The Mediterranean diet, featuring sourdough bread, shows promise in managing metabolic syndrome. This study explored the effects of two sourdough breads, with differing fermentation times but similar nutritional profiles, on inflammation, satiety, and gut microbiota composition in adults with metabolic syndrome. In a double-blind clinical trial, participants were randomized to consume either Elias Boulanger® long-fermentation (48 h) sourdough bread (EBLong) or Elias Boulanger® short-fermentation (2 h) sourdough bread (EBShort) over a two-month period. We assessed clinical parameters, inflammatory biomarkers, satiety-related hormones, and the richness and abundance of gut microbiota at baseline and follow-up. The participants included 31 individuals (mean age, 67, 51.6% female). EBShort was associated with reduced levels of soluble intercellular adhesion molecule (sICAM), and all participants, regardless of the intervention, exhibited a decrease in sICAM and diastolic pressure from baseline (p < 0.017). At follow-up, plasminogen activator inhibitor-1 (PAI-1) levels were lower in EBShort (-744 pg/mL; 95%CI: -282 to -1210 pg/mL) compared to EBLong. No differences in microbiota richness or abundance were observed. EBShort bread was effective in reducing some inflammation markers. The consumption of sourdough bread may offer potential benefits in reducing inflammation markers in individuals with metabolic syndrome; however, longer fermentation times did not show additional benefits.

The paracrine actions of adipokine plasminogen activator inhibitor-1 (PAI-1) are implicated in obesity-associated tumorigenesis. Here, we show that PAI-1 mediates extracellular matrix (ECM) signaling via epigenetic repression of DKK1 in endometrial epithelial cells (EECs). While the loss of DKK1 is known to increase β-catenin accumulation for WNT signaling activation, this epigenetic repression causes β-catenin release from transmembrane integrins. Furthermore, PAI-1 elicits the disengagement of TIMP2 and SPARC from integrin-β1 on the cell surface, lifting an integrin-β1-ECM signaling constraint. The heightened interaction of integrin-β1 with type 1 collagen (COL1) remodels extracellular fibrillar structures in the ECM. Consequently, the enhanced nanomechanical stiffness of this microenvironment is conducive to EEC motility and neoplastic transformation. The formation of extensively branched COL1 fibrils is also observed in endometrial tumors of patients with obesity. The findings highlight PAI-1 as a contributor to enhanced integrin-COL1 engagement and extensive ECM remodeling during obesity-associated neoplastic development.

Senescence is a physiological and pathological cellular program triggered by various types of cellular stress. Senescent cells exhibit multiple characteristic changes. Among them, the characteristic flattened and enlarged morphology exhibited in senescent cells is observed regardless of the stimuli causing the senescence. Several studies have provided important insights into pro-adhesive properties of cellular senescence, suggesting that cell adhesion to the extracellular matrix (ECM), which is involved in characteristic morphological changes, may play pivotal roles in cellular senescence. Matricellular proteins, a group of structurally unrelated ECM molecules that are secreted into the extracellular environment, have the unique ability to control cell adhesion to the ECM by binding to cell adhesion receptors, including integrins. Recent reports have certified that matricellular proteins are closely involved in cellular senescence. Through this biological function, matricellular proteins are thought to play important roles in the pathogenesis of age-related diseases, including fibrosis, osteoarthritis, intervertebral disc degeneration, atherosclerosis, and cancer. This review outlines recent studies on the role of matricellular proteins in inducing cellular senescence. We highlight the role of integrin-mediated signaling in inducing cellular senescence and provide new therapeutic options for age-related diseases targeting matricellular proteins and integrins.

BACKGROUND: Obesity is a chronic inflammatory disorder that increases the risk of cardiovascular diseases (CVDs). Given the high CVD mortality rate among individuals with obesity, early screening should be considered. Plasminogen activator inhibitor (PAI-1), a cytokine that links obesity and CVDs, represents a promising biomarker. However, PAI-1 is not part of the clinical routine due to its high cost. Therefore, it is necessary to find good predictors that would allow an indirect assessment of PAI-1.
METHODS: This study enrolled 47 women with severe obesity (SO). The obtained anthropometric measurements included weight, height, neck (NC), waist (WC), and hip circumference (HC). Blood samples were collected to analyse glucose and lipid profiles, C-reactive protein, liver markers, adiponectin, and PAI-1 (determined by ELISA immunoassay). Homeostasis model assessment-adiponectin (HOMA-AD), homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), triglyceride-glucose index (TyG), and atherogenic index of plasma (AIP) were calculated. The women were grouped according to PAI-1 levels. The data were analysed using IBM SPSS Statistics, version 21. The significance level for the analysis was set at 5%.
RESULTS: Women with SO who have higher levels of PAI-1 have lower values of high-density lipoprotein cholesterol (HDL) (p = 0.037) and QUICKI (0.020) and higher values of HOMA-AD (0.046) and HOMA-IR (0.037). HOMA-IR was demonstrated to be a good predictor of PAI-1 in this sample (B = 0.2791; p = 0.017).
CONCLUSIONS: HOMA-IR could be used as a predictor of PAI-1 levels, pointing out the relevance of assessing glycaemic parameters for the prevention of CVDs in women with SO.

