Han Lin,Yunlong Lv,Huacheng Liu,Zheng Lin,Ning Zhu,Bingwu Huang
Background As a persistent gastrointestinal disorder, irritable bowel syndrome (IBS) influences the gut-brain connection, leading to abdominal pain and altered bowel irregularities. Baicalein, a flavonoid extracted from Scutellaria baicalensis, is frequently utilized in anti-inflammatory treatments. This study aimed to explore baicalein's effectiveness in mitigating IBS symptoms triggered by both chronic and acute stress (CAS) and to uncover its fundamental mechanisms. Methods Sprague-Dawley rats were employed to develop an IBS rat model by inducing CAS for five weeks. Each rat was randomly allocated to one of four experimental groups: model (M), low-dose baicalein (L), high-dose baicalein (H), and control (C). Baicalein was orally administered throughout the experiment. Behavioral assessments were conducted, including forced swimming, marble-burying, intestinal motility, and visceral sensitivity tests. Colonic tissues were collected for histopathological examination, evaluation of oxidative stress (MDA and SOD levels), and analysis of inflammatory cytokines, and ODC1/NF-κB pathway activation using Western blot assay, ELISA, and immunofluorescence. Results Baicalein treatment notably ameliorated IBS-like symptoms, such as fecal pellet output and AWR scores, by alleviating stress-induced behavioral changes. Baicalein bolstered antioxidant defenses through boosting SOD activity and lowering MDA levels. Moreover, baicalein inhibited inflammatory responses, targeting IL-6, IL-1β, and TNF-α, while suppressing the expression of ODC1 and restraining NF-κB p65 phosphorylation within the colon. These results indicate that baicalein modulates oxidative stress and inflammation in CAS-associated IBS. Conclusion Baicalein demonstrates protection against CAS-induced IBS by diminishing intestinal inflammation, oxidative damage, and visceral hypersensitivity via suppression of the ODC1/NF-κB pathway. These findings underscore baicalein's potential as a therapeutic approach for IBS.
Targeting ferroptosis, an iron-dependent form of regulated cell death triggered by the lethal overload of lipid peroxides, in cancer therapy is impeded by our limited understanding of the intersection of tumour’s metabolic feature and ferroptosis vulnerability. In the present study, arginine is identified as a ferroptotic promoter using a metabolites library. This effect is mainly achieved through arginine’s conversion to polyamines, which exerts their potent ferroptosis-promoting property in an H 2 O 2 -dependent manner. Notably, the expression of ornithine decarboxylase 1 (ODC1), the critical enzyme catalysing polyamine synthesis, is significantly activated by the ferroptosis signal——iron overload——through WNT/MYC signalling, as well as the subsequent elevated polyamine synthesis, thus forming a ferroptosis-iron overload-WNT/MYC-ODC1-polyamine-H 2 O 2 positive feedback loop that amplifies ferroptosis. Meanwhile, we notice that ferroptotic cells release enhanced polyamine-containing extracellular vesicles into the microenvironment, thereby further sensitizing neighbouring cells to ferroptosis and accelerating the “spread” of ferroptosis in the tumour region. Besides, polyamine supplementation also sensitizes cancer cells or xenograft tumours to radiotherapy or chemotherapy through inducing ferroptosis. Considering that cancer cells are often characterized by elevated intracellular polyamine pools, our results indicate that polyamine metabolism exposes a targetable vulnerability to ferroptosis and represents an exciting opportunity for therapeutic strategies for cancer.
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