Current Pharmaceutical Design - Volume 26, Issue 29, 2020

Background: Application of chitin attracts much attention in the past decades as the second abundant polysaccharides in the world after cellulose. Chitin oligosaccharides (CTOS) and its deacetylated derivative chitosan oligosaccharides (COS) were shown great potentiality in agriculture by enhancing plant resistance to abiotic or biotic stresses, promoting plant growth and yield, improving fruits quality and storage, etc. Those applications have already served huge economic and social benefits for many years. However, the recognition mode and functional mechanism of CTOS and COS on plants have gradually revealed just in recent years. Objective: Recognition pattern and functional mechanism of CTOS and COS in plant together with application status of COS in agricultural production will be well described in this review. By which we wish to promote further development and application of CTOS and COS–related products in the field.

Chitin, abundant biomass found in crab shells and other marine life, has wide applications in the production of food, pharmaceuticals, and cosmetics. Our recent studies have focused on the development of new functional materials by derivatizing chitin oligosaccharides and monosaccharides. For example, we have prepared various derivatives by chemoenzymatic synthesis using N-acetylglucosamine (GlcNAc) or chitin oligosaccharide prepared from chitin as starting materials. First, we have achieved the total synthesis of two secondary metabolites (furanodictine A and B) with neuronal differentiation-inducing activity on PC12 cells by using a simple heatinduced structural transformation of GlcNAc and esterification reaction. Second, we synthesized both a novel inhibitor that has facilitated a re-examination of the reaction mechanism of hen egg-white lysozyme, and a new substrate for assaying lysozyme activity by using chitin oligosaccharides as raw materials. Thus, the development of new materials by simple derivatization of chitin mono- or oligo-saccharides is paving the way for effective use of chitin.

Chitin contributes to the rigidity of the insect cuticle and serves as an attachment matrix for other cuticular proteins. Deficiency of chitin results in abnormal embryos, cuticular structural defects and growth arrest. When chitin is not turned over during molting, the developing insect is trapped inside the old cuticle. Partial deacetylation of cuticular chitin is also required for proper laminar organization of the cuticle and vertical pore canals, molting, and locomotion. Thus, chitin and its modifications strongly influence the structure of the exoskeleton as well as the physiological functions of the insect. Internal tendons and specialized epithelial cells called “tendon cells” that arise from the outer layer of epidermal cells provide attachment sites at both ends of adult limb muscles. Membrane processes emanating from both tendon and muscle cells interdigitate extensively to strengthen the attachment of muscles to the extracellular matrix (ECM). Protein ligands that bind to membrane-bound integrin complexes further enhance the adhesion between muscles and tendons. Tendon cells contain F-actin fiber arrays that contribute to their rigidity. In the cytoplasm of muscle cells, proteins such as talin and other proteins provide attachment sites for cytoskeletal actin, thereby increasing integrin binding and activation to mechanically couple the ECM with actin in muscle cells. Mutations in integrins and their ligands, as well as depletion of chitin deacetylases, result in defective locomotion and muscle detachment from the ECM. Thus, chitin in the cuticle and chitin deacetylases strongly influence the shape and functions of the exoskeleton as well as locomotion of insects.

Insects are a great menace in agriculture and vectors of human diseases. Hence, controlling insect populations is an important issue worldwide. A common strategy to control insects is the application of insecticides. However, insecticides entail three major problems. First, insecticides are chemicals that stress ecosystems and may even be harmful to humans. Second, insecticides are often unspecific and also eradicate beneficial insect species like the honeybee. Third, insects are able to develop resistance to insecticides. Therefore, the efficient generation of new potent insecticides and their intelligent delivery are the major tasks in agriculture. In addition, acceptance or refusal in society is a major issue that has to be considered in the application of a pest management strategy. In this paper, we unify two issues: 1) we illustrate that our molecular knowledge of the chitin synthesis and organization pathways may offer new opportunities to design novel insecticides that are environmentally harmless at the same time being specific to a pest species; and 2) we advocate that the fruit fly Drosophila melanogaster may serve as an excellent model of insect to study the effects of insecticides at the genetic, molecular and histology level in order to better understand their mode of action and to optimize their impact. Especially, chitin synthesis and organization proteins and enzymes are excellently dissected in the fruit fly, providing a rich source for new insecticide targets. Thus, D. melanogaster offers a cheap, efficient and fast assay system to address agricultural questions, as has been demonstrated to be the case in bio-medical research areas.

