Transforming Growth Factor β1-induced Apoptosis in Podocytes via the Extracellular Signal-regulated Kinase-Mammalian Target of Rapamycin Complex 1-NADPH Oxidase 4 Axis

Das, Ranjan,Xu, Shanhua,Nguyen, Tuyet Thi,Quan, Xianglan,Choi, Seong-Kyung,Kim, Soo-Jin,Lee, Eun Young,Cha, Seung-Kuy,Park, Kyu-Sang American Society for Biochemistry and Molecular Bi 2015 The Journal of biological chemistry Vol.290 No.52

<P>TGF-β is a pleiotropic cytokine that accumulates during kidney injuries, resulting in various renal diseases. We have reported previously that TGF-β1 induces the selective up-regulation of mitochondrial Nox4, playing critical roles in podocyte apoptosis. Here we investigated the regulatory mechanism of Nox4 up-regulation by mTORC1 activation on TGF-β1-induced apoptosis in immortalized podocytes. TGF-β1 treatment markedly increased the phosphorylation of mammalian target of rapamycin (mTOR) and its downstream targets p70S6K and 4EBP1. Blocking TGF-β receptor I with SB431542 completely blunted the phosphorylation of mTOR, p70S6K, and 4EBP1. Transient adenoviral overexpression of mTOR-WT and constitutively active mTORΔ augmented TGF-β1-treated Nox4 expression, reactive oxygen species (ROS) generation, and apoptosis, whereas mTOR kinase-dead suppressed the above changes. In addition, knockdown of mTOR mimicked the effect of mTOR-KD. Inhibition of mTORC1 by low-dose rapamycin or knockdown of p70S6K protected podocytes through attenuation of Nox4 expression and subsequent oxidative stress-induced apoptosis by TGF-β1. Pharmacological inhibition of the MEK-ERK cascade, but not the PI3K-Akt-TSC2 pathway, abolished TGF-β1-induced mTOR activation. Inhibition of either ERK1/2 or mTORC1 did not reduce the TGF-β1-stimulated increase in Nox4 mRNA level but significantly inhibited total Nox4 expression, ROS generation, and apoptosis induced by TGF-β1. Moreover, double knockdown of Smad2 and 3 or only Smad4 completely suppressed TGF-β1-induced ERK1/2-mTORactivation. Our data suggest that TGF-β1 increases translation of Nox4 through the Smad-ERK1/2-mTORC1 axis, which is independent of transcriptional regulation. Activation of this pathway plays a crucial role in ROS generation and mitochondrial dysfunction, leading to podocyte apoptosis. Therefore, inhibition of the ERK1/2-mTORC1 pathway could be a potential therapeutic and preventive target in proteinuric and chronic kidney diseases.</P>

Experimental and numerical studies on the behaviour of corroded cold-formed steel columns

Nie Biao,Xu Shanhua,Zhang Haijiang,Zhang Zongxing 국제구조공학회 2020 Steel and Composite Structures, An International J Vol.35 No.5

Experimental investigation and finite element analysis of corroded cold-formed steel (CFS) columns are presented. 11 tensile coupon specimens and 6 stub columns of corroded CFS that had a channel section of C160x60x20 were subjected to monotonic tensile tests and axial compression tests, respectively. The degradation laws of the mechanical properties of the tensile coupon specimens and stub columns were analysed. An appropriate finite element model for the corroded CFS columns was proposed and the influence of local corrosion on the stability performance of the columns was studied by finite element analysis. Finally, the axial capacity of the experimental results was compared with the predictions obtained from the existing design specifications. The results indicated that with an increasing average thickness loss ratio, the ultimate strength, elastic modulus and yield strength decreased for the tensile coupon specimens. Local buckling deformation was not noticeable until the load reached about 90% of the ultimate load for the non-corroded columns, while local buckling deformation was observed when the load was only 40% of the ultimate load for the corroded columns. The maximum reduction of the ultimate load and critical buckling load was 57% and 81.7%, respectively, compared to those values for the non-corroded columns. The ultimate load of the columns with web thickness reduced by 2 mm was 53% lower than that of the non-corroded columns, which indicates that web corrosion most significantly affects the bearing capacity of the columns with localized corrosion. The results predicted using the design specifications of MOHURD were more accurate than those predicted using the design specifications of AISI.

