Physically and Chemically Compartmentalized Polymersomes for Programmed Delivery and Biological Applications.

Multicompartment polymersomes (MCPs) refer to polymersomes that not only contain one single compartment, either in the membrane or in the internal cavity, but also mimic the compartmentalized structure of living cells, attracting much attention in programmed delivery and biological applications. The investigation of MCPs may promote the application of soft nanomaterials in biomedicine. This Review seeks to highlight the recent advances of the design principles, synthetic strategies, and biomedical applications of MCPs. The compartmentalization types including chemical, physical, and hybrid compartmentalization are discussed. Subsequently, the design and controlled synthesis of MCPs by the self-assembly of amphiphilic polymers, double emulsification, coprecipitation, microfluidics and particle assembly, etc. are summarized. Furthermore, the diverse applications of MCPs in programmed delivery of various cargoes and biological applications including cancer therapy, antimicrobials, and regulation of blood glucose levels are highlighted. Finally, future perspectives of MCPs from the aspects of controlled synthesis and applications are proposed.

Polymeric Toroids Derived from the Fusion-Induced Particle Assembly of Anisotropic Bowl-Shaped Nanoparticles.

Polymeric toroids are fascinating soft nanostructures due to their unique geometry and properties, which have shown potential applications in the fields of nanoreactors, drug delivery, cancer therapy, etc. However, facile preparation of polymeric toroids is still challenging. Herein, we propose a fusion-induced particle assembly (FIPA) strategy to prepare polymeric toroids using anisotropic bowl-shaped nanoparticles (BNPs) as a building block. The BNPs are prepared in ethanol by the self-assembly of an amphiphilic homopolymer, poly(N-(2,2'-bipyridyl)-4-acrylamide) (PBPyAA), synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. Upon incubation in ethanol above the glass transition temperature (Tg) of PBPyAA, the BNPs gradually aggregate to form trimers and tetramers due to the disturbance of the colloidal stability. With the increase in incubation time, the aggregated BNPs fuse with each other and then form toroids. Notably, we find that only anisotropic BNPs can aggregate and fuse to form toroids rather than spherical compound micelles due to high surface free energy and curvature at the edge of the BNPs. Besides, mathematical calculations further confirm the formation of trimers and tetramers during the FIPA process and the driving force for the formation of toroids. Overall, we propose a fresh insight for the facile preparation of polymeric toroids by the FIPA of anisotropic BNPs.

A prognosis prediction chromatin regulator signature for patients with severe asthma.

Severe asthma imposes a physical and economic burden on both patients and society. As chromatin regulators (CRs) influence the progression of multiple diseases through epigenetic mechanisms, we aimed to study the role of CRs in patients with severe asthma. Transcriptome data (GSE143303) from 47 patients with severe asthma and 13 healthy participants was downloaded from the Gene Expression Omnibus database. Enrichment analysis was performed to investigate the functions of differentially expressed CRs between the groups. We identified 80 differentially expressed CRs; they were mainly enriched in histone modification, chromatin organization, and lysine degradation. A protein-protein interaction network was then constructed. The analyzed immune scores were different between sick and healthy individuals. Thus, CRs with a high correlation in the immune analysis, SMARCC1, SETD2, KMT2B, and CHD8, were used to construct a nomogram model. Finally, using online prediction tools, we determined that lanatoside C, cefepime, and methapyrilene may be potentially effective drugs in the treatment of severe asthma. The nomogram constructed using the four CRs, SMARCC1, SETD2, KMT2B, and CHD8, may be a useful tool for predicting the prognosis of patients with severe asthma. This study provided new insights into the role of CRs in severe asthma.

Polymeric Bowl-Shaped Nanoparticles: Hollow Structures with a Large Opening on the Surface.

Polymeric bowl-shaped nanoparticles (BNPs) are anisotropic hollow structures with large openings on the surface, which have shown advantages such as high specific area and efficient encapsulation, delivery and release of large-sized cargoes on demand compared to solid nanoparticles or closed hollow structures. Several strategies have been developed to prepare BNPs based on either template or template-free methods. For instance, despite the widely used self-assembly strategy, alternative methods including emulsion polymerization, swelling and freeze-drying of polymeric spheres, and template-assisted approaches have also been developed. It is attractive but still challenging to fabricate BNPs due to their unique structural features. However, there is still no comprehensive summary of BNPs up to now, which significantly hinders the further development of this field. In this review, the recent progress of BNPs will be highlighted from the perspectives of design strategies, preparation methods, formation mechanisms, and emerging applications. Moreover, the future perspectives of BNPs will also be proposed.

