Comparative Analysis of the Therapeutic Effects of MSCs From Umbilical Cord, Bone Marrow, and Adipose Tissue and Investigating the Impact of Oxidized RNA on Radiation-Induced Lung Injury.

Radiation-induced lung injury (RILI) is frequently observed in patients undergoing radiotherapy for thoracic malignancies, constituting a significant complication that hampers the effectiveness and utilization of tumor treatments. Ionizing radiation exerts both direct and indirect detrimental effects on cellular macromolecules, including DNA, RNA and proteins, but the impact of oxidized RNA in RILI remains inadequately explored. Mesenchymal stem cells (MSCs) can repair injured tissues, and the reparative potential and molecular mechanism of MSCs in treating RILI remains incompletely understood. This study aimed to investigate the therapeutic effects and mechanisms of action of three distinct sources of MSCs, including human umbilical cord mesenchymal stem cells (UCMSCs), bone marrow mesenchymal stem cells (BMSCs), and adipose-derived stem cells (ADSCs), in thoracically irradiated mice. Comparative analysis revealed that all three types of MSCs exhibited the ability to mitigate radiation-induced inflammatory infiltration, alveolar hemorrhage, and alveolar wall thickening in the lung tissue of the mice. MSCs also attenuated RILI by decreasing inflammatory factors, upregulating anti-inflammatory factor expression, and reducing collagen accumulation. Immunohistochemical results showed that all three MSCs reduced radiation-induced cell apoptosis and promoted the regeneration of lung tissue cells. The analysis of malondialdehyde (MDA) and 8-hydroyguanosine (8-OHG) content indicated that MSCs possess reparative properties against radiation-induced oxidative damage in lung tissue. The study provides evidence that UCMSCs are a more appropriate therapeutic option for RILI compared to BMSCs and ADSCs. Additionally, MSCs effectively reduce the accumulation of oxidized RNA in RILI, thereby, presenting a unique avenue for investigating the underlying mechanism of MSC-based treatment for RILI.

Fabrication of MnO2-Modified Decellularized Tendon Membrane for Enhancing Tendon Repair.

Repairing tendon/ligament injuries is a major challenge in sports medicine. It has been reported that tendon injury healing is hindered by massive production of reactive oxygen species (ROS). Manganese oxides nanoparticles are generally non-toxic, can scavenge ROS, promote tissue regeneration, and hold promise for sustainable nanotechnologies. However, the effective and safe integration of MnO2 nanoparticles on decellularized scaffold mediating tissue repair is still a great challenge. To address these issues, an in situ MnO2-modified decellularized scaffold is developed to enhance tendon regeneration through improving microenvironment. The decellularized fibrous membrane is designed and prepared using the central tendon of the porcine diaphragm. Then MnO2 nanozymes are in situ grown on the collagen fibers using tannic acid (TA) as cross-linking agent and reducing agent. The results showed that MnO2-modified scaffold eliminates excessive accumulation of ROS in cells, protects mitochondrial, and maintains the phenotype of tendon cells in an oxidative stress environment. Notably, it is found that the MnO2-modified scaffold exhibits good biocompatibility and is able to promote the tendon healing in the rat patellar tendon defect model. Altogether, this study confirmed that this nanozyme-functionalized decellularized extracellular matrix effectively enhanced tendon repair by scavenging ROS, which provides new strategies for enhancing tendon regeneration.

HSPD1 Supports Osteosarcoma Progression through Stabilizing ATP5A1 and thus Activation of AKT/mTOR Signaling.

Malignant transformation is concomitant with excessive activation of stress response pathways. Heat shock proteins (HSPs) are stress-inducible proteins that play a role in folding and processing proteins, contributing to the non-oncogene addiction of stressed tumor cells. However, the detailed role of the HSP family in osteosarcoma has not been investigated. Bulk and single-cell transcriptomic data from the GEO and TARGET databases were used to identify HSPs associated with prognosis in osteosarcoma patients. The expression level of HSPD1 was markedly increased in osteosarcoma, correlating with a negative prognosis. Through in vitro and in vivo experiments, we systematically identified HSPD1 as an important contributor to the regulation of proliferation, metastasis, and apoptosis in osteosarcoma by promoting the epithelial-mesenchymal transition (EMT) and activating AKT/mTOR signaling. Subsequently, ATP5A1 was determined as a potential target of HSPD1 using immunoprecipitation followed by mass spectrometry. Mechanistically, HSPD1 may interact with ATP5A1 to reduce the K48-linked ubiquitination and degradation of ATP5A1, which ultimately activates the AKT/mTOR pathway to ensure osteosarcoma progression and EMT process. These findings expand the potential mechanisms by which HSPD1 exerts biological effects and provide strong evidence for its inclusion as a potential therapeutic target in osteosarcoma.

