Current Medicinal Chemistry - Volume 27, Issue 28, 2020

Regenerative medicine represents an emerging multidisciplinary field that brings together engineering methods and complexity of life sciences into a unified fundamental understanding of structure-property relationship in micro/nano environment to develop the next generation of scaffolds and hydrogels to restore or improve tissue functions. Chitosan has several unique physico-chemical properties that make it a highly desirable polysaccharide for various applications such as, biomedical, food, nutraceutical, agriculture, packaging, coating, etc. However, the utilization of chitosan in regenerative medicine is often limited due to its inadequate mechanical, barrier and thermal properties. Cellulosic nanomaterials (CNs), owing to their exceptional mechanical strength, ease of chemical modification, biocompatibility and favorable interaction with chitosan, represent an attractive candidate for the fabrication of chitosan/ CNs scaffolds and hydrogels. The unique mechanical and biological properties of the chitosan/CNs bio-nanocomposite make them a material of choice for the development of next generation bio-scaffolds and hydrogels for regenerative medicine applications. In this review, we have summarized the preparation method, mechanical properties, morphology, cytotoxicity/ biocompatibility of chitosan/CNs nanocomposites for regenerative medicine applications, which comprises tissue engineering and wound dressing applications.

Background: Biosensors are widely applied for the detection of bio-molecules in blood glucose , cholesterol, and gene. Cellulose as the most dominating natural polymer has attracted more and more interest, especially in the field of medicine such as advanced medical diagnosis. Cellulose could endow biosensors with improved biocompatibility, biodegradability and nontoxicity, which could help in medical diagnosis. This mini-review summarizes the current development of cellulose-based biosensors as well as their applications in medical diagnosis in recent years. Methods: After reviewing recent years’ publications we can say that, there are several kinds of cellulose used in biosensors including different cellulose derivatives, bacterial cellulose and nanocellulose. Different types of cellulose-based biosensors, such as membrane, nano-cellulose and others were briefly described in addition to the detection principle. Cellulose-based biosensors were summarized as in the previous papers. The description of various methods used for preparing cellulose-based biosensors was also provided. Results: Cellulose and its derivatives with their unique chemical structure proved to be versatile materials providing a good platform for achieving immobilizing bioactive molecules in biosensors. These cellulose-based biosensors possess various desirable properties such as accuracy, sensitivity, convenience, low cost and fast response. Among them, cellulose paper-based biosensors have the advantages of low cost and easy operation. Nano-cellulose has unique properties such as a large aspect ratio, good dispersing ability and high absorption capacity. Conclusion: Cellulose displays a promising application in biosensors which could be used to detect different bio-molecules such as glucose, lactate, urea, gene, cell, amino acid, cholesterol, protein and hydroquinone. In future, the attention will be focused on designing miniaturized, multifunctional, intelligent and integrated biosensors. Creation of low cost and environmentally friendly biosensors is also very important.

Backgrounds: Abundant and renewable biomaterials serve as ideal substrates for the sustainable production of various chemicals, including natural products (e.g., pharmaceuticals and nutraceuticals). For decades, researchers have been focusing on how to engineer microorganisms and developing effective fermentation processes to overproduce these molecules from biomaterials. Despite many laboratory achievements, it remains a challenge to transform some of these into successful industrial applications. Results: Here, we review recent progress in strategies and applications in metabolic engineering for the production of natural products. Modular engineering methods, such as a multidimensional heuristic process markedly improve efficiencies in the optimization of long and complex biosynthetic pathways. Dynamic pathway regulation realizes autonomous adjustment and can redirect metabolic carbon fluxes to avoid the accumulation of toxic intermediate metabolites. Microbial co-cultivation bolsters the identification and overproduction of natural products by introducing competition or cooperation of different species. Efflux engineering is applied to reduce product toxicity or to overcome storage limitation and thus improves product titers and productivities. Conclusion: Without dispute, many of the innovative methods and strategies developed are gradually catalyzing this transformation from the laboratory into the industry in the biosynthesis of natural products. Sometimes, it is necessary to combine two or more strategies to acquire additive or synergistic benefits. As such, we foresee a bright future of the biosynthesis of pharmaceuticals and nutraceuticals in microbes from renewable biomaterials.

