Multilevel Screening Strategy to Identify the Hydrophobic Organic Components of Ambient PM2.5 Associated with Hepatocellular Steatosis.

Hepatic steatosis is the first step in a series of events that drives hepatic disease and has been considerably associated with exposure to fine particulate matter (PM2.5). Although the chemical constituents of particles matter in the negative health effects, the specific components of PM2.5 that trigger hepatic steatosis remain unclear. New strategies prioritizing the identification of the key components with the highest potential to cause adverse effects among the numerous components of PM2.5 are needed. Herein, we established a high-resolution mass spectrometry (MS) data set comprising the hydrophobic organic components corresponding to 67 PM2.5 samples in total from Taiyuan and Guangzhou, two representative cities in North and South China, respectively. The lipid accumulation bioeffect profiles of the above samples were also obtained. Considerable hepatocyte lipid accumulation was observed in most PM2.5 extracts. Subsequently, 40 of 695 components were initially screened through machine learning-assisted data filtering based on an integrated bioassay with MS data. Next, nine compounds were further selected as candidates contributing to hepatocellular steatosis based on absorption, distribution, metabolism, and excretion evaluation and molecular dockingin silico. Finally, seven components were confirmed in vitro. This study provided a multilevel screening strategy for key active components in PM2.5 and provided insight into the hydrophobic PM2.5 components that induce hepatocellular steatosis.

Hsa_circ_0009096/miR-370-3p modulates hepatic stellate cell proliferation and fibrosis during biliary atresia pathogenesis.

Background: Hepatic stellate cell (HSC) activation and hepatic fibrosis mediated biliary atresia (BA) development, but the underlying molecular mechanisms are poorly understood. This study aimed to investigate the roles of circRNA hsa_circ_0009096 in the regulation of HSC proliferation and hepatic fibrosis. Methods: A cellular hepatic fibrosis model was established by treating LX-2 cells with transforming growth factor ß (TGF-ß1). RNaseR and actinomycin D assays were performed to detect hsa_circ_0009096 stability. Expression of hsa_circ_0009096, miR-370-3p, and target genes was detected using reverse transcription-qPCR. Direct binding of hsa_circ_0009096 to miR-370-3p was validated using dual luciferase reporter assay. Cell cycle progression and apoptosis of LX-2 cells were assessed using flow cytometry. The alpha-smooth muscle actin (α-SMA), collagen 1A1 (COL1A1), and TGF beta receptor 2 (TGFBR2) protein levels in LX-2 cells were analyzed using immunocytochemistry and western blotting. Results: Hsa_circ_0009096 exhibited more resistance to RNase R and actinomycinD digestion than UTRN mRNA. Hsa_circ_0009096 expression increased significantly in LX-2 cells treated with TGF-ß1, accompanied by elevated α-SMA and COL1A1 expression. Hsa_circ_0009096 siRNAs effectively promoted miR-370-3p and suppressed TGFBR2 expression in LX-2 cells, mediated by direct association of hsa_circ_0009096 with miR-370-3p. Hsa_circ_0009096 siRNA interfered with the cell cycle progression, promoted apoptosis, and reduced α-SMA and COL1A1 expression in LX-2 cells treated with TGF-ß1. MiR-370-3p inhibitors mitigated the alterations in cell cycle progression, apoptosis, and α-SMA, COL1A1, and TGFBR2 expression in LX-2 cells caused by hsa_circ_0009096 siRNA. In conclusion, hsa_circ_0009096 promoted HSC proliferation and hepatic fibrosis during BA pathogenesis by accelerating TGFBR2 expression by sponging miR-370-3p.

Toward DNN of LUTs: Learning Efficient Image Restoration with Multiple Look-Up Tables.

