Therapeutic Outcomes of Isatin and Its Derivatives against Multiple Diseases: Recent Developments in Drug Discovery

Isatin (1H indole 2, 3-dione) is a heterocyclic, endogenous lead molecule recognized in humans and different plants. The isatin nucleus and its derivatives are owed the attention of researchers due to their diverse pharmacological activities such as anticancer, anti-TB, antifungal, antimicrobial, antioxidant, anti-inflammatory, anticonvulsant, anti-HIV, and so on. Many research chemists take advantage of the gentle structure of isatins, such as NH at position 1 and carbonyl functions at positions 2 and 3, for designing biologically active analogues via different approaches. Literature surveys based on reported preclinical, clinical, and patented details confirm the multitarget profile of isatin analogues and thus their importance in the field of medicinal chemistry as a potent chemotherapeutic agent. This review represents the recent development of isatin analogues possessing potential pharmacological action in the years 2016–2020. The structure–activity relationship is also discussed to provide a pharmacophoric pattern that may contribute in the future to the design and synthesis of potent and less toxic therapeutics

Functional Role of Glutamine 28 and Arginine 39 in Double Stranded RNA Cleavage by Human Pancreatic Ribonuclease

Human pancreatic ribonuclease (HPR), a member of RNase A superfamily, has a high activity on double stranded (ds) RNA. By virtue of this activity HPR appears to be involved in the host-defense against pathogenic viruses. To delineate the mechanism of dsRNA cleavage by HPR, we have investigated the role of glutamine 28 and arginine 39 of HPR in its activity on dsRNA. A non-basic residue glycine 38, earlier shown to be important for dsRNA cleavage by HPR was also included in the study in the context of glutamine 28 and arginine 39. Nine variants of HPR respectively containing Q28A, Q28L, R39A, G38D, Q28A/R39A, Q28L/R39A, Q28A/G38D, R39A/G38D and Q28A/G38D/R39A mutations were generated and functionally characterized. The far-UV CD-spectral analysis revealed all variants, except R39A, to have structures similar to that of HPR. The catalytic activity of all HPR variants on single stranded RNA substrate was similar to that of HPR, whereas on dsRNA, the catalytic efficiency of all single residue variants, except for the Q28L, was significantly reduced. The dsRNA cleavage activity of R39A/G38D and Q28A/G38D/R39A variants was most drastically reduced to 4% of that of HPR. The variants having reduced dsRNA cleavage activity also had reduction in their dsDNA melting activity and thermal stability. Our results indicate that in HPR both glutamine 28 and arginine 39 are important for the cleavage of dsRNA. Although these residues are not directly involved in catalysis, both arginine 39 and glutamine 28 appear to be facilitating a productive substrate-enzyme interaction during the dsRNA cleavage by HPR

Unraveling the Role of RNA Mediated Toxicity of C9orf72 Repeats in C9-FTD/ALS

The most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is intronic hexanucleotide (G4C2) repeat expansions (HRE) in the C9orf72 gene. The non-exclusive pathogenic mechanisms by which C9orf72 repeat expansions contribute to these neurological disorders include loss of C9orf72 function and gain-of-function determined by toxic RNA molecules and dipeptides repeats protein toxicity. The expanded repeats are transcribed bidirectionally and forms RNA foci in the central nervous system, and sequester key RNA-binding proteins (RBPs) leading to impairment in RNA processing events. Many studies report widespread transcriptome changes in ALS carrying a C9orf72 repeat expansion. Here we review the contribution of RNA foci interaction with RBPs as well as transcriptome changes involved in the pathogenesis of C9orf72- associated FTD/ALS. These informations are essential to elucidate the pathology and therapeutic intervention of ALS and/or FTD

PyPAn: An Automated Graphical User Interface for Protein Sequence and Structure Analyses

