Adipose stem cell­derived exosomes promote high glucose-induced wound healing by regulating the TRIM32/STING axis.

Refractory diabetic wounds are still a clinical challenge that can cause persistent inflammation and delayed healing. Exosomes of adipose stem cells (ADSC-exos) are the potential strategy for wound repair; however, underlying mechanisms remain mysterious. In this study, we isolated ADSC-exos and identified their characterization. High glucose (HG) stimulated human umbilical vein endothelial cells (HUVECs) to establish in vitro model. The biological behaviors were analyzed by Transwell, wound healing, and tube formation assays. The underlying mechanisms were analyzed using quantitative real-time PCR, co-immunoprecipitation (Co-IP), IP, and western blot. The results showed that ADSC-exos promoted HG-inhibited cell migration and angiogenesis. In addition, ADSC-exos increased the levels of TRIM32 in HG-treated HUVECs, which promoted the ubiquitination of STING and downregulated STING protein levels. Rescue experiments affirmed that ADSC-exos promoted migration and angiogenesis of HG-treated HUVECs by regulating the TRIM32/STING axis. In conclusion, ADSC-exos increased the levels of TRIM32, which interacted with STING and promoted its ubiquitination, downregulating STING levels, thus promoting migration and angiogenesis of HG-treated HUVECs. The findings suggested that ADSC-exos could promote diabetic wound healing and demonstrated a new mechanism of ADSC-exos.

An Epigenetic Manifestation of Alzheimer's Disease: DNA Methylation.

Alzheimer's disease (AD), the most common form of dementia, has a complex pathogenesis. The number of AD patients has increased in recent years due to population aging, while a trend toward a younger age of onset has arisen, imposing a substantial burden on society and families, and garnering extensive attention. DNA methylation has recently been revealed to play an important role in AD onset and progression. DNA methylation is a critical mechanism regulating gene expression, and alterations in this mechanism dysregulate gene expression and disrupt important pathways, including oxidative stress responses, inflammatory reactions, and protein degradation processes, eventually resulting in disease. Studies have revealed widespread changes in AD patients' DNA methylation in the peripheral blood and brain tissues, affecting multiple signaling pathways and severely impacting neuronal cell and synaptic functions. This review summarizes the role of DNA methylation in the pathogenesis of AD, aiming to provide a theoretical basis for its early prevention and treatment.

The status quo of short video as sources of health information on gastroesophageal reflux disease in China: a cross-sectional study.

Background: Positive lifestyle adjustments have become effective methods in treating gastroesophageal reflux disease (GERD). Utilizing short video platforms to encourage GERD patients for effective self-disease management is a convenient and cost-effective approach. However, the quality of GERD-related videos on short video platforms is yet to be determined, and these videos may contain misinformation that patients cannot recognize. This study aims to assess the information quality of GERD-related short videos on TikTok and Bilibili in China. Methods: Search and filter the top 100 GERD-related videos on TikTok and Bilibili based on comprehensive rankings. Two independent gastroenterologists conducted a comprehensive evaluation of the video quality using the Global Quality Score and the modified DISCERN tool. Simultaneously, the content of the videos was analyzed across six aspects: definition, symptoms, risk factors, diagnosis, treatment, and outcomes. Results: A total of 164 GERD-related videos were collected in this study, and videos from non-gastrointestinal health professionals constitute the majority (56.71%), with only 28.66% originating from gastroenterology health professionals. The overall quality and reliability of the videos were relatively low, with DISCERN and GQS scores of 2 (IQR: 2-3) and 3 (IQR: 2-3), respectively. Relatively speaking, videos from gastrointestinal health professionals exhibit the highest reliability and quality, with DISCERN scores of 3 (IQR: 3-4) and GQS scores of 3 (IQR: 3-4), respectively. Conclusion: Overall, the information content and quality of GERD-related videos still need improvement. In the future, health professionals are required to provide high-quality videos to facilitate effective self-disease management for GERD patients.

