Engineering CaP-Pickering emulsion for enhanced mRNA cancer vaccines via dual DC and NK activations.

mRNA delivery systems, such as lipid nanoparticle (LNP), have made remarkable strides in improving mRNA expression, whereas immune system activation operates on a threshold. Maintaining a delicate balance between antigen expression and dendritic cell (DC) activation is vital for effective immune recognition. Here, a water-in-oil-in-water (w/o/w) Pickering emulsion stabilized with calcium phosphate nanoparticles (CaP-PME) is developed for mRNA delivery in cancer vaccination. CaP-PME efficiently transports mRNA into the cytoplasm, induces pro-inflammatory responses and activates DCs by disrupting intracellular calcium/potassium ions balance. Unlike LNP, CaP-PME demonstrates a preference for DCs, enhancing their activation and migration to lymph nodes. It elicits interferon-γ-mediated CD8+ T cell responses and promotes NK cell proliferation and activation, leading to evident NK cells infiltration and ameliorated tumor microenvironment. The prepared w/o/w Pickering emulsion demonstrates superior anti-tumor effects in E.G7 and B16-OVA tumor models, offering promising prospects as an enhanced mRNA delivery vehicle for cancer vaccinations.

Ecliptasaponin A protects heart against acute ischemia-induced myocardial injury by inhibition of the HMGB1/TLR4/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Eclipta prostrata (Linn.) is a traditional medicinal Chinese herb that displays multiple biological activities, such as encompassing immunomodulatory, anti-inflammatory, anti-tumor, liver-protective, antioxidant, and lipid-lowering effects. Ecliptasaponin A (ESA), a pentacyclic triterpenoid saponin isolated from Eclipta prostrata (Linn.), has been demonstrated to exert superior anti-inflammatory activity against many inflammatory disorders. AIM OF THE STUDY: Inflammation plays a critical role in acute myocardial infarction (AMI). This study aims to explore the treatment effects of ESA in AMI, as well as the underlying mechanism. METHODS: An AMI mouse model was established in mice via left anterior descending coronary artery (LAD) ligation. After surgery, ESA was injected at doses of 0.5, 1.25, and 2.5 mg/kg, respectively. Myocardial infarction size, cardiomyocyte apoptosis and cardiac echocardiography were studied. The potential mechanism of action of ESA was investigated by RNA-seq, Western blot, surface plasmon resonance (SPR), molecular docking, and immunofluorescence staining. RESULTS: ESA treatment not only significantly reduced myocardial infarct size, decreased myocardial cell apoptosis, and inhibited inflammatory cell infiltration, but also facilitated to improve cardiac function. RNA-seq and Western blot analysis proved that ESA treatment-induced differential expression genes mainly enriched in HMGB1/TLR4/NF-κB pathway. Consistently, ESA treatment resulted into the down-regulation of IL-1ß, IL-6, and TNF-α levels after AMI. Furthermore, SPR and molecular docking results showed that ESA could bind directly to HMGB1, thereby impeding the activation of the downstream TLR4/NF-κB pathway. The immunofluorescence staining and Western blot results at the cellular level also demonstrated that ESA inhibited the activation of the HMGB1/TLR4/NF-κB pathway in H9C2 cells. CONCLUSION: Our study was the first to demonstrate a cardiac protective role of ESA in AMI. Mechanism study indicated that the treatment effects of ESA are mainly attributed to its anti-inflammatory activity that was mediated by the HMGB1/TLR4/NF-κB pathway.

Augmenting vaccine efficacy: Tailored immune strategy with alum-stabilized Pickering emulsion.

BACKGROUND: The achievement of optimal vaccine efficacy is contingent upon the collaborative interactions between T and B cells in adaptive immunity. Although multiple immunization strategies have been proposed, there is a notable scarcity of comprehensive investigations pertaining to enhance immune effects through immune strategy adjustments for individual vaccine. METHODS: The hierarchically structured aluminum hydroxide microgel-stabilized Pickering emulsion (ASPE) was prepared by ultrasonic method. This study explored the influence of the immune strategy of ASPE to immune responses, including antigen exposure pattern, adjuvants and antigen dosage, and administration interval. RESULTS: The findings revealed that external antigen adsorption facilitated increased exposure of antigen epitopes, leading to elevated IgG titers and secretion of cytokines such as interferon-gamma (IFN-γ) or interleukin-4 (IL-4). Additionally, even a low dose (1 µg/dose) of antigens of ASPE boosted sufficient neutralizing antibody levels and memory T cells compared to high-dose antigens, which consistent with the adjuvant dosage effect. Furthermore, maintaining a 4-week immunization interval yielded optimal levels of antigen-specific IgG titers in both short-term and long-term scenarios, as compared to intervals of 2, 3, and 5 weeks. A consistent trend was observed in the proliferation of memory B cells, reaching a superior level at the 4-week interval, which could enhance protection against viral re-infection. CONCLUSION: Tailoring immunization strategies for specific vaccines has emerged as powerful driver in maximizing vaccine efficacy and eliciting robust immune responses, thereby presenting cutting-edge approaches to enhanced vaccination.