OBJECTIVE: Glucocorticoid (GC) administration has been associated with adverse drug reactions (ADRs) affecting multiple organ systems. While long-term use is widely recognized as a significant independent predictor of ADRs, it is important to note that even short-term use can lead to serious ADRs. The considerable inter-individual variability in ADRs occurrence may be influenced by genetic factors. This study, we present a case of a child who experienced significant weight gain and osteoporosis, following a brief administration of GC.
METHODS: To comprehensively investigate the underlying mechanisms, we conducted a genomic analysis utilizing the whole exome sequencing (WES) technique. This analysis encompassed the examination of phase I and phase II metabolism, influx transport, efflux transport, and drug targeting. Additionally, a comprehensive analysis was conducted on a cohort of 52,119 children to determine their ABCB1 rs1045642 genotype, and an additional 37,884 children were tested for their CYP3A5 rs776746 genotype.
RESULTS: The pharmacogenetic analysis unveiled the presence of a high-risk variant in ABCB1 rs1045642 and a slow metabolism variant in CYP3A5 rs776746, both of which have the potential to substantially contribute to ADRs. The findings of this study indicate that the prevalence of ABCB1 rs1045642 CT type among patients was 47.58%, with TT type accounting for 15.69 % and CC type accounting for 36.73 %. Furthermore, the distribution of CYP3A5 rs776746 CC genotype was observed in 50.54 % of individuals, while CT and TT genotypes were present in 41.15 % and 8.31 % of the population respectively. The distribution of ABCB1 and CYP3A5 genotypes among the pediatric population in China displays notable features. Specifically, for the ABCB1 rs1045642 genotype, less than 50 % of children exhibit intermediate metabotypes. Conversely, among children with the CYP3A5 rs776746 genotype, the predominant cause for enzyme activity is the slow metabolic type, accounting for up to 90 % of cases.
CONCLUSIONS: Consequently, it is imperative to thoroughly evaluate the impact of allele mutation on the effectiveness and safety of glucocorticoid drugs or other medications metabolized by the ABCB1 and CYP3A5, particularly in the context of Chinese pediatric patients.

UNASSIGNED: Increased levels of plasminogen activator inhibitor-1 (PAI-1) in tumors have been found to correlate with poor clinical outcomes in patients with cancer. Although abundant data support the involvement of PAI-1 in cancer progression, whether PAI-1 contributes to tumor immune surveillance remains unclear. The purposes of this study are to determine whether PAI-1 regulates the expression of immune checkpoint molecules to suppresses the immune response to cancer and demonstrate the potential of PAI-1 inhibition for cancer therapy.
UNASSIGNED: The effects of PAI-1 on the expression of the immune checkpoint molecule programmed cell death ligand 1 (PD-L1) were investigated in several human and murine tumor cell lines. In addition, we generated tumor-bearing mice and evaluated the effects of a PAI-1 inhibitor on tumor progression or on the tumor infiltration of cells involved in tumor immunity either alone or in combination with immune checkpoint inhibitors.
UNASSIGNED: PAI-1 induces PD-L1 expression through the JAK/STAT signaling pathway in several types of tumor cells and surrounding cells. Blockade of PAI-1 impedes PD-L1 induction in tumor cells, significantly reducing the abundance of immunosuppressive cells at the tumor site and increasing cytotoxic T-cell infiltration, ultimately leading to tumor regression. The anti-tumor effect elicited by the PAI-1 inhibitor is abolished in immunodeficient mice, suggesting that PAI-1 blockade induces tumor regression by stimulating the immune system. Moreover, combining a PAI-1 inhibitor with an immune checkpoint inhibitor significantly increases tumor regression.
UNASSIGNED: PAI-1 protects tumors from immune surveillance by increasing PD-L1 expression; hence, therapeutic PAI-1 blockade may prove valuable in treating malignant tumors.

OBJECTIVE: We aimed to characterize the interplay between early life stress (ELS), metabolic syndrome (MetS), and plasminogen activator inhibitor-1 (PAI-1), a major inhibitor of the fibrinolytic system implicated in cardiometabolic diseases. We also examined the understudied intersection of ELS, physical activity and PAI-1.
METHODS: Healthy young adults ages 18-40 (N=200; 68% female) were recruited from the community. Participants with ELS (N=118) experienced childhood maltreatment, and the majority (n=92) also experienced childhood parental loss. Control participants (N=82) had no history of childhood maltreatment or parental loss. Participants had no current cardiometabolic or thrombotic conditions. Fasting plasma samples were assessed for markers of metabolic risk and total PAI-1 using the Bio-Plex Pro Human Diabetes Panel (Bio-Rad Laboratories). A composite metabolic risk z-score (MetS risk) was computed from the mean standardized z-scores of waist-to-height ratio, systolic and diastolic blood pressure, triglycerides, total cholesterol, LDL and HLD cholesterol, fasting plasma glucose, and hemoglobin A1c.
RESULTS: We found that a history of ELS was linked to both higher PAI-1 levels and a higher MetS risk score. ELS was associated with a higher MetS Z-score in adulthood via increased circulating PAI-1 levels (Average Causal Mediation Effect [ACME]= 0.07, p = 0.036). ELS was also linked to increased PAI-1 levels via greater MetS z-scores (ACME = 0.02, p < 0.001). There was a significant interaction effect of ELS and exercise on PAI-1 levels (p = 0.03), such that engaging in higher levels of daily exercise was linked to lower PAI-1 levels in individuals with ELS.
CONCLUSIONS: Healthy young adults with ELS have elevated PAI-1 levels and metabolic risk scores. Among individuals with ELS, exercise is linked to lower PAI-1 levels, suggesting a potential direction for early intervention.

