Matrine protects against experimental autoimmune encephalomyelitis through modulating microglial ferroptosis.

Multiple sclerosis (MS) is an inflammatory demyelination neurodegenerative disease of the central nervous system (CNS). Ferroptosis has been implicated in a range of brain disorders, and iron-loaded microglia are frequently found in affected brain regions. However, the molecular mechanisms linking ferroptosis with MS have not been well-defined. The present study seeks to bridge this gap and investigate the impact of matrine (MAT), a herbal medicine with immunomodulatory capacities, on the regulation of oxidative stress and ferroptosis in the CNS of mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. CNS of EAE mice contained elevated levels of ferroptosis-related molecules, e.g., MDA, LPCAT3 and PTGS2, but decreased expression of antioxidant molecules, including GSH and SOD, GPX4 and SLC7A11. This pathogenic process was reversed by MAT treatment, together with significant reduction of disease severity and CNS inflammatory demyelination. Furthermore, the expression of PTGS2 and LOX was largely increased in microglia of EAE mice, accompanied with increased production of IL-6 and TNF-α, indicating a proinflammatory phenotype of microglia that undergo oxidative stress/ferroptosis, and their expression was significantly reduced after MAT treatment. Together, our results indicate that ferroptosis/inflammation plays an important role in the pathogenesis of CNS autoimmunity, and inhibiting ferroptosis-induced microglial activation/inflammation could be a novel mechanism underlying the therapeutic effects of MAT on CNS inflammatory demyelination in EAE.

Critical Suitability Evaluation of Caco-2 Cells for Gut-on-a-Chip.

Currently, culturing Caco-2 cells in a Gut-on-a-chip (GOC) is well-accepted for developing intestinal disease models and drug screening. However, Caco-2 cells were found to overexpress surface proteins (e.g., P-gp) compared with the normal intestinal epithelial cells in vivo. To critically evaluate the challenge and suitability of Caco-2 cells, a GOC integrated with a carcinoembryonic antigen (CEA) biosensor was developed. This three-electrode system electrochemical sensor detects CEA by antigen-antibody specific binding, and it exhibits high selectivity, excellent stability, and good reproducibility. Under dynamic culturing in the GOC, Caco-2 cells exhibited an intestinal villus-like structure and maintained tissue barrier integrity. Meanwhile, CEA was discovered to be secreted from 0 to 0.22 ng/mL during the 10-day culturing of Caco-2 cells. Especially, CEA secretion increased significantly with the differentiation of Caco-2 cells after 6 days of culturing. The sustained high-level CEA secretion may induce cells to avoid apoptotic stimuli, which faithfully reflects the efficacy of a new drug and the mechanism of intestinal disease. Different kinds of cell types (e.g., intestinal primary cells, stem cell-induced differentiation) in the GOC should be attempted for drug screening in the future.

Meta-Analysis of MRI in Predicting Early Response to Radiotherapy and Chemotherapy in Esophageal Cancer.

