Inhalable FN-binding liposomes or liposome-exosome hybrid bionic vesicles encapsulated microparticles for enhanced pulmonary fibrosis therapy.

Pulmonary fibrosis (PF) is a chronic, progressive and irreversible interstitial lung disease that seriously threatens human life and health. Our previous study demonstrated the unique superiority of traditional Chinese medicine cryptotanshinone (CTS) combined with sustained pulmonary drug delivery for treating PF. In this study, we aimed to enhance the selectivity, targeting efficiency and sustained-release capability based on this delivery system. To this end, we developed and evaluated CTS-loaded modified liposomes-chitosan (CS) microspheres SM(CT-lipo) and liposome-exosome hybrid bionic vesicles-CS microspheres SM(LE). The prepared nano-in-micro particles system integrates the advantages of the carriers and complements each other. SM(CT-lipo) and SM(LE) achieved lung myofibroblast-specific targeting through CREKA peptide binding specifically to fibronectin (FN) and the homing effect of exosomes on parent cells, respectively, facilitating efficient delivery of anti-fibrosis drugs to lung lesions. Furthermore, compared with daily administration of conventional microspheres SM(NC) and positive control drug pirfenidone (PFD), inhaled administration of SM(CT-lipo) and SM(LE) every two days still attained similar efficacy, exhibiting excellent sustained drug release ability. In summary, our findings suggest that the developed SM(CT-lipo) and SM(LE) delivery strategies could achieve more accurate, efficient and safe therapy, providing novel insights into the treatment of chronic PF.

Amelioration of pathologic α-synuclein-induced Parkinson's disease by irisin.

Physical activity provides clinical benefit in Parkinson's disease (PD). Irisin is an exercise-induced polypeptide secreted by skeletal muscle that crosses the blood-brain barrier and mediates certain effects of exercise. Here, we show that irisin prevents pathologic α-synuclein (α-syn)-induced neurodegeneration in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Intravenous delivery of irisin via viral vectors following the stereotaxic intrastriatal injection of α-syn PFF cause a reduction in the formation of pathologic α-syn and prevented the loss of dopamine neurons and lowering of striatal dopamine. Irisin also substantially reduced the α-syn PFF-induced motor deficits as assessed behaviorally by the pole and grip strength test. Recombinant sustained irisin treatment of primary cortical neurons attenuated α-syn PFF toxicity by reducing the formation of phosphorylated serine 129 of α-syn and neuronal cell death. Tandem mass spectrometry and biochemical analysis revealed that irisin reduced pathologic α-syn by enhancing endolysosomal degradation of pathologic α-syn. Our findings highlight the potential for therapeutic disease modification of irisin in PD.

Systemic Administration of Recombinant Irisin Accelerates Fracture Healing in Mice.

To date, pharmacological strategies designed to accelerate bone fracture healing are lacking. We subjected 8-week-old C57BL/6 male mice to closed, transverse, mid-diaphyseal tibial fractures and treated them with intraperitoneal injection of a vehicle or r-irisin (100 µg/kg/weekly) immediately following fracture for 10 days or 28 days. Histological analysis of the cartilaginous callus at 10 days showed a threefold increase in Collagen Type X (p = 0.0012) and a reduced content of proteoglycans (40%; p = 0.0018). Osteoclast count within the callus showed a 2.4-fold increase compared with untreated mice (p = 0.026), indicating a more advanced stage of endochondral ossification of the callus during the early stage of fracture repair. Further evidence that irisin induced the transition of cartilage callus into bony callus was provided by a twofold reduction in the expression of SOX9 (p = 0.0058) and a 2.2-fold increase in RUNX2 (p = 0.0137). Twenty-eight days post-fracture, microCT analyses showed that total callus volume and bone volume were increased by 68% (p = 0.0003) and 67% (p = 0.0093), respectively, and bone mineral content was 74% higher (p = 0.0012) in irisin-treated mice than in controls. Our findings suggest that irisin promotes bone formation in the bony callus and accelerates the fracture repair process, suggesting a possible use as a novel pharmacologic modulator of fracture healing.

