Treatment with β-sitosterol ameliorates the effects of cerebral ischemia/reperfusion injury by suppressing cholesterol overload, endoplasmic reticulum stress, and apoptosis

β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unknown whetherβ-sitosterol treatment reduces the effects of ischemic stroke.Here we found that,in a mouse model of ischemic stroke induced by middle cerebral artery occlusion,β-sitosterol reduced the volume of cerebral infarction and brain edema,reduced neuronal apoptosis in brain tissue,and alleviated neurological dysfunction;moreover,β-sitosterol increased the activity of oxygen-and glucose-deprived cerebral cortex neurons and reduced apoptosis.Further investigation showed that the neuroprotective effects ofβ-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke.In addition,β-sitosterol showed high affinity for NPC1L1,a key transporter of cholesterol,and antagonized its activity.In conclusion,β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.

PDZK1 protects against mechanical overload-induced chondrocyte senescence and osteoarthritis by targeting mitochondrial function

Mechanical overloading and aging are two essential factors for osteoarthritis(OA)development.Mitochondria have been identified as a mechano-transducer situated between extracellular mechanical signals and chondrocyte biology,but their roles and the associated mechanisms in mechanical stress-associated chondrocyte senescence and OA have not been elucidated.

Investigations of the mechanical response of dummy HTPB propellant grain under ultrahigh acceleration overload conditions using onboard flight-test measurements

In this paper,to study the mechanical responses of a solid propellant subjected to ultrahigh acceleration overload during the gun-launch process,specifically designed projectile flight tests with an onboard measurement system were performed.Two projectiles containing dummy HTPB propellant grains were successfully recovered after the flight tests with an ultrahigh acceleration overload value of 8100 g.The onboard-measured time-resolved axial displacement,contact stress and overload values were successfully obtained and analysed.Uniaxial compression tests of the dummy HTPB propellant used in the gunlaunched tests were carried out at low and intermediate strain rates to characterize the propellant's dynamic properties.A linear viscoelastic constitutive model was employed and applied in finite-element simulations of the projectile-launching process.During the launch process,the dummy propellant grain exhibited large deformation due to the high acceleration overload,possibly leading to friction between the motor case and propellant grain.The calculated contact stress showed good agreement with the experimental results,though discrepancies in the overall displacement of the dummy propellant grain were observed.The dynamic mechanical response process of the dummy propellant grain was analysed in detail.The results can be used to estimate the structural integrity of the analysed dummy propellant grain during the gun-launch process.

SiO_(2) Induces Iron Overload and Ferroptosis in Cardiomyocytes in a Silicosis Mouse Model

Objective The aim of this study was to explore the role and mechanism of ferroptosis in SiO_(2)-induced cardiac injury using a mouse model.Methods Male C57BL/6 mice were intratracheally instilled with SiO_(2) to create a silicosis model.Ferrostatin-1(Fer-1)and deferoxamine(DFO)were used to suppress ferroptosis.Serum biomarkers,oxidative stress markers,histopathology,iron content,and the expression of ferroptosis-related proteins were assessed.Results SiO_(2) altered serum cardiac injury biomarkers,oxidative stress,iron accumulation,and ferroptosis markers in myocardial tissue.Fer-1 and DFO reduced lipid peroxidation and iron overload,and alleviated SiO_(2)-induced mitochondrial damage and myocardial injury.SiO_(2) inhibited Nuclear factor erythroid 2-related factor 2(Nrf2)and its downstream antioxidant genes,while Fer-1 more potently reactivated Nrf2 compared to DFO.Conclusion Iron overload-induced ferroptosis contributes to SiO_(2)-induced cardiac injury.Targeting ferroptosis by reducing iron accumulation or inhibiting lipid peroxidation protects against SiO_(2) cardiotoxicity,potentially via modulation of the Nrf2 pathway.

