Neu3 Sialidase Activates the RISK Cardioprotective Signaling Pathway during Ischemia and Reperfusion Injury (IRI)

Coronary reperfusion strategies are life-saving approaches to restore blood flow to cardiac tissue after acute myocardial infarction (AMI). However, the sudden restoration of normal blood flow leads to ischemia and reperfusion injury (IRI), which results in cardiomyoblast death, irreversible tissue degeneration, and heart failure. The molecular mechanism of IRI is not fully understood, and there are no effective cardioprotective strategies to prevent it. In this study, we show that activation of sialidase-3, a glycohydrolytic enzyme that cleaves sialic acid residues from glycoconjugates, is cardioprotective by triggering RISK pro-survival signaling pathways. We found that overexpression of Neu3 significantly increased cardiomyoblast resistance to IRI through activation of HIF-1α and Akt/Erk signaling pathways. This raises the possibility of using Sialidase-3 activation as a cardioprotective reperfusion strategy after myocardial infarction.     

Cyclophilin D Regulates the Nuclear Translocation of AIF,Cardiac Endothelial Cell Necroptosis and Murine Cardiac Transplant Injury

Ischemia-reperfusion injury (IRI) is an inevitable consequence of organ transplant procedure and associated with acute and chronic organ rejection in transplantation. IRI leads to various forms of programmed cell death, which worsens tissue damage and accelerates transplant rejection. We recently demonstrated that necroptosis participates in murine cardiac microvascular endothelial cell (MVEC) death and murine cardiac transplant rejection. However, MVEC death under a more complex IRI model has not been studied. In this study, we found that simulating IRI conditions in vitro by hypoxia, reoxygenation and treatment with inflammatory cytokines induced necroptosis in MVECs. Interestingly, the apoptosis-inducing factor (AIF) translocated to the nucleus during MVEC necroptosis, which is regulated by the mitochondrial permeability molecule cyclophilin D (CypD). Furthermore, CypD deficiency in donor cardiac grafts inhibited AIF translocation and mitigated graft IRI and rejection (n = 7; p = 0.002). Our studies indicate that CypD and AIF play significant roles in MVEC necroptosis and cardiac transplant rejection following IRI. Targeting CypD and its downstream AIF may be a plausible approach to inhibit IRI-caused cardiac damage and improve transplant survival.     

New Insights in Mechanisms and Therapeutics for Short- and Long-Term Impacts of Hepatic Ischemia Reperfusion Injury Post Liver Transplantation

Liver transplantation has been identified as the most effective treatment for patients with end-stage liver diseases. However, hepatic ischemia reperfusion injury (IRI) is associated with poor graft function and poses a risk of adverse clinical outcomes post transplantation. Cell death, including apoptosis, necrosis, ferroptosis and pyroptosis, is induced during the acute phase of liver IRI. The release of danger-associated molecular patterns (DAPMs) and mitochondrial dysfunction resulting from the disturbance of metabolic homeostasis initiates graft inflammation. The inflammation in the short term exacerbates hepatic damage, leading to graft dysfunction and a higher incidence of acute rejection. The subsequent changes in the graft immune environment due to hepatic IRI may result in chronic rejection, cancer recurrence and fibrogenesis in the long term. In this review, we mainly focus on new mechanisms of inflammation initiated by immune activation related to metabolic alteration in the short term during liver IRI. The latest mechanisms of cancer recurrence and fibrogenesis due to the long-term impact of inflammation in hepatic IRI is also discussed. Furthermore, the development of therapeutic strategies, including ischemia preconditioning, pharmacological inhibitors and machine perfusion, for both attenuating acute inflammatory injury and preventing late-phase disease recurrence, will be summarized in the context of clinical, translational and basic research.     

