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Psoriasis is a chronic autoimmune disease with a long disease course and frequent relapse characteristics. It is now recognised to be associated with epidermal environments of inflammatory cytokines. However, its pathogenesis is still not completely clear. We found the haemorheology of psoriatic patients to be abnormal, and ageing and deformed erythrocytes increased in the blood. The abnormal erythrocytes were more likely to induce psoriasis, which was confirmed in a mouse model induced by different blood components of psoriatic patients/healthy volunteers. Spleen filtration dysfunction, which caused abnormal erythrocytes, was also more likely to induce psoriasis, which was confirmed in a mouse model induced by splenectomy. The mechanism was the weakening of the 'eat me' function of spleen macrophages phagocytizing ageing and deformed erythrocytes, resulting in the dysfunction of spleen filtration and the increase of ageing and deformed erythrocytes in the body. Additionally, the decreased oxygen‐carrying capacity and the declined antioxidant capacity of those erythrocytes led to the hypoxia environment, making psoriasis more likely to be induced. These findings demonstrate that spleen filtration dysfunction contributes to the pathogenesis of psoriasis and suggest that improving it may be an effective therapy for psoriasis and control its relapse. [ABSTRACT FROM AUTHOR]

Allma Pitru,1 Dorin Nicolae Gheorghe,2 Dora Maria Popescu,2 Flavia Mirela Nicolae,2 Mihail Virgil Boldeanu,3 Adina Turcu-Stiolica,4 Cristian Cosmin Arsenie,5 Petra Surlin,2 Sergiu Marian Cazacu,6 Ion Rogoveanu6 1Oral Pathology Department, Faculty of Dental Medicine, University of Medicine and Pharmacy of Craiova, Craiova, 200349, Romania; 2Department of Periodontology, Research Center of Periodontal-Systemic Interactions, Faculty of Dental Medicine, University of Medicine and Pharmacy of Craiova, Craiova, 200349, Romania; 3Department of Immunology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Craiova, 200349, Romania; 4Department of Pharmacoeconomics and Statistical Analysis, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, Craiova, 200349, Romania; 5Doctoral School, University of Medicine and Pharmacy of Craiova, Craiova, 200349, Romania; 6Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Craiova, 200349, RomaniaCorrespondence: Petra Surlin, Department of Periodontology, Research Center of Periodontal-Systemic Interactions, Faculty of Dental Medicine, University of Medicine and Pharmacy of Craiova, Craiova, 200349, Romania, Email surlinpetra@gmail.com Sergiu Marian Cazacu, Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Craiova, 200349, Romania, Email sergiucazacu@umfcv.comPurpose: Non-alcoholic fatty liver disease (NAFLD) represents a heterogeneous spectrum of liver diseases that encompass simple steatosis, non-alcoholic steatohepatitis (NASH), and advanced fibrosis or cirrhosis. Periodontitis is a chronic infectious disease with multiple causal factors that presents a complex interaction between the microbial biofilm and the host’s immune response. The aim of this study was to investigate the concentrations of Vascular Adhesion Protein-1 (VAP-1) and Thrombospondin-1 (TSP-1) in patients with coexisting periodontitis and NAFLD.Patients and Methods: This study included 48 patients, who were dental and periodontal assessed. Of these patients, 25 were diagnosed with NAFLD. After performing the periodontal clinical examination, gingival crevicular fluid (GCF) samples were collected. Enzyme-linked immunosorbent assay (ELISA) dedicated kits tests were used for the detection and quantitative determination of VAP-1 and TSP-1 in GCF samples. Statistical methods were applied for the comparison and correlation of data.Results: VAP-1 and TSP-1 levels showed significant differences between all test and control groups (p< 0.0001). Statistically significant correlations (p< 0.05) between VAP-1 and periodontal and liver parameters were found in patients with NAFLD and periodontitis.Conclusion: Periodontal inflammation is more marked in patients with periodontitis-NAFLD association. Vascular adhesion and angiogenesis could be affected in patients with periodontitis and NAFLD. These findings could suggest that addressing periodontal inflammation in individuals with the periodontitis-NAFLD association may have a broader impact on vascular adhesion and angiogenesis, highlighting the interplay between oral health and liver conditions for comprehensive patient care.Keywords: non-alcoholic fatty liver disease, periodontitis, VAP-1, TSP-1, gingival crevicular fluid, periodontal disease

Abstract Background Ovarian cancer (OC) remains one of the most challenging and deadly malignancies facing women today. While PARP inhibitors (PARPis) have transformed the treatment landscape for women with advanced OC, many patients will relapse and the PARPi-resistant setting is an area of unmet medical need. Traditional immunotherapies targeting PD-1/PD-L1 have failed to show any benefit in OC. The CD47/TSP-1 axis may be relevant in OC. We aimed to describe changes in CD47 expression with platinum therapy and their relationship with immune features and prognosis. Methods Tumor and blood samples collected from OC patients in the CHIVA trial were assessed for CD47 and TSP-1 before and after neoadjuvant chemotherapy (NACT) and multiplex analysis was used to investigate immune markers. Considering the therapeutic relevance of targeting the CD47/TSP-1 axis, we used the CD47-derived TAX2 peptide to selectively antagonize it in a preclinical model of aggressive ovarian carcinoma. Results Significant reductions in CD47 expression were observed post NACT. Tumor patients having the highest CD47 expression profile at baseline showed the greatest CD4+ and CD8+ T-cell influx post NACT and displayed a better prognosis. In addition, TSP-1 plasma levels decreased significantly under NACT, and high TSP-1 was associated with a worse prognosis. We demonstrated that TAX2 exhibited a selective and favorable biodistribution profile in mice, localizing at the tumor sites. Using a relevant peritoneal carcinomatosis model displaying PARPi resistance, we demonstrated that post-olaparib (post-PARPi) administration of TAX2 significantly reduced tumor burden and prolonged survival. Remarkably, TAX2 used sequentially was also able to increase animal survival even under treatment conditions allowing olaparib efficacy. Conclusions Our study thus (1) proposes a CD47-based stratification of patients who may be most likely to benefit from postoperative immunotherapy, and (2) suggests that TAX2 is a potential alternative therapy for patients relapsing on PARP inhibitors.

Background: Ovarian cancer (OC) remains one of the most challenging and deadly malignancies facing women today. While PARP inhibitors (PARPis) have transformed the treatment landscape for women with advanced OC, many patients will relapse and the PARPi-resistant setting is an area of unmet medical need. Traditional immunotherapies targeting PD-1/PD-L1 have failed to show any benefit in OC. The CD47/TSP-1 axis may be relevant in OC. We aimed to describe changes in CD47 expression with platinum therapy and their relationship with immune features and prognosis. Methods: Tumor and blood samples collected from OC patients in the CHIVA trial were assessed for CD47 and TSP-1 before and after neoadjuvant chemotherapy (NACT) and multiplex analysis was used to investigate immune markers. Considering the therapeutic relevance of targeting the CD47/TSP-1 axis, we used the CD47-derived TAX2 peptide to selectively antagonize it in a preclinical model of aggressive ovarian carcinoma. Results: Significant reductions in CD47 expression were observed post NACT. Tumor patients having the highest CD47 expression profile at baseline showed the greatest CD4+ and CD8+ T-cell influx post NACT and displayed a better prognosis. In addition, TSP-1 plasma levels decreased significantly under NACT, and high TSP-1 was associated with a worse prognosis. We demonstrated that TAX2 exhibited a selective and favorable biodistribution profile in mice, localizing at the tumor sites. Using a relevant peritoneal carcinomatosis model displaying PARPi resistance, we demonstrated that post-olaparib (post-PARPi) administration of TAX2 significantly reduced tumor burden and prolonged survival. Remarkably, TAX2 used sequentially was also able to increase animal survival even under treatment conditions allowing olaparib efficacy. Conclusions: Our study thus (1) proposes a CD47-based stratification of patients who may be most likely to benefit from postoperative immunotherapy, and (2) suggests that TAX2 is a potential alternative therapy for patients relapsing on PARP inhibitors. [ABSTRACT FROM AUTHOR]

Ovarian cancer is one of the most lethal malignant tumors, characterized by high incidence and poor prognosis. Patients relapse occurred in 65–80% after initial treatment. To date, no effective treatment has been established for these patients. Recently, CD47 has been considered as a promising immunotherapy target. In this paper, we reviewed the biological roles of CD47 in ovarian cancer and summarized the related mechanisms. For most types of cancers, the CD47/Sirpα immune checkpoint has attracted the most attention in immunotherapy. Notably, CD47 monoclonal antibodies and related molecules are promising in the immunotherapy of ovarian cancer, and further research is needed. In the future, new immunotherapy regimens targeting CD47 can be applied to the clinical treatment of ovarian cancer patients. [ABSTRACT FROM AUTHOR]