Analyzing the factors influencing speeding behavior based on quasi-induced exposure and random parameter logit model with heterogeneity in means.

INTRODUCTION: Speeding behavior is a major threat to road traffic safety, which can increase crash risks and result in severe injury outcomes. Although several studies have been conducted to analyze speeding crashes and relevant influential factors, the heterogeneity of variables has not been fully explored. Based on the traffic crash data extracted from the Crash Report Sampling System, the study aims to identify the factors that influence speeding driving with the consideration of variable heterogeneity. METHOD: Quasi-induced exposure technique is adopted to identify the disparities in the propensities of speeding for various driving cohorts. The random parameter logit model with heterogeneity in means is employed to examine the factors impacting speeding behavior. RESULTS: Results indicate that: (a) driving cohorts such as young drivers, male drivers, passenger cars, and pickups appear to have higher propensities of engaging in speeding driving; (b) the propensity of speeding is higher when the driver is drinking, distracted, changing lanes, negotiating a curve, driving in lighted condition, and on curved roads; and (c) the random parameter logit model with heterogeneity in means has better performance as opposed to that without heterogeneity in means. CONCLUSIONS: Speeding behavior can be influenced by various factors in terms of driver-vehicle characteristics, physical condition, driving actions, and environmental conditions. PRACTICAL APPLICATIONS: The findings could serve to develop effective countermeasures to reduce speeding behavior and improve traffic safety.

Mechanistic exploration of the shenlian formula in the suppression of atherosclerosis progression via network pharmacology and in vivo experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: The Shenlian formula (SL) is a Chinese medicine formula used to curb the development of atherosclerosis (AS) and cardiovascular disease in clinical practice. However, owing to the complexity of compounds and their related multiple targets in traditional Chinese medicine (TCM), it remains difficult and urgent to elucidate the underlying mechanisms at a holistic level. AIM: To investigate the intrinsic mechanisms by which SL suppresses AS progression and to gain new insight into its clinical use. METHODS: We proposed a network pharmacology-based workflow to evaluate the mechanism by which SL affects AS via data analysis, target prediction, PPI network construction, GO and KEGG analyses, and a "drug-core ingredient-potential target-key pathway" network. Then, non-targeted lipidomic analysis was performed to explore the differential lipid metabolites in AS rats, revealing the possible mechanism by which SL affects atherosclerotic progression. Moreover, an AS rabbit model was constructed and gavaged for SL intervention. Serum lipid profiles and inflammatory cytokine indices were tested as an indication of the mitigating effect of SL on AS. RESULTS: A total of 89 bioactive compounds and 298 targets related to SL and AS, which play essential roles in this process, were identified, and a component-target-disease network was constructed. GO and KEGG analyses revealed that SL regulated metabolic pathway, lipids and atherosclerosis, the PI3K-Akt pathway, the MAPK pathway and so on. In vivo experimental validation revealed that a total of 43 different lipid metabolites regulated by SL were identified by non-targeted lipidomics, and glycerophospholipid metabolism was found to be an important mechanism for SL to interfere with AS. SL reduced the plaque area and decreased the levels of inflammatory cytokines (TNF-α and IL-4) and blood lipids (TC, TG, LDL-C, and ApoB) in HFD-induced AS models. In addition, HDL and ApoA1 levels are increased. PLA2 and Lipin1 are highly expressed in AS model, indicating their role in destabilizing glycerophosphatidylcholine metabolism and contributing to the onset and progression of ankylosing spondylitis. Moreover, SL intervention significantly reduced the level of pro-inflammatory cytokines; significantly down-regulated NF-kB/p65 expression, exhibiting anti-inflammatory activity. CONCLUSION: The Shenlian formula (SL) plays a pivotal role in the suppression of AS progression by targeting multiple pathways and mechanisms. This study provides novel insights into the essential genes and pathways associated with the prognosis and pathogenesis of AS.

Characteristic abnormal expression of galectin-3 in serrated colon lesions and its pathological significance.

