Reformulating lipid nanoparticles for organ-targeted mRNA accumulation and translation.

Fully targeted mRNA therapeutics necessitate simultaneous organ-specific accumulation and effective translation. Despite some progress, delivery systems are still unable to fully achieve this. Here, we reformulate lipid nanoparticles (LNPs) through adjustments in lipid material structures and compositions to systematically achieve the pulmonary and hepatic (respectively) targeted mRNA distribution and expression. A combinatorial library of degradable-core based ionizable cationic lipids is designed, following by optimisation of LNP compositions. Contrary to current LNP paradigms, our findings demonstrate that cholesterol and phospholipid are dispensable for LNP functionality. Specifically, cholesterol-removal addresses the persistent challenge of preventing nanoparticle accumulation in hepatic tissues. By modulating and simplifying intrinsic LNP components, concurrent mRNA accumulation and translation is achieved in the lung and liver, respectively. This targeting strategy is applicable to existing LNP systems with potential to expand the progress of precise mRNA therapy for diverse diseases.

One-Component Cationic Lipids for Systemic mRNA Delivery to Splenic T Cells.

Unlocking the full potential of mRNA immunotherapy necessitates targeted delivery to specific cell subsets in the spleen. Four-component lipid nanoparticles (LNPs) utilized in numerous clinical trials are primarily limited in hepatocyte and muscular targeting, highlighting the imperative demand for targeted and simplified non-liver mRNA delivery systems. Herein, we report the rational design of one-component ionizable cationic lipids to selectively deliver mRNA to the spleen and T cells with high efficacy. Unlike the tertiary amine-based ionizable lipids involved in LNPs, the proposed cationic lipids rich in secondary amines can efficiently deliver mRNA both in vitro and in vivo as the standalone carriers. Furthermore, these vectors facilitate efficacious mRNA delivery to the T cell subsets following intravenous administration, demonstrating substantial potential for advancing immunotherapy applications. This straightforward strategy extends the utility of lipid family for extrahepatic mRNA delivery, offering new insights into vector development beyond LNPs to further the field of precise mRNA therapy.

An Extrusion Strategy for On-Demand SF5Cl Gas Generation from a Commercial Disulfide.

Herein we report a novel methodology for the ex situ generation of SF5Cl by employing 4,4'-dipyridyl disulfide as a safe commercial reagent, obviating the need for lecture bottles. The method is applicable to certain SF5Cl-involving transformations by using a two-chamber reactor. Moreover, easily applying SF5Cl in different solvents is rendered feasible, while avoiding the use of glovebox techniques. This report also suggests 1H-19F HOESY as a simple and fast stereochemistry indication for chloropentafluorosulfanylated olefins.

Targeting materials and strategies for RNA delivery.

RNA-based therapeutics have shown great promise in various medical applications, including cancers, infectious diseases, and metabolic diseases. The recent success of mRNA vaccines for combating the COVID-19 pandemic has highlighted the medical value of RNA drugs. However, one of the major challenges in realizing the full potential of RNA drugs is to deliver RNA into specific organs and tissues in a targeted manner, which is crucial for achieving therapeutic efficacy, reducing side effects, and enhancing overall treatment efficacy. Numerous attempts have been made to pursue targeting, nonetheless, the lack of clear guideline and commonality elucidation has hindered the clinical translation of RNA drugs. In this review, we outline the mechanisms of action for targeted RNA delivery systems and summarize four key factors that influence the targeting delivery of RNA drugs. These factors include the category of vector materials, chemical structures of vectors, administration routes, and physicochemical properties of RNA vectors, and they all notably contribute to specific organ/tissue tropism. Furthermore, we provide an overview of the main RNA-based drugs that are currently in clinical trials, highlighting their design strategies and tissue tropism applications. This review will aid to understand the principles and mechanisms of targeted delivery systems, accelerating the development of future RNA drugs for different diseases.

Gambogenic acid inhibits proliferation and ferroptosis by targeting the miR-1291/FOXA2 and AMPKα/SLC7A11/GPX4 axis in colorectal cancer.