The widespread usage of high-definition screens on edge devices stimulates a strong demand for efficient image restoration algorithms. The way of caching deep learning models in a look-up table (LUT) is recently introduced to respond to this demand. However, the size of a single LUT grows exponentially with the increase of its indexing capacity, which restricts its receptive field and thus the performance. To overcome this intrinsic limitation of the single-LUT solution, we propose a universal method to construct multiple LUTs like a neural network, termed MuLUT. Firstly, we devise novel complementary indexing patterns, as well as a general implementation for arbitrary patterns, to construct multiple LUTs in parallel. Secondly, we propose a re-indexing mechanism to enable hierarchical indexing between cascaded LUTs. Finally, we introduce channel indexing to allow cross-channel interaction, enabling LUTs to process color channels jointly. In these principled ways, the total size of MuLUT is linear to its indexing capacity, yielding a practical solution to obtain superior performance with the enlarged receptive field. We examine the advantage of MuLUT on various image restoration tasks, including super-resolution, demosaicing, denoising, and deblocking. MuLUT achieves a significant improvement over the single-LUT solution, e.g., up to 1.1dB PSNR for super-resolution and up to 2.8dB PSNR for grayscale denoising, while preserving its efficiency, which is 100× less in energy cost compared with lightweight deep neural networks. Our code and trained models are publicly available at https://github.com/ddlee-cn/MuLUT.

Nature Products Chlorophyll Derivatives for NIR-II Fluorescence Bioimaging and Plant-imaging.

The second near-infrared window (NIR-II, 1000 - 1700 nm) fluorescence imaging has attracted significant attention in research fields because of its unique advantages compared with conventional optical windows (400 - 900 nm). A variety of NIR-II fluorophores have been actively studied because they serve as a key component of fluorescence imaging. Among them, organic small molecule NIR-II fluorophores display outstanding imaging performance and many advantages, but types of small molecule NIR-II fluorophores with high biocompatibility are still quite limited. Novel molecular scaffolds based NIR-II dyes are highly desired. Herein, we hypothesized that chlorophyll is a new promising molecular platform for discovery NIR-II fluorophores. Thus, seven derivatives of derivatives were selected to characterize their optical properties. Interestingly, six chlorophyll derivatives displayed NIR-II fluorescence imaging capability. This characteristic allowed the successful NIR-II imaging of green leaves of various plants. Furthermore, most of these fluorophores showed capacity to monitor viscosity change because of their sensitive for viscosity. For demonstration of its biomedical applications, these probes were successfully used for NIR-II fluorescence-guided surgical resection of lymph nodes. In summary, chlorophylls are novel valuable tool molecules for NIR-II fluorescence imaging and have potential to expand their applications in biomedical field and plant science.

Real time monitoring peripheral nerve function with ICG and BDA-ICG by NIR-II fluorescence imaging.

Neuroanatomical tract tracers are important for studying axoplasmic transport and the complex interconnections of the nervous system. Though traditional fluorescent tracers are widely used, they have several prominent drawbacks when imaging, including low resolutions and low tissue penetrations and inability to be supervised dynamically within a long peripheral nerve during the long term. Here, we explored the potential of ICG as a neural tracer for axoplasmic transport and for the first time demonstrated that ICG could be used to detect transport function within peripheral nerve by near-infrared region II (NIR-II) imaging. On basis of this finding, a novel bi-directional neural tracer biotinylated dextran amine-indocyanine green (BDA-ICG) was prepared and characterized with better long-term stability and higher nerve-to-background ratio than ICG in vivo, and successfully imaged the injured peripheral nerve from the healthy one within 24 h. Our results show that BDA-ICG are promising neural tracers and clinically available dyes with NIR-II emission tail characteristics as ICG.

Empowering pro-environmental behavior in tourists through digital media: the influence of eco-guilt and empathy with nature.

In the digital economy era, leveraging digital media to foster tourists' pro-environmental behavioral intention (TPEBI) has become crucial in the field of sustainable tourism. While existing studies have mainly focused on the driving mechanism of TPEBI within physical tourism contexts, the correlation between digital media information sharing and TPEBI remains unclear. Our study employs the cognitive-affective-conative framework to construct a theoretical model, considering eco-guilt and empathy with nature as mediating variables. It aims to explore the influencing mechanism of destination environmental information sharing through digital media on TPEBI from a presence perspective. Thereby, two scenario experiments were designed: Study 1 examined the impact of different formats of destination environmental threat information presentation on digital media on the sense of presence, while Study 2 explored the influencing mechanism of presence on TPEBI based on the conclusions of Study 1. Results indicate that (1) vivid and visible presentation formats of destination environmental threat information on digital media enhance individuals' sense of presence; (2) sense of presence positively influences TPEBI; and (3) eco-guilt and empathy with nature mediate between presence and TPEBI. These findings not only contribute to theoretical and empirical research on digital media information sharing in sustainable tourism but also offer guidance for governments and tourism destinations to effectively stimulate TPEBI through digital media, achieve the sustainable development of destinations.