Serrated lesions are precursors of some colon cancers. The expression of galectin-3 has been reported to be involved in BRAF and KRAS mutations (the key pathogenic drivers of serrated lesions). This study aimed to investigate the expression intensity and subcellular localization of galectin-3 in serrated colon lesions by immunohistochemistry. The results demonstrated that, regarding expression intensity, galectin-3 expression in serrated colon lesions was significantly upregulated; regarding subcellular localization, the membrane expression of hyperplastic polyps/ sessile serrated lesions (HP/SSL) was weakened, the structure was disorganized and that of traditional serrated adenoma (TSA) was significantly weakened or disappeared, and the nuclear expression of both was positive; in the dysplasia of SSL (SSL-D) and TSA (TSA-HD), galectin-3 expression intensity remained high, and was weakened or disappeared in some nuclei, the expression disorder of the SSL-D cell membrane was reduced, the polarity of the cell was restored, weak expression appeared in the local cell membrane of TSA-HD, and the "serrated" structure of both was reduced or disappeared and seemed to revert more to that seen in common adenomas. In summary, abnormal galectin-3 expression occurs in the early stages of serrated lesions, its expression is characteristic, the dynamic changes in galectin-3 expression are closely related to the histopathological changes and progression of serrated lesions, and further accumulated molecular alterations contribute to this process.

Metabolomics for Clinical Biomarker Discovery and Therapeutic Target Identification.

As links between genotype and phenotype, small-molecule metabolites are attractive biomarkers for disease diagnosis, prognosis, classification, drug screening and treatment, insight into understanding disease pathology and identifying potential targets. Metabolomics technology is crucial for discovering targets of small-molecule metabolites involved in disease phenotype. Mass spectrometry-based metabolomics has implemented in applications in various fields including target discovery, explanation of disease mechanisms and compound screening. It is used to analyze the physiological or pathological states of the organism by investigating the changes in endogenous small-molecule metabolites and associated metabolism from complex metabolic pathways in biological samples. The present review provides a critical update of high-throughput functional metabolomics techniques and diverse applications, and recommends the use of mass spectrometry-based metabolomics for discovering small-molecule metabolite signatures that provide valuable insights into metabolic targets. We also recommend using mass spectrometry-based metabolomics as a powerful tool for identifying and understanding metabolic patterns, metabolic targets and for efficacy evaluation of herbal medicine.

Dose-Response Relationship Between Alcohol Consumption and Gout Risk: Do Subtypes of Alcoholic Beverages Make a Difference?

OBJECTIVE: Although previous studies have explored the association of drinking with gout risk, we sought to explore the dose-response relationship and the evidence between subtypes of alcoholic beverages and gout risk. METHODS: The weekly alcoholic beverage consumption of patients in the UK Biobank was collected and calculated. The Cox regression model was applied to assess the effects of drinking alcohol in general and its subtypes on gout risk by calculating the hazard ratio (HR) and 95% CIs. Additionally, the restricted cubic splines were used to estimate the dose-response relationship between alcohol consumption and gout risk. To evaluate the robustness, we performed subgroup analysis across various demographic characteristics. RESULTS: During a mean follow-up period of 11.7 years, a total of 5728 new incident gout cases were diagnosed among 331,865 participants. We found that light alcohol consumption was linked to a slight decrease in gout incidence among female individuals (HR 0.78, 95% CI 0.65-0.94, P = 0.01), whereas there was no significant association in male individuals. Moreover, the dose-response relationship showed that drinking light red wine and fortified wine could reduce the gout risk, whereas beer or cider, champagne or white wine, and spirits increased the gout risk at any dose. CONCLUSION: Our study suggested a J-shaped dose-response relationship between drinking and gout risk in female individuals, but not in male individuals. For specific alcoholic beverages, light consumption of red wine and fortified wine was associated with reduced gout risk. These findings offer new insights into the roles of alcoholic beverages in gout incidence risk, although further validation is warranted.

