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PubMed2025

MED12-STAT1-TAP2 axis regulates CD8 + T cell cytotoxicity and mediates immunotherapy outcome in non-small cell lung cancer.

Although immunotherapy for late-stage non-small cell lung carcinoma (NSCLC) has been clinically utilized, its prognosis remains highly heterogeneous, prompting us to investigate novel predictive immunotherapy biomarkers for NSCLC. We analyzed the correlations between MED12 nonsynonymous mutations and survival, clinical, genomic, transcriptomic information, and immune infiltration information through data mining across multiple datasets. We also investigated the mechanism of MED12 using luciferase assay, Western blot, ChIP-PCR, and siRNA. MED12 is significantly associated with survival in completely independent immunotherapy datasets, including MSKCC (N = 350), Naiyer2015 (N = 34), our own (N = 295) and the pan-cancer dataset, but not in the TCGA dataset, where patients received non-immunotherapy regimens. Mutations in MED12 showed no significant correlation with known metrics (TMB, IPS/CTLA4/PD1 status, PD-1/PD-L1 expression, and TCR/BCR status) or DNA Damage Repair (DDR) pathway mutations, yet they carried independent prognostic information according to the Cox multivariate regression. On the other hand, MED12 mutation is significantly associated with multiple immune-related pathways and immune infiltration of CD8 + T cells and activated NK cells. Lactate dehydrogenase assay revealed that knockdown of TAP2 restored the upregulation of CD8 + T cell cytotoxicity triggered by MED12 knockdown. ChIP-PCR, luciferase assay and siRNA knock down assay indicate that MED12 binds to the promoter region of STAT1 to suppress its transcription, while the transcription factor STAT1 promotes the transcription of TAP2, thus inhibiting the antigen processing and presentation. Collectively, MED12 mutation is an independent and valuable biomarker for predicting the response to immune checkpoint inhibitor (ICI)therapy in NSCLC by modulating CD8 + T cell cytotoxicity via the STAT1/TAP2 axis.

Humans↗
PubMed2006

Bradykinin-induced chloride conductance in murine proximal tubule epithelial cells.

Despite the recognized role of bradykinin (BK)-induced calcium and chloride conductance in regulating salt transport in the kidney, the signaling pathway involved has not been well examined. Patch clamp of murine proximal tubule (TKPTS) cells revealed that BK (10 nM) produced an increase in an outwardly rectifying current from a basal level of 2.9 +/- 0.6 to 13.8 +/- 1.1 pA/pF following addition of BK (n = 8; p < 0.001). The shift in reversal potential seen with BK on changing the intracellular solution to 152 mM chloride and significant inhibition of the current by 100 microM 4,4'-di-isothiocyanato-stilbene-2,2'-disulphonic acid (DIDS) suggested that BK activated a chloride current. BK-induced current was blocked by B2 receptor antagonist but not by B1 antagonist or pertussis toxin indicating that the current was mediated by B2 receptors possibly through Gq activation. TMB-8 completely blocked the BK-calcium rise in fura-2 studies but did not block the BK-chloride response indicating that BK-mediated chloride current is calcium-independent. BK-induced current was dependent on phospholipase C (PLC) since U73122, a PLC-beta blocker (10 microM) blocked it completely. Furthermore, chloride conductance was not modulated by bisindolylmaleimide, an inhibitor of protein kinase C (PKC), but was enhanced by dibutyryl cAMP. We conclude that BK-induced rise in chloride current is mediated by B2 receptors and dependent on PLC activation but not dependent on calcium rise. Furthermore, the current can be modulated by cAMP but not PKC.

Animals↗
PubMed2026

Exploration and experimental verification of triaptosis-related prognostic genes and cells in gastric cancer.

