Injectable hydrogels activated with copper sulfide nanoparticles for enhancing spatiotemporal sterilization and osteogenesis in periodontal therapy.

Developing biomaterials capable of promoting bone regeneration in bacteria-infected sites is of utmost urgency for periodontal disease therapies. Here we produce a hybrid hydrogel by integrating CuS nanoparticles (CuSNPs), which could kill bacteria through photothermal therapy (PTT) triggered by a near infrared (NIR) light, and a gelatin methacryloyl (GelMA) hydrogel, which is injectable and biocompatible. Specifically, CuSNPs were precipitated by chitosan (CS) firstly, then grafted with methacrylic anhydride (MA) to form CuSNP@CS-MA, which was photo-crosslinked with GelMA to synthesize hybrid hydrogels (GelMA/CuSNP). The hybrid hydrogels exhibited a broad-spectrum antibacterial property that could be spatiotemprorally manipulated through applying a NIR light. Their mechanical properties were adjustable by controlling the concentration of CuSNPs, enabling the hydrogels to become more adapted to the oral diseases. Meanwhile, the hybrid hydrogels showed good cytocompatibility in vitro and improved hemostasis in vivo. Moreover, they accelerated alveolar osteogenesis and vascular genesis, successfully treating periodontis in four weeks in a rat model. GelMA/CuSNP hydrogels showed a broad-spectrum sterilization ability via PTT in vitro and outstanding antibacterial property in vivo, suggesting that the hybrid hydrogels could function in the challenging, bacteria-rich, oral environment. Such injectable hybrid hydrogels, capable of achieving both facilitated osteogenesis and NIR-inducible sterilization, represent a new biomaterial for treating periodontitis.

An antifouling electrochemical biosensor using self-signal for Salmonella typhimurium direct detection in food sample.

Eating food contaminated by foodborne pathogens can lead to illness. The development of electrochemical sensors for pathogen detection has received widespread attention. However, the analytical performance of electrochemical sensors is inevitably affected by the non-specific adsorption of molecules in the sample. Moreover, the external signal probes might be affected by the complex components in the sample accompanied with signal suppression. This work presents an electrochemical aptasensor for Salmonella typhimurium detection based on the self-signal of poly-xanthurenic acid and the antifouling ability of chondroitin sulfate. The detection time was 60 min. The linear range was from 101 to 107 CFU/mL, and the detection limit was 3 CFU/mL. The biosensors presented good repeatability and storage stability. And the biosensors has been successfully applied in milk and orange juice. This strategy is expected to be applied in the design of other antifouling biosensors, to achieve rapid detection of pathogens and ensure food safety.

Comprehensive genomic characterization and expression analysis of calreticulin gene family in tomato.

Calreticulin (CRT) is a calcium-binding endoplasmic reticulum (ER) protein that has been identified for multiple cellular processes, including protein folding, regulation of gene expression, calcium (Ca2+) storage and signaling, regeneration, and stress responses. However, the lack of information about this protein family in tomato species highlights the importance of functional characterization. In the current study, 21 CRTs were identified in four tomato species using the most recent genomic data and performed comprehensive bioinformatics and SlCRT expression in various tissues and treatments. In the bioinformatics analysis, we described the physiochemical properties, phylogeny, subcellular positions, chromosomal location, promoter analysis, gene structure, motif distribution, protein structure and protein interaction. The phylogenetic analysis classified the CRTs into three groups, consensus with the gene architecture and conserved motif analyses. Protein structure analysis revealed that the calreticulin domain is highly conserved among different tomato species and phylogenetic groups. The cis-acting elements and protein interaction analysis indicate that CRTs are involved in various developmental and stress response mechanisms. The cultivated and wild tomato species exhibited similar gene mapping on chromosomes, and synteny analysis proposed that segmental duplication plays an important role in the evolution of the CRTs family with negative selection pressure. RNA-seq data analysis showed that SlCRTs were differentially expressed in different tissues, signifying the role of calreticulin genes in tomato growth and development. qRT-PCR expression profiling showed that all SlCRTs except SlCRT5 were upregulated under PEG (polyethylene glycol) induced drought stress and abscisic acid (ABA) treatment and SlCRT2 and SlCRT3 were upregulated under salt stress. Overall, the results of the study provide information for further investigation of the functional characterization of the CRT genes in tomato.

