A Transcriptional Signature of Induced Neurons Differentiates Virologically Suppressed People Living With HIV from People Without HIV.

Neurocognitive impairment is a prevalent and important co-morbidity in virologically suppressed people living with HIV (PLWH), yet the underlying mechanisms remain elusive and treatments lacking. Here, we explored for the first time, use of participant-derived directly induced neurons (iNs) to model neuronal biology and injury in PLWH. iNs retain age-and disease-related features of the donors, providing unique opportunities to reveal novel aspects of neurological disorders. We obtained primary dermal fibroblasts from six virologically suppressed PLWH (range: 27 - 64 years, median: 53); 83% Male; 50% White) and seven matched people without HIV (PWOH) (range: 27 - 66, median: 55); 71% Male; 57% White). iNs were generated using transcription factors NGN2 and ASCL1, and validated by immunocytochemistry and single-cell-RNAseq. Transcriptomic analysis using bulk-RNAseq identified 29 significantly differentially expressed genes between iNs from PLWH and PWOH. Of these, 16 genes were downregulated and 13 upregulated in PLWH iNs. Protein-protein interaction network mapping indicates that iNs from PLWH exhibit differences in extracellular matrix organization and synaptic transmission. IFI27 was upregulated in iNs from PLWH, which complements independent post-mortem studies demonstrating elevated IFI27 expression in PLWH-derived brain tissue, indicating that iN generation reconstitutes this pathway. Finally, we observed that expression of the FOXL2NB-FOXL2-LINC01391 genome locus is reduced in iNs from PLWH and negatively correlates with neurocognitive impairment. Thus, we have identified an iN gene signature of HIV through direct reprogramming of skin fibroblasts into neurons revealing novel mechanisms of neurocognitive impairment in PLWH. One sentence summary: Direct reprogramming of skin fibroblasts into neurons reveals unique gene signatures indicative of HIV infection in the context of viral suppression.

Study on the Mechanism of Nd:YAG Laser-Assisted Therapy on the Changes of Subgingival Flora in Periodontitis.

PURPOSE: This study evaluated the therapeutic efficacy of combining Neodymium-doped Yttrium Aluminum Garnet (Nd:YAG) laser with subgingival curettage and root planing (SRP) in generalised stage III/grade C periodontitis patients and its effects on cytokine dynamics and microbial community. MATERIALS AND METHODS: Fifteen patients diagnosed with stage III/grade C periodontitis were included in the cohort. The right and left sides of the mouth were randomly assigned either the conventional SRP (control) group or the SRP supplemented with Nd:YAG laser group (experimental group, 160 mJ, 4 W) in a split-mouth design. Clinical periodontal indices were recorded at baseline and at the 6-week follow-up post-treatment. ELISA was utilised to measure IL-1ß and TNF-α levels in gingival crevicular fluid. The subgingival microbiota's composition and variations were characterised using 16S rDNA amplicon sequencing, while quantitative real-time polymerase chain reaction (qRT-PCR) was employed to analyse the changes in the red-complex bacteria in subgingival plaque. RESULTS: The SRP+Nd group exhibited a statistically significant reduction in record probing depth (PD) and bleeding on probing (BOP) compared to the SRP group after treatment (p0.05). The SRP+Nd group showed a markedly lower IL-1ß level than the SRP group (p0.05). Furthermore, there was no statistically significant difference in the dominant subgingival microbiota composition and level of the red-complex bacteria between the two groups (p>0.05). CONCLUSION: The adjunctive use of Nd:YAG laser with SRP demonstrates promising short-term therapeutic benefits for patients with extensive stage III/grade C periodontitis. Both SRP as a standalone treatment and its combination with Nd:YAG laser effectively facilitate a transition in the dominant bacterial community from periodontitis-associated to periodontal health-associated microbiota.

Optical Monitoring of Labile Zinc inside Metastatic Cells with Plasmonic Chemonanosensors.

We report the development and characterization of an optical nanosensor for the detection of labile zinc in biological environments. The readout is based on surface-enhanced Raman scattering promoted by a Raman reporter conjugated to the inner plasmonic cavity of hollow silica nanocapsules. We quantify Zn2+ by obtaining the ratio between a Zn2+-sensitive band and a Zn2+-insensitive band. The Raman reporter measures within the range from 10-5 to 10-11 M and exhibits a limit of detection of 10-11.72 M. The nanosensor discriminates between intracellular and extracellular Zn2+ concentrations.