Grape seed-derived procyanidins decreases neuropathic pain and nerve regeneration by suppression of toll-like receptor 4-myeloid differentiation factor-88 signaling.

Background: Recent studies have shown that peripheral nerve regeneration process is closely related to neuropathic pain. Toll-like receptor 4 (TLR4) signaling was involved in different types of pain and nerve regeneration. TLR4 induced the recruitment of myeloid differentiation factor-88 adaptor protein (MyD88) and NF-κB-depended transcriptional process in sensory neurons and glial cells, which produced multiple cytokines and promoted the induction and persistence of pain. Our study aimed to investigate procyanidins's effect on pain and nerve regeneration via TLR4-Myd88 signaling. Methods: Spinal nerve ligation (SNL) model was established to measure the analgesic effect of procyanidins. Anatomical measurement of peripheral nerve regeneration was measured by microscopy and growth associated protein 43 (GAP43) staining. Western blotting and/or immunofluorescent staining were utilized to detect TLR4, myeloid differentiation factor-88 adaptor protein (MyD88), ionized calcium-binding adapter molecule 1 (IBA1) and nuclear factor kappa-B-p65 (NF-κB-p65) expression, as well as the activation of astrocyte and microglia. The antagonist of TLR4 (LPS-RS-Ultra, LRU) were intrathecally administrated to assess the behavioral effects of blocking TLR4 signaling on pain and nerve regeneration. Result: Procyanidins reduced mechanical allodynia, thermal hyperalgesia and significantly suppressed the number of nerve fibers regenerated and the degree of myelination in SNL model. Compared with sham group, TLR4, MyD88, IBA1 and phosphorylation of NF-κB-p65 were upregulated in SNL rats which were reversed by procyanidins administration. Additionally, procyanidins also suppressed activation of spinal astrocytes and glial cells. Conclusion: Suppression of TLR4-MyD88 signaling contributes to the alleviation of neuropathic pain and reduction of nerve regeneration by procyanidins.

A novel selenium nanocomposite modified by AANL inhibits tumor growth by upregulating CLK2 in lung cancer.

Lung cancer is a malignant tumor with high mortality and drug resistance. Therefore, it is urgent to explore natural and nontoxic drugs to treat lung cancer. In this study, the natural active ingredient AANL extracted from Agrocybe aegirita was used to modify nanoselenium by an oxidation-reduction method. Transmission electron microscope detection and infrared spectroscopy showed that a novel selenium nanocomposite named AANL-SeNPs was successfully prepared. The results of nanoscale characterization showed that AANL-SeNPs had good stability and uniform dispersion in aqueous solution by zeta potential and spectrum analysis. At the cellular level, we found that AANL-SeNPs significantly inhibited the cell viability of lung cancer cells, and the cell inhibition rate of 60 nM AANL-SeNPs was 39 % in H157 cells, 67 % in H147 cells, and 62 % in A549 cells. The IC50 value of AANL-SeNPs was 51.85 nM in A549 cells and 81.57 nM in H157 cells. Moreover, AANL-SeNPs could inhibit the cell proliferation and migration, and enhance the sensitivity of lung cancer cells to osimertinib and has no toxic to normal cells. In vivo, AANL-SeNPs significantly slowed tumor growth in tumor-bearing mice by establishing a subcutaneous transplantation tumor model for lung cancer, and the tumor size was smaller and was reduced about 79 % in 2 mg/kg AANL-SeNPs group compared with PBS group. Mechanistically, a total of 38 differentially expressed proteins were identified by data-independent acquisition mass spectrometry. A significantly upregulated protein, CDC-like kinase 2 (CLK2), was screened and validated for further analysis, which showed that the expression levels of CLK2 were increased in H157 and H1437 cells after AANL-SeNPs treatment. The results obtained in this study suggest that a novel selenium nanocomposite AANL-SeNPs, which inhibits lung cancer by upregulating the expression of CLK2.

[Discrimination of anti-tumor and cardioprotective effect quality markers from Aidi Injection based on "spider web" mode].