Repressing iron overload ameliorates central poststroke pain via the Hdac2-Kv1.2 axis in a rat model of hemorrhagic stroke

Thalamic hemorrhage can lead to the development of central post-stroke pain.Changes in histone acetylation levels,which are regulated by histone deacetylases,affect the excitability of neurons surrounding the hemorrhagic area.However,the regulato ry mechanism of histone deacetylases in central post-stroke pain remains unclea r.Here,we show that iron overload leads to an increase in histone deacetylase 2expression in damaged ventral posterolateral nucleus neurons.Inhibiting this increase restored histone H3 acetylation in the Kcna2 promoter region of the voltage-dependent potassium(Kv)channel subunit gene in a rat model of central post-stroke pain,thereby increasing Kcna2expression and relieving central pain.However,in the absence of nerve injury,increasing histone deacetylase 2 expression decreased Kcna2expression,decreased Kv current,increased the excitability of neurons in the ventral posterolateral nucleus area,and led to neuropathic pain symptoms.Moreover,treatment with the iron chelator deferiprone effectively reduced iron overload in the ventral posterolateral nucleus after intracerebral hemorrhage,reversed histone deacetylase 2 upregulation and Kv1.2 downregulation,and alleviated mechanical hypersensitivity in central post-stroke pain rats.These results suggest that histone deacetylase 2 upregulation and Kv1.2 downregulation,mediated by iron overload,are important factors in central post-stroke pain pathogenesis and co uld se rve as new to rgets for central poststroke pain treatment.

Numerical Simulation-Based Analysis of the Impact of Overloading on Segmentally Assembled Bridges

Segmentally assembled bridges are increasinglyfinding engineering applications in recent years due to their unique advantages,especially as urban viaducts.Vehicle loads are one of the most important variable loads acting on bridge structures.Accordingly,the influence of overloaded vehicles on existing assembled bridge structures is an urgent concern at present.This paper establishes thefinite element model of the segmentally assembled bridge based on ABAQUS software and analyzes the influence of vehicle overload on an assembled girder bridge struc-ture.First,afinite element model corresponding to the target bridge is established based on ABAQUS software,and the load is controlled to simulate vehicle movement in each area of the traveling zone at different times.Sec-ond,the key cross-sections of segmental girder bridges are monitored in real time based on the force character-istics of continuous girder bridges,and they are compared with the simulation results.Finally,a material damage ontology model is introduced,and the structural damage caused by different overloading rates is compared and analyzed.Results show that thefinite element modeling method is accurate by comparing with on-site measured data,and it is suitable for the numerical simulation of segmental girder bridges;Dynamic sensors installed at 1/4L,1/2L,and 3/4L of the segmental girder main beams could be used to identify the dynamic response of segmental girder bridges;The bottom plate of the segmental girder bridge is mostly damaged at the position where the length of the precast beam section changes and the midspan position.With the increase in load,damage in the direction of the bridge develops faster than that in the direction of the transverse bridge.Thefindings of this study can guide maintenance departments in the management and maintenance of bridges and vehicles.

GNSS array receiver faced with overloaded interferences:anti-jamming performance and the incident directions of interferences

Anti-jamming solutions based on antenna arrays enhance the anti-jamming ability and the robustness of global navigation satellite system(GNSS)receiver remarkably.However,the performance of the receiver will deteriorate significantly in the overloaded interferences scenario.We define the overloaded interferences scenario as where the number of interferences is more than or equal to the number of antenna arrays elements.In this paper,the effect mechanism of interferences with different incident directions is found by studying the anti-jamming performance of the adaptive space filter.The theoretical analysis and conclusions,which are first validated through numerical examples,reveal the relationships between the optimal weight vector and the eigenvectors of the input signal autocorrelation matrix,the relationships between the interference cancellation ratio(ICR),the signal to interference and noise power ratio(SINR)of the adaptive space filter output and the number of interferences,the eigenvalues of the input signal autocorrelation matrix.In addition,two simulation experiments are utilized to further corroborate the theoretical findings through soft anti-jamming receiver.The simulation results match well with the theoretical analysis results,thus validating the effect mechanism of overloaded interferences.The simulation results show that,for a four elements circular array,the performance difference is up to 19 dB with different incident directions of interferences.Anti-jamming performance evaluation and jamming deployment optimization can obtain more accurate and efficient results by using the conclusions.

