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Objectives: Patients with moderate-severe Crohn's disease (CD) who are treated with antitumor necrosis factor alpha (TNF-α) agents may be subjected to primary nonresponse or partial response. We aimed to identify tissue markers that may predict response to these agents., Methods: Pediatric patients (6-18 years) with either ileal or ileo-colonic CD who were treated with anti-TNF-α were stratified into three different groups based on their overall response to therapy at the end of induction including clinical and laboratory parameters (group 1-full responders [FR], group 2-partial responders [PR], group 3-nonresponders [NR]). Seven tissue markers (fibronectin, interleukin [IL]-23R, IL-23, TNF-α, collagen-III, IL-13R, and hypoxia-inducible factors [HIF]-1α) were evaluated. Immunofluorescence (IF) analyses were performed on biopsies from the terminal ileum, which were retrieved up to 6 months before treatment initiation., Results: Twenty-six CD patients (16 [61.5%] males; age 13.9 ± 2.9 years), including 8 (30.8%) with ileal disease and 18 (69.2%) with ileo-colonic disease, were enrolled. Terminal ileum biopsies from nine patients from group 1, nine from group 2, and eight from group 3 were evaluated. Three antibodies were found to be significantly different between NR and FR groups; Collagen III and fibronectin stains were significantly more prominent in NR patients, while TNF-α stain was significantly more pronounced in FR, p < 0.05 for each. PR could not have been predicted with neither of markers., Conclusions: Decreased tissue IF intensity of fibronectin and collagen III and increased intensity of TNF-α may predict response to anti-TNF-α treatment., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Backgruound: Renal fibrosis is characterized by the accumulation of extracellular matrix proteins and interstitial fibrosis. Alantolactone is known to exert anticancer, anti-inflammatory, antimicrobial and antifungal effects; however, its effects on renal fibrosis remains unknown. Here, we investigated whether alantolactone attenuates renal fibrosis in mice unilateral ureteral obstruction (UUO) and evaluated the effect of alantolactone on transforming growth factor (TGF) signaling pathway in renal cells., Methods: To evaluate the therapeutic effect of alantolactone, cell counting kit-8 (CCK-8) assay, histological staining, Western blot analysis, and real-time quantitative polymerase chain reaction were performed in UUO kidneys in vivo and in TGF-β-treated renal cells in vitro., Results: Alantolactone (0.25 to 4 µM) did not affect the viability of renal cells. Mice orally administered 5 mg/kg of alantolactone daily for 15 days did not show mortality or liver toxicity. Alantolactone decreased UUO-induced blood urea nitrogen and serum creatinine levels. In addition, it significantly alleviated renal tubulointerstitial damage and fibrosis and decreased collagen type I, fibronectin, and α-smooth muscle actin (α-SMA) expression in UUO kidneys. In NRK-49F cells, alantolactone inhibited TGF-βstimulated expression of fibronectin, collagen type I, plasminogen activator inhibitor-1 (PAI-1), and α-SMA. In HK-2 cells, alantolactone inhibited TGF-β-stimulated expression of collagen type I and PAI-1. Alantolactone inhibited UUO-induced phosphorylation of Smad3 in UUO kidneys. In addition, it not only decreased TGF-β secretion but also Smad3 phosphorylation and translocation to nucleus in both kidney cell lines., Conclusion: Alantolactone improves renal fibrosis by inhibiting the TGF-β/Smad3 signaling pathway in obstructive nephropathy. Thus, alantolactone is a potential therapeutic agent for chronic kidney disease.

Introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have a favorable impact on the kidney function in patients with heart failure (HF), while there is no clear evidence of what factors predict this effect. The aim of the study was to identify plausible predictors for kidney function outcome among patients with HF and investigate their association with SGLT2i., Methods: We prospectively enrolled 480 patients with type 2 diabetes mellitus (T2DM) treated with diet and metformin and concomitant chronic HF and followed them for 52 weeks. In the study, we determined kidney outcome as a composite of ≥ 40% reduced estimated glomerular filtration rate from baseline, newly diagnosed end-stage kidney disease or kidney replacement therapy. The relevant medical information and measurement of the biomarkers (N-terminal natriuretic pro-peptide, irisin, apelin, adropin, C-reactive protein, tumor necrosis factor-alpha) were collected at baseline and at the end of the study., Results: The composite kidney outcome was detected in 88 (18.3%) patients of the entire population. All patients received guideline-recommended optimal therapy, which was adjusted to phenotype/severity of HF, cardiovascular risk and comorbidity profiles, and fasting glycemia. Levels of irisin, adropin and apelin significantly increased in patients without clinical endpoint, whereas in those with composite endpoint the biomarker levels exhibited a decrease with borderline statistical significance (p = 0.05). We noticed that irisin ≤ 4.50 ng/ml at baseline and a ≤ 15% increase in irisin serum levels added more valuable predictive information than the reference variable. However, the combination of irisin ≤ 4.50 ng/ml at baseline and ≤ 15% increase in irisin serum levels (area under curve = 0.91; 95% confidence interval = 0.87-0.95) improved the discriminative value of each biomarker alone., Conclusion: We suggest that low levels of irisin and its inadequate increase during administration of SGLT2i are promising predictors for unfavorable kidney outcome among patients with T2DM and concomitant HF., (© 2023. The Author(s).)

A distinctive signature of the prion diseases is the accumulation of the pathogenic isoform of the prion protein, PrP Sc , in the central nervous system of prion-affected humans and animals. PrP Sc is also found in peripheral tissues, raising concerns about the potential transmission of pathogenic prions through human food supplies and posing a significant risk to public health. Although muscle tissues are considered to contain levels of low prion infectivity, it has been shown that myotubes in culture efficiently propagate PrP Sc . Given the high consumption of muscle tissue, it is important to understand what factors could influence the establishment of a prion infection in muscle tissue. Here we used in vitro myotube cultures, differentiated from the C2C12 myoblast cell line (dC2C12), to identify factors affecting prion replication. A range of experimental conditions revealed that PrP Sc is tightly associated with proteins found in the systemic extracellular matrix, mostly fibronectin (FN). The interaction of PrP Sc with FN decreased prion infectivity, as determined by standard scrapie cell assay. Interestingly, the prion-resistant reserve cells in dC2C12 cultures displayed a FN-rich extracellular matrix while the prion-susceptible myotubes expressed FN at a low level. In agreement with the in vitro results, immunohistopathological analyses of tissues from sheep infected with natural scrapie demonstrated a prion susceptibility phenotype linked to an extracellular matrix with undetectable levels of FN. Conversely, PrP Sc deposits were not observed in tissues expressing FN. These data indicate that extracellular FN may act as a natural barrier against prion replication and that the extracellular matrix composition may be a crucial feature determining prion tropism in different tissues.

Background: Suppurative hidradenitis (HS) is a chronic, inflammatory skin disease of the hair follicle unit. Adalimumab (ADA), an anti-tumor necrosis factor (TNF) alpha, is the only FDA-approved biologic available for the management of HS. TNF-α can also affect glucose and lipid metabolism, promoting insulin resistance and obesity by negatively regulating irisin, a new adipomyokine., Methods: A total of 17 HS patients were enrolled in the study. Blood samples were collected from all patients at baseline and week-16. Plasma irisin levels were detected by ELISA assay., Results: Plasma irisin levels were significantly increased after 16 weeks of ADA therapy in HS patients compared to baseline. Interestingly, plasma irisin levels correlated with clinical response., Conclusions: The link between skin inflammatory diseases and metabolic disorders has aroused great interest in order to research new biomarkers able to early identify metabolic comorbidities. Among these emerging biomarkers, irisin is one of the most recently discovered. We examined a group of patients affected by moderate-severe HS treated with anti-TNF-α, demonstrating for the first time how a therapy able to block an inflammatory cytokine can also affect the metabolic profile by modifying levels of irisin.

Background: The main mechanism underlying cancer dissemination is the epithelial to mesenchymal transition (EMT). This process is orchestrated by cytokines like TGFβ, involving "non-canonical" AKT- or STAT3-driven pathways. Recently, the alteration of copper homeostasis seems involved in the onset and progression of cancer., Methods: We expose different breast cancer cell lines, including two triple negative (TNBC) ones, an HER2 enriched and one cell line representative of the Luminal A molecular subtype, to short- or long-term copper-chelation by triethylenetetramine (TRIEN). We analyse changes in the expression of EMT markers (E-cadherin, fibronectin, vimentin and αSMA), in the levels and activity of extracellular matrix components (LOXL2, fibronectin and MMP2/9) and of copper homeostasis markers by Western blot analyses, immunofluorescence, enzyme activity assays and RT-qPCR. Boyden Chamber and wound healing assays revealed the impact of copper chelation on cell migration. Additionally, we explored whether perturbation of copper homeostasis affects EMT prompted by TGFβ. Metabolomic and lipidomic analyses were applied to search the effects of copper chelation on the metabolism of breast cancer cells. Finally, bioinformatics analysis of data on breast cancer patients obtained from different databases was employed to correlate changes in kinases and copper markers with patients' survival., Results: Remarkably, only HER2 negative breast cancer cells differently responded to short- or long-term exposure to TRIEN, initially becoming more aggressive but, upon prolonged exposure, retrieving epithelial features, reducing their invasiveness. This phenomenon may be related to the different impact of the short and prolonged activation of the AKT kinase and to the repression of STAT3 signalling. Bioinformatics analyses confirmed the positive correlation of breast cancer patients' survival with AKT activation and up-regulation of CCS. Eventually, metabolomics studies demonstrate a prevalence of glycolysis over mitochondrial energetic metabolism and of lipidome changes in TNBC cells upon TRIEN treatment., Conclusions: We provide evidence of a pivotal role of copper in AKT-driven EMT activation, acting independently of HER2 in TNBC cells and via a profound change in their metabolism. Our results support the use of copper-chelators as an adjuvant therapeutic strategy for TNBC., (© 2022. The Author(s).)

