Mitochondrial Dysfunction in Psoriasis Examining Stress Pathways in Protective and Metabolic Tissues /
- 103p. ; 30cm.
Psoriasis, a chronic immune-mediated skin disorder affecting approximately 2–3% of the global population, has gained increasing recognition for its systemic effects. Emerging evidence suggests a link between psoriasis-associated systemic inflammation and neurodegenerative diseases such as dementia and Alzheimer’s disease. This research study combined bioinformatics with experimental methods to examine the connection between psoriasis-related inflammation and neurodegeneration via mitochondrial stress-signaling. Protein-Protein interaction analysis of the target markers MAPT, APP, SIRT2, MAPK1 and PRDX1 revealed that MAPK1 and PRDX1 are central interaction nodes in networks related to neurodegeneration. Protein-ligand docking indicated that turmeric-derived compounds, especially demethoxycurcumin, followed by quercetin, bisdemethoxycurcumin and curcumin, had strong binding affinities whereas promising chamomile-derived ligands were quercimeritrin, stigmasterol, rutin and oleanic acid. The functional enrichment analysis investigated through STRING, SHINYGO, G-Profiler and ENRICHR pathway analysis showed that redox regulation, inflammatory signaling, and synaptic plasticity pathways were coordinately involved in linking the selected markers. Moreover, SwissTarget Prediction Tool and ChEMBL implied that the potential protein targets of synthesized turmeric-chamomile drug formulation were primarily associated with Neuroactive ligand-receptor and GPCR signaling, Serotonergic synapse, Calcium/cAMP signaling, MAPK/PI3K-AKT/ErbB/Notch pathways, Nuclear and extra-nuclear estrogen receptor signaling, Oxidative stress/redox, Eicosanoid and ω-3 PUFA metabolism, Alzheimer’s disease, IL-17/IL-6/IL-5 signaling, Oxytocin signaling, and Gap junction/FoxO signaling to modulate the severity of psoriasis, AD and mitochondrial dysfunction. Based on the promising in-silico analysis, we subsequently performed in vivo experiments. Previously, using polymeric nanoparticle delivery systems, the plant-derived compounds Curcuma longa and Matricaria recutita topical gel was tested in BALB/c IMQ-induced psoriasis murine model. Water Morris and Y Maze Tests cognitive behavioural and histological (H&E staining) assessments pinpointed that untreated psoriatic mice exhibited significant cognitive deficits, supporting the skin–brain interaction hypothesis. Obtaining these findings, we further investigated the molecular transcriptional analysis of protective and metabolic tissues using RT-qPCR. Stress and neurodegeneration markers, MAPT, APP, SIRT2, PRDX1, and MAPK were significantly upregulated in liver, eyes, hippocampus, and cortex samples. Their expression was, however, decreased to control levels using turmeric-chamomile gel. The nanoparticles encapsulated by drug formulation (TDN) xxii showed relatively better therapeutic efficacy than free form drug (TD). Tissue specific responses were also seen in skin tissues where SIRT2 and PRDX1 were downregulated in diseased samples and later returned to normal levels following treatment. These results underscore the importance of the skin–brain axis and potential molecular targets for therapeutic strategies aimed at mitigating cognitive decline in patients with psoriasis. Keywords: Psoriasis, Neurodegeneration, Alzheimer’s Disease, Mitochondrial Dysfunction, Turmeric, Chamomile, Polymeric Nanoparticles, Neuroinflammation, Stress pathways, qRTPCR, In-silico analysis