Suppression of inducible cyclooxygenase and nitric oxide synthase through activation of peroxisome proliferator-activated receptor-γ by flavonoids in mouse macrophages

AbstractPeroxisome proliferator-activated receptor (PPAR)γ transcription factor has been implicated in anti-inflammatory response. Of the compounds tested, apigenin, chrysin, and kaempferol significantly stimulated PPARγ transcriptional activity in a transient reporter assay. In addition, these three flavonoids strongly enhanced the inhibition of inducible cyclooxygenase and inducible nitric oxide synthase promoter activities in lipopolysaccharide-activated macrophages which contain the PPARγ expression plasmids. However, these three flavonoids exhibited weak PPARγ agonist activities in an in vitro competitive binding assay. Limited protease digestion of PPARγ suggested these three flavonoids produced a conformational change in PPARγ and the conformation differs in the receptor bound to BRL49653 versus these three flavonoids. These results suggested that these three flavonoids might act as allosteric effectors and were able to bind to PPARγ and activate it, but its binding site might be different from the natural ligand BRL49653

Elevation of hilar mossy cell activity suppresses hippocampal excitability and avoidance behavior

Modulation of hippocampal dentate gyrus (DG) excitability regulates anxiety. In the DG, glutamatergic mossy cells (MCs) receive the excitatory drive from principal granule cells (GCs) and mediate the feedback excitation and inhibition of GCs. However, the circuit mechanism by which MCs regulate anxiety-related information routing through hippocampal circuits remains unclear. Moreover, the correlation between MC activity and anxiety states is unclear. In this study, we first demonstrate, by means of calcium fiber photometry, that MC activity in the ventral hippocampus (vHPC) of mice increases while they explore anxiogenic environments. Next, juxtacellular recordings reveal that optogenetic activation of MCs preferentially recruits GABAergic neurons, thereby suppressing GCs and ventral CA1 neurons. Finally, chemogenetic excitation of MCs in the vHPC reduces avoidance behaviors in both healthy and anxious mice. These results not only indicate an anxiolytic role of MCs but also suggest that MCs may be a potential therapeutic target for anxiety disorders

Association Between Platelet Count and Components of Metabolic Syndrome in Geriatric Taiwanese Women

SummaryBackgroundThe growing elderly population in Taiwan, as in many other countries, has resulted in increased importance of the metabolic syndrome (MetS). Although it has been reported in different age groups, the relationship between platelets and MetS remains unknown in geriatric patients.Patients and MethodsWe enrolled 1460 women >65 years old. Women with a known history of diabetes, hyperlipidemia or hypertension or those taking medication for these conditions were all excluded. The women were further divided into quartiles arbitrarily according to platelet count (PC) (PC1–PC4, lowest to highest accordingly).ResultsAmong the MetS components, body mass index (BMI), total cholesterol, low-density lipoprotein cholesterol (LDL-C) and log transformation triglyceride (Log TG) were all significantly higher in the PC4 group (p < 0.05), and they were also positively correlated with PC. However, in multiple regression, BMI became nonsignificant. Both LDL-C and Log TG were the only two factors that remained positively and independently correlated with PC. Compared to PC1, all the other three groups had significantly higher odds ratios for having MetS (2.013, 1.473–2.751; 1.486, 1.081–2.042; 1.537, 1.117–2.114; odds ratios and 95% confidence intervals for PC4, PC3 and PC2, respectively).ConclusionElderly women with MetS had higher PC. Among the five components, TG was positively correlated with PC. There was a positive correlation between PC and LDL-C but not high-density lipoprotein cholesterol. The importance of both lipids might be re-evaluated in the future in older women

Epigenetic Repression of RARRES1 Is Mediated by Methylation of a Proximal Promoter and a Loss of CTCF Binding

The cis-acting promoter element responsible for epigenetic silencing of retinoic acid receptor responder 1 (RARRES1) by methylation is unclear. Likewise, how aberrant methylation interplays effectors and thus affects breast neoplastic features remains largely unknown.We first compared methylation occurring at the sequences (-664~+420) flanking the RARRES1 promoter in primary breast carcinomas to that in adjacent benign tissues. Surprisingly, tumor cores displayed significantly elevated methylation occurring solely at the upstream region (-664~-86), while the downstream element (-85~+420) proximal to the transcriptional start site (+1) remained largely unchanged. Yet, hypermethylation at the former did not result in appreciable silencing effect. In contrast, the proximal sequence displayed full promoter activity and methylation of which remarkably silenced RARRES1 transcription. This phenomenon was recapitulated in breast cancer cell lines, in which methylation at the proximal region strikingly coincided with downregulation. We also discovered that CTCF occupancy was enriched at the unmethylayed promoter bound with transcription-active histone markings. Furthermore, knocking-down CTCF expression hampered RARRES1 expression, suggesting CTCF positively regulated RARRES1 transcription presumably by binding to unmethylated promoter poised at transcription-ready state. Moreover, RARRES1 restoration not only impeded cell invasion but also promoted death induced by chemotherapeutic agents, denoting its tumor suppressive effect. Its role of attenuating invasion agreed with data generated from clinical specimens revealing that RARRES1 was generally downregulated in metastatic lymph nodes compared to the tumor cores.This report delineated silencing of RARRES1 by hypermethylation is occurring at a proximal promoter element and is associated with a loss of binding to CTCF, an activator for RARRES1 expression. We also revealed the tumor suppressive roles exerted by RARRES1 in part by promoting breast epithelial cell death and by impeding cell invasion that is an important property for metastatic spread

Effects of Combinatorial Treatment with Pituitary Adenylate Cyclase Activating Peptide and Human Mesenchymal Stem Cells on Spinal Cord Tissue Repair

The aim of this study is to understand if human mesenchymal stem cells (hMSCs) and neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) have synergistic protective effect that promotes functional recovery in rats with severe spinal cord injury (SCI). To evaluate the effect of delayed combinatorial therapy of PACAP and hMSCs on spinal cord tissue repair, we used the immortalized hMSCs that retain their potential of neuronal differentiation under the stimulation of neurogenic factors and possess the properties for the production of several growth factors beneficial for neural cell survival. The results indicated that delayed treatment with PACAP and hMSCs at day 7 post SCI increased the remaining neuronal fibers in the injured spinal cord, leading to better locomotor functional recovery in SCI rats when compared to treatment only with PACAP or hMSCs. Western blotting also showed that the levels of antioxidant enzymes, Mn-superoxide dismutase (MnSOD) and peroxiredoxin-1/6 (Prx-1 and Prx-6), were increased at the lesion center 1 week after the delayed treatment with the combinatorial therapy when compared to that observed in the vehicle-treated control. Furthermore, in vitro studies showed that co-culture with hMSCs in the presence of PACAP not only increased a subpopulation of microglia expressing galectin-3, but also enhanced the ability of astrocytes to uptake extracellular glutamate. In summary, our in vivo and in vitro studies reveal that delayed transplantation of hMSCs combined with PACAP provides trophic molecules to promote neuronal cell survival, which also foster beneficial microenvironment for endogenous glia to increase their neuroprotective effect on the repair of injured spinal cord tissue