Reactive oxygen species (ROS)-driven oxidative stress has been recognized as a critical inducer of cancer cell death in response to therapeutic agents. Our previous studies have demonstrated that zinc finger protein (ZNF)32 is key to cell survival upon oxidant stimulation. However, the mechanisms by which ZNF32 mediates cell death remain unclear. Here, we show that at moderate levels of ROS, Sp1 directly binds to two GC boxes within the ZNF32 promoter to activate ZNF32 transcription. Alternatively, at cytotoxic ROS concentrations, ZNF32 expression is repressed due to decreased binding activity of Sp1. ZNF32 overexpression maintains mitochondrial membrane potential and enhances the antioxidant capacity of cells to detoxify ROS, and these effects promote cell survival upon pro-oxidant agent treatment. Alternatively, ZNF32-deficient cells are more sensitive and vulnerable to oxidative stress-induced cell injury. Mechanistically, we demonstrate that complement 1q-binding protein (C1QBP) is a direct target gene of ZNF32 that inactivates the p38 MAPK pathway, thereby exerting the protective effects of ZNF32 on oxidative stress-induced apoptosis. Taken together, our findings indicate a novel mechanism by which the Sp1-ZNF32-C1QBP axis protects against oxidative stress and implicate a promising strategy that ZNF32 inhibition combined with pro-oxidant anticancer agents for hepatocellular carcinoma treatment.
Zfp637 is a recently identified zinc finger protein, and its functions remain largely unknown. Here, we innovatively demonstrate the effects of Zfp637 on the differentiation of mouse spermatogonia and on its downstream target gene SOX2 in vitro. Obesity has been recognized as a chronic inflammatory disease that leads to decreased sexual function and sexual development disorders. We observed higher levels of IL-6 in serum and testis homogenates from obese mice compared with control mice. We also demonstrated that high levels of IL-6 inhibited Zfp637 expression, and we elucidated the underlying mechanisms. SOCS3 overexpression and STAT3 phosphorylation inhibitor (AG490) were used to investigate the function of the SOCS3/STAT3 pathway during this process. Our results showed that exposure of mouse spermatogonial cells to high levels of IL-6 inhibited Zfp637 expression by increasing SOCS3 expression and inhibiting the phosphorylation of STAT3, further reducing cellular differentiation. Consistent with the in vitro results, we observed increasing expression levels of SOCS3 and SOX2, but a reduction of Zfp637 expression, in obese mouse testes. In conclusion, Zfp637 plays a crucial role in spermatogenesis by downregulating SOX2 expression, and IL-6 can decrease the expression of Zfp637 through the SOCS3/STAT3 signaling pathway.
Background: Cognitive impairment caused by diabetes has been recognized. Berberine is well known for its resistance to peripheral lesions, but it is rarely used for the treatment of spatial learning and memory caused by diabetes. This study explored the mechanism of berberine to alleviate cognitive impairment via the cholinergic anti-inflammatory and insulin signaling pathways.
Methods: Morris water maze was used to appraise spatial learning and memory. Positron-emission tomography (PET) imaging was adopted to detect the transport of glucose, and blood/cerebrospinal fluid (CSF) glucose was checked using commercial blood glucose meter. Insulin level was measured by ELISA kit and β-Amyloid (Aβ) formation was observed by Congo red staining. Western-blot was performed to appraise protein expression.
Results: We found that berberine rectified some aberrant changes in signal molecules concerning inflammation, and cholinergic and insulin signaling pathways in the hippocampus. Furthermore, CSF/blood glucose, inflammatory response or acetyl cholinesterase enzyme (AChE) activity were reduced by berberine. Additionally, acetylcholine levels were enhanced after berberine treatment in diabetic rats. Finally, Aβ formation in diabetic hippocampus was inhibited and spatial learning memory was ameliorated by berberine.
Discussion: In conclusion, berberine clears Aβ deposit and consequently ameliorates spatial learning memory impairment via the activation of the cholinergic anti-inflammatory and insulin signaling pathways in diabetic rats.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.