Chinese medicinal preparations play an equally important role in reducing toxicity and treating tumors. Few studies discriminate the quality markers(Q-markers) conferring different therapeutic effects of traditional Chinese medicine preparations. Therefore, we take Aidi Injection(AD) as an example to comprehensively identify the Q-markers of anti-tumor and cardioprotective effects based on the "spider web" mode. Firstly, based on the principle of measurability, the chemical components in the prescription were qualitatively analyzed, and then the components with high content and capable to be measured were quantitatively analyzed as measurable evaluation indexes. Based on the principle of stability, the effects of light and temperature on the content of each component of AD were investigated as indicators of stability. Based on the principle of compatibility, the compounds were classified according to the law of compatibility of sovereign, minister, assistant, and guide medicinal materials in the prescription. Based on the principle of efficacy, the anti-tumor and antiangiogenic activities of the Q-markers were evaluated, and their synergistic effects with doxorubicin(DOX) in inhibiting tumorigenesis and angiogenesis and lowering cardiotoxicity were evaluated as the evaluation indexes of effectiveness. The seven-dimensional spider web of "compatibility-content-stability-antitumor activity-synergistic anti-tumor activity with DOX-antiangiogenic activity-synergistic anti-angiogenic activity with DOX" and the four-dimensional spider web of "compatibility-content-stability-protective effects against DOX-induced myocardial toxicity" were established, on the basis of which the Q-markers of anti-tumor and cardioprotective effects of AD were comprehensively analyzed. The results showed that 12 components were selected as the Q-markers of AD, among which cantharidin, ginsenoside Re, ginsenoside Rb_1, astragaloside Ⅱ, cryptochlorogenic acid, and ginsenoside Rg_2 were the anti-tumor Q-markers of AD. Ginsenoside Rd, isofraxidin, syringin, eleutheroside E, calycosin-7-O-ß-D-glucoside, and azelaic acid were the cardioprotective Q-markers of AD. Taking into account both the anti-tumor and cardioprotective effects, these Q-markers could cover the four herbs constituting the prescription. The findings provides a scientific basis for the quality control of AD and an effective method for identifying comprehensive and reasonable Q-markers for the two effects of Chinese medicinal preparations.

Detectability of the potential climate change effect on transboundary air pollution pathways in the downwind area of China.

Long-term aerosol optical depth (AOD) datasets focused on the Pacific Ocean in the downwind area of China over a 19-year period from 2003 to 2021 were derived from satellite observations, reanalysis datasets, and numerical simulations. Considering the significant year-to-year changes in the amounts of aerosols transported from China to the Pacific Ocean during this period, we proposed a metric named RAOD. This is defined as the AOD over the ocean relative to that near the eastern coast of China within the same latitude band (25-30°N). RAOD was identified as a valuable metric for quantifying the long-term changes in transboundary air pollution pathways. Our analysis revealed a clear exponential decrease in RAOD values from China toward the Pacific Ocean; this was consistent with the prevailing meteorological conditions observed over the 19-year period. However, the possible long-term changes in RAOD due to climate change were found to be insignificant and were overshadowed by much larger year-to-year variations in the meteorological field. Additionally, significant seasonal variations in the absolute slope of the linear regression between RAOD and longitude were observed, and there correlated with wind patterns in the lower troposphere. Elevated slope values in the spring and winter suggested a west-to-east aerosol transport facilitated by strong winds, whereas the lower slope values in summer and autumn indicated a northward aerosol movement under weaker winds. In recent years, aerosols have become less likely to be transported far eastward from the coast of China. Based on these findings, to enhance the detectability of the climate change impacts on meteorological field affecting transboundary air pollution pathways, the RAOD metric derived using a continued long-term satellite observation of aerosols is proposed.

TCEB3 initiates ovarian cancer apoptosis by mediating ubiquitination and degradation of MCL-1.