Background: Major Depression is the leading cause of disability worldwide. A cohort of patients do not respond adequately to available antidepressants, leading to treatment-resistant depression (TRD). We evaluated the antidepressant efficacy of an acute intravenous ketamine treatment (0.5 mg/kg) for patients with unipolar TRD, and measured peripheral blood-based biomarkers associated with response to treatment., Methods: Fifteen adults diagnosed with TRD completed an open label study of ten infusions of subanesthetic ketamine over four weeks. Out of fifteen patients, blood was collected from eleven patients at three timepoints to analyze peripheral biomarkers in isolated plasma, including IL-6, IL-10, TNF-α, BDNF, and irisin. Irisin analysis was completed using an ELISA assay, and the remaining biomarkers were analyzed together simultaneously using a multiplex immunoassay., Results: Repeated ketamine infusions produced a significant decrease in total average depressive symptoms (MADRS) at all timepoints. Improvements in depressive symptoms were significant at one week, and continued to significantly decrease until two weeks, where it was maintained. Ketamine was generally well tolerated, and we observed improvements in functional impairment, anhedonia, and psychiatric symptoms, with no increases in manic symptoms. Levels of BDNF throughout treatment inversely correlated to decreases in MADRS scores, and higher levels of baseline BDNF predicted mood responses at one- and four weeks., Limitations: The study was observational and uncontrolled, with a sample size of 15. Outpatients remained on their course of medications, unless they were pharmacological agents that have previously been identified to block ketamine's effects., Conclusions: Ketamine may be an efficacious and safe pharmacological option for the acute treatment of patients suffering from severe TRD. BDNF has the potential to function as a prognostic biomarker for predicting response to ketamine treatments., Competing Interests: Conflict of Interest No author or immediate family member has financial relationships with commercial entities that might appear to represent potential conflicts of interest with the information presented., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Liver fibrosis is characterized by the excessive deposition of extracellular matrix components and results from chronic liver injury. At present, there is no approved drug for the treatment of liver fibrosis by the Food and Drug Administration. Here, we have reported a series of novel compounds with phenacrylanilide scaffolds that potently inhibit the transfer growth factor β1 (TGF-β1)-induced activation of LX-2, a hepatic stellate cell (HSC) line. Among them, compound 42 suppressed TGF-β1-induced upregulation of fibrotic markers (α-SMA and fibronectin) and showed excellent safety in vitro. Furthermore, in a carbon tetrachloride (CCl 4 ) -induced liver fibrosis model, 42 at a dose of 30 mg/kg/day through oral administration for 3 weeks effectively improved liver function, restored damaged liver structures, and reduced collagen deposition, with a greater effect than Tranilast. In addition, epithelial-mesenchymal transition (EMT) is inhibited by compound 42 in the process of fibrosis. Meanwhile, the imbalanced immune microenvironment could also be effectively reversed. More interestingly, compound 42 prolongs the survival of CCl 4 mice and ameliorates CCl 4 -induced injury to spleen, kidney, lung and heart. Altogether, these results suggest that 42 could be a potential drug candidate for the treatment of liver fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Depression is a psychiatric disorder increasingly diffused worldwide. Evidence suggests that irisin, a myokine secreted by contracting muscle, mediates beneficial effects on several targets, including the brain. Here, the potential antidepressant properties of long-term intermittent systemic irisin administration (100 µg/kg/weekly for 1 month) were evaluated in mice by the Tail Suspension Test (TST), Forced Swim Test (FST), and Open Field Test (OFT). Furthermore, to deepen the molecular pathways underlying irisin treatment, the expression of irisin precursor, neurotrophic/growth factors, and cytokines was analyzed. Irisin treatment significantly decreased the immobility time in the TST and FST, suggesting an antidepressant effect. Additionally, irisin seemed to display an anxiolytic-like effect increasing the time spent in the OFT arena center. These findings were probably due to the modulation of endogenous brain factors as the gene expression of some neurotrophins, such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF-1), was upregulated only in irisin-treated mouse brain. Moreover, irisin modulated the expression of some cytokines (IL-1β, IL-4, IL-6, and IL-10). To the best of our knowledge, this is the first study demonstrating that the irisin antidepressant effect may be observed even with a systemic administration in mice. This could pave the way toward intriguing preclinical research in humans.

The abundant desmoplastic stroma and the lack of sufficient targets on pancreatic cancer cells render poor drug penetration and cellular uptake, which significantly compromise the chemotherapy efficacy. Herein, we reported a three-step cascade delivery strategy for selective delivery of paclitaxel (PTX) to achieve a targeted therapy for pancreatic cancer. cRGD and cCLT1 peptides, which could target the integrin and fibronectin, respectively, overexpressed in pancreatic cancer cells and stroma, were decorated on PTX-loaded microbubbles, resulting in the formation of dual-targeting PTX-RCMBs. In this strategy, ultrasound in combination with PTX-RCMBs first enhanced the permeability of tumor vessels via cavitation effects and simultaneously helped the generated PTX-RCNPs penetrate into the stroma. Then, the cCLT1 peptide modified on PTX-RCNPs selectively bound the fibronectin highly expressed in the stroma and later targeted the integrin (α 5 β 1 ) on the cell surface. Finally, another targeting cRGD peptide modified on PTX-RCNPs would further promote PTX uptake via targeting the integrin (α v β 3 ) on the cell surface. This strategy significantly increased the delivery of PTX into tumor tissues. Moreover, the in vivo effective accumulation of PTX was monitored by ultrasound and fluorescence bimodal imaging. The tumor growth inhibition was investigated on subcutaneous tumor mouse models with 89.8% growth inhibition rate during 21 days of treatment, showing great potential for improving pancreatic cancer therapy.

Iron-dependent lipid peroxidation causes ferroptosis. This study was aimed at verifying that irisin postconditioning can inhibit ferroptosis and minimize lung ischemia/reperfusion (I/R) damage via activating the Nrf2/HO-1 signal axis. We constructed a murine model of I/R lung damage. At the onset of reperfusion, irisin, ferroptosis inhibitor ferrostatin-1, and ferroptosis inducer Fe-citrate were all administered. We discovered that irisin could reduce lung I/R injury, consistent with ferrostatin-1's action. Furthermore, irisin suppressed ferroptosis in lung I/R damage, as evidenced by lower ROS, MDA, and Fe 2+ , as well as alterations in critical protein expression (GPX4 and ACSL4). However, Fe-citrate abolished the protective effects of irisin. Transcriptome research found that irisin increased the mRNA levels of Nrf2 and HO-1. Thus, we used siRNA to investigate the role of the Nrf2/HO-1 axis in irisin-mediated protection against hypoxia/reoxygenation (H/R) damage in MLE-12 cells. Irisin consistently reduced ferroptosis and improved mitochondrial dysfunction caused by H/R. Irisin's cytoprotective function was eliminated when Nrf2 was silenced. As a result, irisin postconditioning may protect against lung I/R damage by suppressing ferroptosis via the Nrf2/HO-1 signaling axis., Competing Interests: The authors declare that they have no conflict of interests., (Copyright © 2022 Yun Wang et al.)

