Month: September 2020

However, despite notable trends, we did not detect any significant differences in the development of either acute OVA or HDM mediated allergic lung disease in the Nlrp122/2 mice compared to the wild type animals. A number of explanations are possible that may explain our inability to observe significant differences in these lung disease models. The most obvious explanation is that NLRP12 does not have a discernable effect on the pathogenesis of allergic lung disease in the mouse or NLRP12 may function in either a temporal, situational or stimuli specific manner that was not captured in the data generated by the lung inflammation models discussed here. NLRP12 activity may be restricted to a specific cell type or tissue that may contribute to the development of Ibrutinib contact hypersensitivity and atopic dermititis, while not significantly contributing to lung inflammation. This hypothesis is similar to in vivo data published for TLR2, which has been shown to play a vital role in the host immune response during contact hypersensitivity. Similar to NLRP12, TLR2 has been shown to be an essential mediator of the immune response to oxazolone in an allergic contact dermatitis model. However, unlike the findings for OX, Tlr22/2 and wild type mice demonstrated similar levels of inflammation in models involving epicutaneous sensitization with OVA. Other in vivo studies have suggested that TLR2 functions as a negative regulator of allergic airway inflammation following either DMA exposure or acute OVA challenges. In the context of NLRP12, several studies have associated functional studies with gene expression data in humans and rodents. These studies have shown that NLRP12 is differentially expressed between species and transiently increased during various models of lung inflammation. Together, these data support a scenario where NLRP12 does not influence the development of allergic airway inflammation. However, as illustrated by the contact hypersensitivity phenotypes previously reported, it is likely that NLRP12 has a more dramatic role in other models of inflammatory diseases through a temporal and tissue specific mechanism. A second hypothesis for the failure to observe an in vivo phenotype in the lung inflammation models in the Nlrp122/2 mice suggests that the models and analyses we utilized in this study are too broad to effectively discern mild or moderate phenotypes. Indeed, the OVA model described here induced a vigorous Th2 mediated immune response. One valid criticism of this model is that the acute nature and robust inflammation tends to obscure the contribution of several important mediators to the pathogenesis of the disease. To avoid this issue, studies have suggested utilizing chronic models, such as long term OVA exposure or DMA exposure, to assess allergic airway inflammation. Thus, in an effort to address this concern, we also utilized DMA to induce airway inflammation and did not observe any discernable phenotypic differences in the Nlrp122/2 mice. However, we cannot rule out the possibility that higher resolution in vivo models or analysis may reveal a more significant contribution for NLRP12 in mediating subtle aspects of inflammation in the lung. While this study reports that NLRP12 does not affect detectable difference in allergic lung inflammation.

Hippocampal CA3 atrophy, on the other hand, is reversible MLN4924 within the same period of post-stress recovery. Interestingly, the unique temporal features of stress-induced changes in the BLA are not limited to chronic stress alone. A much shorter duration of the same stress, such as a single 2 h episode of immobilization, that fails to affect spine density or dendritic arborization one day later, leads to a significant increase in spine density ten days later. Together, these studies have helped identify novel features of stress-induced plasticity in the amygdala that are quite distinct from those observed in the hippocampus. Although little is known about molecular mechanisms underlying these contrasting effects of stress, previous studies in the hippocampus provide valuable leads. For example, the same chronic stress that elicits hippocampal dendritic atrophy also reduces levels of the neurotrophin brain-derived neurotrophic factor in the rodent hippocampus. Conversely, chronic administration of antidepressants prevents stress-induced decrease in BDNF levels and dendritic atrophy in the hippocampus. Together these and other findings have contributed to the “neurotrophic hypothesis”, which states that symptoms associated with stress-related disorders such as depression are a result of decreased neurotrophic support, and conversely, that increasing neurotrophic support would lead to the correction of these symptoms. This hypothesis has received support from several studies including a report that direct BDNF infusion into the rodent hippocampus produces antidepressant effects. Also, transgenic overexpression of the neurotrophin BDNF has antidepressant effects and prevents chronic stressinduced hippocampal atrophy in mice. Interestingly, in the same transgenic mice, overexpression of BDNF also causes spinogenesis in the BLA. Moreover, BLA spinogenesis is also triggered by chronic stress in control mice but is occluded by BDNF overexpression, thereby suggesting a role for BDNF signaling in stress-induced plasticity in the amygdala. These findings, in turn, are consistent with the significant body of evidence establishing a role for BDNF as a potent regulator of morphological plasticity of dendrites in various brain regions. Therefore, in the present study we test the prediction that if BDNF plays a key role in stress-induced structural plasticity across both hippocampus and amygdala, then the divergent effects of stress should also be manifested as differential patterns of BDNF expression in these two brain areas. This study explored two key facets of stress-induced modulation of BDNF expression in the hippocampus and amygdala – one in terms of region-specific differences, and the other in the temporal domain. Because BDNF regulates dendritic architecture and spines, both major targets of stress-induced structural plasticity, we hypothesized that the levels of BDNF expression would reflect the divergent effects of stress on the hippocampus and amygdala. To test this hypothesis, we used two very different paradigms of immobilization stress – an acute paradigm involving a single 2 h session and a chronic version wherein the same 2-hour stress was repeated for 10 consecutive days. First, we tested whether chronic stress elicits changes in BDNF protein levels that parallel the contrasting patterns of dendritic remodeling observed previously in the amygdala and hippocampus.