Thrombospondins (TSPs) have numerous different roles in cancer, regulating the behavior of cancer cells and non-neoplastic cells, and defining the responses of tumor cells to environmental changes, thorough their ability to orchestrate cellular and molecular interactions in the tumor microenvironment (TME). As a result of these activities, TSPs can also control drug delivery and activity, tumor response and resistance to therapies, with different outcomes depending on the nature of TSP-interacting cell types, receptors, and ligands, in a highly context-dependent manner. This review, focusing primarily on TSP-1, discusses the effects of TSPs on tumor response to chemotherapy, antiangiogenic, low-dose metronomic chemotherapy, immunotherapy, and radiotherapy, by analyzing TSP activity on different cell compartments – tumor cells, vascular endothelial cells and immune cells. We review evidence of the value of TSPs, specifically TSP-1 and TSP-2, as biomarkers of prognosis and tumor response to therapy. Finally, we examine possible approaches to develop TSP-based compounds as therapeutic tools to potentiate the efficacy of anticancer therapy. [ABSTRACT FROM AUTHOR]

Background and aims: Sports activity is an important and protective factor after cardiovascular diseases. The aim of this study was to investigate the response of acute incremental aerobic activity along with electrical stimulation on some markers of angiogenesis in Isoproterenol (ISO) induced rats. Methods: This controlled experimental study involved 50 male rats (eight weeks old, weighing 210±15g) subjected to infarction with ISO (150mg/kg), subsequently divided randomly into 5 groups of 10: healthy, infarcted, engaged in sports activity, exposed to electrical stimulation, and engaged in aerobic activity combined with electrical stimulation. The intervention groups underwent activity (at a speed of 10 to 18m/min for 50 minutes) and electrical stimulation (at an intensity of 0.5mA for 20 minutes) in a single session. Venous blood samples were collected and analyzed using the ELISA method, with statistical analysis performed using the ANOVA test at a significance level of p<0.05. Results: Inducing rats with ISO resulted in a significant elevation in serum levels of VEGF and TSP1 in all groups (p=0.0001 for both). The ANOVA test revealed that a single session of sports activity led to a non-significant increase in VEGF levels and a non-significant decrease in TSP1 levels in infarcted rats in all groups compared to the infarcted group. Conclusion: Incremental aerobic activity and electrical stimulation demonstrated positive effects on angiogenesis processes. However, due to the lack of statistical significance, further studies are warranted to explore the enhancement and proliferation of new capillary vessels in infarcted samples. [ABSTRACT FROM AUTHOR]

Unfolded protein response (UPR) signaling and endoplasmic reticulum (ER) stress have been linked to pulmonary fibrosis. However, the relationship between UPR status and pulmonary function and prognosis in idiopathic pulmonary fibrosis (IPF) patients remains largely unknown. Through a series of bioinformatics analyses, we established a correlation between UPR status and pulmonary function in IPF patients. Furthermore, thrombospondin-1 (TSP-1) was identified as a potential biomarker for prognostic evaluation in IPF patients. By utilizing both bulk RNA profiling and single-cell RNA sequencing data, we demonstrated the upregulation of TSP-1 in lung fibroblasts during pulmonary fibrosis. Gene set enrichment analysis (GSEA) results indicated a positive association between TSP-1 expression and gene sets related to the reactive oxygen species (ROS) pathway in lung fibroblasts. TSP-1 overexpression alone induced mild ER stress and pulmonary fibrosis, and it even exacerbated bleomycin-induced ER stress and pulmonary fibrosis. Mechanistically, TSP-1 promoted ER stress and fibroblast activation through CD47-dependent ROS production. Treatment with either TSP-1 inhibitor or CD47 inhibitor significantly attenuated BLM-induced ER stress and pulmonary fibrosis. Collectively, these findings suggest that the elevation of TSP-1 during pulmonary fibrosis is not merely a biomarker but likely plays a pathogenic role in the fibrotic changes in the lung. [ABSTRACT FROM AUTHOR]

The protein PIAS1 functions as a type of ubiquitin-protease, which is known to play an important regulatory role in various diseases, including cardiovascular diseases and cancers. Its mechanism of action primarily revolves around regulating the transcription, translation, and modification of target proteins. This study investigates role and mechanism of PIAS1 in the RUNX3/TSP-1 axis and confirms its therapeutic effects on diabetes-related complications in animal models. A diabetic vascular injury was induced in human umbilical vein endothelial cells (HUVECs) by stimulation with H2O2 and advanced glycation end product (AGE), and a streptozotocin (STZ)-induced mouse model of diabetes was constructed, followed by detection of endogenous PIAS1 expression and SUMOylation level of RUNX3. Effects of PIAS1 concerning RUNX3 and TSP-1 on the HUVEC apoptosis and inflammation were evaluated using the ectopic expression experiments. Down-regulated PIAS1 expression and SUMOylation level of RUNX3 were identified in the H2O2- and AGE-induced HUVEC model of diabetic vascular injury and STZ-induced mouse models of diabetes. PIAS1 promoted the SUMOylation of RUNX3 at the K148 site of RUNX3. PIAS1-mediated SUMOylation of RUNX3 reduced RUNX3 transactivation activity, weakened the binding of RUNX3 to the promoter region of TSP-1, and caused downregulation of TSP-1 expression. PIASI decreased the expression of TSP-1 by inhibiting H2O2- and AGE-induced RUNX3 de-SUMOylation, thereby arresting the inflammatory response and apoptosis of HUVECs. Besides, PIAS1 reduced vascular endothelial injury and atherosclerotic plaque formation in mouse models of diabetes by inhibiting the RUNX3/TSP-1 axis. Our study proved that PIAS1 suppressed vascular endothelial injury and atherosclerotic plaque formation in mouse models of diabetes via the RUNX3/TSP-1 axis. [ABSTRACT FROM AUTHOR]

Alzheimer disease (AD) is a common form of dementia associated with loss of memory and disruption of synaptic plasticity. There is a strong correlation between the pathophysiological features of AD and diabetes, including induction of oxidative stress, inflammation, and abnormality in blood vessels. Considering the brain's limited capacity to repair damage and the potential of stem cell-derived neural cells in the repair of neurodegenerative disease, we investigated the effects of artemisinin and TSP‑1‑human endometrial-derived-derived stem cells (TSP‑1‑hEDSCs) on the cognitive function and synaptic plasticity in AD-diabetes rats. The authors previously showed that artemisinin and TSP‑1‑hEDSCs suppressed oxidative stress and inflammation in AD-diabetes rats. Thrombospondins-1 (TSPs-1) is a glycoprotein that inhibits angiogenesis. AD and diabetes were induced using streptozotocin. Synaptic plasticity and learning and memory function were studied using the Morris water maze and electrophysiological test, respectively. Streptozotocin increased traveled swimming distance and escape latency in the morris water maze test, decreased the percent time spent in the target quadrant, inhibited the long-term potentiation (LTP), and increased the blood glucose levels. Simultaneous or separate administration of artemisinin and TSP‑1‑hEDSCs decreased the blood levels of glucose and improved cognitive tasks and synaptic plasticity by considerably reducing traveled swimming distance and escape latency, increasing the percent time spent in the target quadrant, and retrieval of the LTP; therefore, they could be utilized as an adjunct treatment for AD treatment. These results may be due to a decrease in oxidative stress and inflammation. [ABSTRACT FROM AUTHOR]