Background: Protein sequence and structure analyses have been essential components of bioinformatics and structural biology. They provide a deeper insight into the physicochemical properties, structure, and subsequent functions of a protein. Advanced computational approaches and bioinformatics utilities help solve several issues related to protein analysis. Still, beginners and non-professional may struggle when encountering a wide variety of computational tools and the sheer number of input parameter variables required by each tool. Methods: We introduce a free-to-access graphical user interface (GUI) named PyPAn \u27Python-based Protein Analysis\u27 for varieties of protein sequence/structure analyses. PyPAn serves as a universal platform to analyze protein sequences, structure, and their properties. PyPAn facilitates onboard analysis of each task in just a single click. It can be used to calculate the physicochemical properties, including instability index and molar extinction coefficient, for a protein. PyPAn is one of the few computational tools that allow users to generate a Ramachandran plot and calculate solvent accessibility and the radius of gyration (Rg) of proteins at once. In addition, it can refine the protein model along with computation and minimization of its energy. Results: PyPAn can generate a recommendation for an appropriate structure modelling method to employ for a query protein sequence. PyPAn is one of the few, if not the only, Python-based computational GUI tools with an array of options for the user to employ as they see fit. Conclusion: PyPAn aims to unify many successful academically significant proteomic applications and is freely available for academic and industrial research uses at https://hassanlab.org/pypan

Green Composites Based on Animal Fiber and Their Applications for a Sustainable Future

Global climate change is already affecting the environment, as glaciers are receding, ice on rivers and lakes is melting, plant and animal range`s have altering, and trees are blooming early. Therefore, focus has shifted towards sustainable materials. There is a growing desire for materials that have a unique combination of qualities that metals, polymers, and other materials cannot provide, therefore scientists are turning their focus to green composites. Green composites offer a wide range of uses in automotive, aerospace, and marine applications. Composites are multiphase resources with separate interfaces that contain chemically different materials. Composites are made up of a variety of materials that are distinct in nature, and they give a set of desirable features that are superior to those of their predecessors or parents. Natural fibers are less expensive, more readily available, rust-resistant, plentiful, nontoxic, and safe for human skin, eyes, and respiratory systems. Green composites are created by combining renewable fibers with polymers (matrix) to create a new class of composites known as “green composites.” This review includes studies on various animal-based fibers and their applications. In this article, recent advancements in the field of these fibers and their composites of fibers are also discussed. The physical, chemical, and mechanical properties are also discussed in this paper. Moreover, the benefits and drawbacks of using these fibers are also discussed in detail. Finally, the paper gives an outline of the topic. The results from composites constructed from each fiber are provided, along with appropriate references for more in-depth analysis studies. This review is specially performed to strengthen the knowledge bank of the young researchers working in the field of natural composites

Investigating regulated signaling pathways in therapeutic targeting of non-small cell lung carcinoma

Non-small cell lung carcinoma (NSCLC) is the most common malignancy worldwide. The signaling cascades are stimulated via genetic modifications in upstream signaling molecules, which affect apoptotic, proliferative, and differentiation pathways. Dysregulation of these signaling cascades causes cancer-initiating cell proliferation, cancer development, and drug resistance. Numerous efforts in the treatment of NSCLC have been undertaken in the past few decades, enhancing our understanding of the mechanisms of cancer development and moving forward to develop effective therapeutic approaches. Modifications of transcription factors and connected pathways are utilized to develop new treatment options for NSCLC. Developing designed inhibitors targeting specific cellular signaling pathways in tumor progression has been recommended for the therapeutic management of NSCLC. This comprehensive review provided deeper mechanistic insights into the molecular mechanism of action of various signaling molecules and their targeting in the clinical management of NSCLC

Biochemical features and therapeutic potential of α-Mangostin: Mechanism of action, medicinal values, and health benefits

α-Mangostin (α-MG) is a natural xanthone obtained from the pericarps of mangosteen. It exhibits excellent potential, including anti-cancer, neuroprotective, antimicrobial, antioxidant, and anti-inflammatory properties, and induces apoptosis. α-MG controls cell proliferation by modulating signaling molecules, thus implicated in cancer therapy. It possesses incredible pharmacological features and modulates crucial cellular and molecular factors. Due to its lesser water solubility and pitiable target selectivity, α-MG has limited clinical application. As a known antioxidant, α-MG has gained significant attention from the scientific community, increasing interest in extensive technical and biomedical applications. Nanoparticle-based drug delivery systems were designed to improve the pharmacological features and efficiency of α-MG. This review is focused on recent developments on the therapeutic potential of α-MG in managing cancer and neurological diseases, with a special focus on its mechanism of action. In addition, we highlighted biochemical and pharmacological features, metabolism, functions, anti-inflammatory, antioxidant effects and pre-clinical applications of α-MG