Platinum resistance remains a major contributor to the poor prognosis of ovarian cancer. Anti-apoptotic protein myeloid cell leukemia-1 (MCL-1) has emerged as a promising target for overcoming drug resistance, but different cancer cells utilize distinct protein degradation pathways to alter MCL-1 level. We systematically investigated E3 ligases to identify novel candidates that mediate platinum resistance in ovarian cancer. Transcription Elongation Factor B (TCEB3) has been identified as a novel E3 ligase recognition subunit that targets MCL-1 in the cytoplasm during platinum treatment other than its traditional function of targeting the Pol II in the nuclear compartment. TCEB3 expression is downregulated in platinum-resistant cell lines and this low expression is associated with poor prognosis. The ubiquitination of MCL-1 induced by TCEB3 leads to cell death in ovarian cancer. Moreover, platinum treatment increased the cytoplasm proportion of TCEB3, and the cytoplasm localization of TCEB3 is important for its targeting of MCL-1. This study emphasizes the dual function of TCEB3 in homeostasis maintenance and in cell fate determination under different conditions, and provides a new insight into drug resistance in ovarian cancer.

Fibroblast Growth Factor 23 is a Potential Prognostic Biomarker in Uterine Sarcoma.

BACKGROUND: Uterine sarcoma (US) is a highly malignant cancer with poor prognosis and high mortality in women. In this study, we evaluated the expression of human fibroblast growth factor 23 (FGF23) in different US subtypes and the relationship between survival and clinicopathological characteristics. METHODS: We conducted a comparative analysis of FGF23 gene expression in different pathological types of US. Utilizing a cohort from The Cancer Genome Atlas of 57 patients, a 50-patient microarray dataset (GSE119043) from the Gene Expression Omnibus and a Suining cohort of 44 patients, we analyzed gene expression profiles and corresponding clinicopathological information. Immunohistochemistry was used to examine the expression level of FGF23 in four US subtypes. Survival analysis was used to assess the relationship between FGF23 expression and prognosis in US patients. RESULTS: Compared with uterine normal smooth muscle and uterine leiomyoma, FGF23 expression was significantly upregulated in US and was differentially expressed in four US subtypes. Uterine carcinosarcoma exhibited the highest expression of FGF23 among the subtypes. Survival analysis revealed no correlation between FGF23 expression and either overall survival or progression-free survival in US (P > 0.05). Similar results were obtained from the validation cohorts. Univariate and multivariate analyses showed no significant correlation between FGF23 expression and the US prognosis. Tumor stage, CA125, and tumor recurrence were independent prognostic factors for survival of US patients. CONCLUSION: FGF23 was highly expressed in US and was promising as a novel potential biomarker for the diagnosis and prognosis of US.

Succinic Acid Ameliorates Concanavalin A-Induced Hepatitis by Altering the Inflammatory Microenvironment and Expression of BCL-2 Family Proteins.

Autoimmune hepatitis (AIH) is a severe immune-mediated inflammatory liver disease that currently lacks feasible drug treatment methods. Our study aimed to evaluate the protective effect of succinic acid against AIH and provide a reliable method for the clinical treatment of AIH. We performed an in vivo study of the effects of succinic acid on concanavalin A (ConA)-induced liver injury in mice. We examined liver transaminase levels, performed hematoxylin and eosin (HE) staining, and observed apoptotic phenotypes in mice. We performed flow cytometry to detect changes in the number of neutrophils and monocytes, and used liposomes to eliminate the liver Kupffer cells and evaluate their role. We performed bioinformatics analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blotting to detect mitochondrial apoptosis-induced changes in proteins from the B-cell lymphoma 2(Bcl-2) family. Succinic acid ameliorated ConA-induced AIH in a concentration-dependent manner, as reflected in the survival curve. HE and TUNEL staining and terminal deoxynucleotidyl transferase dUTP nick end labeling revealed decreased alanine transaminase and aspartate aminotransferase levels, and reduced liver inflammation and apoptosis. RT-qPCR and enzyme-linked immunosorbent assay revealed that succinic acid significantly reduced liver pro-inflammatory cytokine levels. Flow cytometry revealed significantly decreased levels of liver neutrophils. Moreover, the protective effect of succinic acid disappeared after the Kupffer cells were eliminated, confirming their important role in the effect. Bioinformatics analysis, RT-qPCR, and western blotting showed that succinic acid-induced changes in proteins from the Bcl-2 family involved mitochondrial apoptosis, indicating the molecular mechanism underlying the protective effect of succinic acid. Succinic acid ameliorated ConA-induced liver injury by regulating immune balance, inhibiting pro-inflammatory factors, and promoting anti-apoptotic proteins in the liver. This study provides novel insights into the biological functions and therapeutic potential of succinic acid in the treatment of autoimmune liver injury.