RATIONALE AND OBJECTIVES: At present, the application of magnetic resonance imaging (MRI) in the prediction of response to neoadjuvant therapy and concurrent chemoradiotherapy for the treatment of esophageal cancer still needs to be further explored, and its early differential value remains controversial, thus we carried out this systematic review with a meta-analysis. In the application, different MRI sequences and corresponding parameters are used for the differential diagnosis of the response to neoadjuvant therapy and concurrent chemoradiotherapy. METHODS: All relevant studies evaluated the efficacy and response to MRI in neoadjuvant therapy or concurrent chemoradiotherapy for esophageal cancer on Pubmed, Embase, Cohrane Library, and Web of Science databases published before October 10, 2023 (inclusive) were systematically searched. A revised tool was used to assess the quality of diagnostic accuracy studies (QUADAS-2) to assess the risk of bias in the included original studies. A subgroup analysis of MRI sequences diffusion weighted imaging (DWI), dynamic contrast enhanced (DCE) and their corresponding different parameters, as well as the acquisition timepoints (before and after treatment) for different parameters, was performed during the meta-analysis. The bivariate mixed-effects model was used for meta-analysis. RESULTS: 21 studies were finally included, involving 1128 patients with esophageal cancer. The sensitivity, specificity, and area under receiver operating characteristic curve (ROC curve) of DWI sequence for identifying response to concurrent chemoradiotherapy were 0.82 (95% CI: 0.74-0.87), 0.81 (95% CI: 0.72-0.87) and 0.88 (95% CI: 0.56-0.98), respectively. The sensitivity, specificity, and area under ROC curve of DCE sequence for identifying response to concurrent chemoradiotherapy were 0.78 (95% CI: 0.70-0.84), 0.65 (95% CI: 0.59-0.70) and 0.73 (95% CI: 0.50-0.88), respectively. In patients with esophageal cancer, the sensitivity, specificity, and area under the ROC curve of DWI sequences for identifying response to neoadjuvant therapy were 0.80 (95% CI: 0.69 - 0.88), 0.81 (95% CI: 0.69 - 0.89), and 0.88 (95% CI: 0.34 - 0.99), respectively; the sensitivity, specificity, and area under the ROC curve of DCE sequences for identifying response to neoadjuvant therapy were 0.84 (95% CI: 0.76 - 0.90), 0.61 (95% CI: 0.53 - 0.68), and 0.70 (95% CI: 0.27 - 0.94), respectively. CONCLUSIONS: Based on the available evidence, MRI had a very good value in the early identification of response to neoadjuvant therapy and concurrent chemoradiotherapy for esophageal cancer, especially DWI. Apparent diffusion coefficient (ADC) value changes before and after treatment could be used as predictors of pathological response. Also, ADC value changes before and after treatment could be used as a tool to guide clinical decision-making.

Succinate activates UCP2 to suppress neuroinflammation and confer protection following intracerebral hemorrhage.

AIMS: Succinate, a metabolite in the tricarboxylic acid cycle, is increasingly recognized to play essential roles in inflammation by functioning either as an intracellular or extracellular signaling molecule. However, the role and mechanisms of succinate in inflammation remain elusive. Here, we investigated the mechanism underlying the effects of succinate on neuroinflammation in intracerebral hemorrhage (ICH) models. RESULTS: We unexpectedly found that succinate robustly inhibited neuroinflammation and conferred protection following ICH. Mechanistically, oxidation of succinate by succinate dehydrogenase (SDH) drove reverse electron transport (RET) at mitochondrial complex I, leading to mitochondrial superoxide production in microglia. Complex I-derived superoxide, in turn, activated uncoupling protein 2 (UCP2). By using mice with specific deletion of UCP2 in microglia/macrophage, we showed that UCP2 was needed for succinate to inhibit neuroinflammation, confer protection, and activate downstream AMP-activated protein kinase (AMPK) following ICH. Moreover, knockdown of SDH, complex I or AMPK abolished the therapeutic effects of succinate following ICH. INNOVATION AND CONCLUSION: We provide evidence that driving complex I RET to activate UCP2 is a novel mechanism of succinate intracellular signaling and a mechanism underlying the inhibition of neuroinflammation by succinate. KEY WORDS: succinate; uncoupling protein 2; microglia; neuroinflammation; intracerebral hemorrhage.

Combined bacterial translocation and cholestasis aggravates liver injury by activation pyroptosis in obstructive jaundice.