Study on the flexural behavior of corroded built-up cold-formed thin-walled steel beams

Zongxing Zhang,Shanhua Xu,Han Li,Rou Li,Biao Nie 국제구조공학회 2020 Steel and Composite Structures, An International J Vol.37 No.3

Eight cold-formed thin-walled steel beams were performed to investigate the effect of corrosion damage on the flexural behavior of steel beams. The relationships between failure modes or load-displacement curves and corrosion degree of steel beams were investigated. A series of parametric analysis with more than forty finite element models were also performed with different corrosion degrees, types and locations. The results showed that the reduction of cross-section thickness as well as corrosion pits on the surface would lead to a decline in the stiffness and flexural capacity of steel beams, and gradually intensified with the corrosion degree. The yield load, ultimate load and critical buckling load of the corroded specimen IV-B46-4 decreased by 22.2%, 26% and 45%, respectively. The failure modes of steel beams changed from strength failure to stability failure or brittle fracture with the corrosion degree increasing. In addition, thickness damage and corrosion pits at different locations caused the degradation of flexural capacity, the worst of which was the thickness damage of compression zone. Finally, the method for calculating flexural capacity of corroded cold-formed thin-walled steel beams was also proposed based on experimental investigation and numerical analysis results.

Time-Dependent Reliability Analysis of Corroded Steel Beam

Biao Nie,Shanhua Xu,Youde Wang 대한토목학회 2020 KSCE JOURNAL OF CIVIL ENGINEERING Vol.24 No.1

The time-dependent reliability of corroded steel beam was investigated. Nine groups of specimenswere subjected to accelerate corrosion by the outdoor periodic spray test and monotonic tensile test. The surface profile of corroded steel plates and the 3D data of corrosion depth were measured by the three-dimensional non-contact surface topography instrument (PS50 3D). The probability distribution of corrosion depth and nominal yield strength of corroded steel plates were studied. Finally, a probabilistic limit state equation for corroded steel beams was established and the time-dependent failure probability and reliability index of corroded steel beams was calculated by Monte Carlo simulation method (MCS). The results of study show that the corrosion depth on steel plate surface and nominal yield strength of corroded steel plate conformed to the normal distribution. With the increase of corrosion time, the average, the standard deviation of the corrosion depth and relative yield strength increased while the mean of relative yield strength, nominal yield strength, nominal ultimate strength, the elongation decreased. The reliability index decreased rapidly with corrosion time, which shows that the reliability of steel structures under the aggressive environmental should be caused attention.

Random Field Model of Corroded Steel Plate Surface in Neutral Salt Spray Environment

Kong Deliang,Nie Biao,Xu Shanhua 대한토목학회 2021 KSCE JOURNAL OF CIVIL ENGINEERING Vol.25 No.7

The random field model of corrosion depth on steel plate surface in neutral salt spray environment was investigated. 10 groups of specimens were subjected to accelerate corrosion by the neutral salt spray test, and the surface profile of corroded steel plates and the 3D data of corrosion depth were measured by three-dimensional non-contact surface topography instrument. The probability characteristics of corrosion depth were studied and the relationship between the average and the standard deviation of corrosion depth and the mass loss rate were analyzed. The corrosion depth were tested for ergodicity and stationarity and the autocorrelation function model of random field model of corrosiondepth was proposed. The results of the study show that the corrosion depth on steel plate surface in neutral salt spray environment conformed to the normal distribution. With the increase of mass loss rate, the average and the standard deviation of the corrosion depth increased. The corrosion depth has ergodicity and stationarity. The random field model of cosine trigonometric function can accurately characterize the distribution of corrosion depth, which prepared the preliminary preparation for the finite element analysis of the corroded steel structure.