BACKGROUND: Triaptosis is a recently characterized form of programmed cell death with unclear implications in cancer. This study aimed to investigate the prognostic significance and biological relevance of triaptosis in gastric cancer (GC). METHODS: Transcriptomic and clinical data from TCGA-STAD and GSE62254, and single-cell RNA sequencing data from GSE183904 were analyzed. Triaptosis-related gene (TRG) scores were calculated using single-sample gene set enrichment analysis. Differentially expressed genes identified in TRG-score and GC-versus-normal comparisons underwent functional enrichment, Cox regression, and least absolute shrinkage and selection operator regression to develop an externally validated signature. Immune profiles, pathway activity, somatic mutations, tumor mutational burden (TMB), predicted drug sensitivity, and clinical features were compared by risk group. Single-cell analyses assessed TRG activity, prognostic gene expression, cell-cell communication, and pseudotime. Reverse transcription-quantitative PCR and Western blotting assessed mRNA expression and protein levels, respectively. RESULTS: A TRG-based prognostic model comprising ASPN, GRB14, and VTN was developed and externally validated, effectively distinguishing patients into two distinct risk groups with notably different survival outcomes. mRNA expression of all three genes and their protein levels were significantly higher in SGC-7901 cells than in GES-1 cells. High-risk patients had higher stromal scores and distinct immune profiles; 15 immune cell types differed between groups. Single-cell analysis revealed fibroblasts and pericytes among high-TRG-active cell types. Prognostic genes were significantly overexpressed in fibroblasts, which also showed high TRG activity. Fibroblasts demonstrated enhanced communication with pericytes, whereas tumor-derived fibroblasts showed weaker communication with macrophages, indicating immune microenvironment remodeling. CONCLUSION: The three-gene prognostic signature predicted GC prognosis and was associated with distinct immune and genomic features, suggesting potential value for risk stratification and personalized treatment.

Humans↗
PubMed2007

Development of a simple enzyme immunoassay for the determination of ovine luteinizing hormone.

The present study describes the development and validation of a simple sensitive and specific sandwich enzyme immunoassay (EIA) for the quantification of ovine luteinizing hormone (LH) in plasma. Microtitre plates were coated with the capture antibody 518b7 anti-bovine LH. A second peroxidase-labelled anti-ovine LH antibody was used as tracer. A simple 3-step procedure was used for the sample analysis; (1) incubation of standards and samples with the pre-coated antibody plates for 2 h at 37 degrees C; (2) incubation with the peroxidase-labelled antibody for 1 h at room temperature; and (3) colour development with TMB substrate. A linear dose-response curve was obtained in the range 0-10 ng/ml (r2 > 0.99). The detection limit was 0.05 ng/ml, and the intra-assay and inter-assay coefficients of variation were 7% and 11.7%, respectively. The theoretical stability of microplates and reagents was calculated, this being greater than one year. Low or undetectable cross-reactivities were recorded for follicle-stimulating hormone, bovine thyroid-stimulating hormone, equine chorionic gonadotrophin and a gonadotrophin-releasing hormone (GnRH) analogue. The EIA was biologically validated by the determination of plasma LH concentrations of nine Rasa Aragonesa ovariectomized and estradiol-implanted ewes after a double GnRH challenge. In conclusion, this enzyme immunoassay provides an efficient, simple and sensitive method for the routine analysis of ovine LH.

Animals↗
PubMed2026

A pan-cancer analysis of MEX3D in human tumors.