This study explores the mechanism by which obstructive jaundice (OJ) induces liver damage through pyroptosis. We induced OJ in rats via bile duct ligation and assessed liver damage using serum biochemical markers and histological analysis of liver tissue. Pyroptosis was investigated through immunofluorescence, ELISA, Western blot, and quantitative RT-PCR techniques. Additionally, we examined intestinal function and fecal microbiota alterations in the rats using 16S rDNA sequencing. In vitro experiments involved co-culturing Kupffer cells and hepatocytes, which were then exposed to bile and lipopolysaccharide (LPS). Our findings indicated that OJ modified the gut microbiota, increasing LPS levels, which, in conjunction with bile, initiated a cycle of inflammation, fibrosis, and cell death in the liver. Mechanistically, OJ elevated necrotic markers such as ATP, which in turn activated pyroptotic pathways. Increased levels of pyroptosis-related molecules, including NLRP3, caspase-1, gasdermin D, and IL-18, were confirmed. In our co-cultured cell model, bile exposure resulted in cell death and ATP release, leading to the activation of the NLRP3 inflammasome and its downstream effectors, caspase-1 and IL-18. The combination of bile and LPS significantly intensified pyroptotic responses. This study is the first to demonstrate that LPS and bile synergistically exacerbate liver injury by promoting necrosis and pyroptosis, unveiling a novel mechanism of OJ-associated hepatic damage and suggesting avenues for potential preventive or therapeutic interventions.

Highly dispersed ultrafine Ru nanoparticles on a honeycomb-like N-doped carbon matrix with modified rectifying contact for enhanced electrochemical hydrogen evolution.

The manipulation of rectifying contact between metal and semiconductor represents a powerful strategy to modify the electronic configuration of active sites for improved electrocatalytic performance. Herein, we present an NaCl template-assisted approach to rationally construct a Schottky electrocatalyst consisting of a honeycomb-like N-doped carbon matrix decorated with uniformly ultrasmall Ru nanoparticles with an average diameter of 2.5 nm (hereafter abbreviated as Ru NPs@HNC). It is found that the Fermi level difference between Ru and HNC can cause self-driven migration of electrons from Ru NPs to the HNC substrate, which leads to the generation of a built-in electric field and directional flow of electrons, thereby enhancing the intrinsic activity. In addition, the immobilization of ultrafine Ru NPs on the honeycomb-like carbon skeleton can effectively inhibit the undesired migration, agglomeration and detachment of the active sites, thus ensuring remarkable structural stability. As a result, the Ru NPs@HNC with optimal rectifying contact delivers superior electrochemical activity with a small overpotential of 28 mV at 10 mA cm-2 and outstanding long-term stability in an alkaline solution. The design philosophy of grain-size modulation and Schottky contact may widen up insight into the preparation of high-performance electrocatalysts in sustainable energy conversion systems.

Cloning and characterization of a novel Nitric oxide synthase gene from Exiguobacterium profundum and its expression in Escherichia coli.

The recognition and characterization of gene-encoded nitric oxide synthase (NOS) from Exiguobacterium profundum are reported in this study. A new gene was sequenced and cloned from E. profundum and heterologously expressed in E. coli for functional identification, followed by protein purification using the His-tag. The stability and activity characteristics of the recombinant NOS were evaluated using different concentrations of IPTG at various time points. A band of approximately 42 kDa was observed by SDS-PAGE. The Km value of NOS, calculated based on the Michaelis-Menten equation, was 0.59 µmol/L. Additionally, homologous sequence alignment analysis indicated that the new NOS shared 80.48% similarity with the same protein from Bacillus subtilis and Umezawaea. The construction of the NOS expression vector and the purification of the recombinant protein provide a foundation for further functional research and inhibitor development.

Development and characterisation of [18F]TTDP, a novel T cell immunoglobulin and ITIM domain tracer, in humanised mice and non-human primates.

