-
BioRxiv : the Preprint Server For... Feb 2024The precise molecular drivers of abdominal aortic aneurysm (AAA) remain unclear. Thymidine phosphorylase (TYMP) contributes to increased platelet activation, thrombosis,...
AIMS
The precise molecular drivers of abdominal aortic aneurysm (AAA) remain unclear. Thymidine phosphorylase (TYMP) contributes to increased platelet activation, thrombosis, and inflammation, all of which are key factors in AAA development. Additionally, TYMP suppresses the proliferation of vascular smooth muscle cells (VSMCs), which are central to the development and progression of AAA. We hypothesize that TYMP plays a key role in AAA development.
METHODS AND RESULTS
We conducted a histological study using human AAA samples and normal abdominal aortas, revealing heightened levels of TYMP in human AAA vessel walls. To validate this observation, we utilized an Ang II perfusion-induced AAA model in wild-type C57BL/6J (WT) and mice, feeding them a Western diet (TD.88137) starting from 4 weeks of age. We found that mice were protected from Ang II perfusion-induced AAA formation. Furthermore, by using TYMP-expressing VSMCs as well as primarily cultured VSMCs from WT and mice, we elucidated the essential role of TYMP in regulating MMP2 expression and activation. TYMP deficiency or inhibition by tipiracil, a selective TYMP inhibitor, led to reduced MMP2 production, release, and activation in VSMCs. Additionally, TYMP was found to promote pro-inflammatory cytokine expression systemically, and its absence attenuates TNF-α-stimulated activation of MMP2 and AKT. By co-culturing VSMCs and platelets, we observed that TYMP-deficient platelets had a reduced inhibitory effect on VSMC proliferation compared to WT platelets. Moreover, TYMP appeared to enhance the expression of activated TGFβ1 in cultured VSMCs in vitro and in human AAA vessel walls in vivo. TYMP also boosted the activation of thrombospondin-1 type 1 repeat domain-enhanced TGFβ1 signaling, resulting in increased connective tissue growth factor production.
CONCLUSION
Our findings collectively demonstrated that TYMP serves as a novel regulatory force in vascular biology, exerting influence over VSMC functionality and inflammatory responses that promote the development of AAA.
PubMed: 38464026
DOI: 10.1101/2024.02.27.582208 -
JHEP Reports : Innovation in Hepatology Apr 2024Recent studies have implicated platelets, particularly α-granules, in the development of non-alcoholic steatohepatitis (NASH). However, the specific mechanisms involved...
BACKGROUND & AIMS
Recent studies have implicated platelets, particularly α-granules, in the development of non-alcoholic steatohepatitis (NASH). However, the specific mechanisms involved have yet to be determined. Notably, thrombospondin 1 (TSP1) is a major component of the platelet α-granules released during platelet activation. Hence, we aimed to determine the role of platelet-derived TSP1 in NASH.
METHODS
Platelet-specific knockout mice ( and their wild-type littermates () were used. NASH was induced by feeding the mice with a diet enriched in fat, sucrose, fructose, and cholesterol (AMLN diet). A human liver NASH organoid model was also employed.
RESULTS
Although TSP1 deletion in platelets did not affect diet-induced steatosis, mice exhibited attenuated NASH and liver fibrosis, accompanied by improvements in plasma glucose and lipid homeostasis. Furthermore, mice showed reduced intrahepatic platelet accumulation, activation, and chemokine production, correlating with decreased immune cell infiltration into the liver. Consequently, this diminished proinflammatory signaling in the liver, thereby mitigating the progression of NAFLD. Moreover, data revealed that co-culturing TSP1-deficient platelets in a human liver NASH organoid model attenuated hepatic stellate cell activation and NASH progression. Additionally, TSP1-deficient platelets play a role in regulating brown fat endocrine function, specifically affecting Nrg4 (neuregulin 4) production. Crosstalk between brown fat and the liver may also influence the progression of NAFLD.
CONCLUSIONS
These data suggest that platelet α-granule-derived TSP1 is a significant contributor to diet-induced NASH and fibrosis, potentially serving as a new therapeutic target for this severe liver disease.
