Chemical chaperone TUDCA prevents apoptosis and improves survival during polymicrobial sepsis in mice

Doerflinger, Marcel; Glab, Jason; Nedeva, Christina; Jose, Irvin; Lin, Ann; O’Reilly, Lorraine A.; Allison, Cody; Pellegrini, Marc; Hotchkiss, Richard S.; Puthalakath, Hamsa

doi:10.1038/srep34702

Cited by 16 publications

(21 citation statements)

References 36 publications

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“…1A). As previously demonstrated [13], the conditioned macrophage supernatant potently induces cell death in a Bim‐dependent manner (Figs 1B and 3B).…”

Section: Resultssupporting

confidence: 85%

Circulating BiP/Grp78 is a novel prognostic marker for sepsis‐mediated immune cell death

et al. 2020

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Death of immune cells is a significant contributor to the pathology of polymicrobial sepsis. Diagnosis of sepsis‐induced lymphophenia is currently challenged by a lack of accurate biomarkers for the condition. Here, Hamsa Puthalakath and co‐authors report that lipopolysaccharide‐activated macrophages release the ER chaperone BiP (binding immunoglobin protein, also known as GRP78) into the extracellular milieu. This secreted form of BiP binds target cells through an unknown receptor and induces ER stress, resulting in apoptosis. Secreted circulating BiP could be used as a prognostic marker for immune cell death during sepsis.

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“…1A). As previously demonstrated [13], the conditioned macrophage supernatant potently induces cell death in a Bim‐dependent manner (Figs 1B and 3B).…”

Section: Resultssupporting

confidence: 85%

Circulating BiP/Grp78 is a novel prognostic marker for sepsis‐mediated immune cell death

et al. 2020

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“…31 We suggest that the changes in the glycosylation profile my promote a decrease in WBC numbers in TM treated animals. TUDCA is known to maintain lymphocyte homeostasis by significantly reducing lymphocyte apoptosis 32 and this may be the mechanism by which it resulted in relatively stable WBC counts as observed herein.…”

Section: Discussionsupporting

confidence: 56%

Organ function, sphingolipid levels and inflammation in tunicamycin induced endoplasmic reticulum stress in male rats

et al. 2020

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Disorders of the endoplasmic reticulum (ER) lead to cellular damage but can cause cell death if ER dysfunction is prolonged. We aimed to examine liver/kidney functions, neutral sphingomyelinase (N-SMase) activity, sphingolipid levels, cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX-2) protein expression in rats under ER stress. ER stress was induced by tunicamycin (TM) and the ER stress inhibitor taurodeoxycholic acid (TUDCA) was injected before induction of ER stress. ER stress was confirmed by increased tissue levels of GRP78. Hematological and biochemical profiles were measured by autoanalyzers while hepatic and renal injury was evaluated via microscopy and histopathological scoring. Tissue levels of C16-C24 sphingomyelins (SM), C16-C24 ceramides (CERs) and sphingosine-1-phosphate (S1P) were determined by LC-MS/MS. Tissue cPLA2 and COX-2 were measured by western blot and activity assays. Tunicamycin treatment caused kidney and liver function test abnormalities, increased hematocrit and hemoglobin levels but decreased white blood cell counts. Histopathological findings showed hepatic necroinflammation and renal tubular damage in rats treated with TM. TUDCA administration attenuated WBC abnormalities and TM- induced hepatic/renal functional impairment in ER stress, as evident by significantly restored serum ALT, AST, creatinine, and total bilirubin levels. A significant increase was observed in N-SMase activity, tissue levels of C16-C24 CERs, cPLA2 and COX-2 expression in liver and kidney tissue under ER stress. TUDCA administration decreased tissue CER levels, cPLA2 and COX-2 expression as well as prostaglandin E2 (PGE2) formation. These results signify that ER stress causes hepatic and renal toxicity as well as CER-induced PGE2 formation in liver and kidney.

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“… 10 We also recently reported a role for ER stress-mediated BIM induction in lymphocytes during sepsis in mice. 11 Thus, there appears to be a division of labor among various BH3-only proteins (i.e. PUMA largely in neuronal cells, NOXA and PUMA in fibroblasts and BIM in lymphocytes, myeloid cells as well as epithelial cells in inducing ER stress-mediated apoptosis).…”

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confidence: 99%

BH3-only proteins: the thorny end of the ER stress response

2017

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Chemical chaperone TUDCA prevents apoptosis and improves survival during polymicrobial sepsis in mice

Cited by 16 publications

References 36 publications

Circulating BiP/Grp78 is a novel prognostic marker for sepsis‐mediated immune cell death

Circulating BiP/Grp78 is a novel prognostic marker for sepsis‐mediated immune cell death

Organ function, sphingolipid levels and inflammation in tunicamycin induced endoplasmic reticulum stress in male rats

BH3-only proteins: the thorny end of the ER stress response

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