Melatonin-Loaded Nanoparticles Augment Mitophagy to Retard Parkinson's Disease.

The molecular pathways that melatonin follows as a Parkinson's disease (PD) antagonist remain poorly elucidated, despite it being a safe and a potential neurotherapeutic drug with a few limitations such as less bioavailability, premature oxidation, brain delivery, etc. Here, we used a biocompatible protein (HSA) nanocarrier for the delivery of melatonin to the brain. This nanomelatonin showed better antioxidative and neuroprotective properties, and it not only improves mitophagy to remove unhealthy mitochondria but also improves mitochondrial biogenesis to counteract rotenone-induced toxicity in an in vitro PD model. We also showed BMI1, a member of the PRC1 complex that regulates mitophagy, whose protein expression was enhanced after nanomelatonin dosage. These effects were translated to a rodent model, where nanomelatonin improves the TH+ve neuron population in SNPC and protects against rotenone-mediated toxicity. Our findings highlight the significantly better in vitro and in vivo neuroprotective effect of nanomelatonin as well as the molecular/cellular dynamics it influences to regulate mitophagy as a measure of the potential therapeutic candidate for PD.

FTY720 Nanoformulation Induces O-GlcNacylation of Synuclein to Alleviate Synucleinopathy.

The post-translational modification and aggregation of alpha-synuclein are one of the major causes of Parkinson's disease (PD) regulation. In that, the phosphorylation and nitration of synuclein elevate the aggregation, while O-GlcNacylation prevents the aggregation of synuclein. The inhibition of synuclein aggregation directs the development of PD therapy. The endowed O-GlcNacylation of synuclein could be a promising strategy to inhibit synucleinopathy. Therefore, the neuroprotective chitosan-based FTY720 nanoformulation, PP2A (Protein phosphatase 2) activator has been employed to evaluate the PP2A role in the O-GlcNacylation of synuclein in an in vivo PD model. The neuroprotective effect of our nanoformulation is attributed to the upregulation of tyrosine hydroxylase (TH), the PD therapeutic target, with behavioral improvement in animals against rotenone-induced PD deficits. The neuroprotective molecular insights revealed the camouflaged role of PP2A by endowing the OGT activity that induces O-GlcNacylation of synuclein in the reduction of synucleinopathy.

Reconstituted Super Paramagnetic Protein "Magnetotransferrin" for Brain Targeting to Attenuate Parkinsonism.

Transferrin is an iron transporting protein consisting of bilobal protein shells (apotransferrin) with dual domains in each lobe, holding an interdomain iron binding cleft. This cleft is useful in synthesizing an iron oxide core inside the transferrin shell. In vitro reconstitution chemistry provides a nano-dimensional synthesis of the mineral core inside the protein shell. The present study demonstrates the synthesis of magnetotransferrin with reconstitution of apotransferrin to form iron oxide nanoparticles within the transferrin. Transmission electron microscopy investigations along with analysis of electronic diffraction patterns and magnetometry studies indicate entrapment of superparamagnetic iron (III) oxide nanoparticles. In vivo/ex vivo imaging of the brain and immunogold staining of brain sections further validate the brain targeting potential of "magnetotransferrin". The in vivo therapeutic potential of magneto transferrin has been demonstrated by induction of TRPV1 magnetic stimuli protein, having an important regulatory role in Parkinsonism management. In an exploration of neuroprotective mechanisms, deacetylation of H3K27 of synuclein has been revealed through the TRPV1-mediated HDAC3 activation in the treatment of Parkinsonism. Thus, this magnetic protein could be a potent candidate for brain targeting, bio-imaging, and therapy of neurological infirmities.

Melatonin mediated inhibition of EZH2-NOS2 crosstalk attenuates inflammatory bowel disease in preclinical in vitro and in vivo models.

AIMS: Inflammatory Bowel Disease is characterised by abdominal pain, diarrhoea, rectal bleeding and weight loss. Sometimes it may leads to severe health complications resulting in death of an individual. Current research efforts to highlight the role of melatonin in regulating EZH2, a master epigenetic regulator and its beneficiary effect in case of IBD management. MATERIAL METHODS: Murine macrophages (RAW 264.7) were treated with lipopolysaccharides (LPS) to activate them for generating inflammatory response to investigate efficacy of melatonin in-vitro models. Similarly, for developing in vivo models, Dextran sodium sulphate (36-50 kDa) was used. Evaluations of anti-inflammatory activities were carried out by nitrite assay, western blotting, q-PCR, immunofluorescence, and histological studies. KEY FINDINGS: Reduction of epigenetic target, EZH2 by melatonin significantly improves the clinical symptoms of dextran sodium sulphate induced colitis and may be implicated as a potential therapeutic target in IBD management. The present study evaluates the efficacy of melatonin by epigenetic regulation in IBD models. Down regulation of EZH2 by melatonin reduced the chemical induced inflammatory insults in in vitro and in vivo models. Exploration of molecular pathways has revealed interlink of EZH2 and NOS2, a hallmark of inflammation. Molecular mechanistic action of melatonin is attributed to inhibition of the expression and physical interaction of EZH2 and NOS2. SIGNIFICANCE: Our study highlights melatonin therapeutic effect via attenuating interaction between EZH2 and NOS2 which is beneficial in managing IBD treatment.