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Jiaxin Qi,1,2,&ast; Xiayu Ren,1,2,&ast; Yanjuan Hou,2 Yaqing Zhang,1,2 Yanru Zhang,1,2 Enxue Tan,1,2 Lihua Wang2 1Second Department of Clinical Medicine, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 2Division of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lihua Wang, Division of Nephrology, The Second Hospital of Shanxi Medical University, 382 Wuyi Road, Taiyuan, Shanxi, 030000, People’s Republic of China, Tel +8615234166600, Email lihuawang236@126.comPurpose: The triglyceride-glucose (TyG) index is a new index of insulin resistance (IR), and its association with hyperuricemia (HUA) is unclear. The aim of this study was to investigate whether TyG is an independent risk factor for hyperuricemia (HUA) in patients with nonalcoholic fatty liver disease (NAFLD).Patients and Methods: We retrospectively analyzed 461 patients with ultrasound-confirmed NAFLD and calculated the TyG index. Multivariate logistic regression was used to analyze the relationship between the TyG index and HUA in NAFLD patients. The correlation between the TyG index and HUA was further confirmed by a restricted cubic spline. Furthermore, the stability of the association between TyG index and HUA was examined using subgroup analysis. Receiver operating characteristic (ROC) curves were constructed to evaluate the predictive value of the TyG index on HUA. Multivariate linear regression was used to analyze the linear relationship between the TyG index and serum uric acid.Results: A total of 166 HUA patients and 295 non-HUA patients were included in the study. The results of multivariate logistic regression analysis showed that after controlling the confounding risk factors, TyG was still an independent risk factor for HUA (OR = 2.00, 95% CI: 1.38 − 2.91, p < 0.001). Restricted cubic splines showed that HUA risk increased linearly with TyG across the entire TyG range. The ROC curve showed that TyG index was better than triglyceride in predicting HUA in NAFLD patients, with AUC values of 0.62 and 0.59, respectively. Multiple linear regression analysis showed that TyG index was significantly positively correlated with blood uric acid (B = 1.37, 95% CI: 0.67– 2.08, p < 0.001).Conclusion: TyG index is an independent risk factor for HUA in patients with NAFLD. The increase of the TyG index level is closely related to the occurrence and development of HUA in patients with NAFLD.Keywords: triglyceride-glucose index, insulin resistance, non-alcoholic fatty liver disease, hyperuricemia, serum uric acid

Tubulointerstitial inflammation plays a key role in the pathogenesis of diabetic nephropathy (DN). Interleukin-1β (IL-1β) is the key proinflammatory cytokine associated with tubulointerstitial inflammation. The NLRP3 inflammasome regulates IL-1β activation and secretion. Reactive oxygen species (ROS) represents the main mediator of NLRP3 inflammasome activation. We previously reported that CD36, a class B scavenger receptor, mediates ROS production in DN. Here, we determined whether CD36 is involved in NLRP3 inflammasome activation and explored the underlying mechanisms. We observed that high glucose induced-NLRP3 inflammasome activation mediate IL-1β secretion, caspase-1 activation, and apoptosis in HK-2 cells. In addition, the levels of CD36, NLRP3, and IL-1β expression (protein and mRNA) were all significantly increased under high glucose conditions. CD36 knockdown resulted in decreased NLRP3 activation and IL-1β secretion. CD36 knockdown or the addition of MitoTempo significantly inhibited ROS production in HK-2 cells. CD36 overexpression enhanced NLRP3 activation, which was reduced by MitoTempo. High glucose levels induced a change in the metabolism of HK-2 cells from fatty acid oxidation (FAO) to glycolysis, which promoted mitochondrial ROS (mtROS) production after 72 h. CD36 knockdown increased the level of AMP-activated protein kinase (AMPK) activity and mitochondrial FAO, which was accompanied by the inhibition of NLRP3 and IL-1β. The in vivo experimental results indicate that an inhibition of CD36 could protect diabetic db/db mice from tubulointerstitial inflammation and tubular epithelial cell apoptosis. CD36 mediates mtROS production and NLRP3 inflammasome activation in db/db mice. CD36 inhibition upregulated the level of FAO-related enzymes and AMPK activity in db/db mice. These results suggest that NLRP3 inflammasome activation is mediated by CD36 in renal tubular epithelial cells in DN, which suppresses mitochondrial FAO and stimulates mtROS production.

