Vincristine attenuates cardiac fibrosis through the inhibition of NLRP3 inflammasome activation.

Vincristine (VCR) is widely used in cancer therapies, although its benefits on cardiac fibrosis remain unknown. Here, we investigated VCR's efficacy on cardiac fibrosis and elucidated the underlying mechanism of action. Network pharmacology was employed to predict the mechanism of VCR action on cardiac fibrosis. We induced cardiac fibrosis in adult male Sprague-Dawley (SD) rats via isoproterenol (ISO) injection, followed by treatment with VCR or vehicle. After 10 days of treatment, VCR-treated rats exhibited a significantly lower heart/body weight ratio relative to those treated with the vehicle. Moreover, cardiac fibrosis was alleviated in VCR-treated rats relative to vehicle-treated rats. The results revealed the down-regulation of mature caspase-1, interleukin (IL)-1ß, and IL-18 in VCR-treated rats relative to vehicle-treated rats. We also observed less colocalization between the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) and apoptosis-associated speck-like protein containing a CARD (ASC) in VCR-treated rats compared with vehicle-treated rats. We then cultured neonatal rat cardiac fibroblasts (NRCFs) and exposed them to lipopolysaccharide (LPS) and adenosine triphosphate (ATP) in the presence or absence of VCR. The results indicated that VCR mediated the down-regulation of caspase-1, IL-1ß, and IL-18 and the colocalization of NLRP3 and ASC in LPS+ATP-stimulated cardiac fibroblasts (CFs). We found evidence that VCR attenuates cardiac fibrosis by directly suppressing the activation of the NLRP3 inflammasome. These findings provide novel insights into VCR's mechanism of action in alleviating cardiac fibrosis.

Using the synthesized peptide HAYED (5) to protect the brain against iron catalyzed radical attack in a naturally senescence Kunming mouse model.

Alzheimer's disease (AD) is a progressive neurodegenerative disease of the brain. It cannot be cured currently, and those suffering from AD place a great burden on their caregivers and society. AD is characterized by high levels of iron ions in the brain, which catalyze radicals that damage the neurons. Knowing that the Aß42 peptide precipitates iron by binding iron ions at amino acid residues D1, E3, H11, H13, and H14, we synthesized a 5-repeat (HAYED) sequence peptide. By treating iron-stressed SH-SY5Y cells with it and injecting it into the cerebrospinal fluid (CSF) of naturally senescence Kunming mouse, which displaying AD-similar symptoms such as learning and memory dysfunction, neuron degeneration and high level of iron in brain, we found that HAYED (5) decreased the iron and radical levels in the cell culture medium and in the CSF. Specially, the synthesized peptide prevented cell and brain damage. Furthermore, functional magnetic resonance imaging (fMRI), Morris water maze and passive avoidance tests demonstrated that the peptide ameliorated brain blood-oxygen metabolism and slowed cognitive loss in the experimental senescence mice, and clinical and blood tests showed that HAYED (5) was innoxious to the kidney, the liver and blood and offset the AD-associated inflammation and anemia.