PURPOSE: The T cell immunoglobulin and ITIM domain (TIGIT) blockade immunotherapy response is directly associated with individual differences of TIGIT expression on tumour-infiltrating lymphocytes (TILs) in tumour immune microenvironment (TIME) of non-small cell lung cancer (NSCLC). Here, we developed a TIGIT-targeted PET tracer to evaluate its feasibility in predicting immunotherapy efficacy, aiming to manage NSCLC patients accurately. METHODS: We synthesised a 18F-labeled TIGIT-targeted D-peptide, [18F]TTDP, and investigated the specificity of [18F]TTDP both to murine TIGIT and human TIGIT by a series of in vitro and in vivo assays. [18F]TTDP PET imaging was performed in humanised immune system (HIS) mice models bearing NSCLC patient-derived xenografts (PDXs) to evaluate the predictive value of FDA-approved combination immunotherapy of atezolizumab plus tiragolumab. Lastly, rhesus macaque was applied for [18F] TTDP PET to explore the tracer's in vivo distribution and translational potential in non-human primates. RESULTS: [18F]TTDP showed high specificity for both murine TIGIT and human TIGIT in vitro and in vivo. The HIS NSCLC PDX platform was successfully established for [18F]TTDP PET imaging, and tumour uptake of [18F]TTDP was significantly correlated with the TIGIT expression of TILs in the TIME. [18F]TTDP PET imaging, in predicting treatment response to the combination immunotherapy in NSCLC HIS-PDX models, showed a sensitivity of 83.33% and a specificity of 100%. In addition, [18F]TTDP PET also showed cross-species consistency of the tracer biodistribution between non-human primate and murine animals, and no adverse events were observed. CONCLUSION: The combined implementation of the [18F]TTDP and HIS-PDX model creates a state-of-the-art preclinical platform that will impact the identification and validation of TIGIT-targeted PET image-guided diagnosis, treatment response prediction, beneficial patient screening, novel immunotherapies, and ultimately the outcome of NSCLC patients. We first provided in vivo biodistribution of [18F]TTDP PET imaging in rhesus macaque, indicating its excellent translational potential in the clinic.

A novel electrocatalyst from TOCN/CGG hydrogel-supported Fe-rich sludge and its performance in treating azo dyes-contaminated water.

Monolithic electrocatalysts are desired for the electro-Fenton oxidation system. We used a hydrogel consisting of TEMPO-oxidized cellulose nanofibers (TOCN) and cationic guar gum (CGG) to disperse and support Fe-rich sludge and finally obtained a Fe-doped biochar (denoted as C-Sludge@TOCN/CGG) after the freeze-drying and carbonization. This C-Sludge@TOCN/CGG exhibited a porous structure with evenly-distributed Fe due to the inherently three-dimensional porous structure of TOCN/CGG hydrogel and the abundant carbon content. Importantly, Fe and FeO existed in C-Sludge@TOCN/CGG due to the presence of TOCN and CGG during the pyrolysis. The electrochemical properties of C-Sludge@TOCN/CGG demonstrated its good electrocatalytic activity and stability with few side reactions. It had good performance in the electrocatalytic degradation of various azo dyes, attributed to the synergistic integration of TOCN/CGG-derived carbon matrix and carbonized Fe-rich sludge particles. Specifically, two transient radicals (i.e. ·OH and ·O2-) primarily improved the electrocatalytic degradation performance of C-Sludge@TOCN/CGG. This C-Sludge@TOCN/CGG also efficiently degraded a papermill-sourced wastewater containing direct red 23, direct yellow 11, direct black 19 and toner, in which the COD value decreased from 365.12 to 179.13 mg/L within 9 h. This work provides an example of utilizing renewable materials and solid waste to design electrocatalysts to address the wastewater issue.

A multi-task deep learning approach for real-time view classification and quality assessment of echocardiographic images.