Associations of the HMGB1 rs1412125 and rs2249825 polymorphisms with Kawasaki disease.

BACKGROUND: Kawasaki disease is an acute febrile disease causing systemic vasculitis that is common in infants and young children. This study was conducted to explore the relationships of the rs1412125, and rs2249825 single nucleotide polymorphisms of the high mobility group box 1 gene to Kawasaki disease and its complication of coronary artery injury. METHODS: In total, 200 children with Kawasaki disease (49 with coronary artery injury) and 200 healthy controls were enrolled in this study. Polymerase chain reaction was used to amplify the target gene, and direct sequencing was performed to determine distributions at the rs1412125 T/C and rs2249825 C/G loci in the HMGB1 gene. The chi-squared test was used to compare data between groups. Linkage disequilibrium coefficients and single nucleotide polymorphism haplotype analysis were conducted, and a false-positive report probability analysis was used to assess significant associations. Expression quantitative trait loci analysis was performed to determine if single nucleotide polymorphisms affected mRNA levels via the GTEx portal. RESULTS: Significant differences in the genotype TT, TC, and CC distributions (χ2 = 7.918, P = 0.019) and allele T and C frequencies (χ2 = 6.125, P = 0.013) of rs1412125 T/C locus were found between the Kawasaki disease and healthy control groups. The genotype CC was associated with a greater Kawasaki disease risk [odds ratio = 3.205, 95% confidence interval = 1.352-7.595, χ2 = 7.560, P = 0.006]. C allele carriers had a higher Kawasaki disease risk than did T allele carriers (odds ratio = 1.469, 95% confidence interval = 1.083-1.993, χ2 = 6.125, P = 0.013). The rs1412125 genotype T/C distribution (χ2 = 10.906, P = 0.004) and allele frequencies (χ2 = 8.813, P = 0.003) differed significantly between patients with and without coronary artery injury. In the dominant model, the coronary artery injury risk was 3.006 times greater for patients with the TT genotype than for those with the other genotypes (odds ratio = 3.006, 95% confidence interval = 1.540-5.867, χ2 = 10.875, P = 0.001). No significant difference in the rs2249825 genotype C/G distribution or allele frequencies was found between the Kawasaki disease and control groups, or between the coronary artery injury and without coronary artery injury groups. CONCLUSIONS: The rs1412125 polymorphism of the HMGB1 gene is associated with Kawasaki disease and its coronary artery injury complication. The CC genotype may be a risk factor for Kawasaki disease onset, and the TT genotype may be a risk factor for coronary artery injury in Kawasaki disease.

Association between serum pyridoxal 5'-phosphate levels and all-cause, cardiovascular mortality, and cardiovascular disease in adults: a population-based cohort study.

Background: The association between pyridoxal 5'-phosphate (PLP) and cardiovascular disease (CVD) remains a topic of discussion. Objectives: This study aimed to explore the relationship between serum PLP levels and the incidence of all-cause mortality, cardiovascular mortality, and the risk of CVD among the US population. Design: A population-based cohort study. Methods: This study analyzed data from the National Health and Nutrition Examination Survey. Adjusted hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were calculated using weighted Cox proportional hazards regression models to assess the risk associated with all-cause and cardiovascular mortality. Weighted binary logistic regression was utilized to assess the relationship between serum PLP levels and the risk of CVD. Nonlinear associations were evaluated using multivariable-adjusted restricted cubic splines. Results: There were 2546 cases of all-cause mortality and 867 cases of cardiovascular mortality over a mean follow-up of 11.36 years. In the fully adjusted model, the adjusted HRs with 95% CIs for all-cause mortality associated with increases in serum PLP levels corresponding to the interquartile ranges were 0.83 (0.74-0.93), 0.71 (0.63-0.80), and 0.64 (0.56-0.74), respectively. Similarly, cardiovascular mortality decreased by 0.78 (0.62-0.97), 0.63 (0.49-0.81), and 0.62 (0.50-0.77) with each quartile increase in serum PLP levels. Higher serum PLP levels confer protection against CVD risk (odds ratio: 0.87, 95% CI: 0.79-0.96). Serum PLP levels showed nonlinear relationships with risk of all-cause mortality, cardiovascular mortality, and CVD. Conclusion: The results of this study provide evidence that serum PLP serves as a protective factor against all-cause mortality, cardiovascular mortality, and CVD in US adults, with dose-response relationships.