IMPACT AND IMPLICATIONS
Recent studies have implicated platelets, specifically α-granules, in the development of non-alcoholic steatohepatitis, yet the precise mechanisms remain unknown. In this study, through the utilization of a tissue-specific knockout mouse model and human 3D liver organoid, we demonstrated that platelet α-granule-derived TSP1 significantly contributes to diet-induced non-alcoholic steatohepatitis and fibrosis. This contribution is, in part, attributed to the regulation of intrahepatic immune cell infiltration and potential crosstalk between fat and the liver. These findings suggest that platelet-derived TSP1 may represent a novel therapeutic target in non-alcoholic fatty liver disease.
PubMed: 38455470
DOI: 10.1016/j.jhepr.2024.101019 -
Biomaterials and Biosystems Mar 2024Osteoarthritis (OA) is a chronic musculoskeletal disorder characterized by an imbalance between (synthesis) and catabolism (degradation) in altered homeostasis of... (Review)
Review
Osteoarthritis (OA) is a chronic musculoskeletal disorder characterized by an imbalance between (synthesis) and catabolism (degradation) in altered homeostasis of articular cartilage mediated primarily by the innate immune system. OA degenerates the joints resulting in synovial hyperplasia, degradation of articular cartilage with damage of the structural and functional integrity of the cartilage extracellular matrix, subchondral sclerosis, osteophyte formation, and is characterized by chronic pain, stiffness, and loss of function. Inflammation triggered by factors like biomechanical stress is involved in the development of osteoarthritis. In OA apart from catabolic effects, anti-inflammatory anabolic processes also occur continually. There is also an underlying chronic inflammation present, not only in cartilage tissue but also within the synovium, which perpetuates tissue destruction of the OA joint. The consideration of inflammation in OA considers synovitis and/or other cellular and molecular events in the synovium during the progression of OA. In this review, we have presented the progression of joint degradation that results in OA. The critical role of inflammation in the pathogenesis of OA is discussed in detail along with the dysregulation within the cytokine networks composed of inflammatory and anti-inflammatory cytokines that drive catabolic pathways, inhibit matrix synthesis, and promote cellular apoptosis. OA pathogenesis, fluctuation of synovitis, and its clinical impact on disease progression are presented here along with the role of synovial macrophages in promoting inflammatory and destructive responses in OA. The role of interplay between different cytokines, structure, and function of their receptors in the inter-cellular signaling pathway is further explored. The effect of cytokines in the increased synthesis and release of matrix-decomposing proteolytic enzymes, such as matrix metalloproteinase (MMPs) and a disintegrin-like and metalloproteinase with thrombospondin motif (ADAMTS), is elaborated emphasizing the potential impact of MMPs on the chondrocytes, synovial cells, articular and periarticular tissues, and other immune system cells migrating to the site of inflammation. We also shed light on the pathogenesis of OA via oxidative damage particularly due to nitric oxide (NO) via its angiogenic response to inflammation. We concluded by presenting the current knowledge about the tissue inhibitors of metalloproteinases (TIMPs). Synthetic MMP inhibitors include zinc binding group (ZBG), non-ZBG, and mechanism-based inhibitors, all of which have the potential to be therapeutically beneficial in the treatment of osteoarthritis. Improving our understanding of the signaling pathways and molecular mechanisms that regulate the MMP gene expression, may open up new avenues for the creation of therapies that can stop the joint damage associated with OA.
PubMed: 38440290
DOI: 10.1016/j.bbiosy.2024.100090 -
BMC Medicine Mar 2024The key role of thrombospondin 1 (THBS1) in the pathogenesis of acute-on-chronic liver failure (ACLF) is unclear. Here, we present a transcriptome approach to evaluate...
BACKGROUND
The key role of thrombospondin 1 (THBS1) in the pathogenesis of acute-on-chronic liver failure (ACLF) is unclear. Here, we present a transcriptome approach to evaluate THBS1 as a potential biomarker in ACLF disease pathogenesis.