Resistance to lenvatinib mesylate (LEN), a systemic chemotherapy that can be administered orally, has been a major issue for treatment of hepatocellular carcinoma (HCC). Although HCC is the tumor that most exhibits intratumoral hypoxia, which has been shown to be involved in the development of treatment resistance, there are no reports of LEN resistance in HCC treatment under hypoxia. The purpose of our study was to elucidate the mechanism of treatment resistance to LEN under hypoxia using HCC cell lines. We confirmed LEN resistance under hypoxic conditions in HCC cell lines. There was a significant increase in the IC 50 value of PLC/PRF/5 cells from 13.0±0.8 μM in normoxia to 21.3±1.1 μM in hypoxia, but in HepG2 cells, the increase was not significant. To elucidate the LEN resistance mechanism of PLC/PRF/5 cells under hypoxia, we performed microarray analysis and extracted genes that are thought to be related to this mechanism. Furthermore, in-silico analysis confirmed significant changes in the extracellular matrix, and among them, FN1 encoding fibronectin was determined as the hub of the gene cluster. The expression of fibronectin in PLC/PRF/5 cells examined with immunofluorescence staining was significantly elevated in and outside of cells under hypoxia, and tended to decrease when cells were exposed to LEN under normoxia. Furthermore, the fibronectin concentration in the culture solution of PLC/PRF/5 cells examined by ELISA was 2.3 times higher under hypoxia than under normoxia under LEN(-) conditions, and 1.6 times higher under hypoxia than under normoxia under LEN(+) conditions. It is assumed that in PLC/PRF/5 cells, fibronectin is probably suppressed as an indirect effect of LEN under normoxia, but transcription factors such as HIF-1α are induced under hypoxia, thus enhancing the production of fibronectin and attenuating the effect of LEN, resulting in drug resistance. This behavior of fibronectin with LEN exposure under hypoxia is probably specific to PLC/PRF/5 cells. Further studies should verify the combined effective inhibition of fibronectin and the MAPK pathway as a promising therapeutic strategy to enhance the value of LEN in HCC treatment.

Irisin is a clinically significant protein playing a valuable role in regulating various diseases. Irisin attenuates synaptic and memory dysfunction, highlighting its importance in Alzheimer's disease. On the other hand, Microtubule Affinity Regulating Kinase 4 (MARK4) is associated with various cancer types, uncontrolled neuronal migrations, and disrupted microtubule dynamics. In addition, MARK4 has been explored as a potential drug target for cancer and Alzheimer's disease therapy. Here, we studied the binding and subsequent inhibition of MARK4 by irisin. Irisin binds to MARK4 with an admirable affinity ( K = 0.8 × 10 7 M -1 ), subsequently inhibiting its activity (IC 50 = 2.71 µm). In vitro studies were further validated by docking and simulations. Molecular docking revealed several hydrogen bonds between irisin and MARK4, including critical residues, Lys38, Val40, and Ser134. Furthermore, the molecular dynamic simulation showed that the binding of irisin resulted in enhanced stability of MARK4. This study provides a rationale to use irisin as a therapeutic agent to treat MARK4-associated diseases.

Background: Irisin has been considered a prognostic factor in several cardiovascular diseases. Nevertheless, no data are available on the role of irisin in cardiac remodeling., Aim of the Study: This study aimed to determine the potential role of irisin in cardiac remodeling and explore potential mechanisms., Methods: A total of 40 rats that underwent transverse abdominal aortic constriction (TAC) surgery or sham operation were divided into four groups: sham + saline (NS), sham + irisin, TAC + NS, and TAC + irisin. After 6 weeks of treatment, echocardiography was performed to assess in vivo cardiac morphology. The left ventricular myocardium was prepared and observed by pathological examination. The effect of irisin on cardiomyocyte apoptosis and the expression of oxidative stress and cardiac hypertrophy markers were observed. Then, the effect of irisin on the Akt signaling system was also detected., Results: The rats in the TAC group displayed obvious signs of cardiac dysfunction and cardiac hypertrophy, and irisin treatment could reverse these changes. Irisin could inhibit the expression of nicotinamide adenine dinucleotide phosphate oxidase 2 and xanthine oxidase in TAC rats and increase the expression of antioxidant enzymes. Furthermore, the expression of phosphorylated protein kinase B (p-Akt), phosphorylated mammalian target of rapamycin (p-mTOR), and phosphorylated glycogen synthase kinase 3β (p-GSK3β) was much higher in the cardiac remodeling groups (p <0.05 vs. sham rats). Irisin could relieve the inhibition effect and reduce the expression level of these three proteins., Conclusions: Irisin treatment could significantly improve cardiac remodeling by inhibiting oxidative stress via attenuating the Akt signaling activation., (Copyright © 2021 IMSS. Published by Elsevier Inc. All rights reserved.)

Overexpression of the epidermal growth factor receptor (EGFR) on various cancers makes it an important target for cancer immunotherapy. We recently demonstrated that single-chain variable fragment-based bispecific chemically self-assembled nanorings (CSANs) can successfully modify T cell surfaces and function as prosthetic antigen receptors (PARs) allowing selective targeting of tumor antigens while incorporating a dissociation mechanism of the rings. Here, we report the generation of anti-EGFR fibronectin (FN3)-based PARs with high yield, rapid protein production, predicted low immunogenicity, and increased protein stability. We demonstrated the cytotoxicity of FN3-PARs successfully while evaluating FN3 affinities, CSAN valencies, and antigen expression levels. Using an orthotopic breast cancer model, we showed that FN3-PARs can suppress tumor growth with no adverse effects and FN3-PARs reduced immunosuppressive programmed cell death ligand-1 (PD-L1) expression by downregulating EGFR signaling. These results demonstrate the potential of FN3-PARs to direct selective T cell-targeted tumor killing and to enhance antitumor T cell efficacy by modulating the tumor microenvironment.

Background: Cryoprecipitate was developed for the treatment of inherited and acquired coagulopathies. The role of cryoprecipitate in hemorrhaging trauma patients is still speculative. The aim of our study was to assess the role of cryoprecipitate as an adjunct to transfusion in trauma patients., Methods: We performed a 2-year (2015-2016) analysis of the American College of Surgeons-Trauma Quality Improvement Program data set and included all adult trauma patients who received 4 or greater packed red blood cells (pRBCs)/4 hours. Patients were stratified based on receipt of cryoprecipitate within the first 24 hours (cryoprecipitate vs. no-cryoprecipitate). Outcomes were blood products transfused, in-hospital complications, and mortality. Regression analyses were performed., Results: A total of 19,643 (cryoprecipitate, 4,945; no-cryoprecipitate, 14,698) were included. Mean age was 40 ± 22 years, median Injury Severity Score was 27 [18-40], and Glasgow Coma Scale score was 9 [3-14]. The overall complication rate was 45%, mortality was 47%, and 29% of the patients died in the first 24 hours. Patients in the cryoprecipitate group received a lower volume of plasma (p < 0.01), and pRBCs (p < 0.01). Additionally, patients who received cryoprecipitate had lower rates of 24-hour mortality (p < 0.01) and in-hospital mortality (p < 0.01). However, there was no difference between the two groups regarding complications (p = 0.36) or volume of platelet transfused (p = 0.22). On multivariate logistic regression, the use of cryoprecipitate was associated with decreased (odds ratio [OR], 0.78 [0.63-0.84]; p = 0.02), in-hospital mortality (OR, 0.79 [0.77-0.87]; p = 0.01), but had no association with in-hospital complications (OR, 1.48 [0.71-1.99]; p = 0.31). On linear regression analysis, the use of cryoprecipitate was not associated with 24-hour pRBCs (β = -0.12 [-0.28 to 0.27], p = 0.47), 24-hour plasma (β = -0.06 [-0.21 to 0.43], p = 0.29), and 24-hour platelets (β = -0.24 [-0.09 to 0.33], p = 0.17) transfusion requirements., Conclusion: The adjunctive use of cryoprecipitate in hemorrhaging trauma patients may reduce mortality without affecting in-hospital complications and transfusion requirements. Further studies are needed to better understand its potentially beneficial effects., Level of Evidence: Therapeutic, level IV.

Matricellular proteins, which exist in association with the extracellular matrix (ECM) and ECM protein molecules, harbor functional sites within their molecular structures. These functional sites are released through proteolytic cleavage by inflammatory proteinases, such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), and the peptides containing these functional sites have unique biological activities that are often not detected in the parent molecules. We previously showed that tenascin-C (TNC) and plasma fibronectin (pFN), examples of matricellular proteins, have cryptic bioactive sites that have opposite effects on cell adhesion to the ECM. A peptide containing the bioactive site of TNC, termed TNIIIA2, which is highly released at sites of inflammation and in the tumor microenvironment (TME), has the ability to potently and persistently activate β1-integrins. In the opposite manner, the peptide FNIII14 containing the bioactive site of pFN has the ability to inactivate β1-integrins. This review highlights that peptide TNIIIA2 can act as a procancer factor and peptide FNIII14 can act as an anticancer agent, based on the regulation on β1-integrin activation. Notably, the detrimental effects of TNIIIA2 can be inhibited by FNIII14. These findings open the possibility for new therapeutic strategies based on the inactivation of β1-integrin by FNIII14.