The present study aims to investigate the mechanism of the nature compound gambogenic acid (GNA) on the apoptosis and ferroptosis in colorectal cancer (CRC). The effect of GNA on the proliferation of CRC cell lines were detected by MTT and clonogenic assay. The xenograft tumor model was established, and the inhibition effect of GNA were evaluated by observing the tumor growth. The endoplasmic reticulum (ER) of HCT116 was observed by using the ER tracker. The TargrtScan database was used to predict the miRNA binding sites. The level of miRNA with GNA treatment was explored by real-time quantitative PCR. The effect of ferroptosis were evaluated by detect the expression of reactive oxygen species (ROS), intracellular ferrous iron (Fe2+ ), malondialdehyde (MDA), glutathione (GSH), subunit solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase (GPX)4, transferrin, and ferritin by Western blot. GNA isolated from gamboge can inhibit the growth and proliferation of CRC cell lines in a concentration-dependent manner. GNA activated ER stress by upregulating miR-1291, and miR-1291 targeted the forkhead box protein A2 (FOXA2). GNA also induced ROS production and mediated the Fenton reaction by activating transferrin to increase Fe2+ , thus inducing ferroptosis. In addition, GNA could induce ferroptosis through the depletion of GSH and GPX4. Furthermore, GNA treatment regulated iron metabolism by activating AMPKα/SLC7A11/GPX4 signaling. In conclusion, GNA activated ER stress via miR-1291 and induced ferroptosis in CRC cells and might be a new inducer of ferroptosis, which can expand the efficacy of chemotherapy drugs.

Ex situ Generation of Thiazyl Trifluoride (NSF3 ) as a Gaseous SuFEx Hub.

Sulfur(VI)-fluoride exchange (SuFEx) chemistry, an all-encompassing term for substitution events that replace fluoride at an electrophilic sulfur(VI), enables the rapid and flexible assembly of linkages around a SVI core. Although a myriad of nucleophiles and applications works very well with the SuFEx concept, the electrophile design has remained largely SO2 -based. Here, we introduce S≡N-based fluorosulfur(VI) reagents to the realm of SuFEx chemistry. Thiazyl trifluoride (NSF3 ) gas is shown to serve as an excellent parent compound and SuFEx hub to efficiently synthesize mono- and disubstituted fluorothiazynes in an ex situ generation workflow. Gaseous NSF3 was evolved from commercial reagents in a nearly quantitative fashion at ambient conditions. Moreover, the mono-substituted thiazynes could be extended further as SuFEx handles and be engaged in the synthesis of unsymmetrically disubstituted thiazynes. These results provide valuable insights into the versatility of these understudied sulfur functionalities paving the way for future applications.

Traditional Chinese Medicine Targeting Sarcoma Virus Oncogene-related Diseases.

The sarcoma virus oncogene (Src) tyrosine kinase, a nonreceptor protein-tyrosine kinase, plays a crucial role in cell survival, migration, differentiation and proliferation. The study of Src has developed considerably since it was first discovered as a proto-oncogene. Src has also been associated with inflammation and bone-related diseases. Src inhibitors (bosutinib, ponatinib, dasatinib, and vandetanib) have been put into clinical use. However, their side effects and cardiovascular toxicity may be a concern. There is an urgent need to explore new Src inhibitors. Traditional Chinese medicine (TCM), which has a vast history, can provide a broad resource base. Many natural compounds and TCM extracts have the potential for anti-Src treatment. This article describes the natural compounds and extracts from TCM.

Crystal structure and Hirshfeld surface analysis of N-{N-[amino-(di-methyl-amino)-meth-yl]carbamimido-yl}-3-bromo-benzene-sulfonamide.

The title compound, C10H14BrN5O2S, is the bromo-benzene-sulfonamide derivative of the type 2 diabetes drug metformin. The asymmetric unit contains two mol-ecules with almost identical conformations but a different orientation of the bromo-phenyl moiety. Both mol-ecules exhibit intra-molecular N-H⋯N and N-H⋯O hydrogen bonds. The mol-ecular packing features chain formation in the a-axis direction by alternating N-H⋯N and N-H⋯O inter-actions. In addition, ring motifs consisting of four mol-ecules and π-π inter-actions between the phenyl rings contribute to the three-dimensional architecture. A Hirshfeld surface analysis shows that the largest contributions to surface contacts arise from contacts in which H atoms are involved.