Irisin Protects the Human Placenta from Oxidative Stress and Apoptosis via Activation of the Akt Signaling Pathway.

Irisin is a newly discovered exercise-mediated polypeptide hormone. Irisin levels increase during pregnancy however, women with preeclampsia (PE) have significantly lower levels of Irisin compared to women of healthy pregnancies. Even though many studies suggest a role of Irisin in pregnancy, its function in the human placenta is unclear. In the current study, we aimed to understand key roles of Irisin through its ability to protect against apoptosis is the preeclamptic placenta and in ex vivo and in vitro models of hypoxia/re-oxygenation (H/R) injury. Our studies show that Irisin prevents cell death by reducing pro-apoptotic signaling cascades, reducing cleavage of PARP to induce DNA repair pathways and reducing activity of Caspase 3. Irisin caused an increase in the levels of anti-apoptotic BCL2 to pro-apoptotic BAX and reduced ROS levels in an in vitro model of placental ischemia. Furthermore, we show that Irisin treatment acts through the Akt signaling pathway to prevent apoptosis and enhance cell survival. Our findings provide a novel understanding for the anti-apoptotic and pro-survival properties of Irisin in the human placenta under pathological conditions. This work yields new insights into placental development and disease and points towards intervention strategies for placental insufficiencies, such as PE, by protecting and maintaining placental function through inhibiting hypoxic ischemia-induced apoptosis.

Anti-Inflammatory Fibronectin-AgNP for Regulation of Biological Performance and Endothelial Differentiation Ability of Mesenchymal Stem Cells.

The engineering of vascular regeneration still involves barriers that need to be conquered. In the current study, a novel nanocomposite comprising of fibronectin (denoted as FN) and a small amount of silver nanoparticles (AgNP, ~15.1, ~30.2 or ~75.5 ppm) was developed and its biological function and biocompatibility in Wharton's jelly-derived mesenchymal stem cells (MSCs) and rat models was investigated. The surface morphology as well as chemical composition for pure FN and the FN-AgNP nanocomposites incorporating various amounts of AgNP were firstly characterized by atomic force microscopy (AFM), UV-Visible spectroscopy (UV-Vis), and Fourier-transform infrared spectroscopy (FTIR). Among the nanocomposites, FN-AgNP with 30.2 ppm silver nanoparticles demonstrated the best biocompatibility as assessed through intracellular ROS production, proliferation of MSCs, and monocytes activation. The expression levels of pro-inflammatory cytokines, TNF-α, IL-1ß, and IL-6, were also examined. FN-AgNP 30.2 ppm significantly inhibited pro-inflammatory cytokine expression compared to other materials, indicating superior performance of anti-immune response. Mechanistically, FN-AgNP 30.2 ppm significantly induced greater expression of vascular endothelial growth factor (VEGF) and stromal-cell derived factor-1 alpha (SDF-1α) and promoted the migration of MSCs through matrix metalloproteinase (MMP) signaling pathway. Besides, in vitro and in vivo studies indicated that FN-AgNP 30.2 ppm stimulated greater protein expressions of CD31 and von Willebrand Factor (vWF) as well as facilitated better endothelialization capacity than other materials. Furthermore, the histological tissue examination revealed the lowest capsule formation and collagen deposition in rat subcutaneous implantation of FN-AgNP 30.2 ppm. In conclusion, FN-AgNP nanocomposites may facilitate the migration and proliferation of MSCs, induce endothelial cell differentiation, and attenuate immune response. These finding also suggests that FN-AgNP may be a potential anti-inflammatory surface modification strategy for vascular biomaterials.

FNDC5/Irisin attenuates diabetic cardiomyopathy in a type 2 diabetes mouse model by activation of integrin αV/ß5-AKT signaling and reduction of oxidative/nitrosative stress.

