The present studies were undertaken to determine whether neuronal subsets in normal brains constitutively express functionally competent C5a receptors. In situ hybridization studies coupled with immunohistochemical approaches revealed that most neurons in the hippocampal formation, many pyramidal cortical neurons, and cerebellar Purkinje neurons in normal human and murine brains constitutively express C5a receptors. Neuronal C5a receptors bound C5a-coated fluorescent microspheres, and primary rodent hippocampal neurons responded to C5a with increased calcium fluxes via a pertussis-sensitive, presumably Gi-coupled protein. Additional studies with human neuroblastoma cells conducted to address the functional role of C5a receptors revealed that C5a triggered rapid activation of protein kinase C and activation and nuclear translocation of the NF-κB transcription factor. In addition, C5a was found to be mitogenic for undifferentiated human neuroblastoma cells, a novel action for the C5aR. In contrast, C5a protected terminally differentiated human neuroblastoma cells from toxicity mediated by the amyloid Aβ peptide. Thus, normal rodent hippocampal neurons as well as undifferentiated and differentiated human neuroblastoma cells express functional C5a receptors. These results have implications for understanding the role of neuronal C5aR receptors in normal neuronal development, neuronal homeostasis, and neuroinflammatory conditions such as Alzheimer’s disease.
Ginseng, a well-known herb, is often used in combination with anticancer drugs to enhance chemotherapy. Its wide usage as well as many documentations are often cited to support its clinical benefit of such combination therapy. However the literature based on objective evidence to make such recommendation is still lacking. The present review critically evaluated relevant studies reported in English and Chinese literature on such combination. Based on our review, we found good evidence from in vitro and in vivo animal studies showing enhanced antitumor effect when ginseng is used in combination with some anticancer drugs. However, there is insufficient clinical evidence of such benefit as very few clinical studies are available. Future research should focus on clinically relevant studies of such combination to validate the utility of ginseng in cancer.
Several lines of evidence now suggest that aggregation of soluble amyloid beta peptide (A beta) into a cross beta sheet configuration may be an important factor in mediating potential neurotoxicity of A beta. Synthetic A beta has been shown to self aggregate in vitro. Here, we demonstrate that coincubation of freshly solubilized A beta with C1q, a complement component known to bind A beta in vitro and to colocalize with A beta in vivo, results in as much as a 7-fold enhancement of A beta aggregation, as well as a 2-4-fold enhancement of beta structure within aggregates. The addition of C1q to preformed A beta aggregates also results in significantly increased resistance to aggregate resolubilization.
Thyroid hormone negatively regulates the amyloid-beta precursor protein (APP) gene in thyroid hormone receptor (TR)-transfected neuroblastoma cells. A negative thyroid hormone response element (nTRE) that mediates this regulation has been identified in the first exon of the APP gene. We demonstrate in an in vivo system that expression of APP mRNA, APP protein, and APP secretase cleavage products in mouse brain is influenced by thyroid status. Adult female mice were made hyperthyroid or hypothyroid for 3 weeks and compared to euthyroid mice. APP gene product expression was increased in hypothyroid mouse brain and reduced in hyperthyroid mouse brain, when compared to euthyroid controls. We observed similar effects of thyroid hormone on endogenous APP gene expression in human neuroblastoma cells. The incidence of hypothyroidism increases with age, and localized hypothyroidism of central nervous system has been reported in some patients with Alzheimer's disease (AD). Reduced action of thyroid hormone on the APP gene may contribute to AD pathology by increasing APP expression and the levels of processed APP products. These findings may be an underlying mechanism contributing to the association of hypothyroidism with AD in the elderly, as well as identifying a potential therapeutic target. Pharmacologic supplementation of thyroid hormone, or its analogs, may reduce APP gene expression and beta amyloid peptide accumulation.
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