Integrated Electrochemical Aptamer Biosensing and Colorimetric pH Monitoring via Hydrogel Microneedle Assays for Assessing Antibiotic Treatment.

Current methods for therapeutic drug monitoring (TDM) have a long turnaround time as they involve collecting patients' blood samples followed by transferring the samples to medical laboratories where sample processing and analysis are performed. To enable real-time and minimally invasive TDM, a microneedle (MN) biosensor to monitor the levels of two important antibiotics, vancomycin (VAN) and gentamicin (GEN) is developed. The MN biosensor is composed of a hydrogel MN (HMN), and an aptamer-functionalized flexible (Flex) electrode, named HMN-Flex.

Benzofuran and Benzo[b]thiophene-2-Carboxamide Derivatives as Modulators of Amyloid Beta (Aβ42) Aggregation.

A group of N-phenylbenzofuran-2-carboxamide and N-phenylbenzo[b]thiophene-2-carboxamide derivatives were designed and synthesized as a novel class of Aβ42 aggregation modulators. In the thioflavin-T based fluorescence aggregation kinetics study, compounds 4 a, 4 b, 5 a and 5 b possessing a methoxyphenol pharmacophore were able to demonstrate concentration dependent inhibition of Aβ42 aggregation with maximum inhibition of 54 % observed for compound 4 b. In contrast, incorporation of a 4-methoxyphenyl ring in compounds 4 d and 5 d led to a significant increase in Aβ42 fibrillogenesis demonstrating their ability to accelerate Aβ42 aggregation.

Post-Translational Modifications in Tau and Their Roles in Alzheimer's Pathology.

Microtubule-Associated Protein Tau (also known as tau) has been shown to accumulate into paired helical filaments and neurofibrillary tangles, which are known hallmarks of Alzheimer's disease (AD) pathology. Decades of research have shown that tau protein undergoes extensive post-translational modifications (PTMs), which can alter the protein's structure, function, and dynamics and impact the various properties such as solubility, aggregation, localization, and homeostasis. There is a vast amount of information describing the impact and role of different PTMs in AD pathology and neuroprotection.

Small Molecules -Phenylbenzofuran-2-carboxamide and -Phenylbenzo[]thiophene-2-carboxamide Promote Beta-Amyloid (Aβ42) Aggregation and Mitigate Neurotoxicity.

This study reports the unusual ability of small molecules -phenylbenzofuran-2-carboxamide () and -phenylbenzo[]thiophene-2-carboxamide () to promote and accelerate Aβ42 aggregation. In the in vitro aggregation kinetic assays, was able to demonstrate rapid increases in Aβ42 fibrillogenesis ranging from 1.5- to 4.

Differential Effects of Endocannabinoids on Amyloid-Beta Aggregation and Toxicity.

The regulation and metabolism of the endocannabinoid system has received extensive attention for their potential neuroprotective effect in neurodegenerative diseases such as Alzheimer's disease (AD), which is characterized by amyloid β (Aβ) -induced cell toxicity, inflammation, and oxidative stress. Using in vitro techniques and two cell lines, the mouse hippocampus-derived HT22 cells and Chinese hamster ovary (CHO) cells expressing human cannabinoid receptor type 1 (CB1), we investigated the ability of endocannabinoids to inhibit Aβ aggregation and protect cells against Aβ toxicity. The present study provides evidence that endocannabinoids N-arachidonoyl ethanol amide (AEA), noladin and O-arachidonoyl ethanolamine (OAE) inhibit Aβ42 aggregation.

Apigenin directly interacts with and inhibits topoisomerase 1 to upregulate CD26/DPP4 on colorectal carcinoma cells.

CD26/dipeptidyl peptidase IV (DPP4) is a cell-surface glycoprotein present on most epithelial cells that modulates the local response to external signals. We have previously shown that the dietary flavone apigenin (4',5,7-trihydroxyflavone) upregulates cell-surface CD26/DPP4 on human colorectal carcinoma (CRC) cells and regulates its activities. We observed a unique synergistic interaction with the CRC chemotherapeutic agent irinotecan, which through its metabolite SN38 elevates CD26 at doses that are sub-cytotoxic.

Peptide-Modified Gemini Surfactants as Delivery System Building Blocks with Dual Functionalities for Glaucoma Treatment: Gene Carriers and Amyloid-Beta (Aβ) Self-Aggregation Inhibitors.