Performance of ChatGPT on Nursing Licensure Examinations in the United States and China: Cross-Sectional Study.

Background: The creation of large language models (LLMs) such as ChatGPT is an important step in the development of artificial intelligence, which shows great potential in medical education due to its powerful language understanding and generative capabilities. The purpose of this study was to quantitatively evaluate and comprehensively analyze ChatGPT's performance in handling questions for the National Nursing Licensure Examination (NNLE) in China and the United States, including the National Council Licensure Examination for Registered Nurses (NCLEX-RN) and the NNLE. Objective: This study aims to examine how well LLMs respond to the NCLEX-RN and the NNLE multiple-choice questions (MCQs) in various language inputs. To evaluate whether LLMs can be used as multilingual learning assistance for nursing, and to assess whether they possess a repository of professional knowledge applicable to clinical nursing practice. Methods: First, we compiled 150 NCLEX-RN Practical MCQs, 240 NNLE Theoretical MCQs, and 240 NNLE Practical MCQs. Then, the translation function of ChatGPT 3.5 was used to translate NCLEX-RN questions from English to Chinese and NNLE questions from Chinese to English. Finally, the original version and the translated version of the MCQs were inputted into ChatGPT 4.0, ChatGPT 3.5, and Google Bard. Different LLMs were compared according to the accuracy rate, and the differences between different language inputs were compared. Results: The accuracy rates of ChatGPT 4.0 for NCLEX-RN practical questions and Chinese-translated NCLEX-RN practical questions were 88.7% (133/150) and 79.3% (119/150), respectively. Despite the statistical significance of the difference (P=.03), the correct rate was generally satisfactory. Around 71.9% (169/235) of NNLE Theoretical MCQs and 69.1% (161/233) of NNLE Practical MCQs were correctly answered by ChatGPT 4.0. The accuracy of ChatGPT 4.0 in processing NNLE Theoretical MCQs and NNLE Practical MCQs translated into English was 71.5% (168/235; P=.92) and 67.8% (158/233; P=.77), respectively, and there was no statistically significant difference between the results of text input in different languages. ChatGPT 3.5 (NCLEX-RN P=.003, NNLE Theoretical P<.001, NNLE Practical P=.12) and Google Bard (NCLEX-RN P<.001, NNLE Theoretical P<.001, NNLE Practical P<.001) had lower accuracy rates for nursing-related MCQs than ChatGPT 4.0 in English input. English accuracy was higher when compared with ChatGPT 3.5's Chinese input, and the difference was statistically significant (NCLEX-RN P=.02, NNLE Practical P=.02). Whether submitted in Chinese or English, the MCQs from the NCLEX-RN and NNLE demonstrated that ChatGPT 4.0 had the highest number of unique correct responses and the lowest number of unique incorrect responses among the 3 LLMs. Conclusions: This study, focusing on 618 nursing MCQs including NCLEX-RN and NNLE exams, found that ChatGPT 4.0 outperformed ChatGPT 3.5 and Google Bard in accuracy. It excelled in processing English and Chinese inputs, underscoring its potential as a valuable tool in nursing education and clinical decision-making.

Hydraulic sinus floor elevation using advanced platelet-rich fibrin: A randomized clinical trial with two-dimensional radiographic results.

