Cellular preconditioning and mesenchymal stem cell ferroptosis

In this editorial,we comment on the article published in the recent issue of the World Journal of Stem Cells.They focus on stem cell preconditioning to prevent ferroptosis by modulating the cystathionineγ-lyase/hydrogen sulfide(H_(2)S)pathway as a novel approach to treat vascular disorders,particularly pulmonary hypertension.Preconditioned stem cells are gaining popularity in regenerative medicine due to their unique ability to survive by resisting the harsh,unfavorable microenvironment of the injured tissue.They also secrete various paracrine factors against apoptosis,necrosis,and ferroptosis to enhance cell survival.Ferroptosis,a regulated form of cell death characterized by iron accumulation and oxidative stress,has been implicated in various pathologies encompassing dege-nerative disorders to cancer.The lipid peroxidation cascade initiates and sustains ferroptosis,generating many reactive oxygen species that attack and damage multiple cellular structures.Understanding these intertwined mechanisms provi-des significant insights into developing therapeutic modalities for ferroptosis-related diseases.This editorial primarily discusses stem cell preconditioning in modulating ferroptosis,focusing on the cystathionase gamma/H_(2)S ferroptosis pathway.Ferroptosis presents a significant challenge in mesenchymal stem cell(MSC)-based therapies;hence,the emerging role of H_(2)S/cystathionase gamma/H_(2) S signaling in abrogating ferroptosis provides a novel option for therapeutic intervention.Further research into understanding the precise mechanisms of H_(2)S-mediated cytoprotection against ferroptosis is warranted to enhance the thera-peutic potential of MSCs in clinical settings,particularly vascular disorders.

Small extracellular vesicles from hypoxia-preconditioned bone marrow mesenchymal stem cells attenuate spinal cord injury via miR-146a-5p-mediated regulation of macrophage polarization

Spinal cord injury is a disabling condition with limited treatment options.Multiple studies have provided evidence suggesting that small extracellular vesicles(SEVs)secreted by bone marrow mesenchymal stem cells(MSCs)help mediate the beneficial effects conferred by MSC transplantation following spinal cord injury.Strikingly,hypoxia-preconditioned bone marrow mesenchymal stem cell-derived SEVs(HSEVs)exhibit increased therapeutic potency.We thus explored the role of HSEVs in macrophage immune regulation after spinal cord injury in rats and their significance in spinal cord repair.SEVs or HSEVs were isolated from bone marrow MSC supernatants by density gradient ultracentrifugation.HSEV administration to rats via tail vein injection after spinal cord injury reduced the lesion area and attenuated spinal cord inflammation.HSEVs regulate macrophage polarization towards the M2 phenotype in vivo and in vitro.Micro RNA sequencing and bioinformatics analyses of SEVs and HSEVs revealed that mi R-146a-5p is a potent mediator of macrophage polarization that targets interleukin-1 receptor-associated kinase 1.Reducing mi R-146a-5p expression in HSEVs partially attenuated macrophage polarization.Our data suggest that HSEVs attenuate spinal cord inflammation and injury in rats by transporting mi R-146a-5p,which alters macrophage polarization.This study provides new insights into the application of HSEVs as a therapeutic tool for spinal cord injury.

Hypoxia-preconditioned bone marrow-derived mesenchymal stem cells protect neurons from cardiac arrest-induced pyroptosis

Cardiac arrest can lead to severe neurological impairment as a result of inflammation,mitochondrial dysfunction,and post-cardiopulmonary resuscitation neurological damage.Hypoxic preconditioning has been shown to improve migration and survival of bone marrow–derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest,but the specific mechanisms by which hypoxia-preconditioned bone marrow–derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown.To this end,we established an in vitro co-culture model of bone marrow–derived mesenchymal stem cells and oxygen–glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis,possibly through inhibition of the MAPK and nuclear factor κB pathways.Subsequently,we transplanted hypoxia-preconditioned bone marrow–derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia.The results showed that hypoxia-preconditioned bone marrow–derived mesenchymal stem cells significantly reduced cardiac arrest–induced neuronal pyroptosis,oxidative stress,and mitochondrial damage,whereas knockdown of the liver isoform of phosphofructokinase in bone marrow–derived mesenchymal stem cells inhibited these effects.To conclude,hypoxia-preconditioned bone marrow–derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest,and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.