Shuangdong Capsule Activates Insulin Signal Pathway to Improve Urinary Tract Infection in Diabetic Rats.

BACKGROUND AND AIM: Diabetes and Urinary Tract Infections (UTIs) are both common and serious health problems. Shuangdong capsule, a Chinese patent medicine, has been used to treat these conditions. This study assesses its efficacy and mechanism in treating diabetes combined with UTIs. METHODS: We induced diabetes in rats using streptozotocin and UTIs with Escherichia coli, dividing the rats into five groups: control, model, levofloxacin, Shuangdong capsule, and levofloxacin + Shuangdong capsule. After two weeks, we measured blood glucose, insulin, infection indicators, and bladder histology. We also detected the expression of insulin receptor substrate 1 (IRS1)-phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt)-C-X-C motif chemokine ligand 2 (CXCL2) signaling pathway by Western Blot and the myeloperoxidase (MPO) levels by Enzyme-Linked Immunosorbent Assay (ELISA). Additionally, we conducted a Mendelian randomization study using genetic variants of the insulin receptor to assess its causal effect on UTI risk. RESULTS: Shuangdong capsule improved bladder pathology and infection indicators, similar to levofloxacin. It did not affect blood glucose or insulin levels. Moreover, it reversed the suppression of the IRS1-PI3K-Akt-CXCL2 pathway and MPO levels caused by UTI in diabetic rats. The Mendelian randomization study showed that increased insulin receptor expression reduced UTI risk, which was consistent with the results of the animal experiments. CONCLUSION: The Shuangdong capsule was effective in treating diabetes with UTIs. It may function by activating the IRS1-PI3K-Akt signaling pathway, thereby increasing CXCL2 and MPO levels, enhancing innate immunity, and promoting bacterial clearance. The Mendelian randomization study provided further evidence supporting the causal role of the insulin receptor in UTI prevention.

Associations of the Serum KL-6 with Severity and Prognosis in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

BACKGROUND: As a biomarker of alveolar-capillary basement membrane injury, Krebs von den Lungen-6 (KL-6) is involved in the occurrence and development of pulmonary diseases. However, the role of the KL-6 in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) has yet to be elucidated. This prospective study was designed to clarify the associations of the serum KL-6 with the severity and prognosis in patients with AECOPD. METHODS: This study enrolled 199 eligible AECOPD patients. Demographic data and clinical characteristics were recorded. Follow-up was tracked to evaluate acute exacerbation and death. The serum KL-6 concentration was measured via an enzyme-linked immunosorbent assay. RESULTS: Serum KL-6 level at admission was higher in AECOPD patients than in control subjects. The serum KL-6 concentration gradually elevated with increasing severity of AECOPD. Pearson and Spearman analyses revealed that the serum KL-6 concentration was positively correlated with the severity score, monocyte count and concentrations of C-reactive protein, interleukin-6, uric acid, and lactate dehydrogenase in AECOPD patients during hospitalization. A statistical analysis of long-term follow-up data showed that elevated KL-6 level at admission was associated with longer hospital stays, an increased risk of future frequent acute exacerbations, and increased severity of exacerbation in COPD patients. CONCLUSION: Serum KL-6 level at admission is positively correlated with increased disease severity, prolonged hospital stay and increased risk of future acute exacerbations in COPD patients. There are positive dose-response associations of elevated serum KL-6 with severity and poor prognosis in COPD patients. The serum KL-6 concentration could be a novel diagnostic and prognostic biomarker in AECOPD patients.

Electrochemical Oxidative 1,2-Dithiocyanation: Access to Functionalized Alkenes and Alkynes.

