[Research progress in clinical application and pharmacological effect of Yiyi Fuzi Baijiang Powder].

Yiyi Fuzi Baijiang Powder(YFBP), originating from Synopsis of the Golden Chamber, is a classic prescription composed of Coicis Semen, Aconiti Lateralis Radix Praeparata, and Patriniae Herba for the treatment of abscesses and pus discharge. This article presented a systematic analysis of the clinical application of YFBP, including the indicated diseases, the number of cases, efficacy, dosage, administration methods, and compatibility with other drugs. The analysis reveals that YFBP has a wide range of clinical applications. It is commonly used, often with modifications or in combination with western medicine, for diseases in the fields of gastroente-rology, gynecology, urology, dermatology, and others. And most of the Traditional Chinese Medicine(TCM) evidence involved in these diseases are damp-heat evudence. The prescription shows rich variations in clinical administration methods, and most of which are the treatment of aqueous decoction of it. The therapeutic effect is also significant, and the total effective rate of clinical treatment is re-latively high. Additionally, this article summarized the pharmacological research on YFBP and found that it possessed various pharmacological effects, including anti-inflammatory, antioxidant, anticancer, and immune-modulating properties. Finally, correlation analysis was conducted on the main diseases, TCM types, prescription doses, pharmacological effects and action targets of YFBP, which to show the relationship between these five aspects in a visual form, reflecting the relationship between its clinical application and modern pharmacological effects. These findings provide a reference basis for further development and research on YFBP.

Receptor for advanced glycation end product-dependent activation of p38 mitogen-activated protein kinase contributes to amyloid-beta-mediated cortical synaptic dysfunction.

Soluble amyloid-beta (Abeta) peptide is likely to play a key role during early stages of Alzheimer's disease (AD) by perturbing synaptic function and cognitive processes. Receptor for advanced glycation end products (RAGE) has been identified as a receptor involved in Abeta-induced neuronal dysfunction. We investigated the role of neuronal RAGE in Abeta-induced synaptic dysfunction in the entorhinal cortex, an area of the brain important in memory processes that is affected early in AD. We found that soluble oligomeric Abeta peptide (Abeta42) blocked long-term potentiation (LTP), but did not affect long-term depression, paired-pulse facilitation, or basal synaptic transmission. In contrast, Abeta did not inhibit LTP in slices from RAGE-null mutant mice or in slices from wild-type mice treated with anti-RAGE IgG. Similarly, transgenic mice expressing a dominant-negative form of RAGE targeted to neurons showed normal LTP in the presence of Abeta, suggesting that neuronal RAGE functions as a signal transducer for Abeta-mediated LTP impairment. To investigate intracellular pathway transducing RAGE activation by Abeta, we used inhibitors of stress activated kinases. We found that inhibiting p38 mitogen-activated protein kinase (p38 MAPK), but not blocking c-Jun N-terminal kinase activation, was capable of maintaining LTP in Abeta-treated slices. Moreover, Abeta-mediated enhancement of p38 MAPK phosphorylation in cortical neurons was reduced by blocking antibodies to RAGE. Together, our results indicate that Abeta impairs LTP in the entorhinal cortex through neuronal RAGE-mediated activation of p38 MAPK.

RAGE and Alzheimer's disease: a progression factor for amyloid-beta-induced cellular perturbation?

Receptor for Advanced Glycation Endproducts (RAGE) is a multiligand member of the immunoglobulin superfamily of cell surface molecules which serves as a receptor for amyloid-beta peptide (Abeta) on neurons, microglia, astrocytes, and cells of vessel wall. Increased expression of RAGE is observed in regions of the brain affected by Alzheimer's disease (AD), and Abeta-RAGE interaction in vitro leads to cell stress with the generation of reactive oxygen species and activation of downstream signaling mechanisms including the MAP kinase pathway. RAGE-mediated activation of p38 MAP kinase in neurons causes Abeta-induced inhibition of long-term potentiation in slices of entorhinal cortex. Increased expression of RAGE in an Abeta-rich environment, using transgenic mouse models, accelerates and accentuates pathologic, biochemical, and behavioral abnormalities compared with mice overexpressing only mutant amyloid-beta protein precursor. Interception of Abeta interaction with RAGE, by infusion of soluble RAGE, decreases Abeta content and amyloid load, as well as improving learning/memory and synaptic function, in a murine transgenic model of Abeta accumulation. These data suggest that RAGE may be a therapeutic target for AD.