BACKGROUND: MEX3D, a member of the MEX3 RNA-binding protein family, has emerged as a potential regulatory molecule in cancer. However, its role across different tumor types remains largely unexplored. METHODS: We conducted a pan-cancer analysis of MEX3D using transcriptomic and proteomic data from the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Clinical Proteomic Tumor Analysis Consortium (CPTAC). Expression patterns, clinical correlations, survival outcomes, genetic alterations, RNA modification associations, immune infiltration, and functional enrichment were systematically evaluated. RESULTS: MEX3D was significantly dysregulated in numerous cancers at both mRNA and protein levels. Its expression correlated with tumor stage in ACC, LIHC, OV, SKCM, and THCA. Elevated MEX3D expression was associated with poor overall survival (OS) and disease-specific survival (DSS) in multiple malignancies, including ACC, LGG, LUAD, and MESO. Genetic alteration analysis revealed frequent amplifications and mutations, particularly in SARC and OV. MEX3D was positively correlated with RNA modification-related genes (m1A, m5C, m6A) and immune regulatory genes such as CD276, TGFB1, VEGFA, and ICOSLG. Additionally, MEX3D expression showed significant associations with tumor mutational burden (TMB), microsatellite instability (MSI), and cancer-associated fibroblast infiltration. Functional enrichment analyses indicated that MEX3D-related genes are involved in reproductive cellular processes, RNA binding, the Hippo signaling pathway, and microRNA-related oncogenic pathways. CONCLUSION: This pan-cancer analysis highlights the heterogeneous expression and cancer-specific prognostic significance of MEX3D. MEX3D is associated with immune infiltration, immune regulatory genes, RNA modification-related genes, TMB/MSI, and pathways involved in gene regulation and tumor progression. These findings suggest that MEX3D may participate in cancer-specific post-transcriptional and microenvironmental regulatory networks.

Biomarker↗
PubMed2026

Stratifying lung adenocarcinoma: a novel prognostic model based on mitochondrial outer membrane permeabilization activity.

UNLABELLED: Mitochondrial outer membrane permeabilization (MOMP) is a core apoptotic regulatory event that dictates mitochondrial integrity, where full activation drives cell death and sublethal dysregulation contributes to tumor genomic instability. We used the Cancer Genome Atlas lung adenocarcinoma cohort (TCGA-LUAD) as the training cohort and the Gene Expression Omnibus dataset GSE42127 as the validation cohort to identify prognostic genes related to MOMP activity in lung adenocarcinoma (LUAD) and to evaluate their potential biological significance. By intersecting MOMP-related genes with differentially expressed genes, combined with survival analysis, Mendelian randomization analysis, and 101 machine-learning algorithm combinations, seven prognostic genes, namely BIRC5, PSMD11, TNFRSF13C, YWHAZ, YWHAG, CYCS, and LTB, were identified. Next, an optimal prognostic model was constructed based on the gradient boosting machine (GBM) algorithm. Based on the risk score, LUAD patients were stratified into high- and low-risk groups, and patients in the high-risk group exhibited poorer overall survival in both the training and validation cohorts. Furthermore, a nomogram integrating the risk score and clinicopathological factors was developed and showed favorable predictive performance for 1-, 3-, and 5-year survival. Meanwhile, functional and immune analyses revealed that the high-risk group was enriched in DNA replication-related pathways and demonstrated a higher tumor mutation burden (TMB). Correlation analysis indicated that TNFRSF13C was positively correlated with activated B cells, whereas BIRC5 was negatively correlated with eosinophils, suggesting that MOMP-related genes might be involved in remodeling the immune microenvironment of LUAD. Drug sensitivity analysis showed differences in predicted half-maximal inhibitory concentration (IC50) values between the risk groups, suggesting the potential value of this model in assisting therapeutic stratification. Single-cell RNA sequencing (scRNA-seq) further identified T lymphocytes as a key cell type, with numerous prognostic genes exhibiting differential expression in T cells or dynamic changes during differentiation. We suggest that the MOMP-related signature established in this study may provide a reference for prognostic stratification in LUAD and offers candidate prognostic genes for subsequent experimental and clinical validation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s13205-026-05058-6.

Lung adenocarcinoma↗
PubMed1986

Enzymatic detection of native and derivatized horseradish peroxidase in sodium dodecyl sulfate polyacrylamide gels.

