ABSTRACT
A prevalent recessive mutation (c.2485C>T, p.Q829X) within the OTOF gene leads to profound prelingual hearing loss. Here we show that in Otof mice harbouring a mutation (c.2482C>T, p.Q828X) homozygous to human OTOF that faithfully mimics the hearing-loss phenotype, a base editor (consisting of the deaminase ABE7.10max and the Cas9 variant SpCas9-NG) packaged in adeno-associated viruses and injected into the inner ear of the mice via the round-window membrane effectively corrected the pathogenic mutation, with no apparent off-target effects. The treatment restored the levels of the otoferlin protein in 88% of the inner hair cells and stably rescued the auditory function of the mice to near-wild-type levels for over 1.5 years while improving synaptic exocytosis in the inner hair cells. We also show that an adenine base editor that targets the prevalent human OTOF mutation restored hearing in humanized mice to levels comparable to those of the wild-type counterparts. Base editors may be effective for the treatment of hereditary deafness.
ABSTRACT
The tumor microenvironment (TME) comprises immune-infiltrating cells that are closely linked to tumor development. By screening and analyzing genes associated with tumor-infiltrating M0 cells, we developed a risk model to provide therapeutic and prognostic guidance in clear cell renal cell carcinoma (ccRCC). First, the infiltration abundance of each immune cell type and its correlation with patient prognosis were analyzed. After assessing the potential link between the depth of immune cell infiltration and prognosis, we screened the infiltrating M0 cells to establish a risk model centered on three key genes (TMEN174, LRRC19, and SAA1). The correlation analysis indicated a positive correlation between the risk score and various stages of the tumor immune cycle, including B-cell recruitment. Furthermore, the risk score was positively correlated with CD8 expression and several popular immune checkpoints (ICs) (TIGIT, CTLA4, CD274, LAG3, and PDCD1). Additionally, the high-risk group (HRG) had higher scores for tumor immune dysfunction and exclusion (TIDE) and exclusion than the low-risk group (LRG). Importantly, the risk score was negatively correlated with the immunotherapy-related pathway enrichment scores, and the LRG showed a greater therapeutic benefit than the HRG. Differences in sensitivity to targeted drugs between the HRG and LRG were analyzed. For commonly used targeted drugs in RCC, including axitinib, pazopanib, temsirolimus, and sunitinib, LRG had lower IC50 values, indicating increased sensitivity. Finally, immunohistochemistry results of 66 paraffin-embedded specimens indicated that SAA1 was strongly expressed in the tumor samples and was associated with tumor metastasis, stage, and grade. SAA1 was found to have a significant pro-tumorigenic effect by experimental validation. In summary, these data confirmed that tumor-infiltrating M0 cells play a key role in the prognosis and treatment of patients with ccRCC. This discovery offers new insights and directions for the prognostic prediction and treatment of ccRCC.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Tumor Microenvironment , Humans , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/genetics , Prognosis , Tumor Microenvironment/immunology , Kidney Neoplasms/pathology , Kidney Neoplasms/genetics , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Female , Male , Risk Assessment/methods , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Gene Expression Regulation, Neoplastic , Middle Aged , Immunotherapy/methods , Sulfonamides/therapeutic useABSTRACT
Disulfidptosis, a newly discovered mode of cell death caused by excessive accumulation of intracellular disulfide compounds, is closely associated with tumor development. This study focused on the relationship between disulfidptosis and clear cell renal cell carcinoma (ccRCC). Firstly, the characterizations of disulfidptosis-related genes (DRGs) in ccRCC were showed, which included number variation (CNV), single nucleotide variation (SNV), DNA methylation, mRNA expression and gene mutation. Then, the ccRCC samples were classified into three clusters through unsupervised clustering based on DRGs. Survival and pathway enrichment differences were evaluated among the three clusters. Subsequently, the differentially expressed genes (DEGs) among the three clusters were screened by univariate Cox, LASSO, and multivariate Cox analysis, and five key DEGs were obtained. Based on the five key DEGs, the ccRCC samples were reclassified into two geneclusters and the survival differences and immune cell infiltration between two geneclusters was investigated. In next step, ccRCC samples were divided into two groups according to PCA scores of five key DEGs, namely high PCA score group (HPSG) and low PCA score group (LPSG). On this basis, differences in survival prognosis, immune cell infiltration and correlation with immune checkpoint, as well as differences in sensitivity to targeted drugs were compared between HPSG and LPSG. The expression levels of four immune checkpoints were higher in HPSG than in LPSG, whereas the LPSG was more sensitive to targeted drug therapy than the HPSG. Finally, validation experiments on HDAC4 indicated that HDAC4 could increase the proliferation and colony formation ability of ccRCC cells.