Abeta-dependent Inhibition of LTP in different intracortical circuits of the visual cortex: the role of RAGE.

Oligomeric amyloid-beta (Abeta) interferes with long-term potentiation (LTP) and cognitive processes, suggesting that Abeta peptides may play a role in the neuronal dysfunction which characterizes the early stages of Alzheimer's disease (AD). Multiple lines of evidence have highlighted RAGE (receptor for advanced glycation end-products) as a receptor involved in Abeta-induced neuronal and synaptic dysfunction. In the present study, we investigated the effect of oligomeric soluble Abeta1-42 on LTP elicited by the stimulation of different intracortical pathways in the mouse visual cortex. A variety of nanomolar concentrations (20-200 nM) of Abeta1-42 were able to inhibit LTP in cortical layer II-III induced by either white matter (WM-Layer II/III) or the layer II/III (horizontal pathway) stimulation, whereas the inhibition of LTP was more susceptible to Abeta1-42, which occurred at 20 nM of Abeta, when stimulating layer II-III horizontal pathway. Remarkably, cortical slices were resistant to nanomolar Abeta1-42 in the absence of RAGE (genetic deletion of RAGE) or blocking RAGE by RAGE antibody. These results indicate that nanomolar Abeta inhibits LTP expression in different neocortical circuits. Crucially, it is demonstrated that Abeta-induced reduction of LTP in different cortical pathways is mediated by RAGE.

Ovariectomy increases neuronal amyloid-beta binding alcohol dehydrogenase level in the mouse hippocampus.

Ovarian hormone decline after menopause may influence cognitive performance and increase the risk for Alzheimer's disease (AD) in women. Amyloid-beta peptide (Abeta) has been proposed to be the primary cause of AD. In this study, we examined whether ovariectomy (OVX) could affect the levels of cofactors Abeta-binding alcohol dehydrogenase (ABAD) and receptor for advanced glycation endproducts (RAGE), which have been reported to potentiate Abeta-mediated neuronal perturbation, in mouse hippocampus, correlating with estrogen and Abeta levels. Female ICR mice were randomly divided into ovariectomized or sham-operated groups, and biochemical analyses were carried out at 5 weeks after the operation. OVX for 5 weeks significantly decreased hippocampal 17beta-estradiol level, while it tended to reduce the hormone level in serum, compared with the sham-operated control. In contrast, OVX did not affect hippocampal Abeta(1-40) level, although it significantly increased serum Abeta(1-40) level. Furthermore, we demonstrated that OVX increased hippocampal ABAD level in neurons, but not astrocytes, while it did not affect RAGE level. These findings suggest that the expression of neuronal ABAD depends on estrogen level in the hippocampus and the increase in serum Abeta and hippocampal ABAD induced by ovarian hormone decline may be associated with pre-stage of memory deficit in postmenopausal women and Abeta-mediated AD pathology.

RAGE: a potential target for Abeta-mediated cellular perturbation in Alzheimer's disease.

This review focuses on the current findings regarding interaction between amyloid beta peptide (Abeta) and receptor for advanced glycation endproducts (RAGE) and its roles in the pathogenesis of Alzheimer's disease (AD). As a ubiquitously expressed cell surface receptor, RAGE mediates the effects of Abeta on microglia, blood-brain barrier (BBB) and neurons through activating different signaling pathways. Data from autopsy brain tissues, in vitro cell cultures and transgenic mouse models suggest that Abeta-RAGE interaction exaggerates neuronal stress, accumulation of Abeta, impaired learning memory, and neuroinflammation. Blockade of RAGE protects against Abeta-mediated cellular perturbation. These findings may have an important therapeutic implication for neurodegenerative disorders relevant to AD.

D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease.

Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of the nigrostriatal dopaminergic neurons accompanied by a deficit in mitochondrial respiration. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that causes dopaminergic neurodegeneration and a mitochondrial deficit reminiscent of PD. Here we show that the infusion of the ketone body d-beta-hydroxybutyrate (DbetaHB) in mice confers partial protection against dopaminergic neurodegeneration and motor deficits induced by MPTP. These effects appear to be mediated by a complex II-dependent mechanism that leads to improved mitochondrial respiration and ATP production. Because of the safety record of ketone bodies in the treatment of epilepsy and their ability to penetrate the blood-brain barrier, DbetaHB may be a novel neuroprotective therapy for PD.

Central role of RAGE-dependent neointimal expansion in arterial restenosis.