Association between serum pyridoxal 5'-phosphate levels and all-cause, cardiovascular mortality, and cardiovascular disease in US adults Why was the study done? The association between pyridoxal 5'-phosphate (PLP) and cardiovascular disease (CVD) remains a topic of discussion. This study aimed to explore the relationship between serum PLP levels and the incidence of all-cause mortality, cardiovascular mortality, and the risk of CVD among the US population. What did the researchers do? This study used data from National Health and Nutrition Examination Survey (NHANES), applying statistical methods to see if there's a connection between the amount of PLP in the blood and health outcomes. What did the researchers find? The findings showed that over an average of 11 years, people with higher levels of PLP in their blood were less likely to die for any reason. They were also less likely to die from heart-related problems or to develop heart disease. The protection seemed to increase as PLP levels got higher. What do the findings mean? The results of this study provide evidence that serum PLP serves as a protective factor against all-cause mortality, cardiovascular mortality, and cardiovascular disease in US adults, with dose­response relationships.

Molecular subtypes and prognostic factors of lung large cell neuroendocrine carcinoma.

Background: Lung large cell neuroendocrine carcinoma (LCNEC) is an aggressive disease with poor prognosis and short-term survival, which lacks effective prognostic indicators. The study aims to investigate the molecular subtypes and prognostic markers of lung LCNEC. Methods: Patients diagnosed with lung LCNEC at Sun Yat-sen University Cancer Center (SYSUCC) between November 2007 and January 2021 were screened. Baseline clinical data were collected and routine blood indexes including lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) were calculated. Immunohistochemistry (IHC) of ASCL1, NEUROD1, POU2F3, YAP1 were done to perform molecular subtyping, while CD56, Syn, CgA, CD3, CD8, CD20, CD68, and CD163 were also stained on tissue samples. Then prognostic factors of lung LCNEC were explored. Results: One hundred and fifty-one lung LCNEC patients were identified, 103 of whom had complete clinical information, available routine blood and biochemical indexes were eventually included in the present study. Tumor tissue specimens were available from 64 patients. Positive expression rates of ASCL1, NEUROD1, and YAP1 were 82.8%, 50.0%, and 28.1%, respectively. No POU2F3+ cases were detected. Forty (62.5%) patients co-expressed with two or three markers. High LMR (>3.3) was an independent predictor of favorable prognosis of disease-free survival (DFS) [hazard ratio (HR), 0.391; 95% confidence interval (CI): 0.161-0.948; P=0.04] and overall survival (OS) (HR, 0.201; 95% CI: 0.071-0.574; P=0.003). Notably, high LMR was correlated with higher intra-tumoral CD3+ (P=0.004), CD8+ (P=0.01), and CD68+ (P<0.001) immune cell infiltration compared to low LMR in lung LCNEC. Conclusions: Our study validated molecular subtypes by IHC in lung LCNEC, and co-expression was found among different subtypes, with no prognostic effect. High blood LMR level was associated with a favorable prognosis in lung LCNEC, which might partly reflect a hot tumor tissue immune microenvironment. Our findings may benefit clinical practice, and further studies are warranted.

Causal Effects of Gut Microbiota and Metabolites on Chronic Obstructive Pulmonary Disease: A Bidirectional Two Sample Mendelian Randomization Study.

Background: Recent evidence suggests that the gut microbiome and metabolites are intricately involved in Chronic Obstructive Pulmonary Disease (COPD) pathogenesis, yet the precise causal relationships remain unclear due to confounding factors and reverse causation. This study employs bidirectional two-sample Mendelian Randomization (MR) to clarify these connections. Methods: Summary data from publicly available Genome-Wide Association Studies (GWAS) concerning the gut microbiome, metabolites, and COPD were compiled. The selection of genetic instrumental variables (Single Nucleotide Polymorphisms, or SNPs) for MR analysis was conducted meticulously, primarily utilizing the Inverse Variance Weighting (IVW) method, supplemented by MR-Egger regression and the Weighted Median (WM) approach. The evaluation of heterogeneity and horizontal pleiotropy was performed using Cochran's Q test, the MR-Egger intercept test, and the MR-PRESSO global test. Sensitivity analyses, including leave-one-out tests, were conducted to verify the robustness of our results. And the mediation effect of gut microbiota-mediated changes in metabolites on the causal relationship with COPD was analyzed. Results: Our study identified nine significant gut microbiota taxa and thirteen known metabolites implicated in COPD pathogenesis. Moreover, associations between the onset of COPD and the abundance of five bacterial taxa, as well as the concentration of three known metabolites, were established. These findings consistently withstood sensitivity analyses, reinforcing their credibility. Additionally, our results revealed that gut microbiota contribute to the development of COPD by mediating changes in metabolites. Conclusion: Our bidirectional Two-Sample Mendelian Randomization analysis has revealed reciprocal causal relationships between the abundance of gut microbiota and metabolite concentrations in the context of COPD. This research holds promise for identifying biomarkers for early COPD diagnosis and monitoring disease progression, thereby opening new pathways for prevention and treatment. Further investigation into the underlying mechanisms is essential to improve our understanding of COPD onset.