Background & Aims: Polycystic ovary syndrome is one of the common endocrine diseases that affects 5-10% of women of reproductive age. The purpose of this research was to explain the effect of Tabata training in water on TSP-1 and TIMP-3 and insulin resistance in obese women with polycystic ovary syndrome. Methods: To conduct this semi-experimental research, 30 women with a BMI greater than 29.9 in Isfahan city were selected and randomly divided into two experimental groups (metformin + Tabata exercise) (15 people) and control (metformin) (15 people). The Tabata training program consisted of 3 sessions per week for 40 minutes (10 minutes of warm-up, 20 minutes of exercise and 10 minutes of cooling down) consisting of 4-minute periods (20 seconds of activity and 10 seconds of rest) for 12 weeks. Subjects also took 500 mg metformin twice a day after breakfast and dinner. To measure the research variables, blood was taken after 12 to 14 hours of fasting and in two stages before and 48 hours after the last training session. To analyze the data, Shapiro-Wilk tests, one-way analysis of variance and Tukey's post hoc tests were used. People with endocrine diseases, untreated thyroid, Cushing's syndrome (a type of metabolic syndrome in which high levels of glucocorticoids lead to insulin resistance in muscle tissue, liver and fat tissue), congenital adrenal hyperplasia, suspected ovarian or adrenal tumor, heart patients, use of oral contraceptive pills, progestin and hormone induction (Inplanol), use of hormone therapy or herbal medicines during the last 2 months, use of acupuncture during the last 2 months, exercise during Last 2 months, pregnancy, history of abortion or childbirth in the last 6 weeks, history of breastfeeding in the last 4 months, having bariatric surgery in the last 12 months, unwillingness to fill out the consent form to enter the study, patients with or with a history of Cervical, endometrial, or breast cancer were excluded from the study. After selecting the sample, the subjects completed the personal information questionnaire and blood was drawn after 12 hours of overnight fasting to determine the level of insulin resistance factors, TSP-1 and TIMP-3. Then the experimental group did the training program including 12 weeks, 3 sessions per week and each session lasted 40 minutes and also used metformin. But the control group only took metformin. The exercise protocol consisted of 10 minutes of walking forwards, backwards, sideways, and jogging in the shallow part of the pool (where the water level is below the neck) and then doing stretching exercises. Then, Tabata training was performed with a special training song for 20 minutes and 10 minutes of stretching and cooling down. 48 hours after the last training session, blood was drawn again from all subjects. Also, in order to comply with ethical considerations at the end of the research, the treatment protocols in the form of manuals were provided to the control group so that they can use it if they wish. Similar to protocols on land, in water intensity interval training programs, participants complete "very hard" bouts with "easy" recovery periods, and due to the higher viscosity and density of water, large movements with increased speed will have greater resistance to water flow. He said that this leads to the creation of an ideal environment for increasing work efficiency and energy consumption. Also, metformin is a biguanide drug and is sensitive to insulin. This drug is able to limit the secretion of insulin and its increase. It also reduces the amount of androgen secretion that is secreted from the ovary and adrenal gland. Therefore, metformin seems to be an effective drug in patients with PCOS, especially in those who are resistant to clomiphene. Metformin improves the menstrual cycle in patients with the syndrome and causes an increase in the sensitivity of the response of drugs effective in stimulating ovulation, especially in women with PCOS resistant to clomiphene citrate, and leads to a decrease in obesity. Results: The results showed that exercise caused a significant decrease in insulin resistance and a significant increase in TSP-1 and TIMP-3 in the experimental group. The results showed that 12 weeks of Tabata training in water has a significant effect on insulin resistance in obese women with polycystic ovary syndrome (P=0.0001, f3.59=11.097). Also, the results of Tukey's post hoc test showed that there is a significant difference between the pre-test of the water training group and the control post-test group and the post-test of the water training group with test control group, but does not have there is a significant difference between the other groups. In this study, it was found that 12 weeks of Tabata training in water has a significant effect on TIMP-3 in obese women with polycystic ovary syndrome (P=0.0001, f3,59=20/270). Also, the results of Tukey's post hoc test showed that there is a significant difference between the pre-test of the water exercise group and the post-test of the water exercise group and between the post-test of the water exercise group and the control but pretest and the control post-test, There is no significant difference between the other groups. In the present study, it was found that 12 weeks of Tabata training in water has a significant effect on TSP-1 in obese women with polycystic ovary syndrome (P=0.0001, f3,59=111/20). Also, the results of Tukey's post hoc test showed that there is a significant difference between the pre-test of the water exercise group and the post-test of the water exercise group and between the post-test of the water exercise group and the control.but pre-test and the control post-test, There is no significant difference between the other groups. In the present study, it was found that 12 weeks of Tabata training in water has a significant effect on TIMP-3 in obese women with polycystic ovary syndrome. Also, the results of Tukey's post hoc test showed that there is a significant difference between the pre-test of the water exercise group and the post-test of the water exercise group and between the post-test of the water exercise group and the control pre-test and the control post-test, but between the other groups. There is no significant difference. Another finding showed that 12 weeks of Tabata training program in water and metformin intake led to a significant increase in TIMP-3 factor in obese women with polycystic ovary syndrome, so that there was a significant difference between the pre-test of the water training group and the post-test of the water training group. On the one hand, there is a significant difference between the post-test of water training, the control pre-test and the control post-test. According to our studies, the effect of sports activity on TIMP-3 changes has not been investigated yet. Conclusion: The results of the present study confirm the effect of Tabata exercise in water along with metformin on the factors involved in angiogenesis and insulin resistance in women with polycystic ovary syndrome. [ABSTRACT FROM AUTHOR]

• Limited proteolysis of thrombospondins is an important post-translational mechanism to modulate the function in the extracellular space. • Current data from the literature and databases have been collected to summarize the current knowledge of TSP processing by proteases, mainly metalloproteases and serine proteases. • We present an overview of the cleavage of TSPs by proteases, a map of TSP cleavage sites, and considerations on the biological role of the generated fragments in pathological settings, with a particular focus on cancer. Limited proteolysis of thrombospondins is a powerful mechanism to ensure dynamic tuning of their activities in the extracellular space. Thrombospondins are multifunctional matricellular proteins composed of multiple domains, each with a specific pattern of interactions with cell receptors, matrix components and soluble factors (growth factors, cytokines and proteases), thus with different effects on cell behavior and responses to changes in the microenvironment. Therefore, the proteolytic degradation of thrombospondins has multiple functional consequences, reflecting the local release of active fragments and isolated domains, exposure or disruption of active sequences, altered protein location, and changes in the composition and function of TSP-based pericellular interaction networks. In this review current data from the literature and databases is employed to provide an overview of cleavage of mammalian thrombospondins by different proteases. The roles of the fragments generated in specific pathological settings, with particular focus on cancer and the tumor microenvironment, are discussed. [ABSTRACT FROM AUTHOR]

Non‐small cell lung cancer (NSCLC) is one of the most common malignancies with high morbidity and mortality. PKHB1, a serum‐stable Thrombospondin‐1 (TSP‐1) mimic peptide, has shown some effective ability in triggering cell death against several cancers. Here, we aimed to study the potential biological function of PKHB1 and its molecular mechanism in NSCLC. Our results revealed that PKHB1 significantly suppressed NSCLC cell proliferation, cell migration, and induced apoptosis in a dose‐dependent manner. Additionally, we found that PKHB1 treatment resulted in mitochondrial transmembrane potential depolarization, Ca2+ overloading as well as the upregulation of proapoptotic proteins. Mechanistically, PKHB1 induced NSCLC cells apoptosis in a CD47‐independent manner. Further study revealed that PKHB1 provoked endoplasmic reticulum (ER) stress principally through the activation of CHOP and JNK signaling, which could be alleviated in the presence of 4‐PBA, an ER stress inhibitor. Furthermore, xenograft tumor models showed that PKHB1 treatment could notably inhibit NSCLC tumor growth in vivo. In conclusion, these findings suggested that PKHB1 exerted antitumor efficacy in NSCLC via triggering ER stress‐mediated but CD47‐independent apoptosis, potentially functioned as a promising peptide‐based therapeutic agent for NSCLC. [ABSTRACT FROM AUTHOR]

Objective: To analyze the relationship between serum osteocalcin (OC), thrombospondin-1 (TSP-1) and angiopoietin-like protein 2 (ANGPTL2) and insulin resistance (IR), sex hormones and ovarian interstitial blood flow in patients with polycystic ovary syndrome (PCOS). Methods: 125 patients with PCOS who were admitted to People’s Hospital of Inner Mongolia Autonomous Region from January 2020 to April 2022 (PCOS group) selected, and they were divided into IR group with 68 cases and non-IR group with 57 cases according to homeostasis model assessment (HOMA) -IR, another 67 healthy adult women (control group) were selected during the same period. HOMA-IR, sex hormone and ovarian interstitial blood flow indexes of research subjects were collected, and serum OC, TSP-1 and ANGPTL2 levels were detected by enzyme linked immunosorbent assay. The differences of sex hormone, ovarian interstitial blood flow indexes, serum OC, TSP-1 and ANGPTL2 levels between PCOS group and control group, IR group and non-IR group were compared. Pearson/Spearman correlation analysis was used to analyze the correlation between serum OC,TSP-1, ANGPTL2 levels and HOMA-IR, sex hormone and ovarian interstitial blood flow indexes in patients with PCOS. Results: The HOMA-IR, luteinizing hormone (LH), LH/follicle-stimulating hormone (FSH), testosterone (T), peak systolic velocity (PSV) and ANGPTL2 levels in PCOS group were higher than those in control group, while the pulsatile index (PI), resistance index (RI), OC and TSP-1 levels were lower than those in control group (P＜0.05). The LH, LH/FSH, T, PSV and ANGPTL2 in IR group were higher than those in non-IR group, while the PI, RI, OC and TSP-1 levels were lower than those in non-IR group (P＜0.05). Pearson/Spearman correlation analysis showed that serum OC and TSP-1 levels were negatively correlated with HOMA-IR, LH, LH/FSH, T and PSV in patients with PCOS, but positively correlated with PI and RI (P＜0.05). Serum ANGPTL2 level was positively correlated with HOMA-IR,LH, LH/FSH, T and PSV in patients with PCOS, and negatively correlated with PI and RI (P＜0.05). Conclusion: Serum OC and TSP-1 are low expression in patients with PCOS, while ANGPTL2 is high expression in patients with PCOS, which are closely related to IR, sex hormone and ovarian interstitial blood flow. [ABSTRACT FROM AUTHOR]

Introduction: This research investigates the impact of insulin-like growth factor-I (IGF -I)and exercise on mediators associated with angiogenesis (VEGF-A, TSP-1, and NF-кβ) and capillarization status of the diabetic rats’ hearts. Methods: Splitting of forty Wistar male rats into five groups occurred as following: control,diabetes, diabetes+IGF-I, diabetes+exercise, and diabetes+exercise+IGF-I.Through intraperitoneal administration of 60 mg/kg streptozotocin, the condition of Type 1diabetes was escalated. After four weeks of treatment with IGF-I (2 mg/kg/day) or treadmill exercise (17 m/min, zero degrees slope, 30 min/day), in the heart, microvascular density and protein levels of VEGF-A, TSP-1, and NF-кβ were determined by H & E staining and ELISA,respectively. Results: Within the diabetic group, observations present a significant decrease in VEGF-A and MVD levels, whereas an increase in the TSP-1 and NF-Κb levels. While these impacts were reversed by either IGF-I or exercise treatments, simultaneous treatment had synergistic effects. Moreover, among diabetic rats, undesirable histologic alterations of the heart were demonstrated, including myonecrosis, interstitial edema, hemorrhage, and mononuclear immune cell infiltration, whereas treatments improved these changes. Conclusion: These data manifest that IGF-I and exercise can increase the cardiac angiogenesis of diabetic rats through increasing expression of VEGF-A, and decreasing TSP-1 and NF-кβproteins level, also can improve myocardial tissue damages.

