Identification of hub genes associated with diabetic cardiomyopathy using integrated bioinformatics analysis.

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.

CHI3L1 on fibrinolytic system imbalance in chronic rhinosinusitis with nasal polyp.

Background: Chronic rhinosinusitis (CRS) is an inflammatory disease affecting more than 10% of the global adult population. It is classified into Th1, Th2, and Th17 endotypes and eosinophilic and non-eosinophilic types. Th2-based inflammation and eosinophilic CRS (ECRS) are associated with tissue remodeling and fibrinolytic system impairment. Objective: To elucidate the role of eosinophils in inducing fibrin deposition in CRS nasal polyp tissues and explore potential regulatory mechanisms. Methods: We analyzed the expression of genes related to the serpin family and fibrinolytic system using Gene Expression Omnibus and Next-generation sequencing data. Differentially expression genes (DEGs) analysis was used to compare control and nasal polyp tissues, followed by KEGG and Gene ontology (GO) analysis. We measured the expression and correlation of plasminogen activator-1 (PAI-1), tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA), and urokinase plasminogen activator surface receptor (u-PAR) in CRS tissues, and evaluated the effect of eosinophils on the fibrinolytic system using a cytokine array and co-culture. Results: Nasal polyp tissues showed upregulated PAI-1, u-PA, and u-PAR expression and downregulated t-PA expression. Fibrinolytic system-related genes positively correlated with Th2 cytokines, except for t-PA. Eosinophil-derived Chitinase-3-like protein 1 (CHI3L1) increased PAI-1 expression and decreased t-PA levels in fibroblasts and epithelial cells. The inhibition of CHI3L1 suppresses these alterations. Conclusion: CHI3L1 contributes to fibrin deposition by impairing the fibrinolytic system during nasal polyp formation. The regulation of CHI3L1 expression may inhibit fibrin deposition and edema in ECRS, presenting a potential treatment for this condition.

Investigate the potential impact of Hemagglutinin from the H1N1 strain on severe pneumonia.

The most prevalent glycoprotein on the influenza virus envelope is called hemagglutinin (HA), yet little is known about its involvement in the pathophysiology and etiology of severe influenza pneumonia. Here, after stimulating human bronchial epithelial cells (16-HBE) and mice with HA of H1N1 for 12 h, we investigated the proliferation, migration, inflammatory cytokines expression, and apoptosis in 16-HBE and the pathological damage in mouse lung tissue. The expression of inflammatory cytokines plasminogen activator inhibitor 1(PAI-1), urokinase-type (uPA) and tissue-type (tPA) plasminogen activators, and apoptosis were all enhanced by HA, which also prevented the proliferation and migration of bronchial epithelial cells. HA enhanced up-regulated PAI-1, uPA, and tPA protein expression within mouse lung tissue and caused lung injury. In conclusion, HA alone, but not the whole H1N1 virus, induces lung tissue injury by inhibiting cell proliferation and migration, while promoting the expression of inflammatory cytokines and apoptosis.

Evaluating CXCL12 for Effects on Reactive Gene Expression in Primary Astrocytes.

Upon injury to the CNS, astrocytes undergo morphological and functional changes commonly referred to as astrocyte reactivity. Notably, these reactive processes include altered expression of factors that control immune processes and neuronal survival, as well as increased expression of the CXCL12 receptor, CXCR7/ACKR3. We now asked whether these events are related in that the astrocytic CXCL12 system modulates immune responses and/or neuronal survival. Short-term exposure of astrocytes cultured from the postnatal rat cortex to CXCL12 prominently increased the expression of serpine1/PAI1 on the mRNA level, but showed either no or only minor effects on the expression of additional reactive genes, selected from previous array studies. CXCL12-induced increases in PAI1 protein levels were only detectable in the additional presence of chemokines/cytokines, suggesting that translation of serpine1 mRNA depends on the cooperation of various factors. As expected, expression of most of the selected genes increased after acute or chronic activation of astrocytes with either LPS or a combination of IL-1ß and TNFα. CXCL12 partially attenuated expression of some of the LPS and IL-1ß/TNFα-induced genes under acute conditions, in particular those encoding CXCL9, CXCL10, CXCL11, and CCL5. Taken together, these findings argue for the involvement of the astrocyte CXCL12 system in the control of the immune response of the injured CNS, where it may control distinct steps.