Our data suggest that both loci PFI0025c and PFD0070c may also be regulated epigenetically at the studied time points in sporozoites and gametocytes. Our experiments did not show any connection of rif transcription and cytoadherence patterns, since the transcripts found in the re-selected parasite line showed transcripts differing from those identified in our previous study. This view is also supported by a TH-302 recently published microarray-based analysis. We could also not identify any connection between the genomic context, transcribed var genes and rif transcription, at least in the samples from the experiment shown in Figure 2. The dominantly transcribed var gene is distant from transcribed rif genes and no specific pattern of transcript quantity and genomic context was identified. Lopez-Rubio and colleagues showed that var genes that are transcribed after the following reinvasion are marked with H3K4me2 in schizonts when var transcription has ceased.

In our experiments, loci with low or undetectable transcription showed few modification of this type, however, little modification seemed not predictive for absence of transcriptional activity in the same cycle. Even with a very low level of the “poised mark” modification, transcription may occur. We propose that for stronger “poised” modifications in trophozoites, higher transcript quantities are to be expected in schizonts in the same cycle, also coinciding with a higher H3K9 acetylation or low H3K9 trimethylation modification in schizonts. A significant argument against a general rule for the link of active transcription/acetylation at H3K9 and dimethylation at H3K4 is seen at the locus PFD0070c, indicating that other factors or histone modifications may have decisive influence on the transcriptional status of a locus, including perhaps the recently discovered modifications at H4 and H4K8. In any case, more biological replicates would be necessary to clarify the role of the H3K4me2 and possibly the modifications at H4 in the “poised” status of rif genes. Upon its first publication in 2007, the poised mark was only tested for the var2csa locus. During the blood stage replication of P. falciparum, its immune evasion through antigenic variation. Although a number of transcriptional regulators were annotated in the P. falciparum and some of them were already localized to the nucleus or even shown to associate to silenced chromatin such as HP1, PfKMT1, or to var promoter elements, the exact events that orchestrate the dynamics of antigenic variation and allelic exclusion are not yet resolved. Our data demonstrate for the first time that active rif loci are marked not only with the H3K9 acetylation mark, but also the poised mark H3K4me2.

Also, we showed that silenced loci may either associate to H3K9me3 modified loci or unmodified loci, at least in the stages that were looked at. It is possible that unmodified H3K9 residues are associated to an almost permanently silent locus while H3K9me3 loci were recently switched off or may become switched on. Further, the turnover dynamics are probably faster than for var loci. Additional studies targeting the exact chromatin modifications at other histone residues or at H4 comparing active or silent variant gene loci are clearly necessary in order to elucidate the mechanics of recruiting transcription factors to the respective sites.