Unfolded protein response (UPR) signaling and endoplasmic reticulum (ER) stress have been linked to pulmonary fibrosis. However, the relationship between UPR status and pulmonary function and prognosis in idiopathic pulmonary fibrosis (IPF) patients remains largely unknown. Through a series of bioinformatics analyses, we established a correlation between UPR status and pulmonary function in IPF patients. Furthermore, thrombospondin-1 (TSP-1) was identified as a potential biomarker for prognostic evaluation in IPF patients. By utilizing both bulk RNA profiling and single-cell RNA sequencing data, we demonstrated the upregulation of TSP-1 in lung fibroblasts during pulmonary fibrosis. Gene set enrichment analysis (GSEA) results indicated a positive association between TSP-1 expression and gene sets related to the reactive oxygen species (ROS) pathway in lung fibroblasts. TSP-1 overexpression alone induced mild ER stress and pulmonary fibrosis, and it even exacerbated bleomycin-induced ER stress and pulmonary fibrosis. Mechanistically, TSP-1 promoted ER stress and fibroblast activation through CD47-dependent ROS production. Treatment with either TSP-1 inhibitor or CD47 inhibitor significantly attenuated BLM-induced ER stress and pulmonary fibrosis. Collectively, these findings suggest that the elevation of TSP-1 during pulmonary fibrosis is not merely a biomarker but likely plays a pathogenic role in the fibrotic changes in the lung.

The skeletal muscle tissue can adapt to exercise and environmental stressors with a remarkable plasticity. Prolonged cold stress exposure has been associated to increased skeletal muscle capillarization. Angioadaptation refers to the coordinated molecular and cellular processes that influence the remodeling of skeletal muscle microvasculature. Two cell types are central to angioadaptation: the myocytes, representing an important source of angiokines; and the skeletal muscle endothelial cell (SMECs), targets of these angiokines and main constituents of muscle capillaries. The influence of cold stress on skeletal muscle angioadaptation remains largely unknown, particularly with respect to myocyte-specific angiokines secretion or endothelial cell angioadaptive responses. Here, we use an in vitro model to investigate the impact of cold stress (28°C versus 37°C) on C2C12 myotubes and SMECs. Our main objectives were to evaluate: 1) the direct impact of cold stress on C2C12 cellular expression of angiokines and their release in the extracellular environment; 2) the indirect impact of cold stress on SMECs migration via these C2C12-derived angiokines; and 3) the direct effect of cold stress on SMECs angioadaptive responses, including migration, proliferation, and the activation of the vascular endothelial growth factor receptor-2 (VEGFR2). Cold stress reduced the secretion of angiokines in C2C12 myotubes culture media irrespective their pro-angiogenic or angiostatic nature. In SMECs, cold stress abrogated cell proliferation and reduced the activation of VEGFR2 despite a greater expression of this receptor. Finally, SMECs pre-conditioned to cold stress displayed an enhanced migratory response when migration was stimulated in rewarming conditions. Altogether our results suggest that cold stress may be overall angiostatic. However, cold stress accompanied by rewarming may be seen as a pro-angiogenic stressor for SMECs. This observation questions the potential for using pre-cooling in sport-performance or therapeutic exercise prescription to enhance skeletal muscle angioadaptive responses to exercise. [ABSTRACT FROM AUTHOR]

IntroductionMetabolic syndrome (MetS) amplifies the risks of atherosclerosis. Despite well-known sexual dimorphism in atherosclerosis, underlying mechanisms are poorly understood. Our previous findings highlight a proatherogenic protein, thrombospondin-1 (TSP-1), in hyperglycemia- or hyperleptinemia (mimicking obesity)-induced atherosclerosis. However, the role of TSP-1 in the development of atherosclerosis prompted by co-existing hyperglycemia and obesity, characteristic of MetS, is unknown. The goal of this study was to examine sex-specific differences in lesion progression in a model of combined MetS and atherosclerosis (KKAyApoE) and interrogate how these differences relate to TSP-1 expression.MethodsMale and female KKAy+/−ApoE–/– (with ectopic agouti gene expression) and age-matched non-agouti KKAy–/–ApoE–/– littermates were placed on a standard laboratory diet from 4 to 24 weeks age followed by blood and tissue harvests for biochemical, molecular, and aortic root morphometric studies.ResultsMetabolic profiling confirmed MetS phenotype of KKAy+/−ApoE–/–; however, only male genotypes were glucose intolerant with elevated VLDL-cholesterol and VLDL-triglyceride levels. Aortic root morphometry demonstrated profound lipid-filled lesions, increased plaque area, and augmented inflammatory and SMC abundance in MetS vs non-MetS males. This increase in lesion burden was accompanied with elevated TSP-1 and attenuated LMOD-1 (SM contractile marker) and SRF (transcriptional activator of SM differentiation) expression in male MetS aortic vessels. In contrast, while lipid burden, plaque area, and TSP-1 expression increased in MetS and non-MetS female mice, there was no significant difference between these genotypes. Increased collagen content was noted in MetS and non-MetS genotypes, specific to female mice. Measurement of plasma testosterone revealed a link between the atherogenic phenotype and abnormally high or low testosterone levels. To interrogate whether TSP-1 plays a direct role in SMC de-differentiation in MetS, we generated KKAy+/− mice with and without global TSP-1 deletion. Immunoblotting showed increased SM contractile markers in male KKAy+/−TSP-1–/– aortic vessels vs male KKAy+/−TSP-1+/ +. In contrast, TSP-1 deletion had no effect on SM contractile marker expression in female genotypes.ConclusionTogether, the current study implicates a role of plasma testosterone in sex-specific differences in atherosclerosis and TSP-1 expression in MetS vs non-MetS mice. Our data suggest a sex-dependent differential role of TSP-1 on SMC de-differentiation in MetS. Collectively, these findings underscore a fundamental link between TSP-1 and VSMC phenotypic transformation in MetS.

The skeletal muscle tissue can adapt to exercise and environmental stressors with a remarkable plasticity. Prolonged cold stress exposure has been associated to increased skeletal muscle capillarization. Angioadaptation refers to the coordinated molecular and cellular processes that influence the remodeling of skeletal muscle microvasculature. Two cell types are central to angioadaptation: the myocytes, representing an important source of angiokines; and the skeletal muscle endothelial cell (SMECs), targets of these angiokines and main constituents of muscle capillaries. The influence of cold stress on skeletal muscle angioadaptation remains largely unknown, particularly with respect to myocyte-specific angiokines secretion or endothelial cell angioadaptive responses. Here, we use an in vitro model to investigate the impact of cold stress (28°C versus 37°C) on C2C12 myotubes and SMECs. Our main objectives were to evaluate: 1) the direct impact of cold stress on C2C12 cellular expression of angiokines and their release in the extracellular environment; 2) the indirect impact of cold stress on SMECs migration via these C2C12-derived angiokines; and 3) the direct effect of cold stress on SMECs angioadaptive responses, including migration, proliferation, and the activation of the vascular endothelial growth factor receptor-2 (VEGFR2). Cold stress reduced the secretion of angiokines in C2C12 myotubes culture media irrespective their pro-angiogenic or angiostatic nature. In SMECs, cold stress abrogated cell proliferation and reduced the activation of VEGFR2 despite a greater expression of this receptor. Finally, SMECs pre-conditioned to cold stress displayed an enhanced migratory response when migration was stimulated in rewarming conditions. Altogether our results suggest that cold stress may be overall angiostatic. However, cold stress accompanied by rewarming may be seen as a pro-angiogenic stressor for SMECs. This observation questions the potential for using pre-cooling in sport-performance or therapeutic exercise prescription to enhance skeletal muscle angioadaptive responses to exercise.