Cellular proliferation, migration, and expression of extracellular matrix proteins and MMPs contribute to neointimal formation upon vascular injury. Wild-type mice undergoing arterial endothelial denudation displayed striking upregulation of receptor for advanced glycation end products (RAGE) in the injured vessel, particularly in activated smooth muscle cells of the expanding neointima. In parallel, two of RAGE's signal transducing ligands, advanced glycation end products (AGEs) and S100/calgranulins, demonstrated increased deposition/expression in the injured vessel wall. Blockade of RAGE, employing soluble truncated receptor or antibodies, or in homozygous RAGE null mice, resulted in significantly decreased neointimal expansion after arterial injury and decreased smooth muscle cell proliferation, migration, and expression of extracellular matrix proteins. A critical role for smooth muscle cell RAGE signaling was demonstrated in mice bearing a transgene encoding a RAGE cytosolic tail-deletion mutant, specifically in smooth muscle cells, driven by the SM22alpha promoter. Upon arterial injury, neointimal expansion was strikingly suppressed compared with that observed in wild-type littermates. Taken together, these data highlight key roles for RAGE in modulating smooth muscle cell properties after injury and suggest that RAGE is a logical target for suppression of untoward neointimal expansion consequent to arterial injury.

Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response.

While the initiation of the adaptive and innate immune response is well understood, less is known about cellular mechanisms propagating inflammation. The receptor for advanced glycation end products (RAGE), a transmembrane receptor of the immunoglobulin superfamily, leads to perpetuated cell activation. Using novel animal models with defective or tissue-specific RAGE expression, we show that in these animal models RAGE does not play a role in the adaptive immune response. However, deletion of RAGE provides protection from the lethal effects of septic shock caused by cecal ligation and puncture. Such protection is reversed by reconstitution of RAGE in endothelial and hematopoietic cells. These results indicate that the innate immune response is controlled by pattern-recognition receptors not only at the initiating steps but also at the phase of perpetuation.

Amyloid-beta-induced mitochondrial dysfunction.

As an important molecule in the pathogenesis of Alzheimer's disease (AD), amyloid-beta (Abeta) interferes with multiple aspects of mitochondrial function, including energy metabolism failure, production of reactive oxygen species (ROS) and permeability transition pore formation. Recent studies have demonstrated that Abeta progressively accumulates within mitochondrial matrix, providing a direct link to mitochondrial toxicity. Abeta-binding alcohol dehydrogenase (ABAD) is localized to the mitochondrial matrix and binds to mitochondrial Abeta. Interaction of ABAD with Abeta exaggerates Abeta-mediated mitochondrial and neuronal perturbation, leading to impaired synaptic function, and dysfunctional spatial learning/memory. Thus, blockade of ABAD/Abeta interaction may be a potential therapeutic strategy for AD.

Central role of PKCbeta in neointimal expansion triggered by acute arterial injury.

We tested the hypothesis that PKCbeta contributes to vascular smooth muscle cell (SMC) migration and proliferation; processes central to the pathogenesis of restenosis consequent to vascular injury. Homozygous PKCbeta null (-/-) mice or wild-type mice fed the PKCbeta inhibitor, ruboxistaurin, displayed significantly decreased neointimal expansion in response to acute femoral artery endothelial denudation injury compared with controls. In vivo and in vitro analyses demonstrated that PKCbetaII is critically linked to SMC activation, at least in part via regulation of ERK1/2 MAP kinase and early growth response-1. These data highlight novel roles for PKCbeta in the SMC response to acute arterial injury and suggest that blockade of PKCbeta may represent a therapeutic strategy to limit restenosis.

RAGE and amyloid beta interactions: atomic force microscopy and molecular modeling.

In the AD brain, there are elevated amounts of soluble and insoluble Abeta peptides which enhance the expression of membrane bound and soluble receptor for advanced glycation end products (RAGE). The binding of soluble Abeta to soluble RAGE inhibits further aggregation of Abeta peptides, while membrane bound RAGE-Abeta interactions elicit activation of the NF-kappaB transcription factor promoting sustained chronic neuroinflammation. Atomic force microscopy observations demonstrated that the N-terminal domain of RAGE, by interacting with Abeta, is a powerful inhibitor of Abeta polymerization even at prolonged periods of incubation. Hence, the potential RAGE-Abeta structural interactions were further explored utilizing a series of computational chemistry algorithms. Our modeling suggests that a soluble dimeric RAGE assembly creates a positively charged well into which the negative charges of the N-terminal domain of dimeric Abeta dock.

