Journal: RSC Advances

Article Title: Therapeutic potential of adenosine receptor modulators in cancer treatment

doi: 10.1039/d5ra02235e

Figure Lengend Snippet: Synthesis, storage, release, and signalling pathways of adenosine through adenosine receptors. ATP – “Adenosine triphosphate”, CD73 – “Ecto-5′-nucleotidase” cAMP – “Cyclic adenosine monophosphate”, ADA – “Adenosine deaminase”, ADA – “Adenosine deaminase”, XO – “Xanthine oxidase”, CD39 – Ectonucleoside triphosphate diphosphohydrolase-1, PDE – “Phosphodiesterase”, SAH – “S-adenosyl-homocysteine”, 5-AMP – “5-Adenosine monophosphate”, PNP – “Purine nucleoside phosphorylase”, ADP – “Adenosine diphosphate”, 5NT – “5′-Nucleotidase”, ecto-AK – “Extracellular adenosine kinase”, A 1 AR – “A 1 adenosine receptor”, K + channel – “Potassium channels”, A 2B AR – “A 2B adenosine receptor”, cAMP – “cyclic adenosine monophosphate”, G i – “inhibitory G-proteins”, A 2A AR – “A 2A adenosine receptor”, AC – “Adenyl cyclase”, G s – “Stimulatory G-proteins”, PKA – “Protein kinase A” A 3 AR – “A 3 adenosine receptor”. The figure was created in BioRender. Deb, P. (2025).

Article Snippet: Etrumadenant (AB928) , NCT03720678 , I/Ib , Arcus Biosciences , Gastroesophageal cancer and colorectal cancer , , A 2A AR and A 2B AR have K d values of 1.4 nM and 2 nM, respectively, for this new dual-active A 2A /A 2B AR antagonist .

Techniques:

Journal: RSC Advances

Article Title: Therapeutic potential of adenosine receptor modulators in cancer treatment

doi: 10.1039/d5ra02235e

Figure Lengend Snippet: Synthesis, storage, release, and signalling pathways of adenosine through adenosine receptors. ATP – “Adenosine triphosphate”, CD73 – “Ecto-5′-nucleotidase” cAMP – “Cyclic adenosine monophosphate”, ADA – “Adenosine deaminase”, ADA – “Adenosine deaminase”, XO – “Xanthine oxidase”, CD39 – Ectonucleoside triphosphate diphosphohydrolase-1, PDE – “Phosphodiesterase”, SAH – “S-adenosyl-homocysteine”, 5-AMP – “5-Adenosine monophosphate”, PNP – “Purine nucleoside phosphorylase”, ADP – “Adenosine diphosphate”, 5NT – “5′-Nucleotidase”, ecto-AK – “Extracellular adenosine kinase”, A 1 AR – “A 1 adenosine receptor”, K + channel – “Potassium channels”, A 2B AR – “A 2B adenosine receptor”, cAMP – “cyclic adenosine monophosphate”, G i – “inhibitory G-proteins”, A 2A AR – “A 2A adenosine receptor”, AC – “Adenyl cyclase”, G s – “Stimulatory G-proteins”, PKA – “Protein kinase A” A 3 AR – “A 3 adenosine receptor”. The figure was created in BioRender. Deb, P. (2025).

Article Snippet: Etrumadenant (AB928) , NCT03720678 , I/Ib , Arcus Biosciences , Gastroesophageal cancer and colorectal cancer , , A 2A AR and A 2B AR have K d values of 1.4 nM and 2 nM, respectively, for this new dual-active A 2A /A 2B AR antagonist .

Techniques:

Journal: RSC Advances

Article Title: Therapeutic potential of adenosine receptor modulators in cancer treatment

doi: 10.1039/d5ra02235e

Figure Lengend Snippet: Synthesis, storage, release, and signalling pathways of adenosine through adenosine receptors. ATP – “Adenosine triphosphate”, CD73 – “Ecto-5′-nucleotidase” cAMP – “Cyclic adenosine monophosphate”, ADA – “Adenosine deaminase”, ADA – “Adenosine deaminase”, XO – “Xanthine oxidase”, CD39 – Ectonucleoside triphosphate diphosphohydrolase-1, PDE – “Phosphodiesterase”, SAH – “S-adenosyl-homocysteine”, 5-AMP – “5-Adenosine monophosphate”, PNP – “Purine nucleoside phosphorylase”, ADP – “Adenosine diphosphate”, 5NT – “5′-Nucleotidase”, ecto-AK – “Extracellular adenosine kinase”, A 1 AR – “A 1 adenosine receptor”, K + channel – “Potassium channels”, A 2B AR – “A 2B adenosine receptor”, cAMP – “cyclic adenosine monophosphate”, G i – “inhibitory G-proteins”, A 2A AR – “A 2A adenosine receptor”, AC – “Adenyl cyclase”, G s – “Stimulatory G-proteins”, PKA – “Protein kinase A” A 3 AR – “A 3 adenosine receptor”. The figure was created in BioRender. Deb, P. (2025).