Reported herein is the 1,2-dithiocyanation of alkenes and alkynes via an efficient and facile electrochemical method. This approach not only showed a broad substrate scope and good functional-group compatibility but also avoided stoichiometric oxidants. Different from previous reports, various internal alkynes could be tolerated to provide tetra-substituted alkenes. Further gram-scale-up experiments and synthetic transformation demonstrated a potential application in organic synthesis. This process underwent a radical pathway, as evidenced by our mechanistic studies.

Diagnostic efficacy of [68Ga]Ga-DOTA-GPFAPI-04 in patients with solid tumors in a head-to-head comparison with [18F]F-FDG: results from a prospective clinical study.

PURPOSE: To identify the biodistribution and diagnostic performance of a novel fibroblast activation protein (FAP) targeted positron emission tomography (PET) tracer, [68Ga]Ga-DOTA-GPFAPI-04, in patients with solid tumors in a head-to-head comparison with [18F]F-FDG. METHODS: Twenty-six patients histologically proven with cancers of nasopharyngeal (n = 5), esophagus (n = 5), gastro-esophagus (n = 1), stomach (n = 7), liver (n = 3), and colorectum (n = 5) were recruited for [68Ga]Ga-DOTA-GPFAPI-04 and [18F]F-FDG PET/CT scans on consecutive days. The primary endpoint was the diagnostic efficacy, with the histological diagnosis and the follow-up results selected as the gold standard. The secondary endpoint was the background uptake pattern. Two experienced nuclear medicine physicians who were blinded to the gold standard results while having essential awareness of the clinical context reviewed the images and labeled lesions by consensus for subsequent software-assisted lesion segmentation. Additionally, background organs were automatically segmented, assisted by artificial intelligence. Volume, mean, and maximum standard uptake values (SUVmean and SUVmax) of all segmentations were recorded. P < 0.05 was deemed as statistically significant. RESULTS: Significant glandular uptake of [68Ga]Ga-DOTA-GPFAPI-04 was detected in the thyroid, pancreas, and submandibular glands, while moderate uptake was observed in the parotid glands. The myocardium and myometrium exhibited 2-3 times higher uptake of the radiotracer than that of the background levels in blood and liver. A total of 349 targeted lesions, consisting of 324 malignancies and 25 benign lesions, were segmented. [68Ga]Ga-DOTA-GPFAPI-04 is more sensitive than [18F]F-FDG, especially for abdominopelvic dissemination (1.000 vs. 0.475, P < 0.001). Interestingly, [18F]F-FDG demonstrated higher sensitivity for lung metastasis compared to [68Ga]Ga-DOTA-GPFAPI-04 (0.845 vs. 0.682, P = 0.003). The high glandular uptake made it difficult to delineate lesions in close proximity and masked two metastatic lesions in these organs. CONCLUSION: Despite prominent glandular uptake, [68Ga]Ga-DOTA-GPFAPI-04 demonstrates favorable diagnostic performance. It is a promising probe scaffold for further development of FAP-targeted tumor theranostic agents.

Multi-center study of COVID-19 infection in elderly patients with lymphoma: on behalf of Jiangsu Cooperative Lymphoma Group (JCLG).

Elderly patients with lymphoproliferative diseases (LPD) are vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we retrospectively described the clinical features and outcomes of the first time infection of Omicron SARS-CoV-2 in 364 elderly patients with lymphoma enrolled in Jiangsu Cooperative Lymphoma Group (JCLG) between November 2022 and April 2023 in China. Median age was 69 years (range 60-92). 54.4% (198/364) of patients were confirmed as severe and critical COVID-19 infection. In univariable analysis, Age > 70 years (OR 1.88, p = 0.003), with multiple comorbidities (OR 1.41, p = 0.005), aggressive lymphoma (OR 2.33, p < 0.001), active disease (progressive or relapsed/refractory, OR 2.02, p < 0.001), and active anti-lymphoma therapy (OR 1.90, p < 0.001) were associated with severe COVID-19. Multiple (three or more) lines of previous anti-lymphoma therapy (OR 3.84, p = 0.021) remained an adverse factor for severe COVID-19 in multivariable analysis. Moreover, CD20 antibody (Rituximab or Obinutuzumab)-based treatments within the last 6 months was associated with severe COVID-19 in the entire cohort (OR 3.42, p < 0.001). Continuous BTK inhibitors might be protective effect on the outcome of COVID-19 infection (OR 0.44, p = 0.043) in the indolent lymphoma cohort. Overall, 7.7% (28/364) of the patients ceased, multiple lines of previous anti-lymphoma therapy (OR 3.46, p = 0.016) remained an adverse factor for mortality.

