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Biophysics Reviews Sep 2024Polymeric fibrin provides the structural and mechanical stability of a blood clot. Fibrin fibers are rod-like and create a network mesh that holds blood cells. When a...
Polymeric fibrin provides the structural and mechanical stability of a blood clot. Fibrin fibers are rod-like and create a network mesh that holds blood cells. When a clot has performed its physiological function in wound healing and preventing excessive blood loss, it must be resolved by the enzymatic degradation of fibrin, otherwise known as fibrinolysis. If a blood clot forms when or where it is not needed, as occurs in ischemic strokes and myocardial infarctions, the blood clot (thrombus) can obstruct blood flow to downstream organs. Obstructive thrombi must be degraded or removed to prevent further complications. If a clot is not degraded on its own, lytic agents (i.e., tissue plasminogen activator, tPA) are given exogenously to induce fibrinolysis. Here, we fluorescently labeled both fibrin and tPA to visualize degradation at the edge of the clot. The fibers with bound tPA were looped or coiled while the fibers farther into the clot remain straight and stable displaying the diffusion of tPA and depth of lysis. This image provides (1) a new method to monitor fibrinolysis with a commercially available chamber with convenient inlets and (2) the visualization of tPA-bound fibrin and the behavior of fibers during degradation. Future work could utilize this technique to study tPA molecule and fibrin interactions, lysis front degradation, and fibrin fiber linearity to understand the mechanisms of intermolecular dynamics dependent on network structure. An enhanced insight into this process can aid in the development of optimized therapeutics to target stubborn clots.
PubMed: 38962393
DOI: 10.1063/5.0220356 -
Alimentary Pharmacology & Therapeutics Jul 2024
Letter: Helicobacter pylori and metabolic syndrome-related von Willebrand factor and plasminogen activator inhibitor-1 activity levels for outcome prediction of advanced chronic liver disease: Authors' reply.
PubMed: 38961544
DOI: 10.1111/apt.18144 -
Alimentary Pharmacology & Therapeutics Jul 2024
Letter: Helicobacter pylori and metabolic syndrome-related von Willebrand factor and plasminogen activator inhibitor-1 activity levels for outcome prediction of advanced chronic liver disease.
PubMed: 38961543
DOI: 10.1111/apt.18066 -
Scientific Reports Jul 2024Diabetic cardiomyopathy (DCM) is a common cardiovascular complication of diabetes, which may threaten the quality of life and shorten life expectancy in the diabetic...
Diabetic cardiomyopathy (DCM) is a common cardiovascular complication of diabetes, which may threaten the quality of life and shorten life expectancy in the diabetic population. However, the molecular mechanisms underlying the diabetes cardiomyopathy are not fully elucidated. We analyzed two datasets from Gene Expression Omnibus (GEO). Differentially expressed and weighted gene correlation network analysis (WGCNA) was used to screen key genes and molecules. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and protein-protein interaction (PPI) network analysis were constructed to identify hub genes. The diagnostic value of the hub gene was evaluated using the receiver operating characteristic (ROC). Quantitative real-time PCR (RT-qPCR) was used to validate the hub genes. A total of 13 differentially co-expressed modules were selected by WGCNA and differential expression analysis. KEGG and GO analysis showed these DEGs were mainly enriched in lipid metabolism and myocardial hypertrophy pathway, cytomembrane, and mitochondrion. As a result, six genes were identified as hub genes. Finally, five genes (Pdk4, Lipe, Serpine1, Igf1r, and Bcl2l1) were found significantly changed in both the validation dataset and experimental mice with DCM. In conclusion, the present study identified five genes that may help provide novel targets for diagnosing and treating DCM.
Topics: Diabetic Cardiomyopathies; Computational Biology; Animals; Mice; Gene Regulatory Networks; Protein Interaction Maps; Humans; Plasminogen Activator Inhibitor 1; Gene Expression Profiling; Receptor, IGF Type 1; Gene Ontology; Gene Expression Regulation
PubMed: 38961143
DOI: 10.1038/s41598-024-65773-z -
Journal of Neurology Jul 2024United States stroke systems are increasingly transitioning from alteplase (TPA) to tenecteplase (TNK). Real-world data on the safety and effectiveness of replacing TPA...
INTRODUCTION
United States stroke systems are increasingly transitioning from alteplase (TPA) to tenecteplase (TNK). Real-world data on the safety and effectiveness of replacing TPA with TNK before large vessel occlusion (LVO) stroke endovascular treatment (EVT) are lacking.
