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Communications Medicine May 2024Preclinical studies have demonstrated that VT1021, a first-in-class therapeutic agent, inhibits tumor growth via stimulation of thrombospondin-1 (TSP-1) and reprograms...
BACKGROUND
Preclinical studies have demonstrated that VT1021, a first-in-class therapeutic agent, inhibits tumor growth via stimulation of thrombospondin-1 (TSP-1) and reprograms the tumor microenvironment. We recently reported data from the dose escalation part of a phase I study of VT1021 in solid tumors. Here, we report findings from the dose expansion phase of the same study.
METHODS
We analyzed the safety and tolerability, clinical response, and biomarker profile of VT1021 in the expansion portion of the phase I study (NCT03364400). Safety/tolerability is determined by adverse events related to the treatment. Clinical response is determined by RECIST v1.1 and iRECIST. Biomarkers are measured by multiplexed ion beam imaging and enzyme-linked immunoassay (ELISA).
RESULTS
First, we report the safety and tolerability data as the primary outcome of this study. Adverse events (AE) suspected to be related to the study treatment (RTEAEs) are mostly grade 1-2. There are no grade 4 or 5 adverse events. VT1021 is safe and well tolerated in patients with solid tumors in this study. We report clinical responses as a secondary efficacy outcome. VT1021 demonstrates promising single-agent clinical activity in recurrent GBM (rGBM) in this study. Among 22 patients with rGBM, the overall disease control rate (DCR) is 45% (95% confidence interval, 0.24-0.67). Finally, we report the exploratory outcomes of this study. We show the clinical confirmation of TSP-1 induction and TME remodeling by VT1021. Our biomarker analysis identifies several plasmatic cytokines as potential biomarkers for future clinical studies.
CONCLUSIONS
VT1021 is safe and well-tolerated in patients with solid tumors in a phase I expansion study. VT1021 has advanced to a phase II/III clinical study in glioblastoma (NCT03970447).
PubMed: 38773224
DOI: 10.1038/s43856-024-00520-z -
Diabetology & Metabolic Syndrome May 2024Gestational diabetes mellitus (GDM) is a highly prevalent disease and poses a significant risk to the health of pregnant women. Abdominal adipose tissue (AT) contributes...
BACKGROUND
Gestational diabetes mellitus (GDM) is a highly prevalent disease and poses a significant risk to the health of pregnant women. Abdominal adipose tissue (AT) contributes to insulin resistance (IR) associated with GDM. However, the underlying mechanisms remain unclear.
METHODS
In this study, we developed a mouse model of GDM by subjecting mice to a high-fat diet. We collected adipose-derived stem cells (ADSCs) from the abdominal and inguinal regions and examined their role in inducing IR in normal tissues through the secretion of small extracellular vesicles (sEVs). The sEVs derived from ADSCs isolated from GDM mice (ADSC/GDM) were found to inhibit cell viability and insulin sensitivity in AML12, a normal mouse liver cell line.
RESULTS
Through proteomic analysis, we identified high levels of the thrombospondin 1 (Thbs1) protein in the sEVs derived from ADSC/GDM. Subsequent overexpression of Thbs1 protein in AML12 cells demonstrated similar IR as observed with ADSC/GDM-derived sEVs. Mechanistically, the Thbs1 protein within the sEVs interacted with CD36 and transforming growth factor (Tgf) β receptors in AML12 cells, leading to the activation of Tgfβ/Smad2 signaling. Furthermore, the administration of LSKL, an antagonistic peptide targeting Thbs1, suppressed Thbs1 expression in ADSC/GDM-derived sEVs, thereby restoring insulin sensitivity in AML12 cells and GDM mice in vivo.
CONCLUSIONS
These findings shed light on the intercellular transmission mechanism through which ADSCs influence hepatic insulin sensitivity and underscore the therapeutic potential of targeting the Thbs1 protein within sEVs.
PubMed: 38764083
DOI: 10.1186/s13098-024-01276-1 -
Science Advances May 2024Intellectual disability (ID) affects ~2% of the population and ID-associated genes are enriched for epigenetic factors, including those encoding the largest family of...