Strategies to Improve the Biosynthesis of ß-Lactam Antibiotics by Penicillin G Acylase: Progress and Prospects.

ß-Lactam antibiotics are widely used anti-infection drugs that are traditionally synthesized via a chemical process. In recent years, with the growing demand for green alternatives, scientists have turned to enzymatic synthesis. Penicillin G acylase (PGA) is the second most commercially used enzyme worldwide with both hydrolytic and synthetic activities toward antibiotics, which has been used to manufacture the key antibiotic nucleus on an industrial level. However, the large-scale application of PGA-catalyzed antibiotics biosynthesis is still in the experimental stage because of some key limitations, such as low substrate concentration, unsatisfactory yield, and lack of superior biocatalysts. This paper systematically reviews the strategies adopted to improve the biosynthesis of ß-lactam antibiotics by adjusting the enzymatic property and manipulating the reaction system in recent 20 years, including mining of enzymes, protein engineering, solvent engineering, in situ product removal, and one-pot reaction cascade. These advances will provide important guidelines for the future use of enzymatic synthesis in the industrial production of ß-lactam antibiotics.

Structural and Functional Basis of JAMM Deubiquitinating Enzymes in Disease.

Deubiquitinating enzymes (DUBs) are a group of proteases that are important for maintaining cell homeostasis by regulating the balance between ubiquitination and deubiquitination. As the only known metalloproteinase family of DUBs, JAB1/MPN/Mov34 metalloenzymes (JAMMs) are specifically associated with tumorigenesis and immunological and inflammatory diseases at multiple levels. The far smaller numbers and distinct catalytic mechanism of JAMMs render them attractive drug targets. Currently, several JAMM inhibitors have been successfully developed and have shown promising therapeutic efficacy. To gain greater insight into JAMMs, in this review, we focus on several key proteins in this family, including AMSH, AMSH-LP, BRCC36, Rpn11, and CSN5, and emphatically discuss their structural basis, diverse functions, catalytic mechanism, and current reported inhibitors targeting JAMMs. These advances set the stage for the exploitation of JAMMs as a target for the treatment of various diseases.

A case of primary hepatic stromal tumour misdiagnosed as a liver cyst.

Primary hepatic stromal tumours are very rare and there are only sporadic reports in the literature. Due to the lack of specificity in their clinical manifestations and imaging features, these tumours are easily misdiagnosed. This current report presents a case of primary liver stromal tumour that was misdiagnosed as a liver cyst. The 72-year-old male patient was admitted to the hospital due to right upper abdomen fullness and discomfort for more than 2 weeks. Colour Doppler ultrasonography and enhanced computed tomography examinations revealed a cystic mass in the right lobe of the liver. The preoperative diagnosis was a liver cyst and the laparoscopic fenestration was performed. The pathological examination demonstrated that it was a primary hepatic stromal tumour. Gastroenteroscopy was performed postoperatively and no lesions were found in the gastrointestinal tract. Imatinib mesylate was given orally as the salvage therapy and a radical operation was planned at the patient's request. This current case serves as a reminder that clinicians should consider the possibility that it could be a primary hepatic stromal tumour rather than a hepatic cyst. A multidisciplinary team is necessary for the diagnosis and treatment of patients with a primary hepatic stromal tumour.

Bio-mimic particles for the enhanced vaccinations: Lessons learnt from the natural traits and pathogenic invasion.