Thioredoxin-interacting protein (TXNIP) is associated with inflammation, tubulointerstitial fibrosis, and oxidative stress in diabetic kidney disease, yet the potential role of TXNIP in nondiabetic renal injury is not well known. This study aimed to investigate the effect of TXNIP on renal injury by creating a unilateral ureteral obstruction (UUO) model in TXNIP knockout (TKO) mice. We performed sham or UUO surgery in 8-week-old TXNIP KO male mice and age and sex-matched wild-type (WT) mice. Animals were killed at 3, 5, 7, or 14 days after surgery, and renal tissues were obtained for RNA, protein, and other analysis. Our results show that the expression of TXNIP was increased in a time-dependent manner in the ligated kidneys. TXNIP deletion reduced renal fibrosis, apoptosis, α-SMA, TGF-β1 and CTGF expression, and activation of Smad3, p38 MAPK, and ERK1/2 in UUO kidneys. We also found UUO-induced renal F4/80+ macrophage infiltration, MCP-1 expression and activation of NF-κB and NLRP3 inflammasome were attenuated in TKO mice. Furthermore, our study revealed that TXNIP deficiency inhibited the expression of 8-OHdG, heme oxygenase-1 (HO-1) and NADPH oxidase 4 (Nox4) in UUO kidney. In summary, our study suggests that TXNIP plays a key role in the renal inflammation and fibrosis induced by UUO. Inhibition of TXNIP may be a strategy to slow the progression of chronic kidney diseases.

Background Oxidative stress plays an independent role in the pathogenesis of diabetic nephropathy (DN). CD36, a class B scavenger receptor, mediates reactive oxygen species (ROS) production in DN. SS31 is a mitochondria-targeted antioxidant peptide that can scavenge mitochondrial ROS. The antioxidative effects of SS31 on DN and the interaction between SS31 and CD36 remain poorly understood. Herein, we examined the effects of SS31 and investigated whether SS31 treatment attenuates CD36 expression in db/db diabetic mice and high glucose (HG)-induced HK-2 cells. Methods Eight-week-old db/m mice and db/db mice were administered with SS31 (3 mg/kg/day) for 12 weeks by intraperitoneal injection. For the in vitro studies, HG-cultured HK-2 cells were used. Biochemical parameters, body weight and histological changes in the mice were measured. The levels of oxidative stress, activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, Mn superoxide dismutase (MnSOD) and catalase (CAT), and the expression of CD36, nuclear factor-κB (NF-κB) p65 in mice and HK-2 cells were also analyzed. Results The results showed that SS31 alleviated proteinuria, glomerular hypertrophy and tubular injury, and affected creatinine level in db/db mice. SS31 suppressed the levels of oxidative stress, NADPH oxidase subunits, CD36 and NF-κB p65, and activated MnSOD and CAT in db/db mice and HG-induced HK-2 cells. Conclusion Taken together, these data demonstrated a renoprotective role of SS31 in DN by suppression of enhanced oxidative stress and CD36 expression.