Correction of dynamic Brazilian disc tensile strength of rocks under preloading conditions considering the overload phenomenon and invoking the Griffith criterion

Dynamic tensile failure is a common phenomenon in deep rock practices,and thus accurately evaluating the dynamic tensile responses of rocks under triaxial pressures is of great significance.The Brazilian disc(BD)test is the suggested method by the International Society for Rock Mechanics and Rock Engineering(ISRM)for measuring both the static and dynamic tensile strengths of rock-like materials.However,due to the overload phenomenon and the complex preloading conditions,the dynamic tensile strengths of rocks measured by the BD tests tend to be overestimated.To address this issue,the dynamic BD tensile strength(BTS)of Fangshan marble(FM)under different preloading conditions were measured through a triaxial split Hopkinson pressure bar(SHPB).The fracture onset in BD specimen was captured through a strain gage around the disc center.The discrepancy between the traditional tensile strength(TTS,determined by the peak load P_(f) of the BD specimen)and the nominal tensile strength(NTS,obtained from the load P_(i) when the diametral fracture commences in the tested BD specimen)was applied to quantitatively evaluating the overload phenomenon.The Griffith criterion was used to rectify the calculation of the tensile stress at the disc center under triaxial stress states.The results demonstrate that the overload ratio(s)increases with the loading rate(σ)and decreases with the hydrostatic pressure(σ_(s)).The TTS corrected by the Griffith criterion is independent of theσ_(s)due to the overload phenomenon,while the NTS corrected by the Griffith criterion is sensitive to both the andσ.Therefore,it is essential to modify the tensile stress in dynamic confined BD tests using both the overload correction and the Griffith criterion rectification to obtain the accurate dynamic BTS of rocks.

Curcumin attenuates iron-overloaded stress to macrophages via up-regulation of SOD and Nrf2

Background:It is known to all that iron overload is a fatal adverse effect on cells and tissue.Herein,our study aimed to investigate the effects of curcumin on iron-overloaded stress in macrophages.Methods:Ferric ammonium citrate was added to the macrophage cell line(RAW264.7)to establish an iron-overloaded macrophage model.Cell counting kit 8 assay was used to detect cell viability.Superoxide dismutase,reactive oxygen species,malondialdehyde,and apoptosis were performed to analyze the severity of cellular oxidative damage.In addition,quantitative real-time polymerase chain reaction and western blot were used to detect the expression of nuclear factor erythroid 2-related factor 2.Results:The result showed that iron overload of macrophage was visualized by incubating in 40μM ferric ammonium citrate for 24 h.The curcumin significantly reversed the iron overload-induced apoptotic cells at low(10μM)and middle(20μM)concentrations.Additionally,the levels of malondialdehyde and reactive oxygen species activity in the groups of curcumin at low(10μM)and middle(20μM)concentrations were significantly decreased,while superoxide dismutase activity was obviously increased compared with that of the ferric ammonium citrate group alone.Finally,we found that low(10μM)and middle(20μM)dose curcumin up-regulated nuclear factor erythroid 2-related factor 2 expression at mRNA and protein levels compared with the ferric ammonium citrate group alone.Conclusion:Curcumin reduces iron-overloaded stress in macrophages by activating nuclear factor erythroid 2-related factor 2 and enhancing the superoxide dismutase activity,thereby protecting cell apoptosis.

Overloading of Landing Based on the Deformation of the Lunar Lander

Along with the progress of sciences and technologies, a lot of explorations are taken in many countries or organizations in succession. Lunar, the natural satellite of the earth, become a focus of the space discovery again recently because of its abundant resource and high value in use. Lunar exploration is also one of the most important projects in China. A primary objective of the probe in lunar is to soft-land a manned spacecraft on the lunar surface. The soft-landing system is the key composition of the lunar lander. In the overall design of lunar lander, the analysis of touchdown dynamics during landing stage is an important work. The rigid-flexible coupling dynamics of a system with flexible cantilevers attached to the main lander is analyzed. The equations are derived from the subsystem method. Results show that the deformations of cantilevers have considerable effect on the overloading of the lunar lander system.