Oxidative stress and calcium dysregulation by palmitate in type 2 diabetes

Luong Dai Ly,Shanhua Xu,최성경,하채명,THOUDAMTHEMIS,차승규,Andreas Wiederkehr,Claes B. Wollheim,이인규,박규상 생화학분자생물학회 2017 Experimental and molecular medicine Vol.49 No.-

Free fatty acids (FFAs) are important substrates for mitochondrial oxidative metabolism and ATP synthesis but also cause serious stress to various tissues, contributing to the development of metabolic diseases. CD36 is a major mediator of cellular FFA uptake. Inside the cell, saturated FFAs are able to induce the production of cytosolic and mitochondrial reactive oxygen species (ROS), which can be prevented by co-exposure to unsaturated FFAs. There are close connections between oxidative stress and organellar Ca2+ homeostasis. Highly oxidative conditions induced by palmitate trigger aberrant endoplasmic reticulum (ER) Ca2+ release and thereby deplete ER Ca2+ stores. The resulting ER Ca2+ deficiency impairs chaperones of the protein folding machinery, leading to the accumulation of misfolded proteins. This ER stress may further aggravate oxidative stress by augmenting ER ROS production. Secondary to ER Ca2+ release, cytosolic and mitochondrial matrix Ca2+ concentrations can also be altered. In addition, plasmalemmal ion channels operated by ER Ca2+ depletion mediate persistent Ca2+ influx, further impairing cytosolic and mitochondrial Ca2+ homeostasis. Mitochondrial Ca2+ overload causes superoxide production and functional impairment, culminating in apoptosis. This vicious cycle of lipotoxicity occurs in multiple tissues, resulting in β-cell failure and insulin resistance in target tissues, and further aggravates diabetic complications.

Essential Role of Mitochondrial Ca²⁺ Uniporter in the Generation of Mitochondrial pH Gradient and Metabolism-Secretion Coupling in Insulin-releasing Cells

Quan, Xianglan,Nguyen, Tuyet Thi,Choi, Seong-Kyung,Xu, Shanhua,Das, Ranjan,Cha, Seung-Kuy,Kim, Nari,Han, Jin,Wiederkehr, Andreas,Wollheim, Claes B.,Park, Kyu-Sang American Society for Biochemistry and Molecular Bi 2015 The Journal of biological chemistry Vol.290 No.7

<P>In pancreatic β-cells, ATP acts as a signaling molecule initiating plasma membrane electrical activity linked to Ca<SUP>2+</SUP> influx, which triggers insulin exocytosis. The mitochondrial Ca<SUP>2+</SUP> uniporter (MCU) mediates Ca<SUP>2+</SUP> uptake into the organelle, where energy metabolism is further stimulated for sustained second phase insulin secretion. Here, we have studied the contribution of the MCU to the regulation of oxidative phosphorylation and metabolism-secretion coupling in intact and permeabilized clonal β-cells as well as rat pancreatic islets. Knockdown of MCU with siRNA transfection blunted matrix Ca<SUP>2+</SUP> rises, decreased nutrient-stimulated ATP production as well as insulin secretion. Furthermore, MCU knockdown lowered the expression of respiratory chain complexes, mitochondrial metabolic activity, and oxygen consumption. The pH gradient formed across the inner mitochondrial membrane following nutrient stimulation was markedly lowered in MCU-silenced cells. In contrast, nutrient-induced hyperpolarization of the electrical gradient was not altered. In permeabilized cells, knockdown of MCU ablated matrix acidification in response to extramitochondrial Ca<SUP>2+</SUP>. Suppression of the putative Ca<SUP>2+</SUP>/H<SUP>+</SUP> antiporter leucine zipper-EF hand-containing transmembrane protein 1 (LETM1) also abolished Ca<SUP>2+</SUP>-induced matrix acidification. These results demonstrate that MCU-mediated Ca<SUP>2+</SUP> uptake is essential to establish a nutrient-induced mitochondrial pH gradient which is critical for sustained ATP synthesis and metabolism-secretion coupling in insulin-releasing cells.</P>

