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Design, mechanism, delivery and therapeutics of canonical and Dicer-substrate siRNA

Raja MAG, Katas H, Amjad MW

Asian J Pharm Sci, 2019 Sep;14(5):497-510.
PMID: 32104477 DOI: 10.1016/j.ajps.2018.12.005

Upon the discovery of RNA interference (RNAi), canonical small interfering RNA (siRNA) has been recognized to trigger sequence-specific gene silencing. Despite the benefits of siRNAs as potential new drugs, there are obstacles still to be overcome, including off-target effects and immune stimulation. More recently, Dicer substrate siRNA (DsiRNA) has been introduced as an alternative to siRNA. Similarly, it also is proving to be potent and target-specific, while rendering less immune stimulation. DsiRNA is 25-30 nucleotides in length, and is further cleaved and processed by the Dicer enzyme. As with siRNA, it is crucial to design and develop a stable, safe, and efficient system for the delivery of DsiRNA into the cytoplasm of targeted cells. Several polymeric nanoparticle systems have been well established to load DsiRNA for in vitro and in vivo delivery, thereby overcoming a major hurdle in the therapeutic uses of DsiRNA. The present review focuses on a comparison of siRNA and DsiRNA on the basis of their design, mechanism, in vitro and in vivo delivery, and therapeutics.
An insight into the role of Artificial Intelligence in the early diagnosis of Alzheimer's disease

Verma RK, Pandey M, Chawla P, Choudhury H, Mayuren J, Bhattamisra SK, et al.

CNS Neurol Disord Drug Targets, 2021 May 11.
PMID: 33982657 DOI: 10.2174/1871527320666210512014505

BACKGROUND: The complication of Alzheimer's disease (AD) has made the development of its therapeutic a challenging task. Even after decades of research, we have achieved no more than a few years of symptomatic relief. The inability to diagnose the disease early is the foremost hurdle behind its treatment. Several studies have aimed to identify potential biomarkers that can be detected in body fluids (CSF, blood, urine, etc) or assessed by neuroimaging (i.e., PET and MRI). However, the clinical implementation of these biomarkers is incomplete as they cannot be validated.
METHOD: To overcome the limitation, the use of artificial intelligence along with technical tools has been extensively investigated for AD diagnosis. For developing a promising artificial intelligence strategy that can diagnose AD early, it is critical to supervise neuropsychological outcomes and imaging-based readouts with a proper clinical review.
CONCLUSION: Profound knowledge, a large data pool, and detailed investigations are required for the successful implementation of this tool. This review will enlighten various aspects of early diagnosis of AD using artificial intelligence.
Nanoparticles Based Intranasal Delivery of Drug to Treat Alzheimer's Disease: A Recent Update

Pandey M, Choudhury H, Verma RK, Chawla V, Bhattamisra SK, Gorain B, et al.

CNS Neurol Disord Drug Targets, 2020;19(9):648-662.
PMID: 32819251 DOI: 10.2174/1871527319999200819095620

Alzheimer Association Report (2019) stated that the 6th primary cause of death in the USA is Alzheimer's Disease (AD), which leads to behaviour and cognitive impairment. Nearly 5.8 million peoples of all ages in the USA have suffered from this disease, including 5.6 million elderly populations. The statistics of the progression of this disease is similar to the global scenario. Still, the treatment of AD is limited to a few conventional oral drugs, which often fail to deliver an adequate amount of the drug in the brain. The reduction in the therapeutic efficacy of an anti-AD drug is due to poor solubility, existence to the blood-brain barrier and low permeability. In this context, nasal drug delivery emerges as a promising route for the delivery of large and small molecular drugs for the treatment of AD. This promising pathway delivers the drug directly into the brain via an olfactory route, which leads to the low systemic side effect, enhanced bioavailability, and higher therapeutic efficacy. However, few setbacks, such as mucociliary clearance and poor drug mucosal permeation, limit its translation from the laboratory to the clinic. The above stated limitation could be overcome by the adaption of nanoparticle as a drug delivery carrier, which may lead to prolong delivery of drugs with better permeability and high efficacy. This review highlights the latest work on the development of promising Nanoparticles (NPs) via the intranasal route for the treatment of AD. Additionally, the current update in this article will draw the attention of the researcher working on these fields and facing challenges in practical applicability.
Evaluation of ligustrazine based synthetic compounds for mechanism based antiproliferative effects

Bukhari SNA, Alotaibi NH, Ahmad W, Alharbi KS, Abdelgawad MA, Al-Sanea MM, et al.

Med Chem, 2020 Sep 05.
PMID: 32888274 DOI: 10.2174/1573406416666200905125038

BACKGROUND: Ligustrazine and chalcones have been reported previously for various biological activities including anticancer effects.
OBJECTIVES: Based on the multitargeted biological activities approach of ligustrazine based chalcones, in current study 18 synthetic ligustrazine-containing α, β-unsaturated carbonyl-based 1, 3-Diphenyl-2-propen-1-one derivatives were evaluated for their inhibitory effects on growth of five different types of cancer cells.
METHODS: All compounds were evaluated for anticancer effects on various cancer cell lines by propidium iodide fluorescence assay and various other assays were performed for mechanistic studies.
RESULTS: Majority of compounds exhibited strong inhibition of cancer cells especially synthetic compounds 4a and 4b bearing 1-Pyridin-3-yl-ethanone as a ketone moiety in main structural backbone were found most powerful inhibitors of cancer cell growth. Most active 9 compounds among whole series were selected for further studies related to different cancer targets including EGFR TK kinases, tubulin polymerization, KAF and BRAFV600E.
CONCLUSION: Synthetic derivatives including 4a-b and 5a-b showed multitarget approach and showed strong inhibitory effects on EGFR, FAK and BRAF while three compounds including 3e bearing methoxy substitution, 4a and 4b with 1- pyridin-3-yl-ethanone moiety showed the inhibition of tubulin polymerization.