PURPOSE: To assess the radiographic outcomes, complications, and implant survival rates of advanced platelet-rich fibrin versus xenografts in hydraulic sinus floor elevation. METHODS: In this randomized trial, 40 patients with 46 implants were divided into two groups: a test group (advanced platelet-rich fibrin alone) and a control group (xenograft alone). The key outcome measures included bone regeneration, implant survival, and complications. RESULTS: Both groups achieved 100% implant survival. One case of maxillary sinus infection occurred in the control group after surgery. There was no significant difference in bone regeneration between the two groups at 6 months post-surgery and 12 months post-load (P > 0.05). The residual bone height and sinus width at the apex of the implant were significant negative predictors of bone regeneration (P < 0.05), whereas the presence of adjacent teeth was a significant positive predictor (P < 0.05). CONCLUSIONS: Both advanced platelet-rich fibrin and xenografts effectively enhanced bone growth at sinus floor elevation, achieving high implant survival rates over one year. Advanced platelet-rich fibrin alone may be a viable xenograft alternative, necessitating further long-term studies to confirm its efficacy. The study was registered in the Chinese Clinical Trial Registry (http://www.chictr.org.cn/) with the registration number ChiCTR2100042060. This clinical trial was not registered before participant recruitment or randomization.

Immunoregulation in Skull Defect Repair with a Smart Hydrogel Loaded with Mesoporous Bioactive Glasses.

Skull defect repair is a complex and critical medical challenge, and there is an urgent need to develop multifunctional tissue engineering scaffolds for skull regeneration. The success of bone tissue engineering depends on the construction of scaffolds that can regulate the immune microenvironment of bone regeneration and mimic the liquid crystal and viscoelastic properties of natural bone extracellular matrix. Hence, a smart hydrogel (PEGDA5/AM15/CLC-BMP-4@MBG) with good biocompatibility and the ability to modulate the wound immune microenvironment has been developed for the repair of skull defects. The hydrogel consists of chitin liquid crystal hydrogel (PEGDA5/AM15/CLC) and mesoporous bioactive glasses (MBGs) loaded with bone morphogenetic protein-4 (BMP-4). The liquid crystal hydrogel not only offers the necessary biological support and mechanical properties but also maintains the stability of the liquid crystal state, facilitating adhesion and regeneration of surrounding bone tissue. In addition, BMP-4@MBG intelligently regulates the release rate of BMP-4 in response to changes in wound microenvironment, thus effectively promoting the transformation of macrophages from M1 to M2 macrophages. At the same time, Ca2+ and Si4+ released by MBG degradation and BMP-4 synergically promote bone repair process. The PEGDA5/AM15/CLC-BMP-4@MBG hydrogel shows excellent immunomodulatory and osteogenic properties of bone microenvironment and is a promising scaffold material for bone tissue engineering.

Preparation and osteogenesis of a multiple crosslinking silk fibroin/carboxymethyl chitosan/sodium alginate composite scaffold loading with mesoporous silica/poly (lactic acid-glycolic acid) microspheres.

Large bone defect repair is a striking challenge in orthopedics. Currently, inorganic-organic composite scaffolds are considered as a promising approach to these bone regeneration. Silicon ions (Si4+) are bioactive and beneficial to bone regeneration and Si4+-containing inorganic mesoporous silica (MS) can effectively load drugs for bone repair. To better control the release of drug, we prepared biodegradable MS/PLGA (MP) microspheres. MP loaded organic silk fibroin/carboxymethyl chitosan/sodium alginate (MP/SF/CMCS/SA) composite scaffolds were further constructed by genipin and Ca2+ crosslinking. All MP/SF/CMCS/SA scaffolds had good swelling ability, degradation rate and high porosity. The incorporation of 1% MP significantly enhanced the compressive strength of composite scaffolds. Besides, MP loaded scaffold showed a sustained release of Si4+ and Ca2+. Moreover, the release rate of rhodamine (a model drug) of MP/SF/CMCS/SA scaffolds was obviously lower than that of MP. When culturing with rat bone marrow mesenchymal stem cells, scaffolds with 1% MP displayed good proliferation, adhesion and enhanced osteogenic differentiation ability. Based on the results above, the addition of 1% MP in SF/CMCS/SA scaffolds is a prospective way for drug release in bone regeneration and is promising for further in vivo bone repair applications.

Single-Cell Transcriptomics Reveals Early Effects of Ionizing Radiation on Bone Marrow Mononuclear Cells in Mice.