Intellectual disability (ID) affects ~2% of the population and ID-associated genes are enriched for epigenetic factors, including those encoding the largest family of histone lysine acetyltransferases (KAT5-KAT8). Among them is , whose mutations cause KAT6A syndrome, with ID as a common clinical feature. However, the underlying molecular mechanism remains unknown. Here, we find that KAT6A deficiency impairs synaptic structure and plasticity in hippocampal CA3, but not in CA1 region, resulting in memory deficits in mice. We further identify a CA3-enriched gene , encoding Wnt activator R-spondin 2, as a key transcriptional target of KAT6A. Deletion of in excitatory neurons impairs memory formation, and restoring RSPO2 expression in CA3 neurons rescues the deficits in Wnt signaling and learning-associated behaviors in mutant mice. Collectively, our results demonstrate that KAT6A-RSPO2-Wnt signaling plays a critical role in regulating hippocampal CA3 synaptic plasticity and cognitive function, providing potential therapeutic targets for KAT6A syndrome and related neurodevelopmental diseases.
Topics: Animals; Wnt Signaling Pathway; Mice; Histone Acetyltransferases; Cognition; CA3 Region, Hippocampal; Thrombospondins; Neuronal Plasticity; Mice, Knockout
PubMed: 38758792
DOI: 10.1126/sciadv.adm9326 -
Obesity (Silver Spring, Md.) Jul 2024The objective of this study was to explore the effects of a green Mediterranean (green-MED) diet, which is high in dietary polyphenols and green plant-based protein and... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The objective of this study was to explore the effects of a green Mediterranean (green-MED) diet, which is high in dietary polyphenols and green plant-based protein and low in red/processed meat, on cardiovascular disease and inflammation-related circulating proteins and their associations with cardiometabolic risk parameters.
METHODS
In the 18-month weight loss trial Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed Study (DIRECT-PLUS), 294 participants with abdominal obesity were randomized to basic healthy dietary guidelines, Mediterranean (MED), or green-MED diets. Both isocaloric MED diet groups consumed walnuts (28 g/day), and the green-MED diet group also consumed green tea (3-4 cups/day) and green shakes (Mankai plant shake, 500 mL/day) and avoided red/processed meat. Proteome panels were measured at three time points using Olink CVDII.
RESULTS
At baseline, a dominant protein cluster was significantly related to higher phenotypic cardiometabolic risk parameters, with the strongest associations attributed to magnetic resonance imaging-assessed visceral adiposity (false discovery rate of 5%). Overall, after 6 months of intervention, both the MED and green-MED diets induced improvements in cardiovascular disease and proinflammatory risk proteins (p < 0.05, vs. healthy dietary guidelines), with the green-MED diet leading to more pronounced beneficial changes, largely driven by dominant proinflammatory proteins (IL-1 receptor antagonist protein, IL-16, IL-18, thrombospondin-2, leptin, prostasin, galectin-9, and fibroblast growth factor 21; adjusted for age, sex, and weight loss; p < 0.05). After 18 months, proteomics cluster changes presented the strongest correlations with visceral adiposity reduction.
CONCLUSIONS
Proteomics clusters may enhance our understanding of the favorable effect of a green-MED diet that is enriched with polyphenols and low in red/processed meat on visceral adiposity and cardiometabolic risk.
Topics: Humans; Diet, Mediterranean; Female; Male; Middle Aged; Proteome; Obesity, Abdominal; Intra-Abdominal Fat; Weight Loss; Adiposity; Cardiovascular Diseases; Polyphenols; Adult; Cardiometabolic Risk Factors; Inflammation; Tea
PubMed: 38757229
DOI: 10.1002/oby.24036 -
Current Opinion in Hematology May 2024Von Willebrand factor (VWF) plays a pivotal role in primary hemostasis. A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13 (ADAMTS13) is...
PURPOSE OF REVIEW
Von Willebrand factor (VWF) plays a pivotal role in primary hemostasis. A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13 (ADAMTS13) is primarily responsible for cleaving ultra-large VWF multimers into smaller, less adhesive forms. However, plasmin has also been shown to cleave VWF multimers. This proteolytic cleavage of VWF results in a decreased multimer size and, hence, a lower VWF activity. This review aims to present a comprehensive overview of the involvement of plasmin-mediated VWF proteolysis in (micro)thrombosis.