Didang decoction attenuates cancer-associated thrombosis by inhibiting PAD4-dependent NET formation in lung cancer.

This research aims to investigate the impact of Didang decoction (DD) on the formation of neutrophil extracellular traps (NETs) and cancer-associated thrombosis in lung cancer. BALB/c nude mice were used to establish xenograft models for inducing deep vein thrombosis. Tumor growth and thrombus length were assessed. The impact of DD on NET generation was analyzed using enzyme-linked immunosorbent assay, immunofluorescence staining, quantitative real-time PCR, and western blot analysis, both in vivo and in vitro. CI-amidine, a PAD4 inhibitor, was employed to evaluate the role of PAD4 in the generation of NETs. In vivo studies demonstrated that treatment with DD reduced tumor growth, inhibited thrombus formation, and decreased the levels of NET markers in the serum, tumor tissues, neutrophils, and thrombus tissues of mice. Additional data indicated that DD could suppress neutrophil counts, the release of tissue factor (TF), and the activation of thrombin-activated platelets, all of which contributed to increased formation of NETs in mouse models. In vitro, following incubation with conditioned medium (CM) derived from Lewis lung carcinoma cells, the expression of NET markers in neutrophils was significantly elevated, and an extracellular fibrous network structure was observed. Nevertheless, these NET-associated changes were partially counteracted by DD. Additionally, CI-amidine reduced the expression of NET markers in CM-treated neutrophils, consistent with the effects of DD. Collectively, DD inhibits cancer-associated thrombosis in lung cancer by decreasing PAD4-dependent NET formation through the regulation of TF-mediated thrombin-platelet activation. This presents a promising therapeutic strategy for preventing and treating venous thromboembolism in lung cancer.

Exploring the role of ADAMTSL2 across multiple cancer types: A pan-cancer analysis and validated in colorectal cancer.

BACKGROUND: Recent studies have established a correlation between ADAMTSL2 (ADAMTS-like 2) and the development of various cancers. This study aims to conduct a comprehensive pan-cancer analysis in 37 cancer types and investigate its potential role in colon and rectal adenocarcinoma (COADREAD). METHOD: Pan-cancer and mutation data were sourced from The Cancer Genome Atlas (TCGA) database and analyzed using Sangerbox analysis platform. We explored the expression patterns and prognostic implications of ADAMTSL2, and investigated its relationships with tumor heterogeneity, stemness, immune checkpoint genes, immune cell infiltration, RNA modifications, and mutational profiles across different cancers. Additionally, with Ethics Committee approval, we conducted immunohistochemical (IHC) analysis on 120 COADEAD samples to evaluate ADAMTSL2 expression and its association with clinicopathological parameters. RESULTS: ADAMTSL2 expression was positively correlated with the hazard ratio of OS, DSS, DFI and PFI for ESCA and COADREAD. A negative correlation was observed between ADAMTSL2 expression and NEO levels in COAD. Gene alterations in ADAMTSL2 were observed, with a mutation frequency of 5.0% in COAD. There is a significant correlation between ADAMTSL2 expression and immune cell infiltration in a variety of cancers. The expression level of ADAMTSL2 protein was associated with T stage, N stage, M stage (p < 0.05). Kaplan‒Meier survival curves demonstrated that the high ADAMTSL2 group had a shorter OS time (p = 0.047) and progression free survival time (p = 0.026) than the low ADAMTSL2 group. CONCLUSION: In summary, we conducted a comprehensive pan-cancer analysis of ADAMTSL2 and we demonstrated that ADAMTSL2 may serve as a novel prognostic biomarker and immunotherapy target in COADREAD.