Retinal ganglion cell (RGC) neurodegeneration in glaucoma has potential links with amyloid-β (Aβ) deposition. Targeting the Aβ pathway was shown to reduce RGC apoptosis and protect RGCs from degeneration. We report exploratory studies on the amyloid Aβ aggregation inhibition properties of four cell adhesion peptide (CAP)-gemini surfactants that are intended as building blocks for gene carrier nanoparticles for glaucoma treatment.

Therapeutic opportunities in cancer therapy: targeting the p53-MDM2/MDMX interactions.

Ubiquitination is a key enzymatic post-translational modification that influences p53 stability and function. p53 protein regulates the expression of MDM2 (mouse double-minute 2 protein) E3 ligase and MDMX (double-minute 4 protein), through proteasome-based degradation. Exploration of targeting the ubiquitination pathway offers a potentially promising strategy for precision therapy in a variety of cancers.

Strategies in the design and development of (TAR) DNA-binding protein 43 (TDP-43) binding ligands.

The human transactive responsive (TAR) DNA-binding protein 43 (TDP-43) is involved in a number of physiological processes in the body. Its primary function involves RNA regulation. The TDP-43 protein is also involved in many diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD) and even cancers.

Modeling the Inhibition Kinetics of Curcumin, Orange G, and Resveratrol with Amyloid-β Peptide.

The β-amyloid (Aβ) protein aggregation into toxic forms is one of the major factors in the Alzheimer's disease (AD) pathology. Screening compound libraries as inhibitors of Aβ-aggregation is a common strategy to discover novel molecules as potential therapeutics in AD. In this regard, thioflavin T (ThT)-based fluorescence spectroscopy is a widely used in vitro method to identify inhibitors of Aβ aggregation.

Drug Repurposing: Dipeptidyl Peptidase IV (DPP4) Inhibitors as Potential Agents to Treat SARS-CoV-2 (2019-nCoV) Infection.

The current outbreak of severe acute respiratory distress syndrome (SARS) or nCOVID-19 pandemic, caused by the coronavirus-2 (CoV-2), continues to wreak havoc globally. As novel vaccines are being discovered and developed, small molecule drugs still constitute a viable treatment option for SARS-CoV-2 infections due to their advantages such as superior patient compliance for oral therapies, reduced manufacturing costs and ease of large scale distribution due to better stability and storage profiles. Discovering new drugs for SARS-CoV-2 infections is a time consuming and expensive proposition.

Histone Demethylase KDM5B as a Therapeutic Target for Cancer Therapy.

Lysine-specific demethylase 5B (KDM5B/PLU1/JARID1B) is found to be overexpressed in numerous malignancies, including breast, lung, skin, liver, and prostate cancer. Identification of molecules targeting the KDM5B enzyme could be a potential lead in cancer research. Although many KDM5B inhibitors with promising outcomes have been developed so far, its further application in clinical practice is limited due to toxicity and lack of target specificity.

PANX1 in inflammation heats up: New mechanistic insights with implications for injury and infection.

A new study by Yang and colleagues has revealed that TNF-alpha regulates PANX1 levels through an NF-kB-dependent mechanism in human endothelial cells. PANX1 modulates Ca influx contributing to IL-1beta production independent of purinergic signaling. These novel findings expand our understanding of TNF-alpha-mediated upregulation of IL-1beta with implications for responses to tissue injury and infection.

Corrigendum to "Role of UHRF1 in malignancy and its function as a therapeutic target for molecular docking towards the SRA domain" [Int. J. Biochem. Cell Biol. 114 (September 2019) 105558].

Cancer pathogenesis has been attributed to the minor and major disruptions in the cell cycle, with a key role being played by several of the recently discovered epigenetic factors. Lately, UHRF1 (Ubiquitin-like with containing PHD and RING Finger domains 1), an epigenetic regulator has been shown to be evidently over expressed in numerous malignancies through an in-depth review of literature. Molecular docking studies have found that existing drugs such as propranolol, naphthazarin and thymoquinone have favourable interactions with specific domains of UHRF1.

Role of UHRF1 in malignancy and its function as a therapeutic target for molecular docking towards the SRA domain.

The figure describes the location of UHRF1 (Ubiquitin-like with containing PHD and RING Finger domains 1) gene, mRNA and protein synthesis in the tumor cell and its structural domains with a focus on the docking of Naphthazarin on the SRA domain of UHRF1, resulting in reduction of tumor size.

Repurposing nitrocatechols: 5-Nitro-α-cyanocarboxamide derivatives of caffeic acid and caffeic acid phenethyl ester effectively inhibit aggregation of tau-derived hexapeptide AcPHF6.