Postoperative depression is a serious problem with under-optimized treatment. Our previous result demonstrated that single dose of propofol exposure in mice could cause depressive-like behavior. In the present study, we explored the possible preventive strategy that could ameliorate the depressive-like behavior in mice. Irisin was used for co-treatment with propofol in mice to test whether irisin could prevent the depressive-like behavior in mice. We found irisin could significantly reduce the immobility time in tail suspension and forced swimming tests in mice with propofol. We also found irisin was able to protect neurons against high concentration propofol treatment induced cell death in cultures. Meanwhile, irisin could significantly inhibit the increase of cytokines in astrocyte cultures exposed to propofol. These in vitro results suggested that interaction between astrocyte and neuron may be involved in the action mechanism that irisin prevented the mice from developing of depressive-like behavior. Last, we revealed that propofol caused increased surface expression of epidermal growth factor receptor (EGFR) but irisin could reduce the expression level of EGFR on cell surface., Competing Interests: Declaration of competing interest All authors declare there are no competing interests in this study., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Enhancement of endogenous neurogenesis after ischemic stroke may improve functional recovery. We previously demonstrated that medium B, which is a combination with epidermal growth factor (EGF) and fibronectin, can promote neural stem/progenitor cell (NSPC) proliferation and migration. Here, we showed that medium B promoted proliferation and migration of cultured NSPCs onto various 3-dimentional structures. When rat cortical neurons with oxygen glucose deprivation (OGD) were co-cultured with NSPCs, medium B treatment increased neuronal viability and reduced cell apoptosis. In a rat model with transient middle cerebral artery occlusion (MCAO), post-insult intraventricular medium B treatment enhanced proliferation, migration, and neuronal differentiation of NSPCs and diminished cell apoptosis in the infarct brain. In cultured post-OGD neuronal cells and the infarct brain from MCAO rats, medium B treatment increased protein levels of Bcl-xL, Bcl-2, phospho-Akt, phospho-GSK-3β, and β-catenin and decreased the cleaved caspase-3 level, which may be associated with the effects of anti-apoptosis. Notably, intraventricular medium B treatment increased neuronal density, improved motor function and reduced infarct size in MCAO rats. In summary, medium B treatment results in less neuronal death and better functional outcome in both cellular and rodent models of ischemic stroke, probably via promotion of neurogenesis and reduction of apoptosis.

Objective: We aimed to analyze the changes in metabolic parameters after administration of irisin to obese female mice. Materials and Methods: Sixty mice aged 5-6 weeks were randomized into three groups as irisin, exercise, and control. The control and irisin group remained sedentary, whereas the exercise group started free wheel exercising 6 weeks after the start of the study. The irisin group received irisin after 20 weeks. All mice were sacrificed at the 22nd week of the study, and obesity-related metabolic parameters were analyzed. Results: There was no significant difference between the irisin and exercise groups in weight gain ( P  > 0.05). By contrast, weight gain in the control group was significantly higher compared with the irisin and exercise groups ( P  < 0.05). Serum bone morphogenetic protein (BMP), ghrelin, insulin, kisspeptin, leptin, and visfatin levels were statistically lower in the irisin and exercise groups compared with the control group, but no significance was detected between the irisin and exercise groups ( P  < 0.05 for all parameters). Conclusion: Similar to the effect of exercise, irisin injections resulted in the amelioration of certain obesity-related parameters such as the concentration of adipokines, BMP4, insulin, and ghrelin. Its role as a potential alternative to exercise needs to be further studied.

Rationale : Intraoperative bleeding impairs physicians' ability to visualize the surgical field, leading to increased risk of surgical complications and reduced outcomes. Bleeding is particularly challenging during endoscopic-assisted surgical resection of hypervascular tumors in the head and neck. A tool that controls bleeding while marking tumor margins has the potential to improve gross tumor resection, reduce surgical morbidity, decrease blood loss, shorten procedure time, prevent damage to surrounding tissues, and limit postoperative pain. Herein, we develop and characterize a new system that combines pre-surgical embolization with improved visualization for endoscopic fluorescence image-guided tumor resection. Methods : Silk-elastinlike protein (SELP) polymers were employed as liquid embolic vehicles for delivery of a clinically used near-infrared dye, indocyanine green (ICG). The biophysical properties of SELP, including gelation kinetics, modulus of elasticity, and viscosity, in response to ICG incorporation using rheology, were characterized. ICG release from embolic SELP was modeled in tissue phantoms and via fluorescence imaging. The embolic capability of the SELP-ICG system was then tested in a microfluidic model of tumor vasculature. Lastly, the cytotoxicity of the SELP-ICG system in L-929 fibroblasts and human umbilical vein endothelial cells (HUVEC) was assessed. Results : ICG incorporation into SELP accelerated gelation and increased its modulus of elasticity. The SELP embolic system released 83 ± 8% of the total ICG within 24 hours, matching clinical practice for pre-surgical embolization procedures. Adding ICG to SELP did not reduce injectability, but did improve the gelation kinetics. After simulated embolization, ICG released from SELP in tissue phantoms diffused a sufficient distance to deliver dye throughout a tumor. ICG-loaded SELP was injectable through a clinical 2.3 Fr microcatheter and demonstrated deep penetration into 50-µm microfluidic-simulated blood vessels with durable occlusion. Incorporation of ICG into SELP improved biocompatibility with HUVECs, but had no effect on L-929 cell viability. Principle Conclusions : We report the development and characterization of a new, dual-functional embolization-visualization system for improving fluorescence-imaged endoscopic surgical resection of hypervascular tumors., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: The cause of about 95% of hypertension, an important public health problem, is unknown. Intensive studies are underway to understand the physiopathology of hypertension. Irisin, a newly discovered hormone, has been reported to dilate vascular smooth muscle and lower blood pressure acutely., Aims: To investigate the effects of chronic irisin treatment on blood pressure and renal functions in a hypertension model established by nitric oxide synthase inhibition by treatment with Nω-nitro-L-arginine methyl ester hydrochloride., Study Design: Animal experimentation., Methods: Male Sprague−Dawley rats were divided into four groups (n=8). Control and irisin groups received an intravenous saline injection, hypertension and hypertension + irisin (hypertension + irisin) groups received 1.5 mg/100 g Nω-nitro-L-arginine methyl ester hydrochloride. Nω-nitro-L-arginine methyl ester hydrochloride (150 mg/L) was added to the drinking water of rats in groups hypertension and hypertension + irisin for three weeks. In the second week of the experiment, irisin (50 nmol/day) was given to rats in groups irisin and hypertension + irisin, and saline was administered to rats in groups control and hypertension for two weeks through subcutaneously placed osmotic minipumps. Blood pressure was measured by the tail-cuff plethysmography method. On the twenty-first day of the experiment, 24-hour urine, blood, and both kidneys of the rats were collected., Results: The hypertension group had elevated systolic, diastolic, and mean arterial blood pressure values compared with the control group, with decreased glutathione levels in tissue and serum, but an increase in serum oxidized glutathione level (p<0.05). Histopathologically, increased tubular injury, cast formation, glomerular sclerosis, and peritubular fibrosis levels were observed (p<0.05). Irisin treatment did not cause any significant change in blood pressure, renal functions, and injury scores. However, renal nitric oxide levels significantly increased, and endothelial nitric oxide synthase immunoreactivity was determined to be reduced (p<0.05)., Conclusion: Treatment with chronic irisin at a physiological dose does not reduce blood pressure in an experimental model of hypertension. In different models of experimental hypertension, the effects of irisin administration at different doses and at different periods should be thoroughly investigated.

Chronic pediatric inflammatory bowel disease (IBD) leads to lack of bone accrual, bone loss, and increased fractures. Presently there is no cure, and many IBD treatments incur negative side effects. We previously discovered treatment with exogenous irisin resolved inflammatory changes in the colon, gut lymphatics, and bone in a mild IBD rodent model. Here we assess irisin treatment in severe IBD induced via dextran sodium sulfate (DSS). Male Sprague Dawley rats (2-mo-old) were untreated (Con) or given 2% DSS in drinking water. In week two, half of each group (Con + Ir and DSS + Ir) received injections of recombinant irisin (i.p., 2x/wk). After 4 weeks, gut inflammation was associated with declines in bone mineral density and cancellous bone volume. Furthermore, elevated osteocyte TNF-α, interleukin-6, RANKL, OPG, and sclerostin corresponded with higher osteoclast surfaces and lower bone formation rate in DSS animals as well as lower ultimate load. While irisin treatment improved colon inflammation, there were no improvements in bone density or bone mechanical properties; however, irisin elevated bone formation rate, decreased osteoclast surfaces, and reduced osteocyte pro-inflammatory factors. These data highlight the negative impact of chronic gut inflammation on bone as well as the therapeutic potential of irisin as an anti-inflammatory treatment.