Appearance Comparison, Body Appreciation, and Adolescent Depressive Symptoms: Roles of Gender, Age, and Body-Mass Index.

Objective: This study aimed to examine the association between appearance comparison and adolescent depressive symptoms, the mediating role of body appreciation, and the moderating roles of gender and body-mass index (BMI) among adolescents in different age groups. Methods: A cross-sectional sample of 2645 Chinese students aged 12-16 years (44.7% girls) participated. The measurements included depressive symptoms, appearance comparison, body appreciation, weight, and height. Multigroup path analysis was used to examine the moderated mediation model. Results: Compared with boys, adolescent girls presented greater levels of appearance, which increased with age. Body appreciation mediated the association between appearance comparison and depressive symptoms in girls, whereas appearance comparison directly correlated with depressive symptoms in boys. Body appreciation decreased with increasing BMI in boys but remained relatively stable in girls. Similar patterns were observed among junior and senior high school students. Conclusion: This study underscores the significant relationship between appearance comparison and adolescent depressive symptoms, suggesting varied mechanisms based on gender and BMI levels.

Immunosuppressive leucosceptrane-type sesterterpenoids with antipodal cyclopentenones isolated from Leucosceptrum canum.

Ten undescribed leucosceptrane-type sesterterpenoids with antipodal cyclopentenone moieties were isolated from the leaves of Leucosceptrum canum. Their structures including absolute configurations were elucidated by comprehensive spectroscopic analyses (including 1D and 2D NMR, and HRMS) and ECD calculations. In vitro immunosuppressive effects of these sesterterpenoids against the proliferation of T cells and the secretion of cytokine IFN-γ were evaluated. Among them, 11α-H-leucosceptroid C, 5,13-dehydro-11α-H-leucosceptroid C, 5,13-dehydro-11ß-hydroxy-leucosceptroid C, and 5,13-dehydro-11α-hydroxy-leucosceptroid C significantly inhibited IFN-γ secretion with IC50 values of 12.55-23.62 µM. More remarkable inhibitory effects against IFN-γ secretion were observed for 5,13-dehydro-11ß-hydroxy-leucosceptroid D, leucosceptroid U, 14-epi-leucosceptroid U, leucosceptroid V, and 14-epi-leucosceptroid V, with IC50 values of 4.32-9.47 µM.

Modified tai chi movement training based on sEMG and movement analysis on improving upper extremities motor function: a protocol for a clinical randomised controlled trial.

INTRODUCTION: Stroke survivors often face motor dysfunction, increasing fall risk. Lower extremity muscle weakness is a key factor affecting walking ability. Tai chi (TC) has been shown to improve muscle strength and mobility in patients with stroke more effectively than traditional walking training. However, existing TC programmes for stroke rehabilitation are often too simplified and fail to fully use TC's benefits. Additionally, subjective assessment scales are time-consuming and prone to bias. This study proposes integrating TC's early movement features with neurodevelopmental therapy, using surface electromyography and inertial measurement unit (IMU) sensors to thoroughly analyse diverse TC movements. Tailored exercises, based on stroke-induced impairments, will be objectively assessed through biomechanical analysis. METHODS AND ANALYSIS: The study unfolds in two phases. The initial phase employs the IMU sensor and electromyography to objectively analyse TC's biomechanics, informing personalised rehabilitation plans aligned with distinct movement impairments. The second phase adopts a randomised, single-blind, parallel controlled trial design involving 60 patients with stroke randomly assigned to either the intervention or control group. The intervention group undergoes biomechanics-based TC training alongside routine rehabilitation for 12 weeks, practicing the 24-form TC three times weekly. The control group engages in routine rehabilitation thrice weekly for the same duration. Primary and secondary outcomes, including kinematic/dynamic data, surface electromyography, motion analysis, comprehensive the international classification of functioning, disability and health Core Set for Stroke, Modified Barthel Index and Fugl-Meyer Assessment, will be evaluated at baseline and post-intervention. ETHICS AND DISSEMINATION: The study has received approval from the Ethics Committee of Zhongda Hospital Southeast University (2023ZDSYLL378-P01). All prospective participants will receive comprehensive information regarding the study protocol, and their informed consent will be obtained before their participation. Additionally, the trial will be registered with the Chinese Clinical Trial Registry to ensure transparency and compliance with research regulations. Results from this study will be disseminated through peer-reviewed journals, conference presentations and public databases to ensure wide accessibility and to contribute to the advancement of medical knowledge. PROTOCOL VERSION: 2.0 (14 June 2024). TRIAL REGISTRATION NUMBER: www.chictr.org.cn, identifier ChiCTR2400080158.