Changes in bacterial community composition in the uterus of Holstein cow with endometritis before and after treatment with oxytetracycline.

It is important to study the bacteria that cause endometritis to identify effective therapeutic drugs for dairy cows. In this study, 20% oxytetracycline was used to treat Holstein cows (n = 6) with severe endometritis. Additional 10 Holstein cows (5 for healthy cows, 5 for cows with mild endometritis) were also selected. At the same time, changes in bacterial communities were monitored by high-throughput sequencing. The results show that Escherichia coli, Staphylococcus aureus and other common pathogenic bacteria could be detected by traditional methods in cows both with and without endometritis. However, 16S sequencing results show that changes in the abundance of these bacteria were not significant. Endometritis is often caused by mixed infections in the uterus. Oxytetracycline did not completely remove existing bacteria. However, oxytetracycline could effectively inhibit endometritis and had a significant inhibitory effect on the genera Bacteroides, Trueperella, Peptoniphilus, Parvimonas, Porphyromonas, and Fusobacterium but had no significant inhibitory effect on the bacterial genera Marinospirillum, Erysipelothrix, and Enteractinococcus. During oxytetracycline treatment, the cell motility, endocrine system, exogenous system, glycan biosynthesis and metabolism, lipid metabolism, metabolism of terpenoids, polyketides, cofactors and vitamins, signal transduction, and transport and catabolism pathways were affected.

Major source categories of PM2.5 oxidative potential in wintertime Beijing and surroundings based on online dithiothreitol-based field measurements.

Fine particulate matter (PM2.5) causes millions of premature deaths each year worldwide. Oxidative potential (OP) has been proposed as a better metric for aerosol health effects than PM2.5 mass concentration alone. In this study, we report for the first time online measurements of PM2.5 OP in wintertime Beijing and surroundings based on a dithiothreitol (DTT) assay. These measurements were combined with co-located PM chemical composition measurements to identify the main source categories of aerosol OP. In addition, we highlight the influence of two distinct pollution events on aerosol OP (spring festival celebrations including fireworks and a severe regional dust storm). Source apportionment coupled with multilinear regression revealed that primary PM and oxygenated organic aerosol (OOA) were both important sources of OP, accounting for 41 ± 12 % and 39 ± 10 % of the OPvDTT (OP normalized by the sampled air volume), respectively. The small remainder was attributed to fireworks and dust, mainly resulting from the two distinct pollution events. During the 3.5-day spring festival period, OPvDTT spiked to 4.9 nmol min-1 m-3 with slightly more contribution from OOA (42 ± 11 %) and less from primary PM (31 ± 15 %). During the dust storm, hourly-averaged PM2.5 peaked at a very high value of 548 µg m-3 due to the dominant presence of dust-laden particles (88 % of total PM2.5). In contrast, only mildly elevated OPvDTT values (up to 1.5 nmol min-1 m-3) were observed during this dust event. This observation indicates that variations in OPvDTT cannot be fully explained using PM2.5 alone; one must also consider the chemical composition of PM2.5 when studying aerosol health effects. Our study highlights the need for continued pollution control strategies to reduce primary PM emissions, and more in-depth investigations into the source origins of OOA, to minimize the health risks associated with PM exposure in Beijing.

Prediction of mass spectrometry ionization efficiency based on COSMO-RS and machine learning algorithms.