Hypoxia and inflammatory factor preconditioning enhances the immunosuppressive properties of human umbilical cord mesenchymal stem cells

BACKGROUND Mesenchymal stem cells(MSCs)have great potential for the treatment of various immune diseases due to their unique immunomodulatory properties.However,MSCs exposed to the harsh inflammatory environment of damaged tissue after intravenous transplantation cannot exert their biological effects,and therefore,their therapeutic efficacy is reduced.In this challenging context,an in vitro preconditioning method is necessary for the development of MSC-based therapies with increased immunomodulatory capacity and transplantation efficacy.AIM To determine whether hypoxia and inflammatory factor preconditioning increases the immunosuppressive properties of MSCs without affecting their biological characteristics.METHODS Umbilical cord MSCs(UC-MSCs)were pretreated with hypoxia(2%O_(2))exposure and inflammatory factors(interleukin-1β,tumor necrosis factor-α,interferon-γ)for 24 h.Flow cytometry,polymerase chain reaction,enzyme-linked immunosorbent assay and other experimental methods were used to evaluate the biological characteristics of pretreated UC-MSCs and to determine whether pretreatment affected the immunosuppressive ability of UC-MSCs in coculture with immune cells.RESULTS Pretreatment with hypoxia and inflammatory factors caused UC-MSCs to be elongated but did not affect their viability,proliferation or size.In addition,pretreatment significantly decreased the expression of coagulationrelated tissue factors but did not affect the expression of other surface markers.Similarly,mitochondrial function and integrity were retained.Although pretreatment promoted UC-MSC apoptosis and senescence,it increased the expression of genes and proteins related to immune regulation.Pretreatment increased peripheral blood mononuclear cell and natural killer(NK)cell proliferation rates and inhibited NK cell-induced toxicity to varying degrees.CONCLUSION In summary,hypoxia and inflammatory factor preconditioning led to higher immunosuppressive effects of MSCs without damaging their biological characteristics.

Semi-regularized Hermitian and Skew-Hermitian Splitting Preconditioning for Saddle-Point Linear Systems

In this paper,a two-step semi-regularized Hermitian and skew-Hermitian splitting(SHSS)iteration method is constructed by introducing a regularization matrix in the(1,1)-block of the first iteration step,to solve the saddle-point linear system.By carefully selecting two different regularization matrices,two kinds of SHSS preconditioners are proposed to accelerate the convergence rates of the Krylov subspace iteration methods.Theoretical analysis about the eigenvalue distribution demonstrates that the proposed SHSS preconditioners can make the eigenvalues of the corresponding preconditioned matrices be clustered around 1 and uniformly bounded away from 0.The eigenvector distribution and the upper bound on the degree of the minimal polynomial of the SHSS-preconditioned matrices indicate that the SHSS-preconditioned Krylov subspace iterative methods can converge to the true solution within finite steps in exact arithmetic.In addition,the numerical example derived from the optimal control problem shows that the SHSS preconditioners can significantly improve the convergence speeds of the Krylov subspace iteration methods,and their convergence rates are independent of the discrete mesh size.

Two-Parameter Block Triangular Splitting Preconditioner for Block Two-by-Two Linear Systems

This paper proposes a two-parameter block triangular splitting(TPTS)preconditioner for the general block two-by-two linear systems.The eigenvalues of the corresponding preconditioned matrix are proved to cluster around 0 or 1 under mild conditions.The limited numerical results show that the TPTS preconditioner is more efficient than the classic block-diagonal and block-triangular preconditioners when applied to the flexible generalized minimal residual(FGMRES)method.