Ionizing radiation exposure can cause damage to diverse tissues and organs, with the hematopoietic system being the most sensitive. However, limited information is available regarding the radiosensitivity of various hematopoietic cell populations in the bone marrow due to the high heterogeneity of the hematopoietic system. In this study, we observed that granulocyte-macrophage progenitors, hematopoietic stem/progenitor cells, and B cells within the bone marrow showed the highest sensitivity, exhibiting a rapid decrease in cell numbers following irradiation. Nonetheless, neutrophils, natural killer (NK) cells, T cells, and dendritic cells demonstrated a certain degree of radioresistance, with neutrophils exhibiting the most pronounced resistance. By employing single-cell transcriptome sequencing, we investigated the early responsive genes in various cell types following irradiation, revealing that distinct gene expression profiles emerged between radiosensitive and radioresistant cells. In B cells, radiation exposure led to a specific upregulation of genes associated with mitochondrial respiratory chain complexes, suggesting a connection between these complexes and cell radiosensitivity. In neutrophils, radiation exposure resulted in fewer gene alterations, indicating their potential for distinct mechanisms in radiation resistance. Collectively, this study provides insights into the molecular mechanism for the heterogeneity of radiosensitivity among the various bone marrow hematopoietic cell populations.

Integrating ChatGPT in Orthopedic Education for Medical Undergraduates: Randomized Controlled Trial.

BACKGROUND: ChatGPT is a natural language processing model developed by OpenAI, which can be iteratively updated and optimized to accommodate the changing and complex requirements of human verbal communication. OBJECTIVE: The study aimed to evaluate ChatGPT's accuracy in answering orthopedics-related multiple-choice questions (MCQs) and assess its short-term effects as a learning aid through a randomized controlled trial. In addition, long-term effects on student performance in other subjects were measured using final examination results. METHODS: We first evaluated ChatGPT's accuracy in answering MCQs pertaining to orthopedics across various question formats. Then, 129 undergraduate medical students participated in a randomized controlled study in which the ChatGPT group used ChatGPT as a learning tool, while the control group was prohibited from using artificial intelligence software to support learning. Following a 2-week intervention, the 2 groups' understanding of orthopedics was assessed by an orthopedics test, and variations in the 2 groups' performance in other disciplines were noted through a follow-up at the end of the semester. RESULTS: ChatGPT-4.0 answered 1051 orthopedics-related MCQs with a 70.60% (742/1051) accuracy rate, including 71.8% (237/330) accuracy for A1 MCQs, 73.7% (330/448) accuracy for A2 MCQs, 70.2% (92/131) accuracy for A3/4 MCQs, and 58.5% (83/142) accuracy for case analysis MCQs. As of April 7, 2023, a total of 129 individuals participated in the experiment. However, 19 individuals withdrew from the experiment at various phases; thus, as of July 1, 2023, a total of 110 individuals accomplished the trial and completed all follow-up work. After we intervened in the learning style of the students in the short term, the ChatGPT group answered more questions correctly than the control group (ChatGPT group: mean 141.20, SD 26.68; control group: mean 130.80, SD 25.56; P=.04) in the orthopedics test, particularly on A1 (ChatGPT group: mean 46.57, SD 8.52; control group: mean 42.18, SD 9.43; P=.01), A2 (ChatGPT group: mean 60.59, SD 10.58; control group: mean 56.66, SD 9.91; P=.047), and A3/4 MCQs (ChatGPT group: mean 19.57, SD 5.48; control group: mean 16.46, SD 4.58; P=.002). At the end of the semester, we found that the ChatGPT group performed better on final examinations in surgery (ChatGPT group: mean 76.54, SD 9.79; control group: mean 72.54, SD 8.11; P=.02) and obstetrics and gynecology (ChatGPT group: mean 75.98, SD 8.94; control group: mean 72.54, SD 8.66; P=.04) than the control group. CONCLUSIONS: ChatGPT answers orthopedics-related MCQs accurately, and students using it excel in both short-term and long-term assessments. Our findings strongly support ChatGPT's integration into medical education, enhancing contemporary instructional methods. TRIAL REGISTRATION: Chinese Clinical Trial Registry Chictr2300071774; https://www.chictr.org.cn/hvshowproject.html ?id=225740&v=1.0.

Arthroscopic reduction and hollow screw internal fixation for Eyres Type IIIA scapular coracoid fracture: a case report.