Solasodine suppresses the metastasis of gastric cancer through claudin-2 via the AMPK/STAT3/NF-κB pathway.

Gastric cancer (GC) is one of the most common malignancies, and it has become the third most common malignant tumour in the world. Targeting metastasis has also become a key and difficult point in the treatment of GC. Solasodine is an active ingredient isolated from Solanum nigrum L. for the treatment of various cancers, such as breast cancer, pancreatic cancer and lung cancer. In the present study, we investigated the role and mechanism of solasodine in inhibiting GC. In vitro, we found that solasodine not only promoted cell death but also inhibited the migration and invasion of HGC27 and AGS cells. Solasodine regulated epithelial-mesenchymal transition (EMT) and reduced the expression of claudin-2 (CLDN2). Moreover, overexpression of CLDN2 inhibited the prometastatic phenotype and EMT of GC, and solasodine recovered this phenotype. Furthermore, the knockdown of CLDN2 had the opposite effect. We also found that the AMPK activators metformin and AICAR activated phosphorylation of AMPK and downregulated the expression of RhoA and CLDN2, indicating that AMPK was the upstream regulator of CLDN2. Solasodine could also activate AMP-activated protein kinase (AMPK) and inhibit the phosphorylation of STAT3 and the nuclear translocation of NF-κB. Therefore, solasodine may have prevented EMT by modulating the AMPK/STAT3/NF-κB/CLDN2 signalling pathway. In vivo, we established a xenograft model to investigate the phosphorylation of AMPK and the expression of CLDN2 from tumour tissues, and we found that solasodine inhibited tumour growth through AMPK-CLDN2 pathway. To sum up, solasodine prevented EMT by modulating the AMPK/STAT3/NF-κB/CLDN2 signalling pathway, becoming a new solution for inhibiting GC metastasis.

Efficient removal of nano- and micro- sized plastics using a starch-based coagulant in conjunction with polysilicic acid.

Microplastic (MP) pollution has increasingly become an enormous global challenge due to the ubiquity and uncertain environmental performance, especially for nano- and micro- sized MPs. In this work, the performance and mechanisms in coagulation of 100 nm-5.0 µm sized polystyrene particles using an etherified starch-based coagulant (St-CTA) assisted by polysilicic acid (PSA) were systematically studied on the basis of the changes in MPs removal rates under various pH levels and in the presence of different coexisting inorganic and organic substances, zeta potentials of supernatants, and floc properties. St-CTA in conjunction with PSA had a high performance in coagulation of nano- and micro- sized MPs from water with a lower optimal dose and larger and compacter flocs. Besides, the MPs removal rate can be improved in acidic and coexisting salt conditions. The efficient performance in removal of MPs by this enhanced coagulation was owing to the synergic effect, that is, the effective aggregation of MPs through the charge neutralization of St-CTA followed by the efficient netting-bridging effect of PSA. The effectiveness of this enhanced coagulation was further confirmed by removal of two other typical nano-sized MPs, such as poly(methyl methacrylate) and poly(vinyl chloride), from different water sources including tap water, river water, and sludge supernatant from a sewage treatment plant. This work provided a novel enhanced coagulation technique that can effectively remove nano- and micro- sized MPs from water.

Development and Validation of a Risk Prediction Model for Breast Cancer Prognosis Based on Depression-Related Genes.