RNA sequencing analysis reveals PgbHLH28 as the key regulator in response to methyl jasmonate-induced saponin accumulation in Platycodon grandiflorus.

Platycodon grandiflorus (Jacq.) A. DC, known for its saponin content, can potentially prevent and treat cerebrovascular diseases and COVID-19. Triterpenoid saponin biosynthesis in plants is enhanced by methyl jasmonate (MeJA) application. However, the underlying molecular mechanisms of MeJA-induced saponin biosynthesis remain unknown in P. grandiflorus. In the current study, exogenous application of 100 µmol/l MeJA was identified to be optimal for promoting saponin accumulation. RNA sequencing analysis demonstrated the PgbHLH28 gene as a key regulatory factor responding to MeJA during saponin accumulation. Overexpression of PgbHLH28 in P. grandiflorus increased saponin content, while silencing of PgbHLH28 significantly inhibited saponin synthesis, suggesting that PgbHLH28 acts as a positive regulator of saponin biosynthesis. Yeast one-hybrid and dual luciferase assays demonstrated that PgbHLH28 directly bound to the promoters of PgHMGR2 and PgDXS2 to activate gene expression. PgHMGR2 and PgDXS2 transformation promoted saponin accumulation, while silencing of these genes inhibited saponin biosynthesis. This study determined that MeJA promoted saponin accumulation in P. grandiflorus by inducing PgbHLH28 gene expression and activating downstream genes (PgHMGR2 and PgDXS2) involved in saponin biosynthesis. In conclusion, a complex regulatory network governing saponin biosynthesis following MeJA treatment was elucidated, offering a theoretical foundation for enhancing saponin content and biosynthesis efficacy in P. grandiflorus.

Lactobacillus plantarum GUANKE modulate anti-viral function of dendritic cells in mice.

GUANKE is a Lactobacillus plantarum isolated from the feces of healthy volunteer. We have previously shown that GUANKE enhances the efficacy of the SARS-CoV-2 vaccine and prolongs the duration of vaccine protection by upregulating the IFN pathway and T and B lymphocyte functions of the host. The purpose of this study was to evaluate the protective effects and mechanism of oral administration of Lactobacillus plantarum GUANKE in the influenza (A virus A/Puerto Rico/8/34) infection mouse model. In our experiment, oral administration of GUANKE significantly decreased viral load and increased tight junction proteins expression in lung tissues of influenza-infected mice. After GUANKE was co-cultured with mBMDCs in vitro, mBMDCs' maturity and antiviral ability were enhanced, and matured mBMDCs induced polarization of naïve CD4+ T cells into T helper (Th) 1 cells. Adoptive transfer of GUANKE-treated mBMDCs could protect mice from influenza infections. This study suggests that oral administration of Lactobacillus plantarum GUANKE could provide protection against influenza infection in mice, and this protective effect may be mediated, at least in part, by dendritic cells.

Selenium-catalyzed allylic C-H phosphoramidation of alkenes.

We report herein a synthesis of allylic phosphoramidates from alkenes by selenium-catalyzed allylic C-H derivatization. This method features mild conditions, broad substrate scope, and high functional group tolerance, enabling late-stage modification of a number of complex substrates. In addition, this protocol was applied to modify caryophyllene and produced a photoaffinity probe capable of proteomic target labeling in live HeLa cells.

Insights into the potential dual-antibacterial mechanism of Kelisha capsule on Escherichia coli.

Traditional Chinese medicine (TCM), AYURVEDA and Indian medicine are essential in disease prevention and treatment. Kelisha capsule (KLSC), a TCM formula listed in the Chinese Pharmacopoeia, has been clinically proven to possess potent antibacterial properties. However, the precise antimicrobial mechanism of KLSC remained unknown. This study aimed to elucidate the dual antibacterial mechanism of KLSC using network pharmacology, molecular docking, and experimental validation. By analyzing the growth curve of Escherichia coli (E. coli), it was observed that KLSC significantly inhibited its growth, showcasing a remarkable antibacterial effect. Furthermore, SEM and TEM analysis revealed that KLSC damaged the cell wall and membrane of E. coli, resulting in cytoplasmic leakage, bacterial death, and the exertion of antibacterial effects. The network pharmacology analysis revealed that KLSC exhibited an effect on E. coli ATP synthase, thereby influencing the energy metabolism process. The molecular docking outcomes provided evidence that the active compounds of KLSC could effectively bind to the ATP synthase subunit. Subsequently, experimental findings substantiated that KLSC effectively suppressed the activity of ATP synthase in E. coli and consequently decreased the ATP content. This study highlighted the dual antibacterial mechanism of KLSC, emphasizing its effects on cell structure and energy metabolism, suggesting its potential as a natural antibacterial agent for E. coli-related infections. These findings offered new insights into exploring the antibacterial mechanisms of TCM by focusing on the energy metabolism process.