High-quality standard views in two-dimensional echocardiography are essential for accurate cardiovascular disease diagnosis and treatment decisions. However, the quality of echocardiographic images is highly dependent on the practitioner's experience. Ensuring timely quality control of echocardiographic images in the clinical setting remains a significant challenge. In this study, we aimed to propose new quality assessment criteria and develop a multi-task deep learning model for real-time multi-view classification and image quality assessment (six standard views and "others"). A total of 170,311 echocardiographic images collected between 2015 and 2022 were utilized to develop and evaluate the model. On the test set, the model achieved an overall classification accuracy of 97.8% (95%CI 97.7-98.0) and a mean absolute error of 6.54 (95%CI 6.43-6.66). A single-frame inference time of 2.8 ms was achieved, meeting real-time requirements. We also analyzed pre-stored images from three distinct groups of echocardiographers (junior, senior, and expert) to evaluate the clinical feasibility of the model. Our multi-task model can provide objective, reproducible, and clinically significant view quality assessment results for echocardiographic images, potentially optimizing the clinical image acquisition process and improving AI-assisted diagnosis accuracy.

Loss-of-function mutation in anthocyanidin reductase activates the anthocyanin synthesis pathway in strawberry.

Fruit color substantially affects consumer preferences, with darker red strawberries being economically more valuable due to their higher anthocyanin content. However, the molecular basis for the dark red coloration remains unclear. Through screening of an ethyl methanesulfonate mutant library, we identified a rg418 mutant, that demonstrated anthocyanin accumulation during early fruit development stages. Furthermore, the ripening fruits of this mutant had higher anthocyanin content than wild-type (WT) fruits. An analysis of flavonoid content in WT and rg418 mutant fruits revealed substantial changes in metabolic fluxes, with the mutant exhibiting increased levels of anthocyanins and flavonols and decreased levels of proanthocyanidins. Bulked sergeant analysis sequencing indicated that the mutant gene was anthocyanidin reductase (ANR), a key gene in the proanthocyanidin synthesis pathway. Furthermore, transcriptome sequencing revealed the increased expression of MYB105 during the early development stage of mutant fruits, which promoted the expression of UFGT (UDP-glucose flavonoid 3-O-glucosyltransferase), a key gene involved in anthocyanin synthesis, thus substantially enhancing the anthocyanin content in the mutant fruits. Additionally, mutating ANR in a white-fruited strawberry variant (myb10 mutant) resulted in appealing pink-colored fruits, suggesting the diverse roles of ANR in fruit color regulation. Our study provides valuable theoretical insights for improving strawberry fruit color.

The Biological Characteristics of Mycobacterium Phage Henu3 and the Fitness Cost Associated with Its Resistant Strains.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is an infectious disease that seriously affects human life and health. Despite centuries of efforts to control it, in recent years, the emergence of multidrug-resistant bacterial pathogens of M. tuberculosis due to various factors has exacerbated the disease, posing a serious threat to global health. Therefore, a new method to control M. tuberculosis is urgently needed. Phages, viruses that specifically infect bacteria, have emerged as potential biocontrol agents for bacterial pathogens due to their host specificity. In this study, a mycobacterium phage, Henu3, was isolated from soil around a hospital. The particle morphology, biological characteristics, genomics and phylogeny of Henu3 were characterized. Additionally, to explore the balance between phage resistance and stress response, phage Henu3-resistant strains 0G10 and 2E1 were screened by sequence passage and bidirectional validation methods, which significantly improved the sensitivity of phage to antibiotics (cefotaxime and kanamycin). By whole-genome re-sequencing of strains 0G10 and 2E1, 12 genes involved in cell-wall synthesis, transporter-encoded genes, two-component regulatory proteins and transcriptional regulatory factor-encoded genes were found to have mutations. These results suggest that phage Henu3 has the potential to control M. tuberculosis pathogens, and phage Henu3 has the potential to be a new potential solution for the treatment of M. tuberculosis infection.

Adipose-derived stem cell transplantation enhances spinal cord regeneration by upregulating PGRN expression.