BACKGROUND: A coracoid process fracture combined with an acromioclavicular (AC) joint dislocation is an uncommon injury that typically causes significant pain and limits shoulder movement. Open reduction and internal fixation have been the traditional treatment approach. However, arthroscopic techniques are emerging as a promising alternative for managing these injuries. CASE REPRESENTATION: A 35-year-old woman presented with right shoulder pain following an accidental fall. Imaging studies revealed a coracoid process fracture along with an AC joint dislocation. The fracture was classified as an Eyres Type IIIA, which warranted surgical intervention. Our team performed arthroscopic coracoid fracture reduction and internal fixation surgery, as well as AC joint dislocation repair using Kirschner wires. Six months after surgery, the patient demonstrated a satisfactory functional outcome with complete bone healing. CONCLUSION: This case report highlights the potential of arthroscopic reduction and fixation as a novel treatment option for fractures of the coracoid base.

Identification of UNC5B as a novel aggressive biomarker for osteosarcoma based on basement membrane genes.

BACKGROUND: The prognosis of patients with metastatic osteosarcoma is poor, and the variation of basement membrane genes (BMGs) is associated with cancer metastasis. However, the role of BMGs in osteosarcoma has been poorly studied. METHODS: BMGs were collected and differentially expressed BMGs (DE-BMGs) were found through difference analysis. DE-BMGs were further screened by univariate Cox regression and Lasso regression analyses, and six key BMGs were identified and defined as basement membrane genes signatures (BMGS). Then, BMGS was used to construct the osteosarcoma BMGS risk score system, and the osteosarcoma patients were divided into high- and low-risk groups based on the median risk score. Single-sample gene set enrichment analysis (ssGSEA) and ESTIMATE scores were used to investigate the differences in immune infiltration between the two scoring groups. Additionally, we investigated whether UNC5B affects various features in tumors by bioinformatic analysis and whether UNC5B was involved in multiple biological functions of osteosarcoma cells by wound healing assay, transwell assay, and western blot. RESULTS: The osteosarcoma BMGS risk score reliably predicts the risk of metastasis, patient prognosis, and immunity. UNC5B expression was elevated in osteosarcoma, and correlated with various characteristics such as immune infiltration, prognosis, and drug sensitivity. In vitro assays showed that UNC5B knockdown reduced osteosarcoma cells' capacity for migration and invasion, and EMT process. CONCLUSION: A novel BMGS risk score system that can effectively predict the prognosis of osteosarcoma was developed and validated. The UNC5B gene in this system is one of the key aggressive biomarkers of osteosarcoma.

Treatment and prevention of chronic ankle instability: An umbrella review of meta-analyses.

BACKGROUND: Chronic ankle instability (CAI) is a common and highly disabling condition. Although several studies have evaluated and analyzed prevention and treatment strategies for CAI, an unbiased and systematic synthesis of evidence is required to provide the most powerful and comprehensive evidence-based measures for the its prevention and treatment of CAI. This study aimed to synthesize evidence from the existing literature addressing the treatment and prevention of CAI. METHODS: The PubMed, Embase, Cochrane, and Web of Science databases were systematically searched for relevant studies from inception to December 12, 2023. Data on effect sizes and corresponding 95 % confidence intervals for selected intervention measures were extracted. Systematic reviews were assessed for quality of included studies using a measurement tool (i.e., "AMSTAR 2"). RESULTS: In total, 37 studies were included, among which 21 (57 %) were of high or moderate quality. Strong evidence suggested that lower weight (P < 0.001), lower body mass index (P = 0.002), and non-stability defects (P = 0.04) significantly reduced the risk of developing CAI. Strong evidence supported exercise and moderate evidence supported manual therapy, acupuncture, and surgery for improving CAI. Additionally, external support plays an active role in the treatment process of CAI. CONCLUSION: This is the first study synthesizing evidence supporting interventions for the treatment and prevention of CAI. Low body weight and body mass index were effective preventive measures against CAI. Exercise, manual therapy, acupuncture, and surgery can improve ankle function in patients with CAI. Plantar sensory treatment and neuromuscular training may be good therapeutic options for patients with CAI. LEVEL OF EVIDENCE: Level I.

Investigation of prognostic values of immune infiltration and LGMN expression in the microenvironment of osteosarcoma.