Objective: Alveolar epithelial barrier dysfunction in response to inflammatory reaction contributes to pulmonary edema in acute lung injury(ALI).Irisin,a newly-found myokine,exerts the anti-inflammatory effects. This study aims to investigate the protective effects of irisin on lipopolysaccharide (LPS)-induced ALIin vivo and in vitro, and to explore its underlying mechanism., Methods: Male SD rats and A549 cells were divided into 4 groups: control group, LPS group, Irisin pretreated group, and Irisin/Compound C(a special inhibitor of AMPK)-treated group. The ALI model was established by intravenous injection of LPS in rats, and LPS challenge in A549 cells. Pulmonary specimens were harvested for microscopic examination of the pathological changes, and the expression of AMPK,SIRT1,NF-κB, p66Shc and caspase-3 in lung tissues. The pulmonary permeability were examined by wet/dry lung weight ratio(W/D) and lung permeability index(LPI). The apoptotic index, and the expression of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), monocyte chemoattractant activating protein-1 (MCP-1), tight junctions (occludin,ZO-1) were determined both in lung tissue and A549 cells., Results: Irisin alleviated lung histological changes and decreased pulmonary microvascular permeability in LPS-induced rats. Irisin up-regulated the expression of occludin, ZO-1,AMPK,SIRT1, down-regulated the expression of TNF-α,IL-1β,MCP-1,NF-κB, p66Shc caspase-3, and decreased the apoptotic index in LPS-induced rats and A549 cells. All these protective effects of irisin could be reversed by Compound C., Conclusion: Irisin improved LPS-induced alveolar epithelial barrier dysfunction via suppressing inflammation and apoptosis, and this protective effect might be mediated by activating AMPK/SIRT1 pathways., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Intestinal ischemia/reperfusion (I/R) injury is a serious clinical event that may induce intestinal mucosal injury, whose major underlying mechanisms include reactive oxygen species (ROS) generation, release of inflammatory mediators and induction of apoptosis. Irisin is considered an agent with potent protection against many pathological injures. The aim of this study was to investigate the protective effect of irisin pretreatment on intestinal injury and explore its underlying mechanisms in a mouse model of intestinal I/R injury as well as a cell model (IEC-6 cell) of hypoxia/reoxygenation (H/R). The results showed that irisin pretreatment ameliorated I/R and H/R-induced injury in vivo and in vitro. In addition, irisin reduced the levels of tumor necrosis factor (TNF)-α, interleukin(IL)-1β and interleukin(IL)-6 in the intestine. Compared with the I/R group, irisin pretreatment effectively reduced malondialdehyde (MDA) and myeloperoxidase (MPO) levels, but increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in the intestine, and significantly reduced oxidative stress. Furthermore, irisin pretreatment downregulated Bax and cleaved Caspase-3 at the protein level, and increased Bcl-2 protein amounts, significantly reducing apoptosis in the intestine of I/R mice. Moreover, both in vivo and in vitro results showed that irisin pretreatment significantly upregulated nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein. Meanwhile, Nrf2 siRNA treatment partially abrogated the protective effects of irisin pretreatment on H/R induced cellular damage, inflammatory response, oxidative stress, and apoptosis in IEC-6 cells. These findings suggest that irisin pretreatment improves I/R-induced intestinal inflammatory response, reduces oxidative stress and inhibits apoptosis, which could be, at least partially, associated with Nrf2 pathway activation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Fetal fibronectin (FFN) is an extracellular matrix glycoprotein localized at the maternal-fetal interface of the amniotic membranes, between chorion and decidua, where it is concentrated in this area between decidua and trophoblast. In normal conditions, FFN is found at very low levels in cervicovaginal secretions. Levels greater than or equal to 50 ng/mL at or after 22 weeks have been associated with an increased risk of spontaneous preterm birth. In fact, FFN is one of the best predictors of preterm birth in all populations studied so far, and can help in selecting which women are at significant risk for preterm birth. This is an update of a review first published in 2008., Objectives: To assess the effectiveness of management based on knowledge of FFN testing results for preventing preterm birth., Search Methods: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register (7 September 2018), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (7 September 2018), and reference lists of retrieved studies., Selection Criteria: Randomized controlled trials of pregnant women screened with FFN for risk of preterm birth. Studies included are based exclusively on knowledge of FFN results versus no such knowledge, and we have excluded studies including women with only positive or only negative FFN results., Data Collection and Analysis: Two review authors independently assessed trials for inclusion and risk of bias, extracted data, and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach., Main Results: We identified 16 trials, of which six were eligible for inclusion. The six included studies randomized 546 women with singleton gestations and threatened preterm labor (PTL) at 23 0/7 to 34 6/7 weeks. A total of 277 women were randomized to knowledge and 269 to no knowledge of FFN. No trials were identified on asymptomatic women or multiple gestations.The risk of bias of included studies was mixed. For selected important outcomes, preterm birth before 37, 34, and 32 weeks, and maternal hospitalization, we graded the quality of the evidence and created a 'Summary of findings' table. For these outcomes, the evidence was graded as mainly low quality due to the imprecision of effect estimates.Management based on knowledge of FFN results may reduce preterm birth before 37 weeks (21.6%) versus controls without such knowledge (29.2%) (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.52 to 1.01; 4 trials; 357 women; low-quality evidence). However, management based on knowledge of FFN results may make little or no difference to preterm birth before 34 (RR 1.09, 95% CI 0.54 to 2.18; 4 trials; 357 women; low-quality evidence) or maternal hospitalization (RR 1.06, 95% CI 0.79 to 1.43; 5 trials; 441 women; low-quality evidence). The evidence for preterm birth before 32 weeks is uncertain because the quality was found to be very low (average RR 0.79, 95% CI 0.16 to 3.96; 4 trials; 357 women; very low-quality evidence).For all other outcomes, for which there were available data (preterm birth less than 28 weeks; gestational age at delivery (weeks); birthweight less than 2500 g; perinatal death; tocolysis; steroids for fetal lung maturity; time to evaluate; respiratory distress syndrome; neonatal intensive care unit (NICU) admission; and NICU days), knowledge of FFN results may make little or no difference to the outcomes., Authors' Conclusions: The evidence from this review suggests that management based on knowledge of FFN results may reduce preterm birth before 37 weeks. However, our confidence in this result is limited as the evidence was found to be of low quality. Effects on other substantive outcomes are uncertain due to serious concerns in study design, inconsistency, and imprecision of effect estimates. No trials were identified on asymptomatic women, or multiple gestations.Future studies are needed that include specific populations (e.g. singleton gestations with symptoms of preterm labor), a study group managed with a protocol based on the FFN results, and that report not only maternal but also important perinatal outcomes. Cost-effectiveness analyses are also needed.

Diabetes mellitus (DM) patients experience memory and cognitive deficits. The mechanisms underlying this dysfunction in the brain of DM patients are not fully understood, and therefore, no optimized therapeutic strategy has been established so far. The aim of the present study was to assess whether irisin was able to improve memory and cognitive performance in a streptozotocin-induced diabetic mouse model. A diabetic mouse model was established and behavioral tests were performed. We also set up primary cultures for mechanism studies. Western blots and EMSA were used for molecular studies. Significant impairment of cognition and memory was observed in these DM mice, which could be effectively prevented by irisin cotreatment. We also found upregulated levels of GFAP protein, reduced synaptic protein expression, and increased levels of interleukin-1 β (IL-1 β ) and interleukin-6 (IL-6) in the brains; however, irisin significantly attenuated these cellular responses. Meanwhile, our results demonstrated that irisin inhibited the activation of P38, STAT3, and NF κ B proteins of DM mice. Furthermore, our results suggested that irisin might regulate the function of P38, STAT3, and NF κ B in hippocampal tissues of DM mice. Collectively, irisin inhibited neuroinflammation in STZ-induced DM mice by inhibiting cytokine release and improving their cognitive function. Our findings revealed the mechanism of irisin's anti-inflammatory effect in the CNS.