Objective To explore the effect and mechanism of estrogen on endothelial progenitor cells（EPCs）function in diabetic rats. Methods EPCs were isolated from bone marrow of rats and characterized by fluorescence microscopy and flow cytometry. Rat diabetic model was established via streptozotocin induction. The bone marrow was taken to culture EPCs. EPCs of diabetes were incubated with Estrogen 10 nmol/L for 24h. The functions and proliferation of EPCs in vitro were detected. The levels of MnSOD and NO in EPCs and TSP-1 in supernatant were assayed. Results Compared with control group, EPCs proliferation, adhesion and angiogenesis functions were impaired in diabetic rats. The level of MnSOD and NO in diabetic EPCs were significantly decreased, while TSP-1 protein level in the supernatant increased. The above changes can be reversed with estrogen incubation. Conclusion Estrogen improved the EPCs migration and tubule formation in diabetic rats. The mechanism may be related to the reduction of oxidative stress and downregulation of TSP-1 expression in diabetic EPCs. [ABSTRACT FROM AUTHOR]

Perinatal hypoxic/ischemic (HI) brain injury is a major clinical problem with devastating neurodevelopmental outcomes in neonates. During HI brain injury, dysregulated factor production contributes to microvascular impairment. Glycolysis-derived lactate accumulated during ischemia has been proposed to protect against ischemic injury, but its mechanism of action is poorly understood. Herein, we hypothesize that lactate via its G-protein coupled receptor (GPR81) controls postnatal brain angiogenesis and plays a protective role after HI injury. We show that GPR81 is predominantly expressed in neurons of the cerebral cortex and hippocampus. GPR81-null mice displayed a delay in cerebral microvascular development linked to reduced levels of various major angiogenic factors and augmented expression of anti-angiogenic Thrombospondin-1 (TSP-1) in comparison to their WT littermates. Coherently, lactate stimulation induced an increase in growth factors (VEGF, Ang1 and 2, PDGF) and reduced TSP-1 expression in neurons, which contributed to accelerating angiogenesis. HI injury in GPR81-null animals curtailed vascular density and consequently increased infarct size compared to changes seen in WT mice; conversely intracerebroventricular lactate injection increased vascular density and diminished infarct size in WT but not in GPR81-null mice. Collectively, we show that lactate acting via GPR81 participates in developmental brain angiogenesis, and attenuates HI injury by restoring compromised microvasculature. [ABSTRACT FROM AUTHOR]

Increased neovascularization of the atherosclerotic plaque promotes plaque vulnerability, atherosclerosis progression, and increased risk of complications, including myocardial infarction and ischemic stroke. The aim of our study was a comprehensive assessment of the expression of multidirectional regulatory factors of angiogenesis in a carotid atherosclerotic plaque. The study included 33 patients with atherosclerotic carotid stenosis exceeding 60%, who were exposed to carotid endarterectomy followed by pathomorphological examination of removed atherosclerotic plaques throughout their length. The structure of plaques, the number of microvessels per 1 cm2 of the plaque, as well as the expression of vascular endothelial growth factors (VEGFA, VEGFB, VEGFC, and VEGFD) and their receptors (VEGFR1, VEGFR2, VEGFR3), FGF2, PDGF-B, and TSP-1) were assessed using histological and immunohistochemical methods followed by a correlation analysis. According to histological examination, 13 plaques were referred to atheromatous (type Va), 12 to complicated, with either fibrous cap ulceration or massive intraplaque haemorrhage (type VI), 6 to calcified (type Vb), and 2 to fibrous (type Vc). Neovessels were found in all plaques (267.5 vessels/1 cm2 [140.9; 534.8]). Most of the neovessels had a highly permeable phenotype with such features as the compromised endothelial integrity, lack of the pericyte layer, and perivascular hemorrhage. VEGFD was overexpressed, significantly prevailing over the other assessed factors (p < 0.001). The pronounced expression of VEGFA, VEGFR2, VEGFR3, FGF2 and PDGF-B was also found in plaques. Immunoreactivity to VEGFB, VEGFC and TSP-1 was the least, with VEGFR1 detected in trace amounts. The number of plaque microvessels significantly correlated with the expression of VEGFA, VEGFD, FGF2, PDGF-B and VEGFR2 (p < 0.01). Other structural components of the plaque did not correlate with the level of angiogenic factors therein. Thus, we demonstrated a pronounced proangiogenic expression profile of various angiogenic factors in association with a failure of the neovasculature stabilization mechanism in advanced human carotid atherosclerotic plaques. [ABSTRACT FROM AUTHOR]

The appearance of synapses was a crucial step in the creation of the variety of nervous systems that are found in the animal kingdom. With increased complexity of the organisms came a greater number of synaptic proteins. In this review we describe synaptic proteins that contain the structural domains CUB, CCP, or TSP-1. These domains are found in invertebrates and vertebrates, and CUB and CCP domains were initially described in proteins belonging to the complement system of innate immunity. Interestingly, they are found in synapses of the nematode C. elegans , which does not have a complement system, suggesting an ancient function. Comparison of the roles of CUB-, CCP-, and TSP-1 containing synaptic proteins in various species shows that in more complex nervous systems, these structural domains are combined with other domains and that there is partial conservation of their function. These three domains are thus basic building blocks of the synaptic architecture. Further studies of structural domains characteristic of synaptic proteins in invertebrates such as C. elegans and comparison of their role in mammals will help identify other conserved synaptic molecular building blocks. Furthermore, this type of functional comparison across species will also identify structural domains added during evolution in correlation with increased complexity, shedding light on mechanisms underlying cognition and brain diseases. [ABSTRACT FROM AUTHOR]

BackgroundThe parasitic trematode Fasciola hepatica evades host immune defenses through secretion of various immunomodulatory molecules. Fatty Acid Binding Proteins (fhFABPs) are among the main excreted/secreted proteins and have been shown to display anti-inflammatory properties. However, little is currently known regarding their impact on dendritic cells (DCs) and their subsequent capacity to prime specific CD4+ T cell subsets.Methodology/Principal FindingsThe immunomodulatory effects of both native F. hepatica extracts and recombinant fhFABPs were assessed on monocyte-derived human DCs (moDCs) and the underlying mechanism was next investigated using various approaches, including DC-allogenic T cell co-culture and DC phenotyping through transcriptomic, proteomic and FACS analyses. We mainly showed that fhFABP1 induced a tolerogenic-like phenotype in LPS-stimulated moDCs characterized by a dose-dependent increase in the cell-surface tolerogenic marker CD103 and IL-10 secretion, while DC co-stimulatory markers were not affected. A significant decrease in secretion of the pro-inflammatory cytokines IL-12p70 and IL-6 was also observed. In addition, these effects were associated with an increase in both Th2-on-Th1 ratio and IL-10 secretion by CD4+ T cells following DC-T cell co-culture. RNA sequencing and targeted proteomic analyses identified thrombospondin-1 (TSP-1) as a non-canonical factor highly expressed and secreted by fhFABP1-primed moDCs. The effect of fhFABP1 on T cell skewing was abolished when using a TSP-1 blocking antibody during DC-T cell co-culture. Immunomodulation by helminth molecules has been linked to improved metabolic homeostasis during obesity. Although fhFABP1 injection in high-fat diet-fed obese mice induced a potent Th2 immune response in adipose tissue, it did not improved insulin sensitivity or glucose homeostasis.Conclusions/SignificanceWe show that fhFABP1 modulates T cell polarization, notably by promoting DC TSP-1 secretion in vitro, without affecting metabolic homeostasis in a mouse model of type 2 diabetes.

The appearance of synapses was a crucial step in the creation of the variety of nervous systems that are found in the animal kingdom. With increased complexity of the organisms came a greater number of synaptic proteins. In this review we describe synaptic proteins that contain the structural domains CUB, CCP, or TSP-1. These domains are found in invertebrates and vertebrates, and CUB and CCP domains were initially described in proteins belonging to the complement system of innate immunity. Interestingly, they are found in synapses of the nematode C. elegans, which does not have a complement system, suggesting an ancient function. Comparison of the roles of CUB-, CCP-, and TSP-1 containing synaptic proteins in various species shows that in more complex nervous systems, these structural domains are combined with other domains and that there is partial conservation of their function. These three domains are thus basic building blocks of the synaptic architecture. Further studies of structural domains characteristic of synaptic proteins in invertebrates such as C. elegans and comparison of their role in mammals will help identify other conserved synaptic molecular building blocks. Furthermore, this type of functional comparison across species will also identify structural domains added during evolution in correlation with increased complexity, shedding light on mechanisms underlying cognition and brain diseases.