BACKGROUND: Osteosarcoma (OS), the most common primary malignant bone tumor, predominantly affects children and young adults and is characterized by high invasiveness and poor prognosis. Despite therapeutic advancements, the survival rate remains suboptimal, indicating an urgent need for novel biomarkers and therapeutic targets. This study aimed to investigate the prognostic significance of LGMN expression and immune cell infiltration in the tumor microenvironment of OS. METHODS: We performed an integrative bioinformatics analysis utilizing the GEO and TARGET-OS databases to identify differentially expressed genes (DEGs) associated with LGMN in OS. We conducted Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) to explore the biological pathways and functions. Additionally, we constructed protein-protein interaction (PPI) networks, a competing endogenous RNA (ceRNA) network, and applied the CIBERSORT algorithm to quantify immune cell infiltration. The diagnostic and prognostic values of LGMN were evaluated using the area under the receiver operating characteristic (ROC) curve and Cox regression analysis. Furthermore, we employed Consensus Clustering Analysis to explore the heterogeneity within OS samples based on LGMN expression. RESULTS: The analysis revealed significant upregulation of LGMN in OS tissues. DEGs were enriched in immune response and antigen processing pathways, suggesting LGMN's role in immune modulation within the TME. The PPI and ceRNA network analyses provided insights into the regulatory mechanisms involving LGMN. Immune cell infiltration analysis indicated a correlation between high LGMN expression and increased abundance of M2 macrophages, implicating an immunosuppressive role. The diagnostic AUC for LGMN was 0.799, demonstrating its potential as a diagnostic biomarker. High LGMN expression correlated with reduced overall survival (OS) and progression-free survival (PFS). Importantly, Consensus Clustering Analysis identified two distinct subtypes of OS, highlighting the heterogeneity and potential for personalized medicine approaches. CONCLUSIONS: Our study underscores the prognostic value of LGMN in osteosarcoma and its potential as a therapeutic target. The identification of LGMN-associated immune cell subsets and the discovery of distinct OS subtypes through Consensus Clustering Analysis provide new avenues for understanding the immunosuppressive TME of OS and may aid in the development of personalized treatment strategies. Further validation in larger cohorts is warranted to confirm these findings.

Simultaneously Modulating HIF-1α and HIF-2α and Optimizing Macrophage Polarization through the Biomimetic Gene Vector toward the Treatment of Osteoarthritis.

In osteoarthritis (OA), articular cartilage is continuously submerged in a hypoxic environment throughout life, and hypoxia-inducible factors (HIFs) play a crucial role in OA progression. Among the various HIF phenotypes, HIF-1α positively contributes to maintaining the stability of the articular cartilage matrix. In contrast, HIF-2α has a detrimental effect, leading to chondrocyte apoptosis and exacerbating inflammation. Notably, there is currently no simultaneous regulation of HIF-1α and HIF-2α for OA treatment. Thus, the biomimetic gene vector (MENP) was developed for co-delivery of siHIF-2α and Mg2+ to the inflamed regions in OA joints, comprising an inner core consisting of siHIF-2α and Mg2+ and an outer M2 macrophage membrane. In vitro and in vivo studies demonstrate that MENP effectively targets inflamed areas, efficiently silences HIF-2α, and facilitates HIF-1α-mediated cartilage restoration through Mg2+. Furthermore, it indirectly promotes the polarization of macrophages toward an anti-inflammatory M2 phenotype through its action on inflamed synoviocytes. Overall, MENP is an efficient biomimetic vehicle for alleviating inflammation and promoting cartilage repair, representing an appealing approach for OA treatment.

Lycium ruthenicum water extract preserves retinal ganglion cells in chronic ocular hypertension mouse models.