Background: Depression plays a significant role in mediating breast cancer recurrence and metastasis. However, a precise risk model is lacking to evaluate the potential impact of depression on breast cancer prognosis. In this study, we established a depression-related gene (DRG) signature that can predict overall survival (OS) and elucidate its correlation with pathological parameters and sensitivity to therapy in breast cancer. Methods: The model training and validation assays were based on the analyses of 1,096 patients from The Cancer Genome Atlas (TCGA) database and 2,969 patients from GSE96058. A risk signature was established through univariate and multivariate Cox regression analyses. Results: Ten DRGs were determined to construct the risk signature. Multivariate analysis revealed that the signature was an independent prognostic factor for OS. Receiver operating characteristic (ROC) curves indicated good performance of the model in predicting 1-, 3-, and 5-year OS, particularly for patients with triple-negative breast cancer (TNBC). In the high-risk group, the proportion of immunosuppressive cells, including M0 macrophages, M2 macrophages, and neutrophils, was higher than that in the low-risk group. Furthermore, low-risk patients responded better to chemotherapy and endocrine therapy. Finally, a nomogram integrating risk score, age, tumor-node-metastasis (TNM) stage, and molecular subtypes were established, and it showed good agreement between the predicted and observed OS. Conclusion: The 10-gene risk model not only highlights the significance of depression in breast cancer prognosis but also provides a novel gene-testing tool to better prevent the potential adverse impact of depression on breast cancer prognosis.

Influencing factors and strategies of enhancing nanoparticles into tumors in vivo.

The administration of nanoparticles (NPs) first faces the challenges of evading renal filtration and clearance of reticuloendothelial system (RES). After that, NPs infiltrate through the expanded endothelial space and penetrated the dense stroma of tumor microenvironment to tumor cells. As long as possible to prolong the time of NPs remaining in tumor tissue, NPs release active agent and induce pharmacological action. This review provides a comprehensive summary of the physical and chemical properties of NPs and the influence of various biological factors in tumor microenvironment, and discusses how to improve the final efficacy through adjusting the characteristics and structure of NPs. Perspectives and future directions are also provided.

Rhodium-catalyzed ortho-acrylation of aryl ketone O-methyl oximes with cyclopropenones.

An efficient Rh-catalyzed ortho-acrylation reaction for the synthesis of chalcones from O-methyl ketoximes and cyclopropenones via C-H bond activation has been described. This cross-coupling reaction exhibits high functional group tolerance and regioselectivity. A wide range of chalcone derivatives are obtained in moderate to good yields under mild conditions.

Comparison of 3D-printed porous tantalum and titanium scaffolds on osteointegration and osteogenesis.

Metals such as Ta (tantalum) and Ti (titanium) have been popularly used as a bone substitute or implants in orthopedic surgery and dentistry, since they have excellent corrosion. For manufacturing porous implants with precise structure, SLM (Selective laser melting), which is one of the 3D (three-dimensional) printing techniques, is always be chosen. To compare biological performances between porous Ta and Ti implants, we designed them with the same porosity, pore shape, pore size, and pore distribution via CAD (computer aided design), and then produced them by SLM. It was shown that the equivalent stress of porous Ta and Ti were 393.62 ±â€¯1.39 MPa and 139.75 ±â€¯14.50 MPa, and their Young's modulus were 3.10 ±â€¯0.03GPa and 5.42 ±â€¯0.07GPa, respectively. Meanwhile, we investigated their biological performance with hBMMSCs (human Bone marrow mesenchymal stem cells) in vitro. The results revealed that both two scaffolds were in favor of hBMMSCs proliferation and osteogenic differentiation. In addition, porous scaffolds were implanted in the femur bone defects rabbits in vivo showed the both porous scaffolds were beneficial to the bone ingrowth and bone-implant fixation. In summary, porous Ta has an equivalent biological performance as traditional porous Ti implants in small bone defect repair. Taken together, porous Ta is a promising material for bone regeneration.

The effect of 3D-printed Ti6Al4V scaffolds with various macropore structures on osteointegration and osteogenesis: A biomechanical evaluation.

