lines. Neuroinflammatory and steroid receptor mRNA levels were assessed to delineate the potential mechanisms, including inflammatory markers Nfκb, Il6 and Iκba, and steroid receptors Esr1, Esr2, Gpr30, Esrrg, and Pparg. Pre-treatment with anti-inflammatory compounds gonadotropin-releasing hormone, and PS1145, an IκB kinase inhibitor, abrogated the BPA-mediated Pomc induction. Furthermore, T0070907, a PPARγ antagonist, abolished Pomc induction, while the GPR30 antagonist G15 had no effect. These findings indicate that BPA may have direct effects on POMC neurons in the hypothalamus, utilizing neuroinflammatory mechanisms and through PPARγ nuclear receptors.

Topics: Animals; Anti-Inflammatory Agents; Benzamides; Benzhydryl Compounds; Biomarkers; Cell Line; Gene Expression Regulation; Gonadotropin-Releasing Hormone; Heterocyclic Compounds, 3-Ring; Hypothalamus; Inflammation; Mice; Models, Biological; Neurons; Phenols; PPAR gamma; Pro-Opiomelanocortin; Pyridines; RNA, Messenger; Up-Regulation

See Moon (doi:10.1093/awv239) for a scientific commentary on this article.Traumatic brain injury frequently leads to long-term cognitive problems and physical disability yet remains without effective therapeutics. Traumatic brain injury results in neuronal injury and death, acute and prolonged inflammation and decreased blood flow. Drugs that block angiotensin II type 1 receptors (AT1R, encoded by AGTR1) (ARBs or sartans) are strongly neuroprotective, neurorestorative and anti-inflammatory. To test whether these drugs may be effective in treating traumatic brain injury, we selected two sartans, candesartan and telmisartan, of proven therapeutic efficacy in animal models of brain inflammation, neurodegenerative disorders and stroke. Using a validated mouse model of controlled cortical impact injury, we determined effective doses for candesartan and telmisartan, their therapeutic window, mechanisms of action and effect on cognition and motor performance. Both candesartan and telmisartan ameliorated controlled cortical impact-induced injury with a therapeutic window up to 6 h at doses that did not affect blood pressure. Both drugs decreased lesion volume, neuronal injury and apoptosis, astrogliosis, microglial activation, pro-inflammatory signalling, and protected cerebral blood flow, when determined 1 to 3 days post-injury. Controlled cortical impact-induced cognitive impairment was ameliorated 30 days after injury only by candesartan. The neurorestorative effects of candesartan and telmisartan were reduced by concomitant administration of the peroxisome proliferator-activated receptor gamma (PPARγ, encoded by PPARG) antagonist T0070907, showing the importance of PPARγ activation for the neurorestorative effect of these sartans. AT1R knockout mice were less vulnerable to controlled cortical impact-induced injury suggesting that the sartan's blockade of the AT1R also contributes to their efficacy. This study strongly suggests that sartans with dual AT1R blocking and PPARγ activating properties have therapeutic potential for traumatic brain injury.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Apoptosis; Benzamides; Benzimidazoles; Benzoates; Biphenyl Compounds; Brain Injuries; Cerebrovascular Circulation; Gliosis; Inflammation; Mice; Mice, Knockout; Microglia; Neurons; Neuroprotective Agents; PPAR gamma; Pyridines; Receptor, Angiotensin, Type 1; Signal Transduction; Telmisartan; Tetrazoles

Inflammatory responses in the brain are involved in the etiopathogenesis and sequelae of seizures. Ligation of microglial CD40 plays a role in the development of inflammatory responses in the central nervous system (CNS). Our study showed that there was an increased CD40 expression on activated microglia in the brain injury after lithium pilocarpine-induced status epilepticus (SE) in rats. Since peroxisome proliferator-activated receptor gamma (PPARgamma) acts as a regulator of CNS inflammation and a powerful pharmacological target for counteracting CNS diseases, we investigated the role of the PPARgamma agonist, rosiglitazone, in the modulation of CD40 expression and in the pathological processes of inflammation after SE. We found that rosiglitazone inhibited the expression of CD40, tumor necrosis factor (TNF-alpha), and microglial activation in different regions of hippocampus. The results were indicated by immunohistochemistry, Western blot, and ELISA, respectively. Rosiglitazone also prevented neuronal loss in the CA1 area after SE observed by Nissl-staining. These protective effects were significantly reversed by the co-treatment with T0070907, a selective antagonist of the PPARgamma, which clearly demonstrated a PPARgamma-dependent mechanism. Our data provide evidence that rosiglitazone considerably attenuates inflammatory responses after SE by suppressing CD40 expression and microglial activation. Our data also support the idea that rosiglitazone might be a potential neuroprotective agent in epilepsy.