ABSTRACT
Periodontitis is a multifactorial inflammatory disease characterized by severe alveolar bone damage and attachment loss. The imbalance of T help 17 (Th17) / regulatory T cells (Treg) induces excessive interleukin (IL)-17, which leads to alveolar bone damage and aggravates the development of periodontitis. Therefore, we proposed a therapeutic strategy to restore Th17/Treg homeostasis by interfering reactive oxygen species (ROS)-macrophage polarization cascade using active targeting microemulsions-based thermosensitive hydrogel. Folic acid-modified quercetin-loaded microemulsions (FA-Qu-MEs) were dispersed in poloxamer 407 and poly(N-isopropylacrylamide) matrix of hydrogel (FA-Qu-MEs@Gel). FA-Qu-MEs@Gel could be locally injected into the periodontal pocket and sustainedly release drugs. FA-Qu-MEs exhibited excellent ROS scavenging potency by targeting macrophages, resulting M1 phenotype macrophage from to M2 phenotype macrophage. Subsequently, the phenotypic changes of macrophages lead to decreased expression of IL-6 and tumor necrosis factor-α, which inhibited activated Th17, while IL-10 secreted by M2 macrophages promoted Treg differentiation. Finally, the restored Th17/Treg homeostasis reduced the level of IL-17 to accelerate alveolar bone regeneration. This study deigns a novel system that promote alveolar bone regeneration by remodeling Th17/Treg homeostasis via regulating ROS-macrophages polarization cascade for periodontitis treatment.
Subject(s)
Emulsions , Homeostasis , Hydrogels , Macrophages , Periodontitis , Reactive Oxygen Species , T-Lymphocytes, Regulatory , Th17 Cells , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , Reactive Oxygen Species/metabolism , Periodontitis/drug therapy , Periodontitis/immunology , Animals , Th17 Cells/drug effects , Th17 Cells/immunology , Hydrogels/administration & dosage , Homeostasis/drug effects , Macrophages/drug effects , Macrophages/immunology , Mice , Male , Poloxamer/chemistry , RAW 264.7 Cells , Acrylic Resins/chemistry , Bone Regeneration/drug effects , Mice, Inbred C57BLABSTRACT
Magnesium-based coatings have attracted great attention in surface modification of titanium implants due to their superior angiogenic and osteogenic properties. However, their biological effects as a carbonate-based constituent remain unrevealed. In this study, magnesium carbonate coatings were prepared on titanium surfaces under hydrothermal conditions and subsequently treated with hydrogen peroxide. Also, their antibacterial activity and in vitro cell biocompatibility were evaluated. The obtained coatings consisted of nanoparticles without cracks and exhibited excellent adhesion to the substrate. X-ray diffraction (XRD) results indicated pure magnesium carbonate coatings formed on the Ti surface after hydrothermal treatment. After hydrogen peroxide treatment, the phase composition of the coatings had no obvious change. Compared to the untreated coatings, the hydrogen peroxide-treated coatings showed increased surface roughness and hydrophilicity. Co-culture with Staphylococcus aureus (S. aureus) demonstrated that the obtained coatings had good antibacterial activity. In vitro cell culture results showed that the hydrogen peroxide-treated coatings enhanced the viability, proliferation, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). These findings suggest that this MgCO3-based coating exhibits excellent antibacterial performance and osteogenic potential. Based on the above, this study provides a simple method for preparing titanium implants with dual antibacterial and osteogenic capabilities, holding great promise in clinical applications.