Article Snippet: M1069 , NCT05198349 , I , EMD Serono Research & Development Institute , Locally advanced unresectable solid tumors , , A 2A /A 2B AR antagonist.

Techniques:

Journal: bioRxiv

Article Title: Chronic stress impairs autoinhibition in neurons of the locus coeruleus to increase asparagine endopeptidase activity

doi: 10.1101/2025.03.10.642335

Figure Lengend Snippet: ( A, B ) Confocal images of LC neurons showing immunoreactivities for TH and α2A-ARs, together with a merged one in non-stress and 3-day RS mice. Arrowheads indicate the membrane regions of TH-positive neurons, along which α2A-ARs were differentially expressed between the control and the RS mice. Asterisks indicate LC neurons. ( C ) Western blotting analyses showing the expression of α2A-ARs in non-stress and 3-day RS mice ( n = 6 and 7, respectively). Unpaired t -test, † p < 0.001. ( D, E ) Confocal images of LC neurons in non-stress and RS mice. Upper panels from left to right showing the respective immunoreactivity for TH, α2A-ARs (with rabbit anti-α2A-AR) and Na + -K + -pump and an enlarged image of the region enclosed with a rectangle (arrowheads) in its immediate left panel. Lower panels from left to right showing the merged image of TH and α2A-ARs, that of TH, α2A-ARs and Na + -K + -pump, that of α2A-ARs and Na + -K + -pump and an enlarged image of the region enclosed with a rectangle in its immediate left panel. ( F, G ) Western blotting analyses showing expressions of α2A-ARs and Na + -K + -pump in membrane fraction and those of α2A-ARs and β-actin in cytosol fraction in non-stress and 5-day RS mice ( n = 3 and 3 samples, respectively). Each sample represents the analysis result in the LC tissues obtained from 2-3 mice. Membrane; unpaired t -test, † p = 0.016. Cytosol; unpaired t -test, † p = 0.083.

Article Snippet: To examine the distribution of α2A-AR in LC neurons, mouse anti-TH (1:500; sc-25269, Santa Cruz Biotechnology, Santa Cruz, CA, USA), rabbit anti-sodium potassium ATPase (1:1000; ab76020, Abcam, Cambridge, MA, USA) and goat anti-α2A-AR (1:200; ab45871, Abcam) or rabbit anti-α2A-AR (1:500; RA14110, Neuromics, Northfield, MN, USA) were used as primary antibodies, while cy5 donkey anti-mouse IgG (1:500; cy-2500, Vector Laboratories, Burlingame, CA, USA), FITC donkey anti-rabbit IgG (1:500; 711-095-152, Jackson ImmunoResearch, West Grove, PA, USA) and Cy3 donkey anti-goat IgG (1:500; 706-165-147, Jackson ImmunoResearch) were used as secondary antibodies.

Techniques: Membrane, Control, Western Blot, Expressing

Journal: bioRxiv

Article Title: Chronic stress impairs autoinhibition in neurons of the locus coeruleus to increase asparagine endopeptidase activity

doi: 10.1101/2025.03.10.642335

Figure Lengend Snippet: ( A-E ) Representative traces of NA-induced GIRK-I obtained from LC neurons in non-stress and 1-day, 2-day, 3-day, and 5-day RS mice. ( F, G ) Amplitudes of inward and outward components of NA-induced GIRK-I obtained from LC neurons in non-stress and 1-day, 2-day, 3-day, and 5-day RS mice ( n = 8, 7, 5, 6 and 8, respectively) decreased with the increase in the period of RS, in a way that can be described by a saturation function (red interrupted lines). The saturation level ( a + b ) and the half saturation constant ( c ) were determined by fitting the saturation function, defined as y = a + ( b * x) / ( c + x), to the data points. The values of a , b and c for the inward component of GIRK-I were −151.1, 108, and 0.9, respectively, and those for the outward component of GIRK-I were 81.1, –67, and 1.6, respectively. Inward component: one-way ANOVA, p < 0.001, post hoc fisher’s PLSD, 1-day; # p < 0.001 vs Non-stress and * p < 0.05 vs 3-day and 5-day, 2-day; # p < 0.001 vs Non-stress, 3-day; # p < 0.001 vs Non-stress, 5-day; # p < 0.001 vs Non-stress. Outward component: one-way ANOVA, p < 0.001, post hoc fisher’s PLSD, 1-day; p = 0.004 vs Non-stress and * p < 0.05 vs 3-day and 5-day, 2-day; p = 0.015 vs Non-stress, 3-day; p < 0.001 vs Non-stress, 5-day; p < 0.001 vs Non-stress. ( H ) Relative expressions of α2A and α2C mRNAs, normalized to GAPDH in LC neurons ( n = 5). Paired t -test, ‡ p = 0.014. ( I ) Relative expressions of GIRK1, GIRK2, and GIRK3 mRNAs, normalized to GAPDH in LC neurons ( n = 5). One-way RM ANOVA, p < 0.001, post hoc fisher’s PLSD; * p = 0.008 for GIRK1 vs GIRK2, * p < 0.001 for GIRK1 vs GIRK3, * p = 0.008 for GIRK2 vs GIRK3. ( J, K ) Relative expressions of α2A and GIRK1 mRNAs, respectively, normalized to GAPDH in LC neurons in non-stress mice ( n = 8), and 3-day RS mice ( n = 6). α2A-AR: unpaired t -test, † p = 0.020; GIRK1: unpaired t -test, † p = 0.013. (L) Normalized relative expressions of GIRK2 mRNA in LC neurons in non-stress mice ( n = 8) and 3-day RS mice ( n = 6), normalized to the ratio of the mean value of the relative expressions of GIRK1 mRNA to that of GIRK2 mRNA in LC neurons in non-stress mice ( I ). Unpaired t -test, † p = 0.037.