Irisin, the cleaved form of the fibronectin type III domain containing 5 (FNDC5) protein, is involved in metabolism and inflammation. Recent findings indicated that irisin participated in cardiovascular physiology and pathology. In this study, we investigated the effects of FNDC5/irisin on diabetic cardiomyopathy (DCM) in type 2 diabetic db/db mice. Downregulation of myocardial FNDC5/irisin protein expression and plasma irisin levels was observed in db/db mice compared to db/+ controls. Moreover, echocardiography revealed that db/db mice exhibited normal cardiac systolic function and impaired diastolic function. Adverse structural remodeling, including cardiomyocyte apoptosis, myocardial fibrosis, and cardiac hypertrophy were observed in the hearts of db/db mice. Sixteen-week-old db/db mice were intramyocardially injected with adenovirus encoding FNDC5 or treated with recombinant human irisin via a peritoneal implant osmotic pump for 4 weeks. Both overexpression of myocardial FNDC5 and exogenous irisin administration attenuated diastolic dysfunction and cardiac structural remodeling in db/db mice. Results from in vitro studies revealed that FNDC5/irisin protein expression was decreased in high glucose (HG)/high fat (HF)-treated cardiomyocytes. Increased levels of inducible nitric oxide synthase (iNOS), NADPH oxidase 2 (NOX2), 3-nitrotyrosine (3-NT), reactive oxygen species (ROS), and peroxynitrite (ONOO-) in HG/HF-treated H9C2 cells provided evidence of oxidative/nitrosative stress, which was alleviated by treatment with FNDC5/irisin. Moreover, the mitochondria membrane potential (ΔΨm) was decreased and cytochrome C was released from mitochondria with increased levels of cleaved caspase-3 in HG/HF-treated H9C2 cells, indicating the presence of mitochondria-dependent apoptosis, which was partially reversed by FNDC5/irisin treatment. Mechanistic studies showed that activation of integrin αVß5-AKT signaling and attenuation of oxidative/nitrosative stress were responsible for the cardioprotective effects of FNDC5/irisin. Therefore, FNDC5/irisin mediates cardioprotection in DCM by inhibiting myocardial apoptosis, myocardial fibrosis, and cardiac hypertrophy. These findings implicate that FNDC5/irisin as a potential therapeutic intervention for DCM, especially in type 2 diabetes mellitus (T2DM).

Pro-Con Debate: Fibrinogen Concentrate or Cryoprecipitate for Treatment of Acquired Hypofibrinogenemia in Cardiac Surgical Patients.

Cryoprecipitate has been the gold standard for treating acquired hypofibrinogenemia in cardiac surgery for nearly 50 years. More recently, fibrinogen concentrate has been used off-label in the United States and is the standard in European countries and Canada to treat the acquired hypofibrinogenemia during cardiac surgery. Fibrinogen concentrate has multiple potential advantages including rapid reconstitution, greater dose predictability, viral inactivation during processing, and reduced transfusion-related adverse events. However, because fibrinogen concentrate lacks the other components contained in the cryoprecipitate, it may not be the "ideal" product for replacing fibrinogen in all cardiac surgical patients, particularly those with longer cardiopulmonary bypass duration. In this Pro-Con commentary article, we discuss the advantages and disadvantages of using fibrinogen concentrate and cryoprecipitate to treat acquired hypofibrinogenemia in cardiac surgical patients.

Effect of Irisin on LIF and integrin αvß3 in rats of implantation failure.

OBJECTIVE: The aim of this study is to investigate the effect of irisin on leukemia inhibitory factor (LIF) and integrin αvß3 in implantation failure uterus. METHODS: Early pregnant rats were randomly divided into normal group (N), mifepristone treated group (M), irisin group (I) and progestin group (P). The implantation failure model was established using mifepristone. Second, we evaluated the average number of embryos and detected the expression of LIF and integrin αvß3 protein and mRNA in endometrium. RESULTS: Compared with group M, the average number of embryos was significantly higher in group N, P and I, the expression of LIF and integrin αvß3 in endometrium was significantly higher in group N, P and I. CONCLUSION: Irisin could improve the poor receptive state of endometrium by promoting LIF and integrin αvß3 secretion to improve blastocyst implantation in rats of implantation failure.