Overloading and Pavement Service Life <br/>—A Case Study on Narayanghat-Mugling Road, Nepal

The ability of a pavement structure in carrying out its function reduces in line with the increase of traffic load, especially if there are overloaded heavy vehicle passing through the road. This study was done to know the effect of overloading vehicles on the road pavement and remaining service life of the pavement. In this study, the service life of pavement due to overloaded vehicles was analyzed using the AASHTO 1993. In Narayanghat-Mugling road the composition of traffic seems to be 83.76% heavy vehicles, 9.18% medium vehicle and 7.05% light vehicle. For the direction of Narayanghat-Mugling, the pavement service life might be reduced by 59.90% due to overloading condition, while for the opposite direction, the service life would not reduced caused by the same factor. The impact of overload conditions on the road pavement showed premature failure;that is, a condition which the damage reduced the life of roads before the design life of the road is reached. From the results, it can be concluded that overloaded vehicles on the road are very influential to the reduction in pavement service life. Therefore, it is expected that road users to comply with existing regulations in the conduct of transportation. As overloading is increasing, it has to be controlled by rules and regulations with penalty to control the overloading. So fines must be associated with intensified enforcement when considered in further strategy. Regular monitoring, inspection and enforcement are the effective ways to control overloading. Use of technology (Automatic overloading information system) may be the effective way to control the overloading.

Evolution of the Deflection According to Truck Overloading—Comparison between Benkelman Beam Method and FEM of Lateritic Pavements

The study of the deflection due to the passage of an axle on a pavement structure has the advantage to make possible to pronounce on the portance, the rigidity and the homogeneity of this one. In the case where the allowed axle load is not respected, surface deflection leads to premature deterioration of the roadway. In order to study the evolution of these deformations, deflection measurements were made by using the Benkelman method in the Fatick-Kaolack road in Senegal by varying the axle load with the following values: 10, 13 and 16 tons on three different zones. The results show a linear evolution of the deflection as a function of the axle load. Also, the impact of truck overloading was studied by considering different values of the axle load with comparison to the allowed axle load by using frequent types of vehicle. A numerical simulation of the Cast3M pavement was done first, in the case of an isolated single wheel with a radius of 12.5 cm, then in the case of an equivalent dual wheel with a radius of 18.1 cm for loads of 10 to 19 tons. In the same way, the pavement design software (ALIZE) is used to analyse the variation of the axle load. The results show a linear evolution of the deflection, which corroborates the measurements made in the field and those obtained by Samb (2014) with a slope coefficient equal to 1.7. Nevertheless, the case of an isolated single wheel of 12.5 cm radius is closest to the measurements with a straight line of slope coefficient equal to 1.9.

Compound of icariin,astragalus,and puerarin mitigates iron overload in the cerebral cortex of Alzheimer＇s disease mice

Increasing evidence indicates that disruption of normal iron homeostasis may contribute to pathological development of Alzheimer＇s disease.Icariin,astragalus,and puerarin have been shown to suppress iron overload in the cerebral cortex and improve spatial learning and memory disorders in Alzheimer＇s disease mice,although the underlying mechanism remains unclear.In the present study,APPswe/PS1ΔE9 transgenic mice were administered icariin,astragalus,and puerarin（120,80,and 80 mg/kg,respectively,once a day,for 3 months）.Iron levels were detected by flame atomic absorption spectroscopy.Interleukin-1β,interleukin-6,and tumor necrosis factor-α levels were measured in the cerebral cortex by enzyme linked immunosorbent assay.Glutathione peroxidase and superoxide dismutase activity and malondialdehyde content were determined by colorimetry.Our results demonstrate that after treatment,iron levels and malondialdehyde content are decreased,while glutathione peroxidase and superoxide dismutase activities are increased.Further,interleukin-1β,interleukin-6,and tumor necrosis factor-α levels were reduced.These results confirm that compounds of icariin,astragalus,and puerarin may alleviate iron overload by reducing oxidative stress and the inflammatory response.