Investigation of crucial genes and mitochondrial function impairment in diabetic cardiomyopathy.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a special type of cardiovascular disease, termed as a situation of abnormal myocardial structure and function that occurs in diabetic patients. However, the most fundamental mechanisms of DCM have not been fully explicated, and useful targets for the therapeutic strategies still need to be explored. METHODS: In the present study, we combined bioinformatics analysis and in vitro experiments throughout the process of DCM. Differentially Expressed Genes (DEGs) analysis was performed and the weighted gene co-expression network analysis (WGCNA) was constructed to determine the crucial genes that were tightly connected to DCM. Additionally, Functional enrichment analysis was conducted to define biological pathways. To identify the specific molecular mechanism, the human cardiomyocyte cell line (AC16) was stimulated by high glucose (HG, 50 mM D-glucose) and used to imitate DCM condition. Then, we tentatively examined the effect of high glucose on cardiomyocytes, the expression levels of crucial genes were further validated by in vitro experiments. RESULTS: Generally, NPPA, IGFBP5, SERPINE1, and C3 emerged as potential therapeutic targets. Functional enrichment analysis performed by bioinformatics indicated that the pathogenesis of DCM is mainly related to heart muscle contraction and calcium (Ca2+) release activation. In vitro, we discovered that high glucose treatment induced cardiomyocyte injury and exacerbated mitochondrial dysfunction remarkably. CONCLUSION: Our research defined four crucial genes, as well as determined that mitochondrial function impairment compromises calcium homeostasis ultimately resulting in contractile dysfunction is a central contributor to DCM progression. Hopefully, this study will offer more effective biomarkers for DCM diagnosis and treatment.

The basic functions of rabbit ovarian granulosa cell are regulated by adipokines monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1.

The aim of the present study was to examine the influence of monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) on ovarian cell functions. Rabbit ovarian granulosa cells were cultured with or without MCP-1 or PAI-1 (at 0, 0.1, 1, or 10 ng/ml). Cell viability, proliferation, cytoplasmic apoptosis and release of progesterone and estradiol were measured by Cell Counting Kit-8 (CCK-8), BrdU incorporation, and cell death detection assays and ELISA. The addition of either MCP-1 or PAI-1 increased cell viability and proliferation and decreased apoptosis. MCP-1 promoted, while PAI-1 suppressed, progesterone release. Both MCP-1 and PAI-1 reduced estradiol output. The present results suggest that MCP-1 or PAI-1 can be physiological promoters of rabbit ovarian cell viability and proliferation, inhibitors of apoptosis and regulators of ovarian steroidogenesis.

Interleukin-1 increases SERPINE1 expression in human granulosa-lutein cell via P50/P52 signaling pathways.

It has been reported that immune factors are associated with the occurrence of polycystic ovary syndrome (PCOS). Interleukin-1 (IL-1) is a member of the interleukin family that widely participates in the regulation of the inflammatory response in the immune system. In addition, it has been reported that aberrant IL-1 accumulation in serum is associated with the occurrence of PCOS. However, little is known about how IL-1 participates in the pathogenesis of PCOS. In the present study, we demonstrated that the immune microenvironment was altered in follicular fluid from PCOS patients and that the expression levels of two IL-1 cytokines, IL-1α and IL-1ß were increased. Transcriptome analysis revealed that IL-1α and IL-1ß treatment induced primary human granulosa-lutein (hGL) cell inflammatory response and increased the expression of serpin family E member 1 (SERPINE1). Mechanistically, we demonstrated that IL-1α and IL-1ß upregulated SERPINE1 expression through IL-1R1-mediated activation of downstream P50 and P52 signaling pathways in human granulosa cells. Our study highlighted the role of immune state changes in the occurrence of PCOS and provided new insight into the treatment of patients with IL-1-induced ovarian function disorders.

PAI-1 mediates acquired resistance to MET-targeted therapy in non-small cell lung cancer.

Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we investigated the possible mechanisms acquired for crizotinib in MET-amplified lung carcinoma cell lines. Two MET-amplified lung cancer cell lines, EBC-1 and H1993, were established for acquired resistance to MET-TKI crizotinib and were functionally elucidated. Genomic and transcriptomic data were used to assess the factors contributing to the resistance mechanism, and the alterations hypothesized to confer resistance were validated. Multiple mechanisms underlie acquired resistance to crizotinib in MET-amplified lung cancer cell lines. In EBC-1-derived resistant cells, the overexpression of SERPINE1, the gene encoding plasminogen activator inhibitor-1 (PAI-1), mediated the drug resistance mechanism. Crizotinib resistance was addressed by combination therapy with a PAI-1 inhibitor and PAI-1 knockdown. Another mechanism of resistance in different subline cells of EBC-1 was evaluated as epithelial-to-mesenchymal transition with the upregulation of antiapoptotic proteins. In H1993-derived resistant cells, MEK inhibitors could be a potential therapeutic strategy for overcoming resistance with downstream mitogen-activated protein kinase pathway activation. In this study, we revealed the different mechanisms of acquired resistance to the MET inhibitor crizotinib with potential therapeutic application in patients with MET-amplified lung carcinoma.

Cathepsin K deficiency prevented stress-related thrombosis in a mouse FeCl3 model.

BACKGROUND: Exposure to chronic psychological stress (CPS) is a risk factor for thrombotic cardiocerebrovascular diseases (CCVDs). The expression and activity of the cysteine cathepsin K (CTSK) are upregulated in stressed cardiovascular tissues, and we investigated whether CTSK is involved in chronic stress-related thrombosis, focusing on stress serum-induced endothelial apoptosis. METHODS AND RESULTS: Eight-week-old wild-type male mice (CTSK+/+) randomly divided to non-stress and 3-week restraint stress groups received a left carotid artery iron chloride3 (FeCl3)-induced thrombosis injury for biological and morphological evaluations at specific timepoints. On day 21 post-stress/injury, the stress had enhanced the arterial thrombi weights and lengths, in addition to harmful alterations of plasma ADAMTS13, von Willebrand factor, and plasminogen activation inhibitor-1, plus injured-artery endothelial loss and CTSK protein/mRNA expression. The stressed CTSK+/+ mice had increased levels of injured arterial cleaved Notch1, Hes1, cleaved caspase8, matrix metalloproteinase-9/-2, angiotensin type 1 receptor, galactin3, p16IN4A, p22phox, gp91phox, intracellular adhesion molecule-1, TNF-α, MCP-1, and TLR-4 proteins and/or genes. Pharmacological and genetic inhibitions of CTSK ameliorated the stress-induced thrombus formation and the observed molecular and morphological changes. In cultured HUVECs, CTSK overexpression and silencing respectively increased and mitigated stressed-serum- and H2O2-induced apoptosis associated with apoptosis-related protein changes. Recombinant human CTSK degraded γ-secretase substrate in a dose-dependent manor and activated Notch1 and Hes1 expression upregulation. CONCLUSIONS: CTSK appeared to contribute to stress-related thrombosis in mice subjected to FeCl3 stress, possibly via the modulation of vascular inflammation, oxidative production and apoptosis, suggesting that CTSK could be an effective therapeutic target for CPS-related thrombotic events in patients with CCVDs.

Changes and significance of the fibrinolytic system following two pulmonary thromboembolisms in a rabbit model.

In this study, we examined the changes in the fibrinolytic system in a rabbit model of two acute pulmonary thromboembolisms (PTE). Fourteen healthy adult New Zealand white rabbits were divided into three groups: the single PTE group (five rabbits), the double PTE group (five rabbits), and the control group (four rabbits). A rabbit model of acute pulmonary embolism was established, and immunohistochemistry and polymerase chain reaction (PCR) were performed on tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) in plasma, and pulmonary embolism tissue. Plasma results: 1) t-PA levels: one hour following the initial modeling, the levels of t-PA in the modeling groups were significantly lower than those in the control group (P<0.05). In addition, the t-PA levels in the double PTE group were found to be lower after the modeling, as compared to the pre-modeling period (P<0.05). One hour after the second modeling, the double PTE group had lower t-PA levels compared to the control group (P<0.05). However, t-PA rebounded two hours after modeling in the double PTE group. One week after the second modeling, the double PTE group had higher t-PA levels compared to the other two groups (P<0.05). 2) PAI-1 results: one hour after the initial modeling, PAI-1 levels in the two modeling groups were lower compared to the pre-modeling period and control groups (P<0.05). Two hours following modeling, PAI-1 levels in both modeling groups were lower compared to the control group (P<0.05). PAI-1 levels were lower in the double PTE group one and two hours after the second modeling compared to the other two groups and pre-modeling period (P<0.05). 3) The immunohistochemistry results: the expression of PAI-1 decreased in the two modeling groups, while t-PA expression increased compared to the control group. 4) PCR results: t-PA mRNA expression did not differ among the three groups. The PAI-1 mRNA expression was lower in the two PTE groups compared to the control group. We conclude that in the early stages of PTE, the local fibrinolytic activity of the thrombus is increased, which is favorable for thrombolysis. However, as the thrombus persists, the activity of the fibrinolytic system is inhibited, contributing to the development of chronic thromboembolic pulmonary hypertension.