Non-targeted analysis of high-resolution mass spectrometry (MS) can identify thousands of compounds, which also gives a huge challenge to their quantification. The aim of this study is to investigate the impact of mass spectrometry ionization efficiency on various compounds in food at different solvent ratios and to develop a predictive model for mass spectrometry ionization efficiency to enable non-targeted quantitative prediction of unknown compounds. This study covered 70 compounds in 14 different mobile phase ratio environments in positive ion mode to analyze the rules of the matrix effect. With the organic phase ratio from low to high, most compounds changed by 1.0 log units in log IE. The addition of formic acid enhanced the signal but also promoted the matrix effect, which often occurred in compounds with strong ionization capacity. It was speculated that the matrix effect was mainly in the form of competitive charge and charged droplet' gasification sites during MS detection. Subsequently, we present a log IE prediction method built using the COSMO-RS software and the artificial neural network (ANN) algorithm to address this difficulty and overcome the shortcomings of previous models, which always ignore the matrix effect. This model was developed following the principles of QSAR modeling recommended by the Organization for Economic Cooperation and Development (OECD). Furthermore, we validated this approach by predicting the log IE of 70 compounds, including those not involved in the log IE model development. The results presented demonstrate that the method we put forward has an excellent prediction accuracy for log IE (R2pred = 0.880), which means that it has the potential to predict the log IE of new compounds without authentic standards.

Construction of nanoparticles from blueberry anthocyanins-lecithin/gum Arabic improves lipid droplet accumulation and gut microbiota disturbance in HFD-induced obese mice.

The digestive instability of anthocyanins (ACNs) limits their application in food nutrition, especially precision nutrition. Blueberry ACNs-loaded nanoparticles (Lipo/GA-ACNs NPs) were prepared using gum arabic (GA) as the delivery carrier and liposomal vesicles (Lipo) prepared from soy lecithin as the targeting scaffold. The average particle size of the NPs was 99.4 nm, and the polydispersion index (PDI) was 0.46. The results showed that the presence of the Lipo-GA matrix enhanced the NPs' in vitro stability and antioxidant activity. In addition, the in vitro biocompatibility, uptake ability, lipid-lowering activity, and free-radical scavenging ability were improved to a certain extent. In a high-fat diet (HFD)-induced obese mouse model, oral administration of ACNs-LNP (LNP, liver-targeted nanoparticle) showed better effects on body weight, liver injury, and lipid droplet accumulation in the liver than ACNs. In addition, ACNs-LNP also played a role in regulating HFD-induced gut microbiota imbalance. These results provide a promising ACNs delivery strategy with the potential to be developed into a functional food that targets the liver to prevent fatty liver.

Overview of the recent advances in porcine epidemic diarrhea vaccines.

Vaccination is the most effective means of preventing and controlling porcine epidemic diarrhea (PED). Conventional vaccines developed from porcine epidemic diarrhea virus (PEDV) GI-a subtypes (CV777 and SM98) have played a vital role in preventing classical PED. However, with the emergence of PEDV mutants in 2010, conventional PEDV GI-a subtype-targeting vaccines no longer provide adequate protection against PEDV GII mutants, thereby making novel-type PED vaccine development an urgent concern to be addressed. Novel vaccines, including nucleic acid vaccines, genetically engineered subunit vaccines, and live vector vaccines, are associated with several advantages, such as high safety and stability, clear targeting, high yield, low cost, and convenient usage. These vaccines can be combined with corresponding ELISA kits to differentiate infected from vaccinated animals, which is beneficial for disease confirmation. This review provides a detailed overview of the recent advancements in PED vaccines, emphasizing on the research and application evaluation of novel PED vaccines. It also considers the future directions and challenges in advancing these vaccines to widespread use in clinics.

NIR-II fluorescence imaging without intended excitation light.

Nowadays, second near-infrared window (NIR-II) dyes are almost excited by laser diodes, but none of the white light (400-700 nm) excited NIR-II imaging has been studied because of the lack of suitable optical probes. Herein, a novel blue-shifted NIR-II dye, TPA-TQT, has been selected for use in multi-wavelength white light emitting diode (LED) excited NIR-II imaging. This white LED barely caused photo-quenching of the dyes, especially indocyanine green (ICG), whereas the ICG's brightness decreased by 90% under continuous 808 nm laser irradiation. Compared to single-wavelength LED, multi-wavelength LED showed a lower background and similar signal-to-background ratios. This system provided high image resolution to identify blood vessels (103 µm), lymphatic capillaries (129.8 µm), and to monitor hindlimb ischemia-reperfusion and lymphatic inflammation. Furthermore, white LED excited NIR-II fluorescence imaging-guided surgery (FIGS) was successfully performed in 4T1 tumor-bearing mice. Impressively, the lighting LED-based NIR-II FIGS was found to clearly delineate small lesions of metastatic tumors of about ∼350 µm diameter and further was able to guide surgical removal. Overall, multi-wavelength LED-based NIR-II imaging is a promising imaging strategy for tumor delineation and other biomedical applications.