Induction of Petite Colonies in Candida glabrate via Rose Bengal-Mediated Photodynamic Therapy.

Facing a 40% mortality rate in candidemia patients, drug-resistant Candida and their petite mutants remain a major treatment challenge. Antimicrobial photodynamic therapy (aPDT) targets multiple fungal structures, unlike antibiotics/antifungals, potentially thwarting resistance. Traditional methods for inducing petite colonies rely on ethidium bromide or fluconazole, which can influence drug susceptibility and stress responses. This study investigated the application of green light (peak 520 nm) and rose bengal (RB) photosensitizer to combat a drug-resistant Candida glabrata isolate. The findings revealed that aPDT treatment significantly inhibited cell growth (≥99.9% reduction) and effectively induced petite colony formation, as evidenced by reduced size and loss of mitochondrial redox indicator staining. This study provides initial evidence that aPDT can induce petite colonies in a multidrug-resistant C. glabrata strain in vitro, offering a potentially transformative approach for combating resistant fungal infections.

Alleviating Recombinant Tissue Plasminogen Activator-induced Hemorrhagic Transformation in Ischemic Stroke via Targeted Delivery of a Ferroptosis Inhibitor.

Intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) is the primary treatment for ischemic stroke. However, rtPA treatment can substantially increase blood-brain barrier (BBB) permeability and susceptibility to hemorrhagic transformation. Herein, the mechanism underlying the side effects of rtPA treatment is investigated and demonstrated that ferroptosis plays an important role. The ferroptosis inhibitor, liproxstatin-1 (Lip) is proposed to alleviate the side effects. A well-designed macrocyclic carrier, glucose-modified azocalix[4]arene (GluAC4A), is prepared to deliver Lip to the ischemic site. GluAC4A bound tightly to Lip and markedly improved its solubility. Glucose, modified at the upper rim of GluAC4A, imparts BBB targeting to the drug delivery system owing to the presence of glucose transporter 1 on the BBB surface. The responsiveness of GluAC4A to hypoxia due to the presence of azo groups enabled the targeted release of Lip at the ischemic site. GluAC4A successfully improved drug accumulation in the brain, and Lip@GluAC4A significantly reduced ferroptosis, BBB leakage, and neurological deficits induced by rtPA in vivo. These findings deepen the understanding of the side effects of rtPA treatment and provide a novel strategy for their effective mitigation, which is of great significance for the treatment and prognosis of patients with ischemic stroke.

The role of peripheral inflammation-related biomarkers in distinguishing Parkinson's disease.