We developed procedures for the restoration of peroxidatic activity in native horseradish peroxidase (HRP) and HRP conjugated to wheat germ agglutinin (WGA-HRP) following electrophoresis in SDS-polyacrylamide gels (SDS-PAGE). After extraction of SDS with isopropanol from gels containing HRP and WGA-HRP, the peroxidatic activity in these probes could be demonstrated by tetramethylbenzidine (TMB) chemistry. This procedure also showed HRP enzyme activity in electrophoresed tissue homogenates containing HRP. Both free HRP as well as WGA-HRP preparations contain several molecular weight species that display peroxidatic activity. These findings are important for cell biological studies utilizing these substances as molecular probes. The procedures described here should be useful for the analysis of the enzymatically active molecular forms of these frequently used markers in vitro and in vivo.

Animals↗
PubMed1989

Ca2+ mobilization and Cl efflux in submandibular salivary cells of adult and newborn rats.

These cells were isolated by enzymatic digestion from glands of 1-day-old and fully mature rats. The effects of exposure to acetylcholine on cytosolic Ca2+ and Cl efflux were studied by, respectively, spectrofluorimetry of fura-2 and the net efflux of the isotopic tracer 36Cl from preloaded cells. In both types of cells, when incubated in Ca2+-containing solutions, acetylcholine initially caused a rapid, significant increase in cytosolic Ca2+ (from approx. 90 to 480-570 nmol), followed by a slower decrease to a plateau value of 280-290 nmol. The initial peak persisted (315-339 nmol) in Ca2+-free solutions but the cytosolic Ca2+ concentrations decreased rapidly to levels below prestimulation values (30 nmol). 36Cl efflux in tracer preloaded cells incubated in Ca2+-containing medium in the presence of acetylcholine was 18% in cells of new born animals and 35% in adult cells. In Ca2+-free medium, mature cells showed a transient but significant (26%) efflux of 36Cl. Cells of 1-day-old rats did not show a net efflux of 36Cl under these conditions, but subsequent addition of Ca2+ caused a 15% reduction (i.e. efflux) in tracer content. The antagonist 3,4,5-trimethoxybenzoate-8(N,N-dithylamino)octyl ester (TMB 8), which blocks internal Ca2+ release, inhibited both the initial increase in cell Ca2+ in both types of cells and the transient efflux of 36Cl seen in mature cells when incubated in Ca2+-free solutions. At high concentrations (5 mM), LaCl3 inhibited efflux of 36Cl in mature cells but not in those of newborn rats. However, at lower concentrations (0.1 mM), which do not interfere with fluorescence spectra, LaCl3 did not inhibit the effect of acetylcholine on cell Ca2+. These results suggest that Cl efflux in adult submandibular cells is regulated by an increase in cell Ca2+ arising from release of internal Ca2+ and from influx of external Ca2+. Both of these responses are evident in cells of newborn animals but Cl efflux is either decreased or absent. This is likely to be associated with a deficiency in the Cl channels or in the coupling between Ca2+ and the channel substrate through regulatory molecules associated with phosphorylation of the channel protein.

Aging↗
PubMed1991

Calcium dependency of adrenergic and muscarinic cholinergic stimulation of mucin release from dog submandibular gland cells.

Stimulation of muscarinic cholinergic, alpha-adrenergic and beta-adrenergic receptors elicited mucin release from dispersed dog submandibular cells. The secretory response to acetylcholine was much more pronounced than to adrenergic agonists, and largely dependent on the presence of extracellular Ca2+, but the dependency on extracellular Na+ was slight. Ionomycin also stimulated mucin release. In rat submandibular cells, neither muscarinic cholinergic agonists nor ionomycin were as effective mucosecretagogues as beta-adrenergic agonists. alpha-Adrenoceptor-mediated release was decreased by chelating extracellular Ca2+ with EGTA. The beta-adrenoceptor-mediated response was diminished by extensive exposure of cells to EGTA, due at least in part to the requirement of Ca2+ for beta-adrenoceptor stimulation of cAMP formation. 8-br-cAMP stimulated 45Ca2+ release from cells preloaded with 45Ca2+. The 8-br-cAMP-induced mucin release was eliminated in ionomycin-pretreated cells, but not inhibited by chelating extracellular Ca2+ and by the treatment of the cells with TMB-8 or in the cells loaded with BAPTA. These results suggest that not only the adrenergic system but also the muscarinic cholinergic system may participate in the regulation of mucin release in dog submandibular gland, and also provide the possibility that, in addition to a cAMP-mediated mechanism, Ca(2+)-dependent mechanisms may be involved in mucosecretion in dog submandibular acini.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1990

