Cellular inflammation is a biological response triggered by harmful stimuli such as infection, toxins, or stress. Moderate inflammation triggers a protective mechanism essential for healing in our cells, however, chronic or uncontrolled inflammation can cause irreversible damage to cells and tissues. This persistent inflammatory state disrupts normal cellular function, leading to DNA damage, oxidative stress, and impaired cell signaling. Over time, such damage contributes to the development and progression of numerous diseases, including cancer, neurodegenerative diseases, and autoimmune conditions. Understanding the cellular mechanisms behind cell-response to inflammation is crucial for developing strategies to treat these diseases. One studied mechanims is the integrated stress response (ISR) which works by temporarily halting protein synthesis and activating protective genes. When properly regulated, the ISR can restore cellular balance and promote survival. The next section will look at how Dr. Chen aimed to improve cellular ISR by introducing a drug, Sephin1.
One of the diseases associated with cellular inflammation is multiple sclerosis (MS), which causes re-activated T-cells in the central nervous system to release damaging cytokines. Dr. Chen investigated how ISR supports oligodendrocyte survival and promotes remyelination in the CNS. Oligodendrocytes are responsible for forming the myelin sheath that insulates axons and ensures rapid signal conduction. Damage to these cells is a key feature of MS. Using both genetic approaches and pharmacological agents, the paper demonstrated that the prolonged activation of ISR has a protective effect on oligodendrocytes under stress and it supports remyelination. Two small molecules, Bazedoxifene (BZA) and Sephin1, were key to these findings. BZA was found to enhance oligodendrocyte progenitor cell differentiation, promoting remyelination in demyelinated mouse models. Similarly, Sephin1 was found to selectively prolong ISR activation by inhibiting a regulatory phosphatase, improving oligodendrocyte survival and remyelination efficiency. This treatment not only supported the survival of oligodendrocytes in inflammatory conditions, but it also enhanced their capacity to form new myelin sheaths. A key feature of this treatment was Sephin1 being able to prolong ISR, giving the cells more time to respond to the inflammation. A recent study done by Maria Hatzoglou at Case Western Reseve School of Medicine found that ISR can actually be manpulated to improve its response.
Dr. Hatzoglou and other scientists initially thought of ISR as a "linear chain of events" that either enabled cells to respond to manageable stress-induced inflammation or caused them to trigger cell-death if the stress became too intense. From this study it was discovered "a cell's response is more nuanced and compartmentalized". The cell's ISR mechanism is much more adaptive and flexible depending on the different types of stress it is experiencing, as well as the strength and length of them. Dr. Haztoglou coined this response "split-integrated stress response (s-ISR)", suggesting this response enables cells to adapt to various stressors more effectively. Combining Dr. Chen's approach of prolonging ISR by introducing Sephin1 with Dr. Hatzoglou's insight into its adaptability opens new avenues for creating highly targeted therapies. By tailoring treatments to modulate specific branches of the ISR in response to distinct stressors, researchers may develop more effective strategies to combat cellular inflammation and diseases like MS.
Dr. Chen's paper: 10.1101/2023.01.23.525156
Case Western Reserve article: https://www.sciencedaily.com/releases/2025/03/250326122650.htm
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