Introduction: This research investigates the impact of insulin-like growth factor-I (IGF -I) and exercise on mediators associated with angiogenesis (VEGF-A, TSP-1, and NF-κ β) and capillarization status of the diabetic rats' hearts. Methods: Splitting of forty Wistar male rats into five groups occurred as following: control, diabetes, diabetes+IGF-I, diabetes+exercise, and diabetes+exercise+IGF-I. Through intraperitoneal administration of 60 mg/kg streptozotocin, the condition of Type 1 diabetes was escalated. After four weeks of treatment with IGF-I (2 mg/kg/day) or treadmill exercise (17 m/min, zero degrees slope, 30 min/day), in the heart, microvascular density and protein levels of VEGF-A, TSP-1, and NF-κ β were determined by H&E staining and ELISA, respectively. Results: Within the diabetic group, observations present a significant decrease in VEGF-A and MVD levels, whereas an increase in the TSP-1 and NF-κ b levels. While these impacts were reversed by either IGF-I or exercise treatments, simultaneous treatment had synergistic effects. Moreover, among diabetic rats, undesirable histologic alterations of the heart were demonstrated, including myonecrosis, interstitial edema, hemorrhage, and mononuclear immune cell infiltration, whereas treatments improved these changes. Conclusion: These data manifest that IGF-I and exercise can increase the cardiac angiogenesis of diabetic rats through increasing expression of VEGF-A, and decreasing TSP-1 and NF-κ β proteins level, also can improve myocardial tissue damages. [ABSTRACT FROM AUTHOR]

Abstract Background Cardiovascular diseases are still the major cause of death in the Western world, with different outcomes between the two genders. Efforts to identify those at risk are therefore given priority in the handling of health resources. Thrombospondins (TSP) are extracellular matrix proteins associated with cardiovascular diseases. The aim of this study was to investigate variations in single nucleotide polymorphisms (SNPs) of TSP-1 and plasma expression, and associations with mortality from a gender perspective. Methods A population of 470 community-living persons were invited to participate. The participants were followed for 7.9 years and underwent a clinical examination and blood sampling. SNP analyses of TSP-1 rs1478604 and rs2228262 using allelic discrimination and plasma measurement of TSP-1 using ELISA were performed, Results During the follow-up period, 135 (28.7%) all-cause and 83 (17.7%) cardiovascular deaths were registered. In the female population, the A/A genotype of rs2228262 and the T/T genotype of rs1478604 exhibited significantly more cardiovascular deaths compared with the A/G and G/G, or the T/C and C/C genotypes amalgamated (rs2228262: 13.7% vs 2.0%; Χ2:5.29; P = 0.02; rs1478604:17.7% vs 4.7%; Χ2:9.50; P = 0.002). Applied in a risk evaluation, the A/A, or T/T genotypes exhibited an increased risk of cardiovascular mortality (rs2228262: HR: 7.1; 95%CI 1.11–45.8; P = 0.04; rs1478604: HR: 3.18; 95%CI 1.35–7.50; p = 0.008). No differences among the three genotypes could be seen in the male group. Conclusion In this study the female group having the A/A genotype of rs2228262, or the T/T genotype of rs1478604 of TSP-1 exhibited higher cardiovascular mortality after a follow-up of almost 8 years. No corresponding genotype differences could be found in the male group. Genotype evaluations should be considered as one of the options to identify individuals at risk. However, this study should be regarded as hypothesis-generating, and more research in the field is needed.

Abstract Background Published studies present conflicting data regarding the impact of Thrombospondin-1 (TSP-1) expression on prognosis of various cancers. We performed this meta-analysis to illustrate the preliminary predictive value of TSP-1. Methods Twenty-four studies with a total of 2379 patients were included. A comprehensive literature search was performed by using PubMed, Cochrane Library, Web of Science, Embase, and hand searches were also conducted of relevant bibliographies. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for patient survival and disease recurrence were initially identified to explore relationships between TSP-1 expression and patient prognosis. Results A total of 24 eligible studies were included in this meta-analysis. Our results showed that high level of TSP-1 was correlated significantly with poor overall survival (OS) (HR = 1.40, 95% CI: 1.17 ~ 1.68; P

Focal segmental glomerulosclerosis (FSGS), a common cause of primary glomerulonephritis, has a poor prognosis and is pathologically featured by tubulointerstitial injury. Thrombospondin-1 (TSP-1) is an extracellular matrix protein that acts in combination with different receptors in the kidney. Here, we analyzed the tubular expression of TSP-1 and its receptor integrin β3 (ITGB3) in FSGS. Previously the renal interstitial chip analysis of FSGS patients with tubular interstitial injury showed that the expression of TSP-1 and ITGB3 were upregulated. We found that the expression of TSP-1 and ITGB3 increased in the tubular cells of FSGS patients. The plasma level of TSP-1 increased and was correlated to the degree of tubulointerstitial lesions in FSGS patients. TSP-1/ITGB3 signaling induced renal tubular injury in HK-2 cells exposure to bovine serum albumin and the adriamycin (ADR)-induced nephropathy model. THBS1 KO ameliorated tubular injury and renal fibrosis in ADR-treated mice. THBS1 knockdown decreased the expression of KIM-1 and caspase 3 in the HK-2 cells treated with bovine serum albumin, while THBS1 overexpression could induce tubular injury. In vivo, we identified cyclo-RGDfK as an agent to block the binding of TSP-1 to ITGB3. Cyclo-RGDfK treatment could alleviate ADR-induced renal tubular injury and interstitial fibrosis in mice. Moreover, TSP-1 and ITGB3 were colocalized in tubular cells of FSGS patients and ADR-treated mice. Taken together, our data showed that TSP-1/ITGB3 signaling contributed to the development of renal tubulointerstitial injury in FSGS, potentially identifying a new therapeutic target for FSGS., Competing Interests: Conflict of interest The authors declare that they have no conflict of interests with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Valentina Buda,1,* Minodora Andor,2,* Carmen Cristescu,1,* Mirela Cleopatra Tomescu,2 Danina M Muntean,3 Dana Emilia Bâibâță,4,5 Diana Aurora Bordejevic,4,5 Corina Danciu,6 Olivia Dalleur,7 Dorina Coricovac,8 Zorin Crainiceanu,9 Anca Tudor,10 Ionut Ledeti,11 Lucian Petrescu4,5 1Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy, Timisoara 300041, Romania; 2Department of Medical Semiotics, Faculty of Medicine, “Victor Babeş” University of Medicine and Pharmacy, Timisoara 300041, Romania; 3Department of Pathophysiology, Faculty of Medicine, “Victor Babeş” University of Medicine and Pharmacy, Timisoara 300041, Romania; 4Department of Cardiology VI, Faculty of Medicine, “Victor Babeş” University of Medicine and Pharmacy, Timisoara 300041, Romania; 5Cardiovascular Diseases Institute, Timisoara 300310, Romania; 6Department of Pharmacognosy, “Victor Babeş” University of Medicine and Pharmacy, Timisoara 300041, Romania; 7Clinical Pharmacy Research Group, Louvain Drug Research Institute, Université Catholique De Louvain, Woluwe-Saint-Lambert 1200, Bruxelles, Belgium; 8Department of Toxicology, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy, Timisoara 300041, Romania; 9Department of Plastic and Reconstructive Surgery, Faculty of Medicine, “Victor Babeş” University of Medicine and Pharmacy, Timisoara 300041, Romania; 10Department of Statistics and Biomedical Informatics, Faculty of Medicine, “Victor Babeş” University of Medicine and Pharmacy, Timisoara 300041, Romania; 11Department of Physical Chemistry, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy, Timisoara 300041, Romania*These authors contributed equally to this workCorrespondence: Valentina BudaCorina Danciu Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy, 2 Eftimie Murgu Street, Timisoara 300041, RomaniaTel +40-256-494-604Fax +40-256-494-604Email buda.valentina.oana@gmail.comBackground: Thrombospondin-1 (TSP-1) is a matricellular functional protein of the extracellular matrix. As it is not constitutively present extracellularly, its secretion is enhanced in several situations, namely injury, chronic pathology, tissue remodeling, angiogenesis, and aging. Over the last decade, TSP-1 has been reported to be involved in complex and opposing biological effects on vasculature in the context of NO signaling. Several studies have reported high patient TSP-1 plasma levels, indicating that the protein can potentially serve as a prognostic marker for pulmonary arterial hypertension.Materials and methods: Here, we aimed to quantify TSP-1 serum levels in hypertensive patients with endothelial dysfunction before and after one year of treatment with Perindopril (an antihypertensive drug with vasoprotective properties).Results: After one year of treatment, TSP-1 levels increased in hypertensive patients compared to baseline (T0: 8061.9 ± 3684.80 vs T1: 15380±5887 ng/mL, p

CD47, a 50 kDa transmembrane protein, facilitates integrin-mediated cell adhesion and inhibits cell engulfment by phagocytes. Since CD47 blocking promotes engulfment of cancer cells by macrophages, it is important to clarify the mechanism of CD47 signaling in order to develop treatments for diseases involving CD47-overexpressing cancer cells, including breast cancer and lymphoma. Here, we show that CD47 plays an essential role in T-cell lymphoma metastasis by up-regulating basal RhoA activity independent of its anti-phagocytic function. CD47 interacts with AKAP13, a RhoA-specific guanine nucleotide exchange factor (GEF), and facilitates AKAP13-mediated RhoA activation. Our study shows that CD47 has a novel function on the AKAP13-RhoA axis and suggests that CD47–AKAP13 interaction would be a novel target for T-cell lymphoma treatment. [ABSTRACT FROM AUTHOR]