Receptor for advanced glycation end products and the cardiovascular complications of diabetes and beyond: lessons from AGEing.

The presence of elevated blood glucose levels characterizes the diabetic state. Hyperglycemia may be caused by a number of underlying factors; however, the consequences of chronically elevated glucose are similar. Both the macrovasculature and microvasculature are exquisitely sensitive to the long-term effects of elevated blood glucose. Cardiovascular disease remains the leading cause of morbidity and mortality in diabetes, regardless of the underlying cause of hyperglycemia. Although other substrates, such as DNA, are susceptible to glycation, this article addresses the impact of nonenzymatic glycation on the proteome. The impact of Advanced Glycation End products (AGEs) on alteration of protein function and signal transduction mechanisms contributes to the pathogenesis of diabetes complications. This suggests that blocking the generation or molecular impact of AGEs may modulate the complications of diabetes.

Mitochondrial amyloid-beta peptide: pathogenesis or late-phase development?

Mitochondrial and metabolic dysfunction have been linked to Alzheimer's disease for some time. Key questions regarding this association concern the nature and mechanisms of mitochondrial dysfunction, and whether such changes in metabolic properties are pathogenic or secondary, with respect to neuronal degeneration. In terms of mitochondria and Alzheimer's, altered function could reflect intrinsic properties of this organelle, potentially due to mutations in mitochondrial DNA, or extrinsic changes secondary to signal transduction mechanisms activated in the cytosol. This review presents data relevant to these questions, and considers the implication of recent findings demonstrating the presence of amyloid-beta peptide in mitochondria, as well as intra-mitochondrial molecular targets with which it can interact. Regardless of the underlying mechanism(s), it is likely that mitochondrial dysfunction contributes to oxidant stress which is commonly observed in brains of patients with Alzheimer's and transgenic models of Alzheimer's-like pathology.

Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease.

Although amyloid-beta peptide (Abeta) is the neurotoxic species implicated in the pathogenesis of Alzheimer's disease (AD), mechanisms through which intracellular Abeta impairs cellular properties, resulting in neuronal dysfunction, remain to be clarified. Here we demonstrate that intracellular Abeta is present in mitochondria from brains of transgenic mice with targeted neuronal overexpression of mutant human amyloid precursor protein and AD patients. Abeta progressively accumulates in mitochondria and is associated with diminished enzymatic activity of respiratory chain complexes (III and IV) and a reduction in the rate of oxygen consumption. Importantly, mitochondria-associated Abeta, principally Abeta42, was detected as early as 4 months, before extensive extracellular Abeta deposits. Our studies delineate a new means through which Abeta potentially impairs neuronal energetics, contributing to cellular dysfunction in AD.

Mitochondrial dysfunction and Alzheimer's disease.

Mitochondrial dysfunction has been implicated in causing metabolic abnormalities in Alzheimer's disease (AD). The searches for mitochondrial DNA variants associated with AD susceptibility have generated conflicting results. The age-related accumulation of somatic mitochondrial DNA deletion has been suggested to play a pathogenic role in the development of AD. Recent studies have demonstrated that amyloid-beta peptide (Abeta) progressively accumulates in mitochndrial matrix, as demonstrated in both transgenic mice over-expressing mutant amyloid precursor protein (APP) and autopsy brain from AD patients. Abeta-mediated mitochondrial stress was evidenced by impaired oxygen consumption and decreased respiratory chain complexes III and IV activities in brains from AD patients and AD-type transgenic mouse model. Furthermore, our studies indicated that interaction of intramitochondrial Abeta with a mitochondrial enzyme, amyloid binding alcohol dehydrogenase (ABAD), inhibits its enzyme activity, enhances generation of reactive oxygen species (ROS), impairs energy metabolism, and exaggerates Abeta-induced spatial learning/memory deficits and neuropathological changes in transgenic AD-type mouse model. Interception of ABAD-Abeta interaction may be a potential therapeutic strategy for Alzheimer's disease.

Antagonism of RAGE suppresses peripheral nerve regeneration.