Multidimensional screening of Astragalus membranaceus small molecules to mitigate carbon ion radiation-induced bystander effects.

Existing studies have shown that Astragalus membranaceus (AM) and its active ingredients astragalus polysaccharides, oninon, and astragalus methyl glycosides can attenuate X-ray radiation-induced injury. However, there are no studies on how isoliquiritigenin (ISL) attenuate the bystander effect of bone marrow mesenchymal stem cells (BMSCs) induced by carbon ion radiation therapy for lung cancer. This study aimed to investigate the AM-derived small molecule ISL to enhance radiotherapy sensitivity by attenuating the carbon ion radiation-induced bystander effect (RIBE) in BMSCs to elucidate its mechanism of action. In this study, we established a C57BL/6 mouse lung cancer transplantation tumor model in vivo and a co-culture model of A549 cells and BMSCs in vitro, and the models were successfully treated with carbon ions. In further work, we used flow cytometry, immunofluorescence, Western blot, enzyme-linked immunosorbent assay (ELISA), inhibitor, short hairpin RNA (shRNA), Cell Counting Kit-8 (CCK-8), and other methods to illustrate the mechanism. In the next experiments, we found that ISL combined with carbon ion radiotherapy had a significant anti-tumor effect and protected BMSCs from radiation damage. The aim of this study was to investigate the potential of ISL in enhancing the sensitivity of lung cancer cells to radiotherapy and attenuating RIBE in both in vitro and in vivo settings. Traditional Chinese medicine combined with radiation therapy is a promising and innovative treatment for non-small cell lung cancer. These results establish a theoretical foundation for further clinical development of ISL as a potential radiosensitizer option.

Potential of Salvinia biloba Raddi for the remediation of water polluted with ciprofloxacin: Removal, physiological response, and root microbial community.

This paper investigated the removal amount of Ciprofloxacin (CIP) by Salvinia biloba Raddi (S. biloba) under various conditions, the physiological response under different CIP concentrations, the influence of CIP on the root microbial community structure of S. biloba, the possible metabolic pathways and removal mechanism. The results showed that under 4 mg/L CIP, the removal rate of CIP was 98 %. Under different CIP concentration conditions, low CIP concentration promoted the growth of S. biloba, while high CIP inhibited the growth of S. biloba and S. biloba was exposed to different degrees of oxidative stress. CIP affected root microbial community diversity and changed microbial community structure. Five possible degradation pathways were proposed through the determination of intermediate metabolites. According to mass balance calculations, biodegradation was the most critical degradation pathway. This study demonstrated the potential use of S. biloba for treating CIP-contaminated water and provided insights into the mechanisms of plant-based antibiotic degradation.

Triggering receptor expressed on myeloid cells-1 aggravates obliterative bronchiolitis via enhancing the proinflammatory phenotype of macrophages.

BACKGROUND: Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) plays an important role in innate immune system. However, whether and how TREM-1 contributes to obliterative bronchiolitis (OB) progression remains unclear. METHODS: A murine orthotopic tracheal transplantation model was constructed to mimic the pathogenesis of OB. qPCR and immunoblotting were used to measure TREM-1 expression. RNA sequencing was used to investigate the impact of TREM-1 on proinflammatory phenotype of macrophages. Trem-1 knockout mice and Nlrp3 knockout mice were generated to investigate the role of the TREM-1/NLRP3 pathway in the proinflammatory phenotype of macrophages. The infiltration of immune cells within the grafts was quantified using immunofluorescence staining. Flow cytometry was used to detect the proportion of different immune cells in mice spleen and the expression levels of iNOS and co-stimulatory molecules in macrophages. RESULTS: The expression of TREM-1 was upregulated in the mouse OB model. Genetic ablation or pharmacological inhibition of TREM-1 ameliorated OB, whereas the stimulation of TREM-1 using anti-TREM-1 agonistic antibody exacerbated OB. Moreover, Trem-1 ablation reduced the infiltration of iNOS+ macrophages and limited the T cell responses. In vitro studies revealed that Trem-1 deletion impaired the proinflammatory function and antigen presentation ability of macrophages. Additionally, Trem-1 knockout inhibited the activation of NLRP3 signaling pathway. NLRP3 overexpression restored the proinflammatory phenotype of Trem-1 knockout macrophages. CONCLUSIONS: These findings indicated that TREM-1 could promote the proinflammatory phenotype of macrophages through NLRP3 inflammasome activation, thereby exacerbating OB progression. These findings indicated that TREM-1 may serve as a therapeutic target for OB treatment.

