Correction: Formal synthesis of cyclotheonellazole A.

Correction for 'Formal synthesis of cyclotheonellazole A' by Bohua Long et al., Org. Biomol. Chem., 2023, https://doi.org/10.1039/d3ob00038a.

Formal synthesis of cyclotheonellazole A.

A convergent procedure for the formal synthesis of cyclotheonellazole A in high yields and excellent stereoselectivity has been developed. This synthesis features an efficient preparation of O-pivaloyl-protected α-hydroxy-ß-amino amides and a one-pot process to introduce the challenging thiazole moiety. The overall synthesis is very efficient and paves the way for the preparation of analogues for drug development.

Improved Proton Conductivity of Chitosan-Based Composite Proton Exchange Membrane Reinforced by Modified GO Inorganic Nanofillers.

Non-fluorinated chitosan-based proton exchange membranes (PEMs) have been attracting considerable interest due to their environmental friendliness and relatively low cost. However, low proton conductivity and poor physicochemical properties have limited their application in fuel cells. In this work, a reinforced nanofiller (sulfonated CS/GO, S-CS/GO) is accomplished, for the first time, via a facile amidation and sulfonation reaction. Novel chitosan-based composite PEMs are successfully constructed by the incorporation of the nanofiller into the chitosan matrix. Additionally, the effects of the type and amount of the nanofillers on physicochemical and electrochemical properties are further investigated. It is demonstrated that the chitosan-based composite PEMs incorporating an appropriate amount of the nanofillers (9 wt.%) exhibit good membrane-forming ability, physicochemical properties, improved proton conductivity, and low methanol permeability even under a high temperature and low humidity environment. When the incorporated amounts of S-CS/GO are 9 wt.%, the proton conductivity of the composite PEMs was up to 0.032 S/cm but methanol permeability was decreased to 1.42 × 10-7 cm2/s. Compared to a pristine CS membrane, the tensile strength of the composite membrane is improved by 98% and the methanol permeability is reduced by 51%.

Nano-adjuvants and immune agonists promote antitumor immunity of peptide amphiphiles.

Immunostimulatory cues play an important role in priming antitumor immunity and promoting the efficacy of subunit cancer vaccines. However, the clinical use of many immunostimulatory agents is often hampered by their inefficient in vivo delivery which may decrease immune response to the vaccination. To promote vaccine efficacy, we develop vaccine formulations which integrate three key elements: (1) a nano-adjuvant formulated by conjugating an agonistic anti-CD40 monoclonal antibody (αCD40) to the surface of a polyIC-loaded lipid nanoparticle, (2) a peptide amphiphile containing an optimized CD8+ T-cell epitope that derived from a melanoma antigen gp100, (3) an agonistic anti-4-1BB monoclonal antibody (α4-1BB) that boosts the efficacy of vaccinations. In a syngeneic mouse model of melanoma, the vaccine formulations enhanced innate immunity and activated multiple innate immune signaling pathways within draining lymph nodes, as well as promoted antigen-specific immune responses and reduced immunosuppression in the tumor microenvironment, leading to profound tumor growth inhibition and prolonged survival. Thus, our vaccine formulations represent an attractive strategy to stimulate antitumor immunity and control tumor progression. STATEMENT OF SIGNIFICANCE: The clinical use of many immunostimulatory agents is often hampered by their inefficient in vivo delivery which may decrease immune response to the vaccination. To promote the antitumor immunity of subunit vaccines, we develop novel vaccine formulations that integrate multifunctional modalities including (1) a nano-adjuvant containing anti-CD40 monoclonal antibody (αCD40) and TLR3 agonist which activate innate immunity through diverse signaling pathways, (2) a peptide amphiphile containing an optimized CD8+ T-cell epitope from tumor antigen, (3) an anti-4-1BB monoclonal antibody (α4-1BB) that boosts the efficacy of vaccinations. In this study, our vaccine formulations stimulate superior antitumor immunity and control tumor progression. The above nano-engineered platform and immunogenic biomacromolecules can be further applied to other T-cell-inducing vaccines.

A novel colchicine-myricetin heterozygous molecule: design, synthesis, and effective evaluations on the pathological models of acute lung injury in vitro and in vivo.