Helmholtz Decomposition of Vector Fields Using an Optimal Preconditioned Conjugate Gradient Algorithm

In this article, we study numerically a Helmholtz decomposition methodology, based on a formulation of the mathematical model as a saddle-point problem. We use a preconditioned conjugate gradient algorithm, applied to an associated operator equation of elliptic type, to solve the problem. To solve the elliptic partial differential equations, we use a second order mixed finite element approximation for discretization. We show, using 2-D synthetic vector fields, that this approach, yields very accurate solutions at a low computational cost compared to traditional methods with the same order of approximation.

Conventional, but not remote ischemic preconditioning, reduces iNOS transcription in liver ischemia/reperfusion

AIM:To study the effects of preconditioning on inducible nitric oxide synthase(iNOS)and interleukin 1(IL-1)receptor transcription in rat liver ischemia/reperfusion injury(IRI).METHODS:Seventy-two male rats were randomized into 3 groups:the one-hour segmental ischemia(IRI,n=24)group,the ischemic preconditioning(IPC,n=24)group or the remote ischemic preconditioning(RIPC,n=24)group.The IPC and R-IPC were performed as 10 min of ischemia and 10 min of reperfusion.The iNOS and the IL-1 receptor mRNA in the liver tissue was analyzed with real time PCR.The total Nitrite and Nitrate(NOx)in continuously sampled microdialysate(MD)from the liver was analyzed.In addition,the NOx levels in the serum were analyzed.RESULTS:After 4 h of reperfusion,the iNOS mRNA was significantly higher in the R-IPC(ΔCt:3.44±0.57)group than in the IPC(ΔCt:5.86±0.82)group(P=0.025).The IL-1 receptor transcription activity was reduced in the IPC group(ΔCt:1.88±0.53 to 4.81±0.21),but not in the R-IPC group,during reperfusion(P=0.027).In the MD,a significant drop in the NOx levels was noted in the R-IPC group(12.3±2.2 to 4.7±1.2μmol/L)at the end of ischemia compared with the levels in early ischemia(P=0.008).A similar trend was observed in the IPC group(11.8±2.1 to 6.4±1.5μmol/L),although this difference was not statistically significant.The levels of NOx rose quickly during reperfusion in both groups.CONCLUSION:IPC,but not R-IPC,reduces iNOS and IL-1 receptor transcription during early reperfusion,indicating a lower inflammatory reaction.NOx is consumed in the ischemic liver lobe.

Some Properties of the Optimal Preconditioner and the Generalized Superoptimal Preconditioner

The optimal preconditioner and the superoptimal preconditioner were proposed in 1988 and 1992 respectively. They have been studied widely since then. Recently, Chen and Jin [6] extend the superoptimal preconditioner to a more general case by using the Moore-Penrose inverse. In this paper, we further study some useful properties of the optimal and the generalized superoptimal preconditioners. Several existing results are extended and new properties are developed.

Explicit Iterative Methods of Second Order and Approximate Inverse Preconditioners for Solving Complex Computational Problems

Explicit Exact and Approximate Inverse Preconditioners for solving complex linear systems are introduced. A class of general iterative methods of second order is presented and the selection of iterative parameters is discussed. The second order iterative methods behave quite similar to first order methods and the development of efficient preconditioners for solving the original linear system is a decisive factor for making the second order iterative methods superior to the first order iterative methods. Adaptive preconditioned Conjugate Gradient methods using explicit approximate preconditioners for solving efficiently large sparse systems of algebraic equations are also presented. The generalized Approximate Inverse Matrix techniques can be efficiently used in conjunction with explicit iterative schemes leading to effective composite semi-direct solution methods for solving large linear systems of algebraic equations.