Molecular pathogenesis and clinical conse-quences of iron overload in liver cirrhosis

BACKGROUND: The liver, as the main iron storage compart-ment and the place of hepcidin synthesis, is the central organ involved in maintaining iron homeostasis in the body. Exces-sive accumulation of iron is an important risk factor in liver disease progression to cirrhosis and hepatocellular carcinoma. Here, we review the literature on the molecular pathogenesis of iron overload and its clinical consequences in chronic liver diseases. DATA SOURCES: PubMed was searched for English-language articles on molecular genesis of primary and secondary iron overload, as well as on their association with liver disease pro-gression. We have also included literature on adjuvant thera-peutic interventions aiming to alleviate detrimental effects of excessive body iron load in liver cirrhosis. RESULTS: Excess of free, unbound iron induces oxidative stress, increases cell sensitivity to other detrimental factors, and can directly affect cellular signaling pathways, resulting in accelerated liver disease progression. Diagnosis of liver cirrhosis is, in turn, often associated with the identiifcation of a pathological accumulation of iron, even in the absence of genetic background of hereditary hemochromatosis. Iron depletion and adjuvant therapy with antioxidants are shown to cause signiifcant improvement of liver functions in patients with iron overload. Phlebotomy can have beneifcial effects on liver histology in patients with excessive iron accumulation combined with compensated liver cirrhosis of different etiology. CONCLUSION: Excessive accumulation of body iron in liver cirrhosis is an important predictor of liver failure and avail-able data suggest that it can be considered as target for adju-vant therapy in this condition.

Physiology of natriuretic peptides: The volume overload hypothesis revisited

The discovery of the natriuretic peptide system in the early 1980s aroused great interest among clinical cardiologists. The heart was not a mechanical pump alone, but also an endocrine organ that had powerful effects on blood circulation. Natriuretic peptides caused both natriuresis and diuresis, and they responded to a volume overload which caused either stretch or pressure on the heart. As a result, the findings led to the conclusion that the human body had a hormone with effects similar to those of a drug which treats high blood pressure. Later, it became evident that the volume contraction was fortified by extrarenal plasma shift. Here, a hypothesis is presented in which the role of natriuretic peptides is to regulate oxygen transport as the volume contraction leads to hemoconcentration with an increased oxygen-carrying capacity. Wall stress, either chemical or mechanical, changes the oxygen gradient of the myocardium and affects the diffusion of oxygen within a myocyte. In support of this hypothesis, hypoxia-response elements have been found in both the atrial natriuretic peptide and the brain natriuretic peptide genes.

Research on the overload protection reliability of moulded case circuit-breakers and its test device

This paper analyzed the reliability and put forward the reliability index of overload protection for moulded case circuit breaker. The success rate was adopted as its reliability index of overload protection. Based on the reliability index and the reli- ability level, the reliability examination plan was analyzed and a test device for the overload protection of moulded case cir- cuit-breaker was developed. In the reliability test of overload protection, two power sources were used, which reduced the time of conversion and regulation between two different test currents in the overload protection test, which made the characteristic test more accurate. The test device was designed on the base of a Windows system, which made its operation simple and friendly.

Nonalcoholic steatohepatitis in Asian Indians is neither associated with iron overload nor with HFE gene mutations

AIM: The pathogenesis of occurrence of liver inflammation and fibrosis in patients with nonalcoholic steatohepatitis (NASH) is not completely understood. Other than insulin resistance, iron abnormalities have been thought to be one of the triggering factors. Therefore, our aim was to study the role of iron abnormalities and HFE gene mutations in patients with NASH. METHODS: Thirty-one patients of NASH diagnosed on the basis of clinical examination biochemistry, ultrasonography and liver biopsy (n = 14) were included in the study. Serum iron parameters (n = 23) (iron, ferritin, total iron-binding capacity and transferrin saturation), Perls' iron staining on liver biopsies (n = 14) and HFE gene mutations (C282Y and H63D) (n = 16) were studied in these patients. The association between iron staining, necroinflammatory activity and fibrosis stage on liver biopsies was also determined. RESULTS: Elevated serum iron, ferritin and transferrin saturation above 55% were observed in 4.3% of patients. On histology, 71% of the patients had negative iron staining, 21.4% had 1+ staining, 7.2% had 2+ staining and none had 3+ or 4+ staining. There was no association between the degree of iron staining and necroinflammatory activity (P=0.55) and fibrosis stage (P= 0.09) on histology. None of the patients had C282Y HFE gene mutation and four patients (25%) were found to be heterozygotes for H63D gene mutation. CONCLUSION: Our study does not favor iron overload and HFE gene mutations as major factors in the pathogenesis of NASH in Asian Indians.