Multimodal ChatGPT-4V for ECG Interpretation: Promise and Limitations.

UNSTRUCTURED: Electrocardiogram (ECG) interpretation is an essential skill in cardiovascular medicine. This study evaluated the capabilities of newly released ChatGPT-4V, a large language model with visual recognition abilities, in interpreting ECG waveforms and answering related multiple-choice questions. A total of 62 ECG-related multiple-choice questions were collected from reputable medical exams. ChatGPT was prompted to answer the questions by analyzing the accompanying ECG images. Requiring at least 1 of 3 responses to be correct, ChatGPT achieved an overall accuracy of 83.87% across all question types. ChatGPT demonstrated significantly lower performance on counting-based questions like calculating QT intervals compared to diagnostic and treatment recommendation questions. The findings indicate that while ChatGPT shows promising potential in ECG interpretation and decision-making, its diagnostic reliability and quantitative analysis abilities need improvement before real clinical use. Further large-scale studies are warranted to fully evaluate ChatGPT's capabilities and track its progress as the model accumulates more medical knowledge through ongoing training. With technological advancements, multimodal AI like ChatGPT may one day play an important role in assisting clinicians with ECG interpretation and cardiovascular care.

Common and distinct risk profiles of asymptomatic extra- and intracranial atherosclerosis in the Nagahama cohort.

BACKGROUND AND PURPOSE: Atherosclerotic burden increases the risk of both extracranial internal carotid artery stenosis (ICS) and intracranial large artery disease (ICAD). However, the differences in risk profiles have not been thoroughly investigated. METHODS: Participants were recruited from the Nagahama study cohort in Japan. Individuals over 60 years old who underwent 1.5-T head and neck magnetic resonance angiography (MRA) between July 2013 and February 2017 were included. ICAD was defined as WASID ≥ 50%, and ICS was defined as NSCET ≥ 30%. The prevalence and association of risk factors, including proatherogenic and proinflammatory factors, and the p.R4810K variant in the RNF213 gene, were investigated. Multivariable logistic regression analyses were performed. RESULTS: A total of 3089 individuals participated in the study, with a mean age of 68.1 ± 5.3 years, and 36.0% were males. Among them, 52 (1.7%) had ICS, 119 (3.8%) had ICAD, and 15 (0.49%) had both conditions. Alopecia areata was an independent predictor for both ICS (Odds ratio [OR] 3.5; 95% CI 1.3-8.3) and ICAD (OR 2.1; 95% CI 1.0-3.9). Diabetes (OR 3.7; 95% CI 2.0-7.0) and older age (OR 2.4; 95% CI 1.2-4.5) were associated only with ICS, while the RNF213 variant was associated with only ICAD (OR 5.7; 95% CI 1.6-16.0). ICS and ICAD were also independently associated with each other. CONCLUSIONS: In this MRA-based large scale study, alopecia areata, known as a systemic inflammatory disease, was shown to be a common risk factor for ICS and ICAD. While conventional atherosclerotic factors were associated with ICS, non-atherosclerotic factors appear to contribute to ICAD in Japan.

Usefulness of risk assessment tools in predicting hemodynamic outcome after balloon pulmonary angioplasty: a comparative analysis.