Three Novel Adenylate Cyclase Genes Show Significant Biological Functions in Plant.

Adenylate cyclase is the key enzyme solely synthesizing cAMP which participates in cell metabolism regulations and functions as an intracellular second messenger. However, the biological functions of plant ACs have not been elucidated clearly for their poor conservative sequences and low detectable cAMP. We performed a systematic study of plant ACs by using Chinese jujube, whose fruit exhibits the highest cAMP content among plants. Three novel ACs were identified from Chinese jujube, and two types of methods including in vitro and in vivo were used to certificate ZjAC1-3 which can catalyze the conversion of ATP into cAMP. The biological functions of significant accelerations of seed germination, root growth, and flowering were found via overexpression of these AC genes in Arabidopsis, and these functions of ACs were further demonstrated by treating the AC-overexpressing transgenic lines and wild type Arabidopsis with bithionol and dibutyryl-cAMP. At last, transcriptome data revealed that the underlying mechanism of the biological functions of ACs might be regulation of the key genes involved in the circadian rhythm pathway and the hormone signal transduction pathway. This research established a foundation for further investigating plant AC genes and provided strong evidence for cAMP serving as a signaling molecule in plants.

A gossypol derivative effectively protects against Zika and dengue virus infection without toxicity.

BACKGROUND: Zika virus (ZIKV) and dengue virus (DENV) cause microcephaly and dengue hemorrhagic fever, respectively, leading to severe problems. No effective antiviral agents are approved against infections of these flaviviruses, calling for the need to develop potent therapeutics. We previously identified gossypol as an effective inhibitor against ZIKV and DENV infections, but this compound is toxic and not suitable for in vivo treatment. RESULTS: In this study, we showed that gossypol derivative ST087010 exhibited potent and broad-spectrum in vitro inhibitory activity against infections of at least ten ZIKV strains isolated from different hosts, time periods, and countries, as well as DENV-1-4 serotypes, and significantly reduced cytotoxicity compared to gossypol. It presented broad-spectrum in vivo protective efficacy, protecting ZIKV-infected Ifnar1-/- mice from lethal challenge, with increased survival and reduced weight loss. Ifnar1-/- mice treated with this gossypol derivative decreased viral titers in various tissues, including the brain and testis, after infection with ZIKV at different human isolates. Moreover, ST087010 potently blocked ZIKV vertical transmission in pregnant Ifnar1-/- mice, preventing ZIKV-caused fetal death, and it was safe for pregnant mice and their pups. It also protected DENV-2-challenged Ifnar1-/- mice against viral replication by reducing the viral titers in the brain, kidney, heart, and sera. CONCLUSIONS: Overall, our data indicate the potential for further development of this gossypol derivative as an effective and safe broad-spectrum therapeutic agent to treat ZIKV and DENV diseases.

Recent advances in developing small-molecule inhibitors against SARS-CoV-2.

The COVID-19 pandemic caused by the novel SARS-CoV-2 virus has caused havoc across the entire world. Even though several COVID-19 vaccines are currently in distribution worldwide, with others in the pipeline, treatment modalities lag behind. Accordingly, researchers have been working hard to understand the nature of the virus, its mutant strains, and the pathogenesis of the disease in order to uncover possible drug targets and effective therapeutic agents. As the research continues, we now know the genome structure, epidemiological and clinical features, and pathogenic mechanism of SARS-CoV-2. Here, we summarized the potential therapeutic targets involved in the life cycle of the virus. On the basis of these targets, small-molecule prophylactic and therapeutic agents have been or are being developed for prevention and treatment of SARS-CoV-2 infection.

Al-Storage Behaviors of Expanded Graphite as High-Rate and Long-Life Cathode Materials for Rechargeable Aluminum Batteries.

