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Salk scientists discover molecular link between circadian clock disturbances and inflammatory diseases

Scientists have known for some time that throwing off the body's circadian rhythm can negatively affect body chemistry. In fact, workers whose sleep-wake cycles are disrupted by night shifts are more susceptible to chronic inflammatory conditions such as diabetes, obesity and cancer.

Salk researchers have now found a possible molecular link between circadian rhythm disturbances and an increased inflammatory response. In a study published in Proceedings of the National Academy of Sciences, the Salk team found that the absence of a key circadian clock component called cryptochrome (CRY) leads to the activation of a signaling system that elevates levels of inflammatory molecules in the body.

Cryptochrome serves as a brake to slow the circadian clock's activity, signaling our biological systems to wind down each evening. In the morning, CRY stops inhibiting the clock's activity, helping our physiology ramp up for the coming day.

"There is compelling evidence that lowgrade, constant inflammation could be the underlying cause of chronic conditions such as diabetes, obesity and cancer," says senior author Inder Verma. "Our results strongly indicate that an arrhythmic clock system, induced by the absence of CRY proteins, alone is sufficient to increase the stress level of cells, leading to the constant expression of inflammatory proteins and causing low-grade, chronic inflammation."

The researchers demonstrated that a lack of cryptochrome activates proinflammatory molecules, indicating a potential role for cryptochrome in the regulation of inflammatory cytokine expression. They also found that a lack of CRY activated the NF-kB pathway, a molecular signaling conduit that controls many genes involved in inflammation.

"Every time this pathway is turned on, there is a residual amount of inflammation left in the body," says Rajesh Narasimamurthy, a research associate in Verma's laboratory and the paper's first author. "That adds up over time, contributing to inflammation-related conditions like obesity and diabetes."

The researchers say the goal now is to find out how to suppress NF-kB activation in the short term to treat diseases like diabetes. They caution that any long-term suppression of the pathway could lead to chronic infection. "We would like to find molecules that modify this activity and focus on those small-molecule inhibitors to treat disease," Verma adds.