Adipose-Derived Stem/Stromal Cells in Kidney Transplantation: Status Quo and Future Perspectives

Kidney transplantation (KT) is the gold standard treatment of end-stage renal disease. Despite progressive advances in organ preservation, surgical technique, intensive care, and immunosuppression, long-term allograft survival has not significantly improved. Among the many peri-operative complications that can jeopardize transplant outcomes, ischemia–reperfusion injury (IRI) deserves special consideration as it is associated with delayed graft function, acute rejection, and premature transplant loss. Over the years, several strategies have been proposed to mitigate the impact of IRI and favor tolerance, with rather disappointing results. There is mounting evidence that adipose stem/stromal cells (ASCs) possess specific characteristics that could help prevent, reduce, or reverse IRI. Immunomodulating and tolerogenic properties have also been suggested, thus leading to the development of ASC-based prophylactic and therapeutic strategies in pre-clinical and clinical models of renal IRI and allograft rejection. ASCs are copious, easy to harvest, and readily expandable in culture. Furthermore, ASCs can secrete extracellular vesicles (EV) which may act as powerful mediators of tissue repair and tolerance. In the present review, we discuss the current knowledge on the mechanisms of action and therapeutic opportunities offered by ASCs and ASC-derived EVs in the KT setting. Most relevant pre-clinical and clinical studies as well as actual limitations and future perspective are highlighted.     

Human Endothelial Progenitor Cells Protect the Kidney against Ischemia-Reperfusion Injury via the NLRP3 Inflammasome in Mice

Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) and progression to chronic kidney disease (CKD). However, no effective therapeutic intervention has been established for ischemic AKI. Endothelial progenitor cells (EPCs) have major roles in the maintenance of vascular integrity and the repair of endothelial damage; they also serve as therapeutic agents in various kidney diseases. Thus, we examined whether EPCs have a renoprotective effect in an IRI mouse model. Mice were assigned to sham, EPC, IRI-only, and EPC-treated IRI groups. EPCs originating from human peripheral blood were cultured. The EPCs were administered 5 min before reperfusion, and all mice were killed 72 h after IRI. Blood urea nitrogen, serum creatinine, and tissue injury were significantly increased in IRI mice; EPCs significantly improved the manifestations of IRI. Apoptotic cell death and oxidative stress were significantly reduced in EPC-treated IRI mice. Administration of EPCs decreased the expression levels of NLRP3, cleaved caspase-1, p-NF-κB, and p-p38. Furthermore, the expression levels of F4/80, ICAM-1, RORγt, and IL-17RA were significantly reduced in EPC-treated IRI mice. Finally, the levels of EMT-associated factors (TGF-β, α-SMA, Snail, and Twist) were significantly reduced in EPC-treated IRI mice. This study shows that inflammasome-mediated inflammation accompanied by immune modulation and fibrosis is a potential target of EPCs as a treatment for IRI-induced AKI and the prevention of progression to CKD.     

Elongational,hysteresis, and oscillatory flows of complex fluids

The simple model proposed earlier to describe te rheological properties of complex fluids is used to calculate (a) the extensional viscosity, (b) the hysteresis loops, and (c) the complex viscosity. It has been found that the rheological properties predicted by the model agree with experimental observations. It is shown that for some viscoelastic fluids the extensional viscosity is always finite and for some other fluids the extensional viscosity tends t infinity at finite extensional rate. In the latter case, steady flow is not attainable. The shape of the hysteresis loops depends on the maximum shear-rate. It also depends on the material properties. In a small amplitude oscillatory flow, our model reduces t a linear viscoelastic fluid.     

Deletion of the Gamma Subunit of ENaC in Endothelial Cells Does Not Protect against Renal Ischemia Reperfusion Injury