Comprehensive characterization of active components in Salvia miltiorrhiza using polarity-partitioned two-dimensional liquid chromatography coupled with mass spectrometry.

Salvia miltiorrhiza, a widely used traditional Chinese medicine, contains a complex matrix of hydrophobic diterpenoids and hydrophilic phenolic acids, presenting significant challenges in comprehensive analysis. In this study, an online polarity-partitioned two-dimensional liquid chromatography coupled with mass spectrometry (2D-LC-MS) method was developed for comprehensive analysis of both lipophilic and hydrophilic active components in Salvia miltiorrhiza. The method integrated hydrophilic interaction liquid chromatography (HILIC) and reversed-phase liquid chromatography (RPLC), facilitating the efficient separation of compounds across a wide range of polarities. An online dilution strategy was implemented, minimizing sample loss and enhancing the method's utility for quality control and chemical characterization of complex herbal matrices. Compared with other LC methods, this approach significantly improved analyte coverage, resolution, and analysis efficiency. Under optimal conditions, 150 active components were successfully identified, including 33 compounds newly discovered in Salvia miltiorrhiza. Additionally, the validated online method was applied to the quantitative determination of 16 quality markers of Salvia miltiorrhiza from different sources. The results demonstrated the online method's potential as a superior alternative to existing techniques, offering broader applicability in traditional Chinese medicine research.

The vasculogenic mimicry, CD146+ and CD105+ microvessel density in the prognosis of endometrioid endometrial adenocarcinoma: a single-centre immunohistochemical study.

The microvessel compartment is crucial in the tumour microenvironment of endometrioid adenocarcinoma (EA). This study investigated the role of vasculogenic mimicry (VM), CD146, and CD105 microvessel density in the clinical prognosis of EA. A total of 188 EA cases were analyzed, with VM channels and microvessels detected using PAS/CD31, CD146, and CD105 staining. Mann-Whitney and Fisher exact tests were used to compare the study groups according to the evaluated criteria. ROC analysis included determination of the confidence interval (CI) and area under the ROC curve. The Mantel-Cox test was used to analyze progression-free survival. Multivariate Cox proportional hazard analysis was performed using stepwise regression. Results showed that VM channels and CD146 and CD105 microvessels were significantly higher (p < 0.0001) in cases with unfavourable prognosis. Univariate survival analysis highlighted the significant role of these factors in progression-free survival, while multivariate Cox analysis identified VM and CD146+ vessels as predictive factors. This study demonstrates, for the first time, that VM, CD146, and CD105-positive vessels are involved in EA prognosis, suggesting their potential as independent prognostic indicators and targets for antiangiogenic therapy. However, these findings require further validation through large-scale studies.

Integrating Bioinformatics and Experimental Validation to Identify Mitochondrial Permeability Transition-Driven Necrosis-Related lncRNAs that can Serve as Prognostic Biomarkers and Therapeutic Targets in Endometrial Carcinoma.

Endometrial carcinoma (EC) is a common malignant tumor in women with high mortality and relapse rates. Mitochondrial permeability transition (MPT)-driven necrosis is a novel form of programmed cell death. The MPT-driven necrosis related lncRNAs (MRLs) involved in EC development remain unclear. We aimed to predict the outcomes of patients with EC by constructing a novel prognostic model based on MRLs and explore potential molecular functions. A risk prognostic model was developed utilizing multi-Cox regression in conjunction with the Least Absolute Shrinkage and Selection Operator (LASSO) regression algorithm, which was based on MRLs. The predictive efficacy of the model was evaluated through receiver operating characteristic (ROC) curve analysis, as well as nomogram and concordance index (C-index) assessments. Patients were categorized into high- and low-risk groups based on their median risk scores. Notably, the high-risk group exhibited significantly poorer overall survival (OS) outcomes. Gene ontology (GO) and Gene set enrichment analysis (GSEA) demonstrated that Hedgehog and cell cycle pathways were enriched in the high-risk group. Tumor Immune Dysfunction and Exclusion (TIDE) displayed that patients in the high-risk group showed a high likelihood of immune evasion and less effective immunotherapy. A significant disparity in immune function was also observed between two groups. Based on the nine-MRLs, drug sensitivity analysis identified several anticancer drugs with potential efficacy in prognosis. Meanwhile, the results demonstrated that OGFRP1 plays a carcinogenic role by affecting mitochondrial membrane permeability in EC. Therefore, the risk model constructed by nine MRLs could be used to predict the clinical outcomes and therapeutic responses in patients with EC effectively.