ABSTRACT
The potential applications of nanomaterials in agriculture for alleviating diverse biotic and abiotic stresses have garnered significant attention. The reported mechanisms encompass promoting plant growth and development, alleviating oxidative stress, inducing defense responses, modulating plant-microbe interactions, and more. However, individual studies may not fully uncover the common pathways or distinguish the effects of different nanostructures. We examined Arabidopsis thaliana transcriptomes exposed to biotic, abiotic, and metal or carbon-based nanomaterials, utilizing 24 microarray chipsets and 17 RNA-seq sets. The results showed that: 1) from the perspective of different nanostructures, all metal nanomaterials relieved biotic/abiotic stresses via boosting metal homeostasis, particularly zinc and iron. Carbon nanomaterials induce hormone-related immune responses in the presence of both biotic and abiotic stressors. 2) Considering the distinct features of various nanostructures, metal nanomaterials displayed unique characteristics in seed priming for combating abiotic stresses. In contrast, carbon nanomaterials exhibited attractive features in alleviating water deprivation and acting as signaling amplifiers during biotic stress. 3) For shared pathway analysis, response to hypoxia emerges as the predominant and widely shared regulatory mechanism governing diverse stress responses, including those induced by nanomaterials. By deciphering shared and specific pathways and responses, this research opens new avenues for precision nano-agriculture, offering innovative strategies to optimize plant resilience, improve stress management, and advance sustainable crop production practices.
Subject(s)
Arabidopsis , Nanostructures , Stress, Physiological , Transcriptome , Arabidopsis/genetics , Arabidopsis/physiology , Nanostructures/toxicity , Transcriptome/drug effectsABSTRACT
Antimicrobial nanomaterials frequently induce inflammatory reactions within lung tissues and prompt apoptosis in lung cells, yielding a paradox due to the inherent anti-inflammatory character of apoptosis. This paradox accentuates the elusive nature of the signaling cascade underlying nanoparticle (NP)-induced pulmonary inflammation. In this study, we unveil the pivotal role of nano-microflora interactions, serving as the crucial instigator in the signaling axis of NP-induced lung inflammation. Employing pulmonary microflora-deficient mice, we provide compelling evidence that a representative antimicrobial nanomaterial, silver (Ag) NPs, triggers substantial motility impairment, disrupts quorum sensing, and incites DNA leakage from pulmonary microflora. Subsequently, the liberated DNA molecules recruit caspase-1, precipitating the release of proinflammatory cytokines and activating N-terminal gasdermin D (GSDMD) to initiate pyroptosis in macrophages. This pyroptotic cascade culminates in the emergence of severe pulmonary inflammation. Our exploration establishes a comprehensive mechanistic axis that interlinks the antimicrobial activity of Ag NPs, perturbations in pulmonary microflora, bacterial DNA release, macrophage pyroptosis, and consequent lung inflammation, which helps to gain an in-depth understanding of the toxic effects triggered by environmental NPs.
Subject(s)
Pneumonia , Pyroptosis , Pyroptosis/drug effects , Mice , Animals , Pneumonia/chemically induced , Pneumonia/pathology , Silver/toxicity , Metal Nanoparticles/toxicity , Macrophages/drug effects , InflammationABSTRACT
The use of nanomaterials to improve plant immunity for sustainable agriculture is gaining increasing attention; yet, the mechanisms involved remain unclear. In contrast to metal-based counterparts, carbon-based nanomaterials do not release components. Determining how these carbon-based nanomaterials strengthen the resistance of plants to diseases is essential as well as whether shape influences this process. Our study compared single-walled carbon nanotubes (SWNTs) and graphene oxide (GO) infiltration against the phytopathogen Pseudomonas syringae pv tomato DC3000. Compared with plants treated with GO, plants primed with SWNTs showed a 29% improvement in the pathogen resistance. Upon nanopriming, the plant displayed wound signaling with transcriptional regulation similar to that observed under brushing-induced mechanostimulation. Compared with GO, SWNTs penetrated more greatly into the leaf and improved transport, resulting in a heightened wound response; this effect resulted from the tubular structure of SWNTs, which differed from the planar form of GO. The shape effect was further demonstrated by wrapping SWNTs with bovine serum albumin, which masked the sharp edges of SWNTs and resulted in a significant decrease in the overall plant wound response. Finally, we clarified how the local wound response led to systemic immunity through increased calcium ion signaling in distant plant areas, which increased the antimicrobial efficacy. In summary, our systematic investigation established connections among carbon nanomaterial priming, mechanostimulation, and wound response, revealing recognition patterns in plant immunity. These findings promise to advance nanotechnology in sustainable agriculture by strengthening plant defenses, enhancing resilience, and reducing reliance on traditional chemicals.
