Probucol inhibits JAK2−STAT pathway activation and protects human glomerular mesangial cells from tert-butyl hydroperoxide induced premature senescence

Abstract

Human mesangial cells (HMCs) have a finite lifespan and eventually enter irreversible growth arrest known as cellular senescence, which is thought to contribute to kidney ageing and age-related kidney disorders such as chronic kidney disease. The JAK2-STAT pathway plays a pivotal role in transmitting cytokine signals, including cell proliferation, apoptosis, and differentiation, but whether it could regulate HMC senescence still remains to be explored. In our study, tert-butyl hydroperoxide (tBHP)-induced cells accelerated HMC senescence, as judged by increased senescence-associated β-galactosidase stained positive cells, morphological changes, and G0-G1 cell cycle arrest. STAT1 and STAT3 activity were increased in tBHP-induced cells. After tBHP treatment, Bcl-2 protein expression decreased and Bax protein expression increased. Blocking the JAK2-STAT pathway with AG490 and using probucol significantly inhibited the progression of HMC senescence. Bax protein expression decreased, but Bcl-2 protein expression increased after AG490 and probucol treatment. Our results indicated that the JAK2-STAT pathway might mediate tBHP-induced HMC senescence through the Bcl-2-Bax pathway, and that probucol could attenuate HMC senescence by regulating STATs.

The synthesis, characterization and catecholase activity of dinuclear cobalt(ii/iii) complexes of an O-donor rich Schiff base ligand

“…1.5 h the rate was rather enhanced. 10 molar equivalents of probucol (hydroxy radical, peroxide and superoxide inhibitor) 61,62 however showed ca. 13% inhibition throughout the reaction.…”

TNFα-senescence initiates a STAT-dependent positive feedback loop, leading to a sustained interferon signature, DNA damage, and cytokine secretion

“…Mitogen Activated Protein Kinase (MAPK) pathways (ERK, JNK, and p38) are also known to be implicated in senescence [ 26 ]. In particular, activation of p38 MAPK has been reported to play a significant role in stress-induced senescence [ 27 – 29 ]. In addition, cytokine signaling pathways, such as NF-κB, Ras-MEF-ERK, and Janus Kinase (JAK)/ signal transducers and activators of transcription (STAT), are among pathways that contribute to senescence and the SASP [ 30 – 34 ].…”

JAK2 inhibitor combined with DC-activated AFP-specific T-cells enhances tantitumor function in a Fas/FasL signal-independent pathway

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