METHODS
Four Pennsylvania stroke systems transitioned from TPA to TNK during the study period 01/2020-06/2023. LVO stroke patients who received intravenous thrombolysis with TPA or TNK before EVT were reviewed. Multivariate logistic analysis was conducted adjusting for age, sex, National Institute of Health Stroke Scale (NIHSS), occlusion site, last-known-well-to-intravenous thrombolysis time, interhospital-transfer and stroke system.
RESULTS
Of 635 patients, 309 (48.7%) received TNK and 326 (51.3%) TPA prior to EVT. The site of occlusion was the M1 middle cerebral artery (MCA) (47.7%), M2 MCA (25.4%), internal carotid artery (14.0%), tandem carotid with M1 or M2 MCA (9.8%) and basilar artery (3.1%). A favorable functional outcome (90-day mRS ≤ 2) was observed in 47.6% of TNK and 49.7% of TPA patients (p = 0.132). TNK versus TPA groups had similar rates of early recanalization (11.9% vs. 8.4%, p = 0.259), successful endovascular reperfusion (93.5% vs. 89.3%, p = 0.627), symptomatic intracranial hemorrhage (3.2% vs. 3.4%, p = 0.218) and 90-day all-cause mortality (23.1% vs. 21.5%, p = 0.491).
CONCLUSIONS
This U.S. multicenter real-world clinical experience demonstrated that switching from TPA to TNK before EVT for LVO stroke resulted in similar endovascular reperfusion, safety, and functional outcomes.
PubMed: 38960948
DOI: 10.1007/s00415-024-12530-x -
Medicina Clinica Jul 2024The soluble urokinase-type plasminogen activator receptor (suPAR) potentially plays a role in immune-thrombosis, possibly by modulating plasmin activity or contributing...
INTRODUCTION
The soluble urokinase-type plasminogen activator receptor (suPAR) potentially plays a role in immune-thrombosis, possibly by modulating plasmin activity or contributing to chemotaxis in a complex, poorly understood context. The role of suPAR levels in the short-term prognostic of patients with pulmonary embolism (PE) has not been evaluated.
MATERIAL AND METHODS
This observational, prospective, single-center study enrolled consecutive patients aged 18 and above with confirmed acute symptomatic PE and no prior anticoagulant therapy. The primary objective was to assess the prognostic capacity of suPAR levels measured at the time of diagnosis in terms of mortality.
RESULTS
Fifty-two patients, with a mean age of 73.8 years (±17), were included, with gender distribution evenly split at 50%. Seven (13.5%) patients died. The ROC curve for mortality yielded an AUC of 0.72 (95% CI 0.48-0.96), with an optimal suPAR cut-off of 5.5ng/mL. Bivariate analysis for suPAR>5.5ng/mL was associated with a crude odds ratio of 10 (95% CI 1.63-61.27; p=0.01) for 30-day mortality. Survival analysis showed a 30-day mortality hazard ratio of 8.33 (95% CI 1.69-40.99; p<0.01).
CONCLUSION
suPAR emerges as a potential biomarker for short-term mortality prediction and holds the potential for enhanced stratification in patients with acute symptomatic PE.
PubMed: 38960794
DOI: 10.1016/j.medcli.2024.04.019 -
International Journal of Biological... Jul 2024Antisense long non-coding RNAs (lncRNAs) played a crucial role in the precise regulation of essential biological processes and were abundantly present in animals. Many...
Antisense long non-coding RNAs (lncRNAs) played a crucial role in the precise regulation of essential biological processes and were abundantly present in animals. Many of these antisense lncRNAs have been identified as key roles in adipose tissue accumulation in livestock, underscoring their vital role in the regulation of animal physiology. Nonetheless, the functional roles of these antisense lncRNAs in regulating adipogenesis and the specific molecular mechanisms these processes were still unclear, which was a significant gap in current scientific research. In this study, we identified and characterized SERPINE1AS2, a novel natural antisense lncRNA, was highly expressed in the fat tissues of adult cattle and calves. Its expression gradually increased during the differentiation of intramuscular adipocytes. Through functional studies, we observed that knockdown of SERPINE1AS2 inhibited the proliferation and adipogenesis of intramuscular adipocytes, while overexpression of SERPINE1AS2 produced the opposite effect. RNA sequencing (RNA-seq) analysis following SERPINE1AS2 knockdown revealed that differential expression genes (DEGs) were significantly enriched in key signaling pathways, notably the MAPK, Wnt, and mTOR signaling pathways. Furthermore, SERPINE1AS2 interacted with Plasminogen Activator Inhibitor-1 (PAI1), forming RNA dimers through complementary base pairing and consequently influencing PAI1 expression. Interestingly, studies on PAI1 suggested that reduced expression facilitated adipogenesis and the downregulation of PAI1 alleviated the inhibitory effect of reduced SERPINE1AS2 on adipogenesis. In summary, this study suggested that SERPINE1AS2 played a crucial role in the adipogenesis of bovine intramuscular adipocytes by modulating the expression of PAI1. SERPINE1AS2 also regulated adipogenesis by engaging in the MAPK, Wnt, and mTOR signaling pathways. Our results suggested that SERPINE1AS2 had a complex regulatory mechanism on adipogenesis in intramuscular adipocytes.