Subject(s)
Graphite , Nanotubes, Carbon , Pseudomonas syringae , Pseudomonas syringae/drug effects , Nanotubes, Carbon/chemistry , Graphite/chemistry , Graphite/pharmacology , Plant Immunity/drug effects , Plant Diseases/microbiology , Plant Diseases/prevention & control , Plant Leaves/metabolismABSTRACT
Periodontitis is a chronic inflammatory disease caused by the local microbiome and the host immune response, resulting in periodontal structure damage and even tooth loss. Scaling and root planning combined with antibiotics are the conventional means of nonsurgical treatment of periodontitis, but they are insufficient to fully heal periodontitis due to intractable bacterial attachment and drug resistance. Novel and effective therapeutic options in clinical drug therapy remain scarce. Nanotherapeutics achieve stable cell targeting, oral retention and smart release by great flexibility in changing the chemical composition or physical characteristics of nanoparticles. Meanwhile, the protectiveness and high surface area to volume ratio of nanoparticles enable high drug loading, ensuring a remarkable therapeutic efficacy. Currently, the combination of advanced nanoparticles and novel therapeutic strategies is the most active research area in periodontitis treatment. In this review, we first introduce the pathogenesis of periodontitis, and then summarize the state-of-the-art nanotherapeutic strategies based on the triple concerto of antibacterial activity, immunomodulation and periodontium regeneration, particularly focusing on the therapeutic mechanism and ingenious design of nanomedicines. Finally, the challenges and prospects of nano therapy for periodontitis are discussed from the perspective of current treatment problems and future development trends.
Subject(s)
Periodontitis , Humans , Periodontitis/drug therapy , Periodontium , Anti-Bacterial Agents/therapeutic use , Regeneration , Immunomodulation , ImmunityABSTRACT
Nanoparticles (NPs) hold great promise for agricultural applications, yet their potential impact on exogenous gene transfer within plant remains poorly understood. In this study, we utilized the non-conjugative plasmid pCAMBIA1300, harboring the bialaphos resistance (bar) gene expressed in plant and the kanamycin resistance (kanR) gene as selectable marker in bacteria. Our results revealed a significant increase in the transfer of plasmid (via carrier Escherichia coli DH5α), both intra- and inter-species within the endophyte, when Arabidopsis thaliana was exposed to environmentally relevant level of zinc oxide (ZnO) NPs at a concentration of 0.7 µg/mL throughout its lifespan. Intriguingly, the plasmid exhibited selective transfer to growth-promoting endophytes, such as Enterobacter, Serratia, and Achromobacter, with the presence of ZnO NPs expanding the pool of potential recipients. This result is due to the facilitation of an endophytic and mutualistic lifestyle of invasive E. coli DH5α and the enrichment of beneficial bacteria aided by ZnO NPs. The plant's descendant generations did not express the bar gene, and the endophytes carrying the exogenous plasmid did not transmit it to sub sequent generation. This research provides crucial insights for assessing the potential risks associated with gene contamination and ensuring the safe and sustainable use of NPs in agriculture.
Subject(s)
Arabidopsis , Metal Nanoparticles , Nanoparticles , Zinc Oxide , Endophytes , Arabidopsis/genetics , Escherichia coli/genetics , Bacteria/genetics , PlasmidsABSTRACT
In recent years, additive manufacturing techniques have been used to fabricate 3D titanium (Ti)-based scaffolds for production of desirable complex shapes. However, insufficient osteointegration of porous Ti-based scaffolds can elicit long-term complications (e.g., aseptic loosening) and need further revision surgery. In this study, a magnesium (Mg)-incorporating tantalum (Ta) coating was deposited on a 3D Ti6Al4V scaffold using a sol-gel method for enhancing its osteogenic properties. To evaluate the biofunction of this surface, bone mesenchymal stem cells and rabbit femoral condyle were used to assess the cell response and bone ingrowth, respectively. Ta2O5 coatings and Mg-incorporating Ta2O5 coatings were both homogeneously deposited on porous scaffolds. In vitro studies revealed that both coatings exhibit enhanced cell proliferation, ALP activity, osteogenic gene expression and mineralization compared with the uncoated Ti6Al4V scaffold. Especially for Mg-incorporating Ta2O5 coatings, great improvements were observed. In vivo studies, including radiographic examination, fluorochrome labeling and histological evaluation also followed similar trends. Also, bone ingrowth to scaffolds with Mg-incorporating Ta2O5 coatings exhibited the most significant increase compared with uncoated and Ta2O5 coated scaffolds. All the above results indicate that Mg-doped Ta2O5 coatings are an effective tool for facilitating osteointegration of conventional porous Ti6Al4V scaffolds.