Acute kidney injury due to renal ischemia-reperfusion injury (IRI) may lead to chronic or end stage kidney disease. A greater understanding of the cellular mechanisms underlying IRI are required to develop therapeutic options aimed at limiting or reversing damage from IRI. Prior work has shown that deletion of the α subunit of the epithelial Na+ channel (ENaC) in endothelial cells protects from IRI by increasing the availability of nitric oxide. While canonical ENaCs consist of an α, β, and γ subunit, there is evidence of non-canonical ENaC expression in endothelial cells involving the α subunit. We therefore tested whether the deletion of the γ subunit of ENaC also protects mice from IRI to differentiate between these channel configurations. Mice with endothelial-specific deletion of the γ subunit and control littermates were subjected to unilateral renal artery occlusion followed by 48 h of reperfusion. No significant difference was noted in injury between the two groups as assessed by serum creatinine and blood urea nitrogen, levels of specific kidney injury markers, and histological examination. While deletion of the γ subunit did not alter infiltration of immune cells or cytokine message, it was associated with an increase in levels of total and phosphorylated endothelial nitric oxide synthase (eNOS) in the injured kidneys. Our studies demonstrate that even though deletion of the γ subunit of ENaC may allow for greater activation of eNOS, this is not sufficient to prevent IRI, suggesting the protective effects of α subunit deletion may be due, in part, to other mechanisms.     

High-strength functionalized pectin/fibroin hydrogel with tunable properties: A structure–property relationship study

Hydrogels possessing high mechanical strength and well-controlled properties are of utmost interest in bone tissue engineering. In the current study, a strong self-crosslinked hydrogel with variable properties has been developed from a combinatory composition of functionalized pectin and silk fibroin. Pectin chains underwent partial oxidation to be decorated with aldehyde functionalities. Later on, functionalized polysaccharide and protein were blended with different ratios, and corresponding variations in crystalline structure as well as in morphological, mechanical, and rheological properties have been monitored. Some theories have been used to better perceive the relation between blending ratio and hydrogel properties. Avrami equation based on time sweep rheological analysis elucidated that in sample with equivalent ratio of oxidized pectin and fibroin, the crystallization was highly delayed due to dominance of Schiff's base reaction. The Herschel–Bulkley model based on flow curve rheology test corroborated that aforesaid composition revealed the most noticeable shear thinning behavior and accordingly the strongest crosslinked network. Finally, rubber elastic theory based on dynamic mechanical analysis implied that said formulation possessed the highest crosslinking density due to higher availability of aldehyde to amine functionalities. Moreover, cell culture studies proved that P50 F50 sample prevailed over other compositions with respect to cell viability and function. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48859.     

The Protective Role of Prolyl Oligopeptidase (POP) Inhibition in Kidney Injury Induced by Renal Ischemia–Reperfusion

Ischemia/reperfusion injury (IRI) is a complex pathophysiological process characterized by blood circulation disorder caused by various factors, such as traumatic shock, surgery, organ transplantation, and thrombus. Severe metabolic dysregulation and tissue structure destruction are observed upon restoration of blood flow to the ischemic tissue. The kidney is a highly perfused organ, sensitive to ischemia and reperfusion injury, and the incidence of renal IRI has high morbidity and mortality. Several studies showed that infiltration of inflammatory cells, apoptosis, and angiogenesis are important mechanisms involved in renal IRI. Despite advances in research, effective therapies for renal IRI are lacking. Recently it has been demonstrated the role of KYP2047, a selective inhibitor of prolyl oligopeptidase (POP), in the regulation of inflammation, apoptosis, and angiogenesis. Thus, this research focused on the role of POP in kidney ischemia/reperfusion (KI/R). An in vivo model of KI/R was performed and mice were subjected to KYP2047 treatment (intraperitoneal, 0.5, 1 and 5 mg/kg). Histological analysis, Masson’s trichrome and periodic acid shift (PAS) staining, immunohistochemical and Western blots analysis, real-time PCR (RT-PCR) and ELISA were performed on kidney samples. Moreover, serum creatinine and blood urea nitrogen (BUN) were quantified. POP-inhibition by KYP2047 treatment, only at the doses of 1 and 5 mg/kg, significantly reduced renal injury and collagen amount, regulated inflammation through canonical and non-canonical NF-κB pathway, and restored renal function. Moreover, KYP2047 modulated angiogenesis markers, such as TGF-β and VEGF, also slowing down apoptosis. Interestingly, treatment with KYP2047 modulated PP2A activity. Thus, these findings clarified the role of POP inhibition in AKI, also offering novel therapeutic target for renal injury after KI/R.     

