Chitosan, a natural carbohydrate polymer, has long been investigated for drug delivery and medical applications due to its biodegradability, biocompatibility and low toxicity. The micro/nanoparticulate forms of chitosan are reported to enhance the efficiency of drug delivery with better physicochemical properties including improved solubility and bioavailability. This polymer is known to be biodegradable and biocompatible; however, crosslinked chitosan particles may not be biodegradable. Crosslinkers (e.g., tripolyphosphate and glutaraldehyde) are needed for efficient micro/nanoparticle formation, but it is not clear whether the resultant particles are biodegradable or able to release the encapsulated drug fully. To date, no studies have conclusively demonstrated the complete biodegradation or elimination of chitosan nanoparticles in vivo. Herein we review the synthesis and degradation mechanisms of chitosan micro/nanoparticles frequently used in drug delivery especially in pulmonary drug delivery to understand whether these nanoparticles are biodegradable.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has recently emerged in China and caused a disease called coronavirus disease 2019 (COVID-19). The virus quickly spread around the world, causing a sustained global outbreak. Although SARS-CoV-2, and other coronaviruses, SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV) are highly similar genetically and at the protein production level, there are significant differences between them. Research has shown that the structural spike (S) protein plays an important role in the evolution and transmission of SARS-CoV-2. So far, studies have shown that various genes encoding primarily for elements of S protein undergo frequent mutation. We have performed an in-depth review of the literature covering the structural and mutational aspects of S protein in the context of SARS-CoV-2, and compared them with those of SARS-CoV and MERS-CoV. Our analytical approach consisted in an initial genome and transcriptome analysis, followed by primary, secondary and tertiary protein structure analysis. Additionally, we investigated the potential effects of these differences on the S protein binding and interactions to angiotensin-converting enzyme 2 (ACE2), and we established, after extensive analysis of previous research articles, that SARS-CoV-2 and SARS-CoV use different ends/regions in S protein receptor-binding motif (RBM) and different types of interactions for their chief binding with ACE2. These differences may have significant implications on pathogenesis, entry and ability to infect intermediate hosts for these coronaviruses. This review comprehensively addresses in detail the variations in S protein, its receptor-binding characteristics and detailed structural interactions, the process of cleavage involved in priming, as well as other differences between coronaviruses.

Berberine was investigated as an inhibitor of human dipeptidyl peptidase IV (DPP IV) in an attempt to explain its anti-hyperglycemic activities. The investigation included simulated docking experiments to fit berberine within the binding pocket of DPP IV. Berberine was found to readily fit within the binding pocket of DPP IV in a low energy orientation characterized with optimal electrostatic attractive interactions bridging the isoquinolinium positively charged nitrogen atom (berberine) and the negatively charged acidic residue of glutamic acid-205 (GLU205) of DPP IV. Experimentally, berberine was found to inhibit human recombinant DPP IV in vitro with IC₅₀ = 13.3 μM. Our findings suggest that DPP IV inhibition is, at least, one of the mechanisms that explain the anti-hyperglycemic activity of berberine. The fact that berberine was recently reported to potently inhibit the pro-diabetic target human protein tyrosine phosphatase 1B (h-PTP 1B) discloses a novel dual natural h-PTP 1B/DPP IV inhibitor.

Chitosan nanoparticles (NPs) are widely studied as vehicles for drug, protein, and gene delivery. However, lack of sufficient stability, particularly under physiological conditions, render chitosan NPs of limited pharmaceutical utility. The aim of this study is to produce stable chitosan NPs suitable for drug delivery applications. Chitosan was first grafted to phthalic or phenylsuccinic acids. Subsequently, polyphosphoric acid (PPA), hexametaphosphate (HMP), or tripolyphosphate (TPP) were used to achieve tandem ionotropic/covalently crosslinked chitosan NPs in the presence of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC). Thermal and infrared traits confirmed phosphoramide bonds formation tying chitosan with the polyphosphate crosslinkers within NPs matrices. DLS and TEM size analysis indicated spherical NPs with size range of 120 to 350 nm. The generated NPs exhibited excellent stabilities under harsh pH, CaCl₂, and 10% FBS conditions. Interestingly, DLS, NPs stability and infrared data suggest HMP to reside within NPs cores, while TPP and PPA to act mainly as NPs surface crosslinkers. Drug loading and release studies using methylene blue (MB) and doxorubicin (DOX) drug models showed covalent PPA- and HMP-based NPs to have superior loading capacities compared to NPs based on unmodified chitosan, generated by ionotropic crosslinking only or covalently crosslinked by TPP. Doxorubicin-loaded NPs were of superior cytotoxic properties against MCF-7 cells compared to free doxorubicin. Specifically, DOX-loaded chitosan-phthalate polyphosphoric acid-crosslinked NPs exhibited 10-folds cytotoxicity enhancement compared to free DOX. The use of PPA and HMP to produce covalently-stabilized chitosan NPs is completely novel.

Curcumin was investigated as an inhibitor of glycogen synthase kinase-3beta (GSK-3beta) in an attempt to explain some of its interesting multiple pharmacological effects, such as its anti-diabetic, anti-inflammatory, anti-cancer, anti-malarial and anti-alzheimer's properties. The investigation included simulated docking experiments to fit curcumin within the binding pocket of GSK-3beta followed by experimental in vitro and in vivo validations. Curcumin was found to optimally fit within the binding pocket of GSK-3beta via several attractive interactions with key amino acids. Experimentally, curcumin was found to potently inhibit GSK-3beta (IC50 = 66.3 nM). Furthermore, our in vivo experiments illustrated that curcumin significantly increases liver glycogen in fasting Balb/c mice. Our findings strongly suggest that the diverse pharmacological activities of curcumin are at least partially mediated by inhibition of GSK-3beta.