Irisin Protects Against Hind Limb Ischemia Reperfusion Injury.

AIM: The aim of this study was to evaluate the effects of irisin in a murine model of hind limb ischemia reperfusion (I/R). METHODS: The mice were divided into four groups (n = 6 in each group): control, irisin, ischemia reperfusion (I/R), and irisin-ischemia reperfusion (I-I/R). Irisin (0.5 µg.g-1, intraperitoneally [i.p.]) was administered 30 min before the I/R procedure. After 2 h of ischemia and 2.5 h of reperfusion, blood and tissue samples were taken for biochemical and histopathological analysis. The results were analyzed by Kruskal-Wallis and Mann-Whitney U-tests. RESULTS: There was a statistically significant difference in the total antioxidant status (TAS) and total oxidant status (TOS) levels in all the groups. The TAS level in the I/R group was significantly lower than that in the control, irisin, and I-I/R groups, whereas the TOS level was significantly higher in the I/R group as compared with that in the other groups. Caspase-3 activity and caspase-8 activity, indicators of inflammation, were significantly higher in the I/R and I-I/R groups as compared with those in the control and irisin groups. CONCLUSION: Irisin may have protective effects in skeletal muscle ischemia reperfusion injury.

Irisin may have a role in pubertal development and regulation of reproductive function in rats.

Physical exercise and body muscle/fat mass are known to affect the endocrine system, puberty onset and reproductive health. However, the potential effects of irisin, an adipo-myokine and exercise-induced hormone, have not yet been fully elucidated on reproductive maturation. Therefore, the present study aimed to determine the effects of irisin administration on pubertal maturation and reproductive system in female and male rats. Daily i.p. injection of irisin (100 ng/kg; from postnatal day 21 for about 10 weeks) delayed the ages at the vaginal opening (as an external index of puberty onset) and first estrus. Furthermore, continuous administration of irisin to female rats caused a significant decrease in serum follicle-stimulating hormone levels and an increase in serum luteinizing hormone and 17ß-estradiol levels, as well as causing histopathological changes in the ovarian tissue. On the contrary, irisin administration to male rats did not modify the timing of puberty, as estimated by age at preputial separation. However, chronic exposure to irisin produced significant increases in serum luteinizing hormone and testosterone levels and also sperm concentration and seminiferous tubule diameter in male rats. In conclusion, irisin exposure has different effects on both pubertal maturation and reproductive system in female and male rats. The present findings reveal that chronic irisin exposure may lead to disorders in the female reproductive system and may have androgenic potential on the hypothalamic-pituitary-gonadal axis in males.

Traction and attraction: haptotaxis substrates collagen and fibronectin interact with chemotaxis by HGF to regulate myoblast migration in a microfluidic device.

Cell migration is central to development, wound healing, tissue regeneration, and immunity. Despite extensive knowledge of muscle regeneration, myoblast migration during regeneration is not well understood. C2C12 mouse myoblast migration and morphology were investigated using a triple-docking polydimethylsiloxane-based microfluidic device in which cells moved under gravity-driven laminar flow on uniform (=) collagen (CN=), fibronectin (FN=), or opposing gradients (CN-FN or FN-CN). In haptotaxis experiments, migration was faster on FN= than on CN=. At 10 h, cells were more elongated on FN-CN and migration was faster than on the CN-FN substrate. Net migration distance on FN-CN at 10 h was greater than on CN-FN, as cells rapidly entered the channel as a larger population (bulk-cell movement, wave 1). Hepatocyte growth factor (HGF) stimulated rapid chemotaxis on FN= but not CN=, increasing migration speed at 10 h early in the channel at low HGF in a steep HGF gradient. HGF accelerated migration on FN= and bulk-cell movement on both uniform substrates. An HGF gradient also slowed cells in wave 2 moving on FN-CN, not CN-FN. Both opposing-gradient substrates affected the shape, speed, and net distance of migrating cells. Gradient and uniform configurations of HGF and substrate differentially influenced migration behavior. Therefore, haptotaxis substrate configuration potently modifies myoblast chemotaxis by HGF. Innovative microfluidic experiments advance our understanding of intricate complexities of myoblast migration. Findings can be leveraged to engineer muscle-tissue volumes for transplantation after serious injury. New analytical approaches may generate broader insights into cell migration.