Background: Cellulose Nanofibrils (CNFs) are natural nanomaterials with nanometer dimensions. Compared with ordinary cellulose, CNFs own good mechanical properties, large specific surface areas, high Young's modulus, strong hydrophilicity and other distinguishing characteristics, which make them widely used in many fields. This review aims to introduce the preparation of CNFs-based hydrogels and their recent biomedical application advances. Methods: By searching the recent literatures, we have summarized the preparation methods of CNFs, including mechanical methods and chemical mechanical methods, and also introduced the fabrication methods of CNFs-based hydrogels, including CNFs cross-linked with metal ion and with polymers. In addition, we have summarized the biomedical applications of CNFs-based hydrogels, including scaffold materials and wound dressings. Results: CNFs-based hydrogels are new types of materials that are non-toxic and display a certain mechanical strength. In the tissue scaffold application, they can provide a micro-environment for the damaged tissue to repair and regenerate it. In wound dressing applications, it can fit the wound surface and protect the wound from the external environment, thereby effectively promoting the healing of skin tissue. Conclusion: By summarizing the preparation and application of CNFs-based hydrogels, we have analyzed and forecasted their development trends. At present, the research of CNFs-based hydrogels is still in the laboratory stage. It needs further exploration to be applied in practice. The development of medical hydrogels with high mechanical properties and biocompatibility still poses significant challenges.

Background: Hydrogel has a three-dimensional network structure that is able to absorb a large amount of water/liquid and maintain its original structure. Hemicellulose (HC) is the second most abundant polysaccharide after cellulose in plants and a heterogeneous polysaccharide consisting of various saccharide units. The unique physical and chemical properties of hemicellulose make it a promising material for hydrogels. Methods: This review first summarizes the three research hotspots on the hemicellulose-based hydrogels: intelligence, biodegradability and biocompatibility. It also overviews the progress in the fabrication and applications of hemicellulose hydrogels in the drug delivery system and tissue engineering (articular cartilage, cell immobilization, and wound dressing). Results: Hemicellulose-based hydrogels have many unique properties, such as stimuliresponsibility, biodegradability and biocompatibility. Interpenetrating networking can endow appropriate mechanical properties to hydrogels. These properties make the hemicellulose-based hydrogels promising materials in biomedical applications such as drug delivery systems and tissue engineering (articular cartilage, cell immobilization, and wound dressing). Conclusion: Hydrogels have been widely used in biomedicine and tissue engineering areas, such as tissue fillers, drug release agents, enzyme encapsulation, protein electrophoresis, contact lenses, artificial plasma, artificial skin, and tissue engineering scaffold materials. This article reviews the recent progress in the fabrication and applications of hemicellulose-based hydrogels in the biomedical field.

Background: Bio-based materials, as the plentiful and renewable resources for natural constituents which are essential for biomedical and pharmaceutical applications, have not been exploited adequately yet. Chitosan is a naturally occurring polysaccharide obtained from chitin, which has recently attracted widespread attention owing to its excellent activity. This review shows the methods of extraction and modification of chitosan and provides recent progress of synthesis and use of chitosan-based materials in biological applications. Methods: By consulting the research literature of the last decade, the recent progresses of functional chitosan-based materials for biological applications were summarized and divided into the methods of extraction chitosan, the chemical modification of chitosan, chitosan-based materials for biological applications were described and discussed. Results: Chemical modification of chitosan broadens its applications, leading to developing numerous forms of chitosan-based materials with excellent properties. The excellent bioactivity of chitosan-based material enables it serves potential applications in biomedical fields. Conclusion: Chitosan-based materials not only exhibit the excellent activities of chitosan but also show other appealing performance of combined materials, even give the good synergistic properties of chitosan and its composite materials. Further studies are needed to define the ideal physicochemical properties of chitosan for each type of biomedical applications. The development of various functional chitosan-based materials for biological applications will be an important field of research, and this kind of material has important commercial value.