Na(+)-ionophore, monensin-induced rise in cytoplasmic free calcium depends on the presence of extracellular calcium in FRTL-5 rat thyroid cells.

Calcium is an important regulator of cell function, and may be influenced by the intracellular sodium content. In the present study, the Na(+)-ionophore, monensin, was used to investigate the interrelationship between changes in intracellular Na+ concentration ([Na+]i) and elevation of cytosolic Ca2+ concentration ([Ca2+]i) in FRTL-5 thyroid cells. Cytoplasmic Ca2+ levels were measured using the fluorescent dye, indo-1. Monensin induced a dose-dependent increase in [Ca2+]i in FRTL-5 cells. Inhibitors of intracellular Ca2+ release, TMB-8 and ryanodine, were unable to prevent the monensin effect on [Ca2+]i. The alpha 1-receptor antagonist, prazosin, did not block the monensin-stimulated increase in [Ca2+]i. In the absence of extracellular calcium there was a marked diminution in the monensin effect on [Ca2+]i, yet calcium channel antagonists (nifedipine, diltiazem and verapamil) did not inhibit the response. Replacement of Na+ by choline chloride in the medium depressed the monensin-evoked rise in [Ca2+]i by up to 84%. Furthermore, addition of the Na(+)-channel agonist, veratridine, elicited an increase in [Ca2+]i, even though less dramatic than that caused by monensin. Ouabain increased the resting cytosolic Ca2+ concentration as well as the magnitude of the monensin effect on [Ca2+]i. The absence of any effect on the Na(+)-ionophore evoked increase in [Ca2+]i upon addition of tetrodotoxin (TTX) excluded a possible involvement of TTX-sensitive Na+ channels. These data show that the rise in [Ca2+]i induced by increasing [Na+]i is largely dependent on both external Na+ and Ca2+. Calcium entry appears not to involve voltage-dependent or alpha 1-receptor sensitive Ca2+ channels, but may result from activation of an Na(+)-Ca2+ exchange system.

Animals↗
PubMed1984

Activation of the human neutrophil respiratory burst with zymosan-activated serum.

Zymosan-activated serum ( ZAS ) stimulated a time- and concentration-dependent generation of superoxide anion (O-2) by human neutrophils. O-2 production was rapid with maximum generation occurring 2 minutes after cell exposure to ZAS . O-2 generation is markedly reduced if cells are not preincubated with cytochalasin B prior to contact with ZAS . The amount of O-2 produced by ZAS stimulated neutrophils was enhanced in the presence of extra-cellular calcium. However, the intracellular calcium antagonist, 8-(N,N-diethylamino)-octyl-(3,4,5-trimethoxy) benzoate hydrochloride (TMB-8), caused a dose-related inhibition of ZAS -elicited O-2 production. Neutrophils pretreated with ZAS were desensitized to the subsequent exposure to this stimulus. The fact that pretreatment of neutrophils with ZAS did not diminish the capacity of these cells to generate O-2 in response to 1-O-hexadecyl/octadecyl-2-O-acetyl-sn-glyceryl-3-phosphorylcholine (AGEPC),N-formyl-methionyl-leucyl-phenylalanine (FMLP) or 5(5),12(R)-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid (LTB4), demonstrates the stimulus specific nature of ZAS -induced desensitization. Thus, ZAS , which contains the complement-derived neutrophil activator, C5a, a naturally occurring phlogistic mediator, represents a relevant probe for investigating neutrophil function.