METHODS
Biobanked peripheral blood mononuclear cells (PBMCs) from 330 subjects with hepatitis B virus (HBV)-related etiologies, including HBV-ACLF, liver cirrhosis (LC), and chronic hepatitis B (CHB), and normal controls (NC) randomly selected from the Chinese Group on the Study of Severe Hepatitis B (COSSH) prospective multicenter cohort underwent transcriptome analyses (ACLF = 20; LC = 10; CHB = 10; NC = 15); the findings were externally validated in participants from COSSH cohort, an ACLF rat model and hepatocyte-specific THBS1 knockout mice.
RESULTS
THBS1 was the top significantly differentially expressed gene in the PBMC transcriptome, with the most significant upregulation in ACLF, and quantitative polymerase chain reaction (ACLF = 110; LC = 60; CHB = 60; NC = 45) was used to verify that THBS1 expression corresponded to ACLF disease severity outcome, including inflammation and hepatocellular apoptosis. THBS1 showed good predictive ability for ACLF short-term mortality, with an area under the receiver operating characteristic curve (AUROC) of 0.8438 and 0.7778 at 28 and 90 days, respectively. Enzyme-linked immunosorbent assay validation of the plasma THBS1 using an expanded COSSH cohort subjects (ACLF = 198; LC = 50; CHB = 50; NC = 50) showed significant correlation between THBS1 with ALT and γ-GT (P = 0.01), and offered a similarly good prognostication predictive ability (AUROC = 0.7445 and 0.7175) at 28 and 90 days, respectively. ACLF patients with high-risk short-term mortality were identified based on plasma THBS1 optimal cut-off value (< 28 µg/ml). External validation in ACLF rat serum and livers confirmed the functional association between THBS1, the immune response and hepatocellular apoptosis. Hepatocyte-specific THBS1 knockout improved mouse survival, significantly repressed major inflammatory cytokines, enhanced the expression of several anti-inflammatory mediators and impeded hepatocellular apoptosis.
CONCLUSIONS
THBS1 might be an ACLF disease development-related biomarker, promoting inflammatory responses and hepatocellular apoptosis, that could provide clinicians with a new molecular target for improving diagnostic and therapeutic strategies.
Topics: Animals; Humans; Mice; Rats; Acute-On-Chronic Liver Failure; Biomarkers; Hepatitis B virus; Inflammation; Leukocytes, Mononuclear; Liver Cirrhosis; Prospective Studies; Thrombospondin 1
PubMed: 38439091
DOI: 10.1186/s12916-024-03318-x -
European Review For Medical and... Feb 2024The prevalence of both atrial fibrillation (AF) and diabetes is increasing day by day and commonly co-exist with a longer duration of diabetes and poor control, putting... (Review)
Review
The prevalence of both atrial fibrillation (AF) and diabetes is increasing day by day and commonly co-exist with a longer duration of diabetes and poor control, putting the individual at higher risk of AF. This review article presented some traditional and novel biomarkers related to AF in patients with diabetes mellitus. The literature review employed several databases, including Google Scholar, PubMed, and Science Direct. The investigation was finished on October 30, 2023. Many terms are utilized, including "AF", "Biomarkers", "Diabetes Mellitus", and "Pathogenesis". There are numerous biomarkers of diabetes, but this review article reports only leptin, adiponectin, glycated hemoglobin, ceramide, ferritin, fibrinogen, hematological indices, interleukin-18, thrombospondin 1, acylcarnitine, plasminogen activator inhibitor-1 and triglycerides and high-density lipoprotein cholesterol, since those biomarkers play a significant role in the pathogenesis of AF. However, no data was found, including fructosamine, glycated albumin, 1,5 anhydroglucitol, fetuin-A, α-hydroxybutyrate, mannose-binding lectin serine peptidase, transferrin, IL-1 receptor antagonist in AF. Understanding the interplay between diabetes and AF through the measurement of relevant biomarkers can contribute to better risk assessment, early detection, and the development of targeted therapeutic strategies for individuals at risk or already affected by these conditions.
Topics: Humans; Atrial Fibrillation; Diabetes Mellitus; Adiponectin; Biomarkers; Ceramides
PubMed: 38436186
DOI: 10.26355/eurrev_202402_35482 -
Iranian Journal of Public Health Dec 2023A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) is a superfamily of extracellular proteinases found in both mammals and invertebrates. Although...
