Pertactin (PRN) is an autotransporter protein produced by all members of the Bordetella bronchiseptica cluster, which includes B. pertussis, B. parapertussis, and B. bronchiseptica. It is a primary component of acellular pertussis vaccines, and anti-PRN antibody titers correlate with protection. In vitro studies have suggested that PRN functions as an adhesin and that an RGD motif located in the center of the passenger domain is important for this function. Two regions of PRN that contain sequence repeats (region 1 [R1] and R2) show polymorphisms among strains and have been implicated in vaccine-driven evolution. We investigated the role of PRN in pathogenesis using B. bronchiseptica and natural-host animal models. A ⌬prn mutant did not differ from wild-type B. bronchiseptica in its ability to adhere to epithelial and macrophage-like cells in vitro or to establish respiratory infection in rats but was cleared much faster than wild-type bacteria in a mouse lung inflammation model. Unlike wild-type B. bronchiseptica, the ⌬prn mutant was unable to cause a lethal infection in SCID-Bg mice, but, like wild-type bacteria, it was lethal for neutropenic mice. These results suggest that PRN plays a critical role in allowing Bordetella to resist neutrophil-mediated clearance. Mutants producing PRN proteins in which the RGD motif was replaced with RGE or in which R1 and R2 were deleted were indistinguishable from wild-type bacteria in all assays, suggesting that these sequences do not contribute to PRN function.Bordetella pertussis and Bordetella bronchiseptica cause respiratory infections in mammals. These two closely related bacterial subspecies display a high level of biochemical and genomic similarity and produce a similar set of virulence factors that are regulated at the transcriptional level by a highly conserved two-component signaling system called BvgAS (8,46,50,65). However, they differ in symptomatic manifestations and host ranges: B. pertussis infects only humans and causes the acute disease whooping cough, while B. bronchiseptica has been isolated from nearly all mammals and typically causes chronic asymptomatic infections (41, 52). Nevertheless, some crucial factors are functionally interchangeable, such as filamentous hemagglutinin (FHA) (30) and the BvgAS signaling system (40), suggesting that studying B. bronchiseptica can reveal insights into the function of B. pertussis factors and vice versa. B. bronchiseptica and its natural-host animal models are therefore valuable tools for exploring molecular mechanisms of Bordetella pathogenesis.Pertactin (PRN) is a putative Bordetella virulence factor belonging to the autotransporter (AT) family. It was discovered as a surface-localized immunogen of B. bronchiseptica in 1985 (49) and was found to have highly conserved homologs in B. pertussis and B. parapertussis shortly thereafter (5, 38). Many subsequent studies focused on the immunogenic and protective properties of PRN, leading to its inclusion in acellular pertussis vaccines (34, 48), and efficacy trials have...
We recently demonstrated that activation of tyrosine receptor kinase B (TrkB) by 7, 8-dihydroxyflavone (7,, the selective TrkB agonist, increased surface alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors (AMPARs) AMPA receptor subunit GluR1 (GluA1) subunit expression at the synapses of Fragile X Syndrome mutant mice. This present study investigated the effects of 7, 8-DHF on both memory function and synapse structure in relation to the synapse protein level of AMPARs in the Tg2576 Alzheimer's disease (AD) mouse model. The study found that chronic oral administration of 7, 8-DHF significantly improved spatial memory and minimized dendrite loss in the hippocampus of Tg2576 mice. A key feature of 7, 8-DHF action was the increased expression of both GluA1 and GluA2 at synapses. Interestingly, 7, 8-DHF had no effect on the attenuation of amyloid precursor protein or Ab exhibiting in the Tg2576 AD brains, yet it activated the phosphorylation of TrkB receptors and its downstream signals including CaMKII, Akt, Erk1/2, and cAMP-response element-binding protein. Importantly, cyclotraxin B (a TrkB inhibitor), U0126 (a Ras-ERK pathway inhibitor), Wortmannin (an Akt phosphorylation inhibitor), and KN-93 (a CaMKII inhibitor) counteracted the enhanced expression and phosphorylation of AMPAR subunits induced by 7, 8-DHF. Collectively, our results demonstrated that 7, 8-DHF acted on TrkB and resolved learning and memory impairments in the absence of reduced amyloid in amyloid precursor protein transgenic mice partially through improved synaptic structure and enhanced synaptic AMPARs. The findings suggest that the application of 7, 8-DHF may be a promising new approach to improve cognitive abilities in AD.
Sig-1R activation showed an attenuation in the ischaemia/reperfusion model and the activation of Sig-1R increased the expression of BDNF, possibly through the NR2A-CaMKIV-TORC1 pathway, and Sig-1R agonists might function as neuroprotectant agents in vascular dementia.
Zeaxanthin, a type of carotenoid, has been proven to exhibit anti-lipogenesis effect; however, the detailed mechanism of this effect is less known. Herein, we evaluated the effects of zeaxanthin on the inhibition of adipogenesis in 3T3-L1 adipocytes and obesity in high-fat diet fed C57BL/6J mice. Zeaxanthin significantly decreased the intracellular lipid content in a dose-dependent manner (5-15 μM) in adipocytes without causing cytotoxicity. In high-fat-diet-induced obese mice, oral administration of 20 mg kg zeaxanthin attenuated the progression of obesity and improved dyslipidemia. It exhibits an anti-adipogenic effect via down-regulating the transcriptional factors and adipocyte-specific genes involved in adipogenesis, both in vitro and in vivo. Furthermore, zeaxanthin treatment reversed the MDI (0.5 mM 3-isobutyl-1-methylxanthine, 1.0 μM dexamethasone, and 1.0 μg mL insulin) and HFD (high-fat diet)-induced inhibition of AMPK phosphorylation in adipocytes and epididymal adipose tissues, respectively, thereby modulating the energy metabolism. These results indicated that zeaxanthin plays anti-adipogenic and anti-obesity roles by inducing AMPK activation, inhibiting lipogenesis, and decreasing intracellular lipid content, adipocyte size, and adipose weight.
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