Plasminogen activator inhibitor-1 promotes immune evasion in tumors by facilitating the expression of programmed cell death-ligand 1.

Background: 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. Methods: 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. Results: 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. Conclusions: PAI-1 protects tumors from immune surveillance by increasing PD-L1 expression; hence, therapeutic PAI-1 blockade may prove valuable in treating malignant tumors.

The Etiology of the Thrombotic Phenomena Involved in the Process of Coronary Artery Disease-What Is the Role of Thrombophilic Genes in the Development of This Pathology?

Cardiovascular diseases, among which includes coronary artery disease, represent one of the most important causes of mortality and morbidity worldwide. Research aimed at determining the risk factors involved recognizes a group of "traditional" risk factors, but also more recent studies identified over 100 "novel" ones which may have a role in the disease. Among the latter is the thrombophilia profile of a patient, a pathology well-established for its involvement in venous thromboembolism, but with less studied implications in arterial thrombosis. This paper reviews the literature, explaining the pathophysiology of the thrombophilia causes associated most with coronary thrombosis events. Results of several studies on the subject, including a meta-analysis with over 60,000 subjects, determined the significant involvement of factor V Leiden, prothrombin G20210A mutation, plasminogen activator inhibitor-1 and antiphospholipid syndrome in the development of coronary artery disease. The mechanisms involved are currently at different stages of research, with some already established and used as therapeutic targets.

The effect of epigenetic aging on neurodegenerative diseases: a Mendelian randomization study.

Background: Aging has always been considered as a risk factor for neurodegenerative diseases, but there are individual differences and its mechanism is not yet clear. Epigenetics may unveil the relationship between aging and neurodegenerative diseases. Methods: Our study employed a bidirectional two-sample Mendelian randomization (MR) design to assess the potential causal association between epigenetic aging and neurodegenerative diseases. We utilized publicly available summary datasets from several genome-wide association studies (GWAS). Our investigation focused on multiple measures of epigenetic age as potential exposures and outcomes, while the occurrence of neurodegenerative diseases served as potential exposures and outcomes. Sensitivity analyses confirmed the accuracy of the results. Results: The results show a significant decrease in risk of Parkinson's disease with GrimAge (OR = 0.8862, 95% CI 0.7914-0.9924, p = 0.03638). Additionally, we identified that HannumAge was linked to an increased risk of Multiple Sclerosis (OR = 1.0707, 95% CI 1.0056-1.1401, p = 0.03295). Furthermore, we also found that estimated plasminogen activator inhibitor-1(PAI-1) levels demonstrated an increased risk for Alzheimer's disease (OR = 1.0001, 95% CI 1.0000-1.0002, p = 0.04425). Beyond that, we did not observe any causal associations between epigenetic age and neurodegenerative diseases risk. Conclusion: The findings firstly provide evidence for causal association of epigenetic aging and neurodegenerative diseases. Exploring neurodegenerative diseases from an epigenetic perspective may contribute to diagnosis, prognosis, and treatment of neurodegenerative diseases.

Risk Factors of Thrombophilia-Related Mutations for Early and Late Pregnancy Loss.