Cytochalasin B↗
PubMed1984

Serum, bradykinin and vasopressin stimulate release of inositol phosphates from human fibroblasts.

The mitogens serum, vasopressin and bradykinin stimulate a significant rise in the inositol phosphate content of cultured human fibroblasts within 10 seconds, while serum- and bradykinin-stimulated arachidonic acid release does not occur until after 30 seconds. The release of inositol phosphates is not secondary to a rise in Ca activity since the Ca ionophore ionomycin does not stimulate release of inositol phosphates. Moreover, we show that phospholipase C in human fibroblasts is activated by these mitogens at resting Ca levels since TMB-8, which blocks the mitogen-induced rise in Ca activity, does not affect the serum-stimulated accumulation of inositol phosphates.

Arachidonic Acid↗
PubMed1985

Evidence for Ca++-calmodulin control of transplasmalemma electron transport in carrot cells.

Cultured carrot cells exhibit transmembrane ferricyanide reduction through a plasma membrane redox system, which may be associated with an iron reduction and uptake system in plant roots. Here we provide evidence for the inhibition of transplasma membrane ferricyanide reduction by four different Ca2+-calmodulin type antagonists, calmidazolium, trifluoperazine, pimozide and fluphenazine. These compounds inhibit in low concentrations (approximately 5-10 microM) in a time-dependent manner. Higher concentrations (50-100 microM) are required to inhibit transmembrane ferricyanide reduction in 10 min rather than in 30 min. The permeable calcium chelator, TMB-8, also inhibits transmembrane ferricyanide reduction in carrot cells. Since the redox system is controlled by hormones, the effects of anticalmodulin agents on hormone response may be mediated through the redox system.

Calcium↗
PubMed1985

Effects of calcium antagonists and calmodulin inhibitors on angiotensin II-induced prostaglandin productions in the isolated dog renal arteries.

Angiotensin II markedly potentiated both PGE2 and PGI2 productions in the isolated dog renal arteries. This angiotensin II-induced response was significantly reduced by the treatments of EGTA and calcium antagonists such as verapamil, nifedipine and 8-(N,N'-diethylamino)-octyl-3,4,5,-trimethoxybenzoate (TMB-8). Calmodulin inhibitors, trifluoperazine and W-7 also inhibited the angiotensin II-induced PG productions while an inactive analogue of W-7, W-5 did not have any effect. The results suggest that angiotensin II may enhance the intracellular Ca2+ level through the influx of extracellular Ca2+ and then, calmodulin activated with Ca2+ will stimulate both PGE2 and PGI2 productions via its activation of phospholipase A2 in the dog renal arteries.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Inhibition by L-arginine of the endothelin-mediated increase in cytosolic calcium in human neutrophils.

The effect of endothelin (ET) on the cytosolic-free calcium [(Ca2+]i) changes in polymorphonuclear leukocytes (PMN) from normal humans and Wistar rats was investigated. ET induced a dose-related [Ca2+]i peak. This [Ca2+]i transient was blunted by TMB-8 (10(-5)M) and by Ca(2+)-free EGTA medium, therefore suggesting a role of both intracellular Ca2+ release and Ca2+ influx in the generation of the [Ca2+]i peak. Preincubation of PMN with the nitric oxide (NO)-donor L-arginine (L-Arg) markedly blocked the ET-induced [Ca2+]i transient in an enantiomerically-specific manner. A similar blunting effect of L-Arg on the fMLP (10(-7)M)-induced [Ca2+]i transient was detected. The L-Arg antagonist, NG-monomethyl-L-arginine (L-NMMA), reverted the L-Arg blocking effect on both ET- and fMLP-induced [Ca2+]i transients. These data suggest that ET has a potential role in activating Ca2+ mobilization in PMN, an effect that can be inhibited by L-Arg.

