Red blood cell membrane-coated functionalized Cu-doped metal organic framework nanoformulations as a biomimetic platform for improved chemo-/chemodynamic/photothermal synergistic therapy.

Nanoformulations for combining chemotherapy, chemodynamic therapy, and photothermal therapy have enormous potential in tumor treatment. Coating nanoformulations with cell membranes endows them with homologous cellular mimicry, enabling nanoformulations to acquire new functions and properties, including homologous targeting and long circulation in vivo, and can enhance internalization by homologous cancer cells. Herein, we fused multifunctional biomimetic nanoformulations based on Cu-doped zeolitic imidazolate framework-8 (ZIF-8). Hydroxycamptothecin (HCPT), a clinical anti-tumor drug, was encapsulated into ZIF-8, which was subsequently coated with polydopamine (PDA) and red blood cell membrane. The as-fabricated biomimetic nanoformulations showed an enhanced cell uptake in vitro and the potential to prolong blood circulation in vivo, producing effective synergistic chemotherapy, chemodynamic therapy, and photothermal therapy under the 808 nm laser irradiation. Together, the biomimetic nanoformulations showed a prolonged blood circulation and evasion of immune recognition in vivo to provide a bio-inspired strategy which may have the potential for the multi-synergistic therapy of breast cancer.

Red Blood Cell Membrane-Camouflaged Polydopamine and Bioactive Glass Composite Nanoformulation for Combined Chemo/Chemodynamic/Photothermal Therapy.

Combinations of different therapeutic strategies, including chemotherapy (CT), chemodynamic therapy (CDT), and photothermal therapy (PTT), are needed to effectively address evolving drug resistance and the adverse effects of traditional cancer treatment. Herein, a camouflage composite nanoformulation (TCBG@PR), an antitumor agent (tubercidin, Tub) loaded into Cu-doped bioactive glasses (CBGs) and subsequently camouflaged by polydopamine (PDA), and red blood cell membranes (RBCm), was successfully constructed for targeted and synergetic antitumor therapies by combining CT of Tub, CDT of doped copper ions, and PTT of PDA. In addition, the TCBG@PRs composite nanoformulation was camouflaged with a red blood cell membrane (RBCm) to improve biocompatibility, longer blood retention times, and excellent cellular uptake properties. It integrated with long circulation and multimodal synergistic treatment (CT, CDT, and PTT) with the benefit of RBCms to avoid immune clearance for efficient targeted delivery to tumor locations, producing an "all-in-one" nanoplatform. In vivo results showed that the TCBG@PRs composite nanoformulation prolonged blood circulation and improved tumor accumulation. The combination of CT, CDT, and PTT therapies enhanced the antitumor therapeutic activity, and light-triggered drug release reduced systematic toxicity and increased synergistic antitumor effects.

Fermented Chinese Herbs Improve the Growth and Immunity of Growing Pigs through Regulating Colon Microbiota and Metabolites.

(1) Background: the development of new antibiotic substitutes to promote pig growth and health has become an important way to solve the current dilemma and promote the pig industry. (2) Methods: to assess the effects of a fermented Chinese herbal (FCH) formula on the growth and immunity of growing pigs, 100 Duroc × Landrace × Yorshire three-way crossed growing pigs were randomly divided into control and treatment groups that were fed a basal diet, and a basal diet with 1% (group A), 2% (group B), and 3% (group C) FCH formulas, respectively. A sixty-day formal experiment was conducted, and their growth and serum indices, colonic microbiota, and metabolites were analyzed. (3) Results: the daily gain of growing pigs in groups A, B, and C increased by 7.93%, 17.68%, and 19.61%, respectively, and the feed-to-gain ratios decreased by 8.33%, 15.00%, and 14.58%, respectively. Serum immunity and antioxidant activities were significantly increased in all treatment groups. Particularly, adding a 2% FCH formula significantly changed the colon's microbial structure; the Proteobacteria significantly increased and Firmicutes significantly decreased, and the metabolite composition in the colon's contents significantly changed. (4) Conclusions: these results indicate that the FCH formula is a good feed additive for growing pigs, and the recommended addition ratio was 3%.

[Treatment of rheumatoid arthritis by injection of sinomenine solid lipid nanoparticles under a fluorescence endoscopic laser confocal microscope].