OBJECTIVES: Several parameters of widely used risk assessment tools for pulmonary arterial hypertension (PAH) have been linked to hemodynamic outcomes of balloon pulmonary angioplasty (BPA). Therefore, we aimed to determine whether these risk assessment tools could be used to predict hemodynamic outcomes following BPA. METHODS: In this retrospective study, we included 139 patients with chronic thromboembolic pulmonary hypertension who had undergone BPA. We compared the accuracies of seven well-validated risk assessment tools for predicting hemodynamic outcomes following BPA. A favorable hemodynamic outcome was defined as a mean pulmonary arterial pressure <30 mmHg at follow-up. RESULTS: The baseline risk profiles varied significantly among the risk assessment tools. The US Registry to Evaluate Early and Long-Term PAH Disease Management risk scales and the French risk assessment tools rated most patients as high-risk, while the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) series and laboratory examination-based risk scales categorized most patients as having intermediate-risk. COMPERA 2.0 (4-strata) exhibited the highest predictive power among all risk stratifications. Noninvasive risk stratification (COMPERA 2.0 [3-strata]) showed a comparable predictive ability to that of invasive risk stratification (COMPERA 1.0) (area under the curve 0.649 vs. 0.648). Moreover, incorporating diffusing capacity of the lungs for carbon monoxide and tricuspid regurgitation velocity into COMPERA 2.0 (4-strata) further enhanced its predictive power (net reclassification index 0.153, 95% confidence interval 0.009-0.298, p = 0.038). Additionally, this refined COMPERA version had a high calibration accuracy (slope 0.96). CONCLUSION: Although the risk strata distribution varied among different risk assessment tools, the proportion of patients achieving favorable hemodynamics decreased with the escalation of risk stratification in most models. The well-validated risk assessment tools for PAH could also predict hemodynamic outcomes following BPA, and the refined COMPERA 2.0 model exhibited the highest predictive ability among these. Applying risk assessment tools before BPA can facilitate early identification of patients in need of closer monitoring and more intensive interventions, contributing to a better prognosis after BPA.

A small-molecule TrkB ligand improves dendritic spine phenotypes and atypical behaviors in female Rett syndrome mice.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, which encodes methyl-CpG-binding protein 2, a transcriptional regulator of many genes, including brain-derived neurotrophic factor (BDNF). BDNF levels are lower in multiple brain regions of Mecp2-deficient mice, and experimentally increasing BDNF levels improve atypical phenotypes in Mecp2 mutant mice. Due to the low blood-brain barrier permeability of BDNF itself, we tested the effects of LM22A-4, a brain-penetrant, small-molecule ligand of the BDNF receptor TrkB (encoded by Ntrk2), on dendritic spine density and form in hippocampal pyramidal neurons and on behavioral phenotypes in female Mecp2 heterozygous (HET) mice. A 4-week systemic treatment of Mecp2 HET mice with LM22A-4 restored spine volume in MeCP2-expressing neurons to wild-type (WT) levels, whereas spine volume in MeCP2-lacking neurons remained comparable to that in neurons from female WT mice. Female Mecp2 HET mice engaged in aggressive behaviors more than WT mice, the levels of which were reduced to WT levels by the 4-week LM22A-4 treatment. These data provide additional support to the potential usefulness of novel therapies not only for RTT but also to other BDNF-related disorders.

Incidence, prevalence, and treatment of Moyamoya disease in Japan: A population-based descriptive study.

BACKGROUND: Moyamoya disease (MMD) is characterized by progressive stenosis or occlusion of the terminal portions of the bilateral internal carotid arteries. A Japanese survey in 2003 reported an incidence and prevalence of MMD of 0.54 and 6.03 per 100,000 people, respectively, showing an upward trend over previous surveys. An update to these estimates is therefore warranted. Additionally, evidence is lacking on trends in revascularization and antiplatelet therapy in MMD patients. METHODS: We conducted a population-based descriptive study using a Japanese claims database. From fiscal year (FY) 2015 to 2019, we standardized the incidence and prevalence estimates of MMD to the 2015 Japanese census population by age and sex. We also estimated the 1-year cumulative incidence of revascularization among incident MMD patients and the proportion of prevalent MMD patients receiving antiplatelet therapy in each FY. RESULTS: The age-standardized male-to-female ratio of both incident and prevalent MMD patients was approximately 1:2. Standardized incidence and prevalence of MMD per 100,000 population increased slightly from 1.8 to 2.4 and 14.7 to 17.6, respectively. The 1-year cumulative incidence of revascularization among incident MMD patients varied between 21.9 % and 28.9 %. Among prevalent MMD patients, 36.6 % to 39.0 % received antiplatelet therapy. CONCLUSIONS: The incidence and prevalence of MMD in Japan from FY 2015 to 2019 were higher than those estimated in 2003. The trends in revascularization and antiplatelet therapy identified in this study will be useful in further improving the quality of MMD clinical practice.