Background and Objectives: This retrospective cohort study investigates the role of genetic thrombophilia in pregnant women experiencing early pregnancy loss compared to those with late pregnancy loss. Materials and Methods: Participants were categorized into early and late pregnancy loss groups based on gestational age. A total of 156 patients were included, out of which 103 had early-trimester pregnancy losses and 96 had multiple miscarriages. Results: The study revealed a synergistic effect of Factor V Leiden (FVL G1691A) and Methylenetetrahydrofolate Reductase (MTHFR C677T) mutations (coefficient 3.42). Prothrombin (PT) G20210A and ß-Fibrinogen 455 G>A mutations exhibited a significant interaction (coefficient 1.98). Additionally, MTHFR A1298C and Plasminogen Activator Inhibitor-1 (PAI-1 4G/5G) mutations showed a significant interaction (coefficient 1.65). FVL G1691A and Endothelial Protein C Receptor (EPCR) allele A1/A2 mutations also demonstrated a significant association (coefficient 2.10). Lastly, MTHFR C677T and Glycoprotein IIb/IIIa T1565C mutations interacted significantly (coefficient 1.77). Risk factor analysis identified several mutations associated with early pregnancy loss, including PAI-1 4G/5G homozygous (OR 3.01), FVL G1691A heterozygous (OR 1.85), and MTHFR A1298C heterozygous (OR 1.55). Both homozygous and heterozygous MTHFR C677T mutations were significant risk factors (OR 2.38; OR 2.06), as was PT G20210A homozygous mutation (OR 1.92). The PAI-1 4G/4G homozygous variant posed a risk (OR 1.36). Late pregnancy loss was associated with MTHFR A1298C homozygous mutation (OR 3.79), ß-Fibrinogen 455 G>A heterozygous mutation (OR 2.20), and MTHFR A1298C heterozygous mutation (OR 2.65). Factor XIII G1002T heterozygous mutation (OR 1.18) and PAI-1 4G/5G homozygous mutation (OR 2.85) were also significant risk factors. EPCR allele A1/A2 (OR 1.60) and A2/A3 (OR 1.73) mutations were identified as significant risk factors for late pregnancy loss. Furthermore, FVL G1691A homozygous mutation, PT G20210A homozygous mutation, MTHFR C677T heterozygous mutation, MTHFR A1298C heterozygous mutation, and EPCR allele A1/A2 were identified as significant risk factors for multiple miscarriage. Conclusions: This study highlights significant interactions and risk factors related to genetic thrombophilia mutations in different types of pregnancy loss, contributing valuable insights for miscarriage management guidelines.

Time-dependent ultrastructural changes during venous thrombogenesis and thrombus resolution.

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. OBJECTIVES: 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. CONCLUSION: 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.

Impact of L-Arginine on diabetes-induced neuropathy and myopathy: Roles of PAI-1, Irisin, oxidative stress, NF-κß, autophagy and microRNA-29a.

BACKGROUND: T2DM is a chronic disorder with progressive neuromuscular alterations. L-arginine (ARG) is the most common semi-essential amino acid having several metabolic functions. AIM: to investigate the impact of L-arginine in combating diabetic-induced neuromyopathy and its possible mechanisms. MATERIALS & METHODS: 24 rats were divided into CON, CON+ARG, DC, DC+ARG. Behavioral tests, Body weight (BW), fasting blood glucose (FBG), insulin, total antioxidant capacity (TAC), malondialdehyde (MDA), plasminogen activator inhibitor-1 (PAI-1), and irisin were done. Creatine kinase-MM (CK-MM), interleukin 4 (IL-4), interleukin 6 (IL-6), TAC, MDA, expression of microRNA-29a mRNA & light chain 3 protein were determined in muscle. Histological and NF-κß immunohistochemical expression in muscle and nerve were assessed. RESULTS: ARG supplementation to diabetic rats improved altered behavior, significantly increased BW, insulin, TAC, irisin and Il-4, decreased levels of glucose, microRNA-29a, NF-κß and LC3 expression, PAI-1, CK-MM and restored the normal histological appearance. CONCLUSIONS: ARG supplementation potently alleviated diabetic-induced neuromuscular alterations.

miR-30d-5p inhibits proliferation, invasion and migration of breast cancer cells by targeting SERPINE1 and promoting fatty acid ß-oxidation.