A properly designed porous scaffold can accelerate the osseointegration process, and the use of computer-aided design (CAD) and additive manufacturing (AM) techniques has the potential to improve the traditional porous scaffold approach. In this study, we evaluate the effect of porous Ti6Al4V (Ti) with different pore structures on osteointegration and osteogenesis. Porous Ti scaffolds with different pore structures based on four commercially available implants were designed and manufactured by CAD and selective laser melting (SLM). Micro-CT showed that SLM was able to produce Ti scaffolds with different pore structures. The mechanical properties evaluated by finite element analysis and compression tests indicated that the four porous scaffolds in our study were mechanically adapted, despite their different mechanical properties. Then, we used 3D-printed porous discs to culture human bone marrow mesenchymal stem cells (hBMMSCs), the main seed cells of bone tissue engineering. The results showed no significant difference among the four groups in cell morphology, viability and proliferation. In addition, four groups showed a comparable mineralization ability even though Ti-g had a higher alkaline phosphatase activity (ALP). In vivo tests in a rabbit model showed that all four groups were suitable for new bone ingrowth and integration. These findings indicate that the four different pore structures in the Ti scaffolds provided good osteointegration and osteogenesis.

[In vivo study of 3D printed porous tantalum implant on osseointegration].

OBJECTIVE: This work aims to investigate the effect of porous tantalum and porous titanium on osseointegration. METHODS: Two kinds of porous materials with same microporous parameters, namely, porous tantalum and porous titanium, were fabricated by computer-aided design (CAD) modeling and 3D printing technology. A defect model was established in 24 New Zealand white rabbits in the bilateral femoral lateral malleolus at the left and right side of each animal. Then, animals were randomly divided into two groups, and bone defects were repaired by porous tantalum and porous titanium (experimental and control groups, respectively). Animals were sacrificed at two, four, and eight weeks after implantation. Gross observation and methylene blue-acid fuchsin staining were used to observe osseointegration of the implant and bone interface, and the osseointegration strength of implant bone interface was tested by push-out test. RESULTS: At two, four, and eight weeks after operation, the new bone tissue in the two groups increased gradually, and new bone trabecula appeared and grew into the pores of the materials. No significant difference (P>0.05) in osteogenesis and the strength of implant bone tissue interface between the two groups was observed. CONCLUSIONS: 3D
printed porous tantalum implants, which exhibit comparable osseointegration capabilities to porous titanium implants, can form an early biological combination with bone tissue.

3D reconstruction images of cone beam computed tomography applied to maxillofacial fractures: A case study and mini review.

Maxillofacial injuries can be complex and are clinically important due to their functional and cosmetic significance. Maltreated and missed fractures might cause deformity of the face; thus, accurate evaluation of the fracture provided by X-ray images is critical. In this study, we explore the application of cone-beam computed tomography (CBCT) for diagnosis of severe maxillofacial traumas. A patient with a complex fracture that affects the maxilla, mandible, wall of the maxillary sinus, zygoma, zygomatic arch and nasal bone was diagnosed using 3D reconstruction of CBCT images. This diagnostic approach provides detailed information obtained by static images and a systematic model with unique advantages for the following pre-surgical evaluation, surgical treatment and prognostic assessment of complex maxillofacial fractures.

Identification of differentially expressed genes in oral squamous cell carcinoma TCA8113 cells.

Previous studies have demonstrated that cancer cells with increased levels of aldehyde dehydrogenase 'bright' activity (ALDHbr) exhibit stem cell properties compared with cells exhibiting decreased ALDH activity (ALDHlow). To screen possible biomarkers of cancer stem cells in tongue squamous cell carcinoma, ALDHbr and ALDHlow cells were isolated from the tongue squamous cell carcinoma TCA8113 cell line, and suppression subtractive hybridization was performed to identify differentially expressed genes in the two subpopulations. A total of 240 positive clones were randomly selected for sequencing and were functionally characterized using bioinformatical tools. The results of the present study identified the differential expression of 104 clones, 62 of which corresponded to known genes and 42 of which corresponded to unknown genes. Cluster analysis revealed that the known genes were involved in the regulation of the cell cycle and cell differentiation. In addition, analysis of 10 signaling pathways revealed that genes were markedly altered in the ALDHbr cell subpopulation. Additional study is required to identify the function that these genes serve in the biomolecular regulatory mechanisms of cancer stem cells and to assist in explaining the biological behavior of oral squamous cell carcinoma.