BACKGROUND
A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) is a superfamily of extracellular proteinases found in both mammals and invertebrates. Although there is some evidence about the role of ADAMTSs in ocular diseases such as glaucoma and ectopia lentis, but there is little information about the expression patterns of and ADAMTS-like ( and ) genes in human ocular tissues. This study aimed to evaluate the expression profiling of (L) superfamily of genes in different ocular tissues based on age.
METHODS
In 2019, nine human donated eye globes were provided from the Central Eye Bank of Iran, and were divided into three different groups based on age (under 3 yr old, between 20 to 50 and upper 50 yr old). To assess expression patterns of (L) genes in different ocular tissues including trabecular meshwork, lens, retinal pigment epithelium, macula, and optic nerve in the three age groups, total RNA was extracted from the tissues and reverse transcription polymerase chain reaction followed by Real-time PCR was performed.
RESULTS
We demonstrated not only each member of (L) superfamily shows different expression pattern between the five investigated ocular tissues, but also some members have differential expressions among the investigated age groups in same tissues.
CONCLUSION
Differential expression of (L) genes in ocular tissues from different age groups could explain some functional aspects of the tissues and also may be used as prognostic and diagnostic biomarkers for ocular diseases and pathologies. Further studies are required to explore their functional roles associated with ocular pathologies.
PubMed: 38435780
DOI: 10.18502/ijph.v52i12.14324 -
European Journal of Human Genetics :... May 2024Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders caused by mutations in collagen and collagen-interacting genes. We delineate a novel form of EDS...
Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders caused by mutations in collagen and collagen-interacting genes. We delineate a novel form of EDS with vascular features through clinical and histopathological phenotyping and genetic studies of a three-generation pedigree, displaying an apparently autosomal dominant phenotype of joint hypermobility and frequent joint dislocations, atrophic scarring, prolonged bleeding time and age-related aortic dilatation and rupture. Coagulation tests as well as platelet counts and function were normal. Reticular dermis displayed highly disorganized collagen fibers and transmission electron microscopy (TEM) revealed abnormally shaped fibroblasts and endothelial cells, with high amount and irregular shape of extracellular matrix (ECM) substance, especially near blood vessels. Genetic analysis unraveled a heterozygous mutation in THBS2 (NM_003247.5:c.2686T>C, p.Cys896Arg). We generated CRISPR/Cas9 knock-in (KI) mice, bearing the heterozygous human mutation in the mouse ortholog. The KI mice demonstrated phenotypic traits correlating with those observed in the human subjects, as evidenced by morphologic, histologic, and TEM analyses, in conjunction with bleeding time assays. Our findings delineate a novel form of human EDS with classical-like elements combined with vascular features, caused by a heterozygous THBS2 missense mutation. We further demonstrate a similar phenotype in heterozygous THBS2 KI mice, in line with previous studies in Thbs2 homozygous null-mutant mice. Notably, THBS2 encodes Thrombospondin-2, a secreted homotrimeric matricellular protein that directly binds the ECM-shaping Matrix Metalloproteinase 2 (MMP2), mediating its clearance. THBS2 loss-of-function attenuates MMP2 clearance, enhancing MMP2-mediated proteoglycan cleavage, causing ECM abnormalities similar to those seen in the human and mouse disease we describe.
Topics: Ehlers-Danlos Syndrome; Animals; Thrombospondins; Humans; Mice; Male; Female; Heterozygote; Adult; Phenotype; Pedigree; Middle Aged; Mutation, Missense
PubMed: 38433265
DOI: 10.1038/s41431-024-01559-1 -
Internal Medicine (Tokyo, Japan) Mar 2024Recently, immune checkpoint inhibitors (ICIs) have been used to treat several cancer types. ICIs have been reported to cause a wide variety of immune-related adverse...
Recently, immune checkpoint inhibitors (ICIs) have been used to treat several cancer types. ICIs have been reported to cause a wide variety of immune-related adverse events, including endocrine, neurologic, gastrointestinal, and cutaneous disorders. Thrombotic thrombocytopenic purpura (TTP) is an autoimmune hematologic disorder characterized by the presence of autoantibodies against a disintegrin and metalloprotease with thrombospondin-1, member 13. Several previous cases of TTP were thought to have been caused by ICI treatment. We herein report a rare case of TTP that developed after long-term treatment with an ICI (nivolumab) for gastric tube cancer.