The human CGB5 gene encodes chorionic gonadotropin (hCG)β 5, which is aberrantly expressed in trophoblastic neoplasm and in some non‐trophoblastic neoplasms. Fucntional studies observed that it involved tumor initiation, growth, and metastatic outgrowth. In this study, using data from the International Cancer Genome Consortium (ICGC) and the Cancer Genome Atlas (TCGA)‐stomach adenocarcinoma (STAD), we assessed the independent prognostic value of CGB5 expression in patients with primary gastric cancer (GC). Results showed that CGB5 expression was nearly not expressed in normal GC tissues. In comparison, its expression was detected in 214 of the 415 primary GC cases (51.6%) in TCGA‐STAD and was associated with poor response to primary therapy and a higher risk of recurrence and death. In early stages, CGB5 expression was not a prognostic factor in terms of OS (HR: 1.448; 95% CI: 0.811–2.588, P = 0.211) or RFS (HR: 1.659; 95% CI: 0.778–3.540, P = 0.190). However, its expression was independently associated with unfavorable OS (HR: 1.719; 95% CI: 1.115–2.651, P = 0.014) and RFS (HR: 3.602; 95% CI: 1.708–7.598, P = 0.001) in advanced stages. Using deep sequencing data from TCGA‐STAD , we found that CGB5 expression was not related to its genetic amplification or DNA methylation in GC. Based on these findings, we infer that CGB5 expression is common in GC patients and its expression might independently predict poor OS and RFS in advanced stages, but not in early stages of GC.

In urban areas, subway construction inevitably imposes negative impacts on adjacent buried pipelines. During the recent construction of the Beijing subway, several ground failures have occurred due to the pipeline damages induced by tunnel construction. In this paper, a disastrous ground failure of such kind occurred during the Beijing subway Line 10 construction is presented, in which a sinkhole about 20 m long, 14 m wide and 12 m deep formed. Both the tunnel construction and the ground traffic were severely affected. The adopted remedial measures for this failure, including road restoration, dewatering, dredging and tunnel face reinforcement, are systematically illustrated. The probable mechanism of this failure is also analyzed and briefly discussed. The case presented in this paper can serve as a practical reference for the engineers practicing in the similar engineering field.

This paper analyzes wall deflection and ground surface settlement due to deep excavation. 21 case histories of Tianjin subway line 6 are collected and analyzed. And the results are compared with previous field studies worldwide. The mean value of maximum wall deflection δhm is 0.11%H, in which H is the excavation depth. The upper limit of δhm is 0.44%H when H is less than 8m and 35mm when H is more than 8m. When excavation finished, δhm ranges from 0.02%H to 0.24%H with an average value of 0.12%H. The depth of maximum wall deflections Hδhm is within 0.75H±8m and the average Hδhm is 0.69H when excavation finished. It’s greatly affected by the embedded depth ratio. Hδhm can be predicted by exponential function more accurately. The distribution of δvm generally extends to a distance of 2H from the diaphragm wall. The bound of stiff clay line proposed by Clough and O’Rourke (1990) and bilinear curve proposed by Erin H. Y. Leung (2007) can be used as the upper bound for ground surface settlement for excavation of Tianjin subway line 6. The ratio between δvm and δhm generally ranges from 0.34 to 2.66, with an average value of 1.13. It’s consistent with the average value of 1.21 collected from literature in similar soil conditions. This paper is a reference for design and construction of Tianjin’s deep excavation of subway station.

Lot JC3 of the Xianmen Airport Highway Project in China involved building a twin-tube tunnel with each tube serving three-lane one-way traffic. The existence of 79 overlying buildings brought great challenges to the tunnel construction. To safeguard these buildings, two building blocks located above the nearby tunnel portal were approved by the owner of the project to be the trial blocks. Compensation grouting was adopted for ground settlement compensation at this lot. Free-field compensation grouting tests were conducted to derive the suitable grouting parameters. Pretreatment to reinforce the ground prior to the tunneling passage, concurrent grouting to compensate the excessive settlements during the tunneling passage, and regrouting to uplift the distorted buildings after the tunneling passage were designed to protect the trial blocks. According to the monitoring data of the trial blocks and the ground, the characteristics of the soil-structure interaction were studied and the criteria for the safety of the structures were therefore determined.