Assembly of FN-silk with laminin-521 to integrate hPSCs into a three-dimensional culture for neural differentiation.

Three-dimensional (3D) neural tissue cultures recapitulate the basic concepts during development and disease better than what can be obtained using conventional two-dimensional cultures. Here, we use a recombinant spider silk protein functionalized with a cell binding motif from fibronectin (FN-silk) in combination with a human recombinant laminin 521 (LN-521) to create a fully defined stem cell niche in 3D. A novel method to assemble silk blended with LN-521 together with human pluripotent stem cells (hPSC) is used to create centimeter-sized foams, which upon cultivation develop into 3D cell constructs supported by a microfibrillar network. After initial cell expansion, neural differentiation was induced to form a homogenous layer of continuous neuroectodermal tissue that allows further differentiation into neuronal subtypes. The silk-supported 3D cell constructs could then be detached from the bottom of the well and cultured as floating entities, where cells appeared in distinctive radial organization resembling early neural tube. This shows that the neural progenitors retain their cellular self-organization ability in the FN-silk/LN-521-supported 3D culture. Calcium imaging demonstrated spontaneous activity, which is important for the formation of neuronal networks. Together, the results show that hPSCs integrated into FN-silk/LN-521 foam develop into neural progenitors and that these stay viable during long-term differentiations. FN-silk/LN-521 also supports morphogenesis mimicking the human brain development and can serve as base for engineering of hPSC-derived neural tissue.

Irisin induces trophoblast differentiation via AMPK activation in the human placenta.

Irisin, an adipokine, regulates differentiation and phenotype in various cell types including myocytes, adipocytes, and osteoblasts. Circulating irisin concentration increases throughout human pregnancy. In pregnancy disorders such as preeclampsia and gestational diabetes mellitus, circulating irisin levels are reduced compared to healthy controls. To date, there are no data on the role and molecular function of irisin in the human placenta or its contribution to pathophysiology. Aberrant trophoblast differentiation is involved in the pathophysiology of preeclampsia. The current study aimed to assess the molecular effects of irisin on trophoblast differentiation and function. First-trimester placental explants were cultured and treated with low (10 nM) and high (50 nM) physiological doses of irisin. Treatment with irisin dose-dependently increased both in vitro placental outgrowth (on Matrigel™) and trophoblast cell-cell fusion. Adenosine monophosphate-activated protein kinase (AMPK) signaling, an important regulator of cellular energy homeostasis that is involved in trophoblast differentiation and pathology, was subsequently investigated. Here, irisin exposure induced placental AMPK activation. To determine the effects of irisin on trophoblast differentiation, two trophoblast-like cell lines, HTR-8/SVneo and BeWo, were treated with irisin and/or a specific AMPK inhibitor (Compound C). Irisin-induced AMPK phosphorylation in HTR-8/SVneo cells. Additionally, as part of the differentiation process, integrin switching from α6 to α1 occurred as well as increased invasiveness. Overall, irisin promoted differentiation in villous and extravillous cell-based models via AMPK pathway activation. These findings provide evidence that exposure to irisin promotes differentiation and improves trophoblast functions in the human placenta that are affected in abnormal placentation.