Breast cancer (BC) is among the top three most prevalent cancers across the world, especially in women, and its pathogenesis is still unknown. Fatty acid ß-oxidation is highly associated with breast cancer. Serpin family E member 1 (SERPINE1)-induced down-regulation of fatty acid ß-oxidation can facilitate BC cell proliferation, invasion, and metastasis. In this paper, the difference of miR-30d-5p expressions in both cancerous tissues and para-carcinoma tissues was first detected. Next, the expressions of SERPINE1, long-chain acyl-CoA dehydrogenase (LCAD) and medium-chain acyl-CoA dehydrogenase (MCAD) in the aforementioned tissues were analyzed. Finally, miR-30d-5p mimics were supplemented to breast cancer cells to observe the miR-30d-5p effect upon breast cancer cells. Via immunofluorescence assay and Western blotting, it was found that cancerous tissues had lower expressions of miR-30d-5p, MCAD and LCAD and a higher expression of SERPINE1 than para-carcinoma tissues. The miR-30d-5p mimic group had a decreased SERPINE1 expression and increased MCAD and LCAD expressions compared with the NC group, thus inhibiting BC cell proliferation, invasion, and metastasis. To sum up, miR-30d-5p blocks the cell proliferation, invasion and metastasis by targeting SERPINE1 and promoting fatty acid ß-oxidation. Preclinical studies are further required to establish a fatty acid ß-oxidation-targeting therapy for breast cancer.

Critical roles of PAI-1 in lipopolysaccharide-induced acute lung injury.

PURPOSE: Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of fibrinolytic systems. The effect of PAI-1 on inflammatory response is still inconsistent. Our study was conducted to investigate its effects on inflammation to clarify the role of PAI-1 in acute lung injury (ALI) induced by lipopolysaccharide (LPS). MATERIAL AND METHODS: ALI models were established in wild-type (WT) and PAI-1 knockout (KO) mice by LPS intervention for 48 â€‹h. Lung histopathology, wet-dry ratio, total cell count and TNF-α concentration in bronchoalveolar lavage fluid (BALF), and inflammation related proteins were detected. Flow cytometry was used to sort neutrophils, macrophages, regulatory T cells (Treg) and T helper cell 17 (Th17). RNA sequencing was performed to find differentially expressed genes. Masson staining and immunohistochemistry were used to analyze pulmonary fiber deposition and proliferation. RESULTS: Compared with ALI (WT) group, the wet-dry ratio, the total number of BALF cells, the concentration of TNF-α in BALF, and the expression of pp65 in the lung tissue was increased in ALI (PAI-1 KO) group, with increased proportion of neutrophils, decreased proportion of macrophages and decreased proportion of Treg/Th17 in the lung tissue. Collagen fiber deposition and PCNA expression were lighter in ALI (PAI-1 KO) group than ALI (WT) group. PPI analysis showed that PAI-1 was closely related to TNF, IL-6, IL-1ß, Smad2/3 and mainly concentrated in the complement and coagulation system, TNF-α and IL-17 signaling pathways. CONCLUSIONS: PAI-1 KO could aggravate ALI induced by LPS at 48 â€‹h. PAI-1 may be an important target to improve the prognosis of ALI.

Haplotype of the Lipoprotein(a) Gene Variants rs10455872 and rs3798220 Is Associated with Parameters of Coagulation, Fibrinolysis, and Inflammation in Patients after Myocardial Infarction and Highly Elevated Lipoprotein(a) Values.

Lipoprotein(a) (Lp(a)) is an independent risk factor for future coronary events. Variants rs10455872 and rs3798220 in the gene encoding Lp(a) are associated with an increased Lp(a) concentration and risk of coronary artery disease. We aimed to determine whether in high-risk coronary artery disease patients these two genetic variants and the kringle IV type 2 (KIV-2) repeats are associated with impairment of inflammatory and hemostatic parameters. Patients after myocardial infarction with elevated Lp(a) levels were included. Blood samples underwent biochemical and genetic analyses. In carriers of the AC haplotype, the concentrations of tumor necrosis factor (TNF)-α (4.46 vs. 3.91 ng/L, p = 0.046) and plasminogen activator inhibitor-1 (PAI-1) (p = 0.026) were significantly higher compared to non-carriers. The number of KIV-2 repeats was significantly associated with the concentration of high-sensitivity C-reactive protein (ρ = 0.251, p = 0.038) and overall fibrinolytic potential (r = -0.253, p = 0.038). In our patients, a direct association between the AC haplotype and both TNF-α and PAI-1 levels was observed. Our study shows that the number of KIV-2 repeats not only affects proatherosclerotic and proinflammatory effects of Lp(a) but is also associated with its antifibrinolytic properties.