PubMed: 38960265
DOI: 10.1016/j.ijbiomac.2024.133592 -
Health Science Reports Jul 2024
PubMed: 38957858
DOI: 10.1002/hsr2.2181 -
BMC Cancer Jul 2024The in vivo functions of SerpinB2 in tumor cells and tumor-associated macrophages (TAMs) during breast cancer development and metastasis remain elusive....
The in vivo functions of SerpinB2 in tumor cells and tumor-associated macrophages (TAMs) during breast cancer development and metastasis remain elusive. SerpinB2-deficient MMTV-PyMT mice (PyMT) were previously produced to explore the biological roles of SerpinB2 in breast cancer. Compared with MMTV-PyMT wild-type (PyMT) mice, PyMT mice showed delayed tumor progression and reduced CK8 + tumor cell dissemination to lymph nodes. RNA-Seq data revealed significantly enriched genes associated with inflammatory responses, especially upregulated M1 and downregulated M2 macrophage marker genes in PyMT tumors. Decreased CD206M2 and increased NOS2M1 markers were detected in the primary tumors and metastatic lymph nodes of PyMT mice. In an in vitro study, SerpinB2 knockdown decreased the sphere formation and migration of MDA-MB-231 cells and suppressed protumorigenic M2 polarization of RAW264.7 cells. The combination of low SerpinB2, high NOS2, and low CD206 expression was favorable for survival in patients with breast cancer, as assessed in the BreastMark dataset. Our study demonstrates that SerpinB2 deficiency delays mammary tumor development and metastasis in PyMT mice, along with reduced sphere formation and migration abilities of tumor cells and decreased macrophage protumorigenic polarization.
Topics: Animals; Mice; Female; Plasminogen Activator Inhibitor 2; Humans; Breast Neoplasms; Macrophages; Tumor-Associated Macrophages; Cell Line, Tumor; Mice, Knockout; RAW 264.7 Cells; Mammary Neoplasms, Experimental; Nitric Oxide Synthase Type II; Cell Movement
PubMed: 38956496
DOI: 10.1186/s12885-024-12473-6 -
ACS Applied Materials & Interfaces Jul 2024To effectively solve the problem of significant loss of transplanted cells caused by thrombosis during cell transplantation, this study simulates the human fibrinolytic...
To effectively solve the problem of significant loss of transplanted cells caused by thrombosis during cell transplantation, this study simulates the human fibrinolytic system and combines metabolic oligosaccharide engineering with strain-promoted azide-alkyne cycloaddition (SPAAC) click chemistry to construct a cell surface with fibrinolytic activity. First, a copolymer (POL) of oligoethylene glycol methacrylate (OEGMA) and 6-amino-2-(2-methylamido)hexanoic acid (Lys) was synthesized by reversible addition-fragmentation chain transfer (RAFT) copolymerization, and the dibenzocyclooctyne (DBCO) functional group was introduced into the side chain of the copolymer through an active ester reaction, resulting in a functionalized copolymer DBCO-PEG4-POL with ε-lysine ligands. Then, azide functional groups were introduced onto the surface of HeLa model cells through metabolic oligosaccharide engineering, and DBCO-PEG4-POL was further specifically modified onto the surface of HeLa cells via the SPAAC "click" reaction. In vitro investigations revealed that compared with unmodified HeLa cells, modified cells not only resist the adsorption of nonspecific proteins such as fibrinogen and human serum albumin but also selectively bind to plasminogen in plasma while maintaining good cell viability and proliferative activity. More importantly, upon the activation of adsorbed plasminogen into plasmin, the modified cells exhibited remarkable fibrinolytic activity and were capable of promptly dissolving the primary thrombus formed on their surfaces. This research not only provides a novel approach for constructing transplantable cells with fibrinolytic activity but also offers a new perspective for effectively addressing the significant loss of transplanted cells caused by thrombosis.
PubMed: 38954798
DOI: 10.1021/acsami.4c07619