Role of irisin in androgen-deficient muscle wasting and osteopenia in mice.

Androgen deficiency plays a crucial role in the pathogenesis of male osteoporosis and sarcopenia. Myokines have recently been identified as humoral factors that are involved in the interactions between muscle and bone; however, the influence of androgen deficiency on these interactions remains unclear. Therefore, we herein investigated the roles of humoral factors linking muscle to bone using orchidectomized mice with sarcopenia and osteopenia. Orchidectomy (ORX) significantly reduced muscle mass, grip strength, and trabecular bone mineral density (BMD) in mice. Among the myokines examined, ORX only significantly reduced fibronectin type III domain-containing 5 (Fndc5) mRNA levels in both the soleus and gastrocnemius muscles of mice. In simple regression analyses, Fndc5 mRNA levels in the soleus muscle positively correlated with trabecular BMD, but not cortical BMD. The administration of irisin, a product of Fndc5, significantly protected against the decrease induced in trabecular BMD, but not muscle mass, by androgen deficiency in mice. In conclusion, the present results demonstrated that androgen deficiency decreases the expression of irisin in the skeletal muscle of mice. Irisin may be involved in muscle/bone relationships negatively affected by androgen deficiency.

Irisin reverses intestinal epithelial barrier dysfunction during intestinal injury via binding to the integrin αVß5 receptor.

Disruption of the gut barrier results in severe clinical outcomes with no specific treatment. Metabolic disorders and destruction of enterocytes play key roles in gut barrier dysfunction. Irisin is a newly identified exercise hormone that regulates energy metabolism. However, the effect of irisin on gut barrier function remains unknown. The therapeutic effect of irisin on gut barrier dysfunction was evaluated in gut ischemia reperfusion (IR). The direct effect of irisin on gut barrier function was studied in Caco-2 cells. Here, we discovered that serum and gut irisin levels were decreased during gut IR and that treatment with exogenous irisin restored gut barrier function after gut IR in mice. Meanwhile, irisin decreased oxidative stress, calcium influx and endoplasmic reticulum (ER) stress after gut IR. Moreover, irisin protected mitochondrial function and reduced enterocyte apoptosis. The neutralizing antibody against irisin significantly aggravated gut injury, oxidative stress and enterocyte apoptosis after gut IR. Further studies revealed that irisin activated the AMPK-UCP 2 pathway via binding to the integrin αVß5 receptor. Inhibition of integrin αVß5, AMPK or UCP 2 abolished the protective role of irisin in gut barrier function. In conclusion, exogenous irisin restores gut barrier function after gut IR via the integrin αVß5-AMPK-UCP 2 pathway.

Effects of intra-dentate gyrus microinjection of myokine irisin on long-term potentiation in male rats / Efeitos da microinjeção da miocina irisina no giro denteado sobre a potenciação a longo prazo em ratos machos

ABSTRACT Induction of long-term potentiation (LTP) increases the storage capacity of synapses in the hippocampal dentate gyrus (DG). Irisin is a myokine generated from FNDC5 (a gene precursor) during exercise. Although intra-cornu ammonis 1 administration of irisin fortifies LTP in mice with Alzheimer's disease, the effects of intra-DG injection of irisin on the LTP in rats remains to be elucidated in vivo. In this study, male Wistar rats were randomly divided into a control group (saline), irisin (0.5, 1, and 1.5 μg/rat), and dimethyl sulfoxide (DMSO). After treatment, the population spike (PS) amplitude and slope of excitatory postsynaptic potentials (EPSP) were measured in the DG of rats in vivo. Moreover, following completion of the experiments, the stimulating and recording sites in the hippocampus were confirmed histologically from brain sections. Furthermore, biochemical assays like malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidant status (TOS) were evaluated (the antioxidant markers were analyzed in the plasma). Our results suggest that all doses of irisin (0.5, 1, 1.5 μg/rat) caused an increase in the EPSP slope and PS amplitude when compared with the control group. In addition, the results obtained showed that irisin decreased TOS and MDA levels while increasing TAC levels as a marker of lipid peroxidation in plasma. The present report provides direct evidence that irisin affects the activity-dependent synaptic plasticity in the dentate gyrus.