Axotomy of peripheral nerve triggers events that coordinate a limited inflammatory response to axonal degeneration and initiation of neurite outgrowth. Inflammatory and neurite outgrowth-promoting roles for the receptor for advanced glycation end products (RAGE) have been suggested, so we tested its role in peripheral nerve regeneration. Analysis of immunohistochemical localization of RAGE by confocal microscopy revealed that RAGE was expressed in axons and infiltrating mononuclear phagocytes upon unilateral sciatic nerve crush in mice. Administration of soluble RAGE, the extracellular ligand binding domain of RAGE, or blocking F(ab')2 fragments of antibodies raised to either RAGE or its ligands, S100/calgranulins or amphoterin, reduced functional recovery as assessed by motor and sensory nerve conduction velocities and sciatic functional index and reduced regeneration, as assessed by myelinated fiber density after acute crush of the sciatic nerve. In parallel, in mice subjected to RAGE blockade, decreased numbers of mononuclear phagocytes infiltrated the distal nerve segments after crush. These findings provide the first evidence of an innate function of the ligand/RAGE axis and suggest that RAGE plays an important role in regeneration of the peripheral nervous system.

RAGE modulates peripheral nerve regeneration via recruitment of both inflammatory and axonal outgrowth pathways.

Axotomy of peripheral nerve stimulates events in multiple cell types that initiate a limited inflammatory response to axonal degeneration and simultaneous outgrowth of neurites into the distal segments after injury. We found that pharmacological blockade of RAGE impaired peripheral nerve regeneration in mice subjected to RAGE blockade and acute crush of the sciatic nerve. As our studies revealed that RAGE was expressed in axons and in infiltrating mononuclear phagocytes upon injury, we tested the role of RAGE in these distinct cell types on nerve regeneration. Transgenic mice expressing signal transduction-deficient RAGE in mononuclear phagocytes or peripheral neurons were generated and subjected to unilateral crush injury to the sciatic nerve. Transgenic mice displayed decreased functional and morphological recovery compared with littermate controls, as assessed by motor and sensory conduction velocities; and myelinated fiber density. In double transgenic mice expressing signal transduction deficient RAGE in both mononuclear phagocytes and peripheral neurons, regeneration was even further impaired, suggesting the critical interplay between RAGE-modulated inflammation and neurite outgrowth in nerve repair. These findings suggest that RAGE signaling in inflammatory cells and peripheral neurons plays an important role in plasticity of the peripheral nervous system.

Receptor for advanced glycation endproducts: a multiligand receptor magnifying cell stress in diverse pathologic settings.

Receptor for Advanced Glycation Endproducts (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules capable of interacting with a broad spectrum of ligands, including advanced glycation endproducts (AGEs), amyloid fibrils, S100/calgranulins and amphoterin. The biology of RAGE is dictated by the accumulation of these ligands at pathologic sites, leading to upregulation of the receptor and sustained RAGE-dependent cell activation eventuating in cellular dysfunction. Although RAGE is not central to the initial pathogenesis of disorders in which it ultimately appears to be involved, such as diabetes, amyloidoses, inflammatory conditions and tumors (each of these conditions leading to accumulation of RAGE ligands), the receptor functions as a progression factor driving cellular dysfunction and exaggerating the host response towards tissue destruction, rather than restitution of homeostasis. These observations suggest that RAGE might represent a therapeutic target in a diverse group of seemingly unrelated disorders linked only by a multiligand receptor with an unusually wide and diverse repertoire of ligands, namely, RAGE.

Receptor for advanced glycation endproducts (RAGE) and the complications of diabetes.

Receptor for Advanced Glycation Endproducts (RAGE) is a multiligand member of the immunoglobulin superfamily of cell surface molecules with a diverse repertoire of ligands. These ligands include products of nonenzymatic glycation, the Advanced Glycation Endproducts (AGEs, enriched in the diabetic milieu), members of the S100/calgranulin family of proinflammatory mediators, beta-sheet fibrillar structures (characteristic of amyloid) and amphoterin (present at high levels in the tumor bed). Ligation of RAGE by its ligands upregulates expression of the receptor and triggers an ascending spiral of cellular perturbation due to sustained RAGE-mediated cellular activation. For example, in the setting of diabetes, a vascular environment rich in AGEs and S100/calgranulins accelerates atherogenesis in murine models, and this can be blocked by intercepting the interaction of ligands with RAGE. While RAGE is certainly not the cause of diabetes, it functions as a progression factor driving cellular dysfunction underlying the development of diabetic complications as the microenvironment becomes enriched in its ligands. Though further studies will be required to determine the importance of RAGE-mediated cellular activation to human chronic diseases, it represents a novel receptor-ligand system potentially impacting on a range of pathophysiologic conditions.