It is now admitted that in addition to acquired resistance, the tumor microenvironment contributes to the development of chemo-resistance and malignant progression. In a previous study, we showed that Dox induced apoptosis in FTC-133 cells by trigging JNK pathway. This process was accompanied by a decrease of thrombospondin-1 (TSP-1) expression. Moreover, exogenous TSP-1 or its C-terminal-derived peptide interact with receptor CD47 and are able to protect FTC-133 cells against Dox-induced apoptosis. Here, we investigated the involvement of TSP-1/CD47 interaction in a context of acquired multidrug resistance in FTC-133 cells. To that end, we established a Dox-resistant cell line (FTC-133R cells) which developed a resistance against Dox-induced apoptosis. Cell viability was evaluated by Uptiblue assay, nuclear Dox was measured by microspectrofluorimetry, caspase activity was measured by fluorescence of cleaved caspase-3 substrate, gene expression was evaluated by RT-PCR and protein expression was examined by western-blot. Our results showed that FTC-133R overexpressed the P-gp and were 15-fold resistant to Dox. JNK phosphorylation and Dox-induced apoptosis were reduced in FTC-133R cells. Expression of CD47 was increased in FTC-133R cells but TSP-1 expression presented similar levels in two cell lines. VPL restored Dox nuclear uptake and FTC-133R cell sensitivity to apoptosis and induced a decrease in CD47 mRNA expression. Moreover, knockdown of CD47 in FTC-133R cells induced an increase in JNK activation and sensitized FTC-133R cells to Dox. Our data suggest that CD47 is able to contribute to the protection of FTC-133R cells against Dox-induced apoptosis and/or to potentiate the acquired Dox resistance.

It is now admitted that in addition to acquired resistance, the tumor microenvironment contributes to the development of chemo-resistance and malignant progression. In a previous study, we showed that Dox induced apoptosis in FTC-133 cells by trigging JNK pathway. This process was accompanied by a decrease of thrombospondin-1 (TSP-1) expression. Moreover, exogenous TSP-1 or its C-terminal-derived peptide interact with receptor CD47 and are able to protect FTC-133 cells against Dox-induced apoptosis. Here, we investigated the involvement of TSP-1/CD47 interaction in a context of acquired multidrug resistance in FTC-133 cells. To that end, we established a Dox-resistant cell line (FTC-133R cells) which developed a resistance against Dox-induced apoptosis. Cell viability was evaluated by Uptiblue assay, nuclear Dox was measured by microspectrofluorimetry, caspase activity was measured by fluorescence of cleaved caspase-3 substrate, gene expression was evaluated by RT-PCR and protein expression was examined by western-blot. Our results showed that FTC-133R overexpressed the P-gp and were 15-fold resistant to Dox. JNK phosphorylation and Dox-induced apoptosis were reduced in FTC-133R cells. Expression of CD47 was increased in FTC-133R cells but TSP-1 expression presented similar levels in two cell lines. VPL restored Dox nuclear uptake and FTC-133R cell sensitivity to apoptosis and induced a decrease in CD47 mRNA expression. Moreover, knockdown of CD47 in FTC-133R cells induced an increase in JNK activation and sensitized FTC-133R cells to Dox. Our data suggest that CD47 is able to contribute to the protection of FTC-133R cells against Dox-induced apoptosis and/or to potentiate the acquired Dox resistance. [ABSTRACT FROM AUTHOR]

Thrombospondins (TSPs) are a family of five multimeric matricellular proteins. Through a wide range of interactions, TSPs play pleiotropic roles in embryogenesis and in tissue remodeling in adult physiology as well as in pathological conditions, including cancer development and metastasis. TSPs are active in bone remodeling, the process of bone resorption (osteolysis) and deposition (osteogenesis) that maintains bone homeostasis. TSPs are particularly involved in aberrant bone remodeling, including osteolytic and osteoblastic skeletal cancer metastasis, frequent in advanced cancers such as breast and prostate carcinoma. TSPs are major players in the bone metastasis microenvironment, where they finely tune the cross talk between tumor cells and bone resident cells in the metastatic niche. Each TSP family member has different effects on the differentiation and activity of bone cells--including the bonedegrading osteoclasts and the bone-forming osteoblasts--with different outcomes on the development and growth of osteolytic and osteoblastic metastases. Here, we overview the involvement of TSP family members in the bone tissue microenvironment, focusing on their activity on osteoclasts and osteoblasts in bone remodeling, and present the evidence to date of their roles in bone metastasis establishment and growth. [ABSTRACT FROM AUTHOR]

Epilepsy is one of the most common chronic neurological diseases in the world, with a high incidence, a high risk of sudden unexplained death, and diagnostic challenges. Exosomes are nanosized extracellular vesicles that are released into physical environments and carry a variety of biological information. Moreover, exosomes can also be synthesized and released from brain cells, passing through the blood-brain barrier, and can be detected in peripheral blood or cerebrospinal fluid. Our study using the tandem mass tag (TMT) approach showed that a total of 76 proteins were differentially expressed in serum exosomes between epilepsy patients and healthy controls, with 6 proteins increasing and 70 proteins decreasing. Analysis of large clinical samples and two mouse models of chronic epilepsy indicated that two significantly differentially expressed serum exosomal proteins, coagulation factor IX (F9) and thrombospondin-1 (TSP-1), represent promising biomarkers for the diagnosis of epilepsy, with area under the curve (AUC) values of up to 0.7776 (95% CI, 0.7306–0.8246) and 0.8534 (95% CI, 0.8152–0.8916), respectively. This is the first study of exosomal proteins in epilepsy, and it suggests that exosomes are promising new tools for the diagnosis of epilepsy.

Hypertrophic scar (HTS) is a common pathologic dermal fibroproliferative disease after skin injury. Transforming growth factor β (TGF-β) plays a central role in HTS formation and development. Thrombospondin-1 (TSP-1) activates latent TGF-β by binding to latency-associated peptide-β on TGF-β structure. So far, LSKL peptide was shown to selectively antagonize TSP-1. In this study, TSP-1 was first confirmed to be highly expressed in HTS. LSKL peptide was proven to inhibit the overexpression of extracellular matrix and contractile ability of HTS fibroblasts. In vivo, LSKL could attenuate the thickness of HTS, distortion of collagen alignment and fibrogenesis. Results also demonstrated that LSKL peptide not only remarkably attenuated cell proliferation and migration, but also induced cell apoptosis of HTS fibroblasts. Western blot analysis further revealed that LSKL peptide significantly suppressed the phosphorylation of PI3K, AKT, and mTOR, while not affecting the phosphorylation of Smad2/3 and MEK/ERK. These findings suggested that LSKL might be a promising anti-fibrosis agent to HTS through PI3K/AKT/mTOR signaling pathway.

A common allele (402H) of the complement factor H (FH) gene is the major risk factor for age-related macular degeneration (AMD), the leading cause of blindness in the elderly population. Development and progression of AMD involves vascular and inflammatory components partly by deregulation of the alternative pathway of the complement system (AP). The loss of central vision results from atrophy and/or from abnormal neovascularization arising from the choroid. The functional link between FH, the main inhibitor of AP, and choroidal neovascularization (CNV) in AMD remains unclear. In a murine model of CNV used as a model for neovascular AMD (nAMD), intraocular human recombinant FH (recFH) reduced CNV as efficiently as currently used anti-VEGF (vascular endothelial growth factor) antibody, decreasing deposition of C3 cleavage fragments, membrane attack complex (MAC), and microglia/macrophage recruitment markers in the CNV lesion site. In sharp contrast, recFH carrying the H402 risk variant had no effect on CNV indicating a causal link to disease etiology. Only the recFH NTal region (recFH1-7), containing the CCPs1-4 C3-convertase inhibition domains and the CCP7 binding domain, exerted all differential biological effects. The CTal region (recFH7-20) containing the CCP7 and CCPs19-20 binding domains was antiangiogenic but did not reduce the microglia/macrophage recruitment. The antiangiogenic effect of both recFH1-20 and recFH-CCP7-20 resulted from thrombospondin-1 (TSP-1) upregulation independently of the C3 cleavage fragments generation. This study provides insight on the mechanistic role of FH in nAMD and invites to reconsider its therapeutic potential.