A viscoelastic approach from α-Al2O3 suspensions with high solids content

The flow properties of high solids concentration suspensions has been extensively studied and established, however, the rheological behavior for ceramics suspensions with very high solids loading, up to 60 vol.% is poorly known. This is due to both difficulties of preparation and behavior measurement. The theory shows ceramics suspensions with very high solids loading may present viscoelastic properties attributed to interparticle forces active. The oscillatory and creep-recovery rheological measurements can provide this knowledge when discretion used. Thus, rheological behavior of alumina suspensions with high solids loading (>43 vol.%), properly stabilized and the characterization of slip casting shaped samples has been analyzed. High solids loading suspensions, over 43 vol.%, present adequate flow and suspensions with solid content since 60 vol.% present viscoelastic properties attributed to interparticle forces active. The rheological parameters can provide subsidies to obtain after shaping process, such as extrusion, injection and plastic pressing, suitable products for the desired application.     

Understanding the foamability and mechanical properties of foamed polypropylene blends by using extensional rheology

In this article, the influence of the rheological behavior of miscible blends of a linear and a high melt strength, branched, polypropylene (HMS PP), on the cellular structure and mechanical properties of cellular materials, with a fixed relative density, has been investigated. The rheological properties of the PP melts were investigated in steady and oscillatory shear flow and in uniaxial elongation in order to calculate the strain hardening coefficient. While the linear PP does not exhibit strain hardening, the blends of the linear and the HMS PP show pronounced strain hardening, increasing with the concentration of HMS PP. Related to the cellular structure, in general, the amount of open cells, the cell size, and the width of the cell size distribution increase with the amount of linear PP in the blends. Also mechanical properties are conditioned by the extensional rheological behavior of PP blends. Cellular materials with the best mechanical properties are those that have been fabricated using large amounts of HMS PP. The results demonstrate the importance of the extensional rheological behavior of the base polymers for a better understanding and steering of the cellular structure and properties of the cellular materials. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42430.     

Surface modification of sepiolite particles with polyurethane and polyvinyl alcohol

Sepiolite is a clay mineral that has many industrial applications due to its advantageous properties such as white color, low specific gravity, high absorption capacity, chemical composition and low thermal conductivity. In this study, the effect of the addition of polymers, polyvinyl-alcohol and polyurethane, on the rheological properties of the sepiolite dispersions have been investigated. The rheological parameters of clay suspensions can be used to examine particle–particle interactions. The polymers that have been added to the clay suspensions interact with clay particles, depending on their ionic or non-ionic character. Firstly, the sepiolite dispersions were characterized by the rheological properties, mineral structure and content. Then the effect of the polymers on the flow, structural, and surface properties of sepiolite dispersions was investigated by rheological, electrokinetical, and scanning electron microscopy (SEM) measurements. The measurements showed that polymer molecules bind on the surface of sepiolite particles and changed the flow properties of the dispersions as stable dispersions at some certain concentrations. It is also determined that PU polymer covered the surface of the sepiolite faster than PVA, but the coverage of the PVA was much more smoothly. The thermal properties of the sepiolite improved with PVA more than PU, as a result of the homogenous surface coverage.     

Rheological phenomena in polymerization reactors: Rheological properties and flow patterns around agitators in polystyrene–styrene solutions

The rheological properties (viscosity and principal normal stress difference) of poly-styrene–styrene solutions at concentrations of 15, 20, 30, 35, 43, 50 and 57 wt-% have been measured at 60°C. The flow patterns around a sphere, disc, turbine, and screw propellers in such solutions have also been determined. The second-order fluid theory of viscoelastic fluids containing parameters determined from our rheological measurements has been used to predict the flow patterns about the sphere. The observed flow patterns are in good agreement with the theoretical predictions based upon externally measured rheological properties. The implications of this study of this behavior of batch and CSTR polymerization reactors are discussed.     