Acute lung injury (ALI) is an inflammatory condition and there are no effective treatments. A novel new compound----colchicine-myricetin hybrid (CMyrH) was herein designed and synthesized. To evaluate the activity of CMyrH in ALI, we used a bleomycin (BLM) induced BEAS-2B injury model in vitro and established a well-recognized rat model of BLM-induced lung injury in vivo. The results demonstrated that colchicine-myricetin hybrid protected BEAS-2B cells against BLM-induced cell injury in an increased dose manner, and reduced wet/dry weight ratio, histological scoring, and inflammation cytokines IL-1ß, IL-6, IL-18, and TNF-α levels of lung tissue of the rats. Furthermore, we found colchicine-myricetin hybrid inhibited caspase-1, ASC, GSDMD, and NLRP-3 expression in vivo. Meanwhile, we used molecular docking to analyze the binding mode of colchicine-myricetin hybrid and human neutrophil elastase (HNE), it revealed that colchicine-myricetin hybrid showed strong binding affinity toward human neutrophil elastase when compared to its parent molecules. In conclusion, It is suggested that colchicine-myricetin hybrid antagonized acute lung injury by focusing on multi-targets via multi-mechanisms, and might be served as a potential therapeutic agent for acute lung injury.

Chaihu Shugan San ameliorated cognitive deficits through regulating gut microbiota in senescence-accelerated mouse prone 8.

Background: Traditional Chinese medicines exhibit promising preventive effects on Alzheimer's disease. Chaihu Shugan San (CSS) is a well-known traditional herbal formula whose several kinds of ingredients have the potential of ameliorating Alzheimer's disease. The present study aimed to evaluate the effects of CSS on the microbiota-gut-brain axis and cognitive deficits of senescence-accelerated mouse prone 8 (SAMP8) mice as well as investigate the underlying mechanisms. Methods: Thirty 5-month-old SAMP8 mice were randomly divided into the model group (SAMP8), CSS low-dose treatment group (CSSL), and CSS high-dose treatment group (CSSH). Ten SAMR1 mice were used as the normal control, and ten SAMP8 mice treated with donepezil were used as the positive control of cognitive function. CSS was orally administrated to SAMP8 mice for 8 weeks. The Morris water maze test was used to evaluate cognitive function. Histological staining was used to observe neuronal injury and Aß deposition. Transmission electron microscopy was used to observe the synaptic ultrastructure. 16S rRNA gene analysis was performed to measure the changes in intestinal microbiota. Results: The results showed that CSS significantly improved the learning function and memory deficits of aged SAMP8 mice in the Morris water maze examination. CSS ameliorated neuronal injury, synaptic injuries, and Aß deposition in the brain of SAMP8 mice. In addition, CSS also significantly improved microbiota composition in terms of elevating Lactobacillus reuteri and decreasing Staphylococcus xylosus in the feces of aged SAMP8 mice. Conclusion: These findings suggested that CSS might have a preventive potential for cognitive deficits in aging through regulating gut microbiota, which paved the way for the application of CSS for prevention and therapeutic purposes for mild cognitive impairment as well as Alzheimer's disease.

Design, synthesis and biological evaluation of a novel colchicine-magnolol hybrid for inhibiting the growth of Lewis lung carcinoma in Vitro and in Vivo.

Colchicine is a bioactive alkaloid originally from Colchicum autumnale and possesses excellent antiproliferative activity. However, colchicine-associated severe toxicity, gastrointestinal side effects in particular, limits its further therapeutic use. In the current study, we thus designed and synthesized a novel hybrid (CMH) by splicing colchicine and magnolol, a multifunctional polyphenol showing favorable gastrointestinal protection. The antitumor activity of CMH in Lewis lung carcinoma (LLC) was then evaluated in vitro and in vivo. Biologically, CMH inhibited the growth of LLC cells with an IC50 of 0.26 µM, 100 times more potently than cisplatin (26.05 µM) did. Meanwhile, the cytotoxicity of CMH was 10-fold lower than that of colchicine in normal human lung cells (BEAS-2B). In C57BL/6 mice xenograft model, CMH (0.5 mg/kg) worked as efficacious as colchicine (0.5 mg/kg) to inhibit tumor growth and 2 times more potently than cisplatin (1 mg/kg). In terms of mortality, 7 out of 10 mice died in colchicine group (0.75 mg/kg), while no death was observed in groups receiving CMH or cisplatin at 0.75 mg/kg. Mechanistic studies using Western blot revealed that CMH dose-dependently suppressed the protein expression of phosphorylated ERK. Molecular docking analysis further indicated that CMH was well fitted in the colchicine binding site of tubulin and formed several hydrogen bonds with tubulin protein. These results enable our novel hybrid CMH as a potential antineoplastic agent with lower toxicity, and provide perquisites for further investigation to confirm the therapeutic potentiality of this novel hybrid.