RECENT FINDINGS
Plasmin-mediated VWF proteolysis has been suggested to play a role in various pathologies involving microthrombosis in combination with an imbalance in VWF antigen levels and ADAMTS13 activity, as well as activation of the fibrinolytic system, but quantitative assays to demonstrate this were lacking. Recently, a VHH-based bioassay was developed designed specifically to quantify plasmin-cleaved VWF (cVWF). The novel ELISA assay holds significant promise for gaining further insights into the clinical relevance of plasmin-mediated VWF proteolysis in several pathologies. Furthermore, local plasmin activation at the site of microthrombosis has been shown to be a promising treatment strategy by degrading VWF-rich microthrombi.
SUMMARY
Plasmin-mediated proteolysis of VWF is observed during microthrombosis; however, it remains unclear whether it impacts disease severity. A novel ELISA method to detect cVWF will improve our understanding of the clinical role of plasmin-mediated VWF degradation.
PubMed: 38723202
DOI: 10.1097/MOH.0000000000000825 -
PloS One 2024Osteoarthritis is the most prevalent type of degenerative arthritis. It is characterized by persistent pain, joint dysfunction, and physical disability. Pain relief and...
Osteoarthritis is the most prevalent type of degenerative arthritis. It is characterized by persistent pain, joint dysfunction, and physical disability. Pain relief and inflammation control are prioritised during osteoarthritis treatment Mume Fructus (Omae), a fumigated product of the Prunus mume fruit, is used as a traditional medicine in several Asian countries. However, its therapeutic mechanism of action and effects on osteoarthritis and articular chondrocytes remain unknown. In this study, we analyzed the anti-osteoarthritis and articular regenerative effects of Mume Fructus extract on rat chondrocytes. Mume Fructus treatment reduced the interleukin-1β-induced expression of matrix metalloproteinase 3, matrix metalloproteinase 13, and a disintegrin and metalloproteinase with thrombospondin type 1 motifs 5. Additionally, it enhanced collagen type II alpha 1 chain and aggrecan accumulation in rat chondrocytes. Furthermore, Mume Fructus treatment regulated the inflammatory cytokine levels, mitogen-activated protein kinase phosphorylation, and nuclear factor-kappa B activation. Overall, our results demonstrated that Mume Fructus inhibits osteoarthritis progression by inhibiting the nuclear factor-kappa B and mitogen-activated protein kinase pathways to reduce the levels of inflammatory cytokines and prevent cartilage degeneration. Therefore, Mume Fructus may be a potential therapeutic option for osteoarthritis.
Topics: Animals; Male; Rats; ADAMTS5 Protein; Aggrecans; Cartilage, Articular; Cells, Cultured; Chondrocytes; Collagen Type II; Down-Regulation; Fruit; Interleukin-1beta; MAP Kinase Signaling System; Matrix Metalloproteinase 13; Matrix Metalloproteinase 3; Mitogen-Activated Protein Kinases; NF-kappa B; Osteoarthritis; Plant Extracts; Prunus; Rats, Sprague-Dawley
PubMed: 38718039
DOI: 10.1371/journal.pone.0302906 -
European Review For Medical and... Apr 2024Methotrexate (MTX), a widely used chemotherapeutic and immunosuppressive agent, is associated with hepatotoxicity, leading to liver fibrosis and cirrhosis. This study...
OBJECTIVE
Methotrexate (MTX), a widely used chemotherapeutic and immunosuppressive agent, is associated with hepatotoxicity, leading to liver fibrosis and cirrhosis. This study explores the regenerative and reparative effects of fisetin, a flavonoid with known antioxidant and anti-inflammatory properties, on MTX-induced liver fibrosis in a rat model.
MATERIALS AND METHODS
Thirty-six male Wistar albino rats were divided into normal, MTX and saline, and MTX and fisetin. Liver injury was induced in the latter two groups using a single intraperitoneal dose of MTX (20 mg/kg). Fisetin (50 mg/kg/day) or saline was administered intraperitoneally for ten days. After sacrifice, liver tissues were subjected to histopathological evaluation and biochemical analyses, including Transforming Growth Factor-β1 (TGF-beta), sirtuins-1 (SIRT-1), malondialdehyde (MDA), cytokeratin 18, thrombospondin 1, and alanine transaminase (ALT) levels.