Melatonin and Glycine Reduce Uterus Ischemia/Reperfusion Injury in a Rat Model of Warm Ischemia

Ischemia/reperfusion injury (IRI) remains a significant problem to be solved in uterus transplantation (UTx). Melatonin and glycine have been shown to possess direct cytoprotective activities, mainly due to their antioxidative and anti-inflammatory properties. The aim of this study was to investigate the protective effects of melatonin and glycine and their combination on IRI in a rat model of warm ischemia. In this study, Sprague-Dawley rats were assigned to eight groups, including sham and IRI (n = 80). Melatonin and glycine alone or their combination were administered prior to 1 h of uterus ischemia followed by 1 h of reperfusion. Melatonin (50 mg/kg) was administered via gavage 2 h before IRI and glycine in an enriched diet for 5 days prior to intervention. Uterus IRI was estimated by histology, including immunohistochemistry, and biochemical tissue analyses. Histology revealed that uterus IRI was significantly attenuated by pretreatment with melatonin (p = 0.019) and glycine (p = 0.044) alone as well as their combination (p = 0.003). Uterus IRI led to increased myeloperoxidase expression, which was significantly reduced by melatonin (p = 0.004), glycine (p < 0.001) or their combination (p < 0.001). The decline in superoxide dismutase activity was significantly reduced in the melatonin (p = 0.027), glycine (p = 0.038) and combined treatment groups (p = 0.015) when compared to the IRI control group. In conclusion, melatonin, glycine and their combination significantly reduced oxidative stress-induced cell damage after IRI in a small animal warm ischemia model, and, therefore, clinical studies are required to evaluate the protective effects of these well-characterized substances in uterus IRI.     

Nano-Sized Extracellular Matrix Particles Lead to Therapeutic Improvement for Cutaneous Wound and Hindlimb Ischemia

Cell-derived matrix (CDM) has proven its therapeutic potential and been utilized as a promising resource in tissue regeneration. In this study, we prepared a human fibroblast-derived matrix (FDM) by decellularization of in vitro cultured cells and transformed the FDM into a nano-sized suspended formulation (sFDM) using ultrasonication. The sFDM was then homogeneously mixed with Pluronic F127 and hyaluronic acid (HA), to effectively administer sFDM into target sites. Both sFDM and sFDM containing hydrogel (PH/sFDM) were characterized via immunofluorescence, sol–gel transition, rheological analysis, and biochemical factors array. We found that PH/sFDM hydrogel has biocompatible, mechanically stable, injectable properties and can be easily administered into the external and internal target regions. sFDM itself holds diverse bioactive molecules. Interestingly, sFDM-containing serum-free media helped maintain the metabolic activity of endothelial cells significantly better than those in serum-free condition. PH/sFDM also promoted vascular endothelial growth factor (VEGF) secretion from monocytes in vitro. Moreover, when we evaluated therapeutic effects of PH/sFDM via the murine full-thickness skin wound model, regenerative potential of PH/sFDM was supported by epidermal thickness, significantly more neovessel formation, and enhanced mature collagen deposition. The hindlimb ischemia model also found some therapeutic improvements, as assessed by accelerated blood reperfusion and substantially diminished necrosis and fibrosis in the gastrocnemius and tibialis muscles. Together, based on sFDM holding a strong therapeutic potential, our engineered hydrogel (PH/sFDM) should be a promising candidate in tissue engineering and regenerative medicine.     

粘弹塑性流体田菁凝胶本构方程的研究

以石油开采过程中常用的田菁凝胶压裂液为体系,导出了一个描述粘弹塑性流体流变性质的积分型本构方程.通过稳态测粘流实验得到了方程的参数,并利用本构方程分析了小振幅振荡流和挤出胀大流.实验表明,方程计算值能够较好地与实验结果相吻合.同时,利用此本构方程对黄原胶、瓜胶的流变性质进行的分析表明,该方程也适用于这两种凝胶,具有一定的通用性.     