mTOR is not only a downstream target of insulin signaling, but also serves as an effector of the Wnt signaling pathway. Thus, the repressive effect of curcumin on mTOR further supports the notion that curcumin might repress Wnt activity in cancer cells. In the current study, we show that HFD induced hepatic expression of phosphorylated S6K1, a downstream target of mTOR. Curcumin consumption suppressed S6K1 phosphorylation. The importance of Wnt signaling pathway in metabolic homeostasis has been broadly recognized recently. Wnt10b is abundantly expressed in mesenchymal precursor cells. Wnt10b mediated Wnt activation stimulates the expression of osetogenic genes at the expense of adipogenic genes. Furthermore, ectopic expression of Wnt10b in transgenic mice impairs the development of the adipose tissue and these mice are resistant to HFD induced obesity. Very recently, a study demonstrated that in the 3T3-L1 cell model, the repression of adipogenic differentiation was accompanied by Wnt/b-cat activation. The authors found that during adipocyte differentiation, curcumin reduced the expression of the components of the destructive complex that are responsible for b-cat degradation, including CK1a, GSK-3b and Axin, accompanied by increased expression of total b-cat, Wnt10b, the Wnt pathway receptor Fz2, the coreceptor LRP5, as well as the Wnt targets c-Myc and cyclin D1. This study provides a potential novel molecular mechanism to explain the repressive effect of curcumin on adipogenesis. In contrast, we found in the current study that the stimulatory effect of curcumin on Wnt signaling does not occur in mature adipocytes. How this plant dietary compound exerts opposite effects on Wnt signaling pathway in pre-adipocytes versus mature adipocytes deserves further investigations. Nevertheless, we have previously noted cell-type specific effects of Wnt and/or insulin signaling. For example, both insulin and lithium chloride, the latter mimics Wnt activation, stimulate proglucagon gene transcription in gut endocrine L cells, but repress the same gcg gene in pancreatic islets. Furthermore, we found the stimulatory effect of insulin on b-cat Ser675 phosphorylation in the gut, but not in adipocytes. Finally, one study has shown that in skeletal muscle cells, Wnt activation increases insulin sensitivity through reciprocal Z-VAD-FMK Caspase inhibitor regulation of Wnt10b and SREBP-1c, while another group showed that Wnt activation in mature adipocytes leads to adipocyte dedifferentiation and insulin resistance. In this study, curcumin blocked the effect of HFD on macrophage infiltration in adipose tissue, associated with the repression of NF-kB level and JNK activity, the improvement of insulin stimulated PKB phosphorylation in adipose tissue and liver, as well as glucose disposal. These observations are consistent with current concepts that the activation of endogenous antioxidative system and the repression of inflammatory signaling in adipocytes improve insulin resistance. Whether there are additional mechanisms underlying the improvement of insulin signaling by curcumin supplementation deserves further investigations. For example, mTOR is involved in the development of insulin resistance via a negative feedback loop, i.e. the inhibition of IRS-1 tyrosine phosphorylation.

The epidemic of obesity and its related insulin resistance have contributed significantly to the incidence of diabetes. It is now generally Masitinib accepted that both obesity and T2D are associated with low grade chronic inflammation and that adipose tissue appears to be the first organ that is affected. The development of inflammation and oxidative stress in adipose tissue leads to insulin resistance. Furthermore, accelerated hepatic lipogenic gene expression and reduced liver fat export may also contribute to the development of obesity. Many naturally occurring dietary polyphenols possess antioxidant and anti-inflammatory properties. This could be achieved by modulating an inflammatory or oxidative signaling pathway, including NF-kB, Nrf2, and/or MAPK-dependent signaling pathways. Certain dietary polyphenols, such as curcumin, also possess the anti-carcinogenic effects. One potential mechanism of curcumin to repress tumorigenesis has been suggested to be the inhibition of Wnt signaling, an essential pathway for embryogenesis and cell proliferation. Curcumin, a low-molecular-weight polyphenol derived from the herbal remedy and dietary spice turmeric, was found to prevent obesity and diabetes in mouse models. Mechanistically, curcumin may exert its beneficial effects via reducing insulin and leptin resistance, attenuating inflammatory cytokine expression, accelerating fatty acid oxidation, as well as increasing antioxidant enzyme expression. In addition, curcumin could also function as an inhibitor of p300 histone acetyltransferase, a potential molecular mechanism for cancer prevention and cardiovascular improvement. The Wnt/b-catenin signaling pathway was initially discovered in colon cancer and in developmental studies of Drosophila and frogs. The role of the canonical Wnt signaling pathway in metabolic homeostasis has recently received increasing attention. Activation of Wnt pathway increases cellular and nuclear b-cat level, which represses adipogenesis, while the inhibition of Wnt signaling is required for PPARc induction and preadipocyte differentiation. A very recent study showed that curcumin stimulates Wnt/b-cat signaling in 3T3-L1 preadipocytes and hence suppresses adipogenic differentiation. It is contradictory with other reports in two ways. First, numerous studies have indicated that curcumin exerts its anti-cancer effect via repressing Wnt signaling. Second, Wnt activation in mature adipocytes was shown to induce insulin resistance, while curcumin is known to attenuate insulin resistance. In this study we have examined the effect of dietary curcumin in a HFD mouse model in which the development of obesity and insulin insensitivity was relatively slow due to the administration of 45% rather than 60% of calories from fat. In this mouse model as well as in primary rat adipocytes, we did not observe stimulation of curcumin on Wnt pathway components or Wnt target gene expression. However, curcumin attenuated lipogenic gene expression in hepatocytes, and blocked the effect of HFD on the inflammatory response in the adipose tissue, associated with decreased weight/fat gain, and the maintenance of normal glucose tolerance and insulin sensitivity.