This study aims to investigate the effect of adipose-derived stem cells (ADSCs) transplantation on progranulin (PGRN) expression and functional recovery in rats with spinal cord injury (SCI). ADSCs were isolated from the inguinal adipose tissue of rats. A SCI model was created, and ADSCs were injected into the injured area. Various techniques were used to assess the effects of ADSCs transplantation, including hematoxylin-eosin staining, Masson staining, immunofluorescence staining, electron microscopy, MRI, and motor function assessment. The potential mechanisms of ADSC transplantation were investigated using gene expression analysis and protein analysis. Finally, the safety of this therapy was evaluated through hematoxylin-eosin staining and indicators of liver and kidney damage in serum. PGRN expression increased in the injured spinal cord, and ADSCs transplantation further enhanced PGRN levels. The group that received ADSCs transplantation showed reduced inflammation, decreased scar formation, increased nerve regeneration, and faster recovery of bladder function. Importantly, motor function significantly improved in the ADSC transplantation group. ADSCs transplantation enhances functional regeneration in SCI by upregulating PGRN expression, reducing inflammation and scar formation, and promoting nerve regeneration and myelin repair. These findings suggest that ADSC transplantation is a potential therapy for SCI.

Ultralow-resistance and self-sterilization biodegradable nanofibrous membranes for efficient PM0.3 removal and machine learning-assisted health management.

The development of multifunctional nanofibrous membranes (NFMs) that enable anti-viral protection during air purification and respiratory disease diagnosis for health management is of increasing importance. Herein, we unraveled a heterostructure-enhanced electro-induced stereocomplexation (HEIS) strategy to fabrication of poly(lactic acid) (PLA) NFMs enabling a combination of efficient PM removal, respiratory monitoring and self-sterilization. The strategy involved an electro-induced stereocomplexation (EIS) approach to trigger the generation of hydrogen bonds between enantiomeric poly(L-lactic acid) (PLLA) and poly(D-lactic acid) (PDLA) chains, promoting CO dipole alignment and molecular polarization during electrospinning. This was further enhanced by incorporation of Ag-doped TiO2 (Ag-TIO) nanodielectrics to promote the electroactivity and surface activity, conferring profound refinement of PLA nanofibers (from 460 nm to an ultralow level of 168 nm) and high porosities of over 91 %. Arising from the sustainable generation of plentiful charges based on triboelectric nanogenerator (TENG) mechanisms, the electroactive PLA NFMs exhibited remarkable triboelectric properties even in high-humidity environments (80 %RH), excellent PM0.3 filtration efficiency with an ultralow pressure drop (93.1 %, 31.8 Pa, 32 L/min), and 100 % antimicrobial efficiency against both E. coli and S. aureus. Moreover, a deep-learning algorithm based on convolutional neural network (CNN) was proposed to recognize various respiratory patterns. The proposed strategy confers the biodegradable NFMs an unusual combination of ultralow-resistance air purification and machine learning-assisted health management, signifying promising prospects in environmental protection and personal healthcare.

Efficient low-strength diclofenac elimination via adsorption-concentration and peroxydisulfate activation mineralization by distinct pretreated biocarbon composites.

Sodium diclofenac (DCF) widely exists in actual water matrices, which can negatively impact ecosystems and aquatic environments even at low-strength. Herein, the adsorption-concentration-mineralization process was innovatively constructed for low-strength DCF elimination by freeze-dried biocarbon and oven-dried biocarbon coupled with cobalt oxide composites derived from the same waste biomass. Surprisingly, low-strength DCF of 0.5 mg/L was adsorbed rapidly and enriched to high-strength DCF under light with a concentration efficiency of 99.67 % by freeze-dried biocarbon. Subsequently, the concentrated DCF was economically mineralized by bifunctional oven-dried biocarbon coupled with cobalt oxide composites for peroxydisulfate (PDS) activation with full PDS activation and 76.11 % mineralization efficiency. Compared with direct low-strength DCF oxidation, adsorption-concentration-mineralization consumed less energy and none PDS residues. Mechanisms confirmed that DCF was adsorbed by freeze-dried biocarbon through hydrogen bonds and π-π stacking interactions, which were switched on due to electron-induced effect by light in DCF desorption-concentration. Furthermore, nonradical pathway (electron transfer) and radical pathway (SO4•-) were involved in efficient PDS activation by oven-dried biocarbon coupled with cobalt oxide composites for concentrated DCF mineralization, and the former was more prominent, in which graphitic carbon, cobalt redox cycle and carboxy groups were the main active sites. Overall, an energy-efficient strategy was proposed for elimination of low-strength DCF in real water matrices.