Lycium ruthenicum Murray (LR), known as "black goji berry" or "black wolfberry", is widely utilized in chinese herbal medicine. LR fruit showed its antioxidant and/or anti-inflammation activity in treating cardiac injury, experimental colitis, nonalcoholic fatty liver disease, fatigue, and aging. Glaucoma is the leading cause of irreversible blindness. Besides elevated intraocular pressure (IOP), oxidative stress and neuroinflammation were recognized to contribute to the pathogenesis of glaucoma. This study investigated the treatment effects of LR water extract (LRE) on retinal ganglion cells (RGCs) threatened by sustained IOP elevation in a laser-induced chronic ocular hypertension (COH) mouse model and the DBA/2J mouse strain. The antioxidation and anti-inflammation effects of LRE were further tested in the H2O2-challenged immortalized microglial (IMG) cell line in vitro. LRE oral feeding (2 g/kg) preserved the function of RGCs and promoted their survival in both models mimicking glaucoma. LRE decreased 8-hydroxyguanosine (oxidative stress marker) expression in the retina. LRE reduced the number of Iba-1+ microglia in the retina of COH mice, but not in the DBA/2J mice. At the mRNA level, LRE reversed the COH induced HO-1 and SOD-2 overexpressions in the retina of COH mice. Further in vitro study demonstrated that LRE pretreatment to IMG cells could significantly reduce H2O2 induced oxidative stress through upregulation of GPX-4, Prdx-5, HO-1, and SOD-2. Our work demonstrated that daily oral intake of LRE can be used as a preventative/treatment agent to protect RGCs under high IOP stress probably through reducing oxidative stress and inhibiting microglial activation in the retina.

Promoting neurovascularized bone regeneration with a novel 3D printed inorganic-organic magnesium silicate/PLA composite scaffold.

Critical-size bone defect repair presents multiple challenges, such as osteogenesis, vascularization, and neurogenesis. Current biomaterials for bone repair need more consideration for the above functions. Organic-inorganic composites combined with bioactive ions offer significant advantages in bone regeneration. In our work, we prepared an organic-inorganic composite material by blending polylactic acid (PLA) with 3-aminopropyltriethoxysilane (APTES)-modified magnesium silicate (A-M2S) and fabricated it by 3D printing. With the increase of A-M2S proportion, the hydrophilicity and mineralization ability showed an enhanced trend, and the compressive strength and elastic modulus were increased from 15.29 MPa and 94.61 MPa to 44.30 MPa and 435.77 MPa, respectively. Furthermore, A-M2S/PLA scaffolds not only exhibited good cytocompatibility of bone marrow mesenchymal stem cells (BMSCs), human umbilical vein endothelial cells (HUVECs), and Schwann cells (SCs), but also effectively promoted osteogenesis, angiogenesis, and neurogenesis in vitro. After implanting 10% A-M2S/PLA scaffolds in vivo, the scaffolds showed the most effective repair of cranium defects compared to the blank and control group (PLA). Additionally, they promoted the secretion of proteins related to bone regeneration and neurovascular formation. These results provided the basis for expanding the application of A-M2S and PLA in bone tissue engineering and presented a novel concept for neurovascularized bone repair.

Donor-acceptor type COFs with multiple fluorine groups as electron storage units to promote antimicrobial performance.

The novel donor-acceptor (D-A) type covalent organic frameworks TATF-COF and TATP-COF, with multiple fluorine groups as electron storage units, were successfully constructed to achieve efficient charge transfer and photocatalytic activity for antibacterial photocatalytic therapy. Fluorine, the most electronegative element, was utilized as an electron-withdrawing substituent for the acceptor, which could unite the donor unit together and efficiently improve the charge transfer from the donor to acceptor. The unique D-A structures of TATF-COF and TATP-COF ensure that they have narrow band gaps, strong photocurrent responses, long fluorescence lifetimes, and good capacity to generate reactive oxygen species (ROS) to realize good antibacterial activity. Meanwhile, the inclusion of multiple hydrophilic fluorine groups means that TATF-COF and TATP-COF are highly water dispersible, which is also beneficial in terms of promoting the generation of adequate quantities of ROS. Hence, in view of their excellent photoelectric properties and good water dispersibility, further investigations were performed, and excellent antibacterial activities in vitro against both gram-negative and gram-positive bacteria were demonstrated for TATF-COF and TATP-COF. In addition, we also showed that they can function as effective antibacterial dental materials.

BMA-based Mendelian randomization identifies blood metabolites as causal candidates in pregnancy-induced hypertension.