On the Preconditioning Properties of RHSS Preconditioner for Saddle-Point Linear Systems

In this paper,for the regularized Hermitian and skew-Hermitian splitting(RHSS)preconditioner introduced by Bai and Benzi(BIT Numer Math 57:287–311,2017)for the solution of saddle-point linear systems,we analyze the spectral properties of the preconditioned matrix when the regularization matrix is a special Hermitian positive semidefinite matrix which depends on certain parameters.We accurately describe the numbers of eigenvalues clustered at(0,0)and(2,0),if the iteration parameter is close to 0.An estimate about the condition number of the corresponding eigenvector matrix,which partly determines the convergence rate of the RHSS-preconditioned Krylov subspace method,is also studied in this work.

Acupuncture preconditioning protects hippocampal neurons from transient ischemia/reperfusion injury

The present study established a model of brain ischemia in aged rats using four-vessel occlusion.We observed hippocampal CA1 neuronal apoptosis and apoptosis-mediated protease caspase-3 expression following preconditioning of electroacupuncture at Baihui（GV 20）.Our results showed that the number of hippocampal CA1 normal neurons was decreased,and degenerated neurons were increased 12 hours to 3 days following cerebral ischemia/reperfusion.The number of hippocampal CA1 apoptotic neurons and caspase-3-positive neurons in rats with cerebral ischemia/reperfusion injury was significantly decreased following acupuncture preconditioning.Acupuncture preconditioning protects aged rats against ischemia/reperfusion injury by regulating caspase-3 protein expression.

Hypoxic preconditioning stimulates angiogenesis in ischemic penumbra after acute cerebral infarction

Previous studies have demonstrated the protective effect of hypoxic preconditioning on acute cerebral infarction, but the mechanisms underlying this protection remain unclear. To investigate the protective mechanisms of hypoxic preconditioning in relation to its effects on angiogenesis, we in- duced a photochemical model of cerebral infarction in an inbred line of mice （BALB/c）. Mice were then exposed to hypoxic preconditioning 30 minutes prior to model establishment. Results showed significantly increased vascular endothelial growth factor and CD31 expression in the ischemic penumbra at 24 and 72 hours post infarction, mainly in neurons and vascular endothelial cells. Hypoxic preconditioning increased vascular endothelial growth factor and CD31 expression in the ischemic penumbra and the expression of vascular endothelial growth factor was positively related to that of CD31. Moreover, hypoxic preconditioning reduced the infarct volume and improved neu- rological function in mice. These findings indicate that the protective role of hypoxic preconditioning in acute cerebral infarction may possibly be due to an increase in expression of vascular endothelial growth factor and CD31 in the ischemic penumbra, which promoted angiogenesis.

Impact of hypoxic preconditioning on apoptosis and its possible mechanism in orthotopic liver autotransplantation in rats

BACKGROUND: Hepatocyte apoptosis is a severe form of cell death after hepatic ischemia-reperfusion injury (HIRI), and its relief is an important issue in liver transplantation. Hypoxic preconditioning (HP) is considered to have protective effects on HIRI. This study was designed to explore the impact of HP on apoptosis and its possible mechanism during orthotopic liver autotransplantation. METHODS: A modified orthotopic liver autotransplantation model was used to simulate HIRI. Sprague-Dawley rats were randomly divided into normal control, autotransplantation (AT) and HP groups. The HP group was subjected to an 8% oxygen atmosphere for 90 minutes before surgery. At 1, 6 and 24 hours after surgery, the rats were killed and their liver tissue was sampled to assess the expression of Bcl-2 protein. The samples were subjected to blood chemistry study, morphological study under a light or transmission electron microscope, and quantitative study of mitochondria. RESULTS: The serum levels of ALT and AST in the HP group were lower than those in the AT group at 1, 6 and 24 hours after orthotopic liver autotransplantation (P < 0.05). Bcl-2 protein expression was increased in the HP group at each measurement point (P < 0.05). Light microscopy showed that hepatic injury in the AT group was much more severe than in the HP group. Hepatocytes in the AT group showed typical apoptosis signs under a transmission electron microscope. The ultrastructural appearance of hepatocytes in the HP group was much better than in the AT group, and the area, perimeter and diameter of the mitochondria were smaller in the HP group than in the AT group (P < 0.05). CONCLUSIONS: Hepatocytes sense and respond to decreased tissue oxygenation. Stimulation by HP relieves apoptosis by upregulating expression of Bcl-2 protein and its protection of mitochondria after orthotopic liver autotransplantation.

