Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085584 (encephalopathy)
 18,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Eastern Cooperative Oncology Group conducted a Phase I trial to determine the maximally tolerated doses of combination therapy with alpha interferon (IFN-alpha) and all-trans-retinoic acid (tRA). Fifty patients with incurable malignancies received IFN-alpha administered subcutaneously three times weekly, and tRA administered by mouth at bedtime. Doses were escalated between patient groups, starting at tRA dose level of 45 mg/m2 and 3 million units of IFN-alpha. Major, dose-limiting toxicities were attributable to either the tRA (rash, chelitis) or IFN (constitutional symptoms), and were observed only at tRA dose levels of 224 mg/m2 and 291 mg/m2, or 6 million units of IFN-alpha. The maximally tolerated dose level of 172.5 mg/m2 of tRA and 3 million units of IFN-alpha was well-tolerated, with no grade 3 or 4 toxicities attributable to therapy. One patient at the third dose level (75 mg/m2 of tRA and 3 million units of IFN-alpha) developed acute hepatic and renal failure and a metabolic encephalopathy of unclear etiology. We conclude that tRA and IFN-alpha may be safely administered together at the maximally tolerated dose of tRA as a single agent without unexpected side effects. The recommended doses of IFN-alpha and tRA for Phase II trials are 3 million units of IFN-alpha and 172.5 mg/m2 of tRA.
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PMID:An Eastern Cooperative Oncology Group phase I trial of all-trans-retinoic acid and interferon-alpha: E2Y92. 954 74

Human immunodeficiency virus type 1 (HIV-1)-associated central nervous system disorders, including encephalopathy, often occur in the late stage of HIV-1 infection. Some inflammatory cytokines and HIV-1 antigens released from infected microglia or brain macrophages are considered to play an important role in neuropathogenesis. In this study, an in vitro assay system has been established for the evaluation of neural cell death, which would be predictive of the pathogenesis of neural cell death in vivo. The human neuroblastoma cell line SK-N-SH was differentiated to a neural phenotype with retinoic acid, while the promyelocytic cell line HL-60 and its HIV-1-infected clone OM-10.1 were differentiated to macrophages with phorbol myristate acetate. When neural (differentiated SK-N-SH) cells were cocultured with either uninfected or HIV-1-infected macrophages (differentiated HL-60 or OM-10.1 cells, respectively) for 3-5 days, significant neural cell death was observed in the cells cocultured with infected macrophages. Direct contact with macrophages was not necessary for the induction of neural cell death, since indirect coculture or coculture supernatants could also induce neural cell death. Large amounts of cytokines and chemokines were released in the coculture supernatants. The CXCR4 antagonist AMD3100 and the HIV-1 transcription inhibitor K-37 partially inhibited neural cell death. These results indicate that this system seems to be a useful tool for the evaluation of compounds against HIV-1-induced neural cell death.
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PMID:Establishment of an in vitro assay system mimicking human immunodeficiency virus type 1-induced neural cell death and evaluation of inhibitors thereof. 1260 87

Rett syndrome (RTT) is a pervasive developmental disorder caused by mutations in MECP2. Complete loss of MECP2 function in males causes congenital encephalopathy, neurodevelopmental arrest, and early lethality. Induced pluripotent stem cell (iPSC) lines from male patients harboring mutations in MECP2, along with control lines from their unaffected fathers, give us an opportunity to identify some of the earliest cellular and molecular changes associated with MECP2 loss-of-function (LOF). We differentiated iPSC-derived neural progenitor cells (NPCs) using retinoic acid (RA) and found that astrocyte differentiation is perturbed in iPSC lines derived from two different patients. Using highly stringent quantitative proteomic analyses, we found that LIN28, a gene important for cell fate regulation and developmental timing, is upregulated in mutant NPCs compared to WT controls. Overexpression of LIN28 protein in control NPCs suppressed astrocyte differentiation and reduced neuronal synapse density, whereas downregulation of LIN28 expression in mutant NPCs partially rescued this synaptic deficiency. These results indicate that the pathophysiology of RTT may be caused in part by misregulation of developmental timing in neural progenitors, and the subsequent consequences of this disruption on neuronal and glial differentiation.
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PMID:Proteomic analyses reveal misregulation of LIN28 expression and delayed timing of glial differentiation in human iPS cells with MECP2 loss-of-function. 3078 62

Many hypotheses exist regarding the mechanism underlying delayed encephalopathy after acute carbon monoxide poisoning (DEACMP), including the inflammation and immune-mediated damage hypothesis and the cellular apoptosis and direct neuronal toxicity hypothesis; however, no existing hypothesis provides a satisfactory explanation for the complex clinical processes observed in DEACMP. Leucine-rich repeat and immunoglobulin-like domain-containing protein-1 (LINGO-1) activates the Ras homolog gene family member A (RhoA)/Rho-associated coiled-coil containing protein kinase 2 (ROCK2) signaling pathway, which negatively regulates oligodendrocyte myelination, axonal growth, and neuronal survival, causing myelin damage and participating in the pathophysiological processes associated with many central nervous system diseases. However, whether LINGO-1 is involved in DEACMP remains unclear. A DEACMP model was established in rats by allowing them to inhale 1000 ppm carbon monoxide gas for 40 minutes, followed by 3000 ppm carbon monoxide gas for an additional 20 minutes. The results showed that compared with control rats, DEACMP rats showed significantly increased water maze latency and increased protein and mRNA expression levels of LINGO-1, RhoA, and ROCK2 in the brain. Compared with normal rats, significant increases in injured neurons in the hippocampus and myelin sheath damage in the lateral geniculate body were observed in DEACMP rats. From days 1 to 21 after DEACMP, the intraperitoneal injection of retinoic acid (10 mg/kg), which can inhibit LINGO-1 expression, was able to improve the above changes observed in the DEACMP model. Therefore, the overexpression of LINGO-1 appeared to increase following carbon monoxide poisoning, activating the RhoA/ROCK2 signaling pathway, which may be an important pathophysiological mechanism underlying DEACMP. This study was reviewed and approved by the Medical Ethics Committee of Xiangya Hospital of Central South Hospital (approval No. 201612684) on December 26, 2016.
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PMID:Mechanism of delayed encephalopathy after acute carbon monoxide poisoning. 3259 50