Current Drug Targets - Online First

Parkinson's Disease (PD) is a common neurodegenerative disorder with limited treatment options. Thus, there's a need for new therapies. Mucuna pruriens (MP) seeds are used in traditional treatments for PD, but their mechanisms are not well understood. This research uses in silico methods to explore MP's pharmacological effects as a potential PD treatment.

We registered the active ingredients in MP and their targets, then analyzed genes related to Parkinson's Disease (PD). This led to the creation of a Protein-Protein Interaction (PPI) network. We examined the binding interactions between hub proteins and compounds using molecular docking and confirmed the results with molecular dynamics analysis.

We revealed sixteen substances in MP seeds that target 113 therapeutic points in PD. The proteins identified in the enrichment analysis regulate actin, endocytosis, and various other cellular processes. Ultimately, we identified eleven hub proteins (TP53, AKT1, MAPK8, ESR1, MAPK3, BCL2, HSP90AA1, PRKACA, CASP3, EGFR, and IL6) that interact with the sixteen active compounds, a finding confirmed by molecular docking and molecular dynamics.

The identified hub proteins are key therapeutic targets that regulate crucial processes in Parkinson's disease, highlighting the neuroprotective potential of bioactive compounds in MP seeds. These findings justify further experimental studies to confirm their therapeutic potential in treating Parkinson's disease.

Our findings suggest that, in addition to L-DOPA, other compounds in MP seeds may act synergistically to produce antiparkinsonian effects.

Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by the accumulation of mutant huntingtin protein (mHTT) with expanded polyglutamine (polyQ) tracts. These aggregates contribute to neuronal toxicity and disease progression. Targeting aggregation, especially at the N-terminal domain (N17), may offer a therapeutic strategy. This study aims to identify potential small-molecule inhibitors that can bind to aggregation-prone regions of mHTT using computational methods.

We characterized polyQ repeat regions and the N17 domain using CASTp to identify active sites. Pharmacophore models were generated using LigandScout based on the glutamate inhibitor 6-Diazo-5-oxo-L-norleucine (DON). Structurally similar ligands were screened from PubChem. Ten candidates were selected and evaluated through molecular docking. ADME/Toxicity and drug-likeness analyses were performed to assess pharmacokinetic suitability.

Ten DON-like ligands showed favorable pharmacophore features. Docking studies identified five compounds with strong binding affinities and key interactions with the polyQ region. These top candidates also demonstrated acceptable ADMET profiles and drug-likeness.

The five lead compounds identified in this study demonstrate potential to interfere with mHTT aggregation, a key pathological feature of HD. Their favorable binding and pharmacokinetic properties support their candidacy for further development. However, in silico predictions require experimental validation. Future in vitro and in vivo studies are essential to confirm their efficacy and safety.

This study presents five promising small-molecule inhibitors for HD, laying the groundwork for future therapeutic development targeting mHTT aggregation.

Hereditary Angioedema (HAE) is a rare, autosomal dominant disorder characterized by episodic, non-pruritic, non-pitting swelling of the skin, respiratory tract, and gastrointestinal system resulting from C1 esterase inhibitor (C1-INH) deficiency or dysfunction. It is frequently underdiagnosed, particularly in developing countries like India, due to its nonspecific presentation and overlap with allergic angioedema.

We report a case of a 28-year-old Indian woman who presented with a five- month history of progressive facial and periorbital swelling. She had no urticaria, known allergies, or systemic symptoms and did not respond to antihistamines or corticosteroids. The initial workup revealed normocytic anemia and elevated inflammatory markers, with normal renal, hepatic, thyroid, and autoimmune profiles. Radiological evaluation showed bilateral pre-septal edema. Complement C4 was normal; however, serum C1-INH level was markedly reduced, confirming type I HAE. She responded well to intravenous plasma-derived C1-INH concentrate (Cinryze). Unfortunately, she succumbed to a later episode of upper airway edema, highlighting the life-threatening potential of untreated or delayed HAE.

This case emphasizes the need for high clinical suspicion of HAE in patients with unexplained, non-histaminergic angioedema, especially when conventional therapies fail. Early biochemical confirmation and targeted therapy are essential for effectively managing and preventing fatal complications.

Recent studies have established that cytokeratin 8 (CK8) is closely linked to glycogen synthesis; however, its mechanistic role in hepatic glycogen synthesis in type 2 diabetes mellitus (T2DM) remains unclear. This study aimed to elucidate the effects and underlying molecular mechanisms of CK8.

We analyzed CK8 expression and the IRS1 (Insulin Receptor Substrate 1)/PI3K (Phosphoinositide 3-Kinase)/Akt (Protein Kinase B)/GSK3β (Glycogen Synthase Kinase 3 beta) pathway in liver samples from T2DM patients, diabetic C57BL/6J mouse models, and high glucose-treated NCTC 1469 cells using Western blotting, immunohistochemistry, and PAS staining.

CK8 was significantly upregulated in all T2DM models, correlating with suppressed IRS1/PI3K/Akt/GSK3β signaling and reduced glycogen synthesis. Our functional studies demonstrated that CK8 overexpression exacerbated these effects, while CK8 knockdown restored glycogen levels to near-normal.

In our study, CK8 was identified as a negative regulator of hepatic glycogen synthesis by modulating the IRS1/PI3K/Akt/GSK3β pathway.

These findings position CK8 as a promising therapeutic target for T2DM, with CK8 inhibition offering a novel strategy to improve hepatic insulin resistance and glycogen storage without requiring β-cell stimulation.

Astragalus mongholicus is distributed in Inner Mongolia, China, and has a certain therapeutic effect on silicosis. However, the regulatory mechanisms of Astragalus mongholicus mediated by alternative splicing (AS) in silicosis pathology and treatment remain unclear.

The pathological examination was performed on the lung tissue from a constructed mouse model of silicosis. Then, rMATS-based AS detection, target prediction, PPI analysis, and molecular docking were conducted to investigate the mechanism of Astragalus mongholicus-mediated treatment of silicosis in mice from the perspective of AS.

A total of 404 differentially alternatively spliced genes (DASGs) were identified between the Astragalus mongholicus treatment and the silicosis model group. Moreover, 194 potential targets were predicted from 33 active components of Astragalus mongholicus, of which the targets, Rps6ka2 and Clk4, underwent differential AS. Network pharmacology analysis indicated that the Isomucronulatol, 7-o-methylisomucronulatol, and Medicarpin in Astragalus mongholicus might participate in the treatment of silicosis through differential splicing of Rps6ka2 or Clk4. Molecular docking confirmed a strong binding affinity between the protein Rps6ka2 and Medicarpin.

This study suggests that Isomucronulatol, 7-o-methylisomucronulatol, and Medicarpin, being active components in Astragalus mongholicus, may intervene in silicosis pathogenesis through differential splicing of Rps6ka2 or Clk4, involving biological processes such as protein serine/threonine kinase activity. However, further experimental validation is required to confirm these findings.

A large number of DASEs exist in the development and treatment of silicosis. Astragalus mongholicus may alleviate silicosis through AS-regulated mechanisms involving Rps6ka2 and Clk4. This finding provides novel strategies and potential molecular targets for silicosis treatment.