RESULTS
MTX administration significantly increased liver injury markers, including TGF-beta, MDA, cytokeratin 18, thrombospondin 1, and ALT, while reducing SIRT-1 levels. Fisetin treatment attenuated these effects, demonstrating its potential therapeutic impact. Histopathological analysis confirmed that fisetin mitigated MTX-induced hepatocyte necrosis, fibrosis, and cellular infiltration.
CONCLUSIONS
This study proves that fisetin administration can alleviate MTX-induced liver damage in rats. The reduction in oxidative stress, inflammation, and apoptosis, along with the histological improvements, suggests fisetin's potential as a therapeutic agent against MTX-induced hepatotoxicity. Further investigations and clinical studies are warranted to validate these findings and assess fisetin's translational potential in human cases of MTX-induced liver damage.
Topics: Methotrexate; Animals; Rats, Wistar; Male; Rats; Liver Cirrhosis; Flavonols; Flavonoids; Liver; Antioxidants; Sirtuin 1
PubMed: 38708470
DOI: 10.26355/eurrev_202404_36027 -
IScience May 2024During aging, skin homeostasis is essential for maintaining appearance, as well as biological defense of the human body. In this study, we identified thrombospondin-1...
During aging, skin homeostasis is essential for maintaining appearance, as well as biological defense of the human body. In this study, we identified thrombospondin-1 (THBS1) and fibromodulin (FMOD) as positive and negative regulators, respectively, of the TGF-β1-SMAD4 axis in human skin aging, based on and omics analyses and mathematical modeling. Using transcriptomic and epigenetic analyses of senescent dermal fibroblasts, TGF-β1 was identified as the key upstream regulator. Bifurcation analysis revealed a binary high-/low-TGF-β1 switch, with THBS1 as the main controller. Computational simulation of the TGF-β1 signaling pathway indicated that THBS1 expression was sensitively regulated, whereas FMOD was regulated robustly. Results of sensitivity analysis and validation showed that inhibition of SMAD4 complex formation was a promising method to control THBS1 production and senescence. Therefore, this study demonstrated the potential of combining data-driven target discovery with mathematical approaches to determine the mechanisms underlying skin aging.
PubMed: 38706856
DOI: 10.1016/j.isci.2024.109708 -
Arab Journal of Gastroenterology : the... May 2024Immunotherapy has emerged as a hot topic in cancer treatment in recent years and has also shown potential in the treatment of Helicobacter pylori-associated gastric...
BACKGROUND AND STUDY AIMS
Immunotherapy has emerged as a hot topic in cancer treatment in recent years and has also shown potential in the treatment of Helicobacter pylori-associated gastric cancer. However, there is still a need to identify potential immunotherapy targets.
MATERIAL AND METHODS
We used the GSE116312 dataset of Helicobacter pylori-associated gastric cancer to identify differentially expressed genes, which were then overlapped with immune genes from the ImmPort database. The identified immune genes were used to classify gastric cancer samples and evaluate the relationship between classification and tumor mutations, as well as immune infiltration. An immune gene-based prognostic model was constructed, and the expression levels of the genes involved in constructing the model were explored in the tumor immune microenvironment.
RESULTS
We successfully identified 60 immune genes and classified gastric cancer samples into two subtypes, which showed differences in prognosis, tumor mutations, immune checkpoint expression, and immune cell infiltration. Subsequently, we constructed an immune prognostic model consisting of THBS1 and PDGFD, which showed significant associations with macrophages and fibroblasts.
CONCLUSION
We identified abnormal expression of THBS1 and PDGFD in cancer-associated fibroblasts (CAFs) within the tumor immune microenvironment, suggesting their potential as therapeutic targets.
Topics: Stomach Neoplasms; Humans; Tumor Microenvironment; Helicobacter pylori; Helicobacter Infections; Thrombospondin 1; Prognosis; Platelet-Derived Growth Factor; Cancer-Associated Fibroblasts; Mutation; Lymphokines
PubMed: 38705811
DOI: 10.1016/j.ajg.2024.02.001 -
Molecular Therapy : the Journal of the... May 2024
Topics: Humans; Glioblastoma; Thrombospondin 1; Angiogenesis Inhibitors; Brain Neoplasms; Neovascularization, Pathologic; Animals
PubMed: 38702134
DOI: 10.1016/j.ymthe.2024.04.022