Ischemic stroke is the leading cause of disability and death worldwide. An effective therapeutic approach is urgently needed. Stroke-induced angiogenesis and neurogenesis are essential mechanisms in the long-term repair. Extracellular matrix proteins are also involved in tissue self-repair. Recently, a PHSRN (Pro-His-Ser-Arg-Asn) peptide from the fibronectin synergistic motif that can promote wound healing in epithelia and induce endothelial proliferation and cancer cell migration was identified. The therapeutic potential of this peptide in stroke is unknown. Here, we examined the potential of PHSRN in stroke therapy using an ischemic rat model of middle cerebral artery occlusion (MCAO). PHSRN reduced the infarct volume in MCAO rats, improved neurological function, and alleviated motor function impairment. PHSRN targeted the damaged brain region and distributed to endothelial cells after intraperitoneal injection. PHSRN significantly promoted angiogenesis and vascular endothelial growth factor secretion through activation of integrin α5β1 and its downstream intracellular signals, e.g., focal adhesion kinase, Ras, cRaf, and extracellular-signal-regulated kinase. PHSRN treatment also stimulated neurogenesis in MCAO rats, and maintained neuronal survival and neuronal morphologic complexity via induction of VEGF secretion. Together, these results provide insights into the role of integrin α5β1 following ischemia and support the feasibility of using PHSRN peptide in stroke therapy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: This histomorphometric study compared bone regeneration potential of beta-tricalcium phosphate with fibronectin (β-TCP-Fn) in critical-sized calvarial defects (CSDs) in rats to assess whether fibronectin (Fn) improved new bone formation., Material and Methods: Critical-sized calvarial defects were created in 30 adult male Sprague Dawley rats, which were divided into four groups according to the time of euthanasia (6 or 8 weeks of healing) and type of filling (β-TCP-Fn/6 weeks, β-TCP/6 weeks, β-TCP-Fn/8 weeks and β-TCP/8 weeks). The primary variables related to new bone formation were augmented area (AA) and gained tissue (GT; sum of mineralized bone matrix [MBM] and bone substitute [BS]). Secondary variables were the diameter of the defect, MBM, non-mineralized tissue (NMT) and BS., Results: A total of 29 rats and 58 histological samples were evaluated, 28 (48.3%) samples obtained at 6 weeks and 30 (51.7%) at 8 weeks, homogeneously distributed between right and left sides. Thirteen (22.4%) were treated with β-TCP-Fn, 16 (27.6%) with β-TCP and 29 (50%) were controls. At 8 weeks, histomorphometric analysis showed significant differences in AA using β-TCP and β-TCP-Fn versus controls (p = 0.001 and p = 0.005, respectively). Bone turnover expressed as % within the target area was slightly higher but not statistically significant in the β-TCP-Fn than in β-TCP (MBM) at 6 weeks versus 8 weeks (p = 0.067 and p = 0.335, respectively). Finally, the total GT area in mm 2 was higher using β-TCP-Fn as compared to β-TCP (p = 0.044)., Conclusions: β-TCP-Fn was slightly but non-significantly more effective than β-TCP without Fn for improving the volume of regenerated bone in CSDs of rats, possibly allowing a more efficient bone remodelling process. This effect however should continue being investigated., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Evidence has shown therapeutic potential of irisin in cerebral stroke. The present study aimed to assess the effects of recombinant irisin on the infarct size, neurological outcomes, blood-brain barrier (BBB) permeability, apoptosis and brain-derived neurotrophic factor (BDNF) expression in a mouse model of stroke. Transient focal cerebral ischemia was established by middle cerebral artery occlusion (MCAO) for 45 min and followed reperfusion for 23 h in mice. Recombinant irisin was administrated at doses of 0.1, 0.5, 2.5, 7.5, and 15 µg/kg, intracerebroventricularly (ICV), on the MCAO beginning. Neurological outcomes, infarct size, brain edema and BBB permeability were evaluated by modified neurological severity score (mNSS), 2,3,5-triphenyltetrazolium chloride (TTC) staining and Evans blue (EB) extravasation methods, respectively, at 24 h after ischemia. Apoptotic cells and BDNF protein were detected by TUNEL assay and immunohistochemistry techniques. The levels of Bcl-2, Bax and caspase-3 proteins were measured by immunoblotting technique. ICV irisin administration at doses of 0.5, 2.5, 7.5 and 15 µg/kg, significantly reduced infarct size, whereas only in 7.5 and 15 µg/kg improved neurological outcome (P < 0.001). Treatment with irisin (7.5 µg/kg) reduced brain edema (P < 0.001) without changing BBB permeability (P > 0.05). Additionally, irisin (7.5 µg/kg) significantly diminished apoptotic cells and increased BDNF immunoreactivity in the ischemic brain cortex (P < 0.004). Irisin administration significantly downregulated the Bax and caspase-3 expression and upregulated the Bcl-2 protein. The present study indicated that irisin attenuates brain damage via reducing apoptosis and increasing BDNF protein of brain cortex in the experimental model of stroke in mice.

Aim: Irisin is a new peptide produced mainly by the skeletal muscle playing an important role both in glucose/energy homeostasis and bone metabolism. Childhood type 1 diabetes mellitus (T1DM) is associated with decreased bone mass. We aimed to evaluate irisin levels in TD1M children and their correlation with bone metabolism and glycaemic control., Methods: Ninety-six T1DM subjects (12.2 ± 4 years), 56 on multiple daily injections (MDI), 40 on continuous subcutaneous insulin infusion (CSII), and 34 controls were included in the study. Irisin and bone remodeling markers were quantified in sera from patients and controls. Bone mineral density (BMD) was evaluated by QUS., Results: Increased irisin levels were found in T1DM patients respect to controls (p < 0.001). With adjustment for age, irisin levels significantly correlated negatively with HbA1c% (r = -0.105, p < 0.001), years of diabetes (r = -0.07, p < 0.04), 25(OH)-Vitamin D (r = -0.175, p < 0.0001), and positively with BTT-Z-score (r = 0.088, p = 0.016), and osteocalcin (r = 0.059, p < 0.04). We detected the highest levels of irisin in CSII patients compared to MDI and controls (p < 0.001 and p < 0.007 respectively)., Conclusions: We demonstrated high irisin levels in T1DM children and the association of highest irisin amounts to a better glycaemic control and bone health in TDM1 subjects on CSII., (Copyright © 2018. Published by Elsevier B.V.)

Irisin is a hormone-like molecule mainly released by skeletal muscles in response to exercise. Irisin induces browning of the white adipose tissue and has been shown to regulate glucose and lipid homeostasis. Keeping its energy expenditure and metabolic properties in view, numerous studies have focused on its therapeutic potential for the treatment of metabolic disorders like obesity and type 2 diabetes. Recently, the anti-inflammatory, anti-apoptotic and anti-oxidative properties of irisin have received a great deal of attention of the scientific society. These pathogenic processes are often associated with initiation, progression, and prognosis of numerous diseases like myocardial infarction, kidney diseases, cancer, lung injury, inflammatory bowel diseases, atherosclerosis, liver diseases, obesity and type 2 diabetes. In the current review, we present evidence regarding the anti-inflammatory, anti-apoptotic and anti-oxidative potential of irisin pertaining to various pathological conditions. Here, we explore multiple molecular pathways targeted by irisin therapy. Given the promising effects of irisin, many diseases with evident oxidative stress, inflammation and apoptosis can be targeted by irisin., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: In coronary bypass surgery, after cardiopulmonary bypass is initiated by arterial cannulation in the ascending aorta and venous cannulation through a single vein generally in the right atrium, the process of cooling the patient is started., Objective: There is a relation between cooling the patient and irisin, which is responsible for releasing heat. Therefore, the main objective of the present study is to explore how irisin concentrations and some other panel of myocardium injury in patients undergoing coronary artery bypass surgery., Methods: The blood samples collected before induction (T1), before bypass (T2), before (T3) and after (T4) removing the cross-clamp, upon admission to intensive care (T5), and at the postoperative 24 (T6) and 72 (T7) hours, and whether these concentrations are correlated with lactate levels classically used in monitoring this surgery. A total of biological samples, 23 from control individuals and 105 from bypass patients (14-16 samples for each timeframe) were analyzed to determine irisin, CK-MB, TnT and BNP levels by ELISA and lactate levels by lactate assay kit. Both lactate and irisin were seen to increase gradually from the time of induction to the removal of the cross-clamp. After the cross-clamp was removed and the patient was started to be warmed, both parameters began to decrease gradually and were restored to normal levels on the second and third post-operative days. The increase and decrease in irisin were found correlated with lactate levels. CK-MB, TnT and BNP alteration were similar to each other., Results: Based on these results, it is estimated that measurement of irisin along with lactate may prove to be a useful parameter in monitoring the coronary bypass surgery and irisin may be a significant marker of hypothermia. Beside CK-MB, TnT and BNP, measurements of irisin concentration in open heart surgery may also be useful parameters for the panel of myocardium injury., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Purpose: Topical application of the fibronectin-derived peptide PHSRN facilitates corneal epithelial wound healing in healthy animals and in patients with nonhealing epithelial defects. We have now examined the effect of PHSRN eye drops on the healing of corneal epithelial wounds in diabetic rats., Methods: Wistar rats were injected intraperitoneally with streptozotocin to induce diabetes or with a vehicle as a control. Four weeks after confirmation of the corresponding presence or absence of glycosuria, a 3-mm-diameter portion of the corneal epithelium of the right eye was excised and eye drops containing PHSRN (200 μM) or phosphate-buffered saline (PBS) vehicle were administered to the injured eye every 6 hours., Results: The area of the epithelial defect did not differ significantly among the 4 experimental groups (diabetic or nondiabetic rats treated with PHSRN or vehicle) at 12 hours after wounding. At 18 hours, however, the area of the defect in diabetic rats treated with PHSRN (0.50 ± 0.34 mm) was significantly (P < 0.05) smaller than that in diabetic rats treated with PBS (1.06 ± 0.42 mm) and was similar to that in nondiabetic rats treated with PBS (0.60 ± 0.23 mm). The decrease in the size of the epithelial defect in diabetic rats treated with PHSRN was also found to be dependent on the dose of the peptide., Conclusions: Administration of PHSRN significantly facilitated healing of corneal epithelial wounds in diabetic rats, which suggests that PHSRN eye drops warrant further investigation as a treatment option for patients with diabetic keratopathy.

