Brain insulin resistance linked Alzheimer's and Parkinson's disease pathology: An undying implication of epigenetic and autophagy modulation.

In metabolic syndrome, dysregulated signalling activity of the insulin receptor pathway in the brain due to persistent insulin resistance (IR) condition in the periphery may lead to brain IR (BIR) development. BIR causes an upsurge in the activity of glycogen synthase kinase-3 beta, increased amyloid beta (Aß) accumulation, hyperphosphorylation of tau, aggravated formation of Aß oligomers and simultaneously neurofibrillary tangle formation, all of which are believed to be direct contributors in Alzheimer's Disease (AD) pathology. Likewise, for Parkinson's Disease (PD), BIR is associated with alpha-synuclein alterations, dopamine loss in brain areas which ultimately succumbs towards the appearance of classical motor symptoms corresponding to the typical PD phenotype. Modulation of the autophagy process for clearing misfolded proteins and alteration in histone proteins to alleviate disease progression in BIR-linked AD and PD have recently evolved as a research hotspot, as the majority of the autophagy-related proteins are believed to be regulated by histone posttranslational modifications. Hence, this review will provide a timely update on the possible mechanism(s) converging towards BIR induce AD and PD. Further, emphasis on the potential epigenetic regulation of autophagy that can be effectively targeted for devising a complete therapeutic cure for BIR-induced AD and PD will also be reviewed.

Exploring the Epigenetic Regulated Modulation of Fibroblast Growth Factor 21 Involvement in High-Fat Diet Associated Parkinson's Disease in Rats.

Imbalance in brain glucose metabolism and epigenetic modulation during the disease course of insulin resistance (IR) associated with Parkinson's disease (PD) risk remains a prime concern. Fibroblast growth factor 21 (FGF21), the metabolic hormone, improves insulin sensitivity and elicits anti-diabetic properties. Chronic stress during brain IR may modulate the FGF21 expression and its dynamic release via epigenetic modifications. Metformin regulates and increases the expression of FGF21 which can be modulating in obesity, diabetes, and IR. Hence, this study was designed to investigate the FGF21 expression modulation via an epigenetic mechanism in PD and whether metformin (MF), an autophagy activator, and sodium butyrate (NaB), a pan histone deacetylase inhibitor, alone and in combination, exert any therapeutic benefit in PD pathology exacerbated by high-fat diet (HFD). Our results portray that the combination treatment with MF and NaB potentially attenuated the abnormal lipid profile and increased motor performance for the rats fed with HFD for 8 weeks followed by intrastriatal 6-hydroxy dopamine administration. The enzyme-linked immunosorbent assay (ELISA) estimations of C-reactive protein, tumor necrosis factor-α, interleukin-1 beta and 6, and FGF21 exhibited extensive downregulation after treatment with the combination. Lastly, mRNA, western blot, histological, and cresyl violet staining depicted that the combination treatment can restore degenerated neuronal density and increase the protein level compared to the disease group. The findings from the study effectively conclude that the epigenetic mechanism involved in FGF21 mediated functional abnormalities in IR-linked PD pathology. Hence, combined treatment with MF and NaB may prove to be a novel combination in ameliorating IR-associated PD in rats, probably via the upregulation of FGF21 expression.

Exploring Applications of Flexible Vesicular Systems as Transdermal Drug Delivery.

Deformable lipidic-nano carriers are a category of advanced liposomal formulations. Deformable lipidic-nano carriers have a specific character to transform by rearranging the lipidic backbone to squeeze themself through a pore opening ten times smaller than their diameter when exposed to a variable condition like hydration gradient as these have potentially been used as a non-invasive delivery system to transdermally migrate various therapeutic agents for over three decades. Despite their vast application in transdermal drug delivery system, non-uniformity to express their chemical nature still exist and authors use various terms synonymously and interchangeably with each other. The present study delineates the terminologies used to express different derived deformable vesicular carriers to harmonize the terminological use. It also includes the effectiveness of deformable nanocarriers like Transferosomes, Ethosomes, Menthosomes, Invasomes, and Glycerosomes in skin conditions like basal cell carcinoma, fungal and viral infections, and hyperpigmentation disorders, along with others. Various review and research articles were selected from the 'Pubmed' database. The keywords like Transferosomes, Flexi-vesicular system, ultra-deformable vesicles, and nano-vesicular systems were used to extract the data. The data was reviewed and compiled to categorically classify different flexible vesicular systems. The composition of the different vesicular systems is identified and a report of various pathological conditions where the use of flexible lipid nanocarrier systems was implemented is compiled. The review also offers suggestive approaches where the applicability of these systems can be explored further.