Which neuroimaging and fluid biomarkers method is better in theranostic of Alzheimer's disease? An umbrella review.

Biomarkers are measured to evaluate physiological and pathological processes as well as responses to a therapeutic intervention. Biomarkers can be classified as diagnostic, prognostic, predictor, clinical, and therapeutic. In Alzheimer's disease (AD), multiple biomarkers have been reported so far. Nevertheless, finding a specific biomarker in AD remains a major challenge. Three databases, including PubMed, Web of Science, and Scopus were selected with the keywords of Alzheimer's disease, neuroimaging, biomarker, and blood. The results were finalized with 49 potential CSF/blood and 35 neuroimaging biomarkers. To distinguish normal from AD patients, amyloid-beta42 (Aß42), plasma glial fibrillary acidic protein (GFAP), and neurofilament light (NFL) as potential biomarkers in cerebrospinal fluid (CSF) as well as the serum could be detected. Nevertheless, most of the biomarkers fairly change in the CSF during AD, listed as kallikrein 6, virus-like particles (VLP-1), galectin-3 (Gal-3), and synaptotagmin-1 (Syt-1). From the neuroimaging aspect, atrophy is an accepted biomarker for the neuropathologic progression of AD. In addition, Magnetic resonance spectroscopy (MRS), diffusion weighted imaging (DWI), diffusion tensor imaging (DTI), tractography (DTT), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI), can be used to detect AD. Using neuroimaging and CSF/blood biomarkers, in combination with artificial intelligence, it is possible to obtain information on prognosis and follow-up on the different stages of AD. Hence physicians could select the suitable therapy to attenuate disease symptoms and follow up on the efficiency of the prescribed drug.

Synthesis, design, biological evaluation, and computational analysis of some novel uracil-azole derivatives as cytotoxic agents.

The design and synthesis of novel cytotoxic agents is still an interesting topic for medicinal chemistry researchers due to the unwanted side effects of anticancer drugs. In this study, a novel series of uracil-azole hybrids were designed and synthesized. The cytotoxic activity, along with computational studies: molecular docking, molecular dynamic simulation, density functional theory, and ADME properties were also, evaluated. The compounds were synthesized by using 3-methyl-6-chlorouracil as the starting material. Cytotoxicity was determined using MTT assay in the breast carcinoma cell line (MCF-7) and Hepatocellular carcinoma cell line (HEPG-2). These derivatives demonstrated powerful inhibitory activity against breast and hepatocellular carcinoma cell lines in comparison to Cisplatin as positive control. Among these compounds, 4j displayed the best selectivity profile and good activity with IC50 values of 16.18 ± 1.02 and 7.56 ± 5.28 µM against MCF-7 and HEPG-2 cell lines respectively. Structure-activity relationships revealed that the variation in the cytotoxic potency of the synthesized compounds was affected by various substitutions of benzyl moiety. The docking output showed that 4j bind well in the active site of EGFR and formed a stable complex with the EGFR protein. DFT was used to investigate the reactivity descriptors of 4a and 4j. The outputs demonstrated that these uracil-azole hybrids can be considered as potential cytotoxic agents.

Statistical optimization of arachidonic acid synthesis by Mortierella alpina CBS 754.68 in a solid-state fermenter.

Arachidonic acid (ARA) is an omega-6 fatty acid that plays a major role in human health. The present study optimizes the production of ARA by the soil fungus Mortierella alpina CBS 754.68 on oil cakes. In the first step, the best substrate was chosen from four oil cakes, namely soybean, sunflower, olive, and colza oil cakes, of which sunflower oil cake showed the highest yield. In the next step, screening tests were performed using the Plackett-Burman design. Seven variables (substrate particle size, moisture content, time, temperature, yeast extract, glucose, and glutamate) were investigated (each taking values of +1 and -1). Among these variables, time, temperature, and substrate particle size significantly affected ARA production (p < .05), so they were further investigated in the optimization step. The optimal fermentation time, temperature, and substrate particle size calculated by response surface methodology were 8.75 days, 18.5°C, and 1.3 mm-1.7 mm, respectively. Under these conditions, M. alpina was predicted to produce 4.19 mg of ARA/g dry weight of substrate (DWS). The actual yield, determined in evaluation tests, was 4.48 ± 0.16 mg ARA/g DWS, which shows the accuracy of the model. In the final step, the effect of the aeration rate on producing ARA was investigated in a packed-bed solid-state fermenter under the determined optimal conditions. In this stage, the highest ARA yield was 10.13 ± 0.26 mg/g DWS, approximately double that of the optimization step, and this confirms that aeration increases ARA production by M. alpina.