ABSTRACT
BACKGROUND: Most displaced femoral neck fractures can achieve satisfactory anatomical reduction by closed reduction, but there are still some that cannot reset satisfactorily after closed reduction, and open reduction are required. Such fractures that cannot be repositioned successfully by closed reduction are called irreducible displaced femoral neck fractures in this study. The objective of our study was to evaluate the efficacy of direct anterior incision with the Femoral Neck System in the treatment of irreducible displaced femoral fractures. METHODS: A total of 16 young and middle-aged patients with irreducible displaced femoral neck fractures involving Garden type III and IV were treated using Femoral Neck System fixation by open reduction through Direct Anterior Approach between January 2020 to September 2021. Functional outcomes and postoperative complications were assessed during follow-up. Clinical outcomes were evaluated by the Hip Harris score. The postoperative reduction was evaluated by the Garden Index. Observe postoperative complications. RESULTS: All patients were followed up with a mean follow-up time of 21.1(12-30) months, and according to radiological results, all patients achieved fracture healing, with a mean healing time of 4.25 months. All 16 patients received grade Garden I and II reductions, and there was no significant difference in the anteroposterior Garden reduction index between the first day after surgery (166.13 ± 5.61) and the 12th month after surgery(164.94 ± 4.49) (P>0.05) and no significant difference in lateral Garden index between the first day after surgery(171.06 ± 4.46) and the 12th month after surgery(169.38 ± 3.98) (P<0.05). According to the Hip Harris score scale, 13 patients received excellent and 3 patients received good. The postoperative Hip Harris Score(17.19 ± 4.8) was significantly higher than the preoperative score(92.19 ± 3.4), and the difference was statistically significant (P < 0.05). No or mild femoral neck shortness occurred in 12 (75%) patients, moderate shortening occurred in 3 (18.75%) patients, and severe shortening occurred in 1 (6.25%) patient. None of the patients experienced femoral head necrosis, fracture nonunion, or incision infection. One patient developed deep venous thrombosis of the lower extremity. CONCLUSIONS: The Direct Anterior Approach combined with Femoral Neck System is an excellent treatment for irreducible displaced femoral neck fracture and achieved good functional outcomes and anatomical reduction with low complications.
Subject(s)
Femoral Neck Fractures , Femur Neck , Middle Aged , Humans , Fracture Fixation, Internal/methods , Femoral Neck Fractures/diagnostic imaging , Femoral Neck Fractures/surgery , Open Fracture Reduction , Surgical Wound Infection , Treatment Outcome , Retrospective StudiesABSTRACT
Due to the tolerance of mismatches between gRNA and targeting sequence, base editors frequently induce unwanted Cas9-dependent off-target mutations. Here, to develop models to predict such off-targets, we design gRNA-off- target pairs for adenine base editors (ABEs) and cytosine base editors (CBEs) and stably integrate them into the human cells. After five days of editing, we obtain valid efficiency datasets of 54,663 and 55,727 off-targets for ABEs and CBEs, respectively. We use the datasets to train deep learning models, resulting in ABEdeepoff and CBEdeepoff, which can predict off-target sites. We use these tools to predict off-targets for a panel of endogenous loci and achieve Spearman correlation values varying from 0.710 to 0.859. Finally, we develop an integrated tool that is freely accessible via an online web server http://www.deephf.com/#/bedeep/bedeepoff . These tools could facilitate minimizing the off-target effects of base editing.