Pregnancy-induced hypertension (PIH), a prominent determinant of maternal mortality and morbidity worldwide, is hindered by the absence of efficacious biomarkers for early diagnosis, contributing to suboptimal outcomes. Here, we explored potential causal relationships between blood metabolites and the risk of PIH using Mendelian randomization (MR). We employed a two-sample univariable MR approach to empirically estimate the causal relationships between 249 circulating metabolites and PIH. Inverse variance weighted, MR-egger, weight median, simple mode, and weighted mode methods were used for causal estimates. The exposure-to-outcome directionality was confirmed with the MR Steiger test. The Bayesian model averaging MR (MR-BMA) method was applied to detect the predominant causal metabolic traits with alignment for pleiotropy effects. In the primary analysis, analyzing 249 metabolites, we identified 25 causally linked to PIH, including 11 lipid-related traits and 6 associated with fatty acid (un)saturation. Importantly, MR-BMA analyses corroborated the total concentration of branched-chain amino acids(total-BCAA) to be the highest rank causal metabolite, followed by leucine (Leu), phospholipids to total lipids ratio in medium LDL (M-LDL-PL-pct), and Val (all P < 0.05). The directionality of causality predicted by univariable MR and MR-BMA for these metabolites remained consistent. This study highlights the causal connection between metabolites and PIH risk. It highlighted BCAAs as the strongest causal candidates warranting further investigation. Since PIH typically occurs in the second and third trimesters, extending these findings could inform earlier strategies to reduce its risk. Directed acyclic graph of the MR framework investigating the causal relationship between metabolites and PIH. MR: Mendelian randomization; GIVs: genetic instrument variables; SNPs: single-nucleotide polymorphism; IVW: inverse variance weighted; WM: weighted median; PIH: pregnancy-induced hypertension; SM: significant metabolite; MR-BMA: Bayesian model averaging MR.

Toll-like Receptor Agonist CBLB502 Protects Against Radiation-induced Intestinal Injury in Mice.

BACKGROUND/AIM: The small intestine is one of the organs most vulnerable to ionizing radiation (IR) damage. However, methods to protect against IR-induced intestinal injury are limited. CBLB502, a Toll-like receptor 5 (TLR5) agonist from Salmonella flagellin, exerts radioprotective effects on various tissues and organs. However, the molecular mechanisms by which CBLB502 protects against IR-induced intestinal injury remain unclear. Thus, this study aimed to elucidate the mechanisms underlying IR-induced intestinal injury and the protective effects of CBLB502 against this condition in mice. MATERIALS AND METHODS: Mice were administered 0.2 mg/kg CBLB502 before IR at different doses for different time points, and then the survival rate, body weight, hemogram, and histopathology of the mice were analyzed. RESULTS: CBLB502 reduced IR-induced intestinal injury. RNA-seq analysis revealed that different doses and durations of IR induced different regulatory patterns. CBLB502 protected against intestinal injury mainly after IR by reversing the expression of IR-induced genes and regulating immune processes and metabolic pathways. CONCLUSION: This study preliminarily describes the regulatory mechanism of IR-induced intestinal injury and the potential molecular protective mechanism of CBLB502, providing a basis for identifying the functional genes and molecular mechanisms that mediate protection against IR-induced injury.

NAT1 inhibits liver metastasis of colorectal cancer by regulating EMT and glycolysis.

Metastasis is the primary cause of cancer-related deaths, and colorectal cancer (CRC) liver metastasis is a major poor prognostic factor in CRC. NAT1 (N-acetyltransferase 1) plays a crucial role in the invasive and metastatic processes of colorectal cancer. The role and molecular mechanism of NAT1 on tumor cells were verified by establishing a cell model of overexpression and knockdown of NAT1, and further verified by establishing a liver metastasis model of colorectal cancer for animal experiments. In vivo and in vitro experiments have demonstrated that overexpression of NAT1 reduces the ability of metastasis and invasion of colorectal cancer cells. NAT1 overexpression inhibits the PI3K/AKT/mTOR signaling pathway, thereby suppressing the EMT (epithelial-mesenchymal transition) process and glycolytic ability of tumor cells. Additionally, decreased glycolytic ability results in reduced VEGF (Vascular endothelial growth factor) expression in colorectal cancer cells. The decreased VEGF expression leads to decreased angiogenesis and vascular permeability in liver metastases, ultimately reducing the occurrence of liver metastasis. Our findings highlight that overexpression of NAT1 significantly inhibits the PI3K/AKT/mTOR signaling pathway, thereby suppressing EMT, glycolytic ability, and VEGF expression in colorectal cancer cells, collectively preventing the development of liver metastasis.