UNASSIGNED: To modify and evaluate an established chromogenic assay protocol for measuring plasminogen activator inhibitor type-1 (PAI-1) activity to measure tissue plasminogen activator (tPA) activity and compare the enzymatic activity of alteplase as a function of the conditions under which it is thawed.
UNASSIGNED: A 50 mg vial of alteplase was reconstituted with sterile water to make a 1 mg/mL stock solution (nominal concentration). Plastic syringes were loaded with 0.5 mL of alteplase stock solution and stored at -20°C. After 8 days, samples were thawed by 3 methods - via body temperature (37°C), room temperature (20°C), or in a refrigerator (2°C). Thaw times were recorded. The thawed solutions, along with a freshly prepared alteplase solution, were assayed using the modified protocol of the Spectrolyse PAI-1 kit to determine residual tPA enzyme activity.
UNASSIGNED: Validation of the modified protocol for the Spectrolyse PAI-1 kit used to measure tPA activity produced a linear response with coefficients of determination (R2) of greater than 0.9977 when assayed on 2 separate days, which corresponded to an enzymatic activity accuracy between 98.3% and 108.3%. The average percent residual tPA enzyme activity of samples from each group compared to the freshly prepared solution was 106%, 98.7%, and 91.5% for samples thawed at body temperature, room temperature, and refrigerated, respectively.
UNASSIGNED: Modifications to the standard procedure for the Spectrolyse PAI-1 kit allows for accurate determination of tPA activity in aqueous based reconstituted solutions of alteplase. Under thawed conditions, alteplase retained greater than 91% enzyme activity as compared to a freshly prepared control.

To determine the protective mechanism of puerarin against nonalcoholic steatohepatitis (NASH), the pharmacodynamic effects of puerarin on NASH were evaluated by using zebrafish, cells, and mice. Western blotting, flow cytometry, immunofluorescence, and qRT-PCR were used to detect the effects of puerarin on RAW264.7 autophagy and polarization. Key target interactions between autophagy and polarization were detected using immunoprecipitation. Puerarin regulated the M1/M2 ratio of RAW 264.7 cells induced by LPS + INF-γ. Transcriptomics revealed that PAI-1 is a key target of puerarin in regulating macrophage polarization. PAI-1 knockout reduced the number of M1-type macrophages and increased the number of M2-type macrophages. Puerarin regulated PAI-1 and was associated with macrophage autophagy. It increased p-ULK1 expression in macrophages and activated autophagic flux, reducing the level of PAI-1 expression. Stat3/Hif-1α and PI3K/AKT signaling pathways regulated the number of macrophage polarization phenotypes, reducing liver lipid droplet formation, alleviating liver structural abnormalities, decreasing the number of cytoplasmic vacuoles, and decreasing the area of blue collagen in NASH mice. Puerarin is a promising dietary component for NASH alleviation.

BACKGROUND: Deep vein thrombosis is a common vascular event that can result in debilitating morbidity and even death due to pulmonary embolism. Clinically, patients with faster resolution of a venous thrombus have improved prognosis, but the detailed structural information regarding changes that occur in a resolving thrombus over time is lacking.
OBJECTIVE: To define the spatial-morphologic characteristics of venous thrombus formation, propagation, and resolution at the submicron level over time.
METHODS: Using a murine model of stasis-induced deep vein thrombosis along with scanning electron microscopy and immunohistology, we determine the specific structural, compositional, and morphologic characteristics of venous thrombi formed after 4 days and identify the changes that take place during resolution by day 7. Comparison is made with the structure and composition of venous thrombi formed in mice genetically deficient in plasminogen activator inhibitor type 1.
RESULTS: As venous thrombus resolution progresses, fibrin exists in different structural forms, and there are dynamic cellular changes in the compositions of leukocytes, platelet aggregates, and red blood cells. Intrathrombus microvesicles are present that are not evident by histology, and red blood cells in the form of polyhedrocytes are an indicator of clot contraction. Structural evidence of fibrinolysis is observed early during thrombogenesis and is accelerated by plasminogen activator inhibitor type 1 deficiency.
CONCLUSIONS: The results reveal unique, detailed ultrastructural and compositional insights along with documentation of the dynamic changes that occur during accelerated resolution that are not evident by standard pathologic procedures and can be applied to inform diagnosis and effectiveness of thrombolytic treatments to improve patient outcomes.