Dysregulated fibrinolysis and plasmin activation promote the pathogenesis of osteoarthritis.

Joint injury is associated with risk for development of osteoarthritis (OA). Increasing evidence suggests that activation of fibrinolysis is involved in OA pathogenesis. However, the role of the fibrinolytic pathway is not well understood. Here, we showed that the fibrinolytic pathway, which includes plasminogen/plasmin, tissue plasminogen activator, urokinase plasminogen activator (uPA), and the uPA receptor (uPAR), was dysregulated in human OA joints. Pharmacological inhibition of plasmin attenuated OA progression after a destabilization of the medial meniscus in a mouse model whereas genetic deficiency of plasmin activator inhibitor, or injection of plasmin, exacerbated OA. We detected increased uptake of uPA/uPAR in mouse OA joints by microPET/CT imaging. In vitro studies identified that plasmin promotes OA development through multiple mechanisms, including the degradation of lubricin and cartilage proteoglycans and induction of inflammatory and degradative mediators. We showed that uPA and uPAR produced inflammatory and degradative mediators by activating the PI3K, 3'-phosphoinositide-dependent kinase-1, AKT, and ERK signaling cascades and activated matrix metalloproteinases to degrade proteoglycan. Together, we demonstrated that fibrinolysis contributes to the development of OA through multiple mechanisms and suggested that therapeutic targeting of the fibrinolysis pathway can prevent or slow development of OA.

Effect of Helicobacter Pylori Infection on Glucose Metabolism, Lipid Metabolism and Inflammatory Cytokines in Nonalcoholic Fatty Liver Disease Patients.

Objective: To probe into the influence of Helicobacter pylori (Hp) infection on glucose metabolism, lipid metabolism, and inflammatory cytokines in patients with nonalcoholic fatty liver disease (MASLD). Methods: A total of 140 MASLD patients admitted to our Hospital between June 2020 and May 2021 were selected as the research objects. Based on the presence or absence of Hp infection, they were divided into the study group (73 cases with infection) and control group (67 cases without infection). Glucose metabolism indicators [fasting blood glucose (FBG), 2-hour postprandial glucose (2hPG), fasting insulin (FINS), glycated hemoglobin (HbAlc)], lipid metabolism indicators [total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C)], and inflammatory indicators [interleukin-37 (IL-37), interleukin-18 (IL-18)] were measured and compared between the two groups. Results: In terms of glucose metabolism indicators, the study group exhibited higher levels of FBG (5.84±0.49 vs 5.40±0.51, t=2.535, P=0.012), 2hPG (7.26±1.30 vs 6.50±1.53, t=3.321, P<0.001), and FINS (11.13±4.13 vs 9.12±3.72, t=3.224, P<0.001), and Insulin resistance index (HOMA-IR) (2.97±0.35 VS 2.13±0.54, t=3.761, P<0.001) and a lower level of HbAlc (5.25±0.56 vs 6.12±0.57, t=5.473, P<0.001) compared to the control group. Regarding lipid metabolism indicators, the study group exhibited higher levels of TC (5.64±1.49 vs 5.01±1.32, t=3.332, P<0.001), TG (1.89±0.34 vs 1.32±0.43, t=3.411, P<0.001), and LDL-C (3.31±0.43 vs 2.12±0.29, t=4.142, P<0.001), and a lower level of HDL-C (1.45±0.21 vs 1.78±0.42, t=4.347, P<0.001) compared to the control group. As for the inflammatory indicators, the study group exhibited higher levels of IL-37 (45.56±6.02 vs 34.02±3.28, t=9.332, P<0.001) and IL-18 (73.57±5.82 vs 60.34±4.84, t=10.141, P<0.001) compared to the control group. Conclusion: It is crucial to place appropriate emphasis on the impact of Hp infection on the glucose metabolism, lipid metabolism, and inflammatory response in MASLD patients, warranting careful consideration during the treatment of these patients.