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Morphological characterization and selection for high yielding and powdery mildew resistant pea (pisum sativum) lines

Ajmal Iqbal, Shahen Shah, Mohammad Nisar, Abdul Ghafoor

Sains Malaysiana, 2017;46:1727-1734.

Twenty lines of Pisum sativum particularly developed for high yield and resistant to powdery mildew were evaluated along with two parents (Falloner and 11760-3ER) and two checks (Climex and a local cultivar) with the objectives to determine morphological characterization, yield potential and resistance to powdery mildew. On the basis of one way cluster, the 24 lines were mainly grouped into four clusters, especially on the vegetative and yield contributing traits. It was observed that the tall and high yielding lines were grouped in cluster-III while the dwarf and high yielding lines were grouped in cluster-IV. Analysis of variance (ANOVA) showed significant difference (p<0.05) in the yield of 24 pea lines. The average grain yield of the 24 pea lines ranged from 22.87 to 102.54 g. The highest grain yield was produced by PL-4 (102.54 g plant-1) followed by PL-5 (82.14 g plant-1). Of the 24 pea lines, two lines (PL-4 and PL-5) were highly resistant to powdery mildew disease. Therefore, the newly developed PL-4 and PL-5 lines were high yielding and highly resistant. Among the 19 morphological traits, six (Eigenvalue >1.0) contributed more than 80% variability among the materials.
Comparative characterization and cytotoxicity study of TAT-peptide as potential vectors for siRNA and Dicer-substrate siRNA

Katas H, Abdul Ghafoor Raja M, Ee LC

Drug Dev Ind Pharm, 2014 Nov;40(11):1443-50.
PMID: 23962166 DOI: 10.3109/03639045.2013.828222

Recently, a newly discovered Dicer-substrate siRNA (DsiRNA) demonstrates higher potency in gene silencing than siRNA but both suffer from rapid degradation, poor cellular uptake and chemical instability. Therefore, Tat-peptide was exploited to protect and facilitate their delivery into cells. In this study, Tat-peptide was complexed with siRNA or DsiRNA through simple complexation. The physicochemical properties (particle size, surface charge and morphology) of the complexes formed were then characterized. The ability of Tat-peptide to carry and protect siRNA or DsiRNA was determined by UV-Vis spectrophotometry and serum protection assay, respectively. Cytotoxicity effect of these complexes was assessed in V79 cell line. siRNA-Tat complexes had particle size ranged from 186 ± 17.8 to 375 ± 8.3 nm with surface charge ranged from -9.3 ± 1.0 to +13.5 ± 1.0 mV, depending on the Tat-to-siRNA concentration ratio. As for DsiRNA-Tat complexes, the particle size was smaller than the ones complexed with siRNA, ranging from 176 ± 8.6 to 458 ± 14.7 nm. Their surface charge was in the range of +27.1 ± 3.6 to +38.1 ± 0.9 mV. Both oligonucleotide (ON) species bound strongly to Tat-peptide, forming stable complexes with loading efficiency of more than 86%. These complexes were relatively non cytotoxic as the cell viability of ∼90% was achieved. In conclusion, Tat-peptide has a great potential as siRNA and DsiRNA vector due to the formation of stable complexes with desirable physical characteristics, low toxicity and able to carry high amount of siRNA or DsiRNA.
Fulltext Development of Chitosan Nanoparticles as a Stable Drug Delivery System for Protein/siRNA

