Cybermedlife - Therapeutic Actions Ph Modulation - Acidification

Acid pH in tumors and its potential for therapeutic exploitation. 📎

Abstract Title: Acid pH in tumors and its potential for therapeutic exploitation. Abstract Source: Zhongguo Zhong Xi Yi Jie He Za Zhi. 2009 Jul;29(7):639-41. PMID: 2545340 Abstract Author(s): I F Tannock, D Rotin Article Affiliation: Department of Medicine, Ontario Cancer Institute, Toronto, Canada. Abstract: Measurement of pH in tissue has shown that the microenvironment in tumors is generally more acidic than in normal tissues. Major mechanisms which lead to tumor acidity probably include the production of lactic acid and hydrolysis of ATP in hypoxic regions of tumors. Further reduction in pH may be achieved in some tumors by administration of glucose (+/- insulin) and by drugs such as hydralazine which modify the relative blood flow to tumors and normal tissues. Cells have evolved mechanisms for regulating their intracellular pH. The amiloride-sensitive Na+/H+ antiport and the DIDS-sensitive Na+-dependent HCO3-/Cl- exchanger appear to be the major mechanisms for regulating pHi under conditions of acid loading, although additional mechanisms may contribute to acid extrusion. Mitogen-induced initiation of proliferation in some cells is preceded by cytoplasmic alkalinization, usually triggered by stimulation of Na+/H+ exchange; proliferation of other cells can be induced without prior alkalinization. Mutant cells which lack Na+/H+ exchange activity have reduced or absent ability to generate solid tumors; a plausible explanation is the failure of such mutant cells to withstand acidic conditions that are generated during tumor growth. Studies in tissue culture have demonstrated that the combination of hypoxia and acid pHe is toxic to mammalian cells, whereas short exposures to either factor alone are not very toxic. This interaction may contribute to cell death and necrosis in solid tumors. Acidic pH may influence the outcome of tumor therapy. There are rather small effects of pHe on the response of cells to ionizing radiation but acute exposure to acid pHe causes a marked increase in response to hyperthermia; this effect is decreased in cells that are adapted to low pHe. Acidity may have varying effects on the response of cells to conventional anticancer drugs. Ionophores such as nigericin or CCCP cause acid loading of cells in culture and are toxic only at low pHc; this toxicity is enhanced by agents such as amiloride or DIDS which impair mechanisms involved in regulation of pHi. It is suggested that acid conditions in tumors might allow the development of new and relatively specific types of therapy which are directed against mechanisms which regulate pHi under acid conditions. Article Published Date : Jul 01, 2009
Therapeutic Actions Ph Modulation - Acidification

NCBI pubmed

An alternative exon of CAPS2 influences catecholamine loading into LDCVs of chromaffin cells.

Related Articles An alternative exon of CAPS2 influences catecholamine loading into LDCVs of chromaffin cells. J Neurosci. 2018 Nov 02;: Authors: Ratai O, Schirra C, Rajabov E, Brunk I, Ahnert-Hilger G, Chitirala P, Becherer U, Stevens DR, Rettig J Abstract The calcium-dependent activator proteins for secretion (CAPS) are priming factors for synaptic and large dense-core vesicles, promoting their entry into, and stabilizing the release-ready state. A modulatory role of CAPS in catecholamine loading of vesicles has been suggested. Though an influence of CAPS on monoamine transporter function and on vesicle acidification have been reported, a role of CAPS in vesicle loading is disputed. Using expression of naturally occurring splice variants of CAPS2 into chromaffin cells from CAPS1/CAPS2 double-deficient mice of both sexes, we show that an alternative exon of 40 amino acids is responsible for enhanced catecholamine loading of large dense-core vesicles in mouse chromaffin cells. The presence of this exon leads to increased activity of both vesicular monoamine transporters. Deletion of CAPS does not alter acidification of vesicles. Our results establish a splice-variant dependent modulatory effect of CAPS on catecholamine content in large dense-core vesicles.SIGNIFICANCE STATEMENTThe calcium activator protein for secretion (CAPS) promotes and stabilizes the entry of catecholamine-containing vesicles of the adrenal gland into a release-ready state. Expression of an alternatively-spliced exon in CAPS leads to enhanced catecholamine content in chromaffin granules. This exon codes for forty amino acids with a high proline content, consistent with an unstructured loop, present in the portion of the molecule generally thought to be involved in vesicle priming. CAPS variants containing this exon promote 5HT uptake into CHO cells expressing either vesicular monoamine transporter. Epigenetic tuning of CAPS variants may allow modulation of endocrine adrenaline and noradrenaline release. This mechanism may extend to monoamine release in central neurons or in the enteric nervous system. PMID: 30389842 [PubMed - as supplied by publisher]

D1 dopamine receptor is involved in shell formation in larvae of Pacific oyster Crassostrea gigas.

Related Articles D1 dopamine receptor is involved in shell formation in larvae of Pacific oyster Crassostrea gigas. Dev Comp Immunol. 2018 07;84:337-342 Authors: Liu Z, Wang L, Yan Y, Zheng Y, Ge W, Li M, Wang W, Song X, Song L Abstract Dopamine (DA), a significant member of catecholamines, is reported to induce biomineralization of calcium carbonate vaterite microspheres via dopamine receptor (DR) in bivalves, implying the modulation of dopaminergic system on shell formation during larval development. In this research, a homologue of D1 type DR (CgD1DR-1) was identified from oyster Crassostrea gigas, whose full length cDNA was 1197 bp. It was widely expressed in various tissues of C. gigas, with the significantly higher levels in hepatopancreas, mantle, muscle and gill. During developmental stages, the mRNA transcripts of CgD1DR-1 in D-shape larvae were obviously higher (p < 0.05) than those in trochophore and umbo larvae, and CO2 exposure could inhibit the synthesis of DA and mRNA expression of CgD1DR-1. After cell transfection and DA treatment, intracellular cAMP in cells with the expression of CgD1DR-1 increased significantly (p < 0.05). Furthermore, the incubation with SCH 23390 for the blockage of CgD1DR-1 significantly restrained the expressions of six shell formation-related genes including CgTyrosinase-1, CgTyrosinase-3, CgChitinaseLP, CgAMC, CgBMP and CgBMPR in trochophore and D-shape larvae. These results jointly suggested that DA together with its receptor CgD1DR-1 might be involved in shell formation during oyster larval development from trochophore to D-shape larvae, and CO2-induced ocean acidification (OA) might influence marine bivalves by inhibiting the DA-D1DR pathway to prohibit their shell formation. PMID: 29550270 [PubMed - indexed for MEDLINE]