Small interference (RNAi) technique: Exploring its clinical applications, benefits and limitations.

BACKGROUND: Small interference RNA (siRNA) has emerged as the most desired method for researchers and clinicians who wish to silence a specific gene of interest and has been extensively developed as a therapeutic agent. This review points to collecting all clinical trials on siRNA and understanding its benefits, pharmacokinetics and safety by reading articles published in the last 5 years. MATERIALS AND METHODS: Searching in the PubMed database using 'siRNA' and 'in vivo' with limits to articles published in the previous 5 years, article type 'clinical trials' and language 'English' to acquire papers on in vivo studies on siRNA approaches. Features of siRNA clinical trials registered at https://clinicaltrials.gov/ were analysed. RESULTS: So far, 55 clinical studies have been published on siRNA. Many published clinical trials on siRNA showed tolerability, safety and effectiveness in treating cancers like breast, lung, colon, and other organs and other diseases like viral infections and hereditary diseases. Many different routes of administration can silence many genes at the same time. Limitations and uncertainties associated with siRNA treatment include the effectiveness of cellular uptake, precise targeting of the intended tissue or cell and prompt elimination from the body. CONCLUSIONS: The siRNA or RNAi method will be one of the most critical and influential techniques to fight against many different diseases. Although the RNAi approach has certain advantages, it also has limitations concerning clinical applications. Overcoming these limitations remains a daunting challenge.

Synergistic effects of Momordica charantia, Nigella sativa, and Anethum graveolens on metabolic syndrome targets: In vitro enzyme inhibition and in silico analyses.

Momordica charantia, Nigella sativa, and Anethum graveolens are established medicinal plants possessing noted anti-diabetic and anti-obesity properties. However, the molecular mechanisms underscoring their inhibitory effects on pancreatic lipase, α-glucosidase, and HMG-CoA reductase remain unexplored. This study aimed to elucidate the efficacy of various NS, MC, and AG blends in modulating the enzymatic activity of pancreatic lipase, HMG-CoA reductase, and a-glucosidase, utilizing an integrative approach combining in vitro assessments and molecular modeling techniques. A factorial design matrix generated eight distinct concentration combinations of NS, MC, and AG, subsequently subjected to in vitro enzyme inhibition assays. Molecular docking analyses using AutoDock Vina, molecular dynamics simulations, MMPBSA calculations, and principal component analysis, were executed with Gromacs to discern the interaction dynamics between the compounds and target enzymes. A formulation comprising NS:MC:AG at a 215:50:35 µg/mL ratio yielded significant inhibition of pancreatic lipase (IC50: 74.26 ± 4.27 µg/mL). Moreover, a concentration combination of 215:80:35 µg/mL effectively inhibited both α-glucosidase (IC50: 66.09 ± 3.98 µg/mL) and HMGCR (IC50: 129.03 µg/mL). Notably, MC-derived compounds exhibited superior binding affinity towards all three enzymes, compared to their reference molecules, with diosgenin, Momordicoside I, and diosgenin displaying binding affinities of -11.0, -8.8, and -7.9 kcal/mol with active site residues of pancreatic lipase, α-glucosidase, and HMGCR, respectively. Further, 100 ns molecular dynamics simulations revealed the formation and stabilization of non-bonded interactions between the compounds and the enzymes' active site residues. Through a synergistic application of in vitro and molecular modeling methodologies, this study substantiated the potent inhibitory activity of the NS:MC:AG blend (at a ratio of 215:80:35 µg/mL) and specific MC compounds against pancreatic lipase, α-glucosidase, and HMGCR. These findings provide invaluable insights into the molecular underpinnings of these medicinal plants' anti-diabetic and anti-obesity effects and may guide future therapeutic development.

Development and optimization of in-situ gel containing chitosan nanoparticles for possible nose-to-brain delivery of vinpocetine.

Vinpocetine (VIN), a derivative of vincamine found in the vinca plant, widens blood vessels in the brain and has been shown to improve cognitive function, memory, and cerebrovascular disorders. Nevertheless, the clinical utility of VIN is constrained by factors such as low oral bioavailability owing to the first-pass metabolism that often demands frequent dosing of 3-4 tablets/day. In this regard, the present work aimed to develop VIN-loaded chitosan nanoparticles (VIN-CH-NPs) to surmount these limitations and in view to enhance delivery to the brain of VIN by minimizing systemic exposure. The chitosan (CH) nanoparticles (NP) were developed by ionotropic gelation technique employing tripolyphosphate (TPP) as a cross-linking agent. Employing Design of Experiments (DoE), the effect of CH and TPP concentrations and stirring speed were systematically optimized using Box Behnken design (BBD). The optimized batch of nanoparticles displayed a particle size, zeta potential, entrapment efficiency, and drug loading of 130.6 ± 8.38 nm, +40.81 ± 0.11 mV, 97.56 ± 0.04 %, and 61 ± 0.89 %, respectively. Fourier Transform Infrared Spectroscopy indicated the chemical integrity of the drug ruling out the interaction between the VIN and excipients used. DSC and PXRD data indicated that reduction of the crystallinity of VIN in the chitosan matrix. These VIN-CH-NPs manifested good stability, exhibiting an almost spherical morphology. To mitigate rapid mucociliary clearance upon intranasal administration, the optimized VIN-CH-NPs were incorporated into thermosensitive in situ gel (VIN-CHN-ISG). It was observed that the in-situ gel loaded with nanoparticles was opalescent with a pH level of 5.3 ± 0.38. It was also noted that the gelation temperature was 32 ± 0.89 °C, and the gelation time was approximately 15 s. The drug delivery to the brain through the nasal application of optimized VIN-NPs in situ gel was assessed in rats. The results indicated significant nasal application of the in-situ gel nearly doubled the Cmax (P < 0.05) and AUC0-t (P < 0.05) in the brain compared to oral administration. Nasal administration improved drug delivery to the brain by reducing systemic exposure to VIN. A histopathological study of the nasal mucosa revealed no irritation or toxicity, making it safe for nasal administration. These findings suggest that the developed NPs in-situ gel effectively targeted vinpocetine to the brain through the nasal pathway, providing a potential therapeutic strategy for managing Alzheimer's disease.