N-Difluoroacetylhexosamine as a Substrate-Engineering Precursor for Glycosylation Reactions.

We present the application of N-difluoroacetylglucosamine (GlcNDFA) in a chemical evolution strategy to synthesize oligosaccharides. In comparison to conventional N-trifluoroacetylglucosamine, GlcNDFA exhibits superior substrate compatibility with glycosyltransferases as well as stability in aqueous environments. Using our 16-step assembly line, GlcNDFA can be used to produce homogeneous dekaparin, a heparin-like medication, with a yield of 62.2%. This underscores the significant potential of GlcNDFA as a chemical evolution precursor in the precise synthesis of structurally defined polysaccharides.

A multifunctional DNA tetrahedron for imaging, gene therapy, and chemotherapy-phototherapy combination: Binding affinity and anticancer activity.

Imaging, silencing cancer-related microRNA, and chemotherapy-phototherapy (CTPT) combination therapy are crucial for cancer diagnosis and drug resistance overcoming. In this study, we designed a multifunctional DNA tetrahedron (MB-MUC1-TD) for the targeted delivery of combined daunorubicin (DAU) + toluidine blue O (TBO). The detection limit of miRNA-21 was determined to be 0.91 nM. The intercalation of DAU and TBO into MB-MUC1-TD was proved by spectroscopic and calorimetric methods. The thermodynamic parameters for the interactions of DAU and/or TBO with MB-MUC1-TD confirmed high drug loading. The first addition of TBO in the ternary system achieved a higher loading of both drugs and a more stable complex structure. Deoxyribonuclease I (DNase I) accelerated the release of DAU and/or TBO loaded in MB-MUC1-TD. Confocal laser scanning microscope demonstrated that MB-MUC1-TD exhibited good imaging ability for miRNA-21 to accurately identify cancer cells, and DAU/TBO was predominantly distributed within the nucleus of cancer cells. In vitro cytotoxicity showed better gene therapy efficacy of MB on MCF-7 cells, better biocompatibility of loaded DAU and TBO on LO2 cells, and stronger synergistic cytotoxicity of DAU + TBO on MCF-7/ADR cells. This study may establish a theoretical foundation for co-loading CTPT combination drugs based on multifunctional DNA nanostructures.

Global research trends in transcranial magnetic stimulation for stroke (1994-2023): promising, yet requiring further practice.