The red flour beetle, Tribolium castaneum, is a worldwide insect pest of stored products, particularly food grains, and a powerful model organism for developmental, physiological and applied entomological research on coleopteran species. Among coleopterans, T. castaneum has the most fully sequenced and annotated genome and consequently provides the most advanced genetic model of a coleopteran pest. The beetle is also easy to culture and has a short generation time. Research on this beetle is further assisted by the availability of expressed sequence tags and transcriptomic data. Most importantly, it exhibits a very robust response to systemic RNA interference (RNAi), and a database of RNAi phenotypes (iBeetle) is available. Finally, classical transposonbased techniques together with CRISPR/Cas-mediated gene knockout and genome editing allow the creation of transgenic lines. As T. castaneum develops resistance rapidly to many classes of insecticides including organophosphates, methyl carbamates, pyrethroids, neonicotinoids and insect growth regulators such as chitin synthesis inhibitors, it is further a suitable test system for studying resistance mechanisms. In this review, we will summarize recent advances in research focusing on the mode of action of insecticides and mechanisms of resistance identified using T. castaneum as a pest model.

Background: Artificial intelligence (AI) is the way to model human intelligence to accomplish certain tasks without much intervention of human beings. The term AI was first used in 1956 with The Logic Theorist program, which was designed to simulate problem-solving ability of human beings. There have been a significant amount of research works using AI in order to determine the advantages and disadvantages of its applicabication and, future perspectives that impact different areas of society. Even the remarkable impact of AI can be transferred to the field of healthcare with its use in pharmaceutical and biomedical studies crucial for the socioeconomic development of the population in general within different studies, we can highlight those that have been conducted with the objective of treating diseases, such as cancer, neurodegenerative diseases, among others. In parallel, the long process of drug development also requires the application of AI to accelerate research in medical care. Methods: This review is based on research material obtained from PubMed up to Jan 2020. The search terms include “artificial intelligence”, “machine learning” in the context of research on pharmaceutical and biomedical applications. Results: This study aimed to highlight the importance of AI in the biomedical research and also recent studies that support the use of AI to generate tools using patient data to improve outcomes. Other studies have demonstrated the use of AI to create prediction models to determine response to cancer treatment. Conclusion: The application of AI in the field of pharmaceutical and biomedical studies has been extensive, including cancer research, for diagnosis as well as prognosis of the disease state. It has become a tool for researchers in the management of complex data, ranging from obtaining complementary results to conventional statistical analyses. AI increases the precision in the estimation of treatment effect in cancer patients and determines prediction outcomes.

Background: Cancer is characterized by abnormal cell growth and considered one of the leading causes of death around the world. Pharmaceutical Nanotechnology has been extensively studied for the optimization of cancer treatment. Objective: Comprehend the panorama of Pharmaceutical Nanotechnology in cancer treatment, through a survey about nanomedicines applied in clinical studies, approved for use and patented. Methods: Acknowledged products under clinical study and nanomedicines commercialized found in scientific articles through research on the following databases: Pubmed, Science Direct, Scielo and Lilacs. Derwent tool was used for patent research. Results: Nanomedicines based on nanoparticles, polymer micelles, liposomes, dendrimers and nanoemulsions were studied, along with cancer therapies such as Photodynamic Therapy, Infrared Phototherapy Hyperthermia, Magnetic Hyperthermia, Radiotherapy, Gene Therapy and Nanoimmunotherapy. Great advancement has been observed over nanotechnology applied to cancer treatment, mainly for nanoparticles and liposomes. Conclusion: The combination of drugs in nanosystems helps to increase efficacy and decrease toxicity. Based on the results encountered, nanoparticles and liposomes were the most commonly used nanocarriers for drug encapsulation. In addition, although few nanomedicines are commercially available, this specific research field is continuously growing.