Article Snippet: To examine the distribution of α2A-AR in LC neurons, mouse anti-TH (1:500; sc-25269, Santa Cruz Biotechnology, Santa Cruz, CA, USA), rabbit anti-sodium potassium ATPase (1:1000; ab76020, Abcam, Cambridge, MA, USA) and goat anti-α2A-AR (1:200; ab45871, Abcam) or rabbit anti-α2A-AR (1:500; RA14110, Neuromics, Northfield, MN, USA) were used as primary antibodies, while cy5 donkey anti-mouse IgG (1:500; cy-2500, Vector Laboratories, Burlingame, CA, USA), FITC donkey anti-rabbit IgG (1:500; 711-095-152, Jackson ImmunoResearch, West Grove, PA, USA) and Cy3 donkey anti-goat IgG (1:500; 706-165-147, Jackson ImmunoResearch) were used as secondary antibodies.

Techniques:

Journal: bioRxiv

Article Title: Chronic stress impairs autoinhibition in neurons of the locus coeruleus to increase asparagine endopeptidase activity

doi: 10.1101/2025.03.10.642335

Figure Lengend Snippet: ( A, B ) Differential free concentrations of NA to be metabolized by MAO-A into DOPEGAL between control and stress conditions: Under the control condition ( A ), NA in the cytosol is mostly taken up into the cytoplasmic vesicles by vMAT2 (thick arrow 3), rather than being directly metabolized by MAO-A into DOPEGAL (thin interrupted arrow). Vesicular NA is released from cell bodies as autocrine following [Ca 2+ ] i increases caused by action potentials, and the released NA activates α2A-AR-coupled GIRK channels, causing autoinhibition. Subsequently, the autocrine released NA is slowly taken up into the cytosol of LC neurons by NAT after dissociation from α2A-ARs. Under the stress condition ( B ), an activation of CRF receptors in LC neurons by stress inhibits leak K + channels and increases firing activities in LC neurons, subsequently causing a larger [Ca 2+ ] i increase together with Ca 2+ -induced Ca 2+ release (CICR). Impairment of autoinhibiton due to Ca 2+ dependent internalization of α2A-ARs-coupled GIRK channels leads to the persistent excitation in LC neurons, which enhances autocrine release of NA (thick arrow 1). Subsequently, the excessively autocrine released NA is taken up directly and rapidly by NAT into the cytosol without binding to α2A-ARs (thick arrow 2). Such a facilitation of re-uptake of NA by NAT would increase active NA storage into cytoplasmic vesicles by vMAT2 (thick arrow 3), while the rate of NA leakage from cytoplasmic vesicles would also increase (arrow 4) due to a dynamic equilibrium in cytoplasmic vesicles between active NA storage into cytoplasmic vesicles and passive NA leakage from cytoplasmic vesicles. Subsequently, such an increase in the rate of NA leakage would result in an increase in a MAO-A metabolite, DOPEGAL and AEP, leading to a production of cleaved tau N368 fragment and an impairment of learning/memory.

Article Snippet: To examine the distribution of α2A-AR in LC neurons, mouse anti-TH (1:500; sc-25269, Santa Cruz Biotechnology, Santa Cruz, CA, USA), rabbit anti-sodium potassium ATPase (1:1000; ab76020, Abcam, Cambridge, MA, USA) and goat anti-α2A-AR (1:200; ab45871, Abcam) or rabbit anti-α2A-AR (1:500; RA14110, Neuromics, Northfield, MN, USA) were used as primary antibodies, while cy5 donkey anti-mouse IgG (1:500; cy-2500, Vector Laboratories, Burlingame, CA, USA), FITC donkey anti-rabbit IgG (1:500; 711-095-152, Jackson ImmunoResearch, West Grove, PA, USA) and Cy3 donkey anti-goat IgG (1:500; 706-165-147, Jackson ImmunoResearch) were used as secondary antibodies.

Techniques: Control, Activation Assay, Binding Assay