Effects of combination of irbesartan and perindopril on calcineurin expression and sarcoplasmic reticulum Ca^(2+)-ATPase activity in rat cardiac pressure-overload hypertrophy

Aim： To observe effects of angiotensin （Ang） II receptor antagonist （ATI） irbesartan and angiotensin-converting enzyme （ACE） inhibitor perindopril on rat myocardium calcineurin expression and sarcoplasmic reticulum Ca^2＋-ATPase activity in the model of pressure-overload cardiac hypertrophy. Methods： Forty male adult Sprague Dawley rats were divided into 5 groups One group was treated by sham operation; four groups were myocardium hypertrophy cases caused by banding aortic above renal artery. Drugs were given one week after operation. Group 1： sham group, rats （n=8） were gavaged with normal saline 2 ml/（kg·d） （ig）; Group 2： control group, rats （n=8） were treated with normal saline 2 ml/（kg·d） （ig）; Group 3： rats （n=8） were given perindopril 2 mg/（kg·d） （ig）; Group 4： rats （n=8） were treated with irbesartan 20 mg/（kg·d） （ig）; Group 5： rats （n=8） were given irbesartan 20 mg/（kg·d） plus perindopril 2 mg/（kg·d） （ig）. Morphometric determination, calcineurin expression and sarcoplasmic reticulum Ca^2＋-ATPase activity were done at the end of 6 week of drug intervention. Expression of calcineurin in myocardium was detected by immunohistochemistry. Results： Left ventricular mass index （LVMI）, transverse diameter of myocardial cell （TDM）, calcineurin activity were remarkably decreased after drug intervention and this decrease was most remarkable in the combination drug therapy group. Sarcoplasmic reticulum Ca^2＋-ATPase activity was increased after drug intervention, especially in the combined drug therapy group. Calcineurin expression in myocardium was remarkably decreased after drug intervention. LVMI was positively correlated with TDM and calcineurin, negatively correlated with sarcoplasmic reticulum Ca^2＋-ATPase. Conclusion： These data suggest that irbesartan and perindopril inhibit cardiac hypertrophy through the increased activity of sarcoplasmic reticulum Ca^2＋-ATPase and decreased expression of calcineurin. Their combination had better effects on regressing of ventricular hypertrophy.

Effect of iron overload on electrophysiology of slow reaction autorhythmic cells of left ventricular outflow tract in guinea pigs

Objective: To investigate the electrophysiology effects and mechanism of iron overload on the slow response autorhythmic cells in the left ventricular outflow tract of guinea pigs.Methods: Standard microelectrode cell recording techniques were adopted to observe the electrophysiological effects of different concentrations of Fe^(2+)(100 μmol/L, 200 μmol/L) on the left ventricular outflow tract autorhythmic cells.Heart tissues were perfused with FeSO_4(200 μmol/L) combing with CaCl_2(4.2 mmol/L), Verapamil,(1 μmol/L), and nickel chloride(200μmol/L) respectively to observe the influences of these contents on electrophysiology of FeSO_4(200μmol/L) on the left ventricular outflow tract autorhythmic cells.Results: Fe^(2+)at both 100 μmol/L and 200 μmol/L could change the electrophysiological parameters of the slow response autorhythmic cells of the left ventricular outflow tract in a concentrationdependent manner resulting into decrease in Vmax, APA and MDP, slower RPF and VDD, and prolonged APD_(50) and APD_(90)(P all <0.05).Besides, perfusion of increased Ca^(2+) concentration could partially offset the electrophysiological effects of Fe^(2+)(200 μmol/L).The L-type calcium channel(LTCC) blocker Verapamil(1 μmol/L) could block the electrophysiological effects of Fe^(2+)(200 μmol/L).But the T-type calcium channel(TTCC) blocker nickel chloride(NiCl_2, 200 μmol/L) could not block the electrophysiological effects of Fe^(2+)(200 μmol/L).Conclusions: Fe^(2+) can directly change the electrophysiological characteristics of the slow response autorhythmic cells of the left ventricular outflow tract probably through the L-type calcium channel.