A spatial transcriptome map of the developing maize ear.

A comprehensive understanding of inflorescence development is crucial for crop genetic improvement, as inflorescence meristems give rise to reproductive organs and determine grain yield. However, dissecting inflorescence development at the cellular level has been challenging owing to a lack of specific marker genes to distinguish among cell types, particularly in different types of meristems that are vital for organ formation. In this study, we used spatial enhanced resolution omics-sequencing (Stereo-seq) to construct a precise spatial transcriptome map of the developing maize ear primordium, identifying 12 cell types, including 4 newly defined cell types found mainly in the inflorescence meristem. By extracting the meristem components for detailed clustering, we identified three subtypes of meristem and validated two MADS-box genes that were specifically expressed at the apex of determinate meristems and involved in stem cell determinacy. Furthermore, by integrating single-cell RNA transcriptomes, we identified a series of spatially specific networks and hub genes that may provide new insights into the formation of different tissues. In summary, this study provides a valuable resource for research on cereal inflorescence development, offering new clues for yield improvement.

Effect of heat treatment on the structural and emulsifying properties of copra meal protein: Improving interfacial properties to enhance performance of its Pickering emulsion.

This study investigated the impact of different temperatures and durations on the structural and emulsifying properties of copra meal protein. Additionally, the stability of copra meal protein Pickering emulsions was assessed through rheological and interfacial characteristics. Findings revealed a positive correlation between emulsification properties and heating temperature and duration. Thermal aggregates, facilitated by hydrogen bonds, hydrophobic interactions, and disulfide bonds, significantly enhanced surface hydrophobicity. Heat-treated copra meal protein-based Pickering emulsions demonstrate enhanced adsorption at the oil-water interface and resistance to diffusion. The three-phase contact angle increases from 57.7° to 79.8° following heating at 95 °C for 30 min. The addition of NaCl and heating treatment did not affect emulsion particle size or interface adsorption ability. But it improved the rheological properties to varying degrees. These results offer valuable insights for optimizing the physicochemical and functional attributes of copra meal protein in the food industry.

Rare microbial taxa as the major drivers of nutrient acquisition under moss biocrusts in karst area.

Karst rocky desertification refers to the process of land degradation caused by various factors such as climate change and human activities including deforestation and agriculture on a fragile karst substrate. Nutrient limitation is common in karst areas. Moss crust grows widely in karst areas. The microorganisms associated with bryophytes are vital to maintaining ecological functions, including climate regulation and nutrient circulation. The synergistic effect of moss crusts and microorganisms may hold great potential for restoring degraded karst ecosystems. However, our understanding of the responses of microbial communities, especially abundant and rare taxa, to nutrient limitations and acquisition in the presence of moss crusts is limited. Different moss habitats exhibit varying patterns of nutrient availability, which also affect microbial diversity and composition. Therefore, in this study, we investigated three habitats of mosses: autochthonal bryophytes under forest, lithophytic bryophytes under forest and on cliff rock. We measured soil physicochemical properties and enzymatic activities. We conducted high-throughput sequencing and analysis of soil microorganisms. Our finding revealed that autochthonal moss crusts under forest had higher nutrient availability and a higher proportion of copiotrophic microbial communities compared to lithophytic moss crusts under forest or on cliff rock. However, enzyme activities were lower in autochthonal moss crusts under forest. Additionally, rare taxa exhibited distinct structures in all three habitats. Analysis of co-occurrence network showed that rare taxa had a relatively high proportion in the main modules. Furthermore, we found that both abundant and rare taxa were primarily assembled by stochastic processes. Soil properties significantly affected the community assembly of the rare taxa, indirectly affecting microbial diversity and complexity and finally nutrient acquisition. These findings highlight the importance of rare taxa under moss crusts for nutrient acquisition. Addressing this knowledge gap is essential for guiding ongoing ecological restoration projects in karst rocky desertification regions.

γδ T cell profiling in a cohort of preterm infants reveals elevated frequencies of CD83+ γδ T cells in sepsis.

