Protein S-nitros(yl)ation (SNO) is a posttranslational modification involved in diverse processes in health and disease and can contribute to synaptic damage in Alzheimer’s disease (AD). To identify SNO proteins in AD brains, we used triaryl phosphine ( SNO TRAP) combined with mass spectrometry (MS). We detected 1449 SNO proteins with 2809 SNO sites, representing a wide range of S-nitrosylated proteins in 40 postmortem AD and non-AD human brains from patients of both sexes. Integrative protein ranking revealed the top 10 increased SNO proteins, including complement component 3 (C3), p62 (SQSTM1), and phospholipase D3. Increased levels of S-nitrosylated C3 were present in female over male AD brains. Mechanistically, we show that formation of SNO-C3 is dependent on falling β-estradiol levels, leading to increased synaptic phagocytosis and thus synapse loss and consequent cognitive decline. Collectively, we demonstrate robust alterations in the S-nitrosoproteome that contribute to AD pathogenesis in a sex-dependent manner.

Introduction: Traditional Chinese acupuncture has been demonstrated to be beneficial for treatment of type 2 diabetes mellitus (T2DM). The mechanism of acupuncture on T2DM is crucial for their biological activity as well as their usefulness as tools in biology and medicine. However, its mechanism is poorly understood. Methods: In an effort to explore the mechanism, eight db/db mice (a type of spontaneous T2DM mouse) were treated with adjusting internal organs and dredging channel electroacupuncture (AODCEA) for 2 weeks. Another eight db/db mice were fed as T2DM group (T2DMG), and eight db/m mice were set as normal control group (NCG). Lipopolysaccharide (LPS), interleukin-6 (IL-6), and diabetes-related indicators, such as fasting blood glucose (FBG) and triglyceride (TG), were detected by enzyme-linked immune sorbent assay (ELISA). The V4 region of 16S rRNA gene was analyzed by Illumina sequencing to evaluate the effect of AODCEA on intestinal flora. The amount of short-chain fatty acids (SCFAs) in the feces were determined by gas chromatography-mass spectrometry (GC-MS). Results: Our results indicate that AODCEA treatment can reduce diabetes-related indicators. We observed the increased probiotics such as Blautia and Lactobacillus and decreased opportunist pathogens (Alistipes, Helicobacter, Prevotella) by AODCEA interventions. Importantly, the total amount of SCFAs in the feces of T2DM mice was promoted by AODCEA. Finally, obviously alleviated systemic inflammation was exhibited through AODCEA treatment by detection of lipopolysaccharide (LPS) and interleukin-6 (IL-6) in serum. Conclusion: AODCEA can reshape the structure of intestinal flora, which can increase intestinal SCFAs, affect the circulating LPS level, and reduce the inflammatory response.

Background: Accumulating public health and epidemiological literature support the hypothesis that arsenic in drinking water or food affects the brain adversely. Methods: Experiments on the consequences of nitric oxide (NO) formation in neuronal cell culture and mouse brain were conducted to probe the mechanistic pathways of nitrosative damage following arsenic exposure. Results: After exposure of mouse embryonic neuronal cells to low doses of sodium arsenite (SA), we found that Ca²⁺ was released leading to the formation of large amounts of NO and apoptosis. Inhibition of NO synthase prevented neuronal apoptosis. Further, SA led to concerted S-nitrosylation of proteins significantly associated with synaptic vesicle recycling and acetyl-CoA homeostasis. Our findings show that low-dose chronic exposure (0.1–1 ppm) to SA in the drinking water of mice led to S-nitrosylation of proteomic cysteines. Subsequent removal of arsenic from the drinking water reversed the biochemical alterations. Conclusions: This work develops a mechanistic understanding of the role of NO in arsenic-mediated toxicity in the brain, incorporating Ca²⁺ release and S-nitrosylation as important modifiers of neuronal protein function.