| General note |
Psoriasis, a chronic immune-mediated skin disorder affecting approximately 2–3% of the<br/>global population, has gained increasing recognition for its systemic effects. Emerging<br/>evidence suggests a link between psoriasis-associated systemic inflammation and<br/>neurodegenerative diseases such as dementia and Alzheimer’s disease. This research study<br/>combined bioinformatics with experimental methods to examine the connection between<br/>psoriasis-related inflammation and neurodegeneration via mitochondrial stress-signaling.<br/>Protein-Protein interaction analysis of the target markers MAPT, APP, SIRT2, MAPK1 and<br/>PRDX1 revealed that MAPK1 and PRDX1 are central interaction nodes in networks related to<br/>neurodegeneration. Protein-ligand docking indicated that turmeric-derived compounds,<br/>especially demethoxycurcumin, followed by quercetin, bisdemethoxycurcumin and curcumin,<br/>had strong binding affinities whereas promising chamomile-derived ligands were<br/>quercimeritrin, stigmasterol, rutin and oleanic acid. The functional enrichment analysis<br/>investigated through STRING, SHINYGO, G-Profiler and ENRICHR pathway analysis showed<br/>that redox regulation, inflammatory signaling, and synaptic plasticity pathways were coordinately involved in linking the selected markers. Moreover, SwissTarget Prediction Tool<br/>and ChEMBL implied that the potential protein targets of synthesized turmeric-chamomile drug<br/>formulation were primarily associated with Neuroactive ligand-receptor and GPCR signaling,<br/>Serotonergic synapse, Calcium/cAMP signaling, MAPK/PI3K-AKT/ErbB/Notch pathways,<br/>Nuclear and extra-nuclear estrogen receptor signaling, Oxidative stress/redox, Eicosanoid<br/>and ω-3 PUFA metabolism, Alzheimer’s disease, IL-17/IL-6/IL-5 signaling, Oxytocin<br/>signaling, and Gap junction/FoxO signaling to modulate the severity of psoriasis, AD and<br/>mitochondrial dysfunction. Based on the promising in-silico analysis, we subsequently<br/>performed in vivo experiments. Previously, using polymeric nanoparticle delivery systems, the<br/>plant-derived compounds Curcuma longa and Matricaria recutita topical gel was tested in<br/>BALB/c IMQ-induced psoriasis murine model. Water Morris and Y Maze Tests cognitive<br/>behavioural and histological (H&E staining) assessments pinpointed that untreated psoriatic<br/>mice exhibited significant cognitive deficits, supporting the skin–brain interaction hypothesis.<br/>Obtaining these findings, we further investigated the molecular transcriptional analysis of<br/>protective and metabolic tissues using RT-qPCR. Stress and neurodegeneration markers,<br/>MAPT, APP, SIRT2, PRDX1, and MAPK were significantly upregulated in liver, eyes,<br/>hippocampus, and cortex samples. Their expression was, however, decreased to control levels<br/>using turmeric-chamomile gel. The nanoparticles encapsulated by drug formulation (TDN)<br/>xxii<br/>showed relatively better therapeutic efficacy than free form drug (TD). Tissue specific<br/>responses were also seen in skin tissues where SIRT2 and PRDX1 were downregulated in<br/>diseased samples and later returned to normal levels following treatment. These results<br/>underscore the importance of the skin–brain axis and potential molecular targets for therapeutic<br/>strategies aimed at mitigating cognitive decline in patients with psoriasis.<br/>Keywords: Psoriasis, Neurodegeneration, Alzheimer’s Disease, Mitochondrial Dysfunction,<br/>Turmeric, Chamomile, Polymeric Nanoparticles, Neuroinflammation, Stress pathways, qRTPCR, In-silico analysis |