[Treatment of post-stroke fatigue with point-toward-point insertion of elongated needle and Tongdu Tiaoshen therapy of acupuncture: a randomized controlled trial].

OBJECTIVE: To observe the effect of point-toward-point insertion of elongated needle on post-stroke fatigue and explore its underlying mechanism. METHODS: Sixty-four patients with post-stroke fatigue were randomly divided into an observation group (32 cases, 2 cases dropped out) and a control group (32 cases, 2 cases dropped out). In addition to the conventional treatment of western medicine and rehabilitation exercises, Tongdu Tiaoshen (regulating the governor vessel and the spirit) therapy of acupuncture was used in the control group, and acupuncture was applied to Baihui (GV 20), Sishencong (EX-HN 1), Shenting (GV 24), Fengfu (GV 16) and bilateral Fengchi (GB 20) and the needles were retained for 30 min in one treatment. In the observation group, besides the interventions as the control group, point-toward-point insertion of elongated needle was adopted. The needle was inserted from Zhiyang (GV 9) toward Dazhui (GV 14), from Shendao (GV 11) toward Yaoyangguan (GV 3) and from Yaoqi (EX-B 9) toward Yaoyangguan (GV 3); and the needles were retained for 30 min in one treatment. In the two groups, the acupuncture was delivered once daily, 6 times a week, consecutively for 4 weeks. The scores of the fatigue severity scale (FSS), Pittsburgh sleep quality index (PSQI), Hamilton anxiety scale (HAMA), Hamilton depression scale (HAMD), and Fugl-Meyer assessment (FMA) were observed before and after treatment completion in the two groups. Using ELISA, the levels of serum interleukin (IL)-1ß, IL-6, IL-10, high-sensitivity C-reactive protein (hs-CRP), and homocysteine (Hcy) were detected before and after treatment completion; and clinical effect was evaluated. RESULTS: The scores of FSS, PSQI, HAMA and HAMD, as well as the levels of serum IL-1ß, IL-6, hs-CRP and Hcy were reduced (P<0.05), and the scores of FMA and the levels of serum IL-10 were increased (P<0.05) after treatment in comparison with those before treatment in the two groups. Compared with the control group, in the observation group, the scores of FSS, PSQI, HAMA and HAMD, and the levels of serum IL-1ß, IL-6, hs-CRP and Hcy were reduced (P<0.05, P<0.01), and the score of FMA and the level of serum IL-10 were increased (P<0.05). The total clinical effective rate was 83.3% (25/30) in the observation group, which was higher than 73.3% (22/30) of the control group (P<0.05). CONCLUSION: The point-toward-point insertion of elongated needle alleviates fatigue, anxiety and depression, and ameliorates sleep and motor function in the patients with post-stroke fatigue. It may be related to the attenuation of inflammatory responses.

Dual-mode fluorescent and colorimetric sensing of thiourea and aluminum ion in natural water based on CuO nanoparticles.

CuO nanoparticles with good water solubility and uniform particle size were successfully prepared. Interestingly, the oxidase-like activity of CuO NPs was continuously enhanced by the addition of thiourea (TU), and the enzyme activity was further enhanced by the addition of aluminum ion (Al3+). By systematically exploring and optimizing the experimental conditions, including the key parameters such as temperature, reaction time, and pH, a fluorescence-colorimetric dual-mode sensing system based on CuO nanoparticles was constructed. The detection range of TU and Al3+ were 1-100 µM and 1-100 µM, respectively, and the selectivity and precision of detection were further improved. In addition, the catalytic mechanism of CuO NPs as oxidase-like catalysts and the specific process in the reaction were investigated. Finally, the nano-sensing system was successfully applied to the analysis of three real environmental samples, namely, tap water, lake water and river water, which provided an effective new strategy for the future development of nano-sensing technology for TU and Al3+.