The rational design and synthesis of capable cathode materials with low cost that can exhibit good electrochemical performance are key to the development of rechargeable aluminum batteries (RABs). In this article, we have developed low-cost expanded graphite as typical cathode materials for high-performance RABs in pouch cells. Remarkably, the commercial expanded graphite can show high-rate performance, long-term cyclic life, and high energy density (64 Wh kg-1 based on a whole pouch cell). In particular, it delivers a high capacity of 111 mAh g-1 at a current density of 2 A g-1 after 300 cycles and 61.1 mAh g-1 at a high current density of 50 A g-1 after 10 000 cycles. The high-rate performance is derived from the rapid kinetic enhancement caused by the chemisorption-involved-intercalation pseudocapacitance effect. Further, a series of facile electrochemical means are used to confirm the intercalation (1.5-2.4 V)-adsorption mechanism (0.5-1.5 V) of expanded graphite. This work can provide significant support for further understanding the Al-storage behaviors of graphite materials in RABs.

The Compensation Effect Mechanism of Fe-Ni Mixed Prussian Blue Analogues in Aqueous Rechargeable Aluminum-Ion Batteries.

An aluminum-ion battery was assembled with potassium nickel hexacyanoferrate (KNHCF) as a cathode and Al foil as an anode in aqueous electrolyte for the first time, based on Al3+ intercalation and deintercalation. A combination of ex situ XRD, X-ray photoelectron spectroscopy (XPS), galvanostatic intermittent titration technique (GITT), and differential capacity analysis was used to unveil the crystal structure changes and the insertion/extraction mechanism of Al3+ . Al3+ could reversibly insert/extract into/from KNHCF nanoparticles through a single-phase reaction with reduction/oxidation of Fe and Ni. Over long-term cycling, it was Fe rather than Ni that contributed to more capacity owing to the dissolution of Ni from the KNHCF structure, which could be expressed as a compensation effect of mixed redox centers in KNHCF. KNHCF delivered an initial discharge capacity of 46.5 mAh g-1 . The capacity decay could be attributed to the unstable interface between Al foil and the aqueous electrolyte owing to the catalytic activity of the Ni transferring from Ni dissolution of KNHCF to the Al foil anode, rather than KNHCF structure collapse; KNHCF maintained its 3 D framework structure for 500 cycles. This work is expected to inspire more exhaustive investigations of the mechanisms that occur in aluminum-ion batteries.

Development of Small-Molecule Inhibitors Against Zika Virus Infection.

In recent years, the outbreak of infectious disease caused by Zika virus (ZIKV) has posed a major threat to global public health, calling for the development of therapeutics to treat ZIKV disease. Here, we have described the different stages of the ZIKV life cycle and summarized the latest progress in the development of small-molecule inhibitors against ZIKV infection. We have also discussed some general strategies for the discovery of small-molecule ZIKV inhibitors.

Identification of Novel Natural Products as Effective and Broad-Spectrum Anti-Zika Virus Inhibitors.

Zika virus (ZIKV) infection during pregnancy leads to severe congenital Zika syndrome, which includes microcephaly and other neurological malformations. No therapeutic agents have, so far, been approved for the treatment of ZIKV infection in humans; as such, there is a need for a continuous effort to develop effective and safe antiviral drugs to treat ZIKV-caused diseases. After screening a natural product library, we have herein identified four natural products with anti-ZIKV activity in Vero E6 cells, including gossypol, curcumin, digitonin, and conessine. Except for curcumin, the other three natural products have not been reported before to have anti-ZIKV activity. Among them, gossypol exhibited the strongest inhibitory activity against almost all 10 ZIKV strains tested, including six recent epidemic human strains. The mechanistic study indicated that gossypol could neutralize ZIKV infection by targeting the envelope protein domain III (EDIII) of ZIKV. In contrast, the other natural products inhibited ZIKV infection by targeting the host cell or cell-associated entry and replication stages of ZIKV. A combination of gossypol with any of the three natural products identified in this study, as well as with bortezomib, a previously reported anti-ZIKV compound, exhibited significant combinatorial inhibitory effects against three ZIKV human strains tested. Importantly, gossypol also demonstrated marked potency against all four serotypes of dengue virus (DENV) human strains in vitro. Taken together, this study indicates the potential for further development of these natural products, particularly gossypol, as the lead compound or broad-spectrum inhibitors against ZIKV and other flaviviruses, such as DENV.

Development of an on-line analytical platform to screen haptens in shuxuening injection based on high-performance liquid chromatography coupled with ion-trap multistage mass spectrometry and human serum albumin fluorescence detection.

