The antitumor role of a newly discovered α-d-glucan from Holotrichia diomphalia Bates as a selective blocker of aldolase A

2021 ◽  
Vol 255 ◽  
pp. 117532
Author(s):  
Jingmei Wang ◽  
Zezhi Li ◽  
Xin Yang ◽  
Yuhe Qiao ◽  
Caixia Feng ◽  
...  
Keyword(s):  
Selective Blocker ◽  
Aldolase A

scholarly journals A combination of MEF3 and NFI proteins activates transcription in a subset of fast-twitch muscles.

1997 ◽  
Vol 17 (2) ◽  
pp. 656-666 ◽  
Author(s):  
F Spitz ◽  
M Salminen ◽  
J Demignon ◽  
A Kahn ◽  
D Daegelen ◽  
...  
Keyword(s):  
Regulatory Elements ◽  
Specific Expression ◽  
Transgenic Lines ◽  
Slow Twitch ◽  
Myogenic Factors ◽  
Fast Twitch ◽  
Restricted Pattern ◽  
Aldolase A ◽  
Drive Reporter Gene Expression

The human aldolase A pM promoter is active in fast-twitch muscles. To understand the role of the different transcription factors which bind to this promoter and determine which ones are responsible for its restricted pattern of expression, we analyzed several transgenic lines harboring different combinations of pM regulatory elements. We show that muscle-specific expression can be achieved without any binding sites for the myogenic factors MyoD and MEF2 and that a 64-bp fragment comprising a MEF3 motif and an NFI binding site is sufficient to drive reporter gene expression in some but, interestingly, not all fast-twitch muscles. A result related to this pattern of expression is that some isoforms of NFI proteins accumulate differentially in fast- and slow-twitch muscles and in distinct fast-twitch muscles. We propose that these isoforms of NFI proteins might provide a molecular basis for skeletal muscle diversity.

Ifenprodil reduces excitatory synaptic transmission by blocking presynaptic P/Q type calcium channels

2012 ◽  
Vol 107 (6) ◽  
pp. 1571-1575 ◽  
Author(s):  
Andrew J. Delaney ◽  
John M. Power ◽  
Pankaj Sah
Keyword(s):  
Calcium Channels ◽  
Synaptic Transmission ◽  
Nmda Receptors ◽  
Basolateral Amygdala ◽  
Excitatory Transmission ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels ◽  
P Type ◽  
Selective Blocker

Ifenprodil is a selective blocker of NMDA receptors that are heterodimers composed of GluN1/GluN2B subunits. This pharmacological profile has been extensively used to test the role of GluN2B-containing NMDA receptors in learning and memory formation. However, ifenprodil has also been reported to have actions at a number of other receptors, including high voltage-activated calcium channels. Here we show that, in the basolateral amygdala, ifenprodil dose dependently blocks excitatory transmission to principal neurons by a presynaptic mechanism. This action of ifenprodil has an IC50 of ∼10 μM and is fully occluded by the P/Q type calcium channel blocker ω-agatoxin. We conclude that ifenprodil reduces synaptic transmission in the basolateral amygdala by partially blocking P-type voltage-dependent calcium channels.

scholarly journals Role of aldolase A in osteosarcoma progression and metastasis: In vitro and in vivo evidence

2014 ◽  
Vol 32 (5) ◽  
pp. 2031-2037 ◽  
Author(s):  
FENG LONG ◽  
XINYAN CAI ◽  
WEI LUO ◽  
LIANG CHEN ◽  
KANGHUA LI
Keyword(s):  
Aldolase A

scholarly journals Salmonella Typhimurium impairs glycolysis-mediated acidification of phagosomes to evade macrophage defense

2021 ◽  
Vol 17 (9) ◽  
pp. e1009943
Author(s):  
Saray Gutiérrez ◽  
Julia Fischer ◽  
Raja Ganesan ◽  
Nina Judith Hos ◽  
Gökhan Cildir ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Glycolytic Enzyme ◽  
Metabolic Adaptation ◽  
Adaptive Immune ◽  
Adaptive Immune Cells ◽  
Serovar Typhimurium ◽  
Extracellular Stimuli ◽  
Molecular Patterns ◽  
Aldolase A

