The Role of Astrocytes in the Pathophysiology of Schizophrenia.

A glutamate hypothesis of schizophrenia emerged based on pharmacological evidence that N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine (PCP), can induce symptoms similar to those seen in schizophrenia. Subsequently, abnormal expression of various neuronal molecules associated with the glutamate synapse has been reported in schizophrenia. Astrocytes, a prominent glial cell in the brain, play a significant role in maintaining the structure and integrity of neural tissue and in facilitating excitatory neurotransmission, therefore, any breakdown in the structure or function of astrocytes could disrupt neuronal signaling and disturb brain function. I studied structural and functional molecules in astrocytes to determine 1) whether astrocytes are themselves globally compromised in schizophrenia, and 2) whether abnormal expression of glutamatergic molecules in astrocytes could be a contributing factor to brain dysfunction in this illness. I examined the expression of molecular markers of astrocytes as a measure of the integrity of these cells in schizophrenia. S100B, a calcium binding protein previously shown to be increased in the plasma and CSF of patients with schizophrenia, was not altered. I found that the intermediate-filament glial fibrillary acidic protein (GFAP), a component of the astrocyte cytoskeleton, was significantly altered in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in schizophrenia. I also measured the expression of two astrocytic enzymes involved in glutamate function: glutamine synthetase, involved in recycling synaptic glutamate, and serine racemase, which synthesizes the NMDA receptor co-agonist D-serine. Glutamine synthetase was significantly decreased in the superior temporal gyrus and ACC, and protein expression of serine racemase was increased in the hippocampus in schizophrenia. This was the first study to demonstrate altered expression of glutamine synthetase in these brain regions, and the first report of serine racemase expression abnormalities in schizophrenia. These findings suggest that astrocytes contribute to the pathophysiology of schizophrenia and that astrocytic molecules involved in cytoskeletal integrity and glutamatergic function are compromised in this illness. Schizophrenia is a complex illness that requires a reappraisal of the existing neuronal model to include an astrocytic hypothesis of dysfunction, which could lead to a better understanding of schizophrenia, and provide novel treatment strategies in this illness.Ph.D.NeuroscienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/55679/2/asteffek_1.pd

Chemometrics-assisted identification of anti-inflammatory compounds from the green alga klebsormidium flaccidum var. Zivo

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). The green alga Klebsormidium flaccidum var. zivo is a rich source of proteins, polyphenols, and bioactive small-molecule compounds. An approach involving chromatographic fractionation, anti-inflammatory activity testing, ultrahigh performance liquid chromatography-mass spectrometry profiling, chemometric analysis, and subsequent MS-oriented isolation was employed to rapidly identify its small-molecule anti-inflammatory compounds including hydroxylated fatty acids, chlorophyll-derived pheophorbides, carotenoids, and glycoglycerolipids. Pheophorbide a, which decreased intracellular nitric oxide production by inhibiting inducible nitric oxide synthase, was the most potent compound identified with an IC50 value of 0.24 µM in lipopolysaccharides-induced macrophages. It also inhibited nuclear factor kappaB activation with an IC50 value of 32.1 µM in phorbol 12-myristate 13-acetate-induced chondrocytes. Compared to conventional bioassay-guided fractionation, this approach is more efficient for rapid identification of multiple chemical classes of bioactive compounds from a complex natural product mixture

KALGAE™ (Klebsormidium flaccidum var. ZIVO) dried algal biomass - 90-day dietary toxicity study and genotoxicity studies

Consumers are demanding plant-based alternative protein sources to complement traditional animal-based protein sources to fulfill their dietary protein requirements. KALGAE™, a dried algal biomass derived from Klebsormidium flaccidum var. ZIVO, is a potential source of plant-based protein that has been evaluated for safety to support its use as a food ingredient. There were no treatment-related adverse effects observed in the 14-day palatability/toxicity or 90-day dietary toxicity study in CRL Sprague-Dawley CD® IGS rats. In the 90-day study, KALGAE™ was administered to rats in the diet at 0, 37,500, 75,000, or 150,000 ppm. No adverse effects were attributed to the test substance for the following parameters: body weight, body weight gain, mean food consumption and efficiency, hematology, clinical chemistry, urinalysis, gross pathology, histopathology, or organ weights. Although some statistically significant effects were recorded, the effects were not considered to be of toxicological relevance. A No Observable Adverse Effect Level (NOAEL) of 150,000 ppm, equivalent to dietary intakes of 7895.2 (male) and 9708.09 (female) mg KALGAE™/kg body weight/day in rats was established. KALGAE™ was non-mutagenic in the in vitro bacterial reverse mutation assay at concentrations up to 5000 μg/plate (with or without S9 metabolic activation), nor was KALGAE™ genotoxic in the in vivo mammalian erythrocyte micronucleus test in Swiss albino (ICR) mice. These results support the safe use of KALGAE™ as an ingredient in foods. Keywords: Microalgae, Plant-based protein, Toxicity, Mutagenicity, KALGAE™, Klebsormidium flaccidu

Chemometrics-Assisted Identification of Anti-Inflammatory Compounds from the Green Alga Klebsormidium flaccidum var. zivo

The green alga Klebsormidium flaccidum var. zivo is a rich source of proteins, polyphenols, and bioactive small-molecule compounds. An approach involving chromatographic fractionation, anti-inflammatory activity testing, ultrahigh performance liquid chromatography-mass spectrometry profiling, chemometric analysis, and subsequent MS-oriented isolation was employed to rapidly identify its small-molecule anti-inflammatory compounds including hydroxylated fatty acids, chlorophyll-derived pheophorbides, carotenoids, and glycoglycerolipids. Pheophorbide a, which decreased intracellular nitric oxide production by inhibiting inducible nitric oxide synthase, was the most potent compound identified with an IC50 value of 0.24 µM in lipopolysaccharides-induced macrophages. It also inhibited nuclear factor kappaB activation with an IC50 value of 32.1 µM in phorbol 12-myristate 13-acetate-induced chondrocytes. Compared to conventional bioassay-guided fractionation, this approach is more efficient for rapid identification of multiple chemical classes of bioactive compounds from a complex natural product mixture