Shanghai Jiaotong University School of Medicine: The pancreas has an autonomous biological clock Restart pancreatic clock therapy is expected as a treatment strategy

Restart the (pancreas) clock

The pancreas has an autonomous biological clock, but its relationship to chronic pancreatitis (CP) was previously unclear
.
Here, researchers at Shanghai Jiaotong University School of Medicine used human tissue and transgenic mouse models to find that disruption of the pancreatic clock in chronic pancreatitis leads to worsening fibrosis and exocrine insufficiency
.
They found that when this circadian stable cycle is impaired, it leads to the loss of pancreatic Bmal1, which leads to pancreatic stellate cell activation and fiber formation
.
The combination of melatonin and retinic acid receptor-associated solitary receptor A agonist SR1078 mitigated fibrotic changes in mouse models of chronic pancreatitis, suggesting that therapy for pancreatic clock could be further studied
as a strategy for treating chronic pancreatitis in humans.
The article was published in the new issue of the journal Science Translational Medicine
.

Chronic pancreatitis (CP), characterized by progressive fibrosis and exocrine disorders, has long been considered irreversible
.
As a peripheral oscillator, the pancreas has an autonomous and self-sustaining circadian clock system in both its endocrine and exocrine chambers, although its role is unclear
.
By establishing different CP models for mice with pancreatic clock dysfunction, the researchers found that local clocks play an important role in the pathological process of chronic pancreatitis, while genetic or external interference with pancreatic clocks exacerbates fiber formation and exocrine insufficiency
.
Mechanologically, the circadian rhythm stabilization loop—retinoic acid receptor–related orphan receptor A (Rora)/nuclear receptor subfamily 1), group D, (Nr1d1)/aromatic hydrocarbon receptor nuclear translocation (Arntl or).
Bmal1) rings, which cause pancreatic Bmal1 deficiency after the loop is damaged – where Bmal1 is responsible for controlling the fibrotic properties of pancreatic stellate cells (PSCs) and reconnecting the function of
acinar cells in a clock-transforming growth factor signal-IL-11/IL-11RA axis-dependent.
During PSC activation, the antagonistic effect between Nr1d1 and Rolla is unbalanced, which is caused
by the loss of retinoic acid containing lipid droplets in the cytoplasm.
Endogenous melatonin secretion is also reduced
in patients with chronic pancreatitis.
Using a combination of melatonin and the Rolla agonist SR1078, which improves the circadian rhythm stabilization ring by pharmacology, thereby mitigating intrapancreatic pathological changes in a mouse model of CP, this study identified the protective effect
of the pancreatic circadian clock on pancreatic fibrosis and exocrine dysfunction.
Pancreatic clock targeted therapy may be a potential strategy
for the treatment of chronic pancreatitis.