Shuxuening injection (SXNI), one of the traditional Chinese medicine injections (TCMI), is widely used for the treatment of cardiovascular diseases in the clinic. However, its allergic reactions have impeded the clinical applications of SXNI, such adverse reactions have not been well understood due to the lack of methods for detecting haptens. In this study, a high-performance liquid chromatography-diode-array detector-multi-stage mass spectrometry-human serum albumin-fluorescence detector (HPLC-DAD-MSn-HSA-FLD) system was established to identify and screen haptens for the first time. Flavones, flavonols and their glycosides in SXNI showed strong HSA binding ability in different degrees. Fifteen of these compounds were used to study the association of HSA binding ability and sensitizability using isothermal titration calorimetry (ITC) and fluorescence techniques, furthermore, RBL-2H3 cell experiments were conducted to verify the results. It was found that ginkgolides showed no sensitizability, while flavones and flavonol aglycones showed stronger sensitizability than their glycosides. The system was proven to be precise, stable and reproducible, which lays a foundation for screening haptens in SXNI and relevant samples.

Enhanced Ability of Oligomeric Nanobodies Targeting MERS Coronavirus Receptor-Binding Domain.

Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV), an infectious coronavirus first reported in 2012, has a mortality rate greater than 35%. Therapeutic antibodies are key tools for preventing and treating MERS-CoV infection, but to date no such agents have been approved for treatment of this virus. Nanobodies (Nbs) are camelid heavy chain variable domains with properties distinct from those of conventional antibodies and antibody fragments. We generated two oligomeric Nbs by linking two or three monomeric Nbs (Mono-Nbs) targeting the MERS-CoV receptor-binding domain (RBD), and compared their RBD-binding affinity, RBD⁻receptor binding inhibition, stability, and neutralizing and cross-neutralizing activity against MERS-CoV. Relative to Mono-Nb, dimeric Nb (Di-Nb) and trimeric Nb (Tri-Nb) had significantly greater ability to bind MERS-CoV RBD proteins with or without mutations in the RBD, thereby potently blocking RBD⁻MERS-CoV receptor binding. The engineered oligomeric Nbs were very stable under extreme conditions, including low or high pH, protease (pepsin), chaotropic denaturant (urea), and high temperature. Importantly, Di-Nb and Tri-Nb exerted significantly elevated broad-spectrum neutralizing activity against at least 19 human and camel MERS-CoV strains isolated in different countries and years. Overall, the engineered Nbs could be developed into effective therapeutic agents for prevention and treatment of MERS-CoV infection.

PD-1/PD-L1 inhibitor screening of caffeoylquinic acid compounds using surface plasmon resonance spectroscopy.

Following the FDA approval of three monoclonal antibodies of PD-1/PD-L1, this pathway has become a promising target for cancer treatment. Currently small-molecule inhibitors have not been extensively investigated, and appropriate screening methods for such inhibitors are urgently required. In this study, surface plasmon resonance (SPR) technology was used to evaluate the affinity and competitive inhibition of nine caffeoylquinic acid compounds (CQAs) against PD-1/PD-L1. As a result, four small molecules including 1-CQA, 3-CQA, 4-CQA and 5-CQA were determined as PD-1/PD-L1 inhibitors. This study provided an efficient method for screening small-molecule inhibitors targeting PD-1/PD-L1 pathway.

Capillary electrophoresis fingerprinting coupled with chemometrics to evaluate the quality consistency and predict the antioxidant activity of Sanhuang tablet as part of its quality control.

A capillary electrophoresis fingerprint was constructed for Sanhuang tablet, a Chinese traditional patent medicine, that was commonly used in clinical practice, where the isosceles trapezoid method was first applied for the optimization of background electrolyte solution, and the resolution index was performed to assess the experimental conditions; furthermore, a novel linear quantitative fingerprint method was established for accurate qualitative and quantitative discrimination of the test samples from diverse commercial brands. The fingerprint analysis coupled with quantitative determination of two components was employed to elucidate that the quality consistency of the products was relatively good within one manufactory, but poor among different companies for the 30 batches of samples. In addition, the fingerprint-efficacy relationship between chemical components and antioxidant activity in vitro was investigated using partial least squares analysis, and the calibration and prediction of the antioxidant activity of the selected samples via fingerprint data were presented with the desired results. This work illustrates that the proposed fingerprint analysis based on linear quantitative fingerprint method can be applied for the quality evaluation of traditional Chinese medicine and herbal preparations as part of their quality control, and the constructed mathematical model is particularly suitable for depicting the fingerprint-efficacy relationship.