Preconditioning and postconditioning reduce hepatic ischemia-reperfusion injury in rats

BACKGROUND: Ischemia-reperfusion injury occurs when ischemic tissues or organs suffer from further functional and structural damage when their blood supply recovers. This study aimed to contrast the protective effects of ischemic preconditioning and ischemic postconditioning in hepatic ischemia-reperfusion injury in rats. METHODS: Thirty-two healthy male Wistar rats were randomly divided into four groups: sham-operated (SO), ischemia-reperfusion (IR), ischemic preconditioning (I-pre), and ischemic postconditioning (I-post). Blood samples and hepatic tissue were taken from all groups after the experiments. RESULTS: There were significant differences between the IR, I-pre and I-post groups in alanine aminotransferase and aspartate aminotransferase levels, NF-kappa B p65 expression, apoptosis index and superoxide dismutase activity in hepatic tissue. There were no significant differences between the I-pre and I-post groups. CONCLUSIONS: Ischemic postconditioning and ischemic preconditioning reduce hepatic ischemia-reperfusion injury, but in clinical practice the former is a more appropriate choice.

Ischemic preconditioning-induced hyperperfusion correlates with hepatoprotection after liver resection

AIM:To characterize the impact of the Pringle ma-neuver (PM) and ischemic preconditioning (IP) on total blood supply to the liver following hepatectomies. METHODS: Sixty one consecutive patients who un-derwent hepatic resection under in flow occlusion were randomized either to receive PM alone (n = 31) or IP (10 min of ischemia followed by 10 min of reperfusion) prior to PM (n = 30). Quantification of liver perfusion was measured by Doppler probes at the hepatic artery and portal vein at various time points after reperfusion of remnant livers. RESULTS: Occlusion times of 33 ± 12 min (mean ± SD) and 34 ± 14 min and the extent of resected liver tissue (2.7 segments) were similar in both groups. In controls (PM), on reperfusion of liver remnants for 15 min, portal perfusion markedly decreased by 29% while there was a slight increase of 8% in the arterial blood flow. In contrast, following IP + PM the portal vein flow remained unchanged during reperfusion and a significantly increased arterial blood flow (+56% vs baseline) was observed. In accordance with a better postischemic blood supply of the liver, hepatocellular injury, as measured by alanine aminotransferase (ALT) levels on day 1 was considerably lower in group B compared to group A (247 ± 210 U/I vs 550 ± 650 U/I, P < 0.05). Additionally, ALT levels were significantly correlated to the hepatic artery in flow.CONCLUSION: IP prevents postischemic flow reduction of the portal vein and simultaneously increases arterial perfusion, suggesting that improved hepatic macrocirculation is a protective mechanism following hepatectomy.

A Preconditioned Multigrid Method for Efficient Simulation of Three-dimensional Compressible and Incompressible Flows

To develop an efficient and robust aerodynamic analysis method for numerical optimization designs of wing and complex configuration, a combination of matrix preconditioning and multigrid method is presented and investigated. The time derivatives of three-dimensional Navier-Stokes equations are preconditioned by Choi-Merkle preconditioning matrix that is originally designed for two-dimensional low Mach number viscous flows. An extension to three-dimensional viscous flow is implemented, and a method improving the convergence for transonic flow is proposed. The space discretizaition is performed by employing a finite-volume cell-centered scheme and using a central difference. The time marching is based on an explicit Rtmge-Kutta scheme proposed by Jameson. An efficient FAS multigrid method is used to accelerate the convergence to steady-state solutions. Viscous flows over ONERA M6 wing and M100 wing are numerically simulated with Mach numbers ranging from 0.010 to 0.839. The inviscid flow over the DLR-F4 wing-body configuration is also calculated to preliminarily examine the performance of the presented method for complex configuration. The computed results are compared with the experimental data and good agreement is achieved. It is shown that the presented method is efficient and robust for both compressible and incompressible flows and is very attractive for aerodynamic optimization designs of wing and complex configuration.