Background: Airway epithelium plays an essential role in maintaining the homeostasis and function of respiratory system as the first line of host defense. Of note, epithelial sodium channel (ENaC) is one of the victims of LPS-induced airway injury. Regarding the great promise held by mesenchymal stem cells (MSCs) for regenerative medicine in the field of airway injury and the limitations of cell-based MSCs therapy, we focused on the therapeutic effect of MSCs conditioned medium (MSCs-CM) on the ENaC activity in mouse tracheal epithelial cells. Methods: Ussing chamber apparatus was applied to record the short-circuit currents in primary cultured mouse tracheal epithelial cells, which reflects the ENaC activity. Expressions of α and γ ENaC were measured at the protein and mRNA levels by western blot and real-time PCR, respectively. The expression of with-no-lysinekinase- 4 (WNK4) and ERK1/2 were measured at protein levels, and the relationship between WNK4 and ERK1/2 was determined by WNK4 knockdown. Results: MSCs-CM restored the LPS-impaired ENaC activity, as well as enhanced the mRNA and protein expressions of ENaC in primary cultured mouse tracheal epithelial cells. Meanwhile, WNK4 and ERK1/2, both negative-regulators of ENaC, were suppressed accordingly after the administration of MSCs-CM in LPS-induced airway injury. After WNK4 gene was knocked down by siRNA, the level of ERK1/2 phosphorylation decreased. Conclusion: In light of the key role of ENaC in fluid reabsorption and the beneficial effects of MSCs-CM in the injury of airway epithelium, our results suggest that MSCs-CM is effective in alleviating LPS-induced ENaC dysfunction through WNK4-ERK1/2 pathway, which will provide a potent direction for the therapy of airway injury.

Background: Lactobacilli are the dominant bacteria in the healthy vaginal tract, preventing the income of pathogenic microorganisms, either sexually or not transmitted. Probiotics are used to restore the vaginal microbiome by local administration. However, the ascendant colonization is proposed as a way to restore the vaginal balance, and to exert some complementary effects on the host, situation that requires that probiotic strains resist the gastrointestinal tract passage. Objective: To determine which probiotic vaginal strains were able to resist different gastrointestinal factors (pH, bile salts, and enzymes) to advance in the design of oral formulas. Methods: Different protocols were applied to evaluate the growth of 24 beneficial vaginal lactic bacteria (BVL) strains at low pH and high bile salts (individually evaluated) and in combined protocols. The viability of the strains in simulated gastrointestinal tract conditions was studied to select the most resistant strains. Results: A low number of BVL was able to grow at low pH. Most of the strains did not survive at high bile salts concentration. The passage through pH first and bile salts later showed that only three strains were able to survive. In the simulated intestinal conditions, only Lactobacillus gasseri CRL1290, L. jensenii CRL1313, and L. jensenii CRL1349 decrease one or two logarithmic growth units (UFC/ml) at the end of the assay, maintaining their beneficial properties. Conclusion: The behavior of BVL in the conditions assayed is not related to specific strain or metabolic group, because the resistance is strain-specific. The results highlight the importance of the screening performed in a way to select the most adequate strains to be included in the oral designed formula for the restoration of the vaginal tract microbiome.

Background: Psoriasis is a chronic immune mediated skin disorder with global prevalence of 0.2- 11.4%. Despite rare mortality, the severity of the disease could be understood by the accompanying comorbidities, that has even led to psychological problems among several patients. The cause and the disease mechanism still remain elusive. Objective: To identify potential therapeutic targets and affecting pathways for better insight of the disease pathogenesis. Method: The gene expression profile GSE13355 and GSE14905 were retrieved from NCBI, Gene Expression Omnibus database. The GEO profiles were integrated and the DEGs of lesional and non-lesional psoriasis skin were identified using the affy package in R software. The Kyoto Encyclopaedia of Genes and Genomes pathways of the DEGs were analyzed using clusterProfiler. Cytoscape, V3.7.1 was utilized to construct protein interaction network and analyze the interactome map of candidate proteins encoded in DEGs. Functionally relevant clusters were detected through Cytohubba and MCODE. Results: A total of 1013 genes were differentially expressed in lesional skin of which 557 were upregulated and 456 were downregulated. Seven dysregulated genes were extracted in non-lesional skin. The disease gene network of these DEGs revealed 75 newly identified differentially expressed gene that might have a role in development and progression of the disease. GO analysis revealed keratinocyte differentiation and positive regulation of cytokine production to be the most enriched biological process and molecular function. Cytokines -cytokine receptor was the most enriched pathways. Among 1013 identified DEGs in lesional group, 36 DEGs were found to have altered genetic signature including IL1B and STAT3 which are also reported as hub genes. CCNB1, CCNA2, CDK1, IL1B, CXCL8, MKI 67, ESR1, UBE2C, STAT1 and STAT3 were top 10 hub gene. Conclusion: The hub genes, genomic altered DEGs and other newly identified differentially dysregulated genes would improve our understanding of psoriasis pathogenesis, moreover, the hub genes could be explored as potential therapeutic targets for psoriasis.