Recombinant Human Heavy Chain Ferritin Nanoparticles Serve as ROS Scavengers for the Treatment of Ischemic Stroke.

Purpose: Ischemic stroke is a high-incidence disease that threatens human well-being. The potent neuroprotective effects render reactive oxygen species (ROS) scavengers potential agents for acute ischemic stroke therapy. Challenges such as inadequate permeability across the blood-brain barrier (BBB), limited half-life, and adverse effects hinder the widespread utilization of small molecule and inorganic ROS scavengers. Thus, there is an urgent demand for efficacious neuroprotective agents targeting ischemic stroke. Our study discovered the superoxide dismutase (SOD)-mimetic activity of recombinant human heavy chain ferritin (rHF) nanoparticles expressed from Escherichia coli (E. coli). Subsequent investigations delved into the ROS-scavenging proficiency of rHF within neural cells, its therapeutic efficacy against ischemic stroke, and the elucidation of its neuroprotective mechanisms. Methods: rHF protein nanoparticles were expressed in E. coli and purified via size-exclusion chromatography. The superoxide anion (•O2-) scavenging SOD-mimetic activity of rHF nanoparticles was measured using a SOD detection kit. The ROS scavenging ability and protection effects against oxidative damage of rHF nanoparticles were studied in H2O2-induced PC12 cells. Therapeutic effects and neuroprotective mechanisms of rHF against ischemic stroke were investigated with transient middle cerebral artery occlusion (MCAO) reperfusion mice model. Results: rHF nanoparticles can eliminate excessive ROS in nerve cells and alleviate oxidative damage. The results of animal experiments demonstrated that rHF nanoparticles passed across BBB, reduced infarct areas in brain tissue, and lowered the neurological deficit score of ischemia-reperfusion model mice. Additionally, rHF nanoparticles mitigated neuronal apoptosis and ferroptosis, suppressed microglial activation, maintained oxygen homeostasis, and exhibited negligible organ toxicity. Conclusion: rHF nanoparticle could be developed as a new ROS scavenger for nerve cells and has therapeutic potential as a drug for cerebral ischemia-reperfusion injury.

Whole-exome sequencing identifies somatic mutations associated with lung cancer metastasis to the brain.

BACKGROUND: Lung cancer is the most aggressive cancer, resulting in one-quarter of all cancer-related deaths, and its metastatic spread accounts for >70% of these deaths, especially metastasis to the brain. Metastasis-associated mutations are important biomarkers for metastasis prediction and outcome improvement. METHODS: In this study, we applied whole-exome sequencing (WES) to identify potential metastasis-related mutations in 12 paired lung cancer and brain metastasis samples. RESULTS: We identified 1,702 single nucleotide variants (SNVs) and 6,131 mutation events among 1,220 genes. Furthermore, we identified several lung cancer metastases associated genes (KMT2C, AHNAK2). A mean of 3.1 driver gene mutation events per tumor with the dN/dS (non-synonymous substitution rate/synonymous substitution rate) of 2.13 indicating a significant enrichment for cancer driver gene mutations. Mutation spectrum analysis found lung-brain metastasis samples have a more similar Ti/Tv (transition/transversion) profile with brain cancer in which C to T transitions are more frequent while lung cancer has more C to A transversion. We also found the most important tumor onset and metastasis pathways, such as chronic myeloid leukemia, ErbB signaling pathway, and glioma pathway. Finally, we identified a significant survival associated mutation gene ERF in both The Cancer Genome Atlas (TCGA) (P=0.01) and our dataset (P=0.012). CONCLUSIONS: In summary, we conducted a pairwise lung-brain metastasis based exome-wide sequencing and identified some novel metastasis-related mutations which provided potential biomarkers for prognosis and targeted therapeutics.

Melatonin Inhibits the Progression of Oral Squamous Cell Carcinoma via Inducing miR-25-5p Expression by Directly Targeting NEDD9.

Melatonin exerts anti-cancer roles in various types of cancers. However, to the best of our knowledge, its role in oral squamous cell carcinoma (OSCC) is unknown. The present study aimed to investigate the role of melatonin and its underlying mechanism in OSCC. MTT, colony formation, wound healing, and transwell invasion assays proved that melatonin played anti-tumor effects in OSCC cells by inhibiting cell viability, proliferation, migration, and invasion in a concentration-dependent manner. The RT-qPCR analysis showed that miR-25-5p was significantly upregulated after melatonin treatment. Further, miR-25-5p might be involved in melatonin-induced inhibitory effects on the biological behavior of OSCC. The expression of miR-25-5p was decreased in tumor tissues and OSCC cells detected by RT-qPCR. MTT assay, colony formation assay, and TUNEL staining indicated miR-25-5p overexpression inhibited OSCC cell viability, proliferation, and induced OSCC cell apoptosis. Furthermore, wound healing, transwell invasion assay, and animal experiments suggested that miR-25-5p might exert suppressive effects on the migration, invasion, and tumor formation of OSCC cells, while miR-25-5p knockdown exhibited the opposite effects in OSCC cells. Bioinformatics analysis, western blot analysis, and luciferase reporter assay suggested that neural precursor cell expressed developmentally downregulated protein 9 (NEDD9) was proved to be a putative target for miR-25-5p. The role of NEDD9 in inhibiting OSCC cell proliferation, invasion, and migration was verified with NEDD9 siRNA transfection. Thus, melatonin exerted anti-proliferative, anti-invasive, and anti-migrative effects on OSCC via miR-25-5p/NEDD9 pathway. Melatonin could be applied as a potential novel drug on treating OSCC.