Finding a prospective dual-target drug for the treatment of coronavirus disease by theoretical study.

Spike protein of coronavirus is a key protein in binding and entrance of virus to the human cell via binding to the receptor-binding domain (RBD) domain of S1 subunit to peptidase domain region of ACE2 receptor. In this study, the possible effect of 24 antiviral drugs on the RBD domain of spike protein was investigated via docking and molecular dynamics simulation for finding a dual-target drug. At first, all drugs were docked to the RBD domain of spike protein, and then all complexes and free RBD domains were separately used for molecular dynamics simulation for 50 ns via amber18 software. The simulation results showed that 10 ligands from 28 ligands were separated from the RBD domain, and among 18 remained ligands, baloxavir marboxil, and danoprevir drugs, besides endonuclease activity and protease inhibitory, can bind to key residues of the RBD domain. Then these drugs have a dual target and should be more effective than current drugs, and experimental studies should be done on baloxavir marboxil and danoprevir as more potential drugs for coronavirus disease Communicated by Ramaswamy H. Sarma.

In-silico design of peptides for inhibition of HLA-A*03-KLIETYFSK complex as a new drug design for treatment of multiples sclerosis disease.

Multiple sclerosis is recognized as a chronic inflammatory disease. Human leukocyte antigen (HLA) plays an important role in initiating adaptive immune responses. HLA class I is present in almost all nucleated cells and presents the cleaved endogenous peptide antigens to cytotoxic T cells. HLA-A*03 is one of the HLA class I alleles, which is reported as substantially related HLA to MS disease. In 2011, the structure of the HLA-A*03 in complex was identified with an immunodominant proteolipid protein (PLP) epitope (KLIETYFSK). This complex has been reported as an important autoantigen-presenting complex in MS pathogenesis. In this study, new peptides were designed to bind to this complex that may prevent specific pathogenic cytotoxic T cell binding to this autoantigen-presenting complex and CNS demyelination. Herein, 14 new helical peptides containing 19 amino acids were designed and their structures were predicted using the PEP-FOLD server. The binding of each designed peptide to the mentioned complex was then performed. A mutation approach was used by the BeAtMuSiC server to improve the binding affinity of the designed peptide. In each position, amino acid substitutions leading to an increase in the binding affinity of the peptide to the mentioned complex were determined. Finally, the resulting complexes were simulated for 40 ns using AMBER18 software. The results revealed that out of 14 designed peptides, "WRYWWKDWAKQFRQFYRWF" peptide exhibited the highest affinity for binding to the mentioned complex. This peptide can be considered as a potential drug to control multiple sclerosis disease in patients carrying the HLA-A*03 allele.

The effect of platelet-rich plasma on healing of palatal donor site following connective tissue harvesting: a pilot study in dogs.

BACKGROUND: Peri-implant plastic surgery includes soft tissue enhancement by connective tissue grafting. The palatal donor site provides peri-implant keratinized mucosa and soft tissue height. Platelet-rich plasma (PRP) contains growth factors that may enhance early healing. PURPOSE: The present animal study investigated the effect of PRP on wound healing of palatal donor site after connective tissue harvesting. MATERIALS AND METHODS: In 12 mongrel dogs, bilateral palatal connective tissues of 10 × 15 mm were harvested. At test site, PRP was applied into the wound, and the contralateral site served as control. The healing was evaluated clinically and histologically at 1 week, 2 weeks, and 4 weeks after surgeries. Exact binomial probability and Wilcoxon signed-rank test were used to compare the clinical and histologic measurements. RESULTS: No statistically significant differences between PRP and control sites were measured with regard to clinical healing (p = 1.000) and histologic variables, including inflammatory cells (p = .750), collagen fibers (p = .375), and granulation tissue (p = .500) at any time interval. CONCLUSION: The addition of PRP to palatal mucosal wound sites did not accelerate wound healing.