Katas H, Raja MA, Lam KL

Int J Biomater, 2013;2013:146320.
PMID: 24194759 DOI: 10.1155/2013/146320

Chitosan nanoparticles (CS NPs) exhibit good physicochemical properties as drug delivery systems. The aim of this study is to determine the modulation of preparative parameters on the physical characteristics and colloidal stability of CS NPs. CS NPs were fabricated by ionic interaction with dextran sulphate (DS) prior to determination of their storage stability. The smallest CS NPs of 353 ± 23 nm with a surface charge of +56.2 ± 1.5 mV were produced when CS and DS were mixed at pH 4 and with a DS : CS mass ratio of 0.5 : 1. An entrapment efficiency of 98% was achieved when BSA/siRNA was loaded into the nanoparticles. The results also showed that particle size and surface charge of CS NPs were slightly changed up to 2 weeks when stored at 4°C. Greater particle size and surface charge were obtained with increasing the concentration of DS. In conclusion, NPs were sufficiently stable when kept at 4°C and able to carry and protect protein.
Fulltext Stability, Intracellular Delivery, and Release of siRNA from Chitosan Nanoparticles Using Different Cross-Linkers

Raja MA, Katas H, Jing Wen T

PLoS One, 2015;10(6):e0128963.
PMID: 26068222 DOI: 10.1371/journal.pone.0128963

Chitosan (CS) nanoparticles have been extensively studied for siRNA delivery; however, their stability and efficacy are highly dependent on the types of cross-linker used. To address this issue, three common cross-linkers; tripolyphosphate (TPP), dextran sulphate (DS) and poly-D-glutamic acid (PGA) were used to prepare siRNA loaded CS-TPP/DS/PGA nanoparticles by ionic gelation method. The resulting nanoparticles were compared with regard to their physicochemical properties including particle size, zeta potential, morphology, binding and encapsulation efficiencies. Among all the formulations prepared with different cross linkers, CS-TPP-siRNA had the smallest particle size (ranged from 127 ± 9.7 to 455 ± 12.9 nm) with zeta potential ranged from +25.1 ± 1.5 to +39.4 ± 0.5 mV, and high entrapment (>95%) and binding efficiencies. Similarly, CS-TPP nanoparticles showed better siRNA protection during storage at 4˚C and as determined by serum protection assay. TEM micrographs revealed the assorted morphology of CS-TPP-siRNA nanoparticles in contrast to irregular morphology displayed by CS-DS-siRNA and CS-PGA-siRNA nanoparticles. All siRNA loaded CS-TPP/DS/PGA nanoparticles showed initial burst release followed by sustained release of siRNA. Moreover, all the formulations showed low and concentration-dependent cytotoxicity with human colorectal cancer cells (DLD-1), in vitro. The cellular uptake studies with CS-TPP-siRNA nanoparticles showed successful delivery of siRNA within cytoplasm of DLD-1 cells. The results demonstrate that ionically cross-linked CS-TPP nanoparticles are biocompatible non-viral gene delivery system and generate a solid ground for further optimization studies, for example with regard to steric stabilization and targeting.
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.
Synthesis and mechanistic studies of curcumin analog-based oximes as potential anticancer agents

Qin HL, Leng J, Youssif BG, Amjad MW, Raja MA, Hussain MA, et al.

Chem Biol Drug Des, 2017 Feb 10.
PMID: 28186369 DOI: 10.1111/cbdd.12964

The incidence of cancer can be decreased by chemoprevention using either natural or synthetic agents. Apart from synthetic compounds, numerous natural products have exhibited promising potential to inhibit carcinogenesis in vivo. In this study, α, β-unsaturated carbonyl-based anticancer compounds were used as starting materials to synthesize new oxime analogs. The findings from the antiproliferative assay using seven different human cancer cell lines provided a clear picture of structure-activity relationship. The oxime analogs namely 7a and 8a showed strong antiproliferative activity against the cell lines. The mechanistic effects of compounds on EGFR-TK kinases and tubulin polymerization and BRAF(V)(600E) were investigated. In addition, the efficacy of compounds in reversing the efflux-mediated resistance developed by cancer cells was also studied. The compounds 5a and 6a displayed potent activity on various targets such as BRAF(V)(600E) and EGFR-TK kinases and also exhibited strong antiproliferative activity against different cell lines hence showing potential of multifunctional anticancer agents.
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.