Preterm infants are at high risk of developing neonatal sepsis. γδ T cells are thought to be an important set of effector cells in neonates. Here, γδ T cells were investigated in a longitudinal cohort of preterm neonates using next-generation sequencing, flow cytometry, and functional assays. During the first year of life, the Vγ9Vδ2 T cell subset showed dynamic phenotypic changes and elevated levels of fetal-derived Vγ9Vδ2 T cells were evident in infants with sepsis. Single-cell transcriptomics identified HLA-DRhiCD83+ γδ T cells in neonatal sepsis, which expressed genes related to antigen presentation. In vitro assays showed that CD83 was expressed on activated Vγ9Vδ2 T cells in preterm and term neonates, but not in adults. In contrast, activation of adult Vγ9Vδ2 T cells enhanced CD86 expression, which was presumably the key receptor to induce CD4 T cell proliferation. Together, we provide a map of the maturation of γδ T cells after preterm birth and highlight their phenotypic diversity in infections.

Magnaporthe oryzae Effector AvrPik-D Targets Rice Rubisco Small Subunit OsRBCS4 to Suppress Immunity.

Rice blast, caused by the fungal pathogen Magnaporthe oryzae (M. oryzae), is a highly destructive disease that significantly impacts rice yield and quality. During the infection, M. oryzae secretes effector proteins to subvert the host immune response. However, the interaction between the effector protein AvrPik-D and its target proteins in rice, and the mechanism by which AvrPik-D exacerbates disease severity to facilitate infection, remains poorly understood. In this study, we found that the M. oryzae effector AvrPik-D interacts with the Rubisco (ribulose-1,5-bisphosphate carboxylase/oxygenase) small subunit OsRBCS4. The overexpression of the OsRBCS4 gene in transgenic rice not only enhances resistance to M. oryzae but also induces more reactive oxygen species following chitin treatment. OsRBCS4 localizes to chloroplasts and co-localizes with AvrPik-D within these organelles. AvrPik-D suppresses the transcriptional expression of OsRBCS4 and inhibits Rubisco activity in rice. In conclusion, our results demonstrate that the M. oryzae effector AvrPik-D targets the Rubisco small subunit OsRBCS4 and inhibits its carboxylase and oxygenase activity, thereby suppressing rice innate immunity to facilitate infection. This provides a novel mechanism for the M. oryzae effector to subvert the host immunity to promote infection.

Development and validation of a predictive model for the risk of sarcopenia in the older adults in China.

BACKGROUND: Sarcopenia is a progressive age-related disease that can cause a range of adverse health outcomes in older adults, and older adults with severe sarcopenia are also at increased short-term mortality risk. The aim of this study was to construct and validate a risk prediction model for sarcopenia in Chinese older adults. METHODS: This study used data from the 2015 China Health and Retirement Longitudinal Study (CHARLS), a high-quality micro-level data representative of households and individuals aged 45 years and older adults in China. The study analyzed 65 indicators, including sociodemographic indicators, health-related indicators, and biochemical indicators. RESULTS: 3454 older adults enrolled in the CHARLS database in 2015 were included in the final analysis. A total of 997 (28.8%) had phenotypes of sarcopenia. Multivariate logistic regression analysis showed that sex, Body Mass Index (BMI), Mean Systolic Blood Pressure (MSBP), Mean Diastolic Blood Pressure (MDBP) and pain were predictive factors for sarcopenia in older adults. These factors were used to construct a nomogram model, which showed good consistency and accuracy. The AUC value of the prediction model in the training set was 0.77 (95% CI = 0.75-0.79); the AUC value in the validation set was 0.76 (95% CI = 0.73-0.79). Hosmer-Lemeshow test values were P = 0.5041 and P = 0.2668 (both P > 0.05). Calibration curves showed significant agreement between the nomogram model and actual observations. ROC and DCA showed that the nomograms had good predictive properties. CONCLUSIONS: The constructed sarcopenia risk prediction model, incorporating factors such as sex, BMI, MSBP, MDBP, and pain, demonstrates promising predictive capabilities. This model offers valuable insights for clinical practitioners, aiding in early screening and targeted interventions for sarcopenia in Chinese older adults.

Association of non-insulin-based insulin resistance indices with disease severity and adverse outcome in idiopathic pulmonary arterial hypertension: a multi-center cohort study.