In the combat against pathogens, the immune systems were evolved with the immune recognitions against the various danger signals, which responded vigorously upon the pathogen invasions and elicited potent antibodies or T cell engagement against the re-infections. Envisage with the prevailing pandemics and increasing demands for cancer vaccines, bio-mimic particles were developed to imitate the natural traits of the pathogens, which conferred the optimal strategies to stimulate the immune engagement and let to the increased vaccine efficacy. Here, the recent development in bio-mimic particles, as well as the natural cues from the pathogens were discussed. As such, the designing principles that adapted from the physiochemical properties of the pathogens were unfolded as the surface characteristics (hydrophobic, nano-pattern, antigen display, charge), properties (size, shape, softness) and the delivered components (peptide, protein, nuclear acids, toll-like receptor (TLR) agonist, antibody). Additionally, the strategies for the efficient delivery, regarding the biodistribution, internalization and presentation of the antigens were also illustrated. Through reviewing the state-of-art in biomimetic particles, the lesson learnt from the natural traits and pathogenic invasion may shed light on the rational design for the enhanced vaccinations.

Early Research on COVID-19: A Bibliometric Analysis.

In December 2019, an outbreak of pneumonia, which was named COVID-2019, emerged as a global health crisis. Scientists worldwide are engaged in attempts to elucidate the transmission and pathogenic mechanisms of the causative coronavirus. COVID-19 was declared a pandemic by the World Health Organization in March 2020, making it critical to track and review the state of research on COVID-19 to provide guidance for further investigations. Here, bibliometric and knowledge mapping analyses of studies on COVID-19 were performed, including more than 1,500 papers on COVID-19 available in the PubMed and China National Knowledge Infrastructure databases from January 1, 2020 to March 8, 2020. In this review, we found that because of the rapid response of researchers worldwide, the number of COVID-19-related publications showed a high growth trend in the first 10 days of February; among these, the largest number of studies originated in China, the country most affected by pandemic in its early stages. Our findings revealed that the epidemic situation and data accessibility of different research teams have caused obvious difference in emphases of the publications. Besides, there was an unprecedented level of close cooperation and information sharing within the global scientific community relative to previous coronavirus research. We combed and drew the knowledge map of the SARS-CoV-2 literature, explored early status of research on etiology, pathology, epidemiology, treatment, prevention, and control, and discussed knowledge gaps that remain to be urgently addressed. Future perspectives on treatment, prevention, and control are also presented to provide fundamental references for current and future coronavirus research.

Modulation of Donor Alkyl Terminal Chains with the Shifting Branching Point Leads to the Optimized Morphology and Efficient All-Small-Molecule Organic Solar Cells.

Terminal group modification is one of the most influential factors for small-molecular donors compared with their polymer counterparts, resulting in an opportunity to optimize the morphology of all-small-molecule organic solar cells (ASM-OSCs). In this article, we report three novel small-molecular donors with branching points at the 1-, 2-, and 3-positions in alkyl terminal chains, called BSCl-C1, BSCl-C2, and BSCl-C3, respectively. Using IDIC-4Cl as the acceptor, the subtle branching position shift achieves a dramatic disparity in photovoltaic parameters, as indicated by the short circuit current (Jsc) changing from 4.9 to 20.1 to 14.2 mA cm-2 and the fill factor varying from 33.9 to 71.3 to 67.0% for BSCl-C1, BSCl-C2, and BSCl-C3, respectively. The best device performance of 12.40% is obtained by the BSCl-C2:IDIC-4Cl system, which not only ranks among the top values reported to date but also exhibits low energy loss in systems that use IDIC as acceptors. The notable device performance based on BSCl-C2 is attributed to the optimized phase morphology caused by the strong molecular crystallinity and suitable intermolecular interaction with IDIC-4Cl. These results demonstrate that suitably tuning the branching position of terminal groups could promote the high performance of ASM-OSCs.

Improved Treatment and Utilization of Rice Straw by Coprinopsis cinerea.

As one of the most abundant renewable resources, rice straw is an attractive lignocellulosic material for animal feeding or for the production of biochemical. An appropriate pre-treatment technique is essential for converting rice straw to rich fodder or biofuel. Based on previous work, Coprinopsis cinerea can grow on rice straw medium and therefore it is useful for the treatment of rice straw. However, little is known regarding its degradation systems and nutrition values. In this study, we firstly found that C. cinerea could grow rapidly on rice straw without any additives by the production of a series of enzymes (laccase, cellulase, and xylanase) and that the microstructure and contents of rice straw changed significantly after being treated by C. cinerea. We propose that a possible underlying mechanism exists in the degradation. Moreover, C. cinerea has a high nutrition value (23.5% crude protein and 22.2% total amino acids). Hence, fermented rice straw with mycelium could be a good animal feedstuff resource instead of expensive forage. The direct usage of C. cinerea treatment is expected to be a practical, cost-effective, and environmental-friendly approach for enhancing the nutritive value and digestibility of rice straw.