Expression of concern: Compensatory increase of transglutaminase 2 is responsible for resistance to mTOR inhibitor treatment

Pancreatic fibrosis is a pathological characteristic of chronic pancreatitis (CP) and pancreatic cancer. Chaihu Guizhi Ganjiang Decoction (CGGD) is a traditional Chinese medicine, which is widely used in the clinical treatment of digestive diseases. However, the potential anti-fibrosis mechanism of CGGD in treating CP remains unclear. Here, we conducted a series of experiments to examine the effect of CGGD on the CP rat model and primary isolated pancreatic stellate cells (PSCs). The results revealed that CGGD attenuated pancreatic damage, decreased collagen deposition, and inhibited PSC activation in the pancreas of CP rats. However, compared with the CP group, CGGD had no effect on body weight and serum amylase and lipase. In addition, CGGD suppressed autophagy by downregulating Atg5, Beclin-1, and LC3B and facilitated phosphorylation of mTOR and JNK in pancreatic tissues and PSCs. Moreover, the CGGD-containing serum also decreased LC3B or collagen I expression after rapamycin (mTOR inhibitor) or SP600125 (JNK inhibitor) treatment in PSCs. In conclusion, CGGD attenuated pancreatic fibrosis and PSC activation, possibly by suppressing autophagy of PSCs through the JNK/mTOR signaling pathway.

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Early Use of mTOR Inhibitors in Tuberous Sclerosis: Current State and Plan for a Prospective Clinical Trial of Early Prophylactic mTOR Inhibitor Treatment (PROTECT)

10.1055/s-0041-1739702 ◽

2021 ◽

Author(s):

S. Syrbe ◽

A. Saffari

Keyword(s):

Clinical Trial ◽

Tuberous Sclerosis ◽

Mtor Inhibitor ◽

Mtor Inhibitors ◽

Prospective Clinical Trial ◽

Current State ◽

Early Use ◽

Inhibitor Treatment

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Pulse mTOR inhibitor treatment effectively controls cyst growth but leads to severe parenchymal and glomerular hypertrophy in rat polycystic kidney disease

AJP Renal Physiology ◽

10.1152/ajprenal.00430.2009 ◽

2009 ◽

Vol 297 (6) ◽

pp. F1597-F1605 ◽

Cited By ~ 30

Author(s):

Ming Wu ◽

Alexandre Arcaro ◽

Zsuzsanna Varga ◽

Alexander Vogetseder ◽

Michel Le Hir ◽

...

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Kidney Function ◽

Mtor Inhibitor ◽

Autosomal Dominant ◽

Mtor Inhibitors ◽

Glomerular Hypertrophy ◽

Polycystic Kidney ◽

Autosomal Dominant Polycystic Kidney ◽

Inhibitor Treatment

The efficacy of mammalian target of rapamycin (mTOR) inhibitors is currently tested in patients affected by autosomal dominant polycystic kidney disease. Treatment with mTOR inhibitors has been associated with numerous side effects. However, the renal-specific effect of mTOR inhibitor treatment cessation in polycystic kidney disease is currently unknown. Therefore, we compared pulse and continuous everolimus treatment in Han:SPRD rats. Four-week-old male heterozygous polycystic and wild-type rats were administered everolimus or vehicle by gavage feeding for 5 wk, followed by 7 wk without treatment, or continuously for 12 wk. Cessation of everolimus did not result in the appearance of renal cysts up to 7 wk postwithdrawal despite the reemergence of S6 kinase activity coupled with an overall increase in cell proliferation. Pulse everolimus treatment resulted in striking noncystic renal parenchymal enlargement and glomerular hypertrophy that was not associated with compromised kidney function. Both treatment regimens ameliorated kidney function, preserved the glomerular-tubular connection, and reduced proteinuria. Pulse treatment at an early age delays cyst development but leads to striking glomerular and parenchymal hypertrophy. Our data might have an impact when long-term treatment using mTOR inhibitors in patients with autosomal dominant polycystic kidney disease is being considered.

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