The natriuretic peptide receptors are three homologous cell surface proteins, each with a single transmembrane domain. The atrial natriuretic peptide receptor type A (ANPRA) and the homologous receptor type B (ANPRB) are both membrane guanylyl cyclases that synthesize cyclic GMP as an intracellular second messenger. The third receptor in this family, the atrial natriuretic peptide receptor type C (ANPRC), is not coupled to cyclic GMP production. We report on the distribution of the ANPRA, ANPRB, and ANPRC mRNAs in rhesus monkey tissues assayed by in situ hybridization. ANPRA mRNA is most abundantly expressed in the kidney glomerulus, adrenal zona glomerulosa, pituitary, cerebellum, and endocardial endothelial cells of the right and left atrium and right ventricle. In contrast, abundant ANPRB expression appears to be confined to the adrenal medulla, pituitary, and cerebellum. ANPRC mRNA appeared to be expressed very differently than ANPRA and ANPRB. In the heart, ANPRC mRNA is expressed most prominently in endocardial endothelial cells of all four chambers but is also found throughout the myocardium only in the right atrium. These data identify major sites of natriuretic peptide receptor mRNA expression and suggest that there may be prominent cell type-specific differential distribution of these receptors in central and peripheral targets for the natriuretic peptides.Natriuretic peptides are a family of homologous polypeptide hormones that function in both central and peripheral control of fluid volume regulation. As such, these hormones are in dynamic mutual antagonism to the hypertensive renin/angiotensin II/aldosterone system. Of the three known hormones in this family, atrial natriuretic peptide (ANP) (reviewed in reference 13), brain natriuretic peptide (BNP) (37), and type C natriuretic peptide (CNP) (38), ANP has been the most intensely studied, with documented effects on the kidney, adrenals, vasculature, pituitary, and brain. Both ANP and the more recently described BNP are primarily cardiac hormones (26) that are released by the heart in its role as an endocrine organ, regulating fluid and electrolyte homeostasis. A variety of extra-atrial sites of ANP expression have been described (13), suggesting a localized paracrine role for ANP in some tissues. In contrast, the expression of the newly discovered hormone CNP appears to be limited to the nervous system (15).Three members of the natriuretic peptide receptor family have been identified by molecular cloning. The atrial natriuretic peptide receptor type A (ANPRA) (20), also referred to as GC-A (5), is a membrane form of guanylyl cyclase that directly synthesizes the intracellular second messenger cyclic GMP (cGMP) in response to extracellular hormone binding. This receptor responds to stimulation by ANP and BNP (3,5,20,32) but is not a hormonal target for CNP stimulation (1Sa). A second receptor/guanylyl cyclase homologous to ANPRA, referred to as ANPRB (3) for cGMP stimulation (15a). The third receptor in this family, termed ANPRC (10,19), is homolog...
The studies described here examine the involvement of the fibrinolytic cascade and its endogenous inhibitors in the regulation of activity of matrix metalloproteinases and cartilage degradation related to non-inflammatory joint disease, like osteoarthritis. An interleukin-1-induced model of degradation using [35S]-labeled bovine and human articular cartilage explants was utilized. One goal of these studies was to compare the responses of bovine and human articular cartilage. Degradation was not inhibited by alpha 1-PI, PAI-1, alpha 2-macroglobulin, alpha 2-antiplasmin or TIMP-2, when IL-1 alone was added. Addition of human plasminogen to bovine explants, at concentrations found in human synovial fluid, increased degradation by three to four-fold. Under these conditions, the degradation was inhibited effectively by all of the endogenous inhibitors tested, indicating the presence of a cascade where activated chondrocytes are a source of u-PA. Plasminogen activated by u-PA gives plasmin, which is known to further activate pro-stromelysin. Stromelysin is essential for activation of collegenase. Not only TIMP, but also inhibitors at earlier steps of activation like PAI-1, alpha 2-antiplasmin, alpha 1-PI and alpha 2-macroglobulin inhibited degradation, and could provide cartilage protection in vivo. An experiment with human articular cartilage explants showed that very little or no degradation occurred when human articular cartilage explants were stimulated with interleukin-1 alone. Addition of human plasminogen (at physiologically relevant concentrations) resulted in significant degradation, which was inhibited in the same manner as in bovine explants, by inhibitors of the fibrinolytic cascade and TIMP. TIMP is much more efficient in human explants, indicating the limited participation of human plasmin in the degradation of human cartilage. Although speculative, it is possible that in vivo, cartilage degradation could be promoted not only by TIMP/MMP imbalance, but also accelerated by decreased levels of certain serpins in synovial fluid (e.g. PAIs, alpha 2-antiplasmin and alpha 1-PI).
The inhibition of cartilage degradation by glucocorticosteroids may be due to down-regulation of urokinase plasminogen activator (u-PA) activity. It has been shown that u-PA may be the first enzyme in the cascade of activation of pro-matrix metalloproteinases by the fibrinolytic system. Inhibition of u-PA activity may be one explanation for the efficacy of glucocorticosteroids observed in animal models of OA and with intraarticular injection in patients with OA.
Pentacyclic Phytomolecule 3-O-Acetyl-11-keto-β-boswellic acid (AKBA) from Frankincense family has proven for the neuroprotection and recognized as an orphan drug for the treatment of cerebral edema. Nonetheless, AKBA have promising indications with Peroxisome proliferator activated receptor gamma (PPARγ) associated to cognitive function not deliberated so far. In order to substantiate the potential role of AKBA on memory function, we examine the contribution of PPARγ activation and its downstream process. Modified method of scopolamine induced dementia rats were treated with AKBA (5, 10&15 mg/kg,i.p) and Donepezil (2.5 mg/kg,i.p). Scopolamine induced short term spatial, working memory and recognition memory impairment was reversed significantly after AKBA treatment. AKBA administration diminished the Acetylcholine esterase (AchE) activity and preserved brain GABA and glutamate mediated neuronal excitability. Further, gene expression study reveals AKBA ameliorates the memory impairment via activating PPARγ and its downstream regulators, matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) genes in hippocampus. This study concludes that the treatment with AKBA can be a novel Phyto-molecule of interest for treating dementia via up-regulating hippocampus genes mediated cholinergic activation.
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, belonging to the nuclear receptor family, which has high expression of three structurally homologous PPARs isotypes (PPARα, PPARβ/δ, and PPARγ) in brain. Several studies have discovered role of PPARs in oxidative stress, mitochondrial dysfunction, neuroinflammation and production of the toxic proteins in various neurodegenerative disorders such as Parkinson disease, Alzheimer’s disease, Huntington disease, Amyotrophic Lateral Sclerosis, Multiple sclerosis etc. Currently available drugs provide symptomatic relief, but disease progression cannot be stopped, because of their unclear molecular approach. The ability of PPAR to modulate the pathways involved in these conditions paved a path for future studies. Due to increasing challenges to treat central nervous system related disorders, hence PPARs have attracted much attention nowadays. In this review, we discussed various mechanisms of PPARs subtypes in neurodegenerative disorders. We congregate the molecular evidences which support PPARs as a therapeutic target to treat neurodegenerative disorders from preclinical and clinical studies and provide a basis for the potential therapeutic use of PPAR ligands in human diseases.
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