Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0847097 (acidity)
 15,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To assess the possible involvement of cholinergic mechanisms in the hypothalamic nuclei in the stimulatory effect of TRH on gastric secretion, rats were infused with thyrotropin-releasing hormone (TRH), cholinergic agonist or antagonist, and normal saline through previously implanted hypothalamic cannulae. Administration of TRH or pilocarpine into the lateral cerebral ventricle or the anterior hypothalamus caused a dose-related increase in gastric volume and acidity in rats. On the other hand, administration of either atropine or D-tubocurarine into the same brain sites caused the opposite effects. Furthermore, the stimulatory effect of TRH or pilocarpine on gastric secretion was completely abolished by pretreatment of the CSF or the anterior hypothalamus with atropine and to a lower degree, D-tubocurarine. Administration of TRH, pilocarpine, atropine or D-tubocurarine into the lateral hypothalamus produced only a slight effect on gastric volume and acidity. However, the gastric volume or acidity was not affected by administration of either TRH, pilocarpine, atropine or D-tubocurarine into the ventromedial hypothalamus in our rats. The data indicate that the cholinergic muscarinic receptor mechanisms in the anterior hypothalamus may mediate the stimulatory effect of TRH on gastric secretion in rats.
 ...
PMID:Cholinergic mechanisms in the rat's hypothalamus mediate the stimulatory effect of thyrotropin-releasing hormone on gastric secretion. 211 Mar 69

Inorganic bismuth salts are poorly soluble in water: solubility is influenced by the acidity of the medium and the presence of certain compounds with (hydr)oxy or sulfhydryl groups. The analysis of bismuth in biological material is not standardised and is subject to large variation; it is difficult to compare data from different studies, and older data should be approached with caution. The normal concentration of bismuth in blood is between 1 and 15 micrograms/L, but absorption from oral preparations produces a significant rise. Distribution of bismuth in the organs is largely independent of the compound administered or the route of administration: the concentration in kidney is always highest and the substance is also retained there for a long time. It is bound to a bismuth-metal binding protein in the kidney, the synthesis of which can be induced by the metal itself. Elimination from the body takes place by the urinary and faecal routes, but the exact proportion contributed by each route is still unknown. Elimination from blood displays multicompartment pharmacokinetics, the shortest half-life described in humans being 3.5 minutes, and the longest 17 to 22 years. A number of toxic effects have been attributed to bismuth compounds in humans: nephropathy, encephalopathy, osteoarthropathy, gingivitis, stomatitis and colitis. Whether hepatitis is a side effect, however, is open to dispute. Each of these adverse effects is associated with certain bismuth compounds. Bismuth encephalopathy occurred in France as an epidemic of toxicity and was associated with the intake of inorganic salts including bismuth subnitrate, subcarbonate and subgallate. In the prodromal phase patients developed problems in walking, standing or writing, deterioration of memory, changes in behaviour, insomnia and muscle cramps, together with several psychiatric symptoms. The manifest phase started abruptly and was characterised by changes in awareness, myoclonia, astasia and/or abasia and dysarthria. Patients recovered spontaneously after discontinuation of bismuth. Intestinal lavage, forced diuresis and haemodialysis have been tried without positive effects on the clinical condition of the patient or on blood bismuth concentration, and the use of dimercaprol as an antidote has produced reports of both positive and negative findings. To confirm the diagnosis of bismuth encephalopathy, it is essential to find elevated bismuth concentrations in blood, plasma, serum or CSF. A safety level of 50 micrograms/L and an alarm level of 100 micrograms/L have been suggested in the past, but no proof is available to support the choice of these levels.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Pharmacokinetics and toxicity of bismuth compounds. 268 29

To determine the effective stimulus to the central chemoreceptors, we measured CSF and medullary extracellular fluid (ECF) pH and phrenic activity in 11 anesthetized, paralyzed, vagotomized and glomectomized cats. Flat-tipped pH electrodes (2 mm diam.) were used to measure ECF pH on the ventral surface of the medulla and CSF pH 2 mm above the surface. Changes in alveolar/arterial PCO2 were produced by airway occlusions of 10-20 sec durations. Changes in CSF PCO2 and pH were made by infusing 100% CO2 or an acid buffer into the CSF. Airway occlusion caused an increase of alveolar/arterial PCO2. ECF pH began to fall 6-10 sec later, with a maximum decrease of 0.032 pH unit at 21.9 sec. Phrenic activity increased as ECF pH decreased, the greatest activity occurring when ECF pH was most acid. CSF pH decreased after a longer delay. Its maximum decrease at 54.1 sec was smaller (0.026 pH unit) than ECF pH and did not correlate with the increase of phrenic activity. Addition of 100% CO2 or an acid buffer into the CSF produced an acid shift in the CSF pH but no change in ECF pH or phrenic activity. Prolonged (greater than 30 min) increase of acidity of CSF did not alter phrenic activity until ECF pH developed a delayed acid shift. Even then, the change of ECF pH was much smaller than that of CSF. We conclude that medullary chemoreceptors do not respond to changes of CSF pH or PCO2 and that change of pH of CSF minimally affects ECF pH. On the other hand, respiratory responses are closely linked to changes in ECF pH.
 ...
PMID:The roles of medullary extracellular and cerebrospinal fluid pH in control of respiration. 398 82