A fluorescence endoscopic laser confocal microscope(FELCM) was used to direct the injection of sinomenine solid lipid nanoparticles(Sin-SLN) into the joint, and the in vitro effectiveness of Sin-SLN in the treatment of rheumatoid arthritis(RA) was evaluated. Sin-SLN was prepared with the emulsion evaporation-low temperature curing method. The Sin-SLN prepared under the optimal conditions showed the encapsulation efficiency of 64.79%±3.12%, the drug loading of 3.84%±0.28%, the average particle size of(215.27±4.21) nm, and the Zeta potential of(-32.67±0.84) mV. Moreover, the Sin-SLN demonstrated good stability after sto-rage for 30 days. The rabbit model of RA was established by the subcutaneous injection of ovalbumin and complete Freund's adjuvant. Five groups were designed, including a control group, a model group, a Sin(1.5 mg·kg~(-1)) group, a Sin-SLN(1.5 mg·kg~(-1)) group, and a dexamethasone(positive drug, 1.0 mg·kg~(-1), ig) group. The control group and the model group only received puncture treatment without drug injection. After drug administration, the local skin temperature and knee joint diameter were monitored every day. The knee joint diameter and the local skin temperature were lower in the drug administration groups than in the model group(P<0.05, P<0.01). FELCM recorded the morphological alterations of the cartilage of knee joint. The Sin-SLN group showed compact tissue structure and smooth surface of the cartilage. Enzyme-linked immunosorbent assay(ELISA) was employed to determine the serum le-vels of interleukin-1(IL-1) and tumor necrosis factor-α(TNF-α). The findings revealed that the Sin-SLN group had lower IL-1 and TNF-α levels than the model group(P<0.05, P<0.01). Hematoxylin-eosin(HE) staining was employed to reveal the pathological changes of the synovial tissue, which were significantly mitigated in the Sin-SLN group. The prepared Sin-SLN had uniform particle size and high stability. Through joint injection administration, a drug reservoir was formed. Sin-SLN effectively alleviate joint swelling and cartilage damage of rabbit, down-regulated the expression of inflammatory cytokines, and inhibited the epithelial proliferation and inflammatory cell infiltration of the synovial tissue, demonstrating the efficacy in treating RA.

[Application of microneedle-assisted percutaneous drug delivery system in treatment of rheumatoid arthritis:a review].

Rheumatoid arthritis(RA) is a chronic degenerative joint disease characterized by inflammation. Due to the complex causes, no specific therapy is available. Non-steroidal anti-inflammatory agents and corticosteroids are often used(long-term, oral/injection) to interfere with related pathways for reducing inflammatory response and delaying the progression of RA, which, however, induce many side effects. Microneedle, an emerging transdermal drug delivery system, is painless and less invasive and improves drug permeability. Thus, it is widely used in the treatment of RA and is expected to be a new strategy in clinical treatment. This paper summarized the application of microneedles in the treatment of RA, providing a reference for the development of new microneedles and the expansion of its clinical application.

Computation and molecular pharmacology to trace the anti-rheumatoid activity of Angelicae Pubescentis Radix.

BACKGROUND: The mechanism of action of Angelicae Pubescentis Radix in rheumatoid arthritis treatment is complex; the pathways and protein targets involved remain unclear. This study predicted the targets and signaling pathways of Angelicae Pubescentis Radix for rheumatoid arthritis treatment using network pharmacology and molecular docking technology and clarified its mechanism of action using in vitro cellular experiments. METHODS: Angelicae Pubescentis Radix active components and related targets were retrieved from the traditional Chinese medicine systems pharmacology database. All human proteins were mined from the global protein database, and the network of active components and targets of Angelicae Pubescentis Radix was drawn using Cytoscape 3.7.1. GeneCard, Online Mendelian Inheritance in Man, and DrugBank databases were used to mine rheumatoid arthritis-related genes. Metascape was used for Gene Ontology function analysis and Kyoto Encyclopedia of Genes and Genomes enrichment pathways. ß-sitosterol's molecular docking was determined using AutoDock Tools; pathway verification was performed in the Kyoto Encyclopedia of Genes and Genomes database, and the verified genes were input into the Human Protein Atlas database to observe the expression levels in various human body tissues. RESULTS: Eight main active components were screened out of Angelicae Pubescentis Radix from the traditional Chinese medicine systems pharmacology database, and 60 targets related to major active ingredients were obtained. Forty-two core pathogenic rheumatoid arthritis-related genes were screened from GeneCard and other related databases. The enrichment of the Kyoto Encyclopedia of Genes and Genomes pathway included the vascular endothelial growth factor signaling pathway that proved to be the decisive pathway for rheumatoid arthritis treatment by a high degree value. In vitro experiments confirmed that Angelicae Pubescentis Radix mainly regulated cell proliferation and survival through the vascular endothelial growth factor signaling pathway and showed significant therapeutic effects on rheumatoid arthritis. The prostaglandin endoperoxide synthase 2 gene was associated with rheumatoid arthritis via pathway verification and monitoring of human gene expression levels. CONCLUSIONS: The mechanism of the multi-component, multi-target, and multi-channel treatment of rheumatoid arthritis via Angelicae Pubescentis Radix was explored using network pharmacology and molecular docking technology, providing new thinking and research directions for future rheumatoid arthritis treatment using Angelicae Pubescentis Radix.

Correlation analysis of carotid artery intima-media thickness, serum 25(OH)D and men with erectile dysfunction.