Seismic performance of steel columns corroded in general atmosphere

Youde Wang,Tao Shi,Biao Nie,Hao Wang,Shanhua Xu 국제구조공학회 2021 Steel and Composite Structures, An International J Vol.40 No.2

Steel structures exposed to general atmosphere for a long time are highly susceptible to corrosion damage, which would lead to the degradation of service performance of the components and even structures. This article focuses on the effect of corrosion on the seismic performance of steel column. The accelerated corrosion tests in general atmosphere were conducted on 7 H-shaped steel columns and 20 steel plates. Then the obtained plate specimens were subjected to monotonic tensile tests and cyclic loading tests, and the steel columns were subjected to pseudo-static tests, respectively, to study the effects of corrosion on their mechanical properties and seismic performance. Then, a simplified three-dimensional finite element model (FEM) capable of accurately simulating the hysteretic response of corroded steel columns under low-cycle loading was established. Experimental results indicated that the yield strength, tensile strength, elastic modulus and peak strain of corroded steel plate decreased linearly with the proposed corrosion damage parameter Dn, and the energy dissipations under low-cycle loading were significantly reduced. There is a correlation between the cyclic hardening parameters of corroded steel and the yield-tensile strength difference (SD), and then a simplified formula was proposed. Corrosion could result in the premature entrance of each loading stage of corroded columns and the deterioration of buckling deformation range, bearing capacity and energy dissipation, etc. In addition, a larger axial compression ratio (CR) would further accelerate the failure process of corroded columns. The parametric finite element analysis (FEA) indicated that greater damage was found for steel columns with non-uniform corrosion, and hysteretic performance degraded more significantly when corrosion distributed at flanges or foot zone.

Gallic acid regulates body weight and glucose homeostasis through AMPK activation.

Doan, Khanh V,Ko, Chang Mann,Kinyua, Ann W,Yang, Dong Joo,Choi, Yun-Hee,Oh, In Young,Nguyen, Nguyen Minh,Ko, Ara,Choi, Jae Won,Jeong, Yangsik,Jung, Min Ho,Cho, Won Gil,Xu, Shanhua,Park, Kyu Sang,Park, The Endocrine Society 2015 Endocrinology Vol.156 No.1

<P>Gallic acid [3,4,5-trihydroxybenzoic acid (GA)], a natural phytochemical, is known to have a variety of cellular functions including beneficial effects on metabolic syndromes. However, the molecular mechanism by which GA exerts its beneficial effects is not known. Here we report that GA plays its role through the activation of AMP-activated protein kinase (AMPK) and by regulating mitochondrial function via the activation of peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α). Sirtuin 1 (Sirt1) knockdown significantly blunted GA's effect on PGC1α activation and downstream genes, suggesting a critical role of the AMPK/Sirt1/PGC1α pathway in GA's action. Moreover, diet-induced obese mice treated with GA showed significantly improved glucose and insulin homeostasis. In addition, the administration of GA protected diet-induced body weight gain without a change in food intake. Biochemical analyses revealed a marked activation of AMPK in the liver, muscle, and interscapular brown adipose tissue of the GA-treated mice. Moreover, uncoupling protein 1 together with other genes related to energy expenditure was significantly elevated in the interscapular brown adipose tissue. Taken together, these results indicate that GA plays its beneficial metabolic roles by activating the AMPK/Sirt1/PGC1α pathway and by changing the interscapular brown adipose tissue genes related to thermogenesis. Our study points out that targeting the activation of the AMPK/Sirt1/PGC1α pathway by GA or its derivatives might be a potential therapeutic intervention for insulin resistance in metabolic diseases.</P>