Parkinson's disease is a neurodegenerative disorder characterized by oxidative stress and CNS iron deposition. Ceruloplasmin is an extracellular ferroxidase that regulates cellular iron loading and export, and hence protects tissues from oxidative damage. Using two-dimensional electrophoresis, we investigated ceruloplasmin patterns in the CSF of human Parkinson's disease patients. Parkinson's disease ceruloplasmin profiles proved more acidic than those found in healthy controls and in other human neurological diseases (peripheral neuropathies, amyotrophic lateral sclerosis, and Alzheimer's disease); degrees of acidity correlated with patients' pathological grading. Applying an unsupervised pattern recognition procedure to the two-dimensional electrophoresis images, we identified representative pathological clusters. In vitro oxidation of CSF in two-dimensional electrophoresis generated a ceruloplasmin shift resembling that observed in Parkinson's disease and co-occurred with an increase in protein carbonylation. Likewise, increased protein carbonylation was observed in Parkinson's disease CSF, and the same modification was directly identified in these samples on ceruloplasmin. These results indicate that ceruloplasmin oxidation contributes to pattern modification in Parkinson's disease. From the functional point of view, ceruloplasmin oxidation caused a decrease in ferroxidase activity, which in turn promotes intracellular iron retention in neuronal cell lines as well as in primary neurons, which are more sensitive to iron accumulation. Accordingly, the presence of oxidized ceruloplasmin in Parkinson's disease CSF might be used as a marker for oxidative damage and might provide new insights into the underlying pathological mechanisms.
 ...
PMID:Ceruloplasmin oxidation, a feature of Parkinson's disease CSF, inhibits ferroxidase activity and promotes cellular iron retention. 2217 Oct 55

Chemo-immunotherapy which combines chemotherapeutics with immune-modulating agents represents an appealing approach to improving cancer therapy [1, 2]. To maximize its efficacy, differential and precise targeting of the multiple therapeutics into corresponding cells is desirable. Here we develop an immunostimulatory nanocarrier that simultaneously loads platinum (Pt)-based chemotherapeutic prodrug and BLZ-945, a small molecule inhibitor of colony stimulating factor 1 receptor (CSF-1R) of tumor-associated macrophages (TAMs) [3], to spatially target tumor cells and TAMs for cancer chemo-immunotherapy. The nanoparticles (denoted as BLZ-945SCNs/Pt) undergo supersensitive structure collapse through responding to tumor acidity, along with instantaneous release of BLZ-945 and Pt-prodrug conjugated small particles. The extracellularly released BLZ-945 could be taken up by TAMs, which locate preferentially in the perivascular region [4], to directly disturb CSF-1/CSF-1R signaling pathway to suppress TAMs and modulate the tumor immune microenvironment, while the released small particles carrying Pt-prodrug could penetrate deeply into bulk tumor to kill more cancer cells [5], realizing synergistic antitumor effect of chemo- and immunotherapy (Fig. 1). Our in vivo studies demonstrate that the co-delivery nanocarrier outperforms monotherapy in varying tumor models.
 ...
PMID:Spatial targeting of tumor-associated macrophage and tumor cells with a designer nanocarrier for cancer chemo-immunotherapy. 2905 67

Mutations in the ER-associated VAPB/ALS8 protein cause amyotrophic lateral sclerosis and spinal muscular atrophy. Previous studies have argued that ER stress may underlie the demise of neurons. We find that loss of VAP proteins (VAPs) leads to an accumulation of aberrant lysosomes and impairs lysosomal degradation. VAPs mediate ER to Golgi tethering and their loss may affect phosphatidylinositol-4-phosphate (PtdIns4P) transfer between these organelles. We found that loss of VAPs elevates PtdIns4P levels in the Golgi, leading to an expansion of the endosomal pool derived from the Golgi. Fusion of these endosomes with lysosomes leads to an increase in lysosomes with aberrant acidity, contents, and shape. Importantly, reducing PtdIns4P levels with a PtdIns4-kinase (PtdIns4K) inhibitor, or removing a single copy of Rab7, suppress macroautophagic/autophagic degradation defects as well as behavioral defects observed in Drosophila Vap33 mutant larvae. We propose that a failure to tether the ER to the Golgi when VAPs are lost leads to an increase in Golgi PtdIns4P levels, and an expansion of endosomes resulting in an accumulation of dysfunctional lysosomes and a failure in proper autophagic lysosomal degradation. Abbreviations: ALS: amyotrophic lateral sclerosis; CSF: cerebrospinal fluid; CERT: ceramide transfer protein; FFAT: two phenylalanines in an acidic tract; MSP: major sperm proteins; OSBP: oxysterol binding protein; PH: pleckstrin homology; PtdIns4P: phosphatidylinositol-4-phosphate; PtdIns4K: phosphatidylinositol 4-kinase; UPR: unfolded protein response; VAMP: vesicle-associated membrane protein; VAPA/B: mammalian VAPA and VAPB proteins; VAPs: VAMP-associated proteins (referring to Drosophila Vap33, and human VAPA and VAPB).
 ...
PMID:VAMP associated proteins are required for autophagic and lysosomal degradation by promoting a PtdIns4P-mediated endosomal pathway. 3074 20