The epithelial-to-mesenchymal transition (EMT) plays an important role in the progression of diabetic nephropathy. Our recent study showed that ROS mediated high glucose (HG)-induced EMT in renal tubular epithelial cells. CD36, a class-B scavenger receptor, has been reported to mediate the production of ROS in chronic kidney disease. In the present study, we examined the effect of inhibition of CD36 with CD36 siRNA or sulfosuccinimidyl-oleate (SSO), a CD36 antagonist, on HG-induced EMT in HK-2 cells. HG induced CD36 expression in a time-dependent manner in HK-2 cells. HG was shown to induce EMT at 72 h. This was blocked by knockdown of CD36 or treatment with SSO. Meanwhile, we also found that knockdown of CD36 or treatment with SSO inhibited HG-induced ROS generation, activation of ERK1/2 and Smad2, expression of TGF-β1 and synthesis of fibronectin. These data suggest that inhibition of CD36 prevented HG-induced EMT in HK-2 cells, highlighting CD36 as a potential therapeutic target for diabetic nephropathy.

Renal tubular epithelial cells (RTEC) apoptosis, which plays a key role in the pathogenesis and progression of diabetic nephropathy (DN), is believed to be contributive to the hyperglycemia-induced kidney failure, though the exact mechanisms remain elusive. In this study, we investigated how inhibition of c-Src/p38 MAPK pathway would affect RTEC apoptosis. The c-Src inhibitor PP2 i.p. administered every other day for 8 weeks to diabetic db/db mice significantly reduced their kidney weights, daily urinary volumes, blood glucose, blood urea nitrogen, serum creatinine, triglyceride and urine albumin excretion, whereas deactivation of c-Src and p38 MAPK were also observed, along with decreases in both Bax/Bcl-2 ratio and cleaved caspase-3 level in the kidneys. In vitro, exposure of HK-2 cells (a human RTEC line), to high glucose (HG) promoted phosphorylation of c-Src and p38 MAPK, and subsequently, as revealed by western blotting, TUNEL assay and flow cytometry, increased cell death, which can be inhibited by PP2. Especially, a specific p38 MAPK inhibitor, SB203580, that both attenuated HG-induced c-Src activation and abrogated the expression of PPARγ and CHOP, also reduced apoptosis. Taken together, PP2 inhibits c-Src and therefore reduces apoptosis in RTEC, which at least in part, is due to suppressed p38 MAPK activation in diabetic kidney.

Oxidative stress is implicated in the pathogenesis of diabetic kidney injury. SS-31 is a mitochondria-targeted tetrapeptide that can scavenge reactive oxygen species (ROS). Here, we investigated the effect and molecular mechanism of mitochondria-targeted antioxidant peptide SS-31 on injuries in diabetic kidneys and mouse mesangial cells (MMCs) exposed to high-glucose (HG) ambience. CD-1 mice underwent uninephrectomy and streptozotocin treatment prior to receiving daily intraperitoneal injection of SS-31 for 8 wk. The diabetic mice treated with SS-31 had alleviated proteinuria, urinary 8-hydroxy-2-deoxyguanosine level, glomerular hypertrophy, and accumulation of renal fibronectin and collagen IV. SS-31 attenuated renal cell apoptosis and expression of Bax and reversed the expression of Bcl-2 in diabetic mice kidneys. Furthermore, SS-31 inhibited expression of transforming-growth factor (TGF)-β1, Nox4, and thioredoxin-interacting protein (TXNIP), as well as activation of p38 MAPK and CREB and NADPH oxidase activity in diabetic kidneys. In vitro experiments using MMCs revealed that SS-31 inhibited HG-mediated ROS generation, apoptosis, expression of cleaved caspase-3, Bax/Bcl-2 ratio, and cytochrome c (cyt c) release from mitochondria. SS-31 normalized mitochondrial potential (ΔΨm) and ATP alterations, and inhibited the expression of TGF-β1, Nox4, and TXNIP, as well as activation of p38 MAPK and CREB and NADPH oxidase activity in MMCs under HG conditions. SS-31 treatment also could reverse the reduction of thioredoxin (TRX) biologic activity and upregulate expression of thioredoxin 2 (TRX2) in MMCs under HG conditions. In conclusion, this study demonstrates a protective effect of SS-31 against HG-induced renal injury via an antioxidant mechanism in diabetic nephropathy.

