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.

Relationship between lipidslevelsand right ventricular volume overload in congestive heart failure

BackgroundThe relationship between lipids and coronary artery disease has been well established. However, this is not the case between lipids and heart failure. Ironically, high lipid levels are associated with better outcomes in heart failure, but the mechan-isms underlying the phenomenon are not fully understood. This study was performed to test the hypothesis that reduced intestinal lipid absorption due to venous congestion may lead to low lipid levels.MethodsWe collected data of clinical characteristics, echocardio-graph, and lipid profile in 442 unselected patients with congestive heart failure. Correlations between lipid levels[including total cho-lesterol（TCL）, high-density lipoprotein cholesterol（HDL-C）, low-density lipoprotein cholesterol（LDL-C）, and triglycerides（TG）]and right ventricle end diastolic diameter （RVEDD）, left ventricle end diastolic diameter （LVEDD）, right atrium diameter （RA）, left atrium diameter （LA）, or left ventricle ejection fraction （LVEF） were analyzed using Pearson correlation and partial correlation. RVEDD, LVEDD, RA, and LA were indexed to the body surface area.ResultsThere was a significantly inverse correlation between TCL le-vels and RVEDD （r=-0.34,P〈0.001） and RA （r=-0.36,P〈0.001）. Other lipids such as LDL-C, HDL-C, and TG had asimilar inverse correlation with RVEDD and RA. All these correlations remained unchanged after adjusting for age, gender, smoking status, physical activity levels, comorbidities, and medication use.ConclusionsLipid levels were inversely correlated to RVEDD in patients with congestive heart failure; however, because this was an observational study, further investigation is needed to verify our results as wellas identify a causal relationship, if any.

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.

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.

Transformation of myocardial energy metabolism pattern during myocardial remodeling caused by volume overload

Objective To elucidate the transformation of energy metabolism patterns in the process of myocardial remodeling induced by volumeoverload and to explore a novel intervention target for the prevention,delay or even reversal of structural heart dysfunction.Methods Thirty C57/BL6 mice,20-30 g,half male and half female,were randomly divided into model group(n=15)and sham operation group(n=15).Each group was divided into subacute phase(2 weeks after surgery,n=5),cardiac functional compensation phase(5 weeks after surgery,n=5)and decompensation phase(15 weeks after surgery,n=5).

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.

CaCO_(3)-encircled hollow CuS nanovehicles to suppress cervical cancer through enhanced calcium overload-triggered mitochondria damage

Cervical cancer stands is a formidablemalignancy that poses a significant threat towomen’s health.Calcium overload,a minimally invasive tumor treatment,aims to accumulate an excessive concentration of Ca^(2+)within mitochondria,triggering apoptosis.Copper sulfide(CuS)represents a photothermal mediator for tumor hyperthermia.However,relying solely on thermotherapy often proves insufficient in controlling tumor growth.Curcumin(CUR),an herbal compound with anti-cancer properties,inhibits the efflux of exogenous Ca^(2+)while promoting its excretion from the endoplasmic reticulum into the cytoplasm.To harness these therapeutic modalities,we have developed a nanoplatform that incorporates hollow CuS nanoparticles(NPs)adorned with multiple CaCO_(3) particles and internally loaded with CUR.This nanocomposite exhibits high uptake and easy escape from lysosomes,along with the degradation of surrounding CaCO3,provoking the generation of abundant exogenous Ca^(2+)in situ,ultimately damaging the mitochondria of diseased cells.Impressively,under laser excitation,the CuS NPs demonstrate a photothermal effect that accelerates the degradation of CaCO_(3),synergistically enhancing the antitumor effect through photothermal therapy.Additionally,fluorescence imaging reveals the distribution of these nanovehicles in vivo,indicating their effective accumulation at the tumor site.This nanoplatform shows promising outcomes for tumor-targeting and the effective treatment in a murine model of cervical cancer,achieved through cascade enhancement of calcium overload-based dual therapy.

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.

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.

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.

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.

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.

Iron overload and cofactors with special reference to alcohol,hepatitis C virus infection and steatosis/insulin resistance

There are several cofactors which affect body iron metabolism and accelerate iron overload. Alcohol and hepatic viral infections are the most typical examples for clarifying the role of cofactors in iron overload. In these conditions, iron is deposited in hepatocytes and Kupffer cells and reactive oxygen species （ROS） produced through Fenton reaction have key role to facilitate cellular uptake of transferrin-bound iron. Furthermore, hepcidin, antimicrobial peptide produced mainly in the liver is also responsible for intestinal iron absorption and reticuloendothelial iron release. In patients with ceruloplasmin deficiency, anemia and secondary iron overload in liver and neurodegeneration are reported. Furthermore, there is accumulating evidence that fatty acid accumulation without alcohol and obesity itself modifies iron overload states. Ineffective erythropoiesis is also an important factor to accelerate iron overload, which is associated with diseases such as thalassemia and myelodysplastic syndrome. When this condition persists, the dietary iron absorption is increased due to the increment of bone marrow erythropoiesis and tissue iron overload will thereafter occurs. In porphyria cutanea tarda, iron is secondarily accumulated in the liver.

Influence of high overload on the collimating lenses of laser ranging systems

Collimating lenses are an important component of laser ranging systems,and high overload environments severely affect the beam shaping effect of such lenses.This study proposes a buffer isolation method on the basis of impact stress wave attenuation theory for collimating lens spacers,ANSYS finite element software was applied to simulate the high load dynamics of collimating lenses,and the buffer isolation performance of different materials and composite structures was compared and analysed.Optical simulation analysis of the collimating lenses under different buffer conditions was performed using ZEMAX software to study the mechanism by which a high overload affects the collimating lenses.High overload and optical shaping experiments based on theoretical analysis were further conducted.Results showed the superiority of butadiene rubber to polytetrafluoroethylene after application of 70000 g impact acceleration.The combination-gasket method was superior to the single-gasket method,and the sandwich combination-gasket method was superior to the double-layer combination-gasket method.

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.