BACKGROUND: Insulin resistance (IR) plays an important role in the pathophysiology of cardiovascular disease. Recent studies have shown that diabetes mellitus and impaired lipid metabolism are associated with the severity and prognosis of idiopathic pulmonary arterial hypertension (IPAH). However, the relationship between IR and pulmonary hypertension is poorly understood. This study explored the association between four IR indices and IPAH using data from a multicenter cohort. METHODS: A total of 602 consecutive participants with IPAH were included in this study between January 2015 and December 2022. The metabolic score for IR (METS-IR), triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, triglyceride and glucose (TyG) index, and triglyceride-glucose-body mass index (TyG-BMI) were used to quantify IR levels in patients with IPAH. The correlation between non-insulin-based IR indices and long-term adverse outcomes was determined using multivariate Cox regression models and restricted cubic splines. RESULTS: During a mean of 3.6 years' follow-up, 214 participants experienced all-cause death or worsening condition. Compared with in low to intermediate-low risk patients, the TG/HDL-C ratio (2.9 ± 1.7 vs. 3.3 ± 2.1, P = 0.003) and METS-IR (34.5 ± 6.7 vs. 36.4 ± 7.5, P < 0.001) were significantly increased in high to intermediate-high risk patients. IR indices correlated with well-validated variables that reflected the severity of IPAH, such as the cardiac index and stroke volume index. Multivariate Cox regression analyses indicated that the TyG-BMI index (hazard ratio [HR] 1.179, 95% confidence interval [CI] 1.020, 1.363 per 1.0-standard deviation [SD] increment, P = 0.026) and METS-IR (HR 1.169, 95% CI 1.016, 1.345 per 1.0-SD increment, P = 0.030) independently predicted adverse outcomes. Addition of the TG/HDL-C ratio and METS-IR significantly improved the reclassification and discrimination ability beyond the European Society of Cardiology (ESC) risk score. CONCLUSIONS: IR is associated with the severity and long-term prognosis of IPAH. TyG-BMI and METS-IR can independently predict clinical worsening events, while METS-IR also provide incremental predictive performance beyond the ESC risk stratification.

Stem cell exosome-loaded Gelfoam improves locomotor dysfunction and neuropathic pain in a rat model of spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) is a debilitating illness in humans that causes permanent loss of movement or sensation. To treat SCI, exosomes, with their unique benefits, can circumvent limitations through direct stem cell transplantation. Therefore, we utilized Gelfoam encapsulated with exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-EX) in a rat SCI model. METHODS: SCI model was established through hemisection surgery in T9 spinal cord of female Sprague-Dawley rats. Exosome-loaded Gelfoam was implanted into the lesion site. An in vivo uptake assay using labeled exosomes was conducted on day 3 post-implantation. Locomotor functions and gait analyses were assessed using Basso-Beattie-Bresnahan (BBB) locomotor rating scale and DigiGait Imaging System from weeks 1 to 8. Nociceptive responses were evaluated through von Frey filament and noxious radiant heat tests. The therapeutic effects and potential mechanisms were analyzed using Western blotting and immunofluorescence staining at week 8 post-SCI. RESULTS: For the in vivo exosome uptake assay, we observed the uptake of labeled exosomes by NeuN+, Iba1+, GFAP+, and OLIG2+ cells around the injured area. Exosome treatment consistently increased the BBB score from 1 to 8 weeks compared with the Gelfoam-saline and SCI control groups. Additionally, exosome treatment significantly improved gait abnormalities including right-to-left hind paw contact area ratio, stance/stride, stride length, stride frequency, and swing duration, validating motor function recovery. Immunostaining and Western blotting revealed high expression of NF200, MBP, GAP43, synaptophysin, and PSD95 in exosome treatment group, indicating the promotion of nerve regeneration, remyelination, and synapse formation. Interestingly, exosome treatment reduced SCI-induced upregulation of GFAP and CSPG. Furthermore, levels of Bax, p75NTR, Iba1, and iNOS were reduced around the injured area, suggesting anti-inflammatory and anti-apoptotic effects. Moreover, exosome treatment alleviated SCI-induced pain behaviors and reduced pain-associated proteins (BDNF, TRPV1, and Cav3.2). Exosomal miRNA analysis revealed several promising therapeutic miRNAs. The cell culture study also confirmed the neurotrophic effect of HucMSCs-EX. CONCLUSION: Implantation of HucMSCs-EX-encapsulated Gelfoam improves SCI-induced motor dysfunction and neuropathic pain, possibly through its capabilities in nerve regeneration, remyelination, anti-inflammation, and anti-apoptosis. Overall, exosomes could serve as a promising therapeutic alternative for SCI treatment.