A novel biopharmaceutical, consisting of the F8 mAb (specific to a splice isoform of fibronectin) simultaneously fused to both TNF and IL2, was found to react with the majority of solid tumors and hematologic malignancies in mouse and man, but not with healthy adult tissues. The product selectively localized to neoplastic lesions in vivo , as evidenced by quantitative biodistribution studies using radioiodinated protein preparations. When the potency of the cytokine payloads was matched by a single-point mutation, the resulting fusion protein (IL2-F8-TNF mut ) eradicated soft-tissue sarcomas in immunocompetent mice, which did not respond to individual antibody-cytokine fusion proteins or by standard doxorubicin treatment. Durable complete responses were also observed in mice bearing CT26, C1498, and F9 tumors. The simultaneous delivery of multiple proinflammatory payloads to the cancer site conferred protective immunity against subsequent tumor challenges. A fully human homolog of IL2-F8-TNF mut , which retained selectivity similar to its murine counterpart when tested on human material, may open new clinical applications for the immunotherapy of cancer. Mol Cancer Ther; 16(11); 2442-51. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Purpose: To determine the bone regeneration potential of a ceramic biomaterial coated with fibronectin and adipose-derived stem cells covered in three-wall critical-size defects associated with dental implants., Materials and Methods: In a total of 18 dogs, four dehiscence-type and critical-size defects were created surgically in the edentulous alveolar ridge with the simultaneous placement of dental implants. Defects were randomly regenerated using biomaterials coated with particulate ß-tricalcium phosphate (β-TCP), β-TCP with fibronectin (Fn) (β-TCP-Fn), and β-TCP with a combination of Fn and autologous adipose-derived stem cells (ADSCs) (β-TCP-Fn-ADSCs), leaving one defect as the control. The animals were divided into three groups according to the time of euthanasia (1, 2, or 3 months)., Results: Statistically significant differences between the three study groups (β-TCP, β-TCP-Fn, β-TCP-Fn-ADSCs) and the control group in the total area of bone regeneration and mineralized and nonmineralized tissue at 1, 2, and 3 months of healing were not observed. At 2 months, defects treated with β-TCP-Fn-ADSCs showed a significant decrease in the percentage of bone-to-implant contact (BIC) as compared with the β-TCP-Fn (P = .041) and control (P = .012) groups. At 3 months of healing, however, significant differences in BIC between the three study groups and controls were not found (P = .388)., Conclusion: The use of ADSCs in the bone regeneration processes of dehiscencetype defects associated with simultaneous implant insertion does not seem to improve the area of bone regeneration or the percentage of BIC compared with other biomaterials or the control alveolar defect.

Introduction: The gradual aging of the population results in increased incidence of osteoporotic bone fractures. In a good quality bone, the fixation with the usual methods is adequate, but not in osteoporotic bone, in which consolidation delays and other complications are common, with failure rates for screws up to 25%., Objective: To test fibronectin loaded hydroxyapatite as a complementary treatment for osteoporotic fractures., Material and Methods: This study was performed in a vivo model; 42 female osteoporotic adult rabbits 4-5kg (White New Zealand) were used. Two groups (hydroxyapatite and fibronectin loaded hydroxyapatite) and a control group were tested. 3 time points 24h, 48h and 5days were studied. Defects were created in both femurs, in one of them, a cannulated screw (4mm) and a biocompatible material were placed; in the other femur a screw was inserted without supplemented material forming the control group. Osteoporosis was induced from models already known throughout administration of steroids. Samples were analyzed histologically and through imaging (micro Ct)., Results: Basal levels of BMD are observed below to normal when compared to other studies (0.25/0.3 instead of 0.4). Global and dependent of time analysis of samples, show no significant differences for samples analyzed. However, an important trend was noted for variables that define the trabecular bone microarchitecture. Indices that define trabecular microarchitecture in the comparative analysis found to have statistical differences (p<0.01)., Discussion: Osteosynthesis in an osteoporotic bone is a challenge for the surgeon, due to a reduced bone mineral density and different bone architecture. The main finding was the verification of the hypothesis that the trabecular bone parameters increases with our augmentation material in weak rabbit bone quality. Also, the histological analyses of samples show an increase of non inflammatory cells in protein samples (OHAp-Fn) from the first 24hours., Conclusion: An early response of rabbit osteroporotic bone to a complementary treatment with fibronectin loaded hydroxyapatite has been observed. This response is reflected in greater values for indices that define the trabecular bone microarchitecture, thickness and separation, a greater non-inflammatory cellularity after only 24hours and an increased amount of connective tissue observed at 48hours., (© 2016 Elsevier Ltd. All rights reserved.)

Growth factors (GFs) are powerful signaling molecules with the potential to drive regenerative strategies, including bone repair and vascularization. However, GFs are typically delivered in soluble format at supraphysiological doses because of rapid clearance and limited therapeutic impact. These high doses have serious side effects and are expensive. Although it is well established that GF interactions with extracellular matrix proteins such as fibronectin control GF presentation and activity, a translation-ready approach to unlocking GF potential has not been realized. We demonstrate a simple, robust, and controlled material-based approach to enhance the activity of GFs during tissue healing. The underlying mechanism is based on spontaneous fibrillar organization of fibronectin driven by adsorption onto the polymer poly(ethyl acrylate). Fibrillar fibronectin on this polymer, but not a globular conformation obtained on control polymers, promotes synergistic presentation of integrin-binding sites and bound bone morphogenetic protein 2 (BMP-2), which enhances mesenchymal stem cell osteogenesis in vitro and drives full regeneration of a nonhealing bone defect in vivo at low GF concentrations. This simple and translatable technology could unlock the full regenerative potential of GF therapies while improving safety and cost-effectiveness.

Purpose: To assess bone regeneration potential of a fibronectin- and adipose-derived stem cell-covered ceramic biomaterial in three-wall critical-size alveolar ridge defects., Materials and Methods: In 18 dogs, four dehiscence-type and critical-size defects were created surgically in the edentulous alveolar ridge. Defects were randomly regenerated using biomaterials coated with particulate β-tricalcium phosphate (β-TCP), β-TCP with fibronectin (Fn) (β-TCP-Fn), and β-TCP with a combination of Fn and autologous adipose-derived stem cells (ADSCs) (β-TCP-Fn-ADSCs), leaving one defect as control. The animals were divided into three groups according to the time of euthanasia (1, 2, or 3 months of healing)., Results: At the time of sacrifice, statistically significant differences between the four types of defects in the total area of bone regeneration, percentage of neoformed bone matrix, medullary space, or contact between particulate biomaterial and neoformed bone matrix were not found. All defects showed a significant increase in neoformed bone matrix as sacrifice was delayed, but a uniform pattern was not followed. Only defects treated with β-TCP-Fn-ADSCs showed a significant increase in the bone regeneration area when animals sacrificed at 3 months were compared to those sacrificed at 1 month (P = .006)., Conclusion: The use of ADSCs in bone regeneration processes of critical-size defects of the alveolar ridge did not entail an advantage regarding greater bone regeneration as compared with other biomaterials. However, the use of β-TCP coated with a combination of Fn and ADSCs appeared to favor stabilization of the regenerated area, allowing a more efficient maintenance of the space at 3 months of healing.

Background: Biofunctionalized implant surfaces may accelerate bony integration and increase long-term stability., Purpose: The aim of the study was to evaluate the osseous reaction toward biomimetic titanium implants surfaces coated with quasicovalent immobilized fibronectin in an in vivo animal model., Materials and Methods: A total of 84 implants (uncoated [control 1, n = 36], streptavidin-biotin coated [test 1, n = 24], streptavidin-biotin-fibronectin coated [test 2, n = 24]) were inserted 1 mm supracortically in the proximal tibia of 12 rabbits. The samples were examined after 3 and 6 weeks. Total bone-implant contact (tBIC; %), bone-implant contact in the cortical (cBIC; %) and in the spongious bone (sBIC; %) as well as the percentage of linear bone fill (PLF; %) were evaluated., Results: After 3 weeks, streptavidin-biotin-fibronectin implants had a significant higher sBIC (p = .043) and PLF (p = .007) compared with the uncoated samples. After 6 weeks, this difference was significant for tBIC (p = .016) and cBIC (p < .001). Additionally, uncoated screws showed a significant higher sBIC when compared with the fibronectin coating (p < .001). Streptavidin-biotin-coated implants showed less bone growth at both time points of all examined parameters when compared with their counterparts (all p < .001)., Conclusions: Quasicovalent immobilization of biotinylated fibronectin with the streptavidin-biotin-fibronectin system on smooth surface titanium shows a beneficial faster osseous healing in vivo. Besides, an antifouling effect of the streptavidin-biotin coating was proven., (© 2015 Wiley Periodicals, Inc.)