RESUMO A indução de potenciação de longo prazo (LTP) aumenta a capacidade de armazenamento das sinapses no giro denteado (DG) do hipocampo. A irisina é uma miocina gerada a partir do FNDC5 (um precursor genético) durante o exercício. Embora a administração intra-Cornu Ammonis1 de irisina fortaleça a LTP em camundongos com doença de Alzheimer, os efeitos da injeção intra-denteada de irisina sobre a LTP em ratos ainda precisam ser elucidados in vivo. Neste estudo, ratos Wistar machos foram divididos aleatoriamente em um grupo controle (solução salina), irisina (0,5, 1 e 1,5 μg / rato) e dimetilsulfóxido (DMSO). Após o tratamento, a amplitude do pico populacional (PS) e a variação dos potenciais pós-sinápticos excitatórios (EPSP) foram medidos no DG de ratos in vivo. Além disso, após a conclusão das experiências, os locais de estimulação e registro no hipocampo foram confirmados histologicamente a partir de secções do cérebro. Adicionalmente, ensaios bioquímicos como malondialdeído (MDA), capacidade antioxidante total (TAC) e status oxidante total (TOS) foram avaliados (os marcadores antioxidantes foram analisados no plasma). Nossos resultados sugerem que todas as doses de irisina (0,5, 1, 1,5 μg / rato) causaram um aumento na variação da EPSP e na amplitude da PS quando comparadas com o grupo controle. Além disso, os resultados obtidos mostraram que a irisina diminuiu os níveis de TOS e MDA, enquanto aumentou os níveis de TAC como um marcador da peroxidação lipídica no plasma. O presente estudo fornece evidências diretas de que a irisina afeta a plasticidade sináptica dependente de atividade no DG.

Irisin Enhances Doxorubicin-Induced Cell Apoptosis in Pancreatic Cancer by Inhibiting the PI3K/AKT/NF-κB Pathway.

BACKGROUND Irisin, a myokine released from skeletal muscle following exercise, has been shown to affect the proliferation of some cancer cells and chemosensitivity of anticancer drugs like doxorubicin (DOX). However, the effects of irisin on chemosensitivity in pancreatic cancer (PC) cells have not been studied. MATERIAL AND METHODS In this study, the effects of irisin co-treatment with DOX or gemcitabine (GEM) on MIA PaCa-2, BxPC-3 PC cells, and H9c2 cardiomyocytes were investigated. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, flow cytometry, and TUNEL (TdT-mediated dUTP nick-end labeling) assays were conducted to evaluate cytotoxicity induced by DOX or GEM. Fluorescence microscopy and flow cytometry experiments were performed to assess the intracellular accumulation of DOX. Cellular levels of apoptosis-related protein expression and protein phosphorylation were determined by Western blot analyses. RESULTS The results showed that irisin can increase the chemosensitivity of PC cells to DOX or GEM. The analyses of apoptosis indicated that irisin enhances DOX-induced cellular apoptosis by increasing the expression of cleaved PARP (poly ADP-ribose polymerase) and cleaved caspase-3, and reducing the expression of B cell lymphoma/lewkmia-2 (BCL-2) and B cell lymphoma-extra large (BCL-xL) in PC cells but not in H9c2 cells. Irisin attenuated serine/threonine kinase AKT (protein kinase B/PKB) phosphorylation and inhibited the activation of nuclear factor kappaB (NF-kappaB) signaling in PC cells. CONCLUSIONS Irisin can potentiate the cytotoxicity of doxorubicin in PC cells without increasing cardiotoxicity, possibly through inactivating the PI3K/AKT/NF-kappaB signaling pathway.