Background: Scholars have been committed to investigating stroke rehabilitation strategies over many years. Since its invention, transcranial magnetic stimulation (TMS) has been increasingly employed in contemporary stroke rehabilitation research. Evidence has shown the significant potential of TMS in stroke research and treatment. Objective: This article reviews the research conducted on the use of TMS in stroke from 1994 to 2023. This study applied bibliometric analysis to delineate the current research landscape and to anticipate future research hotspots. Method: The study utilized the Web of Science Core Collection to retrieve and acquire literature data. Various software tools, including VOSviewer (version 1.6.19), CiteSpace (version 6.3.R1), Scimago Graphica (version 1.0.36), and WPS (version 11572), were used for data analysis and visualization. The review included analyses of countries, institutions, authors, journals, articles, and keywords. Results: A total of 3,425 articles were collected. The top three countries in terms of publication output were the United States (953 articles), China (546 articles), and Germany (424 articles). The United States also had the highest citation counts (56,764 citations), followed by Germany (35,211 citations) and the United Kingdom (32,383 citations). The top three institutions based on the number of publications were Harvard University with 138 articles, the University of Auckland with 81 articles, and University College London with 80 articles. The most prolific authors were Abo, Masahiro with 54 articles, Fregni, Felipe with 53 articles, and Pascual-Leone, Alvaro with 50 articles. The top three journals in terms of article count were Neurorehabilitation and Neural Repair with 139 articles, Clinical Neurophysiology with 128 articles, and Frontiers in Neurology with 110 articles. The most frequently occurring keywords were stroke (1,275 occurrences), transcranial magnetic stimulation (1,119 occurrences), and rehabilitation (420 occurrences). Conclusion: The application of TMS in stroke research is rapidly gaining momentum, with the USA leading in publications. Prominent institutions, such as Harvard University and University College London, show potential for collaborative research. The key areas of focus include post-stroke cognitive impairment, aphasia, and dysphagia, which are expected to remain significant hotspots in future research. Future research should involve large-scale, randomized, and controlled trials in these fields. Additionally, identifying more effective combined therapies with rTMS should be a priority.

3D printed biopolymer/black phosphorus nanoscaffolds for bone implants: A review.

Bone implantation is one of the recognized and effective means of treating bone defects, but osteoporosis and bone tumor-related bone abnormalities have a series of problems such as susceptibility to infection, difficulty in healing, and poor therapeutic effect, which poses a great challenge to clinical medicine. Three-dimensional things may be printed using 3D printing. Researchers can feed materials through the printer layer by layer to create the desired shape for a 3D structure. It is widely employed in the healing of bone defects, and it is an improved form of additive manufacturing technology with prospective future applications. This review's objective is to provide an overview of the findings reports pertaining to 3D printing biopolymers in recent years, provide an overview of biopolymer materials and their composites with black phosphorus for 3D printing bone implants, and the characterization methods of composite materials are also summarized. In addition, summarizes 3D printing methods based on ink printing and laser printing, pointing out their special features and advantages, and provide a combination strategy of photothermal therapy and bone regeneration materials for black phosphorus-based materials. Finally, the associations between bone implant materials and immune cells, the bio-environment, as well as the 3D printing bone implants prospects are outlined.

Intrathecal administration of MCRT produced potent antinociception in chronic inflammatory pain models via µ-δ heterodimer with limited side effects.

An important goal in the opioid field is to discover effective analgesic drugs with minimal side effects. MCRT demonstrated potent antinociceptive effects with limited side effects, making it a promising candidate. However, its pharmacological properties and how it minimizes side effects remain unknown. Various mouse pain and opioid side effect models were used to evaluate the antinociceptive properties and safety at the spinal level. The targets of MCRT were identified through cAMP measurement, isolated tissue assays, and pharmacological experiments. Immunofluorescence was employed to visualize protein expression. MCRT displayed distinct antinociceptive effects between acute and chronic inflammatory pain models due to its multifunctional properties at the µ opioid receptor (MOR), µ-δ heterodimer (MDOR), and neuropeptide FF receptor 2 (NPFFR2). Activation of NPFFR2 reduced MOR-mediated antinociception, leading to bell-shaped response curves in acute pain models. However, activation of MDOR produced more effective antinociception in chronic inflammatory pain models. MCRT showed limited tolerance and opioid-induced hyperalgesia in both acute and chronic pain models and did not develop cross-tolerance to morphine. Additionally, MCRT did not exhibit addictive properties, gastrointestinal inhibition, and effects on motor coordination. Mechanistically, peripheral chronic inflammation or repeated administration of morphine and MCRT induced an increase in MDOR in the spinal cord. Chronic administration of MCRT had no apparent effect on microglial activation in the spinal cord. These findings suggest that MCRT is a versatile compound that provides potent antinociception with minimal opioid-related side effects. MDOR could be a promising target for managing chronic inflammatory pain and addressing the opioid crisis.