Polyphenols like caffeic acid and its phenethyl ester have been associated with potent anti-aggregating activity. Accordingly, we screened a library of polyphenols and synthetic derivatives thereof for their capacity to inhibit tau-aggregation using a thioflavin T-based fluorescence method. Our results show that the nitrocatechol scaffold is required for a significant anti-aggregating activity, which is enhanced by introducing bulky substituents at the side chain.

Interactions of polyunsaturated fatty acids with amyloid peptides Aβ40 and Aβ42.

Polyunsaturated fatty acids (PUFAs) are reported to exert beneficial effects in Alzheimer's disease. Some PUFAs are known to reduce amyloid-beta (Aβ) toxicity by promoting its degradation and clearance. Studies on the direct interactions of PUFAs with Aβ peptides are limited and contradictory.

Interactions of Selective Serotonin Reuptake Inhibitors with β-Amyloid.

Treating Alzheimer's disease (AD) is a major challenge at the moment with no new drugs available to cure this devastating neurodegenerative disorder. In this regard, drug repurposing, which aims to determine novel therapeutic usage for drugs already approved by the regulatory agencies, is a pragmatic approach to discover novel treatment strategies. Selective serotonin reuptake inhibitors (SSRIs) are a known class of United States Food and Drug Administration approved drugs used in the treatment of depression.

Tau Derived Hexapeptide AcPHF6 Promotes Beta-Amyloid (Aβ) Fibrillogenesis.

We studied the interactions of a tau derived hexapeptide AcPHF6 with β-amyloid peptides Aβ40 and Aβ42 which reveals its unusual ability to promote Aβ fibrillogenesis. The results demonstrate that the N-acetylated and C-amidated AcPHF6 hexapeptide can cause significant acceleration in Aβ40 and Aβ42 fibril growth. Aggregation kinetic studies at pH 7.

Cytochrome P450 binding studies of novel tacrine derivatives: Predicting the risk of hepatotoxicity.

The 1,2,3,4-tetrahydroacridine derivative tacrine was the first drug approved to treat Alzheimer's disease (AD). It is known to act as a potent cholinesterase inhibitor. However, tacrine was removed from the market due to its hepatotoxicity concerns as it undergoes metabolism to toxic quinonemethide species through the cytochrome P450 enzyme CYP1A2.

Synthesis and characterization of asymmetrical gemini surfactants.

The effect of variation in the length of surfactant hydrocarbon tail groups was tested in a series of dissymmetric gemini surfactants (N-alkyl N,N,N,N-tetramethyl-N-(6-pyren-6yl)-hexyl)propane-1,3-diammonium dibromide designated as CCCBr, with m = hexyl pyrene, and n = 8, 12, 14, 16, and 18. The aggregation properties of these surfactants have been investigated by means of H NMR, fluorescence spectroscopy, surface tension and electrical conductivity measurements. The critical micelle concentration (CMC) was determined using surface tension and confirmed using the specific conductance method.

Droplet Microfluidic System with On-Demand Trapping and Releasing of Droplet for Drug Screening Applications.

96-Well plate has been the traditional method used for screening drug compounds libraries for potential bioactivity. Although this method has been proven successful in testing dose-response analysis, the microliter consumption of expensive reagents and hours of reaction and analysis time call for innovative methods for improvements. This work demonstrates a droplet microfluidic platform that has the potential to significantly reduce the reagent consumption and shorten the reaction and analysis time by utilizing nanoliter-sized droplets as a replacement of wells.

2,4-Disubstituted quinazolines as amyloid-β aggregation inhibitors with dual cholinesterase inhibition and antioxidant properties: Development and structure-activity relationship (SAR) studies.

A library of fifty-seven 2,4-disubstituted quinazoline derivatives were designed, synthesized and evaluated as a novel class of multi-targeting agents to treat Alzheimer's disease (AD). The biological assay results demonstrate the ability of several quinazoline derivatives to inhibit both acetyl and butyrylcholinesterase (AChE and BuChE) enzymes (IC range = 1.6-30.

Development of Blood-Brain Barrier Permeable Nitrocatechol-Based Catechol O-Methyltransferase Inhibitors with Reduced Potential for Hepatotoxicity.

Recent efforts have been focused on the development of centrally active COMT inhibitors, which can be valuable assets for neurological disorders such as Parkinson's disease, due to the severe hepatotoxicity risk associated with tolcapone. New nitrocatechol COMT inhibitors based on naturally occurring caffeic acid and caffeic acid phenethyl ester were developed. All nitrocatechol derivatives displayed potent inhibition of peripheral and cerebral COMT within the nanomolar range.