The effect of ischemic precondition to IL-6 on rat liver ischemiareperfusion injury in transplantation

Objective:To investigate the effect of ischemic precondition to protect ischemia-reperfusion injury and reduce IL-6 expression in the rats liver transplantation.Methods:The rat portal vein infusion of autologous liver transplantation model were used.The rats were divided into ischemic preconditioning rats liver transplantation group(A group),the rats liver transplantation group(B group) and the normal rat control group(C group).Then we analyzed the changes of liver function,liver microstructure and the expression of IL-6,SOD and MDA within 48 h.Results: The pathology of liver in group A showed lobular architecture essentially normal,the liver cells was slightly swell and no significant changes in postoperative 12 h.In transmission electron microscope(46 000X).the mitochondria of liver cells in group A i】ecame swelling,elliptical can cristae partially broken.But there still has a small amount of arrangement.While that in group, the mitochondria were swollen,became round,serious visible crest reduce or ruptured.The result of over function test showed that the serum ALT and AST levels in group A and B were both higher than that in group C at each time period,but the serum ALT and AST levels in group A were lower than that in group B.The expression changes of IL-6 in group B were higher than that in group A and R(P【0.05).The expression of MDA in group A is more obvious than that in group B(P【0.05).Conclusions:Ischemic precondition could alleviate part of ischemia-reperfusion injury in the rat liver transplantation,and also could reduce IL-6 expression to protect the liver cells against liver damage and inflammatory cytokine production.

Construction and Analysis of Structured Preconditioners for Block Two-by-Two Matrices

For the large sparse block two-by-two real nonsingular matrices, we establish a general framework of structured preconditioners through matrix transformation and matrix approximations. For the specific versions such as modified block Jacobi-type, modified block Gauss-Seidel-type, and modified block unsymmetric (symmetric) Gauss-Seidel-type preconditioners, we precisely describe their concrete expressions and deliberately analyze eigenvalue distributions and positive definiteness of the preconditioned matrices. Also, we show that when these structured preconditioners are employed to precondition the Krylov subspace methods such as GMRES and restarted GMRES, fast and effective iteration solvers can be obtained for the large sparse systems of linear equations with block two-by-two coefficient matrices. In particular, these structured preconditioners can lead to high-quality preconditioning matrices for some typical matrices from the real-world applications.

Neuroprotective effect of ischemic preconditioning in focal cerebral infarction: relationship with upregulation of vascular endothelial growth factor

Neuroprotection by ischemic preconditioning has been confirmed by many studies, but the precise mechanism remains unclear. In the present study, we performed cerebral ischemic pre- conditioning in rats by simulating a transient ischemic attack twice （each a 20-minute occlusion of the middle cerebral artery） before inducing focal cerebral infarction （2 hour occlusion-reper- fusion in the same artery）. We also explored the mechanism underlying the neuroprotective effect of ischemic preconditioning. Seven days after ocdusion-reperfusion, tetrazolium chloride staining and immunohistochemistry revealed that the infarct volume was significantly smaller in the group that underwent preconditioning than in the model group. Furthermore, vascular endothelial growth factor immunoreactivity was considerably greater in the hippocampal CA3 region of preconditioned rats than model rats. Our results suggest that the protective effects of ischemic preconditioning on focal cerebral infarction are associated with upregulation of vascu- lar endothelial growth factor.