Arginine↗
PubMed1991

Phospholipase D in cultured rat vascular smooth muscle cells and its activation by phorbol ester.

We determined the phospholipase D (PLD) activity in rat vascular smooth muscle cells by the formation of phosphatidylethanol in cells prelabeled with [3H] myristic acid. The enzyme was markedly activated by a phorbol ester (TPA). Down regulation of protein kinase C (PKC) resulted in almost complete inhibition indicating PKC-dependent mechanism of its activation. Depletion of calcium by EGTA and TMB-8 caused 53% inhibition. Chelator-stable association of PKC to membrane by TPA was observed in the absence of extracellular Ca2+. The mitogenic peptide PDGF also caused a marked stimulation of PLD. These results indicate that PLD in vascular smooth muscle cells is stimulated by TPA through the activation of PKC both by calcium-dependent and independent mechanisms.

Animals↗
PubMed1986

Reactivation by imidazo-pyridinium oximes of acetylcholinesterase inhibited by organophosphates. A study with an immobilized enzyme method.

A new procedure is described for studying inhibition and reactivation of acetylcholinesterase (AChE). The enzyme, electric eel AChE, is immobilized on fiberglass and the enzymatic activity is continuously monitored in an open reactor by an assay adapted from the Ellman's method. The use of immobilized AChE permits independent inhibition and reactivation of the enzyme. Side-reactions between substrate, inhibitor and reactivator are avoided. This method is used to determine the reactivating efficiency of a new series of imidazo-pyridinium oximes for the enzyme inhibited by different organophosphorous compounds. Kinetic parameters of reactivation were determined after AChE inhibition by sarin, VX and paraoxon. The more efficient reactivators have a short methylene bridge (C3 to C6) between imidazolium and pyridinium rings. Against soman inhibition, the pyrimidoxime or 1-(1-methyl-imidazolinium) 3-(4-carbaldoxime-pyridinium) propane dibromide, introduced immediately after the inhibitor, gives the same result as TMB-4 (37% reactivation). 1-benzyl 2-carbaldoxime pyridinium bromide was found to be more potent in reactivating tabun inhibited AChE than pyrimidoxime. Imidazo-pyridinium oximes with a long methylene bridge (C8 to C10) are good reversible inhibitors of free AChE (Ki less than 1 microM).

Acetylcholinesterase↗
PubMed1987

Inhibitors of inositol trisphosphate-induced Ca2+ release from isolated platelet membrane vesicles.

Platelet membrane vesicles accumulated Ca2+ in an ATP-dependent fashion, and 25-50% of the accumulated Ca2+ was released by the addition of 10 microM inositol 1,4,5-trisphosphate (IP3). The concentration of IP3 required for half-maximal Ca2+ release was approximately 0.5 microM. The inhibition of IP3-induced Ca2+ release from these membrane vesicles by various agents was examined. Of the plasma membrane Ca2+ channel blockers, cinnarizine and flunarizine were found to be potent inhibitors of IP3-induced Ca2+ release while having no effect on ATP-dependent Ca2+ uptake. The IC50 value for both cinnarizine and flunarizine as inhibitors of IP3-induced Ca2+ release was below 10(-6) M. Nifedipine, verapamil, bepridil, and diltiazem did not significantly inhibit IP3-induced Ca2+ release at the highest concentration tested (50 microM). The "intracellular Ca2+ antagonists" ryanodine, TMB-8 (8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate), dantroline, trifluoperazine and chlorpromazine were not inhibitors of IP3-induced Ca2+ release at 50 microM. The local anesthetics benzocaine and lidocaine weakly inhibited the IP3-induced Ca2+ release with IC50 values of approximately 5 and 50 microM, respectively, whereas other local anesthetics tested were less potent inhibitors. The potent inhibitors described may prove useful as probes of the IP3-induced Ca2+ release channels.

Adenosine Triphosphate↗