A Selective Adenosine A Receptor Antagonist, HL3501, Has Therapeutic Potential in Preclinical Liver and Renal Fibrosis Models.

Background/aim: Adenosine and 4 G-protein-associated membrane receptors (A, A, A, and A) and their derivatives regulate the central nervous, cardiovascular, peripheral, and immune system. We developed a novel selective A AR antagonist, HL3501, and examined its anti-fibrotic effects across various models.

Materials And Methods: The anti-fibrotic activity of HL3501 was evaluated in three cell lines (HK2, LX2, and Primary hepatic stellate cell) and a methionine-choline-deficient (MCD) model including use of mouse pharmacokinetics (PK).

HL3501, a Novel Selective A3 Adenosine Receptor Antagonist, Lowers Intraocular Pressure (IOP) in Animal Glaucoma Models.

Purpose: The A3 adenosine receptor (A3AR) is a known therapeutic target for glaucoma treatment. In this study, we developed HL3501 and examined its selectivity profile and in vitro and in vivo effects.

Methods: For the rabbit model, intraocular pressure (IOP) was increased by laser photocoagulation of the trabecular meshwork (TM).

1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) attenuates gemcitabine-induced neutrophil extravasation.

Cancer patients treated with chemotherapy often experience a rapid decline of blood neutrophils, a dose-limiting side effect called chemotherapy-induced neutropenia. This complication brings about dose reductions or cessation of chemotherapy during treatment of cancer patients because a rapid decline of neutrophil counts increases susceptibility to infection. Here, we found that 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) attenuates gemcitabine-induced neutrophil extravasation via the inhibition of neutrophil-attracting chemokine production in macrophages using in vivo and in vitro approaches.

Microvasculature remodeling in the mouse lower gut during inflammaging.

Inflammaging is defined as low-grade, chronic, systemic inflammation in aging, in the absence of overt infection. Age-associated deterioration of gastrointestinal function could be ascribed to the inflammaging, although evidence is yet to emerge. Here we show that microvessels in aging mouse intestine were progressively deprived of supportive structures, microvessel-associated pericytes and adherens junction protein vascular endothelial (VE)-cadherin, and became leaky.

Spred-1 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness.

T helper 2 cytokines, including interleukin (IL)-4, IL-5, and IL-13, play a critical role in allergic asthma. These cytokines transmit signals through the Janus kinase/signal transducer and activator of transcription (STAT) and the Ras-extracellular signal-regulated kinase (ERK) signaling pathways. Although the suppressor of cytokine signaling (SOCS) family proteins have been shown to regulate the STAT pathway, the mechanism regulating the ERK pathway has not been clarified.

Abrogation of autoimmune disease in Lyn-deficient mice by the deletion of IL-5 receptor alpha chain gene.

Lyn, the src-family protein tyrosine kinase, plays a crucial role in the regulation of B cell antigen receptor (BCR)- and IL-5-receptor (IL-5R)-mediated signaling. Lyn-deficient mice have been reported to exhibit an increase in B-1 cell numbers, splenomegaly and accumulation of lymphoblast-like cells in the spleen with age, resulting in hyperimmunoglobulinemia and glomerulonephritis caused by the deposition of autoantibody complexes. To elucidate the role of IL-5 in B-1 cell activation, autoantibody production and autoimmune diseases, Lyn-deficient mice were crossed with IL-5Ralpha chain (IL-5Ralpha)-deficient mice and generated Lyn- and IL-5Ralpha-deficient (DKO) mice.

The role of IL-5 for mature B-1 cells in homeostatic proliferation, cell survival, and Ig production.

B-1 cells, distinguishable from conventional B-2 cells by their cell surface marker, anatomical location, and self-replenishing activity, play an important role in innate immune responses. B-1 cells constitutively express the IL-5R alpha-chain (IL-5Ralpha) and give rise to Ab-producing cells in response to various stimuli, including IL-5 and LPS. Here we report that the IL-5/IL-5R system plays an important role in maintaining the number and the cell size as well as the functions of mature B-1 cells.