There is a wide spectrum of blood-derived products that have been used in many different medical and surgical specialties with success. Blood-derived products for clinical use can be extracted from autologous or allogeneic specimens of blood, but recombinant products are also commonly used. A number of blood derivatives have been used for a wide range of ocular conditions, from the ocular surface to the retina. With stringent preparation guidelines, the potential risk of transmission of blood-borne diseases is minimized. We review blood-derived products and how they are improving the management of ocular disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Adnectins are a family of binding proteins derived from the 10th type III domain of human fibronectin (10Fn3), which is part of the immunoglobulin superfamily and normally binds integrin. The 10Fn3 has the potential for broad therapeutic applications given its structural stability, ability to be manipulated, and its abundance in the human body. The most commonly studied adnectin is CT-322, which is an inhibitor of vascular endothelial growth factor receptor-2. A bispecific adnectin, El-Tandem, has also been developed and binds to epidermal growth factor receptor and insulin-like growth factor-1 receptor simultaneously. Pre-clinical studies have shown promising results in relation to reducing tumor growth, decreasing microvessel density, and promoting normalization of tumor architecture. The phase I trial with CT-322 demonstrates relatively low toxicities. However, the phase II study done with CT-322 in recurrent glioblastoma does not reveal as promising results.

The condition of the corneal epithelium is a critical determinant of corneal transparency and clear vision. The corneal epithelium serves as a barrier to protect the eye from external insults, with its smooth surface being essential for its optical properties. Disorders of the corneal epithelium include superficial punctate keratopathy, corneal erosion, and persistent epithelial defects (PEDs). The prompt resolution of these disorders is important for minimization of further damage to the cornea. Currently available treatment modalities for corneal epithelial disorders are based on protection of the ocular surface in order to allow natural healing to proceed. PEDs remain among the most difficult corneal conditions to treat, however. On the basis of characterization of the pathobiology of PEDs at the cell and molecular biological levels, we have strived to develop new modes of treatment for these defects. These treatments rely on two key concepts: provision of a substrate, such as the adhesive glycoprotein fibronectin, for the attachment and migration of corneal epithelial cells, and activation of these cells by biological agents such as the combination of substance P and insulin-like growth factor-1 (IGF-1). Central to both approaches is the role of the fibronectin-integrin system in corneal epithelial wound healing. Determination of the minimum amino acid sequences required for the promotion of corneal epithelial wound closure by fibronectin (PHSRN) and by substance P (FGLM-amide) plus IGF-1 (SSSR) has led to the development of peptide eyedrops for the treatment of PEDs that are free of adverse effects of the parent molecules., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

VEGF signaling through VEGFR-2 is the major factor in glioblastoma angiogenesis. CT-322, a pegylated protein engineered from the 10th type III human fibronectin domain, binds the VEGFR-2 extracellular domain with high specificity and affinity to block VEGF-induced VEGFR-2 signaling. This study evaluated CT-322 in an open-label run-in/phase 2 setting to assess its efficacy and safety in recurrent glioblastoma. Eligible patients had 1st, 2nd or 3rd recurrence of glioblastoma with measurable tumor on MRI and no prior anti-angiogenic therapy. The initial CT-322 dose was 1 mg/kg IV weekly, with plans to escalate subsequent patients to 2 mg/kg weekly if tolerated; within each CT-322 dose cohort, patients were randomized to ±irinotecan IV semiweekly. The primary endpoint was 6-month progression-free survival (PFS-6). Sixty-three patients with a median age of 56 were treated, the majority at first recurrence. One-third experienced serious adverse events, of which four were at least possibly related to study treatment (two intracranial hemorrhages and two infusion reactions). Twenty-nine percent of subjects developed treatment-emergent hypertension. The PFS-6 rate in the CT-322 monotherapy groups was 18.6 and 0.0 % in the 1 and 2 mg/kg treatment groups, respectively; results from the 2 mg/kg group indicated that the null hypothesis that PFS-6 ≤12 % could not be rejected. The study was terminated prior to reaching the planned enrollment for all treatment groups because data from the completed CT-322 2 mg/kg monotherapy treatment arm revealed insufficient efficacy. Despite biological activity and a tolerable side effect profile, CT-322 failed to meet the prespecified threshold for efficacy in recurrent glioblastoma.

Background: The aim of this study was to investigate the clinical efficacy of RetroNectin-activated cytokine-induced killer cell (R-CIK) therapy following conventional therapies in patients with metastatic brain tumors., Methods: This study included 20 patients with metastatic brain tumors. Patients received R-CIK therapy following conventional therapies (including chemotherapy and target therapy). Progression-free survival (PFS), overall survival (OS), and prognostic factors were evaluated., Results: Of the 4 breast cancer patients in our cohort, 2 remained alive and 2 died. Of the 14 non-small cell lung cancer (all adenocarcinoma) patients, 3 had a partial response, 8 had stable disease, and 3 had progressive disease after receiving R-CIKs. The overall response rate was 21.4% (3/14), and the disease control rate was 78.6% (11/14). The median PFS and OS were 7.7 months (95% confidence interval (CI) 3-16.5 months) and 12.6 months (95% CI 6-21 months), respectively., Conclusion: R-CIKs combined with conventional therapies could improve the prognosis of metastatic brain tumor patients, especially of those with adenocarcinoma of the lung., (© 2015 S. Karger GmbH, Freiburg.)

Ischemic stroke is one of the leading causes of morbidity and mortality worldwide and characterized by defective angiogenesis. The functional sequences (RGDs, GRGDSPASSPISC) derived from fibronectin have been confirmed to augment angiogenesis in vivo and in vitro. However, delivery of peptides into the brain parenchyma has been hampered by the presence of the blood-brain barrier (BBB). We fused RGDs with penetratin (Antp) derived from Drosophila antennapedia homeodomain protein to improve the penetration of peptides through BBB into ischemic hemisphere. We found Antp-RGDs successfully not only penetrate the SH-SY5Y cells but also penetrated through BBB into ischemic hemisphere by intraperitoneal injection. In addition, application of Antp-RGDs to the focal cerebral ischemic reperfusion injury in rats resulted in the reduction of cerebral ischemic volume and the improvement of neurologic score according to the 21-point score. We further demonstrated that activation of phosphorylation-extracellular-signal related kinase 1/2 (p-ERK 1/2) and upregulation of gene VEGF resulted from post-treatment with Antp-RGDs 2 hours after reperfusion onset might at least partly contribute to the benefic changes after focal cerebral ischemic reperfusion injury in rats. Our data suggested that Antp-RGDs may serve as an attractive therapeutic intervention for treating ischemic stroke., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Specific delivery of TNF-α antagonist to the inflamed site can increase its efficacy and reduce the side effects. In this study, we constructed a bispecific diabody (BsDb) that targets TNF-α and ED-B-containing fibronectin (B-FN), a fibronectin isoform specifically expressed in the pannus of the inflamed joint in rheumatoid arthritis. BsDb was produced in Escherichia coli as inclusion bodies, purified to homogeneity, and refolded to the functional form. Our data demonstrate that BsDb could simultaneously bind to human TNF-α and B-FN and neutralize TNF-α action. In the collagen-induced arthritis mouse model, we compared the biodistrubtion and therapeutic efficacy of BsDb with those of the anti-TNF-α scFv (TNF-scFv). Similar to TNF-scFv, BsDb penetrated into the synovial tissue quickly, showing a rapid clearance from blood and normal organs. In contrast, BsDb could selectively accumulate and retain in arthritic joints of mice for a long period time, resulting in a much stronger inhibition of arthritis progression in mice than TNF-scFv. The findings described herein indicate that BsDb has a good specificity to the inflamed joint, with low toxicity to normal organs and seems to be an ideal biological agent for the treatment of RA and other chronic inflammatory disease., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Introduction: Dental pulp stem cells (DPSCs) have therapeutic potential for dentin and dental pulp regeneration. For regenerative approaches to gain clinical acceptance, protocols are needed to determine feasible ways to store teeth, isolate DPSCs, and expand them to clinical scale numbers., Methods: In this study, 32 third molars were obtained from patients and immediately placed in saline or tissue culture medium followed by overnight storage at 4°C or immediate isolation of DPSCs. Upon isolation, cells were expanded in medium containing either fetal bovine serum (FBS) or human serum (HS). Cell proliferation (population doubling time [PDT]), cell surface marker expression, and multipotency were compared between DPSCs in FBS and DPSCs in HS., Results: The time frame of storage and storage medium did not affect the ability to isolate DPSCs. However, using HS instead of FBS in the initial isolation of DPSCs significantly decreased (P < .01) the isolation success rate from 89% (FBS) to 23% (HS). Yet, incorporating fibronectin in the DPSC initial isolation (using HS) significantly (P < .01) increased the isolation success rate to 83%. Interestingly, it was found that the proliferation rate was significantly (P < .05) higher for DPSCs in HS (PDT = 1.59 ± 0.46) than that for DPSCs in FBS (PDT = 2.84 ± 2.5). Finally, there was no difference in the expression of CD73, CD90, CD105, or multipotency (as measured by osteogenic, adipogenic, and chondrogenic differentiation) between DPSCs in FBS and DPSCs in HS., Conclusions: These findings show a clinically feasible method of storing third molars for the isolation of DPSCs. Additionally, DPSCs can be isolated and expanded to clinical scale numbers in media devoid of FBS and still maintain their phenotypic properties., (Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)