Regulation of cellular metabolism is now recognized as a crucial mechanism for the activation of innate and adaptive immune cells upon diverse extracellular stimuli. Macrophages, for instance, increase glycolysis upon stimulation with pathogen-associated molecular patterns (PAMPs). Conceivably, pathogens also counteract these metabolic changes for their own survival in the host. Despite this dynamic interplay in host-pathogen interactions, the role of immunometabolism in the context of intracellular bacterial infections is still unclear. Here, employing unbiased metabolomic and transcriptomic approaches, we investigated the role of metabolic adaptations of macrophages upon Salmonella enterica serovar Typhimurium (S. Typhimurium) infections. Importantly, our results suggest that S. Typhimurium abrogates glycolysis and its modulators such as insulin-signaling to impair macrophage defense. Mechanistically, glycolysis facilitates glycolytic enzyme aldolase A mediated v-ATPase assembly and the acidification of phagosomes which is critical for lysosomal degradation. Thus, impairment in the glycolytic machinery eventually leads to decreased bacterial clearance and antigen presentation in murine macrophages (BMDM). Collectively, our results highlight a vital molecular link between metabolic adaptation and phagosome maturation in macrophages, which is targeted by S. Typhimurium to evade cell-autonomous defense.

scholarly journals In guinea pig sperm, aldolase A forms a complex with actin, WAS, and Arp2/3 that plays a role in actin polymerization

Reproduction ◽  
2009 ◽  
Vol 137 (4) ◽  
pp. 669-678 ◽  
Author(s):  
Natalia Chiquete-Felix ◽  
José Manuel Hernández ◽  
J Alfredo Méndez ◽  
Armando Zepeda-Bastida ◽  
Alicia Chagolla-López ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Energy Production ◽  
Actin Polymerization ◽  
Glycolytic Enzymes ◽  
Cellular Processes ◽  
Aldolase A

Glycolytic enzymes have, in addition to their role in energy production, other functions in the regulation of cellular processes. Aldolase A has been reported to be present in sperm, playing a key role in glycolysis; however, despite its reported interactions with actin and WAS, little is known about a non-glycolytic role of aldolase A in sperm. Here, we show that in guinea pig spermatozoa, aldolase A is tightly associated to cytoskeletal structures where it interacts with actin, WAS, and Arp2/3. We show that aldolase A spermatozoa treatment increases their polymerized actin levels. In addition, we show that there is a direct correlation between the levels of polymerized actin and the levels of aldolase A–actin interaction. Our results suggest that aldolase A functions as a bridge between filaments of actin and the actin-polymerizing machinery.

Kv1.1-Containing Channels Are Critical for Temporal Precision During Spike Initiation

2006 ◽  
Vol 96 (3) ◽  
pp. 1203-1214 ◽  
Author(s):  
Joshua X. Gittelman ◽  
Bruce L Tempel
Keyword(s):  
Brain Slices ◽  
Temporal Precision ◽  
Medial Nucleus ◽  
Whole Cell Patch Clamp ◽  
Latency Variability ◽  
Low Threshold ◽  
Rapid Stimulation ◽  
Spike Initiation ◽  
Selective Blocker

Low threshold, voltage-gated potassium currents ( Ikl) are widely expressed in auditory neurons that can fire temporally precise action potentials (APs). In the medial nucleus of the trapezoid body (MNTB), channels containing the Kv1.1 subunit (encoded by the Kcna1 gene) underlie Ikl. Using pharmacology, genetics and whole cell patch-clamp recordings in mouse brain slices, we tested the role of Ikl in limiting AP latency-variability (jitter) in response to trains of single inputs at moderate to high stimulation rates. With dendrotoxin-K (DTX-K, a selective blocker of Kv1.1-containing channels), we blocked Ikl maximally (≈80% with 100 nM DTX-K) or partially (≈50% with 1-h incubation in 3 nM DTX-K). Ikl was similar in 3 nM DTX-K–treated cells and cells from Kcna1−/− mice, allowing a comparison of these two different methods of Ikl reduction. In response to current injection, Ikl reduction increased the temporal window for AP initiation and increased jitter in response to the smallest currents that were able to drive APs. While 100 nM DTX-K caused the largest increases, latency and jitter in Kcna1 −/ − cells and in 3 nM DTX-K–treated cells were similar to each other but increased compared with +/+. The near-phenocopy of the Kcna1−/− cells with 3 nM DTX-K shows that acute blockade of a subset of the Kv1.1-containing channels is functionally similar to the chronic elimination of all Kv1.1 subunits. During rapid stimulation (100–500 Hz), Ikl reduction increased jitter in response to both large and small inputs. These data show that Ikl is critical for maintaining AP temporal precision at physiologically relevant firing rates.

scholarly journals Role of EDHF in type 2 diabetes-induced endothelial dysfunction

2008 ◽  
Vol 295 (5) ◽  
pp. H1982-H1988 ◽  
Author(s):  
Yoonjung Park ◽  
Stefano Capobianco ◽  
Xue Gao ◽  
John R. Falck ◽  
Kevin C. Dellsperger ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Dysfunction ◽  
Neutralizing Antibody ◽  
Prostaglandin Synthase ◽  
Mrna And Protein Expression ◽  
Synthase Inhibitor ◽  
Selective Blocker ◽  
Small Conductance