BACKGROUND: Peripheral inflammation plays a significant role in Parkinson's disease (PD). Conflicting studies on whether inflammatory indicators in blood could serve as biomarkers to distinguish PD. OBJECTIVE: Include a wider range of biomarkers and control confounding factors to comprehensively evaluate the value of peripheral inflammation-related indicators. METHODS: A total of 80 PD patients were recruited and 80 one-to-one matched healthy controls (HCs). The levels of B-cell, T-cell, and natural killer (NK)-cell in blood were measured using flow cytometry. The levels of neurodegeneration-related proteins in serum were detected and clinical blood test results were collected. Multivariable logistic regression analysis was conducted to explore the role of significant variables in PD. Receiver operating characteristic curve analysis was performed to assess the potential value of these variables. RESULTS: Compared to HCs, PD patients showed lower levels of lymphocyte, B-cell, T-cell, high-density lipoprotein cholesterol (HDL-C) and lymphocyte-to-monocyte ratio, while the levels of neutrophil, NK-cell, ß-amyloid40, neurofilament light chain, neutrophil-to-lymphocyte ratio, and neutrophil-to-HDL-C ratio (NHR) were increased. A higher B-cell count was associated with a lower risk of PD, while higher levels of NK-cell and NHR were associated with a higher risk of PD. B-cell, NK-cell and NHR have potential value in distinguishing PD from non-PD. B-cell and NHR levels were significantly correlated with PD dyskinesia scores. CONCLUSIONS: B-cell, NK-cell, and NHR may potentially contribute to distinguishing PD patients from HCs. There could be a correlation between the number of B-cell, the level of NHR, and the severity of PD dyskinesia.

Cardiac computed tomography angiography-derived pulmonary vein volumetry as a predictor for atrial fibrillation recurrence after catheter ablation.

Background: There is an increasing evidence that pulmonary vein (PV) enlargement is associated with atrial fibrillation (AF); however, the predictive value of PV enlargement in AF recurrence remains unclear. This study sought to evaluate whether PV volume quantification derived from cardiac computed tomographic angiography (CCTA) could serve as a predictive indicator of the success of the catheter ablation (CA) procedure. Methods: The data of 160 patients diagnosed with AF who underwent both CCTA and CA treatments from January to June 2020 were retrospectively examined; the CCTA was conducted before the CA surgery. The study focused on documenting the PV structure, and the volume of the PV and left atrium (LA). The clinical, CCTA, and echocardiographic predictors of the recurrence and no-recurrence groups were compared. A multivariable logistic regression analysis was performed to adjust for confounders. Receiver operating characteristic (ROC) curves were analyzed to assess the predictive performance of the predictors of AF recurrence. Results: Of the 160 patients [55.6% male, 62.00 (55.25-68.00) years, 23.1% with persistent AF], 45 (28.1%) experienced AF recurrence within a one-year period. Notably, patients with AF recurrence had elevated CHADS2 scores (P=0.020) and increased LA and PV volumes (P<0.05). Patients with persistent AF (n=37) had significantly larger LA volume indexes (P<0.001) than those with paroxysmal AF, but there was no difference between the two groups in terms of the PV maximum volume index (P=0.200). Moreover, the PV maximum volume index [odds ratio (OR): 1.244, 95% confidence interval (CI): 1.008-1.536, P=0.042] and the LA minimum volume index (OR: 1.026, 95% CI: 1.001-1.052, P=0.038) were found to be significant predictors of AF recurrence. The ROC curves revealed that the PV maximum volume index threshold for predicting AF recurrence was 7.13 mL/m2, with a sensitivity of 84.4% and a specificity of 34.8% [area under the curve (AUC): 0.635, 95% CI: 0.540-0.730, P=0.008], and the LA minimum volume index threshold for predicting AF recurrence was 46.16 mL/m2, with a sensitivity of 88.9% and a specificity of 31.3% (AUC: 0.629, 95% CI: 0.534-0.723, P=0.012). A sub-analysis of patients with a lower left atrial dimension (LAD ≤38 mm in females, LAD ≤40 mm in males, n=120) demonstrated that the PV maximum volume index was a noteworthy indicator of AF recurrence (OR: 1.443: 95% CI: 1.145-1.820, P=0.002). Conversely, no significant correlation between AF recurrence and the LA volume index was found. The AUC value for the PV maximum volume index predictive of recurrent AF was 0.680 (95% CI: 0.577-0.781, P=0.003), with a sensitivity of 75.8%, specificity of 54%, and the cut-off value of the maximum AUC was 7.89 mL/m2. Conclusions: PV volume, derived from CCTA, may help to predict the recurrence of AF after CA, and is superior to the LA size in patients with less pronounced LA enlargement.