The next-generation immunotherapy can only be effective if researchers have an in-depth understanding of the function and regulation of Treg cells in antitumor immunity combined with the discovery of new immunity targets. This can enhance clinical efficacy of future and novel therapies and reduces any adverse reactions arising from the latter. This review discusses tumor treatment strategies using regulatory T (Treg) cell therapy in a Tumor Microenvironment (TME). It also discusses factors affecting TME instability as well as relevant treatments to prevent future immune disorders. It is prognosticated that PD-1 inhibitors are risky and their adverse effects should be taken into account when they are administered to treat Acute Myeloid Leukemia (AML), lung adenocarcinoma, and prostate adenocarcinoma. In contrast, Treg molecular markers FoxP3 and CD25 analyzed here have stronger expression in almost all kinds of cancers compared with normal people. However, CD25 inhibitors are more effective compared to FoxP3 inhibitors, especially in combination with TGF-β blockade, in predicting patient survival. According to the data obtained from the Cancer Genome Atlas, we then concentrate on AML immunotherapy and discuss different therapeutic strategies including anti-CD25/IL-2, anti-CTLA-4, anti-IDO, antityrosine kinase receptor, and anti-PI3K therapies and highlight the recent advances and clinical achievements in AML immunotherapy. In order to prognosticate the risk and adverse effects of key target inhibitors (namely against CTLA-4, FoxP3, CD25, and PD-1), we finally analyzed and compared the Cancer Genome Atlas derived from ten common cancers. This review shows that Treg cells are strongly increased in AML and the comparative review of key markers shows that Tregbased immunotherapy is not effective for all kinds of cancer. Therefore, blocking CD25(+)FoxP3(+) Treg cells is suggested in AML more than other kinds of cancer; meanwhile, Treg markers studied in other cancers have also great lessons for AML immunotherapy.

At present, diseases such as obesity, type II diabetes and cancer have brought serious health problems, which are closely related to mTOR pathway. 70 kDa ribosomal protein S6 kinase (p70S6K), as a significant downstream effector of mTOR, mediates protein synthesis, RNA processing, glucose homeostasis, cell growth and apoptosis. Inhibiting the function of p70S6K can reduce the risk of obesity which helps to treat dyslipidemia, enhance insulin sensitivity, and extend the life span of mammals. Therefore, p70S6K has become a potential target for the treatment of these diseases. So far, except for the first p70S6K specific inhibitor PF-4708671 developed by Pfizer and LY2584702 developed by Lilai, all of them are in preclinical research. This paper briefly introduces the general situation of p70S6K and reviews their inhibitors in recent years, which are mainly classified into two categories: natural compounds and synthetic compounds. In particular, their inhibitory activities, structure-activity relationships (SARs) and mechanisms are highlighted.

Multi-target drugs have gained considerable attention in the last decade owing to their advantages in the treatment of complex diseases and health conditions linked to drug resistance. Single-target drugs, although highly selective, may not necessarily have better efficacy or fewer side effects. Therefore, more attention is being paid to developing drugs that work on multiple targets at the same time, but developing such drugs is a huge challenge for medicinal chemists. Each target must have sufficient activity and have sufficiently characterized pharmacokinetic parameters. Multi-target drugs, which have long been known and effectively used in clinical practice, are briefly discussed in the present article. In addition, in this review, we will discuss the possible applications of multi-target ligands to guide the repositioning of prospective drugs.

Background: Cannabinoid receptor 1 has its crystallographic structure available in complex with agonists and inverse agonists, which paved the way to establish an understanding of the structural basis of interactions with ligands. Dipyrone is a prodrug with analgesic capabilities and is widely used in some countries. Recently some evidence of a dipyrone metabolite acting over the Cannabinoid Receptor 1has been shown. Objective: Our goal here is to explore the dipyrone metabolite 4-aminoantipyrine as a Cannabinoid Receptor 1 agonist, reviewing dipyrone characteristics, and investigating the structural basis for its interaction with the Cannabinoid Receptor 1. Method: We reviewed here recent functional studies related to the dipyrone metabolite focusing on its action as a Cannabinoid Receptor 1 agonist. We also analyzed protein-ligand interactions for this complex obtained through docking simulations against the crystallographic structure of the Cannabinoid Receptor 1. Results: Analysis of the crystallographic structure and docking simulations revealed that most of the interactions present in the docked pose were also present in the crystallographic structure of Cannabinoid Receptor 1 and agonist. Conclusion: Analysis of the complex of 4-aminoantipyrine and Cannabinoid Receptor 1 revealed the pivotal role played by residues Phe 170, Phe 174, Phe 177, Phe 189, Leu 193, Val 196, and Phe 379, besides the conserved hydrogen bond at Ser 383. The mechanistic analysis and the present computational study suggest that the dipyrone metabolite 4-aminoantipyrine interacts with the Cannabinoid Receptor 1.