Endothelium-derived hyperpolarizing factor (EDHF) plays a crucial role in modulating vasomotor tone, especially in microvessels when nitric oxide-dependent control is compromised such as in diabetes. Epoxyeicosatrienoic acids (EETs), potassium ions (K+), and hydrogen peroxide (H2O2) are proposed as EDHFs. However, the identity (or identities) of EDHF-dependent endothelial dilators has not been clearly elucidated in diabetes. We assessed the mechanisms of EDHF-induced vasodilation in wild-type (WT, normal), db/db (advanced type 2 diabetic) mice, and db/db mice null for TNF (dbTNF−/dbTNF−). In db/db mice, EDHF-induced vasodilation [ACh-induced vasodilation in the presence of NG-nitro-l-arginine methyl ester (l-NAME, 10 μmol/l) and prostaglandin synthase inhibitor indomethacin (Indo, 10 μmol/l)] was diminished after the administration of catalase (an enzyme that selectively dismutates H2O2 to water and oxygen, 1,000 U/ml); administration of the combination of charybdotoxin (a nonselective blocker of intermediate-conductance Ca2+-activated K+ channels, 10 μmol/l) and apamin (a selective blocker of small-conductance Ca2+-activated K+ channels, 50 μmol/l) also attenuated EDHF-induced vasodilation, but the inhibition of EETs synthesis [14,15-epoxyeicosa-5(Z)-enoic acid; 10 μmol/l] did not alter EDHF-induced vasodilation. In WT controls, EDHF-dependent vasodilation was significantly diminished after an inhibition of K+ channel, EETs synthesis, or H2O2 production. Our molecular results indicate that mRNA and protein expression of interleukin-6 (IL-6) were greater in db/db versus WT and dbTNF−/dbTNF− mice, but neutralizing antibody to IL-6 (anti-IL-6; 0.28 mg·ml−1·kg−1 ip for 3 days) attenuated IL-6 expression in db/db mice. The incubation of the microvessels with IL-6 (5 ng/ml) induced endothelial dysfunction in the presence of l-NAME and Indo in WT mice, but anti-IL-6 restored ACh-induced vasodilation in the presence of l-NAME and Indo in db/db mice. In dbTNF−/dbTNF− mice, EDHF-induced vasodilation was greater and comparable with controls, but IL-6 decreased EDHF-mediated vasodilation. Our results indicate that EDHF compensates for diminished NO-dependent dilation in IL-6-induced endothelial dysfunction by the activation of H2O2 or a K+ channel in type 2 diabetes.

TRPC6, a Therapeutic Target for Pulmonary Hypertension

2021 ◽  
Author(s):  
Pritesh P. Jain ◽  
Ning Lai ◽  
Mingmei Xiong ◽  
Jiyuan Chen ◽  
Aleksandra Babicheva ◽  
...  
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Vasoconstriction ◽  
Good Target ◽  
Trpc6 Channel ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle ◽  
Orally Bioavailable ◽  
Selective Blocker

Idiopathic pulmonary arterial hypertension (PAH) is a fatal and progressive disease. Pulmonary vasoconstriction due to pulmonary arterial smooth muscle cell (PASMC) contraction and pulmonary arterial remodeling due to PASMC proliferation are causes for increased pulmonary vascular resistance in patients with PAH. We and others observed upregulation of TRPC6 channels in PASMC from patients with PAH. An increase in cytosolic Ca2+ concentration ([Ca2+]cyt) in PASMC triggers PASMC contraction and vasoconstriction, while Ca2+-dependent activation of PI3K/AKT/mTOR pathway is pivotal for cell proliferation and gene expression. Despite evidence supporting a pathological role of TRPC6, no selective and orally bioavailable TRPC6 blocker has yet been developed and tested for treatment of PAH. We sought to investigate whether block of receptor-operated Ca2+ channels or TRPC6 can reverse established PH in mice via inhibiting Ca2+-dependent activation of AKT/mTOR signaling. Here we report that intrapulmonary application of 2-aminoethyl diphenyl borniate (2-APB), a non-selective blocker of cation channels or BI-749237, a selective blocker of TRPC6, significantly and reversibly inhibited acute hypoxic pulmonary vasoconstriction. Intraperitoneal injection of 2-APB significantly attenuated the development of PH and partially reversed established PH. Oral gavage of the selective TRPC6 blocker BI-749237 reversed established PH by 50% via regression of pulmonary vascular remodeling. Furthermore, 2-APB and BI-749237 both inhibited PDGF- and serum-mediated phosphorylation of AKT and mTOR in PASMC. These results indicates that the receptor-operated and mechanosensitive TRPC6 channel is a good target for developing novel treatment for PAH. BI-749237, a selective TRPC6 blocker, is potentially a novel and effective drug for treating PAH.

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