Epithelial to mesenchymal transition (EMT) of tubular cells contributes to the renal accumulation of matrix protein that is associated with diabetic nephropathy. Both high glucose and transforming growth factor-β (TGF-β) are able to induce EMT in cell culture. In this study, we examined the role of the thioredoxin-interacting protein (TXNIP) on EMT induced by high glucose or TGF-β1 in HK-2 cells. EMT was assessed by the expression of α-smooth muscle actin (α-SMA) and E-cadherin and the induction of a myofibroblastic phenotype. High glucose (30mM) was shown to induce EMT at 72h. This was blocked by knockdown of TXNIP or antioxidant NAC. Meanwhile, we also found that knockdown of TXNIP or antioxidant NAC inhibited high glucose-induced generation of reactive oxygen species (ROS), phosphorylation of p38 MAPK and ERK1/2 and expression of TGF-β1. HK-2 cells that were exposed to TGF-β1 (4ng/ml) also underwent EMT. The expression of TXNIP gene and protein was increased in HK-2 cells treated with TGF-β1. Transfection with TXNIP shRNA was able to attenuate TGF-β1 induced-EMT. These results suggested that knockdown of TXNIP antagonized high glucose-induced EMT by inhibiting ROS production, activation of p38 MAPK and ERK1/2, and expression of TGF-β1, highlighting TXNIP as a potential therapy target for diabetic nephropathy.

Chunyang Du,1,2,* Yonghong Shi,1,2,* Yunzhuo Ren,1,2 Haijiang Wu,1,2 Fang Yao,1,2 Jinying Wei,1,2 Ming Wu,1,2 Yanjuan Hou,1,2 Huijun Duan1,2 1Department of Pathology, Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People’s Republic of China *These authors contributed equally to this work Abstract: The dysregulation of cholesterol metabolism and inflammation plays a significant role in the progression of diabetic nephropathy (DN). Anthocyanins are polyphenols widely distributed in food and exert various biological effects including antioxidative, anti-inflammatory, and antihyperlipidemic effects. However, it remains unclear whether anthocyanins are associated with DN, and the mechanisms involved in the reciprocal regulation of inflammation and cholesterol efflux are yet to be elucidated. In this study, we evaluated the regulation of cholesterol metabolism and the anti-inflammatory effects exerted by anthocyanins (cyanidin-3-O-β-glucoside chloride [C3G] or cyanidin chloride [Cy]) and investigated the underlying molecular mechanism of action using high-glucose (HG)-stimulated HK-2 cells. We found that anthocyanins enhanced cholesterol efflux and ABCA1 expression markedly in HK-2 cells. In addition, they increased peroxisome proliferator-activated receptor alpha (PPARα) and liver X receptor alpha (LXRα) expression and decreased the HG-induced expression of the proinflammatory cytokines intercellular adhesion molecule-1 (ICAM1), monocyte chemoattractant protein-1 (MCP1), and transforming growth factor-β1 (TGFβ1), as well as NFκB activation. Incubation with the PPARα-specific inhibitor GW6471 and LXRα shRNA attenuated the anthocyanin-mediated promotion of ABCA1 expression and cholesterol efflux, suggesting that anthocyanins activated PPARα-LXRα-ABCA1-dependent cholesterol efflux in HK-2 cells. Moreover, the knockout of LXRα abrogated the anti-inflammatory effect of anthocyanins, whereas the PPARα antagonist GW6471 does not have this effect. Further investigations revealed that LXRα might interfere with anthocyanin-induced decreased ICAM1, MCP1, and TGFβ1 expression by reducing the nuclear translocation of NFκB. Collectively, these findings suggest that blocking cholesterol deposition and inhibiting the LXRα pathway-induced inflammatory response might be one of the main mechanisms by which anthocyanins exert their protective effects in DN. Keywords: 3-O-β-glucoside chloride, cyanidin chloride, diabetic nephropathy, inflammation, liver X receptor alpha