Our goal is to investigate the connection between serum 25(OH)D and carotid artery intima-media thickness (CIMT) in men with erectile dysfunction (ED).Serum 25(OH)D and CIMT were measured in 124 participants with erectile dysfunction and 39 healthy controls. The relationship between them and different patient-related parameters and disease-related parameters was studied. Compared with the control group and mild ED group, the level of serum 25(OH)D in moderate ED group and severe ED group decreased significantly(P<0.05). The CIMT values of moderate ED group and severe ED group were higher than those of the control group(P<0.05). The CIMT value of severe ED group was significantly higher than that of mild ED group(P<0.05). IIEF-5 score was positively correlated with serum 25(OH)D level, but negatively correlated with CIMT value(P<0.05). After adjusting for the influence of confounding factors, The CIMT values, 25(OH)D and IIEF-5 score were substantially associated(P<0.05). The serum level of 25(OH)D and IIEF-5 score were positively correlated, while the CIMT values and IIEF-5 score were negatively correlated. The level of serum 25(OH)D should be analyzed in men with ED, especially in patients with vasculogenic ED, and supplementation is recommended for those who were with vitamin D deficiency.

[Mechanism of Linderae Radix against gastric cancer based on network pharmacology and in vitro experimental validation].

The present study explored the main active ingredients and the underlying mechanism of Linderae Radix the treatment of gastric cancer by network pharmacology, molecular docking, and in vitro cell experiments. TCMSP, OMIM and GeneCards database were used to obtain the active ingredients of Linderae Radix to predict the related targets of both Linderae Radix and gastric cancer. After screening the common potential action targets, the STRING database was used to construct the PPI network for protein interaction of the two common targets. Enrichment analysis of GO and KEGG by DAVID database. Based on STRING and DAVID platform data, Cytoscape software was used to construct an "active ingredient-target" network and an "active ingredient-target-pathway" network. Molecular docking was performed using the AutoDock Vina to predict the binding of the active components to the key action targets, and finally the key targets and pathways were verified in vitro. According to the prediction results, there were 9 active components, 179 related targets of Radix Linderae, 107 common targets of Linderae Radix and gastric cancer, 693 biological processes, 57 cell compositions, and 129 molecular functions involved in the targets, and 161 signaling pathways involved in tumor antigen p53, hypoxia-indu-cible factor 1, etc. Molecular docking results showed that the core component, jimadone, had high binding activity with TP53. Finally, in an in vitro experiment, the screened radix linderae active ingredient gemmadone is used for preliminarily verifying the core targets and pathways of the human gastric cancer cell SGC-7901, The results showed that germacrone could significantly inhibit the proliferation of gastric cancer cells and induce the apoptosis of SGC-7901 by regulating the expression of p53, Bax, Bcl-2 and other key proteins. In summary, Radix Linderae can control the occurrence and development of gastric cancer through multi-components, multi-targets and multi-pathways, which will provide theoretical basis for further clinical discussion on the mechanism of Radix Linderae in treating gastric cancer.

Network Pharmacology Analysis, Molecular Docking, and In Vitro Verification Reveal the Action Mechanism of Prunella vulgaris L. in Treating Breast Cancer.

Background: Prunella vulgaris L. is effective in the treatment of breast cancer (BRCA); however, the underlying mechanism is still unclear. The aim of this study was to elucidate the mechanism of treatment of BRCA by P. vulgaris using network pharmacology and molecular docking technology, and to verify the experimental results using human BRCA MDA-MB-231 cells. Methods: Active components and action targets of P. vulgaris were determined using the TCMSP™, SwissTarget Prediction™, and TargetNet™ databases. GeneCards™ and OMIM™ provided BRCA targets. After obtaining common targets, a protein-protein interaction (PPI) network was constructed using the STRING™ database, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted using the Xiantao™ academic database. Cytoscape™ was used to construct "single drug-disease-component-target" and "single drug-disease-component-target-pathway" networks. The Human Protein Atlas™ was used to determine protein expression levels in BRCA cell lines. AutoDock tools™ were used to carry out molecular docking for the first 10 targets of quercetin and the PPI network. Finally, the abovementioned results were verified using cell experiments. Results: We obtained 11 active components, 198 targets, and 179 common targets, including DUOX2, MET, TOP2A, and ERBB3. The results of KEGG pathway analysis screened 188 related signaling pathways and indicated the potential key role of PI3K-Akt and MAPK signaling pathways in the antibreast cancer process of P. vulgaris. The results of molecular docking showed that the first 10 targets of quercetin interacted well with the protein network. Cell experiments showed that quercetin effectively inhibited the proliferation of MDA-MB-231 cells by regulating apoptosis and cell cycle, which may be partly related to the MAPK signaling pathway. Conclusion: Synergistic effects of multiple components, targets, and pathways on the anti-BRCA activity of P. vulgaris could provide a theoretical basis for further study on its complex anti-BRCA mechanism.