Subject(s)
Deep Learning , Gene Editing , Adenine , CytosineABSTRACT
Bacterial memory refers to the phenomenon in which past experiences influence current behaviors in response to changing environments. It serves as a crucial process that enables adaptation and evolution. We first summarize the state-of-art approaches regarding history-dependent behaviors that impact growth dynamics and underlying mechanisms. Then, the phenotypic and genotypic origins of memory and how encoded memory modulates drug tolerance/resistance are reviewed. We also provide a summary of possible memory effects induced by antimicrobial nanoparticles. The regulatory networks and genetic underpinnings responsible for memory building partially overlap with nanoparticle and drug exposures, which may raise concerns about the impact of nanotechnology on adaptation. Finally, we provide a perspective on the use of nanotechnology to harness bacterial memory based on its unique mode of actions on information processing and transmission in bacteria. Exploring bacterial memory mechanisms provides valuable insights into acclimation, evolution, and the potential applications of nanotechnology in harnessing memory.
ABSTRACT
PURPOSE: Disulfidptosis is a novel type of cell death induced by disulphide stress that depends on the accumulation of cystine disulphide, causing cytotoxicity and triggering cell death. However, the direct prognostic effect and regulatory mechanism of disulfidptosis-related genes in bladder urothelial carcinoma (BLCA) remain unclear. METHODS: To explore the role of 10 disulfidptosis-related genes, the multiomic data of 10 genes were comprehensively analysed. Next, based on seven disulfidptosis-related differentially expressed genes, a novel disulfidptosis-related gene score was developed to help predict the prognosis of BLCA. Immunohistochemistry, EDU, Real-time PCR and western blot were used to verify the model. RESULTS: Significant functional differences were found between the high- and low-risk score groups, and samples with a higher risk score were more malignant. Furthermore, the tumour exclusion and Tumour Immune Dysfunction and Exclusion scores of the high-risk score group were higher than those of the low-risk score group. The risk score was positively correlated with the expression of immune checkpoints. Drug sensitivity analyses revealed that the low-risk score group had a higher sensitivity to cisplatin, doxorubicin, docetaxel and gemcitabine than the high-risk score group. Moreover, the expression of the TM4SF1 was positively correlated with the malignancy degree of BLCA, and the proliferation ability of BLCA cells was reduced after knockdown TM4SF1. CONCLUSION: The present study results suggest that disulfidptosis-related genes influence the prognosis of BLCA through their involvement in immune cell infiltration. Thus, these findings indicate the role of disulfidptosis in BLCA and its potential regulatory mechanisms.
ABSTRACT
Skin is the largest organ of the human body. It plays a vital role as the body's first barrier: stopping chemical, radiological damage and microbial invasion. The importance of skin to the human body can never be overstated. Delayed wound healing after a skin injury has become a huge challenge in healthcare. In some situations, this can have very serious and even life-threatening effects on people's health. Various wound dressings have been developed to promote quicker wound healing, including hydrogels, gelatin sponges, films, and bandages, all work to prevent the invasion of microbial pathogens. Some of them are also packed with bioactive agents, such as antibiotics, nanoparticles, and growth factors, that help to improve the performance of the dressing it is added to. Recently, bioactive nanoparticles as the bioactive agent have become widely used in wound dressings. Among these, functional inorganic nanoparticles are favored due to their ability to effectively improve the tissue-repairing properties of biomaterials. MXene nanoparticles have attracted the interest of scholars due to their unique properties of electrical conductivity, hydrophilicity, antibacterial properties, and biocompatibility. The potential for its application is very promising as an effective functional component of wound dressings. In this paper, we will review MXene nanoparticles in skin injury repair, particularly its synthesis method, functional properties, biocompatibility, and application.
ABSTRACT
Black phosphorus (BP) shows encouraging utility in many fields, and metal doping has been suggested as an efficient way to improve stability. However, controversial results and inconsistent mechanisms have been reported for doping modulation and stability change. We observed the unforeseen evolution of singlet oxygen (1O2) from BP integrated with gold nanoparticles (BP@Au) under dark conditions, and this led to rapid BP deterioration, even though enhanced stability is commonly thought via surface doping. Briefly, the BP reacted with oxygen and water to yield superoxide (O2â¢-) and hydrogen peroxide. Au0 acted as an enzyme mimic and catalyzed the conversion of these derivatives, and Au0 was converted to a mixture of Au3+ and Au+. The O2â¢- was converted to 1O2 via direct donation of electrons to the Au3+/+. The Au-catalyzed redox reactions accelerated the degradation of the BP nanosheets. BP@Au showed significant toxicity toward marine alga that produce O2â¢- in the dark, as indicated by a more than 30% reduction in cell viability after 12 h of incubation with 7.56 mg/L BP@Au. The novelty of this work lies in the demonstration of a dopant-related degradation pathway of BP that shows unrevealed toxicity toward O2â¢--producing marine algae.