Low Serum Irisin Concentration Is Associated with Poor Outcomes in Patients with Acute Pancreatitis, and Irisin Administration Protects Against Experimental Acute Pancreatitis.

Aims: Severe acute pancreatitis (AP) is a serious condition without specific treatment. Mitochondrial dysfunction plays a crucial role in the pathogenesis of AP. Irisin, a novel exercise-induced hormone, contributes to many health benefits of physical activity. We and others have shown that irisin protects against ischemia reperfusion-induced organ injury by alleviating mitochondrial damage. However, the role of irisin in AP has not been evaluated. The purpose of this study was to investigate the role of serum irisin levels in patients with AP and the effect of irisin administration in experimental AP. Results: Serum irisin levels were decreased in AP patients, and low serum irisin levels were associated with worse outcomes in these patients. Treatment with exogenous irisin increased survival and mitigated pancreatic injury in experimental AP. The protective effects of irisin in AP were associated with improvement in mitochondrial function and reduction in ER stress. Moreover, irisin upregulated UCP2 expression in the pancreas, and administration of genipin, a specific UCP2 antagonist, abolished irisin's beneficial effects in L-arginine-induced AP. Innovation and Conclusion: Low serum irisin was associated with poor outcomes in AP patients, and irisin administration protected against experimental AP by restoring mitochondrial function via activation of UCP2. Restoration of mitochondrial function by irisin may offer therapeutic potential for patients with AP. Antioxid. Redox Signal. 31, 771-785.

Effects of intra-dentate gyrus microinjection of myokine irisin on long-term potentiation in male rats.

OBJECTIVE: Induction of long-term potentiation (LTP) increases the storage capacity of synapses in the hippocampal dentate gyrus (DG). Irisin is a myokine generated from FNDC5 (a gene precursor) during exercise. METHODS: Although intra-cornu ammonis 1 administration of irisin fortifies LTP in mice with Alzheimer's disease, the effects of intra-DG injection of irisin on the LTP in rats remains to be elucidated in vivo. In this study, male Wistar rats were randomly divided into a control group (saline), irisin (0.5, 1, and 1.5 µg/rat), and dimethyl sulfoxide (DMSO). RESULTS: After treatment, the population spike (PS) amplitude and slope of excitatory postsynaptic potentials (EPSP) were measured in the DG of rats in vivo. Moreover, following completion of the experiments, the stimulating and recording sites in the hippocampus were confirmed histologically from brain sections. Furthermore, biochemical assays like malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidant status (TOS) were evaluated (the antioxidant markers were analyzed in the plasma). CONCLUSION: Our results suggest that all doses of irisin (0.5, 1, 1.5 µg/rat) caused an increase in the EPSP slope and PS amplitude when compared with the control group. In addition, the results obtained showed that irisin decreased TOS and MDA levels while increasing TAC levels as a marker of lipid peroxidation in plasma. The present report provides direct evidence that irisin affects the activity-dependent synaptic plasticity in the dentate gyrus.

Multifibrillar bundles of a self-assembling hyaluronic acid derivative obtained through a microfluidic technique for aortic smooth muscle cell orientation and differentiation.

A hyaluronic acid derivative that is able to physically crosslink in a saline aqueous environment was employed for the production of fibers with a mean diameter of 50 µm using a microfluidic technique. The microfibers were collected in a tailored rotating collector and assembled to form multifibrillar bundles. The orientation of the microfibers on the collected bundles was evaluated by microCT analysis. The bundles were biofunctionalized by physical addition of fibronectin or chemical tethering of a cyRGDC peptide to achieve control of Aortic Smooth Muscle Cell (AoSMC) attachment, elongation and alignment. The mechanical performances of these bundles were evaluated by elongation tests, related to the kind of biological functionalization and compared to non-functionalized samples. The alignment and differentiation of AoSMCs on single fibers and on the bundles were evaluated by microscopy and histochemical analyses.