PubMed: 38432967
DOI: 10.2169/internalmedicine.2931-23 -
Frontiers in Immunology 2024The ubiquitously expressed transmembrane glycoprotein CD47 participates in various important physiological cell functions, including phagocytosis, apoptosis,... (Review)
Review
The ubiquitously expressed transmembrane glycoprotein CD47 participates in various important physiological cell functions, including phagocytosis, apoptosis, proliferation, adhesion, and migration, through interactions with its ligands, including the inhibitory receptor signal regulatory protein α (SIRPα), secreted glycoprotein thrombospondin-1 (TSP-1), and integrins. Elevated expression of CD47 is observed in a wide range of cancer cells as a mechanism for evading the immune system, blocking the interaction between the CD47 and SIRPα is the most advanced and promising therapeutic approach currently investigated in multiple clinical trials. The widely held view that a single type of CD47 protein acts through membrane interactions has been challenged by the discovery of a large cohort of CD47 proteins with cell-, tissue-, and temporal-specific expression and functional profiles. These profiles have been derived from a single gene through alternative splicing and post-translational modifications, such as glycosylation, pyroglutamate modification, glycosaminoglycan modification, and proteolytic cleavage and, to some extent, via specific CD47 clustering in aging and tumor cells and the regulation of its subcellular localization by a pre-translational modification, alternative cleavage and polyadenylation (APA). This review explores the origins and molecular properties of CD47 proteoforms and their roles under physiological and pathological conditions, mentioning the new methods to improve the response to the therapeutic inhibition of CD47-SIRPα immune checkpoints, contributing to the understanding of CD47 proteoform diversity and identification of novel clinical targets and immune-related therapeutic candidates.
Topics: Humans; CD47 Antigen; Receptors, Immunologic; Antigens, Differentiation; Phagocytosis; Integrins
PubMed: 38426113
DOI: 10.3389/fimmu.2024.1329562 -
Journal of the American Heart... Mar 2024Identifying novel molecular drivers of disease progression in heart failure (HF) is a high-priority goal that may provide new therapeutic targets to improve patient...
BACKGROUND
Identifying novel molecular drivers of disease progression in heart failure (HF) is a high-priority goal that may provide new therapeutic targets to improve patient outcomes. The authors investigated the relationship between plasma proteins and adverse outcomes in HF and their putative causal role using Mendelian randomization.
METHODS AND RESULTS
The authors measured 4776 plasma proteins among 1964 participants with HF with a reduced left ventricular ejection fraction enrolled in PHFS (Penn Heart Failure Study). Assessed were the observational relationship between plasma proteins and (1) all-cause death or (2) death or HF-related hospital admission (DHFA). The authors replicated nominally significant associations in the Washington University HF registry (N=1080). Proteins significantly associated with outcomes were the subject of 2-sample Mendelian randomization and colocalization analyses. After correction for multiple testing, 243 and 126 proteins were found to be significantly associated with death and DHFA, respectively. These included small ubiquitin-like modifier 2 (standardized hazard ratio [sHR], 1.56; <0.0001), growth differentiation factor-15 (sHR, 1.68; <0.0001) for death, A disintegrin and metalloproteinase with thrombospondin motifs-like protein (sHR, 1.40; <0.0001), and pulmonary-associated surfactant protein C (sHR, 1.24; <0.0001) for DHFA. In pathway analyses, top canonical pathways associated with death and DHFA included fibrotic, inflammatory, and coagulation pathways. Genomic analyses provided evidence of nominally significant associations between levels of 6 genetically predicted proteins with DHFA and 11 genetically predicted proteins with death.
CONCLUSIONS
This study implicates multiple novel proteins in HF and provides preliminary evidence of associations between genetically predicted plasma levels of 17 candidate proteins and the risk for adverse outcomes in human HF.
Topics: Humans; Blood Proteins; Heart Failure; Proteomics; Stroke Volume; Ventricular Function, Left; Mendelian Randomization Analysis
PubMed: 38420755
DOI: 10.1161/JAHA.123.031154