Epilepsy is one of the most common chronic neurological diseases in the world, with a high incidence, a high risk of sudden unexplained death, and diagnostic challenges. Exosomes are nanosized extracellular vesicles that are released into physical environments and carry a variety of biological information. Moreover, exosomes can also be synthesized and released from brain cells, passing through the blood-brain barrier, and can be detected in peripheral blood or cerebrospinal fluid. Our study using the tandem mass tag (TMT) approach showed that a total of 76 proteins were differentially expressed in serum exosomes between epilepsy patients and healthy controls, with 6 proteins increasing and 70 proteins decreasing. Analysis of large clinical samples and two mouse models of chronic epilepsy indicated that two significantly differentially expressed serum exosomal proteins, coagulation factor IX (F9) and thrombospondin-1 (TSP-1), represent promising biomarkers for the diagnosis of epilepsy, with area under the curve (AUC) values of up to 0.7776 (95% CI, 0.7306–0.8246) and 0.8534 (95% CI, 0.8152–0.8916), respectively. This is the first study of exosomal proteins in epilepsy, and it suggests that exosomes are promising new tools for the diagnosis of epilepsy. [ABSTRACT FROM AUTHOR]

Background: Published studies present conflicting data regarding the impact of Thrombospondin-1 (TSP-1) expression on prognosis of various cancers. We performed this meta-analysis to illustrate the preliminary predictive value of TSP-1. Methods: Twenty-four studies with a total of 2379 patients were included. A comprehensive literature search was performed by using PubMed, Cochrane Library, Web of Science, Embase, and hand searches were also conducted of relevant bibliographies. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for patient survival and disease recurrence were initially identified to explore relationships between TSP-1 expression and patient prognosis. Results: A total of 24 eligible studies were included in this meta-analysis. Our results showed that high level of TSP-1 was correlated significantly with poor overall survival (OS) (HR = 1.40, 95% CI: 1.17 ~ 1.68; P<0.001). However, high TSP-1 expression predicted no significant impact on progression-free survival (PFS)/ metastasis-free survival (MFS) (HR = 1.35, 95%CI: 0.87–2.10; P = 0.176) and disease-free survival (DFS)/ recurrence-free survival (RFS) (HR = 1.40, 95%CI: 0.77–2.53; P = 0.271). In addition, we performed subgroup analyses which showed that high TSP-1 expression predicted poor prognosis in breast cancer and gynecological cancer. Additionally, the relatively small number of studies on PFS/MFS and DFS/RFS is a limitation. The data extracted through Kaplan-Meier curves may not be accurate. Moreover, only English articles were included in this article, which may lead to deviations in the results. Conclusions: Our findings indicated high TSP-1 expression may act as a promising biomarker of poor prognosis in cancers, especially in breast cancer and gynecological cancer. [ABSTRACT FROM AUTHOR]

A common allele (402H) of the complement factor H (FH) gene is the major risk factor for age-related macular degeneration (AMD), the leading cause of blindness in the elderly population. Development and progression of AMD involves vascular and inflammatory components partly by deregulation of the alternative pathway of the complement system (AP). The loss of central vision results from atrophy and/or from abnormal neovascularization arising from the choroid. The functional link between FH, the main inhibitor of AP, and choroidal neovascularization (CNV) in AMD remains unclear. In a murine model of CNV used as a model for neovascular AMD (nAMD), intraocular human recombinant FH (recFH) reduced CNV as efficiently as currently used anti-VEGF (vascular endothelial growth factor) antibody, decreasing deposition of C3 cleavage fragments, membrane attack complex (MAC), and microglia/macrophage recruitment markers in the CNV lesion site. In sharp contrast, recFH carrying the H402 risk variant had no effect on CNV indicating a causal link to disease etiology. Only the recFH NTal region (recFH1-7), containing the CCPs1-4 C3-convertase inhibition domains and the CCP7 binding domain, exerted all differential biological effects. The CTal region (recFH7-20) containing the CCP7 and CCPs19-20 binding domains was antiangiogenic but did not reduce the microglia/macrophage recruitment. The antiangiogenic effect of both recFH1-20 and recFH-CCP7-20 resulted from thrombospondin-1 (TSP-1) upregulation independently of the C3 cleavage fragments generation. This study provides insight on the mechanistic role of FH in nAMD and invites to reconsider its therapeutic potential. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Sepsis is a systemic inflammatory disease. LncRNA NEAT1 has been reported to be up-regulated in sepsis patients. Nevertheless, the modulatory network of NEAT1 in sepsis remains to be revealed. PATIENTS AND METHODS: The abundance of long noncoding RNA nuclear enriched abundant transcript 1 (lncRNA NEAT1), miR-370-3p, and thrombospondin-1 (TSP-1) were determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) in sepsis patients and lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Enzyme-linked immunosorbent assay (ELISA) was performed to examine the concentration of cytokines in RAW 264.7 cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry assay, and Western blot assay were conducted to detect the proliferation and apoptosis of RAW 264.7 cells. Dual-Luciferase reporter assay, RNA immunoprecipitation (RIP) assay, and RNA-pull down assay were conducted to confirm the combination between miR-370-3p and NEAT1 or TSP-1 in RAW 264.7 cells. RESULTS: The enrichment of NEAT1 was enhanced in sepsis patients and LPS-stimulated RAW 264.7 cells. NEAT1 contributed to LPS-induced inflammation and apoptosis of RAW 264.7 cells. MiR-370-3p bound to NEAT1, and it was negatively regulated by NEAT1 in RAW 264.7 cells. LPS promoted the inflammation and apoptosis while restrained the proliferation of RAW 264.7 cells via NEAT1/miR-370-3p axis. TSP-1 was a target of miR-370-3p in RAW 264.7 cells, and miR-370-3p suppressed the inflammation and apoptosis while it facilitated the proliferation of LPS-induced RAW 264.7 cells via TSP-1. CONCLUSIONS: LncRNA NEAT1 promoted the inflammation and apoptosis while restrained the proliferation of LPS-stimulated RAW 264.7 cells through the miR-370-3p/TSP-1 axis. [ABSTRACT FROM AUTHOR]

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• TSP-1 is downregulated in OA human articular cartilage. • TSP-1 has potential as a biomarker for diagnosing early OA. • TSP-1 suppresses catabolic responses and enhances anabolism in vitro and vivo. • TSP-1 affects autophagy level by upregulating HSP27 to delay OA progression. • TSP-1 promotes chondrocyte proliferation and inhibits apoptosis in vitro and in vivo. This study aimed to determine whether Thrombospondin-1 (TSP-1) can be used as a biomarker to diagnose early osteoarthritis (OA) and whether it has a chondroprotective effect against OA. We examined TSP-1 expression in cartilage, synovial fluid, and serum at different time points after anterior cruciate ligament transection (ACLT) surgery in rats. Subsequently, TSP-1 was overexpressed or silenced to detect its effects on extracellular matrix (ECM) homeostasis, autophagy level, proliferation and apoptosis in chondrocytes. Adenovirus encoding TSP-1 was injected into the knee joints of ACLT rats to test its effect against OA. Combined with proteomic analysis, the molecular mechanism of TSP-1 in cartilage degeneration was explored. Intra-articular injection of an adenovirus carrying the TSP-1 sequence showed chondroprotective effects against OA. Moreover, TSP-1 expression decreases with OA progression and can effectively promote cartilage proliferation, inhibit apoptosis, and helps to sustain the balance between ECM anabolism and catabolism. Overexpression of TSP-1 also can increase autophagy by upregulating Heat Shock Protein 27 (HSP27, hspb1), thereby enhancing its effect as a stimulator of autophagy. TSP-1 is a hopeful strategy for OA treatment. [ABSTRACT FROM AUTHOR]

Accumulating evidence on the role of Thrombospondin-1 (TSP-1) in the immune response has emerged during the last years. In spite of the importance of TSP-1 not only as anti-angiogenic factor but also as an immunomodulatory molecule, studies on the role of TSP-1 in psoriasis have been neglected. TSP-1 and CD47 expression were analyzed in skin samples from psoriasis patients and control subjects using RT-PCR and immunofluorescence. Expression of these molecules was also evaluated in peripheral blood CD4+ T cells, moDCs, and circulating primary DCs. The functional role of TSP-1/CD47 signaling axis in psoriasis was assessed in Th17 and Treg differentiation assays. Additionally, small interfering RNA assays specific to TSP-1 were performed in CD4+ T cells and monocyte derived DC to specifically evaluate the function of this protein. Lesional skin of psoriasis patients expressed lower TSP-1 and CD47 mRNA levels compared to non-lesional skin or skin from controls. Immunofluorescence staining revealed decreased expression of CD47 in CD45+ dermal cells from psoriasis samples compared to control subjects. Peripheral CD4+ T cells and circulating primary DCs from psoriasis also expressed lower levels of CD47 compared to controls. Although no significant differences were detected in TSP-1 expression in CD4+ T cells and moDCs between patients and controls, TSP-1 expression in psoriasis patients inversely correlated with disease activity evaluated by the Psoriasis Area and Index Activity. Furthermore, exogenous TSP-1 inhibited Th17 differentiation and stimulated the differentiation of CD4+ T cells toward Treg cells. Furthermore, RNA interference specific for TSP-1 confirmed the role of this molecule as a negative regulator of T cell activation. Because of the impact of TSP-1/CD47 signaling axis in Th17 and Treg differentiation, a dysregulated expression of these molecules in the immune cells from psoriasis patients may favor the exacerbated inflammatory response in this disease.