Topics: Animals; Benzamides; Blotting, Western; Brain Injuries; CD40 Antigens; Central Nervous System Diseases; Enzyme-Linked Immunosorbent Assay; Epilepsy; Hippocampus; Immunohistochemistry; Inflammation; Lithium Compounds; Male; Pilocarpine; PPAR gamma; Pyridines; Rats; Rats, Sprague-Dawley; Rosiglitazone; Seizures; Status Epilepticus; Thiazolidinediones; Tumor Necrosis Factor-alpha; Vasodilator Agents

Peroxisome proliferator-activated receptor-gamma is a nuclear receptor transcription factor that regulates cell growth, differentiation and homeostasis. PPARgamma agonists have been used to treat obesity, diabetes, cancer and inflammation and recent studies have shown the protective effects of PPARgamma agonists on experimental allergic encephalomyelitis (EAE), a Th1 cell-mediated autoimmune disease model of multiple sclerosis (MS). Our studies have further demonstrated that the PPARgamma agonists, 15d-PGJ2 and Ciglitazone, inhibit EAE through blocking IL-12 signaling leading to Th1 differentiation and the PPARgamma deficient heterozygous mice (PPARgamma+/-) or those treated with PPARgamma antagonists develop an exacerbated EAE in association with an augmented Th1 response. In this study, we show that the PPARgamma antagonists, Bisphenol A diglycidyl ether (BADGE) and 2-chloro-5-nitro-N-(4-pyridyl)benzamide (T0070907), reverse the inhibition of EAE by the PPARgamma agonists, Ciglitazone and 15-Deoxy-Delta(12,14)-Prostaglandin J2, in C57BL/6 wild-type and PPARgamma+/- mice. The reversal of EAE by BADGE and T0070907 was associated with restoration of neural antigen-induced T cell proliferation, IFNgamma production and Th1 differentiation inhibited by Ciglitazone and 15d-PGJ2. These results suggest that Ciglitazone and 15d-PGJ2 ameliorate EAE through PPARgamma-dependent mechanisms and further confirm a physiological role for PPARgamma in the regulation of CNS inflammation and demyelination in EAE.

Topics: Animals; Antigens; Benzamides; Benzhydryl Compounds; Cell Differentiation; Cell Proliferation; Demyelinating Diseases; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Epoxy Compounds; Female; Immunologic Factors; Inflammation; Interferon-gamma; Mice; Mice, Inbred C57BL; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; PPAR gamma; Prostaglandin D2; Pyridines; Th1 Cells; Thiazolidinediones

Peroxisome proliferator-activated receptor-gamma is a nuclear receptor transcription factor that regulates cell growth, differentiation and homeostasis. PPARgamma agonists have been used in the treatment of obesity, diabetes, cancer and inflammation. We and others have shown recently that PPARgamma agonists ameliorate experimental allergic encephalomyelitis (EAE), a Th1 cell-mediated autoimmune disease model of multiple sclerosis (MS). We have further shown that PPARgamma agonists inhibit EAE through blocking IL-12 signaling leading to Th1 differentiation and the PPARgamma-deficient heterozygous mice (PPARgamma(+/-)) develop an exacerbated EAE. In this study, we show that in vivo treatment (i.p.) with 100 mug PPARgamma antagonists, Bisphenol A diglycidyl ether (BADGE) or 2-Chloro-5-nitro-N-(4-pyridyl)benzamide (T0070907), on every other day from day 0 to 30, increased the severity and duration of EAE in C57BL/6 wild-type and PPARgamma(+/-) mice. The exacerbation of EAE by PPARgamma antagonists associates with an augmented neural antigen-induced T cell proliferation, IFNgamma production or Th1 differentiation. These results further suggest that PPARgamma is a critical physiological regulator of CNS inflammation and demyelination in EAE.

Topics: Animals; Benzamides; Benzhydryl Compounds; Cell Proliferation; Demyelinating Diseases; Dose-Response Relationship, Immunologic; Drug Administration Schedule; Drug Interactions; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Epoxy Compounds; Female; Glycoproteins; Inflammation; Interferon-gamma; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; PPAR gamma; Pyridines; Th1 Cells; Thymidine; Time Factors; Tritium