Subject(s)
Metal Nanoparticles , Singlet Oxygen , Superoxides , Gold/toxicity , Phosphorus , Metal Nanoparticles/toxicity , OxygenABSTRACT
BACKGROUND: Nux Vomica (NV) has the effects of dredging collaterals, relieving pain, dispersing knots, and detumescence, and has a verified effect in treating ischemic stroke (IS), but its molecular mechanism for treating IS remains unclear. In this study, network pharmacology and molecular docking methods were adopted to explore the pharmacological mechanism of NV in treating IS. METHODS: The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the HERB database were searched to screen the active components and targets of NV. IS disease targets were retrieved from the DisGeNET, DrugBank, GeneCards, and Therapeutic Target Database. Venn diagram and intersection targets were obtained from the Venny website. Subsequently, the STRING database was employed to analyze the interrelationship of the intersection targets. Metascape database was used for Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of intersection targets. Furthermore, Cytoscape was employed to plot a drug-component-target network, and other networks, and molecular docking method was adopted to predict the effective components and targets of NV for treating IS. RESULTS: A total of 14 active compounds and 59 targets of NV were screened, of which 35 targets were related to IS. Stigmasterol, brucine, isobrucine, isostrychnine N-oxide (I), (S)-stylopine, icaride A, and (2R)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one were the main active ingredients, and SLC6A4, NR3C1, SLC6A3, HTR3A, CHRNA7, MAOA, PTGS2, ESR1, catalase (CAT), ADRB2, and AR were the core targets. Molecular docking shows that these compounds bind well to the core targets. In addition, the treatment of IS by NV may mainly involve salivary secretion, serotonergic synapse, calcium signaling pathway, cGMP-PKG signaling pathway, and neuroactive ligand-receptor interaction. CONCLUSIONS: This study revealed that NV exerts its therapeutic effect on IS through multi-component, multi-target, and multi-pathway, which provides a basis for clinical treatment of IS.
Subject(s)
Drugs, Chinese Herbal , Ischemic Stroke , Strychnos nux-vomica , Molecular Docking Simulation , Network Pharmacology , Ischemic Stroke/drug therapy , Calcium Signaling , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Medicine, Chinese TraditionalABSTRACT
BACKGROUND: Spasticity is one of the most common complications and sequelae of stroke, with the main clinical manifestations being increased muscle tension, pain, stiffness, and other disorders. It not only increases the length of hospitalization and medical costs but also affects the quality of daily life and the stress of returning to society, increasing the burden on patients and their families. At present, 2 driver types of deep muscle stimulator (DMS) have been used in the clinical treatment of post-stroke spasticity (PSS) with good clinical results, but there is no evidence of clinical efficacy and safety. Therefore, this study aims to integrate direct and indirect comparative clinical evidence through a systematic review and network meta-analysis (NMA). According to the data, different driver types for DMS with the same body of evidence will be collected, analyzed, and sequenced in a quantitative and comprehensive manner and then screened for the optimal driver type of DMS device for PSS treatment. The study also aims to provide reference value and an evidence-based theoretical basis for the clinical optimization of DMS equipment selection. METHODS: A comprehensive retrieval of China National Knowledge Infrastructure, Chinese scientific journal database, China biological feature database, Wanfang Chinese databases and the Cochrane Library, PubMed, Web of Science, and Embase foreign databases will be conducted. Randomized controlled trials of these 2 driver types of DMS devices combined with conventional rehabilitation training of PSS will be searched and published. The retrieval time is from the establishment of the database to December 20, 2022. The 2 first authors will screen references that meet the inclusion criteria, independently extract data according to predesigned rules, and assess the quality of the included studies and the risk of bias according to the Cochrane 5.1 Handbook criteria. R programming and Aggregate Data Drug Information System software will be used to perform a combined NMA of the data and to evaluate the probability of ranking for all interventions. RESULTS: The NMA and probability ranking will determine the best driver type of DMS device for PSS. CONCLUSION: This study will offer a comprehensive evidence-based approach to DMS therapy and assist doctors, PSS patients, and decision-makers in selecting a more efficient, secure, and cost-effective treatment option.