A new rheometer for direct measurement of the flow properties of coal ash at high temperatures

Development of more effective technologies of utilising low rank coals for power generation has been driven by a demand for higher efficiency, low capital costs and minimal environmental impacts. Fluidised bed systems are regarded as one of the more promising alternative technologies for power generation to overcome the disadvantage of the existing pulverised coal burning power generation plants for low rank coals. However, ash deposition and bed agglomeration are potential problems in fluidised bed processing of coals with high alkali and sulphur contents. In order to gain a better understanding of the mechanism of agglomeration in fluidised beds, a good knowledge of the rheological behaviour of coal ash deposits at high temperatures and under the processing conditions is necessary. Rheological characterisation of materials at high temperatures is difficult due to lack of standard instruments and reliable measurement techniques. We have recently developed a rheometer that has the capability of measuring the rheological properties of coal ash slag over a wide range of temperatures from 600 to 1300°C and under different processing atmospheres. In this paper the features of this unique instrument are described and the experimental technique developed for flow property measurement is outlined. Some typical measured rheological properties of coal ashes from different Australian low-rank coals are presented and discussed to illustrate the potential applicability of the rheometer for high-temperature rheological characterisation. Furthermore, by means of the experimental results obtained it is demonstrated that the alkali content of the coal ash plays a significant role in controlling the rheological characteristics of the ash deposit, which in turn has an important implication on agglomeration in fluidised bed combustion processes.     

Modulation of Prostanoids Profile and Counter-Regulation of SDF-1α/CXCR4 and VIP/VPAC2 Expression by Sitagliptin in Non-Diabetic Rat Model of Hepatic Ischemia-Reperfusion Injury

Molecular mechanisms underlying the beneficial effect of sitagliptin repurposed for hepatic ischemia-reperfusion injury (IRI) are poorly understood. We aimed to evaluate the impact of IRI and sitagliptin on the hepatic profile of eicosanoids (LC-MS/MS) and expression/concentration (RTqPCR/ELISA) of GLP-1/GLP-1R, SDF-1α/CXCR4 and VIP/VPAC1, VPAC2, and PAC1 in 36 rats. Animals were divided into four groups and subjected to ischemia (60 min) and reperfusion (24 h) with or without pretreatment with sitagliptin (5 mg/kg) (IR and SIR) or sham-operated with or without sitagliptin pretreatment (controls and sitagliptin). PGI₂, PGE₂, and 13,14-dihydro-PGE₁ were significantly upregulated in IR but not SIR, while sitagliptin upregulated PGD₂ and 15-deoxy-12,14-PGJ₂. IR and sitagliptin non-significantly upregulated GLP-1 while Glp1r expression was borderline detectable. VIP concentration and Vpac2 expression were downregulated in IR but not SIR, while Vpac1 was significantly downregulated solely in SIR. IRI upregulated both CXCR4 expression and concentration, and sitagliptin pretreatment abrogated receptor overexpression and downregulated Sdf1. In conclusion, hepatic IRI is accompanied by an elevation in proinflammatory prostanoids and overexpression of CXCR4, combined with downregulation of VIP/VPAC2. Beneficial effects of sitagliptin during hepatic IRI might be mediated by drug-induced normalization of proinflammatory prostanoids and upregulation of PGD₂ and by concomitant downregulation of SDF-1α/CXCR4 and reinstating VIP/VCAP2 signaling.     

Influence of shearing history on the rheological properties and processability of branched polymers. IV. Capillary flow and die swell of low-density polyethylene

Low-density polyethylene (LDPE) melts show anomalous rheological behavior; their viscoelastic properties vary with their shearing histories although their molecular structural parameters do not change. Capillary flow and die swell behavior were dependent not only on the experimental conditions such as temperature or shear stress but also on the processing index (PI), which was introduced in a preceding article in order to quantify the anomalous rheological behavior of LDPE melts. In addition, it was found that the flow activation energy at constant shear stress also varied with the shearing histories. The experimental findings are discussed in terms of the rheological flow units of LDPE melts.